Dry suspension containing aspirin and preparation method thereof

Abstract

According to the aspirin-containing dry suspension and the preparation method thereof, ethyl cellulose and calcium carbonate serve as coating powder and are mixed with ethyl alcohol to prepare a coating solution, aspirin particles are coated, due to the wrapping effect of the ethyl cellulose and the calcium carbonate, aspirin is effectively isolated from dihydroxyaluminum aminoacetate and heavy magnesium carbonate, and the aspirin-containing dry suspension is prepared. Compared with the existing dosage forms in the market, good stability and taste masking effect are accidentally obtained, the preparation method is simple, the operability is high, the content of effective substances in the dry suspension can be increased, and the dry suspension has good dissolution effect, stability, taste masking effect and compliance, is more suitable for the old and children and has great clinical significance compared with the existing dosage forms in the market.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a dry suspension containing aspirin and a preparation method thereof. Background Art

[0002] Aspirin is a commonly used antipyretic and analgesic. A small dose of aspirin can inhibit the formation of thromboxane A2, thereby irreversibly inhibiting the normal platelet aggregation process and inhibiting thrombosis in diseases such as angina pectoris, myocardial infarction and ischemic cerebrovascular disorders. However, aspirin has a direct irritating effect on the gastric mucosa, which may cause symptoms such as upper abdominal discomfort, nausea, and vomiting. Long-term use may also induce or aggravate peptic ulcers and cause gastrointestinal bleeding.

[0003] Aluminum glycohydroxy and heavy magnesium carbonate can neutralize gastric acid, reduce gastric acidity and the acid load entering the duodenum. By reducing gastric acid, the activity of pepsin is reduced, thus alleviating upper abdominal pain symptoms. It also has an astringent and hemostatic effect, promoting ulcer healing and recovery of chronic gastritis.

[0004] The combination of aspirin with the acid-suppressing drugs aluminum glycoside and heavy magnesium carbonate can protect the gastrointestinal mucosa. Compared with aspirin alone, animal experimental results show that this product is absorbed faster, has less irritation to the gastric mucosa, and has better clinical prospects.

[0005] However, aspirin is acidic, while aluminum glycolate and heavy magnesium carbonate are alkaline, and there is a significant incompatibility between the two. The aspirin preparations widely used in China are all enteric-coated preparations, but the drug absorption of enteric-coated preparations is significantly slower than that of ordinary preparations, and the pain relief time is also correspondingly prolonged. In addition, enteric-coated formulations are mostly tablets and capsules, which are not conducive to patients with dysphagia, the elderly, and children.

[0006] Aspirin has poor stability in hot and humid conditions and alkaline environments, and is easily hydrolyzed to form salicylic acid. During the preparation of the preparation, it is necessary to focus on controlling the moisture and isolating the alkaline environment to ensure its stability. In addition, the proportion of aspirin raw materials is relatively large and its compressibility is relatively poor. When preparing the preparation, it is preferred to use granules or dry suspensions that do not require a tableting process. The proportion of the main drug aspirin is extremely high and it has a strong bitter taste. When preparing it into a dry suspension for oral use, it is necessary to pay special attention to its taste-masking effect.

[0007] Chinese patent CN106727380A discloses a preparation process of aluminum-magnesium aspirin tablets, which are made of an aspirin layer and a buffer layer. The aspirin layer is made of aspirin, mannitol, corn starch, tartaric acid, gelatin, aluminum citrate lake, and silicon dioxide; the buffer layer is made of aluminum glycolate, heavy magnesium carbonate, mannitol, corn starch, gelatin, and silicon dioxide. The aspirin layer is wet granulated, and the wet and hot conditions are not conducive to the stability of aspirin. In addition, aspirin accounts for a large proportion, and there are risks of poor compressibility and sticking during the tableting process. The tableting equipment used is a double-layer tablet press, which has high requirements for the equipment.

[0008] Therefore, it is of great significance to develop a method for preparing a dry suspension containing aspirin with a simple preparation process, stable and controllable process, rapid sample dissolution, and good taste, and to obtain a solid preparation with stable quality. Summary of the invention

[0009] The purpose of the present invention is to provide a dry suspension containing aspirin on the basis of the prior art, which has good dissolution effect, stability, taste masking effect and compliance. Compared with the existing dosage forms on the market, the dry suspension is more suitable for the elderly and children and has great clinical significance.

[0010] Another object of the present invention is to provide a method for preparing the above-mentioned dry suspension containing aspirin.

[0011] The technical solution of the present invention is as follows:

[0012] A dry suspension containing aspirin, wherein the dry suspension is prepared from the following components in parts by weight: 70-90 parts of aspirin, 10-30 parts of corn starch, 0.7-2.4 parts of ethyl cellulose, 0.15-0.65 parts of calcium carbonate, 1-3 parts of talcum powder, 15-30 parts of heavy magnesium carbonate, 7-15 parts of aluminum glycolate, 30-50 parts of mannitol, 0.1-1 parts of gelatin, 5-15 parts of xanthan gum, 0.5-2.5 parts of sucralose and 0.3-2 parts of flavor.

[0013] In the preparation process of the present invention, aspirin, corn starch and talcum powder are firstly mixed uniformly, and dry granulated to obtain aspirin particles, and the obtained aspirin particles are coated with a coating liquid made of ethyl cellulose, calcium carbonate and ethanol to prepare aspirin coated particles; heavy magnesium carbonate, aluminum glycolate and mannitol are then mixed uniformly, and wet granulated with gelatin as a binder to obtain aluminum-magnesium particles, which are then mixed uniformly again with aspirin coated particles, xanthan gum, sucralose and essence to obtain a dry suspension.

[0014] In the present invention, ethyl cellulose and calcium carbonate are used as coating powders, which are mixed with ethanol to form a coating liquid, and aspirin particles are coated. Due to the encapsulation effect of ethyl cellulose and calcium carbonate, aspirin is effectively isolated from aluminum glycolate and heavy magnesium carbonate, and unexpectedly obtains good stability; in addition, due to the protection of the isolation layer, an excellent taste masking effect is obtained at the same time. Calcium carbonate also has the effect of neutralizing gastric acid. After oral administration, calcium carbonate forms pores on the surface of aspirin coated particles under the action of gastric acid. When water enters, aspirin is quickly released under the disintegration effect of corn starch.

[0015] In the present invention, the flavor corrector is sucralose; the suspending agent is xanthan gum. After being suspended in water, xanthan gum increases the viscosity of the suspension and reduces the sensitivity of the taste buds. On the other hand, due to the encapsulation effect of ethyl cellulose, the bitterness of aspirin is masked, and an excellent taste masking effect is obtained. For the present invention, the ratio of calcium carbonate to ethyl cellulose and its particle size have a great influence on the dissolution of the active ingredient. If the ratio of calcium carbonate to ethyl cellulose is too low, the pore arrangement ratio of the encapsulation layer is small, and the release may be slow or incomplete; if the ratio is too high, the coating effect is affected, resulting in poor stability; if the calcium carbonate particle size is too large, the pores will form slowly, affecting the release; if the particle size is too small, it may also cause aspirin to be released too quickly, affecting the safety of use.

[0016] In a preferred embodiment, the particle size D90 of calcium carbonate is 100 μm to 300 μm, preferably 190 to 210 μm, and more preferably 198.4 μm.

[0017] In addition, the effect of xanthan gum and its particle size on the dissolution and taste of the active components cannot be ignored. If the suspending agent xanthan gum is not added to the formula, the obtained dry suspension particles will be completely precipitated and the taste will be poor. If the particle size of the xanthan gum is too large, the obtained dry suspension will not swell quickly and completely after suspension, which will affect the taste and sedimentation volume. If the amount of xanthan gum is too high, it will not be able to be suspended quickly after contacting water, and a large number of lumps will appear and cannot be dispersed, and high humidity conditions will make it easier to agglomerate. If the amount of xanthan gum is too low, the suspending effect will deteriorate and the taste will deteriorate. Therefore, in the present invention, the particle size D90 of the xanthan gum is controlled to be 50μm to 100μm; preferably, the particle size D90 of the xanthan gum is controlled to be 70μm to 90μm; more preferably, the xanthan gum is from CPKelco. Type 75, particle size D90 is 80.6μm.

[0018] In the present invention, aspirin, corn starch and talcum powder are firstly mixed uniformly, and dry granulation is adopted to obtain aspirin particles, and the obtained aspirin particles are coated in a fluidized bed with a coating liquid made of ethyl cellulose, calcium carbonate and ethanol to obtain aspirin coated particles; then heavy magnesium carbonate, aluminum glycolate and mannitol are mixed uniformly, and wet granulation is carried out with gelatin as a binder to obtain aluminum-magnesium particles.

[0019] In a preferred embodiment, during the preparation process, aspirin and corn starch are first mixed and sieved, and then talcum powder is added for dry granulation. The obtained granules are sized by a 0.6-1.0 mm aperture sieve to obtain aspirin granules; the obtained aspirin granules are coated with a coating liquid made of ethyl cellulose, calcium carbonate and ethanol to obtain aspirin coated granules. Then, heavy magnesium carbonate, aluminum glycolate and mannitol are mixed evenly, and gelatin is used as a binder for wet granulation. The obtained wet granules are dried and sized to obtain aluminum-magnesium granules. When drying, the obtained wet granules are dried to a moisture content of <1%.

[0020] In the present invention, the particle size of the two antacids, heavy magnesium carbonate and aluminum glycolate, has a great influence on the safety of the product. After oral administration, heavy magnesium carbonate and aluminum glycolate quickly form a gel protective layer under the action of gastric acid and adhere to the surface of the damaged mucosal layer. If the particle size is too large, the formation time of the gel protective layer is prolonged, and the protective effect on the stomach is weakened. Therefore, the particle size D90 of heavy magnesium carbonate is not higher than 50 μm, preferably not more than 30 μm, and more preferably 27.3 μm. The particle size D90 of aluminum glycolate is not higher than 50 μm, preferably not more than 30 μm, and more preferably 23.1 μm.

[0021] For the present invention, the binder used in the aluminum-magnesium particles is gelatin, which is derived from skin gelatin and has a gel strength greater than 400. Aluminum glycolate and heavy magnesium carbonate in the aluminum-magnesium particles are both inorganic mineral raw materials with poor molding properties and granulation effects. Gelatin is used as a binder, and the particles become hard after drying, which can greatly improve the fluidity of materials that are difficult to mold.

[0022] In a preferred embodiment, the dry suspension containing aspirin provided by the present invention is prepared from the following components in parts by weight: 80-85 parts of aspirin, 15-20 parts of corn starch, 1-3 parts of talc, 0.7-2.4 parts of ethyl cellulose, 0.2-0.6 parts of calcium carbonate, 20-25 parts of heavy magnesium carbonate, 9-12 parts of aluminum glycolate, 35-45 parts of mannitol, 0.3-0.8 parts of gelatin, 7-9 parts of xanthan gum, 1-2 parts of sucralose, and 0.6-1 parts of flavor.

[0023] In a more preferred embodiment, the dry suspension containing aspirin provided by the present invention is prepared from the following components in parts by weight: 81 parts of aspirin, 15-20 parts of corn starch, 1-3 parts of talc, 0.7-2.4 parts of ethyl cellulose, 0.2-0.6 parts of calcium carbonate, 22 parts of heavy magnesium carbonate, 11 parts of aluminum glycolate, 35-45 parts of mannitol, 0.3-0.8 parts of gelatin, 7-9 parts of xanthan gum, 1-2 parts of sucralose, and 0.6-1 parts of flavor.

[0024] In a particularly preferred embodiment, the dry suspension containing aspirin provided by the present invention is made of the following components in parts by weight:

[0025] 81 parts of aspirin, 18 parts of corn starch, 2 parts of talc, 1.8 parts of ethyl cellulose, 0.2 parts of calcium carbonate, 22 parts of heavy magnesium carbonate, 11 parts of aluminum glycolate, 40 parts of mannitol, 0.5 parts of gelatin, 8 parts of xanthan gum, 1.5 parts of sucralose, and 0.8 parts of flavor;

[0026] 81 parts of aspirin, 15 parts of corn starch, 1 part of talc, 0.7 parts of ethyl cellulose, 0.3 parts of calcium carbonate, 22 parts of heavy magnesium carbonate, 11 parts of aluminum glycolate, 35 parts of mannitol, 0.3 parts of gelatin, 7 parts of xanthan gum, 1 part of sucralose, and 0.6 parts of flavor;

[0027] 81 parts of aspirin, 20 parts of corn starch, 3 parts of talc, 2.4 parts of ethyl cellulose, 0.6 parts of calcium carbonate, 22 parts of heavy magnesium carbonate, 11 parts of aluminum glycolate, 45 parts of mannitol, 0.8 parts of gelatin, 9 parts of xanthan gum, 2 parts of sucralose, and 1 part of flavor.

[0028] The present invention also provides a method for preparing the above-mentioned dry suspension containing aspirin, which comprises the following steps:

[0029] (1) Preparation of aspirin granules: sieving aspirin; drying corn starch and sieving it; mixing the sifted aspirin, corn starch and talcum powder uniformly, performing dry granulation, and granulating to obtain aspirin granules;

[0030] (2) Aspirin coated particles: ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain a weight of 1 to 3%;

[0031] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried and granulated to obtain aluminum-magnesium particles;

[0032] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0033] In the present invention, in step (1), during the sieving process, the sieve is sieved through a 20-60 mesh sieve, preferably a 40 mesh sieve. During dry granulation, the obtained granules are sized through a 0.6-1.0 mm aperture sieve, preferably, sized through a 0.8 mm aperture sieve.

[0034] In the present invention, in step (2), the particle size D90 of calcium carbonate is 100 μm to 300 μm, preferably 190 to 210 μm, and more preferably 198.4 μm.

[0035] For the present invention, in step (3), the particle size D90 of heavy magnesium carbonate is not more than 50 μm, preferably not more than 30 μm, and more preferably 27.3 μm; the particle size D90 of aluminum glycolate is not more than 50 μm, preferably not more than 30 μm, and more preferably 23.1 μm.

[0036] In step (3), the obtained wet granules are dried until the moisture content is not higher than 1%; after drying, the granules are sieved using a 20-40 mesh sieve, preferably a 30 mesh sieve.

[0037] In the present invention, in step (4), the particle size D90 of xanthan gum is 50 μm to 100 μm, preferably 70 μm to 90 μm, more preferably CPKelco's Type 75, particle size D90 is 80.6μm.

[0038] Adopt the technical scheme of the present invention, the advantages are as follows:

[0039] (1) The dry suspension containing aspirin provided by the present invention, wherein the main component aspirin is used in combination with the acid-suppressing drugs aluminum glycolate and heavy magnesium carbonate, can protect the gastrointestinal mucosa. Compared with aspirin alone, the dry suspension of the present invention is absorbed faster, has a lighter irritation to the gastric mucosa, and has a more excellent clinical prospect.

[0040] (2) Before preparing aspirin granules, corn starch is dried to a moisture content of no more than 4%, and then uniformly mixed with aspirin and talcum powder for dry granulation. The obtained aspirin granules are fluidized-bed coated with a coating solution made of ethyl cellulose, calcium carbonate and ethanol to prepare aspirin coated granules. During the coating, ethanol is used as a solvent without introducing any additional moisture, so that the moisture content of the aspirin granules can be kept at a low level. In addition, due to the encapsulation effect of ethyl cellulose and calcium carbonate, aspirin is effectively isolated from aluminum glycolate and heavy magnesium carbonate, and surprisingly, excellent stability is obtained.

[0041] (3) The aspirin coated particles provided by the present invention have a good isolation effect of ethyl cellulose as a component in the coating solution, which, together with xanthan gum, can achieve an excellent taste masking effect and mouthfeel.

[0042] (4) The calcium carbonate in the coating layer of aspirin particles also has the function of neutralizing gastric acid. After oral administration, calcium carbonate forms pores on the surface of aspirin coated particles under the action of gastric acid. When water enters, aspirin is quickly released under the disintegration of corn starch.

[0043] (5) The dry suspension prepared by the method of the present invention has a simple preparation method and strong operability, can increase the content of effective substances in the dry suspension, reduce the total impurity content and the maximum single impurity content in the product, and increase the dissolution rate of the active component, thereby improving the bioavailability. It has good dissolution effect, stability, taste masking effect and compliance. Compared with existing dosage forms on the market, it is more suitable for the elderly and children, and has great clinical significance. DETAILED DESCRIPTION

[0044] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0045] Example 1

[0046] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 80.6 μm;

[0047]

[0048] The preparation method comprises the following steps:

[0049] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0050] (2) Aspirin coated particles: Ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain 2% in weight;

[0051] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0052] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0053] Example 2

[0054] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 80.6 μm;

[0055]

[0056] The preparation method comprises the following steps:

[0057] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0058] (2) Aspirin coated particles: Ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain 1% in weight;

[0059] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0060] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0061] Example 3

[0062] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 80.6 μm;

[0063]

[0064] The preparation method comprises the following steps:

[0065] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0066] (2) Aspirin coated particles: Ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain 1% in weight;

[0067] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0068] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0069] Comparative Example 1

[0070] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 80.6 μm;

[0071]

[0072] The preparation method comprises the following steps:

[0073] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0074] (2) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0075] (3) Total mixing: uniformly mixing the aspirin particles, aluminum-magnesium particles, xanthan gum, sucralose and essence in step (1) to obtain a dry suspension.

[0076] Comparative Example 2

[0077] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 80.6 μm;

[0078]

[0079] The preparation method comprises the following steps:

[0080] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0081] (2) Aspirin coated particles: Ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain 2% in weight;

[0082] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0083] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0084] Comparative Example 3

[0085] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 80.6 μm;

[0086]

[0087] The preparation method comprises the following steps:

[0088] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0089] (2) Aspirin coated particles: Ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain 2% in weight;

[0090] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0091] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0092] Comparative Example 4

[0093] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 80.6 μm;

[0094]

[0095] The preparation method comprises the following steps:

[0096] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0097] (2) Aspirin coated particles: Ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain 2% in weight;

[0098] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using hydroxypropyl cellulose as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0099] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0100] Comparative Example 5

[0101] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 80.6 μm;

[0102]

[0103]

[0104] The preparation method comprises the following steps:

[0105] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0106] (2) Aspirin coated particles: Ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain 2% in weight;

[0107] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0108] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0109] Comparative Example 6

[0110] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 80.6 μm;

[0111]

[0112] The preparation method comprises the following steps:

[0113] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0114] (2) Aspirin coated particles: Ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain 2% in weight;

[0115] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0116] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0117] Comparative Example 7

[0118] A dry suspension containing aspirin, wherein each 1000 dosage units are made of the following components by weight, wherein the particle size D90 of calcium carbonate is 198.4 μm, the particle size D90 of heavy magnesium carbonate is 27.3 μm, the particle size D90 of aluminum glycolate is 23.1 μm, and the model of xanthan gum is that of CPKelco 75, particle size D90 is 110.2 μm;

[0119]

[0120] The preparation method comprises the following steps:

[0121] (1) Preparation of aspirin granules: aspirin is sieved through a 40-mesh sieve; corn starch is dried to a moisture content of no more than 1% and sieved through a 40-mesh sieve; the sieved aspirin, corn starch and talcum powder are mixed evenly, and dry granulated using a dry granulator. The obtained granules are sieved through a 0.8 mm pore size sieve to obtain aspirin granules;

[0122] (2) Aspirin coated particles: Ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain 2% in weight;

[0123] (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried to a moisture content of no more than 1%, and granulated using a 30-mesh sieve to obtain aluminum-magnesium particles;

[0124] (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

[0125] Comparative Example 8

[0126] Aluminum-magnesium sheet (II) was prepared according to Example 1 in Chinese patent CN106727380A.

[0127] Effect verification:

[0128] 1. Testing the difference in filling amount, taste and sedimentation volume ratio between the examples and comparative examples

[0129] Table 1 Comparison of filling volume, taste and sedimentation volume in the examples

[0130]

[0131]

[0132] Note: According to the 2020 edition of the Chinese Pharmacopoeia, the operation is as follows: take the test sample, shake it vigorously to disperse the suspension evenly, quickly measure 50 ml with a stoppered measuring cylinder, stopper it, let it stand for 3 hours, and at the same time record the liquid level height H0 of the suspension and the final height H of the suspension, the sedimentation volume ratio = H / H0; the dissolution medium uses 0.1M hydrochloric acid, 900 ml.

[0133] Examples 1 to 3 are samples obtained by the formula and preparation method of the present invention, and the aluminum-magnesium particles have good fluidity and good quality of various indicators. The samples obtained by the formula and preparation method provided by the present invention have good particle fluidity, filling difference, mouthfeel, sedimentation volume ratio, dissolution and stability.

[0134] Table 2 Comparison of filling volume, taste and sedimentation volume in comparative examples 1

[0135]

[0136] Note: According to the 2020 edition of the Chinese Pharmacopoeia, the operation is as follows: take the test sample, shake it vigorously to disperse the suspension evenly, quickly measure 50 ml with a stoppered measuring cylinder, stopper it, let it stand for 3 hours, and at the same time record the liquid level height H0 of the suspension and the final height H of the suspension, the sedimentation volume ratio = H / H0; the dissolution medium uses 0.1M hydrochloric acid, 900 ml.

[0137] Table 3 Comparison of filling volume, taste and sedimentation volume in comparative examples 2

[0138]

[0139] Note: According to the 2020 edition of the Chinese Pharmacopoeia, the operation is as follows: take the test sample, shake it vigorously to disperse the suspension evenly, quickly measure 50 ml with a stoppered measuring cylinder, stopper it, let it stand for 3 hours, and at the same time record the liquid level height H0 of the suspension and the final height H of the suspension, the sedimentation volume ratio = H / H0; the dissolution medium uses 0.1M hydrochloric acid, 900 ml.

[0140] It can be seen from Tables 1-3 that the dry suspensions obtained in Examples 1-3 of the present invention have good particle fluidity and small differences in loading amounts, while Comparative Example 4 does not use gelatin as a binder for granulation, so the particle proportion is small, the fluidity is poor, and the loading amount difference is large.

[0141] The products in Examples 1-3 are uniform and delicate after suspension, have no bitter taste, have sweet taste, and the sedimentation volume ratio is close to 1.0, indicating that the dry suspension prepared according to the formula and method of the present invention is physically highly stable and basically does not settle; in Comparative Example 1, since the aspirin particles are not isolated and coated with ethyl cellulose and calcium carbonate, the bitterness cannot be masked and the taste is poor; in Comparative Example 3, since the amount of calcium carbonate is large, the film-forming effect when the isolation layer is coated is general, so the taste-masking effect is poor; in Comparative Example 5, since the amount of xanthan gum is large, it cannot be quickly suspended after encountering water, a large number of lumps appear, and it cannot be dispersed; in Comparative Example 6, since the amount of xanthan gum is small and the supporting force is insufficient, the drug solution is separated within 20 minutes after dispersion; in Comparative Example 7, since the xanthan gum particle size is large, the obtained dry suspension does not swell rapidly and completely after suspension, affecting the taste and sedimentation volume.

[0142] The products in Examples 1-3 are completely dissolved in the hydrochloric acid medium because the calcium carbonate in the isolation layer forms pores on the surface of the aspirin coated particles under the action of acid. When water enters, aspirin is rapidly released under the disintegration of corn starch; Comparative Example 2 does not contain calcium carbonate, so pores cannot be formed in hydrochloric acid, and water cannot enter, resulting in the inability to release aspirin; Comparative Example 5 has a serious agglomeration due to the excessive amount of xanthan gum added, which blocks the release of the drug.

[0143] The stability of the products in Examples 1-3 is good, because the encapsulation effect of ethyl cellulose and calcium carbonate effectively isolates aspirin from aluminum glycolate and heavy magnesium carbonate; in Comparative Example 1, because no isolation coating is applied, aspirin is continuously hydrolyzed to generate salicylic acid, which is very unstable; in Comparative Example 3, because a large amount of calcium carbonate is used, the coating film-forming property is poor during coating, and the coating effect is average, resulting in aspirin not being completely isolated from aluminum glycolate and heavy magnesium carbonate, and having poor stability; in Comparative Example 8, because the aspirin layer is wet granulated, the salicylic acid content on day 0 is high, and under the environment of 30°C and 65% RH, impurities grow rapidly, and the stability is poor.

[0144] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A dry suspension containing aspirin, characterized in that: The dry suspension is prepared from the following components in parts by weight: 70-90 parts of aspirin, 10-30 parts of corn starch, 0.7-2.4 parts of ethyl cellulose, 0.15-0.65 parts of calcium carbonate, 1-3 parts of talc, 15-30 parts of heavy magnesium carbonate, 7-15 parts of aluminum glycolate, 30-50 parts of mannitol, 0.1-1 parts of gelatin, 5-15 parts of xanthan gum, 0.5-2.5 parts of sucralose, and 0.3-2 parts of flavor.

2. The dry suspension containing aspirin according to claim 1, characterized in that In its preparation process, aspirin, corn starch and talcum powder are firstly mixed evenly, and dry granulated to obtain aspirin particles, and the obtained aspirin particles are coated with a coating liquid made of ethyl cellulose, calcium carbonate and ethanol to prepare aspirin coated particles; then heavy magnesium carbonate, aluminum glycolate and mannitol are mixed evenly, and wet granulated with gelatin as a binder to obtain aluminum-magnesium particles, which are mixed evenly again with the aspirin coated particles, xanthan gum, sucralose and essence to obtain a dry mixed suspension.

3. The dry suspension containing aspirin according to claim 2, characterized in that, The particle size D90 of the calcium carbonate is 100 μm to 300 μm, preferably 190 to 210 μm, and more preferably 198.4 μm; the particle size D90 of the heavy magnesium carbonate is not more than 50 μm, preferably not more than 30 μm, and more preferably 27.3 μm; the particle size D90 of the aluminum glycolate is not more than 50 μm, preferably not more than 30 μm, and more preferably 23.1 μm; the particle size D90 of the xanthan gum is 50 μm to 100 μm, preferably 70 μm to 90 μm, and more preferably CPKelco's Type 75, particle size D90 is 80.6μm.

4. The dry suspension containing aspirin according to claim 3, characterized in that The dry suspension is prepared from the following components in parts by weight: 80-85 parts of aspirin, 15-20 parts of corn starch, 1-3 parts of talc, 0.7-2.4 parts of ethyl cellulose, 0.2-0.6 parts of calcium carbonate, 20-25 parts of heavy magnesium carbonate, 9-12 parts of aluminum glycolate, 35-45 parts of mannitol, 0.3-0.8 parts of gelatin, 7-9 parts of xanthan gum, 1-2 parts of sucralose, and 0.6-1 parts of flavor.

5. The dry suspension containing aspirin according to claim 4, characterized in that: The dry suspension is prepared from the following components in parts by weight: 81 parts of aspirin, 15-20 parts of corn starch, 1-3 parts of talc, 0.7-2.4 parts of ethyl cellulose, 0.2-0.6 parts of calcium carbonate, 22 parts of heavy magnesium carbonate, 11 parts of aluminum glycolate, 35-45 parts of mannitol, 0.3-0.8 parts of gelatin, 7-9 parts of xanthan gum, 1-2 parts of sucralose, and 0.6-1 parts of flavor.

6. The dry suspension containing aspirin according to claim 5, characterized in that The dry suspension is made of the following components in parts by weight: 81 parts of aspirin, 18 parts of corn starch, 2 parts of talc, 1.8 parts of ethyl cellulose, 0.2 parts of calcium carbonate, 22 parts of heavy magnesium carbonate, 11 parts of aluminum glycolate, 40 parts of mannitol, 0.5 parts of gelatin, 8 parts of xanthan gum, 1.5 parts of sucralose, and 0.8 parts of flavor; 81 parts of aspirin, 15 parts of corn starch, 1 part of talc, 0.7 parts of ethyl cellulose, 0.3 parts of calcium carbonate, 22 parts of heavy magnesium carbonate, 11 parts of aluminum glycolate, 35 parts of mannitol, 0.3 parts of gelatin, 7 parts of xanthan gum, 1 part of sucralose, and 0.6 parts of flavor; 81 parts of aspirin, 20 parts of corn starch, 3 parts of talc, 2.4 parts of ethyl cellulose, 0.6 parts of calcium carbonate, 22 parts of heavy magnesium carbonate, 11 parts of aluminum glycolate, 45 parts of mannitol, 0.8 parts of gelatin, 9 parts of xanthan gum, 2 parts of sucralose, and 1 part of flavor.

7. The method for preparing the dry suspension containing aspirin according to claim 1, characterized in that: It includes the following steps: (1) Preparation of aspirin granules: sieving aspirin; drying corn starch and sieving it; mixing the sifted aspirin, corn starch and talcum powder uniformly, performing dry granulation, and granulating to obtain aspirin granules; (2) Aspirin coated particles: ethyl cellulose, calcium carbonate and ethanol are uniformly mixed to prepare a coating solution, and the aspirin particles obtained in step (1) are subjected to fluidized bed coating to prepare aspirin coated particles, wherein the coated particles gain a weight of 1 to 3%; (3) Preparation of aluminum-magnesium particles: heavy magnesium carbonate, aluminum glycolate and mannitol are uniformly mixed, and wet granulation is performed using gelatin as a binder. The obtained wet granules are dried and granulated to obtain aluminum-magnesium particles; (4) Total mixing: uniformly mixing the aspirin coated granules, aluminum-magnesium granules, xanthan gum, sucralose and essence in step (2) to obtain a dry suspension.

8. The method for preparing aspirin-containing dry suspension according to claim 7, characterized in that: In step (1), during the sieving process, the sieve is passed through a 20-60 mesh sieve, preferably a 40 mesh sieve; during the dry granulation process, the obtained granules are sized through a 0.6-1.0 mm aperture sieve, preferably, sized through a 0.8 mm aperture sieve; in step (3), the obtained wet granules are dried to a moisture content of no more than 1%; after drying, they are sized through a 20-40 mesh sieve, preferably a 30 mesh sieve.

9. The method for preparing aspirin-containing dry suspension according to claim 7, characterized in that: In step (2), the particle size D90 of the calcium carbonate is 100 μm to 300 μm, preferably 190 to 210 μm, and more preferably 198.4 μm; in step (3), the particle size D90 of the heavy magnesium carbonate is not more than 50 μm, preferably not more than 30 μm, and more preferably 27.3 μm; the particle size D90 of the aluminum glycolate is not more than 50 μm, preferably not more than 30 μm, and more preferably 23.1 μm; in step (4), the particle size D90 of the xanthan gum is 50 μm to 100 μm, preferably 70 μm to 90 μm, and more preferably CPKelco's Type 75, particle size D90 is 80.6μm.

10. The method for preparing aspirin-containing dry suspension according to claim 9, characterized in that: The dry suspension is prepared from the following components in parts by weight: 80-85 parts of aspirin, 15-20 parts of corn starch, 1-3 parts of talc, 0.7-2.4 parts of ethyl cellulose, 0.2-0.6 parts of calcium carbonate, 20-25 parts of heavy magnesium carbonate, 9-12 parts of aluminum glycolate, 35-45 parts of mannitol, 0.3-0.8 parts of gelatin, 7-9 parts of xanthan gum, 1-2 parts of sucralose, and 0.6-1 parts of flavor.

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