Aspirin enteric-coated micro-tablet capsule and preparation method thereof

Abstract

The invention discloses an aspirin enteric-coated micro-tablet capsule and a preparation method thereof. The micro-tablet core auxiliary materials of the enteric-coated micro-tablet capsule comprise an excipient, a disintegrating agent, a stabilizer, a flow aid and a lubricant. Tartaric acid is adopted as a stabilizer of aspirin, gel silicon dioxide is adopted as a flow aid, a moisture absorption agent and a swelling agent, and a direct powder tabletting method is adopted to prepare a micro-tablet core; the invention provides the aspirin enteric-coated micro-tablet capsule which is good in powder flowability, stable and easy to control in process, good in stability, uniform in dissolution and release characteristics, stable in blood concentration and high in bioavailability.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly discloses an aspirin enteric micro-tablet capsule and a preparation method thereof. BACKGROUND

[0002] Aspirin belongs to non-steroidal antipyretic analgesic and anti-inflammatory drug, and has a history of more than 100 years so far, and has become one of the three classic drugs in the history of medicine. Up to now, it is still the most widely used antipyretic, analgesic and anti-inflammatory drug in the world, and is also used as a standard preparation compared with other drugs. Aspirin can inhibit the synthesis of thromboxane TXA2 by inhibiting the activity of cyclo-oxygenase in platelets, so as to inhibit the aggregation of platelets and avoid the occurrence of thrombosis, and is used for preventing the onset of cardiovascular and cerebrovascular diseases in clinic.

[0003] At present, commercially available aspirin drugs include various dosage forms, such as ordinary tablets, enteric-coated tablets, enteric-coated micro-pellet capsules and the like.

[0004] The existing aspirin enteric-coated tablets belong to a single unit preparation, and are mainly absorbed in the small intestine. The random nature of gastric emptying time leads to a large difference in the time of aspirin tablets entering the small intestine. After eating, the gastric emptying rate is reduced, so that the aspirin tablets enter the small intestine with a delay, and thus the absorption is delayed. Therefore, the intra-individual and inter-individual variations of aspirin are large, and the Tmax of the same individual at different time periods is also inconsistent. Compared with the ordinary dosage form, the delayed absorption of aspirin enteric-coated tablets leads to a decrease in Cmax after taking the medicine, and the bioavailability is significantly reduced, so that the anti-platelet effect is weakened, and the drug efficacy is reduced. Moreover, the delayed absorption of the drug makes it impossible for the patient to quickly relieve acute symptoms. Therefore, it is of great significance to improve the original enteric-coated tablet dosage form and reduce the content of free salicylic acid in the aspirin enteric-coated tablets.

[0005] Chinese patent application CN200810203384.1 provides an aspirin enteric-coated tablet with low content of free salicylic acid, wherein a certain amount of tartaric acid is added in the tablet core formula, so as to effectively reduce the content of free salicylic acid.

[0006] Chinese patent application CN201410310585.7 discloses an aspirin enteric-coated sustained-release capsule and a preparation method thereof. The preparation method is to first adopt a wet granulation tabletting method or a powder direct compression into micro-tablets. The formula contains 30%-60% aspirin, 30%-60% filler, 1%-10% release modifier, and 2%-20% matrix material. The filler is one or more of mannitol, sorbitol, xylitol, lactose, sucrose, glucose, starch, dextrin, pregelatinized starch, and microcrystalline cellulose. The release modifier is one or more of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, and microcrystalline cellulose. The matrix material is one or more of hydroxypropyl methyl cellulose, ethyl cellulose, carbomer, sodium alginate, and stearic acid. The wet granulation tabletting into micro-tablets includes the following steps: uniformly mixing aspirin, filler, release modifier, and matrix material according to the formula, adding an ethanol solution containing a binder to prepare a soft material, sieving and granulating, drying, whole granulation, adding a lubricant, compressing into micro-tablets, filling, and then it is ready. The ethanol solution containing a binder contains 50%-100% ethanol, preferably 70%-85%, and the percentage is volume percentage. The powder direct compression into micro-tablets includes the following steps: uniformly mixing aspirin, filler, release modifier, and matrix material according to the formula, adding a lubricant, compressing into micro-tablets, filling, and then it is ready. The preparation process of the invention is complex, the preparation process requires high production equipment and operators, has poor repeatability, low yield, high production cost, and it is difficult to control the degradation of aspirin due to the use of the wet granulation process.

[0007] Chinese patent application CN202011245244.8 discloses an aspirin enteric-coated microtablet capsule and a preparation method thereof. The aspirin enteric-coated microtablet capsule is composed of aspirin and tablet core excipients with a mass ratio of 1:0.1-0.5. The aspirin enteric-coated microtablet capsule is composed of aspirin enteric-coated microtablet capsule, enteric-coated and capsule shell, wherein the mass ratio of enteric-coated to aspirin is 0.1-0.5:1. The aspirin enteric-coated microtablet core is composed of aspirin and tablet core excipients. The mass ratio of aspirin to tablet core excipients in the aspirin enteric-coated microtablet capsule is 1:0.1-0.5. The tablet core excipients include excipients, disintegrants, glidants and binders. The mass ratio of the excipients, disintegrants, glidants and binders is 5-20:5-20:0.1-5:0.1-5. The excipients include one or more of microcrystalline cellulose, powdered cellulose and silicified microcrystalline cellulose. The disintegrants include one or more of corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch. The glidants are selected from silicon dioxide, talc or a combination of the two. The binders include one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. The invention uses powder direct compression method to prepare the tablet core, avoiding the use of organic solvents and moisture, reducing solvent residues while avoiding the hydrolysis of aspirin, improving the stability of the preparation and storage process; the coating material uses enteric-coated excipients to avoid premature hydrolysis in the stomach and reduce individual differences. However, the use of a large number of excipients has poor flowability, and it is difficult to control the tablet weight difference during the tabletting process. In addition, the excipients have strong hygroscopicity, and the moisture content of the granules during the preparation process is high, which is not easy to operate.

[0008] Chinese patent CN202011447274.7 discloses an aspirin and rivaroxaban compound preparation and a preparation method thereof. The compound preparation is a capsule filled with aspirin enteric-coated microtablets and rivaroxaban sustained-release microtablets in a certain proportion. The aspirin enteric-coated microtablet is composed of an aspirin tablet core and a coating component. The aspirin tablet core is composed of aspirin, powder cellulose and corn starch in a mass ratio of (8-12):(1-2):(1-2). The specific composition of the coating component in mass percentage is: Eudragit L30D-55 45-50%, talc 45-50%, and triethyl citrate 4-5%. The preparation process of the aspirin enteric-coated microtablet is: direct compression or dry granulation followed by mixing and compression. The tablet core has a diameter of 2-6 mm, preferably 4.5-5.5 mm. Then, high-efficiency coating machine is used for coating. The aspirin enteric-coated microtablet of the patent has the following disadvantages: the invention uses a powder direct compression tablet core process, but uses less excipients, has a higher requirement for the particle size range of the raw materials, and a particle size that is too small will result in poor tablet flow, large tablet weight difference during compression, a particle size that is too large will result in poor compressibility and uneven content, ultimately leading to large batch-to-batch differences and uncontrollable product quality.

[0009] Chinese patent application CN202210064244.0 discloses a clopidogrel bisulfate aspirin microtablet capsule and a preparation method thereof. The clopidogrel bisulfate aspirin microtablet capsule is composed of clopidogrel bisulfate microtablets, aspirin microtablets and a capsule shell. The preparation process of the aspirin microtablet is as follows: aspirin is sieved through an 80-mesh sieve, mixed with a first filler, a first disintegrant and a first glidant to obtain a first mixture; a first lubricant is added to the first mixture, and the mixture is compressed to obtain aspirin microtablets; the aspirin microtablets and the clopidogrel bisulfate microtablets are filled into an enteric-coated capsule shell to obtain a microtablet capsule. The filler is one or more of microcrystalline cellulose, lactose, corn starch, silicified microcrystalline cellulose and mannitol; the disintegrant is one or more of microcrystalline cellulose and low-substituted hydroxypropyl cellulose. Specifically, the glidant is one or more of silicon dioxide and talc; and the lubricant is one or more of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol and glyceryl behenate.

[0010] The prescription of Example 1 is as follows:

[0011]

[0012] The prescription of Example 2 is as follows:

[0013]

[0014] The asprin enteric micro-tablet of the patent has the following shortcomings: the tablet core process of the invention is prepared by directly compressing powder, ① the moisture of the used excipients is not controlled, the moisture of the used excipients is high, and the excipients have high hygroscopicity, so the stability of the tablet is poor; ② corn starch is used in the prescription, and the flowability of the corn starch is poor, so that the tablet weight difference is large in the tabletting process, and the content of the finished product is not uniform.

[0015] Therefore, it is necessary to design a preparation method of asprin micro-tablet capsules which can effectively control the degradation of asprin in the preparation and storage process, has simple process, smooth tabletting process, low cost, and strong repeatability of dissolution characteristics. SUMMARY

[0016] In order to overcome the shortcomings of the prior art asprin enteric micro-tablet capsules, the present application provides a new asprin enteric micro-tablet capsule and a preparation method.

[0017] Specifically, the present application needs to solve the following technical problems:

[0018] 1. To solve the problem that asprin is easily hydrolyzed due to moisture absorption during the preparation and storage of asprin enteric micro-tablet capsules.

[0019] 2. To solve the problem that the powder flow difference leads to unsmooth tabletting process during the preparation of asprin enteric micro-tablet capsules.

[0020] 3. To solve the problem that the dissolution release of asprin enteric micro-tablet capsules is not uniform, leading to large differences in product batch and batch dissolution release.

[0021] 4. To solve the problem that the large dissolution release difference of asprin enteric micro-tablet capsules leads to large inter-individual and intra-individual variation after patients take the medicine, the drug-time curve is not stable enough, and the bioavailability difference is large.

[0022] In order to solve the above technical problems, the present application adopts the following technical solutions:

[0023] On the one hand, the present application provides an asprin enteric micro-tablet capsule, which is composed of a micro-tablet core wrapped with an enteric coating and a capsule shell, wherein the active ingredient of the micro-tablet core is asprin; the excipients are excipients, disintegrants, stabilizers, glidants and lubricants.

[0024] Further, the active ingredient of asprin can include crystals or amorphous, salts, anhydrides or hydrates, solvates, prodrugs, metabolites, etc. of asprin, all of which can be used in the preparation of the present application, preferably the crystals of asprin, and further preferably the particle size of the crystals of asprin is in the range of 150-250 μm.

[0025] Further, the aspirin enteric-coated microcapsules are characterized in that the core of the enteric-coated microcapsules contains 60%–70% active ingredient, 15%–26% excipients, 5%–7% disintegrants, 0.1%–1% stabilizers, 0.5%–6% flow aids, and 0.1%–1% lubricants; more preferably, the active ingredient accounts for 65%–70%, and the excipients comprise 20%–25%, the disintegrants 6%–7%, the stabilizers 0.8%–1%, the flow aids 1%–4%, and the lubricant 1%.

[0026] Furthermore, the excipient includes one or more of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose.

[0027] Furthermore, the disintegrant includes one or more of corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, crospovidone, sodium crospovidone carboxymethyl cellulose, and sodium carboxymethyl starch.

[0028] Further, the stabilizer is tartaric acid, including racemic tartaric acid or its single optical isomers dextrorotatory tartaric acid and levorotatory tartaric acid, preferably racemic tartaric acid, and even more preferably, the particle size D90 of the pulverized tartaric acid is ≤75μm.

[0029] Further, the flow aid is selected from silica, preferably gelled silica, and more preferably gelled silica with a particle size range of 6.5–8.1 μm (D90: 7.5 μm, pore size 0.4 ml / g), more preferably gelled silica with a particle size range of 6.5–7.5 μm (D90: 7.0 μm, pore size 0.4 ml / g). The amount of gelled silica used ranges from 0.1% to 6% of the total weight of the core, preferably from 0.5% to 6%, more preferably from 1% to 4%, and most preferably from 1%. The gelled silica is preferably manufactured by Grace Trading (Germany) GmbH. AL-1FP.

[0030] During our sample dissolution curve determination, we unexpectedly discovered that using the aforementioned gelled silica, especially... The tablets prepared with AL-1FP showed obvious swelling of the tablet core after being ruptured in an alkaline medium after 2 hours of acid resistance, and the dissolution data of each tablet was uniform. The swelling phenomenon was not obvious when using silica from other manufacturers, and the dissolution curves were not uniform.

[0031] It is presumed that the principle is: gel silica evenly dispersed in the drug powder, repair irregular surface of particles, reduce the flow of particles hinder; after the rupture of the enteric layer, due to the larger pore size of the gel silica, the inner and outer surface area is larger, can instantaneously absorb moisture and expand, resulting in the enteric layer burst, tablet core rapid disintegration release, thus improving the slow release of enteric coated tablets, tablet dissolution uneven phenomenon.

[0032] Further, the lubricant comprises one or more of magnesium stearate, stearic acid, talc, preferably stearic acid.

[0033] Further, the enteric micro tablet capsule of aspirin also comprises an enteric coating and a capsule shell wrapped on the above-mentioned micro tablet core. The enteric coating and the capsule shell can use the enteric coating materials and the capsule shell widely used in the prior art, especially the enteric coating materials and the capsule shell used in the enteric micro tablet capsule of aspirin in the prior art.

[0034] Further, the enteric coating comprises film coating material, plasticizer and anti-adhesive agent. Among them, the film coating material, plasticizer and anti-adhesive agent can use the enteric coating materials and the composition ratio widely used in the prior art, for example, the mass percentage of the total weight gain is 55%~65%:25%~30%:5%~10% respectively.

[0035] Further, the film coating material is selected from at least one of cellulose acetate phthalate (CAP), methacrylic acid copolymer (Eudragit L, Eudragit L30D and Eudragit S, etc.), hydroxypropyl methyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP). The film coating material is preferably selected from enteric type, which is a high molecular film coating material that is insoluble in gastric acid and begins to dissolve in intestinal fluid environment.

[0036] Further, the plasticizer is selected from at least one of citrate series (for example: tributyl citrate (TBC), acetyl tributyl citrate (ATBC)), glycerol acetate and glycerol triacetate.

[0037] Further, the anti-adhesive agent is talc.

[0038] Further, the capsule shell is made of hard capsule or soft capsule material. The capsule shell is a well-known hard capsule and / or soft capsule material, such as gelatin hard capsule or gelatin soft capsule or hydroxypropyl methyl cellulose capsule shell, which can be purchased or prepared by commercial means, and the capsule type can be one of 1#, 2# or 3#, which is not specially limited here.

[0039] In another aspect, the present application provides a preparation method of an enteric micro tablet capsule of aspirin, the specific steps are as follows:

[0040] 1) Aspirin is mixed with excipients, stabilizers, disintegrants, glidants and lubricants to form a total mixture; the mixing can be done in various ways, such as sieving, stirring, shaking, etc., with the purpose of improving the stability and uniformity of the mixture.

[0041] 2) The total mixture is tabletted to form the base microtablet; preferably, the microtablet has a diameter of 2-3 mm

[0042] 3) The enteric coating solution is sprayed into a container containing the base microtablet to form a coated tablet; after air drying, the coated tablet is obtained.

[0043] 4) The coated tablet is filled into a capsule shell to form an aspirin enteric microtablet capsule.

[0044] Further, the punch model used in the tableting process is a 2 mm or 3 mm diameter round punch.

[0045] Further, the enteric coating solution is prepared as follows: the film coating material, plasticizer and anti-adhesive are mixed with purified water to form an enteric coating solution.

[0046] Further, the coating process is as follows: the air inlet temperature is controlled at 40-50°C, the air outlet temperature is controlled at 30-40°C, the pressure is controlled at 4-6 MPa, the flow rate of the enteric coating solution sprayed by the spray gun is 1-10 ml / min, until the coating is complete, and the air is continuously blown at 30-50°C for 30 min to dry the coated tablet. In the coating process of the present application, spray gun spraying and air drying are used to quickly dry the water adhering to the surface of the aspirin base microtablet, reducing the effect of water on the hydrolysis of aspirin, and ensuring the stability and purity of the prepared aspirin microtablet.

[0047] As a preferred technical solution, the present application provides a preparation method of an aspirin enteric microtablet capsule, the specific steps of which are as follows:

[0048] a Aspirin, excipients, stabilizers, disintegrants, glidants and lubricants are mixed uniformly using a mixing device;

[0049] b A 3 mm diameter round punch is installed on the tablet press, and the mixture is directly tabletted into a base microtablet;

[0050] c Preparation of enteric microtablet:

[0051] ① The film coating material, plasticizer, anti-adhesive and purified water are mixed uniformly to form an enteric coating solution,

[0052] ② The base microtablet is placed in the coating pan, the air inlet temperature is controlled at 40-50°C, the air outlet temperature is controlled at 30-40°C, the pressure is controlled at 4-6 MPa, the flow rate of the enteric coating solution sprayed by the spray gun is 8 ml / min, until the coating is complete, and the air is continuously blown at 30-50°C for 30 min to dry the coated tablet.

[0053] d Fill the coated tablets into 3# gelatin hollow capsules, namely aspirin enteric micro-tablet capsules.

[0054] The technical scheme adopted by the present application has good powder flowability, easy-to-control process parameters, stable process, strong reproducibility, and can effectively reduce the content of free salicylic acid while improving the bioavailability of aspirin and reducing the absorption difference of different individuals.

[0055] The enteric micro-tablet capsule prepared by the present application has the following advantages compared with ordinary enteric capsules:

[0056] The capsule shell of the enteric capsule is prone to twisting and breaking in the stomach due to the influence of food extrusion and the like, which easily causes the drug to be released in the stomach in advance; due to the relatively large size of the enteric capsule, the entire capsule is not easy to pass through the pylorus into the intestinal tract, causing the drug to be released late, and the release process of the drug in the body has a large difference;

[0057] The enteric micro-tablet capsule prepared by the present application has the following advantages compared with ordinary enteric capsules:

[0058] Compared with enteric tablets, the present application has the following advantages:

[0059] 1) Compared with ordinary enteric tablets, the micro-tablet of the present application has a larger contact surface with digestive juice in the intestinal tract, thereby promoting the dispersion, dissolution, stable absorption, and release speed of the drug, which can significantly improve the shortcomings of ordinary enteric tablets that cannot quickly relieve acute symptoms due to delayed absorption, and effectively improve the bioavailability of aspirin.

[0060] 2) The capsule shell of the micro-tablet capsule of the present application dissolves rapidly in the stomach to release the micro-tablets, since the micro-tablets have a small size and are multiple small tablets, the time of drug entering the intestinal tract is less affected by the gastric emptying rate, which is beneficial to reduce the intra-individual and inter-individual variability caused by factors such as gastric emptying time difference, so as to make the drug-time curve more stable.

[0061] 3) The drug release behavior of the micro-tablet is the sum of the drug release behaviors of multiple small units constituting a dose, and the failure or defect of individual tablets in preparation will not have a great impact on the overall drug release behavior, avoiding the drug absorption difference caused by the batch or inter-batch difference of the preparation. The drug can be released smoothly and slowly, avoiding the high blood drug concentration after taking the drug which causes serious adverse reactions of the digestive system, and also avoiding the influence of unqualified dissolution, significantly reducing adverse reactions and improving efficacy.

[0062] Compared with the prior art aspirin enteric micro-tablet capsule, the present application has the following advantages:

[0063] The present application is based on the powder direct compression method of the prior art enteric-coated aspirin micro-tablets, tartaric acid is used as the hydrolysis stabilizer of aspirin, and gel silicon dioxide is used as the flow aid, water absorbent and swelling agent, which produces the following significant advantages:

[0064] 1. The powder direct compression method does not need to introduce solvent, avoids the influence of water and heat on aspirin during preparation, reduces solvent residue, avoids the hydrolysis of aspirin, and improves the stability during preparation and storage. On this basis, tartaric acid is used as the hydrolysis stabilizer of aspirin, and gel silicon dioxide is used as the water absorbent, which further improves the inhibition degree of aspirin hydrolysis and improves the stability during preparation and storage.

[0065] 2. The powder direct compression method has high requirements for the flowability of materials, the raw material has a large proportion, and the particle size of the raw material has a great influence on the flowability of the product. Therefore, the particle size range of the raw material is controlled (the preferred particle size range: D90: 150-250 μm), and gel silicon dioxide is used as the flow aid, which is uniformly dispersed in the drug powder, repairs the irregular surface of the particles, reduces the flowability of the particles, significantly improves the flowability of the powder, improves the process stability, and the process parameters are easy to control and have strong reproducibility. The principle of flowability improvement is shown in the accompanying Figure 1 .

[0066] 3. Gel silicon dioxide is used as the swelling agent, which has a large internal and external surface area, can swell and expand instantaneously after the enteric-coated layer of the micro-tablet is broken, causes the enteric-coated layer to burst, and the tablet core is rapidly disintegrated and released, thereby improving the uneven dissolution of the enteric-coated tablet. Other types of silicon dioxide do not have obvious swelling phenomenon, and the dissolution curves of the tablets are uneven and have a large RSD.

[0067] 4. The use of the above-mentioned preferred particle size range of gel silicon dioxide and the preferred particle size of aspirin raw material crystals has a significant improvement effect on the flowability of the powder, the hydrolysis stability and the dissolution uniformity, which may be related to the state of the gel silicon dioxide adsorbed and wrapped on the surface of the aspirin raw material crystal particles.

[0068] 5. The improvement of dissolution uniformity significantly improves the blood concentration stability and the bioavailability.

[0069] In summary, the present application provides an enteric-coated aspirin micro-tablet capsule with good powder flowability, easy-to-control process stability, good stability, uniform dissolution and release characteristics, stable blood concentration and high bioavailability. BRIEF DESCRIPTION OF DRAWINGS

[0070] Figure 1 Principle diagram of flowability improvement

[0071] Figure 2 Mean plasma profiles of test and reference formulations of Example 13 DETAILED DESCRIPTION

[0072] Comparative Example 1 Aspirin enteric micro-tablet capsule, prescription (patent CN202011245244.8 Example 3 prescription) as follows:

[0073]

[0074] Preparation method:

[0075] a Aspirin, excipients, disintegrants, binders, and glidants are mixed uniformly using a mixing device;

[0076] b The tablet press is equipped with a 2mm diameter round punch, and the mixture is directly compressed into a blank micro-tablet. The test results of the blank micro-tablet are as follows:

[0077] Monitoring item Actual measured value Tablet weight difference (mg) ﹣3.7％～﹢3.0％ Hardness 12～14N Tablet thickness 2.0 mm Friability 0.24％

[0078] c Preparation method of enteric micro-tablet:

[0079] ① The film coating material, plasticizer, anti-sticking agent and purified water are mixed uniformly to form an enteric coating solution,

[0080] ② The blank micro-tablet is placed in the coating pan, the inlet air temperature is controlled at 40-50℃, the outlet air temperature is controlled at 30-40℃, the pressure is controlled at 4-6MPa, the flow rate of the enteric coating solution sprayed by the spray gun is 10ml / min, and the coating is completed until the coating is completed., continuously blow 30-50℃ air dry for 30min to form a coated tablet.

[0081] d The coated tablet is filled into a 2# gelatin hollow capsule to form an aspirin enteric micro-tablet capsule.

[0082] Phenomenon: Using the prior art patent CN202011245244.8 Example 3 prescription, it is found that the granules are prone to moisture absorption during tabletting, it is difficult to control the moisture, and the flowability is poor, the tablet weight difference is large, and the punch is sticky. In addition, the stability test results show that when placed in a constant temperature and humidity box at 40℃ / RH 75%, samples are taken at 1, 2, 3, and 6 months, and aspirin content, dissolution, and related substances (salicylic acid) are tested. The results show that the content and dissolution decrease significantly, and the hydrolysis product (salicylic acid) increases significantly.

[0083] Example 1

[0084] Table 1-1 Aspirin micro-tablet capsule prescription composition (patent CN202011245244.8 Example 3 prescription + tartaric acid)

[0085]

[0086] Preparation method:

[0087] a. Aspirin, excipient, disintegrant, stabilizer tartaric acid, binder and glidant were mixed evenly using a mixing device; the powder rest angle was measured as follows:

[0088] Test method: funnel measurement method

[0089] Calculation formula: tan θ = height / radius

[0090] Evaluation index: the rest angle α of the powder is < 30°, and the flowability is good; if the rest angle α of the powder is > 45°, the flowability is poor.

[0091] Table 1-2 Rest angle measurement results

[0092]

[0093]

[0094] b. A 3mm diameter circular punch was installed on the tablet press, and the mixture was directly pressed into a tablet core. The test results of the tablet core are as follows:

[0095]

[0096] c. Intermediate process monitoring and testing (mixing throughout the process, tablet press chamber humidity ≤ RH 40%)

[0097] Before tabletting, the moisture content of the product after mixing was measured, and the moisture content of the material in the feeder and hopper of the tablet press was monitored every 5 minutes during the tabletting process.

[0098] d. The moisture content measurement (drying at 105°C to constant weight) results are as follows:

[0099] Time (min) Moisture % 0 0.81 10 0.85 15 0.92 20 1.02

[0100] Based on the prescription in Example 3 of patent CN202011245244.8, in order to improve the degradation of aspirin, a stabilizer tartaric acid was added, and the environmental humidity was controlled to control the moisture absorption of the product granules. It was found during the process that the product granules were prone to moisture absorption during the tabletting process, it was difficult to control the moisture, and the flowability was poor, the tablet weight difference was large, and the sticking was difficult.

[0101] Example 2 (remove binder)

[0102] Table 2-1 Aspirin tablet capsule prescription composition

[0103]

[0104]

[0105] Preparation method:

[0106] a. Aspirin, excipient, disintegrant, stabilizer and glidant were mixed evenly using mixing equipment;

[0107] The angle of repose of the powder was determined as follows:

[0108] Test method: funnel test method;

[0109] Calculation formula: tan θ = height / radius;

[0110] Evaluation index: the angle of repose of the powder is < 30°, and the flowability is good; if the angle of repose of the powder is > 45°, the flowability is poor.

[0111] Table 2-2 Angle of repose determination results

[0112] h1＝ 4.8 cm h2＝ 4.8 cm h3＝ 4.7 cm h1 + h2 + h3 = 4.77 mm r＝ 5.5 mm h / r＝ 0.87 arctan (h / r) = 40.91°

[0113] b. The mixture was directly compressed into a tablet core using a tablet press equipped with a 3 mm diameter circular punch. The test results of the tablet core are as follows:

[0114] Monitoring item Actual measured value Tablet weight difference ﹣4.1％～﹢3.3％ Hardness 12～15N Tablet thickness 2.1 mm Tablet appearance Pits appeared on tablet face with tabletting time

[0115] c. Intermediate process monitoring and testing (mixing is controlled throughout, and the humidity in the tabletting chamber is ≤ RH 40%)

[0116] Before tabletting, the moisture content of the product after mixing was determined. The moisture content of the material in the feeder and hopper of the tablet press was monitored every 5 min during the tabletting process.dTable 2-3 Moisture determination (105°C) is as follows:

[0117] Table 2-3 Moisture determination results

[0118] Time (min) Moisture % 0 0.81 10 0.85 15 0.87 20 0.92

[0119] From the experimental results, it can be seen that after removing the binder, the granules absorb moisture, the moisture content is not improved, and the flowability is poor, and the tablet core is slightly sticky.

[0120] Example 3 (increasing lubricant)

[0121] Table 3-1 Aspirin tablet core capsule formulation composition

[0122]

[0123] Preparation method:

[0124] a. Aspirin, excipient, tartaric acid, disintegrant, glidant and lubricant were mixed evenly using mixing equipment;

[0125] The angle of repose of the powder was determined as follows:

[0126] Test method: funnel method

[0127] Calculation formula: tan θ = height / radius

[0128] Evaluation index: the powder has good flowability if the angle of repose α is < 30°; the powder has poor flowability if the angle of repose α is > 40°.

[0129] Table 3-2 Angle of repose test

[0130] h1＝ 4.7 cm h2＝ 4.7 cm h3＝ 4.6 cm h1 + h2 + h3 = 4.67 mm r＝ 5.5 mm h / r＝ 0.85 arctan (h / r) = 40.31°

[0131] b The mixture was directly compressed into a tablet by installing a 3 mm diameter circular punch on a tablet press, and the test results of the tablet were as follows:

[0132] Monitoring item Actual measured value Tablet weight difference ﹣4.1％～﹢3.4％ Hardness 13～16N Tablet thickness 2.1 mm Friability 0.18％

[0133] c Intermediate process monitoring test (mixing is controlled throughout, and the humidity in the tabletting chamber is ≤ RH 40%)

[0134] Before tabletting, the moisture content of the product after mixing was determined, and the tablet press was monitored every 5 min during the tabletting process

[0135] Moisture content of the material in the feeders and hoppers.

[0136] d Moisture test (105°C)

[0137] Table 3-3 Moisture test (105°C)

[0138] Time (min) Moisture % 0 0.79 10 0.81 15 0.84 20 0.90

[0139] In this example, the lubricant was increased, but the moisture content of the granules could not be improved, and the flowability was poor, the tablet weight difference was large, the compressibility was general, and the punch was slightly sticky.

[0140] Example 4 (change of glidant manufacturer and type)

[0141] Table 4-1 Silica source

[0142]

[0143] Table 4-2 Aspirin tablet capsule prescription composition

[0144]

[0145]

[0146] Preparation method:

[0147] a Aspirin, excipients, tartaric acid, disintegrants, glidants, and lubricants were uniformly mixed using a mixing device;

[0148] Powder angle of repose measurement, as follows:

[0149] Test method: funnel measurement method;

[0150] Calculation formula: tan θ = height / radius;

[0151] Evaluation index: the powder has good flowability when the angle of repose α is < 30°, and has poor flowability when the angle of repose α is > 40°.

[0152] Table 4-3 Angle of repose measurement

[0153] h1＝ 4.1 cm h2＝ 4.1 cm h3＝ 4.2 cm h1 + h2 + h3 = 4.13 mm r＝ 5.5 mm h / r＝ 0.75 arctan (h / r) = 36.93°

[0154] b The tablet press is equipped with a 3 mm diameter circular punch, and the mixture is directly compressed into a blank microtablet. The test results of the blank microtablet are as follows:

[0155] Monitoring item Actual measured value Tablet weight difference (mg) ﹣2.2％～﹢2.1％ Hardness 15～17N Tablet thickness 2.2 mm Friability 0.22％

[0156] c. Intermediate process monitoring and testing (mixing is controlled throughout the process, and the humidity in the tabletting chamber is ≤ RH 40%)

[0157] Before tabletting, the moisture content of the product after mixing is determined, and the moisture content of the material in the feeder and hopper of the tablet press is monitored every 5 min during the tabletting process.

[0158] d. Moisture determination (105°C)

[0159] Table 4-4 Moisture determination (105°C) results

[0160] Time (min) Moisture % 0 0.77 10 0.80 15 0.81 20 0.89

[0161] e. Method for preparing enteric microtablets:

[0162] ① The film coating material, plasticizer, anti-adhesive, and purified water are mixed uniformly to form an enteric coating solution,

[0163] ② The blank microtablet is placed in the coating pan, and the inlet air temperature is controlled at 40-50°C, the outlet air temperature is controlled at 30-40°C, the pressure is controlled at 4-6 MPa, the flow rate of the enteric coating solution sprayed by the spray gun is 8 ml / min, until the coating is completed, and the air is continuously blown at 30-50°C for 30 min to dry the coated tablets.

[0164] d. The coated tablets are filled into 1# gelatin hollow capsules to form aspirin enteric microtablet capsules.

[0165] After the glidant is replaced with colloidal silicon dioxide in this example, the flowability of the granules is improved, the tablet weight difference is smaller, and the requirements are met.

[0166] Examples 5-11 (Investigation of the effects of different types of silicon dioxide produced by different manufacturers on the product)

[0167] Table 5-1 Silica source

[0168]

[0169] Table 5-2 Aspirin enteric micro-tablet capsule prescription composition

[0170]

[0171] Preparation method:

[0172] a Aspirin, excipients, tartaric acid, disintegrants, glidants and lubricants are mixed evenly using a mixing device;

[0173] The powder rest angle is determined according to the method of Example 4, and the results are as follows:

[0174] Evaluation index: the powder rest angle a < 30°, and the flowability is good; the powder rest angle a < 35°, and the flowability is good; if the powder rest angle a > 40°, the flowability is poor.

[0175] Table 5-3 Rest angle determination results

[0176]

[0177] b The tablet press is equipped with a 3mm diameter round punch, and the mixture is directly compressed into a micro-tablet. The test results of the micro-tablet are as follows:

[0178]

[0179]

[0180] c Preparation method of enteric micro-tablet:

[0181] ① The film coating material, plasticizer, anti-adhesive and purified water are mixed evenly to form an enteric coating solution,

[0182] ② The micro-tablet is placed in the coating pan, and the air inlet temperature is controlled at 40-50°C, the air outlet temperature is controlled at 30-40°C, the pressure is controlled at 4-6MPa, the flow rate of the enteric coating solution sprayed by the spray gun is 8ml / min, until the coating is completed, and the air is continuously blown at 30-50°C for 30min, and dried for 30min to form a coated tablet.

[0183] d The coated tablet (8 tablets per particle) is filled into a 1# gelatin hollow capsule to form an aspirin enteric micro-tablet capsule.

[0184] By comparing different types of silica produced by different manufacturers, we unexpectedly found that the particle flowability was improved, the tablet weight difference was smaller, and the friability was smaller after using gel silica in Examples 8 and 9. In addition, in the sample dissolution curve determination, the tablet prepared by using gel silica AL-1FP in Example 9 had obvious swelling of the tablet core after acid resistance for 2 hours and after membrane rupture in alkaline medium, and the dissolution data of each tablet was uniform; using silica from other manufacturers and different types (244FP) of silica from the same manufacturer, the swelling phenomenon was not obvious after acid resistance in alkaline medium, and the dissolution curve was not uniform.

[0185] The presumed principle is that the gel silica is uniformly dispersed in the drug powder, repairing the irregular surface of the particles, especially the particles of aspirin which accounts for 60-70% of the weight of the tablet core, adsorbing and wrapping the gel silica particles, reducing the flowability hindrance of the particles, and the principle is shown in the attached Figure 1 ; and after the enteric layer is broken, it can be instantly hygroscopic, making the tablet swell and disperse, improving the dispersion speed and dissolution uniformity of the enteric-coated tablet, and greatly reducing the dissolution non-uniformity of the tablet. This phenomenon is because the gel silica, especially AL-1FP, has a particle size range of 6.5-8.1 microns, which can perfectly wrap the outer layer of the aspirin particles which account for 60-70% of the weight of the tablet core, significantly increasing the flowability; at the same time, it has a pore size of up to 0.4 ml / g, and the porous structure makes the gel silica particles have strong hygroscopicity and active swelling characteristics after water absorption, which can quickly absorb water, swell and disintegrate the micro-tablet, and at the same time quickly disperse the wrapped aspirin particles into the dissolution medium, significantly improving the dissolution speed and dissolution uniformity; while ordinary micro-tablets do not have the above characteristics, not only the tablet core disintegrates and disperses slowly in the enteric medium, but also due to the weak active swelling characteristics, it is easily affected by the environment, and the speed of the raw drug particles exposed to the medium varies greatly, finally resulting in non-uniform dissolution of the tablet, low bioavailability in vivo, and large individual and inter-tablet differences.

[0186] Examples 12-16 (screening of the amount of gel silica)

[0187] The amount of silica in the above examples accounts for about 6% of the total weight of the tablet core. On this basis, the influence of different amounts of gel silica AL-1FP on the product was further screened to confirm the amount of use.

[0188] Table 12-1 Source of silica

[0189]

[0190] Table 12-2 Formulation composition of aspirin micro-tablet capsules in Example 12 (gel silica accounts for 0.5% of the tablet core)

[0191]

[0192] Table 12-3 Formulation composition of aspirin microtablet capsule (gel silica 1% of tablet core)

[0193]

[0194] Table 12-4 Formulation composition of aspirin microtablet capsule (gel silica 2% of tablet core)

[0195]

[0196] Table 12-5 Formulation composition of aspirin microtablet capsule (gel silica 3% of tablet core)

[0197]

[0198] Table 12-6 Formulation composition of aspirin microtablet capsule (gel silica 4% of tablet core)

[0199]

[0200]

[0201] Preparation method:

[0202] a. Aspirin, excipient, disintegrant, stabilizer, glidant, lubricant were mixed evenly using a mixing device;

[0203] Powder rest angle determination, method same as example 4, results as follows:

[0204] Table 12-7 Rest angle determination results

[0205]

[0206] b. The mixture was directly compressed into a microtablet using a tablet press equipped with a 3 mm diameter round punch, and the test results of the microtablet were as follows:

[0207] Monitoring item Tablet weight difference % Hardness N Tablet thickness mm Friability % Example 12 -2.9～+2.8 14～18 2.2 0.22 Example 13 -2.8～+2.8 15～18 2.2 0.21 Example 14 -2.6～+2.5 15～18 2.2 0.21 Example 15 -2.5～+2.4 15～19 2.2 0.19 Example 16 -2.1～+2.3 15～19 2.2 0.18

[0208] c. Preparation method of enteric microtablet:

[0209] ①The film coating material, plasticizer, anti-adhesive and purified water were mixed evenly to form an enteric coating solution,

[0210] ②The microtablet was placed in the coating pan, the inlet air temperature was controlled at 40-50°C, the outlet air temperature was controlled at 30-40°C, the pressure was controlled at 4-6 MPa, the flow rate of the enteric coating solution sprayed by the spray gun was 8 ml / min, until the coating was completed, the air was continuously blown at 30-50°C for 30 min, and the coated tablet was dried.

[0211] d Fill the coated tablets (8 tablets per pellet) into 1# gelatin empty capsule, i.e. aspirin enteric micro-tablet capsule.

[0212] Examples 12-16 show that the amount of gel silica AL-1FP in the range of 0.5%-4% of the total tablet weight, with the increase of the amount, the angle of repose becomes smaller, the flowability increases, and the friability decreases. When the amount is 1% or more of the total tablet weight, its performance has met the needs of the preparation, in order to save costs, preferably the amount of gel silica AL-1FP is 1% of the total tablet weight.

[0213] Examples 17-20 investigate the effect of the particle size range of aspirin crystals on the dissolution curve.

[0214] According to the results of Examples 12-16 above, when the gel silica AL-1FP takes 1% of the total weight of the tablet core portion, keeping other excipients unchanged, different particle size ranges of aspirin crystal raw materials are screened to investigate the effect on the flowability of the powder and the dissolution curve of the product, and the particle size range of aspirin crystals is confirmed.

[0215] Table 17-1 Prescription composition of aspirin micro-tablet capsule in Example 17

[0216]

[0217] Table 17-2 Prescription composition of aspirin micro-tablet capsule in Example 18

[0218]

[0219]

[0220] Table 17-3 Prescription composition of aspirin micro-tablet capsule in Example 19

[0221]

[0222] Table 17-4 Prescription composition of aspirin micro-tablet capsule in Example 20

[0223]

[0224]

[0225] Preparation method:

[0226] a Aspirin, excipients, disintegrants, stabilizers, glidants, and lubricants are mixed uniformly using a mixing device;

[0227] The powder angle of repose is determined by the method of Example 4, and the results are as follows:

[0228] Table 17-4 Resting angle measurement results

[0229]

[0230] b The mixture was directly compressed into a tablet core by installing a 3mm diameter circular punch on the tablet press, and the test results of the tablet core were as follows:

[0231] Monitoring item Tablet weight difference % Hardness N Tablet thickness mm Friability % Example 17 -3.8～+4.2 12～14 / / Example 18 -2.4～+2.2 15～18 2.2 0.21 Example 19 -2.6～+2.7 16～19 2.2 0.22 Example 20 -4.8～+3.9 16～19 / /

[0232] c The method for preparing the enteric-coated tablet core was as follows:

[0233] ① The film coating material, plasticizer, anti-adhesion agent and purified water were mixed uniformly to form an enteric-coated solution,

[0234] ② The tablet core was placed in a coating pan, the air inlet temperature was controlled at 40-50°C, the air outlet temperature was controlled at 30-40°C, the pressure was controlled at 4-6MPa, the flow rate of the enteric-coated solution sprayed by the spray gun was 8ml / min, until the coating was completed, and the air was continuously blown at 30-50°C for 30min to dry the tablet core.

[0235] d The coated tablet (8 tablets per particle) was filled into a 1# gelatin hollow capsule to obtain the aspirin enteric-coated tablet capsule.

[0236] According to the above results, it can be seen that:

[0237] When the mass percentage of the gel silica AL-1FP in the total weight of the tablet core part was 1%, the particle size D90 of the raw material in Example 17 was greater than 250μm, the material flowability was good, but the compressibility was general, the tablet weight difference was large, and the sticking and sticking were serious; the particle size D90 of the raw material in Example 20 was less than 150μm, the compressibility was good, but the material flowability was poor, the tablet weight difference was large, and the sticking and sticking were serious; the particle size D90 of the raw material in Examples 18 and 19 was 150-250μm, the material flowability was good, and the compressibility was good, the tablet weight difference was small, and the sticking and sticking were not serious.

[0238] The experimental results show that when the types and proportions of the excipients in the present application are selected, the preferred particle size range of the aspirin crystal is D90: 150-250μm.

[0239] Dissolution curve test

[0240] Test method: method 1 determination according to Chinese Pharmacopoeia 2020 edition four general rules 0931 first method

[0241] 1. Acid dissolution

[0242] Solvent: 0.1mol / L hydrochloric acid solution 750ml

[0243] Rotary basket method: 100rpm

[0244] Time: 2 hours

[0245] Temperature: 37 ± 0.5 °C

[0246] Procedure:

[0247] 1) Preparation of the reference solution: accurately weigh 20 mg of aspirin reference substance into a 50 ml volumetric flask, dissolve and dilute to the mark with 1% glacial acetic acid solution, shake well; accurately transfer 5 ml into a 25 ml volumetric flask, dilute to the mark with 1% glacial acetic acid solution, and you get it.

[0248] 2) Preparation of the test solution: put the capsules of the example into the dissolution instrument rotating basket respectively, start the instrument and rotate for 2 hours, take 10 ml of the solution, filter, and get the test solution

[0249] Determination: high performance liquid chromatography

[0250] Inject 20 μL of the reference solution and the test solution into the high performance liquid chromatograph respectively

[0251] Acceptance criteria: the measured aspirin should not exceed 10% of the labeled amount within 2 hours

[0252] 2, the release amount in the buffer

[0253] Solvent: 1000 ml of standard phosphate buffer with pH 6.8

[0254] Rotating basket method: 100 rpm

[0255] Time: 10 / 15 / 20 / 30 / 45 / 60 min

[0256] Temperature: 37 ± 0.5 °C

[0257] Procedure:

[0258] 1) Preparation of the reference solution: accurately weigh 20 mg of aspirin reference substance into a 100 ml volumetric flask, dissolve and dilute to the mark with 1% glacial acetic acid solution, shake well; accurately transfer 5 ml into a 10 ml volumetric flask, dilute to the mark with 1% glacial acetic acid solution, and you get it

[0259] 2) Preparation of the test solution: after the acid 2 hours microtablet is washed with purified water, it is immediately transferred to the phosphate buffer preheated to 37 ± 0.5 °C, and samples are taken at 10, 15, 30, 45 and 60 min respectively, 10 ml of the solution is taken, filtered, and the test solution is obtained, and then the same temperature phosphate buffer is immediately added to the dissolution cup.

[0260] Determination: high performance liquid chromatography

[0261] Inject 20 μL of the reference solution and the test solution into the high performance liquid chromatograph respectively

[0262] Acceptance criteria: Aspirin should not be less than 80% of the labeled amount at 45 min

[0263] The dissolution test results of the aspirin enteric micro-tablet capsules are shown in the data table below:

[0264]

[0265] According to the above results, it can be seen that:

[0266] 1) The micro-tablet capsules of Examples 4-19 meet the requirements of the dissolution test in Appendix XD of the Chinese Pharmacopoeia: the dissolution in acid is not more than 10% of the labeled amount, and the dissolution in buffer at 45 min is not less than 80% of the labeled amount,

[0267] 2) As can be seen from the above table, the dissolution uniformity (RSD value) of Examples 4, 9, 12, 13, 14, 15, 16, 18 and 19 after replacing the gel silica is better than that of Comparative Example 1 and other products. The reason is speculated to be that the gel silica AL-1FP is adsorbed on the aspirin crystal particles, and after swelling by absorbing water, the tablet core swells, causing the aspirin to be rapidly and uniformly dispersed in the dissolution medium.

[0268] Accelerated test: The commercially available enteric tablets, enteric micro-tablet capsules (Comparative Example 1) and aspirin enteric micro-tablet capsules obtained in Examples were placed in a constant temperature and humidity chamber at 40°C / RH 75%, and samples were taken at 1, 2, 3 and 6 months, and the aspirin content and related substances were examined, respectively. The results are shown in the table below.

[0269]

[0270]

[0271] As can be seen from the above table, the enteric micro-tablets prepared in Examples 4, 9, 12, 13, 18 and 19 do not have significant changes in various indicators under the condition of being placed in an accelerated test at 40°C / RH 75% for 6 months, and all meet the requirements. The product stability and quality are better than those of Comparative Example 1 and commercially available preparations. The reason is speculated to be that, in addition to the effect of the stabilizer tartaric acid, the gel silica AL-1FP is adsorbed on the aspirin crystal particles, absorbs water, prevents water from contacting with aspirin, and further inhibits the decomposition of aspirin. At the same time, the gel silica AL-1FP swells by absorbing water, and the micro-tablet rapidly disintegrates and disperses, causing the aspirin to be rapidly and uniformly dispersed in the dissolution medium, reducing the decrease in the dissolution of the sample in the accelerated test.

[0272] The crystal of aspirin adopted in the present application has a particle size range of D90: 150-250 μm, and the gel silica with a particle size of 6.5-8.1 μm and a pore size of 0.4 ml / g shows good stability to the tablet, guarantees the uniformity of dissolution of the aspirin tablet core, and thus ensures the drug efficacy of aspirin.

[0273] Clinical trial (evaluation of relative bioavailability)

[0274] The sample of Example 13 was used as the test preparation (SPIEC-100), and aspirin enteric-coated tablets of Bayer Corporation (ASPENT) were used as the reference preparation to evaluate the relative bioavailability of the two in Chinese healthy subjects after oral administration under fasting conditions.

[0275] Overall design

[0276] A single-center, randomized, open, single-dose, two-preparations, two-sequence, four-period, full-repetition, cross-dosing design was used to evaluate the relative bioavailability of the test preparation SPIEC-100 and the reference preparation in Chinese healthy subjects after oral administration under fasting conditions.

[0277] Drug information

[0278] Test preparation: SPIEC-100, specification: 100 mg, batch number: 20240226, Example 13 of the present application.

[0279] Reference preparation: ASPENT, specification: 100 mg, batch number: BJ67093, expiration date: 2025.02.02, produced by Bayer HealthCare Manufacturing S.r.1. (Italy).

[0280] Dosing dose

[0281] The test preparation (T) or the reference preparation (R) was administered at a dose of 100 mg.

[0282] Body position and activity restrictions

[0283] The subjects remained upright for 4 hours after administration. After administration, vigorous exercise was avoided. If the subjects needed to go to the bathroom within 4 hours after administration, the researchers accompanied them to prevent hiding or vomiting of the drug.

[0284] Water and food restrictions

[0285] The fasting test prohibited drinking 1 hour before administration to 1 hour after administration (except for 240 mL of water required for administration) in each period, and drinking was allowed to start 1 hour after administration.

[0286] Number of subjects 12 healthy subjects

[0287] Washout period 5 days

[0288] Study design

[0289] This study is a single center, randomized, open, single-dose, two formulations, two sequences, four-period, full-replicated, crossover study in healthy adult subjects under fasting condition.

[0290] According to the random table, each subject will be randomly assigned to one of the two groups (TRTR and RTRT). In the first period, after fasting for at least 10 hours, the first subject is expected to start taking medicine at 08:00 (± 1 hour) in the morning, and the subjects take the corresponding study drug with 240 mL of water in a fasting state, one group of subjects orally takes 100 mg of the test preparation, and the other group of subjects orally takes 100 mg of the reference preparation. After the washout period, the next period of study is performed by crossover administration, and the administration time of the second, third and fourth periods is consistent with the first period. The crossover administration scheme is shown in the table below:

[0291]

[0292] Blood sampling time points

[0293] In each period, venous blood is collected at 0 h (within 60 min before administration) and 1, 2, 2.5, 3, 3.5, 4, 4.33 (4h 20min), 4.67 (4h 40min), 5, 5.33 (5h 20min), 5.67 (5h 40min), 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 14, 16, 20h, 24h, a total of 27 time points.

[0294] Test results: relative bioavailability

[0295] In this study, the subjects orally take the test preparation SPIEC-100 100mg under fasting condition and the reference preparation ASPENT 100mg under fasting condition, and the average drug-time curves of the test preparation and the reference preparation are shown in the attached Figure 1 The results show that, compared with the reference preparation, the relative bioavailability of AUC 0-t is 128%, the relative bioavailability of AUC 0-∞ is 124%, both of which are improved, and the individual variation of the test preparation (25.71%) is significantly lower than that of the reference preparation (62.34%), which preliminarily achieves the design expectation. It is shown that the enteric-coated aspirin micro-tablet capsule of the application significantly improves the stability of blood drug concentration and has high bioavailability due to the improvement of micro-tablet disintegration and dispersion ability and dissolution uniformity.

Claims

1. An enteric coated microtablet capsule of aspirin consisting of a microtablet core coated with an enteric coating and a capsule shell, characterized in that, The active ingredient of the microtablet core is aspirin, and the excipients are excipient, disintegrant, stabilizer, glidant and lubricant.

2. The aspirin enteric-coated microflake capsule according to claim 1, characterized by The active ingredient of the microtablet core is aspirin, including crystal or amorphous, salt, anhydride or hydrate, solvate, prodrug, metabolite, etc. of aspirin, preferably crystal of aspirin, and further preferably the particle size range of the crystal of aspirin is D90: 150-250 μm. In the microtablet core, the weight percentage of the active ingredient is 60-70%, the excipient is 15-26%, the disintegrant is 5-7%, the stabilizer is 0.1-1%, the glidant is 0.5-6%, and the lubricant is 0.1-1%; further preferably, the weight percentage of the active ingredient is 65-70%, the excipient is 20-25%, the disintegrant is 6-7%, the stabilizer is 0.8-1%, the glidant is 1-4%, and the lubricant is 1%.

3. The aspirin enteric-coated microflake capsule according to claim 1, wherein In the microtablet core, the excipient includes one or more of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose.

4. The aspirin enteric-coated microflake capsule according to claim 1, wherein In the microtablet core, the disintegrant includes one or more of corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, and sodium carboxymethyl starch.

5. The aspirin enteric-coated microflake capsule according to claim 1, wherein In the microtablet core, the stabilizer is tartaric acid, including racemic tartaric acid or its single optical isomer d-tartaric acid, l-tartaric acid, preferably racemic tartaric acid, and further preferably the particle size D90 of the crushed tartaric acid is ≤75 μm.

6. The aspirin enteric-coated microflake capsule according to claim 1, wherein In the microtablet core, the glidant is selected from silica, preferably gel silica, preferably gel silica with a particle size range of 6.5-8.1 μm, D90: 7.5 μm, and a pore size of 0.4 ml / g, and further preferably gel silica with a particle size range of 6.5-7.5 μm, D90: 7.0 μm, and a pore size of 0.4 ml / g.

7. The aspirin enteric-coated microflake capsule according to claim 1, wherein In the microtablet core, the glidant is selected from gel silica, and the amount is 0.5-6% of the total weight of the core, further preferably 1-4%, and most preferably 1% of the total weight of the core.

8. The aspirin enteric-coated microflake capsule according to claim 7, characterized in that In the microtablet core, the lubricant includes one or more of magnesium stearate, stearic acid, polyethylene glycol, and talc, and is preferably stearic acid.

9. The aspirin enteric-coated microflake capsule according to claim 1, wherein 10. The preparation method of the enteric-coated aspirin microtablet capsule according to claims 1-8, comprising the following steps: 1) uniformly mixing aspirin with excipient, tartaric acid, disintegrant, glidant and lubricant to obtain a total mixture; the mixing method can be various, such as sieving, stirring, and shaking, etc., aiming to improve the stability and uniformity of the mixture; 2) compressing the total mixture to obtain microtablet cores; preferably, the microtablet cores with a diameter of 2-3 mm are obtained; 3) spraying enteric-coated liquid into a container containing the microtablet cores to coat, and drying to obtain coated tablets; 4) filling the coated tablets into a capsule shell to obtain an enteric-coated aspirin microtablet capsule. ​

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