An enteric-coated atovaquone tablet for dogs and its preparation method

Abstract

The present invention discloses an atovaquone enteric-coated tablet, which preparation comprises atovaquone, glyceryl behenate, tyloxapol, a filler, a binder, a disintegrant and an enteric coating, and the particle size D90 of atovaquone is 30-50 μm. The atovaquone enteric-coated tablet of the present invention has a stable and continuous release, high bioavailability, can be released at a specific position in the intestine, reduce the hepatic circulation, thereby reducing the occurrence of phenomena such as liver injury, and has no phenomena such as sticking to the punch and capping during the tabletting process, with qualified and stable quality, and ensures its dissolution performance and stability.

Description

Technical Field

[0001] The present invention relates to the field of animal pharmaceutical preparations, and particularly to an enteric-coated atovaquone tablet for dogs and a preparation method thereof. Background Art

[0002] Babesia, commonly known as piroplasm, is a blood protozoal disease mainly transmitted by ticks. Canine babesiosis is a worldwide disease. At present, at least nine unique genotypes of Babesia that can infect dogs have been reported. The dominant species in the Chinese region is Babesia gibsoni, which is mainly transmitted by Haemaphysalis longicornis, Rhipicephalus sanguineus, and Haemaphysalis bispinosa. The geographical range of the disease is related to the geographical distribution range of tick vectors. Babesia parasitizes in red blood cells to obtain nutrients, triggers the immune system, the dog produces antibodies, and monocytes phagocytize infected red blood cells, causing anemia and hemoglobinuria. In addition, Babesia can also attach to the surface of uninfected red blood cells and platelets, leading to the production of antibodies. The antibodies attach to the surface of red blood cells to form complexes, resulting in further hemolytic anemia and thrombocytopenia. The infection of Babesia will also cause peroxidation of the red blood cell membrane, resulting in enhanced rigidity of red blood cells, and slowing down the speed of blood passing through capillaries. After being infected with Babesia, sick dogs will show high fever, jaundice and difficulty breathing. Some sick dogs have an enlarged spleen, which is sensitive to touch. Protein appears in the urine, and there may be hemoglobin. If not treated in time, the life of the sick dog will be endangered.

[0003] Atovaquone is a compound with significant antimalarial activity and has antimalarial protozoal activity. After a dog is infected with Babesia, it can effectively reduce the content of Babesia gibsoni in the blood. Atovaquone belongs to BCS class II drugs, which have high drug permeability, high liposolubility and poor water solubility. Therefore, its solubility is low, which limits the bioavailability after oral administration. In order to achieve sufficient therapeutic effects throughout the body, a large dose of the drug needs to be orally administered to circumvent this limitation and reach the therapeutic concentration in the systemic circulation. However, large-dose use is likely to cause certain damage to liver function and result in drug resistance. Atovaquone has the following structure:

[0004]

[0005] Chinese Patent CN202310218800.X discloses an atovaquone suspension with high bioavailability, including atovaquone, excipients and a dispersion medium. Among them, the atovaquone suspension with high bioavailability is made by subjecting the atovaquone and excipients to a nanotechnology process. The excipient is a suspending carrier, a wetting agent or a combination of a suspending carrier and a wetting agent. However, this suspension uses a nanotechnology process, which is complex and has a poor taste, making it unfavorable for dogs to take, prone to cause stress in dogs, and not conducive to application and promotion in the treatment of canine diseases.

[0006] Chinese Patent CN202010402550.1 discloses a flavored tablet of atovaquone for dogs. Although adding meat powder to the flavored tablet can well cover the bitterness of atovaquone, it fails to solve the disadvantages of low solubility and low bioavailability of atovaquone.

[0007] Although foreign literature reports using solid dispersion technology to improve the dissolution of atovaquone and thus improve bioavailability, due to the complex technology process and poor stability of this technology, it also has the disadvantage of being not conducive to popularization in animal husbandry such as dogs.

[0008] In summary, atovaquone has poor water solubility, low bioavailability, and the unabsorbed atovaquone after administration is metabolized by the liver, which is likely to cause liver function damage to dogs, and is prone to drug resistance. Currently, there is an urgent need for a new type of atovaquone preparation to improve pharmacokinetics, increase the bioavailability of atovaquone oral drugs, thereby improving the drug effect and reducing side effects, and can be used on a large scale in canine babesiosis. Summary of the Invention

[0009] In view of the deficiencies of the prior art, the purpose of the present invention is to provide an enteric-coated tablet of atovaquone and its preparation method, which has good dissolution performance, can be located and released in the small intestine, has a stable release, reduces liver damage caused by hepatorenal circulation, and at the same time has a high acceptance rate for dogs to take, reduces the occurrence of drug resistance, and is suitable for large-scale production.

[0010] To achieve the above purpose, through a large number of experimental studies and improvements on the existing formulation and process, the present invention has obtained the following technical solution: an enteric-coated tablet of atovaquone, the preparation contains atovaquone, glyceryl behenate, tyloxapol, filler, binder, disintegrant and enteric coating, and the particle size of the atovaquone is D90 = 30 - 50 μm.

[0011] In the present invention, glyceryl behenate and tyloxapol are important technical keys to achieve the technical effects. Glyceryl behenate can not only play a lubricating role in the preparation process of the preparation, but also be used as a sustained-release matrix material to make atovaquone release slowly after taking, without affecting the stability of the drug. However, when glyceryl behenate is used alone, it is easy to cause the phenomenon of too slow release in the early stage and incomplete release in the later stage of atovaquone. As a water-soluble carrier material, tyloxapol has excellent dispersion ability. Its addition can adjust the release rate of atovaquone from glyceryl behenate, so as to further achieve the effect of stable release, achieving the effect of timely release in the early stage and complete release in the later stage.

[0012] In the present invention, the mass ratio of atovaquone, glyceryl behenate, and tyloxapol is one of the key factors for achieving the technical effects. When the mass ratio of atovaquone, glyceryl behenate, and tyloxapol is 1:0.5 - 0.8:0.4 - 0.6, the release of atovaquone has the best steady effect, with timely release in the early stage and complete release in the later stage, and the comprehensive performance of atovaquone in terms of drug loading, stability, and dispersibility is relatively good. Preferably, the mass ratio of atovaquone, glyceryl behenate, and tyloxapol is 1:0.6:0.5.

[0013] In the present invention, the phospholipids contained in the enteric coating are an important technical key for achieving the technical effects. Atovaquone has low bioavailability. Although its bioavailability can be improved under the condition of fat feeding, at the same time, high-fat intake is not conducive to the growth and development of canine animals, and for canine animals with liver damage, it further aggravates the liver burden. In the present invention, adding phospholipids to the enteric coating can further improve the bioavailability of atovaquone and at the same time has a protective effect on the liver. When the mass ratio of atovaquone, coating material, plasticizer, anti-adhesive, and phospholipids is 1:0.4 - 0.7:0.05 - 0.1:0.05 - 0.1:0.1 - 0.3, the enteric-coated tablets of atovaquone have the best effect of improving bioavailability, are conducive to the formation of the enteric coating, have a good taste masking effect, and are convenient for canine animals to take directly or indirectly. Preferably, the mass ratio of atovaquone, coating material, plasticizer, anti-adhesive, and phospholipids is 1:0.5:0.08:0.08:0.2. In the present invention, the phospholipids are one or a mixture of phosphatidylinositol, phosphatidic acid, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, and egg yolk sphingomyelin. Preferably, the phospholipids are egg yolk sphingomyelin.

[0014] In the present invention, the particle size of atovaquone is one of the key factors for achieving the technical effects. This relationship between particle size and bioavailability is well-known in the pharmaceutical industry and involves many drug products. Since atovaquone has poor water solubility, in order to increase its dissolution effect, the prior art generally reduces its particle size. For example, Chinese Patent CN200980129098.8 discloses an atovaquone or a pharmaceutically acceptable salt thereof, which has a particle size diameter range of D90 greater than 3 μm to about 10 μm. Although it can improve the bioavailability of atovaquone, the excipients used in the mixing stage of the formulation process have particle sizes that are difficult to match with such small-sized raw materials. Excipients with larger particle sizes are likely to cause uneven mixing, especially not conducive to industrial production. For products with too small particle sizes, the content uniformity of the feedback products becomes poor, and it is likely to cause unstable dissolution and release. In the present invention, the particle size of atovaquone is D90 = 30 - 50 μm. At this particle size, without affecting dissolution, atovaquone can be fully mixed with the excipients, and the tablet release process proceeds smoothly, improving the final release amount. Preferably, the particle size of atovaquone is D90 = 35 - 45 μm.

[0015] In the present invention, the selection of the formulation is one of the key factors for achieving the technical effect. Specifically, the increase in the amount of excipients is beneficial to increasing compressibility and reducing the possibility of sticking to the punch, but the increase in the amount of excipients will lead to a relatively large tablet weight, which is not conducive to patient taking. Unless otherwise specified, the dosage of the active ingredient in the formulation of the present invention is calculated as atovaquone. Preferably, the filler is one or a mixture of several of microcrystalline cellulose, pregelatinized starch, and starch, the binder is one or a mixture of several of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and ethylcellulose, and the disintegrant is one or a mixture of several of sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, cross-linked carboxy starch sodium, and cross-linked polyvinylpyrrolidone. Preferably, the filler is microcrystalline cellulose, the binder is hydroxypropyl methylcellulose, and the disintegrant is sodium carboxymethylcellulose. Further, the mass ratio of atovaquone to the filler is 1:0.5 - 0.9, the mass ratio of atovaquone to the binder is 1:0.035 - 0.060, and the mass ratio of atovaquone to the disintegrant is 1:0.25 - 0.40. Preferably, the mass ratio of atovaquone to the filler is 1:0.7, the mass ratio of atovaquone to the binder is 1:0.050, and the mass ratio of atovaquone to the disintegrant is 1:0.30.

[0016] In the present invention, the type of enteric coating material for enteric coating is one of the key factors for achieving the technical effect. Different types of enteric coatings have different effects on the release in the gastrointestinal tract. When the coating material is polyacrylic resin II, the plasticizer is one or a mixture of several of triethyl citrate, propylene glycol, polyethylene glycol, or diethyl phthalate, and the anti-adhesive agent is one or a mixture of several of talc, colloidal silica, or glyceryl monostearate, the atovaquone enteric-coated tablets are not damaged by gastric acid, and the atovaquone enteric-coated tablets can be better positioned for release in the small intestine. Preferably, the plasticizer is triethyl citrate and the anti-adhesive agent is talc.

[0017] The present invention also provides an atovaquone enteric-coated tablet, comprising the following components:

[0018]

[0019] Specifically, an atovaquone enteric-coated tablet comprises the following components:

[0020]

[0021] The second object of the present invention is to provide a method for preparing the aforementioned atovaquone enteric-coated tablet, and the method comprises the following steps:

[0022] 1) Add hydroxypropyl methylcellulose to purified water and mix evenly to obtain a hydroxypropyl methylcellulose solution;

[0023] 2) Place atovaquone, microcrystalline cellulose, glyceryl behenate, and tyloxapol in a granulator, preheat the temperature to 50 - 60°C, perform spraying granulation, with the inlet air temperature being 60 ± 10°C and the fan frequency being 25 - 30 Hz; the material temperature ≤ 50°C;

[0024] 3) Screen the granules, add sodium carboxymethylcellulose and mix, set the total mixing rotation speed to 6 - 10 r / min, and mix for about 30 min;

[0025] 4) Compress tablet cores according to an average hardness of 30 - 60 N, and during the process, inspect the appearance for sticking to the punch, loose tablets, and capping;

[0026] 5) Place the tablet cores with qualified appearance and hardness in a coating pan for coating;

[0027] 6) Prepare the coating solution;

[0028] 7) Spray the coating solution on the surface of the atovaquone tablet cores. Place the coating solution in a peristaltic pump, and then the peristaltic pump rotates at a rate of 150 - 200 revolutions per minute and discharges the coating solution. The atovaquone tablet cores are placed in the coating pan, and the temperature of the atovaquone tablet cores is 40 - 50°C. At the same time, hot air with a temperature of 65 - 70°C is introduced into the coating pan, and the coating time is 2 - 3 hours.

[0029] The present invention has the following prominent advantages and beneficial effects compared with the prior art:

[0030] 1) The present invention uses a specific proportion combination of glyceryl behenate and tyloxapol, which can enable the tablets to be released smoothly, achieving the effects of timely release in the early stage and complete release in the later stage, and improving the bioavailability of atovaquone.

[0031] 2) The present invention uses phospholipids in enteric coating, which further improves the bioavailability of atovaquone while facilitating the formation of enteric coating, having a good taste - masking effect and being convenient for direct or indirect administration to canine animals.

[0032] 3) The atovaquone enteric - coated tablets obtained by the present invention are released in the intestine, reducing the hepatic circulation, and thus reducing the occurrence of phenomena such as liver damage.

[0033] 4) The process of the present invention is simple to operate, suitable for large - scale industrial production, and has great application value in animal husbandry. Detailed Embodiments

[0034] The following further describes the present invention in detail with reference to embodiments, but the embodiments of the invention are not limited thereto.

[0035] Example 1 Preparation of Atovaquone Enteric - Coated Tablets

[0036] Prescription composition of 1000 tablets of the atovaquone enteric - coated tablets

[0037]

[0038] Preparation method:

[0039] 1) Add the prescribed amount of hydroxypropyl methylcellulose to purified water and mix evenly while stirring. Continue stirring for 35 min after adding, with a stirring speed of 600 rpm (two-blade impeller). After stirring, set aside to obtain the hydroxypropyl methylcellulose solution;

[0040] 2) Place atovaquone, microcrystalline cellulose, glyceryl behenate, and tyloxapol in a granulator, preheat to 55 °C, spray granulate, with an inlet air temperature of 60 ± 10 °C and a fan frequency of 25 - 30 Hz; the material temperature ≤ 50 °C, the liquid supply speed is about 1.5 kg / min; the atomization pressure is 0.4 MPa, and the particle moisture is controlled below 5.0%;

[0041] 3) Screen and size the granules, add sodium carboxymethylcellulose and mix for 20 min. Set the total mixing speed to 10 r / min and mix for about 30 min;

[0042] 4) Press the tablet cores with an average hardness of 30 - 60 N, and during the process, inspect the appearance for sticking to the punch, capping, and lamination;

[0043] 5) Place the tablet cores with qualified appearance and hardness in a coating pan for coating;

[0044] 6) Prepare the coating solution;

[0045] 7) Spray the coating solution on the surface of the atovaquone tablet cores. Place the coating solution in a peristaltic pump, then the peristaltic pump rotates at a rate of 200 revolutions per minute and discharges the coating solution. The atovaquone tablet cores are placed in a coating pan, and the temperature of the atovaquone tablet cores is 45 °C. At the same time, hot air at a temperature of 65 °C is introduced into the coating pan, and the coating time is 2.5 hours.

[0046] Preparation of enteric-coated atovaquone tablets in Example 2

[0047] Prescription composition of 1000 tablets of the enteric-coated atovaquone tablets

[0048]

[0049] The preparation method is as in Example 1.

[0050] Preparation of enteric-coated atovaquone tablets in Example 3

[0051] Prescription composition of 1000 tablets of the enteric-coated atovaquone tablets

[0052]

[0053] The preparation method is as in Example 1.

[0054] Example 4 Preparation of Atovaquone Enteric-coated Tablets

[0055] Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0056]

[0057] The preparation method is the same as Example 1.

[0058] Example 5 Preparation of Atovaquone Enteric-coated Tablets

[0059] Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0060]

[0061] The preparation method is the same as Example 1.

[0062] Comparative Example 1 Preparation of Atovaquone Enteric-coated Tablets

[0063] Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0064]

[0065] The preparation method is as in Example 1. In the prescription of Comparative Example 1, the dosage of glyceryl behenate and tyloxapol is relatively small, the dosage of phospholipids in the enteric coating is relatively small, and the dosage of other fillers, disintegrants, binders, polyacrylic acid resin II, plasticizers and anti-adherents is also relatively small.

[0066] Comparative Example 2 Preparation of Atovaquone Enteric-coated Tablets

[0067] Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0068]

[0069] The preparation method is as in Example 1. In the prescription of Comparative Example 2, the dosages of glyceryl behenate and tyloxapol are too high, the dosage of phospholipids in the enteric coating is too high, and the dosages of other fillers, disintegrants, binders, polyacrylic acid resin II, plasticizers and anti-adherents are also too high.

[0070] Comparative Example 3 Preparation of Atovaquone Enteric-coated Tablets

[0071] Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0072]

[0073] The preparation method is the same as that in Example 1, except that in the prescription of Comparative Example 3, tyloxapol is replaced by poloxamer.

[0074] Comparative Example 4 Preparation of Atovaquone Enteric-coated Tablets

[0075] Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0076]

[0077] The preparation method is the same as that of Example 1. In the formulation of Comparative Example 4, the enteric coating does not contain phospholipids.

[0078] Comparative Example 5 Preparation of Atovaquone Enteric-coated Tablets

[0079] Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0080]

[0081] The preparation method is the same as in Example 1. In the prescription of Comparative Example 5, the particle size of atovaquone is relatively large, which is 60-90 μm.

[0082] Example 6

[0083] The atovaquone enteric-coated tablets prepared in Examples 1-5 and Comparative Examples 1-5 were subjected to quality inspection, and the results were as follows:

[0084] Table 1 Quality inspection of atovaquone enteric-coated tablets

[0085]

[0086] From the above results, it can be seen that the atovaquone enteric-coated tablets prepared in Examples 1-5 and Comparative Examples 1-5 are all white or off-white in shape, but in Comparative Example 1, during the tableting process, sticking, loose tablets and cracking, and the content uniformity are relatively large. Analysis shows that the amount of binder used in Comparative Example 1 is relatively small, and some raw materials are agglomerated. Due to the electrostatic agglomeration effect, the mixing is uneven and the tableting loose tablets and cracks are sticky. In Comparative Example 2, due to the high content of behenic acid glyceride and the high content of phospholipids, the sticking phenomenon occurs and the mixing is uneven, so the content uniformity slightly exceeds the standard. Examples 1-5 are preferred embodiments of this scheme, and various parameters in Example 1, including the types and proportions of excipients, are all the most preferred. For example, a more suitable amount of behenic acid glyceryl and tyloxapol, a more suitable amount of phospholipids in the enteric coating, and a better match between the excipients, the obtained tablet core has a higher quality and thus has better compressibility. The overall combination of the above conditions allows the atovaquone enteric-coated tablets to achieve the best performance during the preparation process.

[0087] Example 7 Testing of Atovaquone Enteric-coated Tablets for Dogs

[0088] According to the disintegration test method in the Chinese Veterinary Pharmacopoeia 2020 Edition, take 6 enteric-coated tablets prepared in Examples 1-5 and Comparative Examples 3-5 respectively. After placing them in artificial gastric juice for 2 hours, observe whether there are any damages or cracks on the appearance of the enteric-coated tablets. After rinsing with a small amount of water, immediately put them into artificial intestinal juice. The time for the complete disintegration of the enteric-coated tablets should be within 1 hour for each tablet. The test results are shown in Table 2.

[0089] Table 2 Detection Test of Atovaquone Enteric-coated Tablets

[0090]

[0091] As can be seen from Table 2, there are no damages or cracks on the appearance of the enteric-coated tablets prepared in Examples 1-5 and Comparative Examples 3-5 in gastric juice, and they all completely disintegrate within 1 hour in intestinal juice. However, the disintegration time in Comparative Example 3 is slightly longer, and it is analyzed that the addition of poloxamer may affect the disintegration time limit. The enteric-coated tablets prepared in Examples 1-5 do not disintegrate and absorb in the stomach, but disintegrate and absorb in the intestine. Thus, it can be seen that the canine atovaquone enteric-coated tablets of the present invention disintegrate and absorb in the canine intestine, release in a targeted manner, reduce the hepatic circulation, and thus reduce the occurrence of phenomena such as liver injury.

[0092] Example 8 Dissolution Experiment

[0093] Take the enteric-coated tablets prepared in Example 1 and Comparative Examples 3-5, and perform dissolution determination in phosphate buffer solution (pH 6.8). The in vitro dissolution determination results are shown in Table 3.

[0094] Table 3 Release Degree Determination Results of Atovaquone Enteric-coated Tablets in Each Group

[0095]

[0096] According to the dissolution test results in Table 3, it can be seen that the atovaquone enteric-coated tablets prepared in Example 1 can be completely released within 20 h, and there is no phenomenon of rapid drug release in the early stage and slow drug release in the later stage during the release process, and stable and constant-rate drug release can be achieved. In Comparative Example 3, due to the failure to add tyloxapol to regulate the release rate of atovaquone and the use of poloxamer that has an impact on disintegration, combined with multiple factors, the release is too slow in the early stage and cannot be completely released within 24 h, and the release amount within 24 h only reaches 81.2%. In Comparative Example 5, due to the relatively large particle size of the atovaquone raw material drug, the dissolution and release efficiency is slowed down, so it cannot be completely released within 24 h. The experimental personnel also carried out the same dissolution test on Examples 2-5, and finally obtained results similar to those of Example 1, indicating that Examples 1-5 are the preferred solutions in this scheme, and various parameters in Example 1, including the types and proportions of excipients, etc., are the most preferred. For example, atovaquone, glyceryl behenate, and tyloxapol are in appropriate proportions, and combined with atovaquone raw materials with appropriate particle sizes, the overall combination of the above conditions enables the drug to be released linearly, stably, and at a constant rate.

[0097] Example 9 Bioavailability Experiment

[0098] Four healthy beagle dogs were randomly divided into 2 groups, with 2 dogs in each group, half male and half female. The beagle dogs were fasted overnight for 10 h before the experiment. On the morning of the second day, the atovaquone enteric-coated tablets prepared in Example 1 and Comparative Example 4 were fed to the dogs on an empty stomach. The enteric-coated tablets were directly sent to the pharynx of the beagle dogs and then administered by pouring 20 mL of warm water. Blank blood was collected before taking the medicine, and about 4 mL of blood was taken from the hind limb vein at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 h after taking the medicine, placed in a heparinized centrifuge tube, and centrifuged at 3000 r·min -1 for 10 min to separate the plasma, which was stored in a refrigerator at -20 °C for future measurement. The main pharmacokinetic parameters are shown in Table 4.

[0099] Table 4 Results of Bioavailability Determination of Atovaquone Enteric-Coated Tablets in Each Group

[0100]

[0101] From the results in Table 4, it can be seen that since the atovaquone enteric-coated tablets prepared in Example 1 added an appropriate amount of phospholipid to the enteric coating, while Comparative Example 4 did not add phospholipid, the bioavailability of atovaquone was improved in Example 1, and the bioavailability of the atovaquone enteric-coated tablets prepared in Example 1 was higher than that of the atovaquone enteric-coated tablets prepared in Comparative Example 4.

[0102] Example 10 Therapeutic Effect and Toxic and Side Effects Test of Atovaquone Enteric-Coated Tablets on Babesia Canis

[0103] 10 dogs diagnosed with Babesia canis were treated. Among them, 5 dogs were given the atovaquone enteric-coated tablets prepared in Example 1, and 5 dogs were given commercially available atovaquone suspension orally, three times a day for 3 consecutive days. The treatment effects are shown in Table 5.

[0104] Table 5 Therapeutic effects and side effects of atovaquone enteric-coated tablets on Babesia canis

[0105]

[0106] From the results in Table 5, it can be seen that the atovaquone enteric-coated tablets prepared by the present invention have a relatively high cure rate for Babesia canis, without obvious related symptoms, with small side effects and a large safety range.

[0107] In summary, the atovaquone enteric-coated tablets prepared by this scheme have a stable and continuous release, high bioavailability, can be released in the intestine, reduce liver circulation, and thus reduce the occurrence of phenomena such as liver damage. There are no phenomena such as sticking to the punch and cracking during the tableting process, and the quality is qualified and stable, ensuring its dissolution performance and stability.

[0108] The above embodiments are the preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. An atovaquone enteric-coated tablet, characterized in that: Contains the following ingredients: 。 2. An atovaquone enteric-coated tablet, characterized in that: Contains the following ingredients: 。 3. An atovaquone enteric-coated tablet, characterized in that: Contains the following ingredients: 。 4. The method for preparing atovaquone enteric-coated tablets according to claim 1, characterized in that: The steps include: 1) adding hydroxypropyl methylcellulose into purified water and mixing evenly to obtain a hydroxypropyl methylcellulose solution; 2) Place atovaquone, microcrystalline cellulose, glyceryl behenate and tyloxapol in a granulator, preheat the temperature to 50-60°C, spray granulate, inlet air temperature 60±10°C, fan frequency 25-30Hz; material temperature ≤50°C; 3) After granulation, add sodium carboxymethyl cellulose and mix, set the total mixing speed to 6-10r / min, and mix for about 30min; 4) Compressing the tablet core at an average hardness of 30-60N, and inspecting the appearance to see if there is stickiness, looseness or cracking; 5) The tablet cores with qualified appearance and hardness are placed in a coating pan for coating; 6) preparing a coating solution; 7) Spray the coating liquid on the surface of the atovaquone tablet core, place the coating liquid in a peristaltic pump, and then rotate the peristaltic pump at a rate of 150-200 rpm to discharge the coating liquid. The atovaquone tablet core is set in a coating pot. The temperature of the atovaquone tablet core is 40-50°C. At the same time, hot air at a temperature of 65-70°C is introduced into the coating pot. The coating time is 2-3 hours.

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