Atorvaquone enteric-coated tablet for dogs and preparation method thereof

Abstract

The invention discloses an atorvaquone enteric-coated tablet, the preparation comprises atorvaquone, glyceryl behenate, teloxpol, a filler, an adhesive, a disintegrating agent and an enteric coating, and the particle size D90 of the atorvaquone is 30-50 [mu] m. The atorvaquone enteric-coated tablet disclosed by the invention is stable and continuous in release and high in bioavailability, can be positioned and released in intestinal tracts and reduce liver circulation, so that the occurrence of phenomena such as liver injury is reduced, the phenomena such as sticking and cracking are avoided in a tabletting process, the quality is qualified and stable, and the dissolution performance and the stability of the atorvaquone enteric-coated tablet are also ensured.

Description

Technical Field

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

[0002] Babesia, commonly known as babesiosis, is a blood protozoan disease mainly transmitted by ticks. Canine babesiosis is a worldwide disease. At least nine unique genotypes of Babesia that can infect dogs have been reported. The dominant species in China is Babesia gibbsii, which is mainly transmitted by long-horned ticks, red-headed ticks, and two-spined ticks. The geographical range of the disease is related to the geographical distribution range of tick vectors. Babesia parasitizes in red blood cells to obtain nutrition, triggering the immune system, dogs produce 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. Antibodies attach to the surface of red blood cells to form complexes, which further lead to hemolytic anemia and thrombocytopenia. Babesia infection can also cause peroxidation of red blood cell membranes, resulting in increased rigidity of red blood cells and slower blood flow through capillaries. Dogs infected with Babesia will have high fever, jaundice and difficulty breathing. Some dogs have enlarged spleens and are sensitive to touch. Protein and possibly hemoglobin appear in the urine. If not treated in time, the dog's life will be in danger.

[0003] Atovaquone is a compound with significant antimalarial activity and anti-Plasmodium activity. It can effectively reduce the content of Babesia gibbsii in the blood of dogs infected with Babesia. Atovaquone belongs to BCS Class II drugs. It has high drug permeability, high lipid solubility and poor water solubility, so its solubility is low, which limits its bioavailability after oral administration. In order to achieve sufficient therapeutic effects throughout the body, large doses of drugs need to be taken orally to circumvent this limitation and reach therapeutic concentrations in the systemic circulation, but large doses are likely to cause certain damage to liver function and cause drug resistance. Atovaquone has the following structure:

[0004] Chinese patent CN202310218800.X discloses a highly bioavailable atovaquone suspension, comprising atovaquone, an excipient and a dispersion medium, wherein the highly bioavailable atovaquone suspension is prepared by treating the atovaquone and the excipient via a nanotechnology, wherein the excipient is a suspending carrier, a wetting agent or a combination of a suspending carrier and a wetting agent, but the suspension adopts a nanotechnology, the process is complex, and the taste is poor, which is not conducive to dog consumption, is prone to cause dog stress, and is not conducive to application and promotion in the treatment of canine diseases.

[0005] Chinese patent CN202010402550.1 discloses an atovaquone flavor tablet for dogs, in which meat powder is added to the flavor tablet. Although it can well mask the bitter taste of atovaquone, it fails to solve the shortcomings of low solubility and low bioavailability of atovaquone.

[0006] Although foreign literature has reported the use of solid dispersion technology to improve the dissolution of atovaquone and thus improve bioavailability, the technology is complex and has poor stability, which also has disadvantages that are not conducive to its promotion in livestock such as dogs.

[0007] In summary, atovaquone has poor water solubility and low bioavailability, and atovaquone that is not absorbed after administration is metabolized by the liver, which can easily cause liver damage in dogs and easily lead to drug resistance. Currently, there is an urgent need for a new atovaquone formulation that can improve the pharmacokinetics and increase the bioavailability of oral atovaquone, thereby improving the efficacy and reducing side effects, which can be used on a large scale in canine babesiosis. Summary of the invention

[0008] In view of the deficiencies in the prior art, the object of the present invention is to provide an atovaquone enteric-coated tablet and a preparation method thereof, which has good dissolution performance and can be released in the small intestine with stable release, thereby reducing liver damage caused by liver-kidney circulation. At the same time, the canines have a high acceptance rate, reduce the occurrence of drug resistance, and are suitable for large-scale production.

[0009] To achieve the above-mentioned purpose, the present invention has obtained the following technical scheme by conducting a large number of experimental studies and improvements on the existing preparation prescriptions and processes: an atovaquone enteric-coated tablet, which comprises atovaquone, glyceryl behenate, tyloxapol, a filler, a binder, a disintegrant and an enteric coating, and the atovaquone particle size is D90=30-50 μm.

[0010] In the present invention, glyceryl behenate and tyloxapol are important technical keys to achieve the technical effect. Glyceryl behenate can not only play a lubricating role in the preparation process, but also can be used as a sustained-release skeleton material to slowly release atovaquone after taking it, without affecting the stability of the drug. However, when glyceryl behenate is used alone, it is easy to cause the phenomenon that atovaquone is released too slowly in the early stage and incompletely in the later stage. Tyloxapol, as a water-soluble carrier material, has a relatively good dispersibility. Its addition can adjust the release rate of atovaquone from glyceryl behenate, thereby further achieving the effect of stable release, and achieving the effect of timely release in the early stage and complete release in the later stage.

[0011] In the present invention, the mass ratio of atovaquone, behenic acid glyceryl and tyloxapol is one of the key factors to achieve the technical effect. When the mass ratio of atovaquone, behenic acid glyceryl and tyloxapol is 1: 0.5-0.8: 0.4-0.6, the release stability of atovaquone is optimal, the early release is timely, the later release is complete, and atovaquone has good comprehensive performance in drug loading, stability and dispersibility. Preferably, the mass ratio of atovaquone, behenic acid glyceryl and tyloxapol is 1: 0.6: 0.5.

[0012] The phospholipids contained in the enteric coating of the present invention are an important technical key to achieve the technical effect. The bioavailability of atovaquone is low. Although its bioavailability can be improved under the condition of fat feeding, high fat intake is not conducive to the growth and development of canines, and for canines with liver damage, it further increases the burden on the liver. The present invention adds phospholipids to the enteric coating, which can further improve the bioavailability of atovaquone and protect the liver. When the mass ratio of atovaquone, coating material, plasticizer, anti-adhesive agent and phospholipid is 1: 0.4-0.7: 0.05-0.1: 0.05-0.1: 0.1-0.3, the atovaquone enteric-coated tablets have the best effect of improving bioavailability, and are conducive to the formation of enteric coating, and have a good taste masking effect, which is convenient for canines to take directly or indirectly. Preferably, the mass ratio of atovaquone, coating material, plasticizer, anti-adhesive agent and phospholipid is 1: 0.5: 0.08: 0.08: 0.2. In the present invention, the phospholipid is one or a mixture of phosphatidylinositol, phosphatidic acid, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, and egg yolk sphingomyelin. Preferably, the phospholipid is egg yolk sphingomyelin.

[0013] In the present invention, the particle size of atovaquone is one of the key factors to achieve the technical effect. This relationship between particle size and bioavailability is well known in the pharmaceutical industry and involves many pharmaceutical products. Due to the poor water solubility of atovaquone, in order to increase its dissolution effect, the prior art generally reduces its particle size, such as Chinese patent CN200980129098.8 discloses a kind of atovaquone or its pharmaceutically acceptable salt, which has a particle size diameter range of D90 greater than 3μm to about 10μm. Although it can improve the bioavailability of atovaquone, the excipients used in the mixing stage of the preparation process have a particle size that is difficult to match with such a small particle size raw material. Excipients with a large particle size are prone to uneven mixing, which is particularly unfavorable for industrial production. The content uniformity of the feedback product obtained by too small a particle size deteriorates, which easily leads to instability in dissolution and release. In the present invention, the particle size of atovaquone is D90=30-50 μm, which can fully mix atovaquone and excipients without affecting dissolution, so that the tablet release process is smooth and the final release amount is increased. Preferably, the particle size of atovaquone is D90=35-45 μm.

[0014] In the present invention, the selection of prescription is one of the key factors to achieve the technical effect. Specifically, the increase in the amount of excipients is conducive to increasing compressibility and reducing the possibility of sticking, but the increase in the amount of excipients will cause the weight of the tablets to be too large, which is not conducive to patients taking. Unless otherwise specified, the amount of active ingredients in the prescription of the preparation of the present invention is calculated in terms of atovaquone. Preferably, the filler is a mixture of one or more of microcrystalline cellulose, pregelatinized starch and starch, the binder is a mixture of one or more of hydroxypropyl methylcellulose, povidone, and ethyl cellulose, and the disintegrant is a mixture of one or more of sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxy starch, and cross-linked polyvinylpyrrolidone. Preferably, the filler is microcrystalline cellulose, the binder is hydroxypropyl methylcellulose, and the disintegrant is sodium carboxymethyl cellulose. Further, the mass ratio of atovaquone to filler is 1:0.5-0.9, the mass ratio of atovaquone to binder is 1:0.035-0.060, and the mass ratio of atovaquone to disintegrant is 1:0.25-0.40. Preferably, the mass ratio of atovaquone to filler is 1:0.7, the mass ratio of atovaquone to binder is 1:0.050, and the mass ratio of atovaquone to disintegrant is 1:0.30.

[0015] In the present invention, the type of enteric coating material of enteric coating is one of the key factors to achieve technical effect. Different types of enteric coating have different impacts on the release of gastrointestinal tract. When coating material is polyacrylic resin II, plasticizer is one or more mixture of triethyl citrate, propylene glycol, polyethylene glycol or diethyl phthalate, and antiadherent is one or more mixture of talcum powder, micropowder silica gel or glyceryl monostearate, atovaquone enteric-coated tablets are not destroyed by gastric acid, and atovaquone enteric-coated tablets can be better positioned and released in the small intestine. Preferably, the plasticizer is triethyl citrate, and the antiadherent is talcum powder.

[0016] The present invention also provides an atovaquone enteric-coated tablet comprising the following components:

[0017] Specifically, an atovaquone enteric-coated tablet comprises the following components:

[0018] The second object of the present invention is to provide a method for preparing the aforementioned atovaquone enteric-coated tablets, the method comprising the following steps: 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 cores at an average hardness of 30-60N, and inspecting the appearance of the tablets to see if they are sticky, loose, or cracked; 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.

[0019] Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects: 1) The present invention uses a specific ratio of glyceryl behenate and tyloxapol to achieve a smooth release of the tablet, achieving the effect of timely release in the early stage and complete release in the later stage, thereby improving the bioavailability of atovaquone.

[0020] 2) The present invention uses lecithin in the enteric coating, which further improves the bioavailability of atovaquone and facilitates the formation of the enteric coating, has a good taste masking effect, and is convenient for canines to take directly or indirectly.

[0021] 3) The atovaquone enteric-coated tablets obtained by the present invention are locally released in the intestine, reducing liver circulation, thereby reducing the occurrence of liver damage and the like.

[0022] 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 DESCRIPTION

[0023] The present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0024] Example 1 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0025] Preparation method: 1) Add the prescribed amount of hydroxypropyl methylcellulose to purified water and mix well, stirring while adding, and continue stirring for 35 minutes after the addition is completed, with the stirring speed being 600 rpm (two-blade paddle). After the stirring is completed, the hydroxypropyl methylcellulose solution is prepared for use; 2) Place atovaquone, microcrystalline cellulose, glyceryl behenate and tyloxapol in a granulator, preheat the temperature to 55°C, spray granulate, inlet air temperature 60±10°C, fan frequency 25-30Hz; material temperature ≤50°C, liquid supply speed about 1.5kg / min; atomization pressure 0.4MPa, granule moisture controlled below 5.0%; 3) Sieve the granules, add sodium carboxymethyl cellulose and mix for 20 minutes, set the total mixing speed to 10r / min, and mix for about 30 minutes; 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 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 45°C. At the same time, hot air at a temperature of 65°C is introduced into the coating pot. The coating time is 2.5 hours.

[0026] Example 2 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0027] The preparation method is the same as Example 1.

[0028] Example 3 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0029] The preparation method is the same as Example 1.

[0030] Example 4 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0031] The preparation method is the same as Example 1.

[0032] Example 5 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0033] The preparation method is the same as Example 1.

[0034] Comparative Example 1 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0035] 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.

[0036] Comparative Example 2 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0037] 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.

[0038] Comparative Example 3 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0039] 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.

[0040] Comparative Example 4 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0041] 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.

[0042] Comparative Example 5 Preparation of Atovaquone Enteric-coated Tablets Prescription composition of 1000 tablets of atovaquone enteric-coated tablets

[0043] 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.

[0044] Example 6 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: Table 1 Quality inspection of atovaquone enteric-coated tablets

[0045] 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.

[0046] Example 7 Testing of Atovaquone Enteric-coated Tablets for Dogs According to the disintegration time limit inspection method of the 2020 edition of the Veterinary Pharmacopoeia of the People's Republic of China, 6 enteric-coated tablets prepared in Examples 1-5 and Comparative Examples 3-5 were taken respectively, placed in artificial gastric juice for 2 hours, and the appearance of the enteric-coated tablets was observed for damage and fragmentation; after being rinsed with a small amount of water, they were immediately placed in artificial intestinal juice, and the enteric-coated tablets were completely disintegrated. Each tablet should be completely disintegrated within 1 hour. The test results are shown in Table 2.

[0047] Table 2 Test results of atovaquone enteric-coated tablets

[0048] As shown in Table 2, the enteric-coated tablets prepared in Examples 1-5 and Comparative Examples 3-5 have no appearance of broken pieces in gastric juice, and all disintegrate in intestinal juice within 1 hour, but the disintegration time in Comparative Example 3 is slightly longer, which may be due to the addition of poloxamer affecting 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. It can be seen that the atovaquone enteric-coated tablets for dogs of the present invention disintegrate and absorb in the intestine of dogs, release in a localized manner, reduce liver circulation, and thus reduce the occurrence of liver damage and the like.

[0049] Example 8 Dissolution Test Enteric-coated tablets prepared in Comparative Examples 3-5 of Example 1 were placed in phosphate buffer (pH 6.8) for dissolution testing. The results of the in vitro dissolution testing are shown in Table 3.

[0050] Table 3 Release test results of atovaquone enteric-coated tablets in each group

[0051] According to the release test results in Table 3, the atovaquone enteric-coated tablets prepared in Example 1 can be completely released within 20 hours, and there is no phenomenon of fast release in the early stage and slow release in the later stage during the release process, and the stable and constant release rate of the drug can be achieved. However, in Comparative Example 3, since tyloxapol was not added to adjust the release rate of atovaquone, and poloxamer, which has an effect on disintegration, was used, multiple factors combined, resulting in too slow release in the early stage, and it was not possible to completely release within 24 hours, and the 24-hour release amount was only 81.2%. In Comparative Example 5, since the particle size of the atovaquone raw material drug was large, the dissolution release efficiency was slowed down, and therefore, it was not possible to completely release within 24 hours. The experimenters also conducted the same dissolution experiment on Examples 2-5, and finally obtained results similar to those of Example 1, indicating that Examples 1-5 are preferred schemes in this scheme, and various parameters in Example 1, including the types and proportions of excipients, are all the most preferred, such as atovaquone, behenic acid glyceryl and tyloxapol are in appropriate proportions, and with atovaquone raw materials of suitable particle size, the overall combination of the above conditions makes the release of the drug linear, stable and constant release.

[0052] Example 9 Bioavailability Experiment Four healthy beagles were randomly divided into two groups, with two dogs in each group, half male and half female. The beagles were fasted for 10 hours overnight before the experiment, and were fed with atovaquone enteric-coated tablets prepared in Example 1 and Comparative Example 4 on an empty stomach in the morning of the second day. The enteric-coated tablets were directly delivered to the pharynx of the beagles, and then 20 mL of warm water was gavagely administered. Blank blood was collected before medication, and about 4 mL of blood was collected 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 hours after medication, and placed in a heparinized centrifuge tube and centrifuged at 3000 r·min -1 The mixture was centrifuged for 10 min to separate the plasma, which was then stored in a -20°C refrigerator for testing. The main pharmacokinetic parameters are shown in Table 4.

[0053] Table 4 Bioavailability determination results of atovaquone enteric-coated tablets in each group

[0054] From the results in Table 4, it can be seen that since an appropriate amount of phospholipids is added to the enteric coating of the atovaquone enteric-coated tablets prepared in Example 1, while no phospholipids are added in Comparative Example 4, Example 1 improves the bioavailability of atovaquone, and the bioavailability of the atovaquone enteric-coated tablets prepared in Example 1 is higher than that of the atovaquone enteric-coated tablets prepared in Comparative Example 4.

[0055] Example 10 Test on the therapeutic effect and toxic and side effects of atovaquone enteric-coated tablets on canine Babesia Ten dogs diagnosed with canine babesiosis were treated with atovaquone enteric-coated tablets prepared in Example 1 in five cases and with commercially available atovaquone suspension in five cases. The treatment was orally administered for three consecutive days, three times a day. The treatment effects are shown in Table 5.

[0056] Table 5 The therapeutic effect and toxic side effects of atovaquone enteric-coated tablets on canine Babesia

[0057] From the results in Table 5, it can be seen that the atovaquone enteric-coated tablets prepared by the present invention have a high cure rate for canine babesiosis, have no obvious related symptoms, have few side effects, and have a wide safety range.

[0058] In summary, the atovaquone enteric-coated tablets prepared in this scheme have a smooth and continuous release, high bioavailability, can be released in the intestine, reduce liver circulation, and thus reduce the occurrence of liver damage and the like. There is no sticking, splitting and other phenomena during the tableting process. The quality is qualified and stable, and its dissolution performance and stability are guaranteed.

[0059] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. An atovaquone enteric-coated tablet, characterized in that: Contains the following ingredients: atovaquone, glyceryl behenate, tyloxapol, fillers, binders, disintegrants, and enteric coating; The enteric coating comprises a coating material, a plasticizer, an anti-adherent agent and phospholipids; The mass ratio of atovaquone, behenic acid glyceryl and tyloxapol is 1:0.5-0.8:0.4-0.6; The atovaquone particle size D90 is 30-50 μm.

2. The atovaquone enteric-coated tablets according to claim 1, characterized in that: The filler is one or a mixture of microcrystalline cellulose, pregelatinized starch and starch; The binder is one or a mixture of hydroxypropyl methylcellulose, povidone, and ethyl cellulose; The disintegrant is one or a mixture of sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxy starch, and cross-linked polyvinylpyrrolidone; The phospholipid is one of phosphatidylinositol, phosphatidic acid, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and egg yolk sphingomyelin, or a mixture of several of them.

3. The atovaquone enteric-coated tablets according to claim 2, characterized in that: The filler is microcrystalline cellulose, the binder is hydroxypropyl methylcellulose, the disintegrant is sodium carboxymethyl cellulose, and the phospholipid is egg yolk sphingomyelin.

4. The atovaquone enteric-coated tablets according to claim 1, characterized in that: The coating material is polyacrylic acid resin II; The plasticizer is one or a mixture of triethyl citrate, propylene glycol, polyethylene glycol or diethyl phthalate; The anti-sticking agent is one or a mixture of talcum powder, micro-powder silica gel or glyceryl monostearate.

5. The atovaquone enteric-coated tablets according to claim 4, characterized in that: The plasticizer is triethyl citrate and the anti-sticking agent is talc.

6. The atovaquone enteric-coated tablets according to any one of claims 1 to 5, characterized in that: The mass ratio of atovaquone to filler is 1:0.5-0.9, the mass ratio of atovaquone to binder is 1:0.035-0.060, and the mass ratio of atovaquone to disintegrant is 1:0.25-0.40; The mass ratio of atovaquone, coating material, plasticizer, anti-adhesive agent and phospholipid is 1:0.4-0.7:0.05-0.1:0.05-0.1:0.1-0.

3.

7. The atovaquone enteric-coated tablets according to claim 6, characterized in that: The mass ratio of atovaquone, glyceryl behenate and tyloxapol is 1:0.6:0.5; the mass ratio of atovaquone to filler is 1:0.7, the mass ratio of atovaquone to binder is 1:0.050, and the mass ratio of atovaquone to disintegrant is 1:0.30; the mass ratio of atovaquone, coating material, plasticizer, anti-adherent and phospholipid is 1:0.5:0.08:0.08:0.

2.

8. The atovaquone enteric-coated tablets according to claim 7, characterized in that: Contains the following ingredients: 。 9. The method for preparing atovaquone enteric-coated tablets according to claim 8, 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 cores at an average hardness of 30-60N, and inspecting the appearance of the tablets to see if they are sticky, loose, or cracked; 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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