Pharmaceutical composition for preventing nausea and vomiting caused by chemotherapy as well as preparation method and application of pharmaceutical composition

Abstract

The invention provides the aprepitant and palonosetron hydrochloride compound emulsion for injection, the compound emulsion has better stability, nausea and vomiting can be more conveniently and effectively prevented and treated, and the medication compliance of patients is improved.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a compound emulsion for injection of aprepitant and palonosetron hydrochloride, and its prescription composition, preparation method and use. Background Art

[0002] Chemotherapy-induced nausea and vomiting (CINV) is one of the most common adverse reactions in cancer patients during chemotherapy. A survey based on 2,388 clinical cancer doctors and nurses found that 45% of the doctors and nurses reported delaying or terminating chemotherapy due to CINV, and 70% of the doctors and nurses believed that the convenience of patients taking medicine was the factor they valued most. Therefore, timely and effective prevention of CINV is of great significance to improving the quality of life of patients and ensuring the smooth progress of chemotherapy.

[0003] Aprepitant is a representative drug among NK1 inhibitors. It blocks the action point of substance P by binding to NK1 receptors. It can pass through the blood-brain barrier and occupy NK1 receptors in the brain. It has high selectivity and high affinity, but has very low affinity for NK2 and NK3 receptors. It is better than other drugs in reducing nausea and vomiting. Its oral preparation was approved for marketing by the US FDA in 2003, but due to its poor water solubility and membrane permeability, aprepitant has poor oral absorption and low bioavailability. In order to improve the shortcomings of oral preparations, Heron Therapeutics developed aprepitant into a fat emulsion injection, which was approved for marketing by the FDA in 2017.

[0004] Palonosetron is a second-generation serotonin 3-receptor antagonist (5-HT3RA). Its half-life is longer than that of the first-generation 5-HT3RA, about 40 hours, and its receptor affinity is 30 to 100 times that of the first generation. The single dose is only 0.25 mg. It is a highly effective and selective 5-HT3 receptor blocker that can effectively prevent delayed nausea and vomiting induced by chemotherapy drugs.

[0005] At present, various important guidelines in the field of CINV recommend a triple antiemetic regimen of NK1 receptor antagonist + 5-HT3 receptor antagonist + dexamethasone, which is widely used to prevent CINV caused by highly emetogenic chemotherapy, with significant clinical effects. However, this regimen requires administration on different days after chemotherapy, and the dosage and route of administration are relatively complicated, which brings inconvenience to clinical application. Studies have found that the current compliance with guidelines in clinical practice at home and abroad is not satisfactory: a single-center study in my country found that among patients in the single-day chemotherapy group, the compliance with the acute and delayed CINV guidelines was only 45% and 7%, respectively. On the other hand, some studies have pointed out that the non-compliance of patients with medication due to the overly complex multi-drug antiemetic regimen is an important factor in the failure of CINV prevention. Therefore, it is of great clinical significance to develop a simple and effective antiemetic drug that can improve patient compliance, such as a compound preparation. However, the precautions in the instructions for aprepitant injection clearly state that aprepitant injection should not be mixed with solutions whose physical and chemical compatibility has not yet been determined. The precautions in the instructions for palonosetron hydrochloride injection also state that this product should not be mixed with other drugs, and that the infusion line should be flushed with normal saline before and after infusion. Earlier related reports also recorded that palonosetron hydrochloride is stable in a low pH range and in a slightly acidic environment, and is most stable at a pH of 5 (CN1758911). Aprepitant injection is stable in relatively high pH and slightly alkaline conditions, with a pH of 7.5-9.0, preferably 8-9, and it is clearly stated that the pH should be controlled during manufacturing, and a decrease in pH may be an indication of chemical degradation (CN106852118); and studies have shown that palonosetron hydrochloride is easily oxidized to produce impurity A, and aprepitant injection contains a large amount of unsaturated fatty acids such as soybean oil and phospholipids that are easily oxidized to produce peroxide excipients. Therefore, in the development process of compound preparations, how to find a formulation system that can make both stable is a difficult problem that needs to be solved urgently.

[0006] Summary of the invention

[0007] In view of the complexity of drug administration of multiple antiemetic regimens in the prior art and the poor compliance of patients, the present invention provides a stable compound injection emulsion of aprepitant and palonosetron hydrochloride and a preparation method thereof.

[0008] Specifically,

[0009] The first aspect of the present disclosure provides a compound emulsion for injection, comprising aprepitant, palonosetron hydrochloride and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises an antioxidant.

[0010] In some embodiments of the present disclosure, the pharmaceutically acceptable carrier in the above-mentioned compound emulsion comprises an antioxidant and a metal chelator.

[0011] In some embodiments of the present disclosure, the pharmaceutically acceptable carrier in the above-mentioned compound emulsion comprises an antioxidant, a metal chelator, an emulsifier, an emulsifier aid, an injection oil, an osmotic pressure regulator, a pH regulator and water for injection.

[0012] In some embodiments of the present disclosure, the above-mentioned compound emulsion is composed of aprepitant, palonosetron hydrochloride and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is an antioxidant, a metal chelator, an emulsifier, an emulsifier aid, an injection oil, an osmotic pressure regulator, a pH regulator and water for injection.

[0013] In some embodiments of the present disclosure, the antioxidant in the above-mentioned compound emulsion is selected from one or a mixture of two or more of sodium bisulfite, anhydrous sodium sulfite, sodium metabisulfite, sodium thiosulfate, ascorbic acid, cysteine, citric acid, sodium citrate, and vitamin C.

[0014] In some embodiments of the present disclosure, the antioxidant in the above-mentioned compound emulsion is selected from a mixture of sodium bisulfite and anhydrous sodium sulfite.

[0015] In some embodiments of the present disclosure, the mass percentage of the antioxidant in the above-mentioned compound emulsion is 0.01% to 0.783%, preferably, the mass percentage of the antioxidant is 0.02%.

[0016] In some embodiments of the present disclosure, the antioxidant in the above-mentioned compound emulsion is selected from a mixture of sodium bisulfite and anhydrous sodium sulfite, and the weight ratio of sodium bisulfite to anhydrous sodium sulfite is 1:1, the mass percentage of sodium bisulfite is 0.01%, and the mass percentage of anhydrous sodium sulfite is 0.01%.

[0017] In some embodiments of the present disclosure, the metal chelator in the above-mentioned compound emulsion is selected from edetic acid, disodium edetate, tetrasodium edetate, disodium nitrilotriacetate, pentetic acid, citric acid, tartaric acid, and gluconic acid.

[0018] In some embodiments of the present disclosure, the metal chelator in the above-mentioned compound emulsion is selected from disodium edetate.

[0019] In some embodiments of the present disclosure, the mass percentage of the metal chelator in the above-mentioned compound emulsion is 0.004% to 0.055%, preferably, the mass percentage of the metal chelator is 0.004% to 0.008%, and more preferably, the mass percentage of the metal chelator is 0.005%.

[0020] In some embodiments of the present disclosure, the emulsifier in the above-mentioned compound emulsion is selected from one or a mixture of two or more of egg yolk lecithin, soybean lecithin or polyethylene glycol 15 hydroxystearate.

[0021] In some embodiments of the present disclosure, the emulsifier in the above-mentioned compound emulsion is selected from egg yolk lecithin.

[0022] In some embodiments of the present disclosure, the co-emulsifier in the above-mentioned compound emulsion is selected from one of anhydrous ethanol, oleic acid, sodium oleate, poloxamer, polysorbate 80, or a mixture of two or more thereof.

[0023] In some embodiments of the present disclosure, the co-emulsifier in the above-mentioned compound emulsion is selected from anhydrous ethanol.

[0024] In some embodiments of the present disclosure, the injection oil in the above-mentioned compound emulsion is selected from one of soybean oil, olive oil, safflower oil, camellia oil, peanut oil, fish oil, castor oil, medium-chain triglycerides, polyoxyethylene castor oil, rapeseed oil, corn oil, and sesame oil, or a mixture of two or more thereof.

[0025] In some embodiments of the present disclosure, the injection oil in the above-mentioned compound emulsion is selected from soybean oil.

[0026] In some embodiments of the present disclosure, the osmotic pressure regulator in the above-mentioned compound emulsion is selected from one of sucrose, glycerol, mannitol, glucose, or a mixture of two or more thereof.

[0027] In some embodiments of the present disclosure, the osmotic pressure regulator in the above-mentioned compound emulsion is selected from sucrose.

[0028] In some embodiments of the present disclosure, the pH adjuster in the above-mentioned compound emulsion is selected from one of sodium oleate, oleic acid, sodium hydroxide, hydrochloric acid, or a mixture of two or more thereof.

[0029] In some embodiments of the present disclosure, the pH adjuster in the above-mentioned compound emulsion is selected from sodium oleate.

[0030] In some embodiments of the present disclosure, the mass ratio of aprepitant to palonosetron hydrochloride (calculated as palonosetron) in the above-mentioned compound emulsion is 520:1.

[0031] In some embodiments of the present disclosure, the above-mentioned compound emulsion contains 130 mg of aprepitant per unit preparation and 0.25 mg of palonosetron hydrochloride (calculated as palonosetron) per unit preparation.

[0032] In some embodiments of the present disclosure, the compound emulsion is 18 mL / unit preparation.

[0033] In some embodiments of the present disclosure, the pH value limit of the above-mentioned compound emulsion is 7.0-9.0.

[0034] In some embodiments of the present disclosure, the above-mentioned compound emulsion can be used in combination with a glucocorticoid drug.

[0035] In some embodiments of the present disclosure, the above-mentioned compound emulsion can be used in combination with a glucocorticoid drug, and the glucocorticoid is dexamethasone or nipresone.

[0036] In some embodiments of the present disclosure, the components and their weight proportions in the above-mentioned compound emulsion are:

[0037]

[0038] In some embodiments of the present disclosure, the components and their weight proportions in the above-mentioned compound emulsion are:

[0039]

[0040]

[0041] In some embodiments of the present disclosure, the components and their mass fractions in the above-mentioned compound emulsion are:

[0042]

[0043] The second aspect of the present disclosure provides a method for preparing the above-mentioned compound emulsion, comprising the following steps:

[0044] (1) mixing aprepitant, an emulsifier, and a co-emulsifier with oil for injection to prepare an oil phase;

[0045] (2) mixing water for injection, an osmotic pressure regulator, a pH regulator, and a metal chelating agent to prepare an aqueous phase;

[0046] (3) mixing the oil phase and the water phase, and dispersing them by high-speed shearing to prepare a crude emulsion;

[0047] (4) homogenizing the crude milk through a microfluidizer under high pressure to obtain final milk;

[0048] (5) Add antioxidants and palonosetron hydrochloride to the final emulsion and stir to dissolve.

[0049] (6) Sterilize, nitrogen-fill and bottle the drug emulsion.

[0050] Wherein, the antioxidant, metal chelating agent, emulsifier, co-emulsifier, injection oil, osmotic pressure regulator, and pH regulator are as defined above.

[0051] The third aspect of the present disclosure provides the use of the above-mentioned compound emulsion:

[0052] In some embodiments of the present disclosure, the above-mentioned composite emulsion is used to prevent acute and delayed nausea and vomiting occurring during initial and repeated treatments with highly emetogenic chemotherapy drugs (HEC).

[0053] In some embodiments of the present disclosure, the above-mentioned composite emulsion is used to prevent acute and delayed nausea and vomiting occurring during the initial and repeated treatments with moderately emetogenic chemotherapy drugs (MEC).

[0054] Technical Effects

[0055] The compound emulsion provided by the present disclosure has good stability, which can not only make the aprepitant in the system encapsulated in the emulsified oil droplet particles, but also keep it stable under the preparation and storage conditions without demulsification or stratification; at the same time, it can also make the palonosetron hydrochloride stable, and the representative oxidized impurity A does not increase significantly. In addition, the compound emulsion of the present disclosure has a significant effect in preventing / treating nausea and vomiting.

[0056] Description and Definition

[0057] Emulsions are thermodynamically unstable heterogeneous dispersion systems, and stratification, flocculation, phase transition, rupture and rancidity often occur during the preparation or storage process.

[0058] (1) Stratification: It refers to the phenomenon that dispersed phase particles float up or sink during the storage of emulsion. Stratification is a reversible process. The main reason is the density difference between the dispersed phase and the continuous phase.

[0059] The commonly used methods to slow down the stratification rate are: reducing the particle size of the emulsion droplets, increasing the viscosity of the continuous phase, and reducing the density difference between the dispersed phase and the continuous phase.

[0060] (2) Flocculation: The phenomenon that dispersed emulsion droplets in an emulsion aggregate to form loose aggregates and can be restored to a uniform emulsion after shaking is called emulsion flocculation, which is the prelude to emulsion rupture. The reason for this is the decrease in zeta potential.

[0061] (3) Phase inversion: refers to the change in the type of emulsion, which is caused by adding another substance to the emulsion, which changes the properties of the emulsifier.

[0062] (4) Rupture: The separation of an emulsion into two phases, oil and water, is called emulsion rupture, which eventually makes free oil visible on the surface of the emulsion. It is an irreversible process.

[0063] (5) Rancidity: The phenomenon that the oil, emulsifier, etc. in the emulsion deteriorate due to external factors (light, heat, air, etc.) and microorganisms is called rancidity. In addition, unsaturated fatty acids in the structure of soybean oil and phospholipid auxiliary materials are easily oxidized to form peroxides. Peroxides are very unstable and can continue to decompose into small molecular compounds such as aldehydes, ketones, acids, etc., which increase the anisidine value of the system. Adding antioxidants and preservatives can prevent or delay rancidity.

[0064] The type and amount of excipients in the emulsion, the properties of the drug, the zeta potential of the system, pH value, residual oxygen content, dissolved oxygen content, preparation process, packaging materials, storage conditions, etc. will all affect the physicochemical stability of the emulsion.

[0065] Data show that palonosetron hydrochloride is easily catalyzed by metal ions in water and undergoes oxidative degradation. Forced degradation test studies have shown that palonosetron hydrochloride is sensitive to oxidation and is very likely to undergo oxidation reactions to generate impurity A in this emulsion system.

[0066] Therefore, in order to take into account the stability of the emulsion system and active ingredients of this product during preparation, transportation, storage and use, and fully ensure the efficacy and safety of clinical medication, we have determined the prescription composition and process parameters of this product in accordance with the QbD research and development concept through systematic prescription screening and process optimization research; determined the production process of this product through step-by-step process research; the results of quality research and stability research show that the quality of this product is controllable and the stability is good.

[0067] Unless otherwise specified, the "unit dosage form" in the present disclosure refers to the smallest dosage form of a drug, such as one pill, one tablet, one bottle, one patch, and the like.

[0068] Unless otherwise specified, "combined use" in the present disclosure means that two drugs are respectively contained in preparation units of different strengths and can be administered simultaneously, sequentially or intermittently. DETAILED DESCRIPTION

[0069] In order to better illustrate the present invention, the preferred embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that the following examples are provided only for the purpose of illustration and are not intended to limit the scope of the present invention. Simple improvements to the present invention under the premise of the technical solution of the present invention belong to the protection scope of the present invention.

[0070] 1. Prescription design

[0071] According to the specifications and clinical dosage of single-ingredient preparations of aprepitant injection and palonosetron hydrochloride injection, the development specification of the compound emulsion of this product is determined to be 18ml: 130mg aprepitant and 0.25mg palonosetron. With reference to the prescription composition of single-ingredient emulsions of aprepitant injection that have been marketed at home and abroad, the basic prescription composition was initially formulated, namely, aprepitant and palonosetron hydrochloride as active ingredients, egg yolk lecithin as emulsifier, anhydrous ethanol as co-emulsifier, soybean oil as oil phase solvent, sodium oleate as pH regulator, sucrose as osmotic pressure regulator, and water for injection as water phase solvent.

[0072] The basic prescription composition determined preliminarily is shown in Table 1.

[0073] Table 1 Basic formula composition of compound emulsion

[0074]

[0075] 2. Prescription screening and optimization

[0076] (1) Determination of the dosage of edetate disodium

[0077] Data show that palonosetron hydrochloride is easily catalyzed by metal ions in water and undergoes oxidative degradation. In order to inhibit the oxidative degradation of this product during production and storage, the metal ion chelator disodium edetate is added to the prescription to form a complex with the metal ions in the liquid, thereby improving the stability of this product. According to the basic prescription, other components in the prescription were fixed, and samples with different amounts of disodium edetate (0%, 0.005%, 0.05%) were prepared to investigate the effect of the amount of disodium edetate on the stability of this product during storage.

[0078] Table 2 Edetate disodium dosage screening prescription composition

[0079]

[0080]

[0081] Table 3 Effect of edetate disodium dosage on related substances II

[0082]

[0083] The results showed that the Palonosetron impurity A (oxidation impurity) increased significantly in the prescription without disodium edetate at 2-8°C for one month, while the impurity A in the prescriptions with 0.005% and 0.05% disodium edetate increased less and there was no significant difference between the two. However, the impurity A of the three batches of samples placed at 25°C / 60% for one month increased significantly, and the impurity A of the prescriptions without disodium edetate and with 0.005% disodium edetate exceeded the limit. This shows that adding a certain amount of disodium edetate to the prescription can inhibit the growth of impurity A to a certain extent, but the antioxidant effect is not obvious under accelerated conditions, and it is necessary to add antioxidants to the prescription.

[0084] Detection method for related substance II:

[0085] Octylsilane bonded silica gel was used as the filler (Agilent ZORBAX RX-C8, 4.6 mm × 250 mm, 5 μm or a chromatographic column of equivalent performance); acetonitrile-water-trifluoroacetic acid (300:700:0.67) was used as the mobile phase A, and tetrahydrofuran-water (80:20) was used as the mobile phase B, and gradient elution was performed according to the table below [Ghost Trap DS pre-column (specification: 7.6 mm × 30 mm) was installed between the gradient mixer and the autosampler]; the flow rate was 1.0 ml per minute; the column temperature was 30°C; the detection wavelength was 210 nm; and the injection volume was 100 μl.

[0086]

[0087] (2) Screening of antioxidant types and dosage

[0088] The excipients soybean oil and lecithin in the prescription of this product contain unsaturated fatty acids that are easily oxidized to form peroxides. Peroxides are very unstable and can continue to decompose into small molecular compounds such as aldehydes, ketones, acids, etc., which increase the anisidine value of the system. Palonosetron hydrochloride is more sensitive to oxidation and is very prone to oxidative degradation in this system. Based on the proposed basic prescription composition, samples containing different types and amounts of antioxidants were prepared, placed at 30℃ / 65% for 30 days, and key physical and chemical indicators were measured to investigate the stability of different prescriptions.

[0089] Table 4-1 Antioxidant type and dosage screening formula composition (1)

[0090]

[0091] Table 4-2 Antioxidant type and dosage screening formula composition (2)

[0092]

[0093] Table 5 Effect of antioxidant type and dosage on stability

[0094]

[0095] Result analysis:

[0096] The formulation with 0.1% vitamin C as antioxidant was placed at 30℃ / 65% for 30 days. The impurity A of palonosetron was equivalent to that at zero time, but the properties changed significantly. The particle size increased significantly and the average particle size and D 90 The upper limit has been exceeded, the pH value is close to the lower limit, and the stability is poor;

[0097] The peroxide value of the formulation with 0.03% citric acid as antioxidant exceeded the limit at zero time. The properties changed after being placed at 30℃ / 65% for 30 days. The impurity A and particle size of palonosetron increased significantly, and the stability was poor.

[0098] The peroxide value of the formulation with 0.5% tocopherol as antioxidant was far above the upper limit at zero time. After being placed at 30℃ / 65% for 30 days, the impurity A of palonosetron increased significantly and far exceeded the upper limit, indicating poor stability.

[0099] The antioxidant formulation with 0.01% anhydrous sodium sulfite changed its properties after being placed at 30℃ / 65% for 30 days. The pH value decreased slightly, the impurity A and peroxide value of palonosetron increased significantly, the particle size increased slightly, and the stability was poor.

[0100] When the antioxidant was 0.01% sodium bisulfite, the pH value decreased slightly after being placed at 30℃ / 65% for 30 days, the impurity A of palonosetron increased significantly, the particle size increased slightly, and the stability was poor.

[0101] When the formulation with 0.05% sodium bisulfite as antioxidant was placed at 30℃ / 65% for 30 days, the impurity A of palonosetron was equivalent to that at zero time, but the particle size increased significantly, indicating poor stability.

[0102] When the antioxidant was 0.01% sodium bisulfite + 0.01% anhydrous sodium sulfite, the impurity A of palonosetron slightly increased compared with the zero time when placed at 30℃ / 65% for 30 days, and the pH value slightly decreased. Other key physical and chemical indicators such as properties, particle size, Zeta potential, peroxide value, and anisidine value were equivalent to those at zero time, and all the inspection indicators met the requirements. This shows that the formulation has good stability and is significantly better than other antioxidant formulations. The reason for this is that the combined use of anhydrous sodium sulfite and sodium bisulfite can produce a synergistic effect and better play an antioxidant role;

[0103] Therefore, the antioxidants in the prescription of this product are preferably sodium bisulfite and anhydrous sodium sulfite, and the dosage of the two is 0.01%.

[0104] (3) pH value investigation

[0105] The pH value is an important quality indicator of the preparation, and the pH value may have a certain impact on the key quality attributes of this product. The effects of different pH values ​​on the key physical and chemical indicators of the finished product were investigated. The formulation composition is shown in Table 6, and the test results are shown in Table 7.

[0106] Table 6 pH value investigation using sample prescription

[0107]

[0108] ① Preparation of aqueous phase: Weigh sucrose, sodium oleate and disodium edetate, add to water for injection, and heat at 40-80°C to dissolve.

[0109] ② Preparation of oil phase: Weigh aprepitant, egg yolk lecithin, soybean oil, and anhydrous ethanol, and heat to dissolve in the range of 40-80°C.

[0110] ③ Preparation of crude emulsion by combining phases: Mix the oil and water phases and disperse them by high-speed shearing in the range of 40-80°C.

[0111] ④ Preparation of final milk: The crude milk is homogenized by passing it through a microfluidizer at 20-70° C. and 3000 psi-25000 psi to obtain the final milk.

[0112] ⑤ Dissolution of antioxidant and palonosetron hydrochloride raw materials: Add sodium bisulfite, anhydrous sodium sulfite and palonosetron hydrochloride into the final emulsion and stir to dissolve.

[0113] ⑥ Adjust the pH value and filter and sterilize: Use dilute hydrochloric acid and 1M sodium hydroxide solution to adjust the pH value to 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, and 9.5 respectively, and then filter and sterilize the liquid.

[0114] The samples with different pH values ​​were filled into vials, filled with nitrogen, stoppered, and capped. The key physical and chemical indicators (properties, viscosity, emulsions, Zeta potential, related substances II, free fatty acids, lysophosphatidylcholine, and lysophosphatidylethanolamine) were then tested.

[0115] Table 7 Effect of pH value on key quality attributes of products

[0116]

[0117]

[0118] The results showed that within the pH range of 6.5 to 9.5, the viscosity decreased slightly with the decrease of pH value; the impurity A of palonosetron increased significantly with the increase of pH value, and the impurity A was the highest at pH 9.5, exceeding 0.5%; the pH value had a slight effect on the product emulsion particles, with the largest particle size at pH 6.5, and no significant difference in particle size at pH 7.0 to 9.5; the pH value had no significant effect on free fatty acids, lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC). Based on the above results, the pH limit of this product was determined to be 7.0 to 9.0 after comprehensive consideration.

[0119] 3. Pharmacodynamic comparison experiment

[0120] 1. Purpose of the experiment

[0121] The antiemetic effect of the disclosed compound emulsion on the cisplatin-induced vomiting model of ferrets was evaluated by observing and recording the latency and frequency of retching and vomiting induced by cisplatin in ferrets, and the pharmacodynamic differences between the disclosed compound emulsion and the control single drug at the same dose were compared.

[0122] 2. Experimental Materials

[0123] Animal acclimation and grouping: 6-month-old male ferrets, 1.3-2.0 kg, were randomly divided into groups according to their body weight after acclimation in the animal facility for at least one week.

[0124] Table 8 Source of materials

[0125]

[0126] 3. Experimental Procedure

[0127] 3.1 Grouping

[0128] Before experimental testing, animals were acclimated in the animal facility for at least one week and randomly grouped according to their body weight.

[0129] Table 9 Experimental groups

[0130]

[0131] 3.2. Medication and Observation

[0132] The animals were weighed, and 10 minutes before the administration of cisplatin, the vehicle control, cisplatin, aprepitant, palonosetron, the low-dose group of the compound emulsion of the present disclosure, and the high-dose group of the compound emulsion of the present disclosure were respectively administered with normal saline, normal saline, aprepitant, palonosetron, the low-dose group of the compound emulsion of the present disclosure, and the high-dose group of the compound emulsion of the present disclosure; the administration volume was 2 ml / kg.

[0133] Ten minutes after administration, all groups of animals were intraperitoneally injected with cisplatin at a dose of 10 mg / kg and a volume of 5 mL / kg.

[0134] The latency and frequency of retching and vomiting in ferrets were observed and recorded within 4 hours after cisplatin induction.

[0135] 1) Dry heave latency: After the animal is given cisplatin, the timing is started and the time when the animal first retches (without vomitus) is recorded.

[0136] 2) Vomiting latency: After the animal is given cisplatin, the timing is started and the time when the animal first vomits (vomitus appears) is recorded.

[0137] 3) Number of dry heaves: After the animals are given cisplatin, the timer is started to record the number of dry heaves (without vomiting).

[0138] 4) Number of vomiting: After the animal is given cisplatin, the timer is started to record the number of times the animal vomits (vomitus appears).

[0139] Animal care

[0140] After the experiment, the animals were euthanized promptly.

[0141] Data collection and analysis

[0142] Data were collected using Excel software. Data were statistically analyzed using Prism (Graph pad software, Inc.) software. When the P value was less than 0.05, it was considered statistically significant. The specific analysis method is as follows:

[0143] Test whether each group of data conforms to normal distribution and whether they have homogeneity of variance (F test). If the data conform to normal distribution and have homogeneity of variance, use unpaired T test to compare the difference between the two groups of data or use one / two-way ANOVA to compare the difference between multiple groups of data. If the data conform to normal distribution but at least one group of data has heterogeneity of variance, use Welch's t test to compare and analyze the difference between the two groups of data or use nonparametric test to analyze the difference between multiple groups of data. If the data do not conform to normal distribution, use Mann-Whitney rank sum test to analyze the difference between the two groups of data or Kruskal-Wallis test to analyze the difference between multiple groups of data.

[0144] 4 Experimental results

[0145] 4.1. Weight and grouping

[0146] All animals were randomly divided into groups (n=8) before administration, and there was no significant difference in body weight between the groups. During the experiment, there was no significant difference in body weight between the groups.

[0147] Table 10. Ferrets randomized and weight on the day of drug administration

[0148]

[0149] 4.2. Observation of antiemetic effect

[0150] The results of this study showed that ferrets (cisplatin group) that were not given antiemetics experienced retching 70±8.6 minutes after cisplatin administration and vomiting 74±7.9 minutes after cisplatin administration, with 164±25.3 retching and 15±3.5 vomiting within 4 hours.

[0151] Compared with the cisplatin group: Aprepitant (0.2 mg / kg) had a smaller effect on the retching latency of ferrets (72±3.6 min), and prevented vomiting in one ferret. The vomiting latency was slightly prolonged (101±20.5 min), but there was no significant difference compared with the cisplatin group. Aprepitant (0.2 mg / kg) can significantly reduce (p<0.05) the number of retching (73±10.9 times) and vomiting (5±1.1 times) in ferrets within 4 hours. Administration of palonosetron (0.0004 mg / kg) prevented vomiting and retching in one ferret in the group within 4 hours, but the retching and vomiting latency, retching and vomiting frequency of most ferrets were similar to those of the cisplatin group. Overall, the vomiting indexes of the compound did not show significant differences from those of the cisplatin group (99±24.3 min, 97±24.5 min, 121±26.9 times and 9±2.5 times, respectively). Administration of a low dose of the disclosed compound milk (0.1002 mg / kg) slightly prolonged the retching and vomiting latency induced by cisplatin in ferrets (83±4.3 and 129±24.6 min, respectively), but there was no statistical difference; the retching frequency was significantly reduced (99±12.4 times, p<0.05); and vomiting did not occur in 2 ferrets in the group within 4 hours (4±1.0 times, p<0.05). Administration of a high dose of the disclosed compound emulsion (0.2004 mg / kg) can slightly prolong the latency period of cisplatin-induced retching in ferrets (93±5.5 min, p>0.05), and none of the five ferrets in this group showed vomiting within 4 hours (204±19.3 min, p<0.05), and the frequency of retching and vomiting was significantly reduced (34±6.8 and 1±0.6 times, respectively, p<0.05). When the pharmacodynamic activity of the test compound emulsion of the present invention was compared with that of the single drug at 0.2004 mg / kg, there was no significant difference among the three in the latency of retching (p>0.05). In the latency of vomiting, the pharmacodynamic activity of the compound emulsion of the present invention was superior to that of aprepitant and palonosetron (the p values ​​of the compound emulsion of the present invention compared with aprepitant and palonosetron were 0.0015 and 0.0010, respectively); in the number of retching ... pharmacodynamic activity of the compound emulsion of the present invention compared with aprepitant and palonosetron, there was no significant difference among the three in the latency of retching (p>0.05). There were no statistically significant differences in the pharmacodynamic activity of the compound emulsion disclosed herein and aprepitant in terms of the p values ​​compared with palonosetron: 0.3509, 0.0030, respectively) and the number of vomiting (the p values ​​of the compound emulsion disclosed herein and aprepitant, palonosetron: 0.5456, 0.0223, respectively), but the number of retching and vomiting of the compound emulsion disclosed herein (34 times, 1 time) was lower than that of aprepitant (73 times, 5 times), and was better than that of palonosetron (121 times, 9 times).

[0152] Table 11. Latency of retching in each group of ferrets

[0153]

[0154] Note: For animals that did not vomit within 4 hours after cisplatin administration, the vomiting latency was recorded as 240 minutes.

[0155] Table 12. Vomiting latency of ferrets in each group

[0156]

[0157] Note: For animals that did not vomit within 4 hours after cisplatin administration, the vomiting latency was recorded as 240 minutes.

[0158] Table 13. Number of retching times of ferrets in each group

[0159]

[0160] Table 14. Vomiting frequency of ferrets in each group

[0161]

[0162] Table 15. Number of retching and vomiting in each group of ferrets

[0163]

[0164] Conclusion and discussion

[0165] In summary, under the conditions of the present experiment, the test substance, the compound emulsion of the present invention, can dose-dependently inhibit the number of retching and vomiting induced by cisplatin in ferrets within the dosage range of 0.1002 and 0.2004 mg / kg, and is dose-dependent; compared with the model group, aprepitant can significantly reduce the number of retching and vomiting in ferrets, but the average number of retching and vomiting is higher than that of the compound emulsion 0.2004 mg / kg group of the present invention; in addition, palonosetron has little effect on the vomiting-related indicators observed in this experiment, and its efficacy is significantly weaker than that of the compound emulsion 0.2004 mg / kg of the present invention.

Claims

1. A compound emulsion for injection, comprising aprepitant, palonosetron hydrochloride and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises an antioxidant.

2. The compound emulsion according to claim 1, wherein the pharmaceutically acceptable carrier further comprises a metal chelating agent.

3. The compound emulsion according to claim 2, wherein the pharmaceutically acceptable carrier further comprises an emulsifier, an emulsifier aid, an injection oil, an osmotic pressure regulator, a pH regulator and water for injection.

4. The compound emulsion according to any one of claims 1 to 3, wherein the antioxidant is selected from one of sodium bisulfite, anhydrous sodium sulfite, sodium metabisulfite, sodium thiosulfate, ascorbic acid, cysteine, citric acid, sodium citrate, vitamin C, or a mixture of two or more thereof.

5. The compound emulsion according to any one of claims 2 to 4, wherein the metal chelator is selected from one of edetic acid, disodium edetate, tetrasodium edetate, disodium nitrilotriacetate, pentetic acid, citric acid, tartaric acid, and gluconic acid, or a mixture of two or more thereof.

6. The compound emulsion according to any one of claims 3 to 5, wherein the emulsifier is selected from one or a mixture of two or more of egg yolk lecithin, soybean lecithin or polyethylene glycol 15 hydroxystearate.

7. The compound emulsion according to any one of claims 3 to 6, wherein the co-emulsifier is selected from one of anhydrous ethanol, oleic acid, sodium oleate, poloxamer, polysorbate 80, or a mixture of two or more thereof.

8. The compound emulsion according to any one of claims 3 to 7, wherein the injection oil is selected from one of soybean oil, olive oil, safflower oil, camellia oil, peanut oil, fish oil, castor oil, medium-chain triglycerides, polyoxyethylene castor oil, rapeseed oil, corn oil, and sesame oil, or a mixture of two or more thereof.

9. The compound emulsion according to any one of claims 3 to 8, wherein the osmotic pressure regulator is selected from one of sucrose, glycerol, mannitol, glucose or a mixture of two or more thereof.

10. The compound emulsion according to any one of claims 3 to 9, wherein the pH regulator is selected from one of sodium oleate, oleic acid, sodium hydroxide, hydrochloric acid, or a mixture of two or more thereof.

11. The compound emulsion according to any one of claims 1 to 10, wherein the mass ratio of aprepitant to palonosetron hydrochloride (calculated as palonosetron) is 520:

1.

12. The compound emulsion according to any one of claims 1 to 11, comprising 130 mg of aprepitant per unit preparation and 0.25 mg of palonosetron hydrochloride (calculated as palonosetron) per unit preparation.

13. The compound emulsion according to any one of claims 1 to 12, wherein the pH value limit is 7.0 to 9.

0.

14. The compound emulsion according to any one of claims 1 to 13, which can be used in combination with a glucocorticoid drug.

15. A method for preparing the compound emulsion according to any one of claims 1 to 14, comprising the following steps: (1) mixing aprepitant, an emulsifier, and a co-emulsifier with oil for injection to prepare an oil phase; (2) mixing water for injection, an osmotic pressure regulator, a pH regulator, and a metal chelating agent to prepare an aqueous phase; (3) mixing the oil phase and the water phase, and dispersing them by high-speed shearing to prepare a crude emulsion; (4) homogenizing the crude milk through a microfluidizer under high pressure to obtain final milk; (5) adding antioxidants and palonosetron hydrochloride to the final emulsion and stirring to dissolve; (6) sterilizing, nitrogen filling, and filling the drug emulsion; in, The antioxidant, metal chelating agent, emulsifier, co-emulsifier, oil for injection, osmotic pressure regulator, pH regulator are as defined in any one of claims 1-14.

16. Use of the compound emulsion according to any one of claims 1 to 15 for preventing acute and delayed nausea and vomiting during initial and repeated treatment with highly emetogenic chemotherapy (HEC).

17. Use of the compound emulsion according to any one of claims 1 to 15 for preventing acute and delayed nausea and vomiting during initial and repeated treatment with moderately emetogenic chemotherapy (MEC).

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