Ondansetron hydrochloride soft chewing composition for pets and preparation method of ondansetron hydrochloride soft chewing composition

Abstract

The invention relates to an ondansetron hydrochloride soft chewing composition for pets and a preparation method of the ondansetron hydrochloride soft chewing composition. The ondansetron hydrochloride soft chewing composition comprises the following components in percentage by mass: 3%-6% of ondansetron hydrochloride, 7.2%-8.2% of glycerol, 10.3%-14.5% of medium chain triglyceride, 19%-22% of an adhesive, 20%-30% of chicken liver powder and 25%-35% of corn starch. The preparation method comprises the following steps: uniformly mixing the raw material medicine powder with the corn starch, the chicken liver powder and the adhesive, adding the glycerol, stirring, adding the medium chain triglyceride, and stirring; the ondansetron hydrochloride soft chewing composition is good in palatability, simple in preparation process, convenient for industrial production and stable in property.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and relates to an ondansetron hydrochloride soft chew composition for pets and a preparation method thereof. Background Art

[0002] Ondansetron Hydrochloride, chemically named 2,3-dihydro-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-4(1H)-carbazolone dihydrochloride, is a selective 5-hydroxytryptamine 3 (5-HT3) receptor antagonist that can reduce the vomiting reflex by blocking 5-HT3 receptors in the gastrointestinal tract and the brain. Although it is mainly used for human clinical treatment, in some cases, ondansetron hydrochloride is also used by veterinarians to treat vomiting problems in pets (especially cats and dogs).

[0003] Ondansetron Hydrochloride has produced significant effects in controlling or at least significantly reducing the vomiting frequency in dogs and cats with frequent or severe vomiting, including dogs with severe parvovirus enteritis, patients with pancreatitis, and cats with hepatic steatosis. Usually, dogs that appear very distressed due to nausea and vomiting look more relaxed and comfortable 15 minutes after taking ondansetron. No serious side effects such as diarrhea, sedation, or extrapyramidal signs have been reported in human and animal trials.

[0004] Currently, there is no domestic ondansetron hydrochloride preparation for pets. Commonly used drugs are mainly for human use, and their dosage form is hard tablets, with a hard texture and poor palatability. Pets that need this drug usually do not eat actively due to illness, and pet owners need to use a feeding device to feed them, which is not suitable for pets. Summary of the Invention

[0005] The purpose of the present invention is to address the technical problem of the lack of an analytical detection method for related substances of alfaxalone intermediates in the prior art, and to propose an ondansetron hydrochloride soft chew composition with good palatability, simple preparation process, convenient for industrial production, and stable properties.

[0006] The purpose of the present invention can be achieved by the following technical solutions:

[0007] An ondansetron hydrochloride soft chew composition for pets, the ondansetron hydrochloride soft chew composition for pets comprises the following components in mass percentage:

[0008] Ondansetron Hydrochloride 3% - 6%,

[0009] Glycerol 7.2% - 8.2%,

[0010] Medium-chain triglycerides 10.3% - 14.5%,

[0011] Binder: 19% - 22%,

[0012] Chicken liver powder: 20% - 30%,

[0013] Corn starch: 25% - 35%.

[0014] Preferably, the binder is hydroxypropyl cellulose and polyethylene glycol 3350.

[0015] Preferably, the mass ratio of hydroxypropyl cellulose to polyethylene glycol 3350 is 1:(0.6 - 1).

[0016] In the formula of the ondansetron hydrochloride soft chewable composition for pets of the present invention, the main function of glycerol is to keep moisture, and the main function of medium-chain triglycerides is to moisten. The two jointly affect the hardness, appearance and demolding of the product. Chicken liver powder, as a flavoring agent, can improve the palatability of the product and encourage dogs to eat actively. Through the screening of fillers and binders in the formula, the present invention makes the product have good formability and stable properties.

[0017] Another object of the present invention is to provide a method for preparing an ondansetron hydrochloride soft chewable composition for pets. The preparation method includes the following steps:

[0018] (1) Crush the ondansetron hydrochloride raw material medicine to obtain raw material medicine powder;

[0019] (2) Mix the raw material medicine powder obtained in step (1) with corn starch, chicken liver powder and binder to obtain a mixed material;

[0020] (3) Slowly and uniformly add glycerol to the mixed material obtained in step (2), conduct the first stirring. After mixing, add medium-chain triglycerides, and then conduct the second stirring. After mixing, the ondansetron hydrochloride soft chewable composition is obtained.

[0021] Preferably, in step (1), the particle size D90 of the raw material medicine powder ≤ 35 μm.

[0022] Preferably, in step (2), the raw material medicine powder is mixed with corn starch, chicken liver powder and binder in a wet granulator. Control the rotation speed of the stirring paddle of the wet granulator at 100 rpm - 200 rpm, the rotation speed of the cutter at 400 rpm - 800 rpm, and the time at 8 minutes - 12 minutes.

[0023] Preferably, in step (3), the first stirring and the second stirring are continuously carried out in a wet granulator. Control the rotation speed of the stirring paddle of the wet granulator at 40 rpm - 100 rpm. The time of the first stirring is 5 minutes - 10 minutes, and the time of the second stirring is 10 minutes - 15 minutes.

[0024] Preferably, the preparation method further comprises the step of putting the ondansetron hydrochloride soft chewable composition obtained in step (3) into a hydraulic molding machine to press into tablets.

[0025] Preferably, when putting the ondansetron hydrochloride soft chewable composition into a hydraulic molding machine to press into tablets, the pressing pressure is 3 KN - 5 KN.

[0026] In the preparation process of the ondansetron hydrochloride soft chewable composition of the present invention, first mix the solid raw materials of ondansetron hydrochloride, corn starch, chicken liver powder, hydroxypropyl cellulose and polyethylene glycol 3350, then add the liquid raw material of glycerol for moist granulation, and finally add medium-chain triglycerides to form the ondansetron hydrochloride soft chewable composition, which can be pressed into tablets by a hydraulic molding machine. The preparation method of the ondansetron hydrochloride soft chewable composition and soft chewable tablets of the present invention has a simple process, only needs to mix the liquid material and the solid material evenly, and does not require additional heat source during the mixing process, and can be carried out at room temperature; there is no need to additionally control the temperature and humidity of the soft material during the molding process, which greatly simplifies the operation process in the preparation of the ondansetron hydrochloride soft chewable preparation and is convenient for industrialization. In addition, the production equipment used in the preparation method of the present invention is a common wet granulator and hydraulic molding machine in the preparation process, which does not need special customization and is easier to realize and popularize in the industrialization process, indirectly reducing the production cost.

[0027] Compared with the prior art, the present invention has the following beneficial effects: The ondansetron soft chewable composition prepared by the present invention, especially the soft chewable tablets, has stable properties, good palatability, and a simple preparation method, and is suitable for large-scale production and clinical application. Detailed Embodiments

[0028] The following combines specific embodiments to further describe and explain the technical solutions of the present invention to fully understand the purpose, features and effects of the present invention.

[0029] Unless otherwise specified, the reagents and raw materials used in the embodiments of the present invention are all obtained commercially. Among them, medium-chain triglycerides refer to triglyceride compositions containing fatty acids with 8 - 12 straight-chain carbon atoms, more preferably 8 - 10 carbon atoms, and are derived from coconut oil or palm oil, and the content of caprylic acid (C8H 16 O2) and capric acid (C 10 H 20 O2) in them is not less than 95%.

[0030] Example 1

[0031] The component formulation (by mass percentage) of the ondansetron hydrochloride soft chewable composition in this example is shown in Table 1:

[0032] Table 1: Formulation of Ondansetron Hydrochloride Soft Chewable Composition in Example 1

[0033]

[0034] The ondansetron hydrochloride soft chewable composition was prepared according to each formulation in Table 1 by the following preparation method:

[0035] (1) The ondansetron hydrochloride raw material drug was pulverized to obtain raw material drug powder with the particle size D90 ≤ 35 μm;

[0036] (2) The raw material drug powder, corn starch, chicken liver powder, hydroxypropyl cellulose and polyethylene glycol 3350 were added to a wet granulator. The rotation speed of the stirring paddle of the wet granulator was controlled at 150 rpm, and the rotation speed of the cutter was 600 rpm. Stir for 10 minutes to mix the materials evenly to obtain a mixed material;

[0037] (3) Glycerol was added to the mixed material in the wet granulator at a uniform and slow speed for the first stirring for 7 minutes. After mixing evenly, medium-chain triglycerides were added, and then the second stirring was carried out for 13 minutes. After mixing evenly, the ondansetron hydrochloride soft chewable composition was obtained. The rotation speed of the stirring paddle of the wet granulator was controlled at 70 rpm;

[0038] (4) The ondansetron hydrochloride soft chewable composition was put into a hydraulic molding machine and pressed into tablets with a pressing pressure of 4 KN.

[0039] The dosages of the liquid components glycerol and medium-chain triglycerides in the formulation of the ondansetron hydrochloride soft chewable composition will significantly affect the softness, appearance and demolding during the preparation process of the soft chewable tablets. When the dosages of glycerol and medium-chain triglycerides are low (glycerol content is less than 7.2%, medium-chain triglycerides are less than 10.3%), the soft chewable tablets cannot be demolded smoothly during the preparation process, and the prepared soft chewable tablets have defects and burrs; when the dosages of glycerol and medium-chain triglycerides are appropriate (glycerol content is between 7.2% and 8.2%, medium-chain triglycerides are between 10.3% and 14.5%), the soft chewable tablets can be demolded smoothly during the preparation process, and the finished tablets have a complete and smooth shape without defects; when the dosages of glycerol and medium-chain triglycerides are excessive (glycerol content is higher than 8.2%, medium-chain triglycerides are higher than 14.5%), the prepared soft chewable tablets are too soft and prone to deformation after demolding. The appearance and hardness of the ondansetron hydrochloride soft chewable composition tablets prepared according to Formulations 1-5 in this example are shown in Table 2 below.

[0040] Table 2: Appearance and Hardness of Ondansetron Hydrochloride Soft Chewable Composition in Example 1

[0041]

[0042] Example 2

[0043] In this embodiment, the component formulation (by mass percentage) of ondansetron hydrochloride soft chewable composition is shown in Table 3 as follows:

[0044] Table 3: Formulation of ondansetron hydrochloride soft chewable composition in Example 2

[0045]

[0046]

[0047] The ondansetron hydrochloride soft chewable composition was prepared according to each formulation in Table 3 by the preparation method in Example 1, and a palatability test was carried out. The palatability test method is as follows:

[0048] According to the "Guideline on the demonstration of palatability of veterinary medicinal products", 30 pet dogs with normal mental appetite and not treated with relevant products in the last month were selected. Take the chewable tablets continuously produced according to Formulas 6 - 10 and the commercially available ondansetron hydrochloride tablets (Tianheng Pharmaceutical) for comparison. In the whole test, the palatability of the 6 drugs was investigated 6 times, and only one drug was investigated each time. Within the range of ensuring the safe dose, considering that the test dogs have a certain memory function for the smell and taste of the same drug in a short time, after each drug was investigated, an interval of more than 48 hours was ensured before the next test. In each test, a fixed time period was selected as the drug administration time.

[0049] Before the test, the weight of each test dog was evaluated, and the drug was administered according to the weight. The test personnel put the drug into the dog's food bowl and let the dog eat it voluntarily or put the drug in the palm and feed it. The stopwatch was used to time for 2 minutes. Observe the feeding situation of each dog for the test sample, which was expressed as "eat all, eat part or not eat at all", and this was used as the main criterion for judging palatability. If the drug was eaten all within 2 minutes, accurately record the time from the start of eating to the complete swallowing by the dog, which was used as the secondary criterion for judging palatability. The specific judgment is shown in Table 4, and the test results are shown in Table 5.

[0050] Table 4: Judgment criteria for dog feeding situation

[0051] Feeding situation Standard All eaten All eaten within 2 minutes Partially eaten Partially eaten within 2 minutes Not eaten at all Carried into the mouth and then spat out or completely rejected

[0052] Table 5: Results of palatability test of soft chewable composition (tablets) in Example 2

[0053]

[0054]

[0055] As can be seen from Table 5, when the dosage of chicken liver powder is 20% - 30% (Formulas 6 - 8), the soft chewable tablets prepared have good palatability, and the overall acceptance rate is greater than 80%. When the dosage of chicken liver powder in the formula is 10% - 15% (Formulas 9, 10), the palatability of the prepared soft chewable tablets is poor, and the overall acceptance rate is lower than 70%. Compared with the commercially available ondansetron hydrochloride tablets (Tianheng Pharmaceutical), the palatability of the ondansetron hydrochloride soft chewable tablets prepared by the present invention is better, and the overall acceptance rate is greater than 80%. However, the palatability of the commercially available ondansetron hydrochloride tablets is poor, and the overall acceptance rate is less than 50%, showing no obvious advantage in palatability compared with the ondansetron hydrochloride soft chewable tablets prepared by the present invention.

[0056] Example 4

[0057] Clinical pharmacodynamic comparison test

[0058] According to the requirements of the "Good Clinical Practice for Veterinary Drugs", 120 pet dogs suffering from nausea caused by canine parvovirus enteritis were randomly selected to conduct a randomized, double - blind clinical trial of different drugs. Test method: The 120 selected test dogs were randomly divided into 4 groups, with 30 dogs in each group. They were orally administered the soft chewable tablets 6, chewable tablets 7, chewable tablets 8 prepared according to Formulas 6 - 8 in Example 2 and the comparative commercially available ondansetron hydrochloride tablets (Tianheng Pharmaceutical), with a dosing dose of 1 mg / kg. Before dosing (T0) and every hour within 4 hours after dosing (T1, T2, T3, T4), a behavioral assessment was performed according to the canine nausea degree behavior scale, and the occurrence of vomiting was recorded. Serum arginine vasopressin AFP has been proven to be related to the clinical symptoms of nausea. In addition, serum was collected at T0, T2, and T4 to detect the AFP concentration. The canine nausea degree behavior scale is shown in Table 6, and the test results are shown in Table 7.

[0059] Table 6 Canine nausea degree behavior scale

[0060]

[0061] Table 7 Clinical pharmacodynamic test results of 4 drugs for dogs

[0062]

[0063] As can be seen from Table 7, significant remission of the clinical symptoms of nausea can be observed in each group 1 hour after dosing, and the drug effect can be maintained for at least 4 hours, with no significant difference among the groups. 4 hours after dosing, the serum AFP concentration in each group decreased significantly, with no significant difference among the groups; indicating that the ondansetron hydrochloride soft chewable tablets 6, soft chewable tablets 7, and soft chewable tablets 8 prepared by the present invention have the same clinical pharmacodynamic effect as the commercially available ondansetron hydrochloride tablets.

[0064] Example 5

[0065] Stability test

[0066] The ondansetron hydrochloride chewable tablets 6, chewable tablets 7, and chewable tablets 8 prepared according to Formulas 6 to 8 in Example 2 were all packaged in double-aluminum blister packs and placed under accelerated conditions for 6 months (40°C ± 2°C, 75% RH ± 5% RH) and long-term conditions for 12 months (25°C ± 2°C, 60% RH ± 5% RH) to observe the stability of the samples. The results are shown in Table 8.

[0067] Table 8 Results of the stability test of the chewable tablets

[0068]

[0069] As can be seen from Table 8, the ondansetron hydrochloride soft chewable tablets 6, chewable tablets 7, and chewable tablets 8 prepared by the present invention have good stability under accelerated conditions for 6 months and long-term conditions for 12 months, and there is no significant change in quality compared with day 0, indicating that the ondansetron hydrochloride soft chewable tablets prepared by the present invention have good stability.

[0070] In some other embodiments of the present invention, in the formulation of the ondansetron hydrochloride soft chewable composition, the mass percentage of ondansetron hydrochloride can also be 3.0%, 3.3%, 3.7%, 4.5%, 4.9%, 5.0%, 5.2%, 5.6%, 6.0% and any value between 3% and 6%; the mass percentage of glycerol can also be 7.3%, 7.4%, 7.8%, 8.0% and any value between 7.2% and 8.2%; the mass percentage of medium-chain triglycerides can also be 10.5%, 12.0%, 13.0%, 13.5% and any value between 10.3% and 14.5%; the mass percentage of the binder can also be 19.0%, 19.5%, 20.0%, 20.5%, 21.5%, 22.0% and any value between 19.0% and 22.0%; the mass ratio of the binder components hydroxypropyl cellulose and polyethylene glycol 3350 can also be 1:0.7, 1:0.8, 1:0.9, 1:1 and any value between 1:(0.6 and 1); the mass percentage of chicken liver powder can also be 22%, 23%, 26%, 27%, 29% and any value between 20% and 30%; the mass percentage of corn starch can also be 26%, 27%, 28%, 31%, 32%, 33%, 34% and any value between 25% and 35%; in the preparation method of the ondansetron hydrochloride soft chewable composition, when the active pharmaceutical ingredient powder is mixed with corn starch, chicken liver powder and the binder in a wet granulator, the rotation speed of the stirring paddle of the wet granulator can also be 100 rpm, 110 rpm, 120 rpm, 130 rpm, 140 rpm, 160 rpm, 170 rpm, 180 rpm, 190 rpm, 200 rpm and any value between 100 rpm and 200 rpm, the rotation speed of the cutter can also be 400 rpm, 420 rpm, 450 rpm, 470 rpm, 500 rpm, 550 rpm, 580 rpm, 650 rpm, 700 rpm and any value between 400 rpm and 800 rpm, and the mixing time can also be 8 minutes, 8.5 minutes, 9 minutes, 9.5 minutes, 10.5 minutes, 11 minutes, 12 minutes, and any value between 8 minutes and 12 minutes; in step (3), the rotation speed of the stirring paddle of the wet granulator in the wet granulator during the first stirring and the second stirring can also be 40 rpm, 50 rpm, 60 rpm, 80 rpm, 90 rpm, 100 rpm, and any value between 40 rpm and 100 rpm. The time of the first stirring can also be 5 minutes, 6 minutes, 8 minutes, 9 minutes, 10 minutes, and any value between 5 minutes and 10 minutes. The time of the second stirring can also be 11 minutes, 12 minutes, 14 minutes, 15 minutes, and any value between 10 minutes and 15 minutes; when the ondansetron hydrochloride soft chewable composition is put into a hydraulic molding machine to be pressed into tablets, the pressing pressure can also be 3 KN, 3.2 KN, 3.5 KN, 3.8 KN, 4.1 KN, 4.5 KN, 5 KN, and any value between 3 KN and 5 KN; all can achieve the technical effects of the present invention, and the hardness of the obtained chewable tablets is 10 N to 30 N, and the palatability and stability are good.

[0071] It should be understood that the specific embodiments described herein are only a part of the embodiments of the present invention, rather than all embodiments. They are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that based on reading the present invention, other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present invention.

Claims

1. An ondansetron hydrochloride soft chewable composition for pets, characterized in that, The ondansetron hydrochloride soft chewable composition for pets comprises the following components in mass percentage: Ondansetron hydrochloride 3% - 6%, Glycerol 7.2% - 8.2%, Medium-chain triglyceride 10.3% - 14.5%, Binder 19% - 22%, Chicken liver powder 20% - 30%, Corn starch 25% - 35%.

2. The ondansetron hydrochloride soft chewable composition for pets according to claim 1, characterized in that, The binder is hydroxypropyl cellulose and polyethylene glycol 3350.

3. The preparation method of the ondansetron hydrochloride soft chewable composition for pets according to claim 2, characterized in that, The mass ratio of the hydroxypropyl cellulose to the polyethylene glycol 3350 is 1∶(0.6 - 1).

4. A method for preparing the ondansetron hydrochloride soft chewable composition for pets according to any one of claims 1 to 3, characterized in that, The preparation method comprises the following steps: (1) Crushing the ondansetron hydrochloride raw material medicine to obtain raw material medicine powder; (2) Mixing the raw material medicine powder obtained in step (1) with corn starch, chicken liver powder and binder to obtain a mixed material; (3) Slowly and uniformly adding glycerol to the mixed material obtained in step (2), performing the first stirring, adding medium-chain triglyceride after mixing, and then performing the second stirring. After mixing, the ondansetron hydrochloride soft chewable composition is obtained.

5. The preparation method of the ondansetron hydrochloride soft chewable composition for pets according to claim 4, characterized in that, In step (1), the particle size D90 of the raw material medicine powder ≤ 35 μm.

6. The preparation method of the ondansetron hydrochloride soft chewable composition for pets according to claim 4, characterized in that, In step (2), the raw material medicine powder, corn starch, chicken liver powder and binder are mixed in a wet granulator, and the rotation speed of the stirring paddle of the wet granulator is controlled at 100 rpm - 200 rpm, the rotation speed of the cutter is 400 rpm - 800 rpm, and the time is 8 minutes - 12 minutes.

7. The preparation method of the ondansetron hydrochloride soft chewable composition for pets according to claim 4, wherein In step (3), the first stirring and the second stirring are carried out in a wet granulator, and the rotation speed of the stirring paddle of the wet granulator is controlled at 40 - 100 rpm. The time of the first stirring is 5 minutes - 10 minutes, and the time of the second stirring is 10 minutes - 15 minutes.

8. The preparation method of the ondansetron hydrochloride soft chewable composition for pets according to claim 4, characterized in that, The preparation method further comprises the step of putting the ondansetron hydrochloride soft chewable composition obtained in step (3) into a hydraulic molding machine to be pressed into tablets.

9. The preparation method of the ondansetron hydrochloride soft chewable composition for pets according to claim 8, characterized in that, When the ondansetron hydrochloride soft chewable composition is put into a hydraulic molding machine to be pressed into tablets, the pressing pressure is 3 KN - 5 KN.

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