An antiemetic pharmaceutical preparation, a method for preparing the same, and use thereof

Abstract

The present application relates to a kind of antiemetic pharmaceutical preparation and its preparation method and application.A kind of antiemetic pharmaceutical preparation, main component includes citric acid maropitant, filling agent, flavouring agent, disintegrant, binder and lubricant;By mass fraction, citric acid maropitant is 10-30 parts, filling agent is 20-50 parts, flavouring agent is 10-30 parts, disintegrant is 10-30 parts, binder is 1-4 parts, lubricant is 0.1-5 parts;Wherein the disintegrant and binder are (7-10):1 by mass ratio.This application citric acid maropitant chewable tablet has good stability, high safety, good curative effect, preparation method is simple, and is suitable for mass production.

Description

Technical Field

[0001] This invention relates to the field of veterinary drug technology, specifically to an antiemetic drug preparation, its preparation method, and its application. Background Technology

[0002] Maropitan citrate is a potent and selective type 1 neurokinin (NK-1) receptor antagonist that acts on the central nervous system by inhibiting substance P (a key neurotransmitter that induces vomiting), thus suppressing both peripheral and central vomiting. It was the first drug approved for the prevention and treatment of severe vomiting and motion sickness in dogs, and the first drug approved for the treatment of canine motion sickness, demonstrating significant clinical value and market potential.

[0003] Currently, in existing technologies, maropistan citrate is a drug that is almost insoluble in water. If it is manufactured into tablets, the first drawback is that several excipients need to be added to the tablets, and compression molding may result in a slower dissolution rate, sometimes affecting the drug's bioavailability. Secondly, if the tablets contain volatile components, their content will decrease after long-term storage, reducing the stability of maropistan citrate. These disadvantages, to some extent, limit the scope and efficacy of maropistan citrate. Summary of the Invention

[0004] To address the aforementioned technical limitations, based on existing research, this invention provides a maripitan citrate chewable tablet that employs dry granulation, improving tablet stability and adjusting the ratio of disintegrant and binder to facilitate absorption after entering the body, thus overcoming the aforementioned defects.

[0005] The first inventive point of this invention is: an antiemetic drug formulation, the main components of which include malopistan citrate, filler, flavoring agent, disintegrant, binder and lubricant;

[0006] By weight, the amount of maropitane citrate is 10-30 parts, the amount of filler is 20-50 parts, the amount of flavoring agent is 10-30 parts, the amount of disintegrant is 10-30 parts, the amount of binder is 1-4 parts, and the amount of lubricant is 0.1-5 parts.

[0007] Furthermore, the disintegrant and the binder are in a mass ratio of (7-10):1.

[0008] Furthermore, the filler is selected from one of powdered sugar, starch, microcrystalline cellulose, and dextrin.

[0009] Furthermore, the flavoring agent is selected from L-malic acid, lactose, sucralose, or stevia, preferably stevia.

[0010] Furthermore, the disintegrant is selected from sodium carboxymethyl starch, croscarmellose, and croscarmellose sodium, preferably croscarmellose.

[0011] Furthermore, the adhesive is selected from one of methylcellulose, sodium carboxymethylcellulose, and ethylcellulose.

[0012] Furthermore, the lubricant is selected from stearic acid, calcium stearate, magnesium stearate, and magnesium dodecyl sulfate, preferably magnesium stearate.

[0013] The second inventive point of this invention is: a pharmaceutical preparation according to the above description, wherein the pharmaceutical preparation is for oral administration, and the dosage form for oral administration is selected from powder, granules, tablets, pills, capsules, soft capsules and capsules, preferably tablets.

[0014] The third inventive point of this invention is: a method for preparing an antiemetic drug formulation, the specific steps of which are as follows:

[0015] 1) Weigh out the main components, malopitant citrate, filler, flavoring agent, disintegrant, lubricant, and binder, respectively, according to their respective mass parts;

[0016] 2) Dry mixing step: Add malopistan citrate, filler, flavoring agent, disintegrant and binder to the trough mixer, start stirring, dry mixing is completed, place the mixed material in the hopper of the dry granulator for granulation, sieve the obtained dry granules, fine powder below 80 mesh is granulated a second time, transfer the sieved dry granules to the mixer, add lubricant and mix, install the die and clean and disinfect, compress into tablets to obtain antiemetic drug tablets.

[0017] Further, in step 2), the sieving mesh size is 80 mesh, until the proportion of fine powder below 80 mesh is 20-40%, and the sieving ends.

[0018] Preferably, during dry mixing, the stirring speed is 20-50 rpm.

[0019] Preferably, during dry mixing, the stirring time is 0.1-0.3 hours.

[0020] The fourth inventive point of this invention is: the use of a pharmaceutical preparation according to the above description or the pharmaceutical preparation prepared above in the preparation of a drug for preventing vomiting caused by chemotherapy drugs, or in the preparation of a drug for treating and preventing vomiting other than motion sickness vomiting.

[0021] Compared with the prior art, the advantages of this invention are:

[0022] This invention employs dry granulation, ensuring the stability of the pharmaceutical formulation and good material compatibility. The fixed filtration mesh size and dry granule size ensure that the tablet hardness and friability meet the requirements for clinical use and storage. This invention's formulation is for oral administration, significantly expanding the clinical application range of maropistan citrate. In summary, the maropistan citrate chewable tablets of this invention exhibit good stability, high safety, and good efficacy, and the preparation method is simple, making it suitable for mass production.

[0023] Specific implementation methods

[0024] To make the objectives, technical solutions, and advantages of this application clearer, a more detailed description is provided below. However, it should be understood that the description herein is merely for explaining this application and is not intended to limit its scope.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of this application. All reagents and instruments used herein are commercially available, and the characterization methods involved can be found in relevant descriptions in the prior art, and will not be repeated here.

[0026] To further understand this application, the following detailed description is provided in conjunction with the preferred embodiments.

[0027] Example 1

[0028] This embodiment provides an antiemetic formulation, the main components of which include maropistan citrate, fillers, flavoring agents, disintegrants, binders, and lubricants. By weight, the main components are: maropistan citrate 10-30 parts, fillers 20-50 parts, flavoring agents 10-30 parts, disintegrants 10-30 parts, binders 1-4 parts, and lubricants 0.1-5 parts. More preferably, by weight, the main components are: maropistan citrate 15-25 parts, fillers 25-45 parts, flavoring agents 15-25 parts, disintegrants 15-25 parts, binders 2-4 parts, and lubricants 0.5-4.5 parts.

[0029] The ratio of disintegrant to binder can better ensure the fragility and disintegration time of tablets, ensuring that tablets are not easily damaged during storage and are more easily disintegrated and absorbed after entering the body.

[0030] The following further explanation is provided regarding the above-mentioned main components and their mass fractions:

[0031] Maropitan Citrate: Pharmacodynamics Maropitan is a neurokinin (NK1) receptor antagonist. Vomiting is a complex regulatory process of the vomiting center, mainly caused by the brainstem chemoreceptor zone (CTZ) receiving and integrating stimuli from the central nervous system, peripheral nervous system, and chemicals in the blood circulation and cerebrospinal fluid. Substance P is a neurotransmitter associated with vomiting; blocking the binding of substance P to its receptors can effectively inhibit central nervous system vomiting, peripheral nervous system vomiting, and vomiting caused by chemical factors. Maropitan can block the binding of substance P to its receptors in the central nervous system, thus exerting an antiemetic effect. Preferably, the mass fractions of maropitan citrate are: for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 parts, or any value between any two values.

[0032] Fillers: Diluents and absorbents, also known as fillers, are mainly used to increase the weight and volume of tablets. For ease of application and production, tablet diameters are generally not less than 6 mm, and tablet weights are generally above 100 mg. Therefore, when the drug dosage is less than 100 mg, tableting is difficult. Additionally, when traditional Chinese medicine tablets contain a large amount of extract or the extract is too viscous, diluents are needed to facilitate tableting. If the raw material contains a large amount of volatile oil, fatty oil, or other liquids, an appropriate amount of absorbent must be added first for absorption before tableting. Preferably, the filler, by mass parts, can be: for example, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50 parts, or any value between any two values.

[0033] As a further embodiment, the ratio of the disintegrant to the binder should be (7-10):1.

[0034] Preferably, the filler is selected from at least one of powdered sugar, starch, microcrystalline cellulose, and dextrin.

[0035] Flavoring agents: Flavoring agents refer to pharmaceutical excipients used to improve or mask unpleasant odors and tastes of drugs, making it difficult for patients to detect strong bitterness (or other unpleasant odors such as spiciness, irritation, etc.) of the drug. Preferably, the flavoring agent can be in parts by weight of, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 parts, or any value between any two values.

[0036] Preferably, the flavoring agent is selected from L-malic acid, lactose, sucralose or stevia, with stevia being the most preferred.

[0037] Stevia, a natural sweetener also known as stevia glycoside, is a pale yellow-white powder that is odorless and has a refreshing sweet taste. It is approximately 300 times sweeter than sucrose, has a long-lasting sweetness, and is not absorbed by the body; therefore, it is a calorie-free sweetener.

[0038] Disintegrants: Disintegrants are excipients added to tablets that promote rapid disintegration of the tablets into small particles in gastrointestinal fluids. Because drugs are compressed into tablets under high pressure, their porosity is very small and their binding force is very strong. Even water-soluble drugs require a certain amount of time to dissolve and disintegrate in water after being compressed into tablets. Therefore, the dissolution rate of poorly water-soluble drugs in tablets becomes a limiting factor in the rate of drug absorption in the body. Tablet disintegration is generally the first step in tablet dissolution. To ensure that tablets can exert their therapeutic effect rapidly, disintegrants are generally added, except for slow-release tablets such as lozenges, sublingual tablets, implantable tablets, and long-acting tablets. Disintegrants are mostly hydrophilic substances with good swelling and water absorption properties. Preferably, the disintegrant can be in the following proportions by mass: for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 parts or any value between any two values.

[0039] Preferably, the disintegrant is selected from sodium carboxymethyl starch, croscarmellose, and croscarmellose sodium, with croscarmellose being the most preferred.

[0040] Adhesives: Adhesives play an important role in drug preparation. Their main function is to promote the adhesion of drug powders, thereby facilitating the shaping and processing of the drug. Preferably, the adhesives, by weight, can be 1, 2, 3, 4 parts, or any value between any two values.

[0041] Preferably, the adhesive is selected from one of methylcellulose, sodium carboxymethylcellulose, and ethylcellulose.

[0042] Lubricants: Used to reduce friction between particles and between particles and die orifices and punches, improving force transmission and distribution. Generally, any auxiliary material that performs any of these functions is referred to as a lubricant, and lubricants must be extremely fine powders. Preferably, the lubricant, by weight parts, can be, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 parts, or any value between any two values.

[0043] Preferably, the lubricant is selected from stearic acid, calcium stearate, magnesium stearate, and magnesium dodecyl sulfate, with magnesium stearate being the most preferred.

[0044] Example 2

[0045] A pharmaceutical preparation comprising oral administration, wherein the dosage form is selected from powder, granules, tablets, pills, capsules, soft capsules and pouches, preferably tablets.

[0046] The route of administration for the pharmaceutical formulations described herein may be supplied in bulk or unit dosage forms, depending on the intended route of administration. For example, for oral administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules, and capsules as solid dosage forms may be acceptable.

[0047] The use of a pharmaceutical preparation according to the above description or the pharmaceutical preparation prepared above in the preparation of a drug for preventing vomiting caused by chemotherapy drugs, or in the preparation of a drug for treating and preventing vomiting other than motion sickness vomiting.

[0048] Example 3

[0049] A method for preparing an antiemetic drug formulation, characterized by the following specific steps:

[0050] 1) Weigh out the main components, malopitum citrate, filler, flavoring agent, disintegrant, lubricant, and binder respectively;

[0051] 2) Dry mixing step: Add malopistan citrate, filler, flavoring agent, disintegrant and binder to the trough mixer, start stirring, dry mixing is completed, place the mixed material in the hopper of the dry granulator for granulation, sieve the obtained dry granules, fine powder below 80 mesh is granulated a second time, transfer the sieved dry granules to the mixer, add lubricant magnesium stearate and mix for 10 minutes, set the die and clean and disinfect, compress into tablets to obtain antiemetic drug tablets.

[0052] As a further preferred embodiment, in step 2), the sieving mesh is 80 mesh, and sieving is completed when the proportion of fine powder below 80 mesh is 20-40%. The amount of fine powder below the 80 mesh screen should not be too high, because subsequent tableting requires dry particles larger than 80 mesh.

[0053] Preferably, during dry mixing, the stirring speed is 20-50 rpm.

[0054] Preferably, during dry mixing, the stirring time is 0.1-0.3 hours.

[0055] Example 4

[0056] The pharmaceutical formulation prepared according to this application is described in detail below:

[0057] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0058] The present invention will be further described in detail below with reference to specific embodiments, which should not be construed as limiting the scope of protection claimed by the present invention.

[0059] The sources of at least some of the reagents and materials involved in the experimental examples, comparative examples, and test examples of this invention are as follows:

[0060] Maropitane citrate: Source: Self-made by China Agricultural University

[0061] L-malic acid: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0062] Starch: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0063] Sodium carboxymethyl starch: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0064] Methylcellulose: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0065] Magnesium stearate: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0066] Sucralose: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0067] Microcrystalline cellulose: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0068] Cross-linked polyvinylpyrrolidone: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0069] Sodium carboxymethyl cellulose: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0070] Dextrin: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0071] Cross-linked carboxymethyl cellulose sodium: purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0072] Ethyl cellulose: Purchased from: Sinopharm Chemical Reagent Co., Ltd.

[0073] Experimental Example 1

[0074] Weigh out the following ingredients separately: 60g of maropitant citrate, 40g of L-malic acid (flavoring agent), 66g of starch (filler), 49g of sodium carboxymethyl starch (disintegrant), 7g of methylcellulose (binder), and 2g of magnesium stearate (lubricant). Dry mixing procedure: Add maropitant citrate, starch, L-malic acid, sodium carboxymethyl starch, and methylcellulose to a trough mixer, start stirring at 30 rpm for 0.15 hours. After dry mixing, place the mixed material in the hopper of a dry granulator for granulation. Pass the resulting dry granules through an 80-mesh sieve. Perform secondary granulation on the fine powder below the 80-mesh sieve until the fine powder below the 80-mesh sieve accounts for 20%. Transfer the resulting dry granules to a mixer, add magnesium stearate, and mix for 10 minutes. Install and clean the die, then compress into tablets to obtain 2270 maropitant citrate chewable tablets, each weighing approximately 0.1g.

[0075] Experimental Example 2

[0076] Weigh out the following ingredients separately: 60g of maropitane citrate, 50g of sucralose (flavoring agent), 75g of microcrystalline cellulose (filler), 90g of crosporinone (disintegrant), 10g of sodium carboxymethyl cellulose (binder), and 10g of magnesium stearate (lubricant). Dry mixing procedure: Add maropitane citrate, sucralose, microcrystalline cellulose, crosporinone, and sodium carboxymethyl cellulose to a trough mixer. Start stirring at 40 rpm for 0.25 hours. After dry mixing, place the mixed material in the hopper of a dry granulator for granulation. Pass the resulting dry granules through an 80-mesh sieve. Perform secondary granulation on the fine powder below the 80-mesh sieve until the fine powder below the 80-mesh sieve accounts for 30%. After sieving, transfer the resulting dry granules to a mixer and add magnesium stearate, mixing for 10 minutes. After setting up the die and cleaning and disinfecting it, the tablets were compressed to obtain 2880 moropistan citrate chewable tablets, with each tablet weighing approximately 0.1g.

[0077] Experimental Example 3

[0078] Weigh out the following ingredients separately: 67g of maropitan citrate, 65g of stevia (flavoring agent), 88g of dextrin (filler), 64g of croscarmellose sodium (disintegrant), 8g of ethyl cellulose (binder), and 3g of magnesium stearate (lubricant). Dry mixing procedure: Add maropitan citrate, stevia, dextrin, ethyl cellulose, and croscarmellose sodium to a trough mixer, start stirring at 30 rpm for 0.20 hours. After dry mixing, place the mixed material in the hopper of a dry granulator for granulation. Pass the obtained dry granules through an 80-mesh sieve. Perform a second granulation on the fine powder below the 80-mesh sieve until the fine powder below the 80-mesh sieve accounts for 40%. After sieving, transfer the obtained dry granules to a mixer, add magnesium stearate, and mix for 10 minutes. After setting up the die and cleaning and sterilizing it, the tablets were compressed to obtain 2860 maripitan citrate chewable tablets, with each tablet weighing approximately 0.1g.

[0079] Comparative Example 1: No screening

[0080] Weigh out the following ingredients separately: 60g of maropitant citrate, 65g of stevia (flavoring agent), 88g of dextrin (filler), 64g of sodium croscarmellose (disintegrant), 8g of ethyl cellulose (binder), and 3g of magnesium stearate (lubricant). Dry mixing procedure: Add maropitant citrate, stevia, dextrin, ethyl cellulose, and sodium croscarmellose to a trough mixer, start stirring at 30 rpm for 0.20 hours. After dry mixing, place the mixed material in the hopper of a dry granulator for granulation. Transfer the resulting dry granules to a mixer, add magnesium stearate, and mix for 10 minutes. Install and clean the die, then compress into tablets to obtain 2790 maropitant citrate chewable tablets, each weighing approximately 0.1g.

[0081] Comparative Example 2: The ratio of disintegrant to binder was 4:1.

[0082] Weigh out the following ingredients separately: 60g of maropitant citrate, 65g of stevia (flavoring agent), 88g of dextrin (filler), 40g of sodium croscarmellose (disintegrant), 10g of ethyl cellulose (binder), and 3g of magnesium stearate (lubricant). Dry mixing procedure: Add maropitant citrate, stevia, dextrin, ethyl cellulose, and sodium croscarmellose to a trough mixer, start stirring at 30 rpm for 0.20 hours. After dry mixing, place the mixed material in the hopper of a dry granulator for granulation. Pass the resulting dry granules through an 80-mesh sieve. Transfer the dry granules to a mixer, add magnesium stearate, and mix for 10 minutes. Install and clean the die, then compress into tablets to obtain 2520 maropitant citrate chewable tablets, each weighing approximately 0.1g.

[0083] Comparative Example 3: The ratio of disintegrant to binder was 20:1.

[0084] Weigh out the following ingredients separately: 60g of maropitant citrate, 65g of stevia (flavoring agent), 88g of dextrin (filler), 140g of croscarmellose sodium (disintegrant), 7g of ethyl cellulose (binder), and 3g of magnesium stearate (lubricant). Dry mixing procedure: Add maropitant citrate, stevia, dextrin, ethyl cellulose, and croscarmellose sodium to a trough mixer, start stirring at 30 rpm for 0.20 hours. After dry mixing, place the mixed material in the hopper of a dry granulator for granulation. Pass the resulting dry granules through an 80-mesh sieve. Transfer the dry granules to a mixer, add magnesium stearate, and mix for 10 minutes. Install and clean the die, then compress into tablets to obtain 3550 maropitant citrate chewable tablets, each weighing approximately 0.1g.

[0085] Comparative Example 4: The flavoring agent was replaced with another reagent (sucrose).

[0086] Weigh out the following ingredients separately: 60g of maropitane citrate, 65g of sucrose (flavoring agent), 88g of dextrin (filler), 64g of crosporin (disintegrant), 8g of ethyl cellulose (binder), and 3g of magnesium stearate (lubricant). Dry mixing procedure: Add maropitane citrate, sucrose, dextrin, ethyl cellulose, and crosporin sodium carboxymethyl cellulose to a trough mixer, start stirring at 30 rpm for 0.20 h. After dry mixing, place the mixed material in the hopper of a dry granulator for granulation. Pass the obtained dry granules through an 80-mesh sieve. Transfer the dry granules to a mixer, add magnesium stearate, and mix for 10 min. Install and clean the die, then compress into tablets to obtain 2760 maropitane citrate chewable tablets.

[0087] Experimental Example 1

[0088] The stability of the influencing factors was investigated for the samples in Experiment Examples 1-3.

[0089] High temperature test: Take the samples from test examples 1-3, open them and place them in a constant temperature chamber at 60℃ for 10 days, and take samples for testing on the 5th and 10th days.

[0090] High humidity test: Take samples from tests 1-3, place them open in a stabilizing chamber with a humidity of 75% for 10 days, and take samples for testing on the 5th and 10th days.

[0091] Light exposure test: Take samples from test examples 1-3 and place them under an illuminance of 4500lx±500lx for 10 days. Take samples for testing on the 5th and 10th days.

[0092] The results show that the test samples have good stability under high temperature, high humidity and light conditions, as shown in Table 1.

[0093] Table 1 shows the stability test results of samples from Test Examples 1-3.

[0094]

[0095] Experiment Example 2

[0096] The friability and disintegration time of the samples from Test Example 3, Comparative Example 1, and Comparative Example 2 were tested.

[0097] Friability: The friability test is conducted according to the friability test method in the Chinese Veterinary Pharmacopoeia (Appendix 0923). The method is as follows: For tablets weighing 0.6g or less, take several tablets to make the total weight approximately 6.5g; for tablets weighing more than 0.65g, take 10 tablets. Use a blower to remove any loose powder from the tablets, accurately weigh them, place them in a cylinder, and rotate 100 times. Remove them, remove the powder using the same method, and accurately weigh them. The weight loss should not exceed 1%, and no broken, cracked, or pulverized tablets should be detected. This test is generally performed only once. If the weight loss exceeds 1%, it should be repeated twice. The average weight loss from the three tests should not exceed 1%, and no broken, cracked, or pulverized tablets should be detected, as shown in Table 2.

[0098] Disintegration time limit: The test shall be conducted in accordance with the disintegration time limit test method of the Chinese Veterinary Pharmacopoeia (Appendix 0921), and shall meet the requirements as shown in Table 2.

[0099] Table 2. Friability and Disintegration Time of Samples

[0100] Experimental Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 friability Meets requirements Meets requirements Does not meet requirements Does not meet requirements Disintegration time limit Meets requirements Does not meet requirements Does not meet requirements Does not meet requirements

[0101] As shown in Experiment 2, the hardness and friability of the tablets prepared by this invention meet the pharmacopoeia standards, allowing for better preservation. Meanwhile, the results of Comparative Examples 1-3 show that the hardness and friability of the tablets prepared by other processes in Comparative Examples 1-3 cannot meet the pharmacopoeia requirements, proving that our preparation process has a significant impact on the hardness and friability of the tablets.

[0102] Experimental Example 3

[0103] This study included only dogs that developed vomiting after chemotherapy. Forty-two beagles, aged 8 to 10 years, were included in the study. They were randomly assigned to seven groups of six dogs each, using samples from experimental cases 1, 2, and 3, and comparative cases 1, 2, 3, and 4, respectively. All dogs were treated with the following dosage: Oral administration: 2.0 mg per kg of body weight, once daily, for a maximum of five days.

[0104] The observation of treatment response was divided into three categories: significant efficacy, effective, and ineffective. Significant efficacy means that vomiting has been eliminated or reduced to a very mild level; effective means that vomiting has been significantly reduced (at least 50%); and ineffective means that vomiting has not changed or has worsened, or that the dog has experienced an adverse reaction that requires discontinuation of the medication.

[0105] The experimental results of this study are shown in Table 3 below.

[0106] Table 3. Treatment outcomes of Beagle dogs after medication.

[0107]

[0108]

[0109] As can be seen from Experimental Example 3, the tablets prepared by the present invention in Experimental Examples 1-3 can meet the requirements for clinical use, resulting in significant efficacy when used in animals. The results of Comparative Examples 1-4 show that the efficacy of tablets prepared by other processes is reduced, proving that the parameters of this product are irreplaceable.

[0110] Experiment Example 4: Bioequivalence Test

[0111] 1. Test materials

[0112] 1.1 Test Drug

[0113] Test formulation (test drug): Maropitan citrate tablets from Test Example 3, with a content of 16 mg, manufactured by China Agricultural University;

[0114] Test formulation (control drug): Maropitan citrate tablets (Cerenia Tablets), 16mg*4 tablets / box, manufactured by Fareva Amboise, France.

[0115] 1.2 Experimental Animals

[0116] Species / Breed: Beagle; Grade: General; Sex: Half male and half female; Age: Approximately 1-3 years; Weight: 8.9-10 kg at selection; Number: 24. The beagles used in the experiment were provided by the Animal Center of Beijing Anmersys Biotechnology Co., Ltd. The center was responsible for the harmless disposal of the animals after the experiment.

[0117] 2. Test Methods

[0118] 2.1 Grouping and Blinding of Experimental Animals

[0119] During the acclimatization period, 24 beagle dogs were randomly divided into two groups of 12 each, with half males and half females. The RT group received the reference formulation in the first cycle and the test formulation in the second cycle; the TR group received the test formulation in the first cycle and the reference formulation in the second cycle.

[0120] This is an open-label study, where participants are aware of both the reference and test formulations. However, the analysis phase is blinded, and analysts are unaware of the animal IDs for both the test and reference formulations. Blinding will be initiated after the data are locked following the completion of the analysis phase.

[0121] 2.2 Route of administration and dosage

[0122] Each beagle will be administered the following medication according to the following principles: randomized single-dose, two-cycle, two-treatment, two-sequence crossover design; washout period of at least 7 days and at least 5 drug half-lives. Both the test and reference formulations will be administered orally as recommended. The recommended dose for both the test and reference formulations is 0.5 mg / kg BW. The dosage of the test and reference formulations will be calculated based on the body weight measured the day before administration.

[0123] 2.3 Sample Collection

[0124] At different time points during each cycle, 1 ml of blood was collected from the buccal vein of the beagle and placed in a human anticoagulant blood collection tube. Specific blood collection time points were as follows: 0 h (before drug administration), and 0.08, 0.167, 0.25, 0.33, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 12 h after drug administration. 384 blood samples were collected in each experimental phase, meaning a total of 768 blood samples were required to complete the entire experiment.

[0125] 2.4 Pharmacokinetic Parameters

[0126] After the bioanalytical phase is completed, plasma concentration values ​​will be entered into the pharmacokinetic analysis software. Non-compartmental analysis methods will be used to evaluate the pharmacokinetic parameters; this method can analyze important pharmacokinetic parameters.

[0127] When calculating pharmacokinetic parameters and their properties, the following principles should be followed: All plasma concentration values ​​validated by a bioanalytical laboratory and submitted to the project leader must be included in the pharmacokinetic analysis. The theoretical blood collection time after administration will be used for calculation. Any concentration below the LOQ between 0:00 and the first concentration equal to or higher than the LOQ will be set to 0; concentrations below the LOQ between two LOQ values ​​will be considered missing. Tail peaks below the LOQ will not be used in the calculation. After each administration, the following pharmacokinetic parameters were calculated for each beagle dog, and the results are shown in Table 4:

[0128] C max The maximum concentration of the drug in the plasma after administration was calculated using WinNolin software.

[0129] t max The concentration of the drug in the plasma reached C max The time point was calculated using WinNolin software.

[0130] λ Z To eliminate the rate constant, log-linear regression is typically used to calculate the rate constant for evaluable data.

[0131] To obtain a reliable slope for the elimination phase, the following guidelines should be followed: the terminal elimination data points should be randomly distributed along approximately a straight line (visual inspection); the regression statistics should contain at least three data points, including the last measured data point, but excluding C. max .

[0132] If the above two conditions cannot be met, then the slope of the terminal elimination portion is considered uncalculated, and is determined by AUC. 0-∞ t 1 / 2 All calculated parameters were reported as incalculable (NC). The elimination half-life (t) was calculated according to the following formula. 1 / 2 ):t 1 / 2 =0.693 / λz.

[0133] Table 4. Average pharmacokinetic parameters of malopitum citrate tablets reagent and reference formulation.

[0134]

[0135] The results show that the Tmax and C of the maropistan citrate prepared using the method of this invention are... max The upper and lower limits of the 90% confidence interval of the parameters both meet the equivalence standard of 80-125%, proving that the maropistan citrate prepared in this invention is bioequivalent to the reference preparation.

[0136] This study demonstrates that this product can be used to prevent vomiting caused by chemotherapy drugs and to treat and prevent vomiting other than motion sickness vomiting. It also demonstrates that due to non-screening and changes in the ratio of disintegrants, maripitan citrate is ineffective in treating vomiting in dogs. In comparison 4, due to changes in the flavoring agent, most dogs refused to take the tablets, resulting in ineffective treatment in 5 dogs, which has a significant impact on the treatment of vomiting.

[0137] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. An animal anti-emetic pharmaceutical formulation characterised in that, Maropitant citrate, fillers, flavoring agents, disintegrants, binders and lubricants; maropitant citrate is 10-30 parts by mass, fillers are 20-50 parts, flavoring agents are 10-30 parts, disintegrants are 10-30 parts, binders are 1-4 parts, and lubricants are 0.1-5 parts; The disintegrant and the binder are in a mass ratio of (7-10) : 1; The fillers are selected from one of sugar powder, starch, microcrystalline cellulose, and dextrin; The flavoring agents are selected from one of L-malic acid, lactose, sucralose, or stevia sugar; The disintegrants are selected from one of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; The binders are selected from one of methyl cellulose, sodium carboxymethyl cellulose, and ethyl cellulose; The lubricants are selected from one of stearic acid, calcium stearate, magnesium stearate, and magnesium lauryl sulfate.

2. The pharmaceutical preparation according to claim 1, characterized in that, The dosage form of the pharmaceutical preparation is selected from powder, granules, tablets, pills, and capsules.

3. The pharmaceutical preparation according to claim 2, characterized in that, The dosage form is tablets.

4. A process for the preparation of an antiemetic pharmaceutical formulation according to any one of claims 1 to 3, characterized in that, The specific steps are as follows: 1) Maropitant citrate, fillers, flavoring agents, disintegrants, lubricants, and binders are weighed respectively according to the mass fraction; 2) Dry mixing step: maropitant citrate, fillers, flavoring agents, disintegrants, and binders are added to a trough mixer, stirring is started, and dry mixing is completed. The mixed material is placed in the hopper of a dry granulator for granulation. The dry granules obtained are sieved, and the fine powder below 80 mesh sieve is subjected to secondary granulation. The sieved dry granules are transferred to the mixer, lubricants are added and mixed, the die is prepared and cleaned and disinfected, and the tablets are pressed to obtain the antiemetic pharmaceutical preparation tablets.

5. The preparation method according to claim 4, characterized in that, The sieving mesh is 80 mesh sieve, and the fine powder below 80 mesh sieve accounts for 20-40% until the sieving is completed.

6. The preparation method according to claim 4, characterized in that, During dry mixing, the stirring speed is 20-50 rpm.

7. The preparation method according to claim 4, characterized in that, During dry mixing, the stirring time is 0.1-0.3 hours.

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