Vomiting arresting medicinal preparation as well as preparation method and application thereof

Abstract

The invention relates to a vomiting arresting medicinal preparation as well as a preparation method and application thereof. The vomiting arresting medicinal preparation comprises the following main components: maropitant citrate, a filling agent, a flavoring agent, a disintegrating agent, an adhesive and a lubricating agent, the maropitant citrate tablet is prepared from the following components in parts by mass: 10 to 30 parts of maropitant citrate, 20 to 50 parts of filling agent, 10 to 30 parts of flavoring agent, 10 to 30 parts of disintegrating agent, 1 to 4 parts of adhesive and 0.1 to 5 parts of lubricating agent, wherein the mass ratio of the disintegrating agent to the adhesive is (7-10): 1. The maropitant citrate chewable tablet disclosed by the invention is good in stability, high in safety, good in curative effect, simple and convenient in preparation method and suitable for mass production.

Description

Technical Field

[0001] The present invention relates to the technical field of veterinary drugs, and in particular to an antiemetic drug preparation and a preparation method and application thereof. Background Art

[0002] Maropitant citrate is an effective and selective type 1 neurokinin (NK-1) receptor antagonist that can act on the central nervous system by inhibiting substance P (a key neurotransmitter that causes vomiting), and can inhibit peripheral and central vomiting. It is the first drug used to prevent and treat severe vomiting and motion sickness in dogs, and is also the first drug approved for the treatment of canine motion sickness. It has good clinical application value and market prospects.

[0003] At present, in the prior art, maropitant citrate is a drug that is almost insoluble in water. If it is made into tablets, its disadvantages are that several excipients need to be added to the tablets and compressed, which may lead to a slow dissolution rate and sometimes affect the bioavailability of the drug. Secondly, if the tablets contain volatile components, their content will decrease after long-term storage, reducing the stability of maropitant citrate. These disadvantages limit the scope of use and effect of maropitant citrate to a certain extent. Summary of the invention

[0004] In view of the above-mentioned technical limitations, based on existing research, the present invention provides a maropitant citrate chewable tablet, which adopts dry granulation to improve the stability of the tablet, adjust the ratio of disintegrant and binder, and make it easier to be absorbed after entering the body, thereby overcoming the above-mentioned defects.

[0005] The first invention of the present invention is: an antiemetic drug preparation, the main components of which include maropitant citrate, a filler, a flavoring agent, a disintegrant, a binder and a lubricant;

[0006] Calculated by weight, the amount of maropitant 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 mass ratio of the disintegrant to the binder is (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 one of L-malic acid, lactose, sucralose or stevioside, preferably stevioside.

[0010] Furthermore, the disintegrant is selected from sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and cross-linked sodium carboxymethyl cellulose, preferably cross-linked polyvinyl pyrrolidone.

[0011] Furthermore, the binder is selected from one of methyl cellulose, sodium carboxymethyl cellulose and ethyl cellulose.

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

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

[0014] The third invention of the present invention is: a method for preparing an antiemetic drug preparation, the specific steps are as follows:

[0015] 1) Weigh the main ingredient maropitant citrate, filler, flavoring agent, disintegrant, lubricant and binder respectively according to their mass proportions;

[0016] 2) Dry mixing step: add maropitant citrate, filler, flavoring agent, disintegrant and binder into a trough mixer, start stirring, finish dry mixing, place the mixed materials into the hopper of a dry granulator, granulate, sieve the obtained dry granules, granulate the fine powder below 80 mesh sieve for secondary granulation, transfer the sieved dry granules into a mixer, add a lubricant and mix, install the punch die and clean and disinfect, and press the tablets to obtain antiemetic drug preparation tablets.

[0017] Furthermore, in step 2), the sieving mesh number is 80 mesh, and the sieving is completed until the proportion of fine powder below the 80 mesh sieve is 20-40%.

[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 the present invention is: an application of the above-mentioned pharmaceutical preparation or the above-mentioned pharmaceutical preparation 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 present invention has the following advantages:

[0022] The present invention adopts dry granulation to ensure the stability of the pharmaceutical preparation, and the material compatibility is good, and the fixed filtration mesh number and the particle size of the dry particles make the hardness and friability of the tablets meet the clinical medication and storage requirements. The preparation of the present invention is for oral administration, which greatly expands the clinical application range of maropitant citrate. In summary, the maropitant citrate chewable tablets of the present invention have good stability, high safety, good efficacy, simple preparation method, and are suitable for mass production.

[0023] Specific implementation method

[0024] In order to make the purpose, technical solution and advantages of the present application more clear, the present application is further described in detail below. However, it should be understood that the description here is only used to explain the present application and is not used to limit the scope of the present application.

[0025] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present application, and the terms used herein in the specification of the present application are only for the purpose of describing specific embodiments and are not intended to limit the present application. The reagents and instruments used herein are all commercially available, and the characterization means involved can refer to the relevant descriptions in the prior art, which will not be repeated herein.

[0026] In order to further understand the present application, the present application is further described in detail below in conjunction with the best embodiment.

[0027] Example 1

[0028] The present embodiment provides an antiemetic drug preparation, the main ingredients of which include maropitant citrate, a filler, a flavoring agent, a disintegrant, a binder and a lubricant; the main ingredients are calculated by weight, and the maropitant citrate is 10-30 parts, the filler is 20-50 parts, the flavoring agent is 10-30 parts, the disintegrant is 10-30 parts, the binder is 1-4 parts, and the lubricant is 0.1-5 parts. The main ingredients can be further preferably calculated by weight: maropitant citrate is 15-25 parts, the filler is 25-45 parts, the flavoring agent is 15-25 parts, the disintegrant is 15-25 parts, the binder is 2-4 parts, and the lubricant is 0.5-4.5 parts.

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

[0030] The following is a further description of the above main components and their mass fractions:

[0031] Maropitant citrate: Pharmacodynamics Maropitant is a neurokinin (NK1) receptor antagonist. Vomiting is a complex adjustment process of the vomiting center, which is mainly caused by the emetic chemoreceptor zone (CTZ) of the brainstem receiving and integrating the reactions from central nervous stimulation, peripheral nerve stimulation, and chemical stimulation in the blood circulation and cerebrospinal fluid. Substance P is a type of neurotransmitter related to vomiting. Blocking the binding between substance P and receptors can effectively inhibit central nervous vomiting, peripheral nervous vomiting, and vomiting caused by chemical factors. Maropitant can block the binding of substance P to receptors in the central nervous system and play an antiemetic role. Preferably, maropitant citrate can be taken as follows 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.

[0032] Filler: diluent and absorbent are also called fillers, and their main purpose is to increase the weight and volume of tablets. For the convenience of application and production, the diameter of the tablet is generally not less than 6mm, and the tablet weight is generally more than 100mg, so when the dosage of the drug is less than 100mg, tableting is difficult. In addition, when the Chinese medicine tablet contains a lot of extract or the viscosity of the extract is too large, a diluent must be added to facilitate tableting. If the raw material contains more volatile oils, fatty oils or other liquids, it is necessary to add an appropriate amount of absorbent to absorb and then tablet. Preferably, the filler can be taken as follows by mass: 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 agent: Flavoring agent refers to a pharmaceutical excipient used in medicines to improve or mask the bad smell and taste of medicines, so that patients can hardly perceive the strong bitter taste (or other peculiar smells such as spicy, irritating, etc.) of the medicines. Preferably, the flavoring agent can be taken as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 parts by mass or any value between any two values.

[0036] Preferably, the flavoring agent is selected from one of L-malic acid, lactose, sucralose or stevioside, preferably stevioside.

[0037] The natural sweetener stevioside, also known as stevioside, is a yellowish white powder, odorless, and has a refreshing sweet taste. Its sweetness is about 300 times that of sucrose, and its sweetness lasts long and is not absorbed. It is a non-caloric sweetener.

[0038] Disintegrants: Disintegrants refer to excipients added to tablets that can cause the tablets to quickly disintegrate into small particles in gastrointestinal fluids. Since the porosity of the drug is very small and the binding force is very strong after it is pressed into tablets under great pressure, even if the drug that is easily soluble in water is pressed into tablets, it takes a certain amount of time for it to dissolve and disintegrate in water. Therefore, the dissolution rate of water-insoluble drugs in tablets becomes the limiting factor for the absorption rate of drugs in the body, and the disintegration of tablets is generally the first step in tablet dissolution. In order for the tablets to quickly exert their efficacy, disintegrants are generally required, except for buccal tablets, sublingual tablets, implants, long-acting tablets, etc. that require slow drug release. Disintegrants are mostly hydrophilic substances with good swelling and water absorption. Preferably, the disintegrant can be taken as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 parts by mass or any value between any two values.

[0039] Preferably, the disintegrant is selected from sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and cross-linked sodium carboxymethyl cellulose, preferably cross-linked polyvinyl pyrrolidone.

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

[0041] Preferably, the binder is selected from one of methyl cellulose, sodium carboxymethyl cellulose and ethyl cellulose.

[0042] Lubricant: used to reduce the friction between particles and between particles and die holes and punches, and improve the transmission and distribution of force. Generally, auxiliary materials with any of the above functions are collectively referred to as lubricants, and lubricants must be extremely fine powders. Preferably, the lubricant can be taken as, 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 by mass or any value between any two values.

[0043] Preferably, the lubricant is selected from stearic acid, calcium stearate, magnesium stearate, magnesium lauryl sulfate, preferably magnesium stearate.

[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 caplets, preferably tablets.

[0046] Administration route Since the pharmaceutical preparations provided herein can be supplied in bulk or unit dosage form depending on the intended administration route. For example, for oral administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules and caplets can be acceptable as solid dosage forms.

[0047] A use of the above-mentioned pharmaceutical preparation or the pharmaceutical preparation prepared above in preparing a drug for preventing vomiting caused by chemotherapy drugs, or in preparing a drug for treating and preventing vomiting other than motion sickness vomiting.

[0048] Example 3

[0049] A method for preparing an antiemetic drug preparation, characterized in that the specific steps are as follows:

[0050] 1) Weigh the main ingredient maropitant citrate, filler, flavoring agent, disintegrant, lubricant and binder respectively;

[0051] 2) Dry mixing step: Add maropitant citrate, filler, flavoring agent, disintegrant and binder to a trough mixer, start stirring, and finish dry mixing. Place the mixed materials in the hopper of a dry granulator for granulation. Sieve the obtained dry granules, and perform secondary granulation on the fine powder below 80 mesh. Transfer the sieved dry granules to the mixer, add lubricant magnesium stearate and mix for 10 minutes. Put on the punch die, clean and disinfect it, and press it into tablets to obtain antiemetic drug preparation tablets.

[0052] As a further preferred embodiment, in step 2), the sieving is performed with an 80-mesh sieve until the proportion of fine powder below the 80-mesh sieve is 20-40%, and the sieving is completed. The fine powder below the 80-mesh sieve should not be too much, because the subsequent tableting requires the dry particles to be 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] According to the content of this application, the pharmaceutical preparation of the example is prepared, and the specific description is as follows:

[0057] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0058] The present invention is further described in detail below in conjunction with specific embodiments. These embodiments 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 the present invention are as follows:

[0060] Maropitant citrate: Source: 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] Methyl cellulose: 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 polyvinyl pyrrolidone: 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] Test Example 1

[0074] Weigh the main ingredients of Maropitant citrate 60g, flavoring agent L-malic acid 40g, filler starch 66g, disintegrant sodium carboxymethyl starch 49g, adhesive methyl cellulose 7g and lubricant magnesium stearate 2g respectively. Dry mixing step: Add Maropitant citrate, starch, L-malic acid, sodium carboxymethyl starch and methyl cellulose to a trough mixer, start stirring, the speed is 30rpm, and stir for 0.15h. After the dry mixing is completed, the mixed material is placed in the hopper of the dry granulator for granulation. The obtained dry granules are passed through an 80-mesh sieve, and the fine powder below the 80-mesh sieve is subjected to secondary granulation until the fine powder below the 80-mesh sieve accounts for 20%. After the sieving is completed, the obtained dry granules are transferred to a mixer, and magnesium stearate is added and mixed for 10min. Put on the punch die and clean and disinfect it, and compress it into tablets to obtain 2270 Maropitant citrate chewable tablets, and the tablet weight is basically about 0.1g.

[0075] Test Example 2

[0076] Weigh the main ingredients of Maropitant citrate 60g, flavoring agent sucralose 50g, filler microcrystalline cellulose 75g, disintegrant cross-linked polyvinyl pyrrolidone 90g, binder sodium carboxymethyl cellulose 10g and lubricant magnesium stearate 10g respectively. Dry mixing step: Add Maropitant citrate, sucralose, microcrystalline cellulose, cross-linked polyvinyl pyrrolidone and sodium carboxymethyl cellulose in a trough mixer, start stirring, the speed is 40rpm, and stir for 0.25h. After the dry mixing is completed, the mixed material is placed in the hopper of the dry granulator for granulation. The obtained dry granules are passed through an 80-mesh sieve, and the fine powder below the 80-mesh sieve is subjected to secondary granulation until the fine powder below the 80-mesh sieve accounts for 30%. After the sieving is completed, the dry granules obtained are transferred to the mixer, and magnesium stearate is added and mixed for 10min. The punching die was installed, cleaned and disinfected, and tableting was performed to obtain 2880 maropitant citrate chewable tablets, with a tablet weight of about 0.1 g.

[0077] Test Example 3

[0078] Weigh the main ingredients of Maropitant citrate 67g, flavoring agent stevioside 65g, filler dextrin 88g, disintegrant cross-linked carboxymethyl cellulose sodium 64g, binder ethyl cellulose 8g and lubricant magnesium stearate 3g respectively. Dry mixing step: Add Maropitant citrate, stevioside, dextrin, ethyl cellulose and cross-linked carboxymethyl cellulose sodium to a trough mixer, start stirring, the speed is 30rpm, and stir for 0.20h. After the dry mixing is completed, the mixed material is placed in the hopper of the dry granulator for granulation. The obtained dry granules are passed through an 80-mesh sieve, and the fine powder below the 80-mesh sieve is subjected to secondary granulation until the fine powder below the 80-mesh sieve accounts for 40%. The sieving is completed, and the obtained dry granules are transferred to the mixer, and magnesium stearate is added and mixed for 10min. The punching die was installed, cleaned and disinfected, and tableting was performed to obtain 2860 maropitant citrate chewable tablets, with a tablet weight of about 0.1 g.

[0079] Comparative Example 1: No screening

[0080] Weigh the main ingredient Maropitant citrate 60g, flavoring agent stevioside 65g, filler dextrin 88g, disintegrant cross-linked carboxymethyl cellulose sodium 64g, adhesive ethyl cellulose 8g and lubricant magnesium stearate 3g respectively. Dry mixing step: add Maropitant citrate, stevioside, dextrin, ethyl cellulose and cross-linked carboxymethyl cellulose sodium in a trough mixer, start stirring, the speed is 30rpm, and stir for 0.20h. After dry mixing, the mixed material is placed in the hopper of the dry granulator for granulation. The obtained dry granules are transferred to the mixer, and magnesium stearate is added and mixed for 10min. Put on the punch die and clean and disinfect, and tablet compression is performed to obtain 2790 Maropitant citrate chewable tablets, and the tablet weight is basically about 0.1g.

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

[0082] Weigh the main ingredient Maropitant citrate 60g, flavoring agent stevioside 65g, filler dextrin 88g, disintegrant cross-linked carboxymethyl cellulose sodium 40g, adhesive ethyl cellulose 10g and lubricant magnesium stearate 3g respectively. Dry mixing step: add Maropitant citrate, stevioside, dextrin, ethyl cellulose and cross-linked carboxymethyl cellulose sodium in a trough mixer, start stirring, the speed is 30rpm, and stir for 0.20h. After dry mixing, the mixed material is placed in the hopper of the dry granulator for granulation. The obtained dry granules are passed through an 80-mesh sieve, and the obtained dry granules are transferred to a mixer, and magnesium stearate is added and mixed for 10min. Put on the punch die and clean and disinfect, and tablet compression is performed to obtain 2520 Maropitant citrate chewable tablets, and the tablet weight is basically about 0.1g.

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

[0084] Weigh the main ingredients of Maropitant citrate 60g, flavoring agent stevioside 65g, filler dextrin 88g, disintegrant cross-linked carboxymethyl cellulose sodium 140g, adhesive ethyl cellulose 7g and lubricant magnesium stearate 3g respectively. Dry mixing step: add Maropitant citrate, stevioside, dextrin, ethyl cellulose and cross-linked carboxymethyl cellulose sodium in a trough mixer, start stirring, the speed is 30rpm, and stir for 0.20h. After dry mixing, the mixed material is placed in the hopper of the dry granulator for granulation. The obtained dry granules are passed through an 80-mesh sieve, and the obtained dry granules are transferred to a mixer, and magnesium stearate is added and mixed for 10min. Put on the die and clean and disinfect, and tablet compression is performed to obtain 3550 Maropitant citrate chewable tablets, and the tablet weight is basically about 0.1g.

[0085] Comparative Example 4: Flavor corrector changed to other reagents (sucrose)

[0086] Weigh the main ingredient Maropitant citrate 60g, flavoring agent sucrose 65g, filler dextrin 88g, disintegrant cross-linked polyvinyl pyrrolidone 64g, adhesive ethyl cellulose 8g and lubricant magnesium stearate 3g respectively. Dry mixing step: Add Maropitant citrate, sucrose, dextrin, ethyl cellulose and cross-linked sodium carboxymethyl cellulose in a trough mixer, start stirring, the speed is 30rpm, and stir for 0.20h. After dry mixing, the mixed material is placed in the hopper of the dry granulator for granulation. The obtained dry granules are passed through an 80-mesh sieve, and the obtained dry granules are transferred to a mixer, and magnesium stearate is added and mixed for 10min. Put on the die and clean and disinfect, and tablet compression is performed to obtain 2760 Maropitant citrate chewable tablets.

[0087] Experimental Example 1

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

[0089] High temperature test: Take the samples of Test Examples 1-3, open them and place them in a constant temperature box at 60°C for 10 days, and take samples for testing on the 5th and 10th days.

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

[0091] Lighting test: Take the samples of Test Examples 1-3 and place them under an illumination of 4500 lx ± 500 lx 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 Stability test results of samples of test examples 1-3

[0094]

[0095] Experimental Example 2

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

[0097] Friability: Test according to the friability test method (Appendix 0923) of the Chinese Pharmacopoeia of Veterinary Medicine. Test method: For tablets weighing 0.6g or less, take a number of tablets to make a total weight of about 6.5g; for tablets weighing more than 0.65g, take 10 tablets. Use a hair dryer to blow away the powder that falls off the tablets, weigh accurately, place in a cylinder, and rotate 100 times. Take out, remove the powder in the same way, weigh accurately, the weight loss shall not exceed 1%, and no broken, cracked or crushed tablets shall be detected. This test is generally performed only once. If the weight loss exceeds 1%, it should be retested twice, and the average weight loss of 3 times shall not exceed 1%, and no broken, cracked or crushed tablets shall be detected, as shown in Table 2.

[0098] Disintegration time: Check according to the disintegration time test method (Appendix 0921) of the "Chinese Pharmacopoeia of Veterinary Medicine" and it should comply with the regulations, as shown in Table 2.

[0099] Table 2 Friability and disintegration time of samples

[0100] Test Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 friability Meet the requirements Meet the requirements Not meeting the requirements Not meeting the requirements Disintegration time Meet the requirements Not meeting the requirements Not meeting the requirements Not meeting the requirements

[0101] It can be seen from Experimental Example 2 that the hardness and friability of the tablets prepared by the present invention meet the pharmacopoeia standards and can be better preserved. At the same time, the results of Comparative Examples 1-3 show that the hardness and friability of the tablets of Comparative Examples 1-3 prepared by other processes cannot meet the pharmacopoeia requirements, proving that our preparation process has a significant effect on the hardness and friability of the tablets.

[0102] Experimental Example 3

[0103] This study only included dogs with clinical symptoms of vomiting after using chemotherapy drugs. 42 test dogs, 8 to 10 years old beagles. Randomly divided into 7 groups, 6 in each group, and tested with samples of test examples 1, 2, 3 and comparative examples 1, 2, 3, 4. All dogs were treated with this product, and the dosage was: oral: a single dose, 2.0 mg per 1 kg body weight, once a day, up to 5 consecutive 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 the dog has an adverse reaction that requires drug discontinuation.

[0105] In this study, the test results are shown in Table 3 below.

[0106] Table 3 Treatment of beagle dogs after medication

[0107]

[0108]

[0109] It can be seen from Experimental Example 3 that the tablets of Experimental Examples 1-3 prepared by the present invention can meet clinical medication requirements, making the therapeutic effect significant when used on animals. However, it can be seen from the results of Comparative Examples 1-4 that the efficacy of tablets prepared by other processes has decreased, proving that the parameters of this product are irreplaceable.

[0110] Experimental Example 4 Bioequivalence Test

[0111] 1. Test materials

[0112] 1.1 Trial Drugs

[0113] Test preparation (test drug): Maropitant citrate tablets of Test Example 3, with a content of 16 mg, produced by China Agricultural University;

[0114] Test preparation (control drug): Maropitant citrate tablets (Cerenia Tablets), specification is 16 mg*4 tablets / box, manufacturer: Fareva Amboise, France.

[0115] 1.2 Experimental animals

[0116] Species / strain: beagle; Grade: general grade; Gender: half male and half female; Age: about 1-3 years old; Weight: 8.9-10 kg at the time of selection; Number: 24. The beagle dogs were provided by the Animal Center of Beijing Amerses Biotechnology Co., Ltd. The test center was responsible for harmless disposal after the test was completed.

[0117] 2. Test methods

[0118] 2.1 Experimental Animal Grouping and Blinding

[0119] During the adaptation period, 24 beagle dogs were randomly divided into two groups, 12 in each group, half male and half female. RT group: the reference preparation was given in the first cycle and the test preparation was given in the second cycle; TR group: the test preparation was given in the first cycle and the reference preparation was given in the second cycle.

[0120] This study is an open trial, and the drug administerers are aware of the reference and test preparations. However, the analysis phase is blinded, and the analysts are unaware of the animal numbers of the test and reference preparations. After the analysis phase is completed, the blinding is lifted after the data is locked.

[0121] 2.2 Administration route and dosage

[0122] Each beagle dog will be dosed according to the following principles: randomized single dose, two-period, two-treatment group, two-sequence crossover design; washout period of at least 7 days, not less than 5 drug half-lives. Both the test and reference products are administered by the recommended oral route. The recommended dose of the test and reference products is 0.5 mg / kg BW. The dosage of the test and reference products is calculated based on the body weight results of the day before dosing.

[0123] 2.3 Test sample collection

[0124] At different time points in each cycle, 1 ml of blood was collected from the brachiocephalic vein of the beagle dogs and placed in human medical anticoagulant blood collection tubes. The specific blood collection time points are as follows: 0h (before administration), 0.08, 0.167, 0.25, 0.33, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8 and 12h after administration. 384 blood samples were collected in each experimental stage, that is, 768 blood samples were collected to complete the entire experiment.

[0125] 2.4 Pharmacokinetic parameters

[0126] After the bioanalytical phase of the study is completed, the plasma concentration values ​​will be entered into the pharmacokinetic analysis software. The pharmacokinetic parameters will be evaluated using a non-compartmental analysis method that allows the analysis of important pharmacokinetic parameters.

[0127] When calculating pharmacokinetic parameters and their properties, the following principles should be followed: All plasma concentration values ​​verified by the bioanalytical laboratory and submitted to the project leader must participate in the pharmacokinetic analysis process. The theoretical blood collection time after the end of administration will be used for calculation. From 0 o'clock to the first concentration equal to or higher than LOQ, any concentration below LOQ is set to 0; concentrations below LOQ between 2 concentrations equal to or higher than LOQ are considered missing. Tailing peaks below LOQ are not used for calculation. After each dose, 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 detected in plasma after administration, calculated by WinNolin software.

[0129] t max :The concentration of drug in plasma reaches C max The time point was calculated by WinNolin software.

[0130] λ Z : Elimination rate constant, usually calculated by log-linear regression of evaluable data.

[0131] In order to obtain a reliable slope of the elimination phase, the following rules should be followed: the terminal elimination data points should be randomly distributed on approximately a straight line (visual inspection); the regression statistics should contain at least 3 data points, including the last measured data point but excluding C max .

[0132] If the above two regulations cannot be met, it is considered that the slope of the terminal elimination part cannot be calculated, and the AUC 0-∞ ,t 1 / 2 All the calculated parameter results were reported as not calculable (NC). The elimination half-life (t 1 / 2 ): t 1 / 2 =0.693 / λz.

[0133] Table 4 Mean values ​​of pharmacokinetic parameters of Maropitant Citrate Tablets and Reference Preparations

[0134]

[0135] From the results, the Tmax, C max The upper and lower limits of the 90% confidence interval of the parameter both meet the equivalence standard of 80-125%, which proves that the maropitant citrate prepared by the present invention is bioequivalent to the reference preparation.

[0136] This study proves that this product can be used to prevent vomiting caused by chemotherapy drugs; to treat and prevent vomiting other than motion sickness vomiting. It also proves that due to the lack of screening and the change in the proportion of disintegrants, maropitant citrate is ineffective in treating vomiting in dogs. In Example 4, due to the change in the flavoring agent, most dogs did not eat the tablets, which led to 5 dogs being ineffective, which has a great impact on the treatment of vomiting.

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

Claims

1. An antiemetic drug preparation, characterized in that: The main ingredients include maropitant citrate, filler, flavoring agent, disintegrant, binder and lubricant; calculated by weight, the maropitant citrate is 10-30 parts, the filler is 20-50 parts, the flavoring agent is 10-30 parts, the disintegrant is 10-30 parts, the binder is 1-4 parts, and the lubricant is 0.1-5 parts.

2. The pharmaceutical preparation according to claim 1, characterized in that The mass ratio of the disintegrant to the binder is (7-10):

1.

3. The pharmaceutical preparation according to claim 1, characterized in that The filler is selected from one of powdered sugar, starch, microcrystalline cellulose and dextrin.

4. The pharmaceutical preparation according to claim 1, characterized in that The flavoring agent is selected from one of L-malic acid, lactose, sucralose or stevioside, preferably stevioside.

5. The pharmaceutical preparation according to claim 1, characterized in that The disintegrant is selected from sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and cross-linked sodium carboxymethyl cellulose, preferably cross-linked polyvinyl pyrrolidone.

6. The pharmaceutical preparation according to claim 1, characterized in that The binder is selected from one of methyl cellulose, sodium carboxymethyl cellulose and ethyl cellulose.

7. The pharmaceutical preparation according to claim 1, characterized in that The lubricant is selected from stearic acid, calcium stearate, magnesium stearate, and magnesium lauryl sulfate, preferably magnesium stearate.

8. A pharmaceutical preparation according to any one of claims 1 to 7, characterized in that The pharmaceutical preparation includes oral administration, and the dosage form for oral administration is selected from powder, granules, tablets, pills, capsules, soft capsules and caplets, preferably tablets.

9. A method for preparing the antiemetic pharmaceutical preparation according to any one of claims 1 to 7, characterized in that: The specific steps are as follows: 1) Weigh the main ingredient maropitant citrate, filler, flavoring agent, disintegrant, lubricant and binder respectively according to their mass proportions; 2) Dry mixing step: adding maropitant citrate, filler, flavoring agent, disintegrant and binder into a trough mixer, starting stirring, and finishing dry mixing, placing the mixed materials into a hopper of a dry granulator for granulation, sieving the obtained dry granules, performing secondary granulation on the fine powder below 80 mesh, transferring the sieved dry granules into a mixer, adding a lubricant for mixing, attaching a punch die, cleaning and disinfecting the die, and performing tableting to obtain antiemetic drug preparation tablets; Preferably, the sieving mesh number is 80 mesh, and the sieving ends when the proportion of fine powder below the 80 mesh is 20-40%; Preferably, during dry mixing, the stirring speed is 20-50 rpm; Preferably, during dry mixing, the stirring time is 0.1-0.3 hours.

10. Use of the pharmaceutical preparation according to any one of claims 1 to 8 or the pharmaceutical preparation prepared according to any one of claim 9 in the preparation of a drug for preventing vomiting caused by chemotherapeutic drugs, or in the preparation of a drug for treating and preventing vomiting other than motion sickness vomiting.

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