Method for preparing domperidone tablet through fluidized bed spraying process

Abstract

The invention provides a method for preparing domperidone tablets through a fluidized bed spraying process. The method comprises the following steps: preparing particles containing domperidone by using the fluidized bed spraying process; and tabletting the particles containing the domperidone to obtain the domperidone tablet. According to the domperidone tablet prepared through the preparation method, the comprehensive performance of the tablet is greatly improved, the prepared tablet has the advantages of being high in hardness, low in friability, high in in-vitro dissolution similarity, better in content uniformity and the like, the prepared tablet is more beneficial to packaging, storage and transportation, the production capacity is improved through the preparation method, the cost is saved, and the preparation method is suitable for industrial production. And production dust is reduced, and the method is more environment-friendly and better in application prospect.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and more particularly to a method for preparing domperidone tablets by a fluidized bed spray process. Background Art

[0002] Janssen Pharmaceuticals first launched domperidone in 1979 under the brand name Motilium in Switzerland and Germany. In 1981, domperidone tablets entered the European market and were soon introduced to the United States and other countries. In 1989, it entered China under the trade name Motilium. In 1996, domperidone tablets were approved by the U.S. Food and Drug Administration and became the first proton pump inhibitor on the U.S. market.

[0003] Domperidone is a synthetic phenylimidazole derivative, similar in structure to propyl methyl ketone phenyl. The oral bioavailability is 13% to 17%, and the elimination half-life is 7.5h (intravenous) and 13 to 16h (oral); the time for domperidone to reach the peak plasma concentration after oral administration is 30 minutes. Domperidone can selectively block dopamine 2 (DA2) receptors in the peripheral nervous system. Since DA2 receptors are also the main receptors in the gastrointestinal tract, they can reduce dopamine-mediated relaxation of gastric smooth muscle, thereby promoting gastric emptying, increasing gastric antrum and duodenal motility, coordinating pyloric contraction, and also enhancing esophageal peristalsis and the lower esophageal sphincter, inhibiting nausea and vomiting.

[0004] Granulation technology is the most critical technology in the preparation process of solid preparations. The material is formed into granular materials through granulation technology, so that it has good mixing uniformity, fluidity, filling property, and compressibility, which can achieve the effects of improving the appearance of the drug, reducing agglomeration, facilitating storage and transportation, controlling solubility, improving heat transfer, and ensuring the accurate dosage of the drug. At present, the granulation methods of tablets mainly include wet granulation, dry granulation, and spray granulation. At present, most of the domestic domperidone tablets adopt wet granulation technology. Chinese patent CN 115569121 B discloses a domperidone tablet and a preparation method thereof. The method is a wet granulation process. The tablets prepared by the method are slower in dissolution than the original research, which may affect the efficacy of the product; and the tablets prepared by the method have a low hardness, which is not conducive to the transportation and storage of the product. Chinese patent CN 109481410 A discloses a preparation method of domperidone tablets. The method is a wet granulation process. The tablets prepared by the method have a high friability, which is not conducive to packaging, transportation and storage. Summary of the invention

[0005] In response to the above technical problems, the present invention provides for the first time a method for preparing domperidone tablets by a fluidized bed spray process. Compared with traditional high-shear wet granulation, the tablets prepared by this method have high content uniformity, high hardness, low friability, and a dissolution behavior that is highly similar to that of a reference preparation. At the same time, this method can also improve production capacity, save manpower and material costs, reduce production dust, and be more environmentally friendly.

[0006] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0007] A method for preparing domperidone tablets by fluidized bed spraying process,

[0008] preparing granules containing domperidone by using a fluidized bed spray process, and compressing the granules containing domperidone to obtain domperidone tablets;

[0009] The conditions of the fluidized bed spray process are: the air inlet temperature is 50° C. to 70° C., the atomization pressure is 1 bar to 3 bar, and the particle moisture is controlled below 3.0%.

[0010] In the domperidone particles, the particle size D90 of domperidone is less than 40 μm; preferably, the particle size D90 of domperidone is less than 20 μm.

[0011] The weight percentages of the components in the domperidone tablets include 10% (w / w) of domperidone, 40% to 90% (w / w) of fillers, 2% to 4% (w / w) of disintegrants, 1% to 4% (w / w) of binders, 0.05% to 0.3% (w / w) of surfactants, and 0.5% to 2.0% (w / w) of lubricants.

[0012] The filler is one or more of lactose, sucrose, corn starch, pregelatinized starch, microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate dihydrate, preferably one or more of lactose, corn starch, and microcrystalline cellulose.

[0013] The disintegrant is one or more of pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinyl pyrrolidone, preferably pregelatinized starch.

[0014] The binder is one or more of povidone K90, povidone K30, sodium alginate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and starch, preferably one of povidone K90, sodium alginate, and hydroxypropyl cellulose, and more preferably povidone K90.

[0015] The surfactant is sodium lauryl sulfate or polysorbate 80. Sodium lauryl sulfate is preferred.

[0016] The lubricant is one or more of polyethylene glycol and magnesium lauryl sulfate, micro-powder silica gel, talcum powder, hydrogenated vegetable oil, and magnesium stearate, preferably one or more of hydrogenated vegetable oil and magnesium stearate.

[0017] The specific steps include:

[0018] S1, crushing domperidone;

[0019] S2, placing the domperidone treated in step S1 and the filler in a fluidized bed and mixing them evenly, spraying granulation with a binder solution and drying;

[0020] S3, after granulating the granules dried in step S2, adding an additional auxiliary material and mixing evenly, then adding a lubricant and mixing evenly to obtain granules containing domperidone;

[0021] S4. Compressing the granules containing domperidone into tablets to obtain domperidone tablets.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) The present invention uses a fluidized bed spray process for the first time and adopts specific process conditions to prepare domperidone tablets. The mixing, granulation and drying of conventional wet granulation are completed in the same equipment, which improves the production capacity, saves manpower and material costs, reduces production dust, and is more environmentally friendly.

[0024] (2) The particles prepared by the present invention have more uniform particle size, better fluidity and compression formability, and are more conducive to production, packaging, transportation and storage.

[0025] (3) The domperidone tablets prepared by the present invention have high content uniformity, high hardness, low friability, and a dissolution behavior that is highly similar to that of the reference preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the dissolution curve of the domperidone tablets of the present invention (pH 6.0). DETAILED DESCRIPTION

[0027] In order to more clearly understand the purpose, features and advantages of the present invention, the present invention is further described in detail below in conjunction with specific embodiments. It should be noted that the specific examples described here are only used to explain the present invention and are not used to limit the present invention.

[0028] Example 1

[0029] Prescribing Information:

[0030] name 5000 tablets prescription quantity (g) effect Domperidone 50.0 Active ingredients lactose 271.0 Fillers Corn starch 100.0 Fillers Pregelatinized starch 15.0 Disintegrants Povidone K90 7.50 Adhesives Sodium Lauryl Sulfate 0.75 Surfactants Microcrystalline Cellulose 50.0 Fillers Magnesium Stearate 3.0 Lubricants Hydrogenated vegetable oil 2.5 Lubricants

[0031] Preparation method:

[0032] (1) Pretreatment of raw materials and auxiliary materials: Domperidone was crushed to control its particle size D90 to be less than 20 μm; hydrogenated vegetable oil was sieved through an 80-mesh sieve and set aside.

[0033] (2) Ingredients: Weigh the above-prescribed amounts of domperidone, lactose, corn starch, povidone K90, sodium lauryl sulfate, microcrystalline cellulose, hydrogenated vegetable oil, and magnesium stearate.

[0034] (3) Preparation of adhesive: Sodium lauryl sulfate and povidone K90 were added to 142.5 g of purified water and stirred to dissolve to obtain an adhesive solution.

[0035] (4) Granulation: Add lactose, domperidone, pregelatinized starch and corn starch into a fluidized bed and mix evenly; add the binder solution by top spraying, set the air inlet temperature to 60°C and the air volume to 20-50m 3 / h (adjusted in real time according to the material height), the atomization pressure is 2 bar, and spray granulation is performed; after granulation, the inlet air temperature is set to 60°C and the air volume is 40m 3 / h, and drying is performed until the moisture content is less than 3.0% to obtain dry granules.

[0036] (5) Granulation: Granulation was performed using a pulverizer with a conical sieve having a diameter of 1.2 mm.

[0037] (6) Total mixing: Add the granulated granules and microcrystalline cellulose into a mixer and mix them evenly; then add hydrogenated vegetable oil and magnesium stearate and mix them evenly.

[0038] (7) Tabletting: Tablets are pressed using a rotary tablet press. Tablets are pressed according to 100 mg. The weight difference is controlled within ±5.0% and the hardness is controlled within 30 to 80 N.

[0039] Example 2

[0040] Prescribing Information:

[0041] name 5000 tablets prescription quantity (g) effect Domperidone 50.0 Active ingredients lactose 271.0 Fillers Corn starch 100.0 Fillers Pregelatinized starch 15.0 Disintegrants Hydroxypropylcellulose 7.50 Adhesives Sodium Lauryl Sulfate 0.75 Surfactants Microcrystalline Cellulose 50.0 Fillers Magnesium Stearate 3.0 Lubricants Hydrogenated vegetable oil 2.5 Lubricants

[0042] Preparation method:

[0043] (1) Pretreatment of raw materials and auxiliary materials: Domperidone was crushed to control its particle size D90 to be less than 20 μm; hydrogenated vegetable oil was sieved through an 80-mesh sieve and set aside.

[0044] (2) Ingredients: Weigh the above-prescribed amounts of domperidone, lactose, corn starch, hydroxypropyl cellulose, sodium lauryl sulfate, microcrystalline cellulose, hydrogenated vegetable oil, and magnesium stearate.

[0045] (3) Preparation of adhesive: Sodium lauryl sulfate and hydroxypropyl cellulose were added to 142.5 g of purified water and stirred to dissolve to obtain an adhesive solution.

[0046] (4) Granulation: Add lactose, domperidone, pregelatinized starch and corn starch into a fluidized bed and mix evenly; add the binder solution by top spraying, set the air inlet temperature to 60°C and the air volume to 20-50m 3 / h (adjusted in real time according to the material height), the atomization pressure is 2 bar, and spray granulation is performed; after granulation, the inlet air temperature is set to 60°C and the air volume is 40m 3 / h, and drying is performed until the moisture content is less than 3.0% to obtain dry granules.

[0047] (5) Granulation: Granulation was performed using a pulverizer with a conical sieve having a diameter of 1.2 mm.

[0048] (6) Total mixing: Add the granulated granules and microcrystalline cellulose into a mixer and mix them evenly; then add hydrogenated vegetable oil and magnesium stearate and mix them evenly.

[0049] (7) Tabletting: Tablets are pressed using a rotary tablet press. Tablets are pressed according to 100 mg. The weight difference is controlled within ±5.0% and the hardness is controlled within 30 to 80 N.

[0050] Example 3

[0051] Prescribing Information:

[0052] name 5000 tablets prescription quantity (g) effect Domperidone 50.0 Active ingredients lactose 277.75 Fillers Corn starch 100.0 Fillers Pregelatinized starch 15.0 Disintegrants Sodium alginate 0.75 Adhesives Sodium Lauryl Sulfate 0.75 Surfactants Microcrystalline Cellulose 50.0 Fillers Magnesium Stearate 3.0 Lubricants Hydrogenated vegetable oil 2.5 Lubricants

[0053] Preparation method:

[0054] (1) Pretreatment of raw materials and auxiliary materials: domperidone was crushed to control its particle size D90 to be less than 20 μm; hydrogenated vegetable oil was sieved through an 80-mesh sieve and set aside.

[0055] (2) Ingredients: Weigh the above-prescribed amounts of domperidone, lactose, corn starch, sodium alginate, sodium lauryl sulfate, microcrystalline cellulose, hydrogenated vegetable oil, and magnesium stearate.

[0056] (3) Preparation of adhesive: Sodium lauryl sulfate and sodium alginate were added to 149.25 g of purified water and stirred to dissolve to obtain an adhesive solution.

[0057] (4) Granulation: Add lactose, domperidone, pregelatinized starch and corn starch into a fluidized bed and mix them evenly; add the binder solution by top spraying, set the air inlet temperature to 60°C and the air volume to 20-50m 3 / h (adjusted in real time according to the material height), the atomization pressure is 2 bar, and the spray granulation is completed. After the granulation is completed, the inlet air temperature is set to 60 ° C and the air volume is 40m3 / h, and drying is performed until the moisture content is less than 3.0% to obtain dry granules.

[0058] (5) Granulation Granulation was performed using a pulverizer with a conical screen having a diameter of 1.2 mm.

[0059] (6) Total mixing: Add the granulated granules and microcrystalline cellulose into a mixer and mix them evenly; then add hydrogenated vegetable oil and magnesium stearate and mix them evenly.

[0060] (7) Tabletting: Tablets are pressed using a rotary tablet press. Tablets are pressed according to 100 mg. The weight difference is controlled within ±5.0% and the hardness is controlled within 30 to 80 N.

[0061] Comparative Example 1

[0062] The prescription is the same as that of Example 1.

[0063] Preparation method:

[0064] (1) Pretreatment of raw materials and auxiliary materials: domperidone was crushed to control its particle size D90 to be less than 20 μm; hydrogenated vegetable oil was sieved through an 80-mesh sieve and set aside.

[0065] (2) Ingredients: Weigh the above-prescribed amounts of domperidone, lactose, corn starch, povidone K90, sodium lauryl sulfate, microcrystalline cellulose, hydrogenated vegetable oil, and magnesium stearate.

[0066] (3) Preparation of adhesive: Sodium lauryl sulfate and povidone K90 were added to 86.25 g of purified water and stirred to dissolve to obtain an adhesive solution.

[0067] (4) Granulation: lactose, domperidone, pregelatinized starch and corn starch were added into a wet mixing granulator and mixed evenly; a binder solution was added for granulation, and after completion, the granules were sieved through a conical sieve with a diameter of 2.5 mm for granulation.

[0068] (5) Drying: Add the wet granules to the fluidized bed and set the air inlet temperature to 60°C and the air volume to 40m 3 / h, and drying is performed until the moisture content is less than 3.0% to obtain dry granules.

[0069] (6) Granulation: Granulation was performed using a pulverizer with a conical screen having a diameter of 1.2 mm.

[0070] (7) Total mixing: Add the granulated granules and microcrystalline cellulose into a mixer and mix them evenly; then add hydrogenated vegetable oil and magnesium stearate and mix them evenly.

[0071] (8) Tabletting: Tablets are pressed using a rotary tablet press. Tablets are pressed according to 100 mg. The weight difference is controlled within ±5.0% and the hardness is controlled within 30 to 80 N.

[0072] The hardness, friability and content uniformity of the samples prepared in Example 1, Example 2, Example 3 and Comparative Example 1 were tested respectively. The testing method was based on the Chinese Pharmacopoeia. The specific results are shown in Table 1.

[0073] Table 1 Domperidone tablets test results

[0074]

[0075] It can be seen from the measurement results in Table 1 that the domperidone tablets prepared by the preparation method of the embodiment of the present invention have higher hardness, lower friability and better content uniformity compared with the traditional high shear wet granulation.

[0076] Dissolution determination: refer to the dissolution and release determination method of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, 900ml of pH 6.0 phosphate buffer was used as the dissolution medium, and the paddle method was used at 50r / min. The dissolution solution was taken at different time points, and the content of the subsequent filtrate was detected by HPLC to draw the dissolution curve. The dissolution curves of Example 1, Example 2, Example 3, Comparative Example 1 and the national recommended reference preparation (Xi'an Janssen Pharmaceutical Co., Ltd., approval number: National Medicine Standard H10910003) were respectively detected and compared. The test results are shown in Table 2 and Figure 1 shown.

[0077] Table 2 Dissolution results of domperidone tablets

[0078]

[0079] From Table 2 and Figure 1 It can be seen from the data that, compared with Comparative Example 1, the dissolution behaviors of Example 1, Example 2, and Example 3 are more similar to the reference preparation.

[0080] Examples 4-7 and Comparative Examples 2-5

[0081] The formulation composition information of Examples 4-7 and Comparative Examples 2-5 is the same as that of Example 1.

[0082] Except for the granulation process of Examples 4-7 and Comparative Examples 2-5, which is different from that of Example 1, the preparation processes of other steps are the same as those of Example 1, which will not be repeated here. The granulation process parameters of Examples 4-7 and Comparative Examples 2-5 are shown in Table 3.

[0083] Table 3 Summary of spray granulation parameters

[0084]

[0085] The preparation processes of Example 1, Examples 4-7 and Comparative Examples 2-5 and the powder properties of the total mixed particles are recorded respectively, as shown in Table 4.

[0086] Table 4 Summary of spray granulation results

[0087]

[0088] It can be seen from Table 4 that the particles prepared by the spray granulation parameters provided in the embodiment of the present invention are more uniform, the preparation process is good, the particles have a small angle of repose and better fluidity.

[0089] In summary, the spray drying granulation process of the present invention can effectively improve the uniformity and fluidity of the particles, which is beneficial to subsequent tableting; the domperidone tablets prepared by the present invention have high hardness and good brittleness, which is beneficial to product packaging, transportation and storage; and the domperidone tablets prepared by the present invention have better content uniformity and higher dissolution curve similarity, thereby improving product quality.

[0090] The above description is only a preferred embodiment of the present invention and cannot limit the scope of the present invention. The present invention can also be subjected to various changes and variations. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A method for preparing domperidone tablets by fluidized bed spraying process, characterized in that: preparing granules containing domperidone by using a fluidized bed spray process, and compressing the granules containing domperidone to obtain domperidone tablets; The conditions of the fluidized bed spray process are: the air inlet temperature is 50° C. to 70° C., the atomization pressure is 1 bar to 3 bar, and the particle moisture is controlled below 3.0%.

2. The method for preparing domperidone tablets by fluidized bed spraying process according to claim 1, characterized in that: In the domperidone particles, the particle size D90 of domperidone is less than 40 μm.

3. The method for preparing domperidone tablets by fluidized bed spraying process according to claim 1, characterized in that: The weight percentages of the components in the domperidone tablets include 10% (w / w) of domperidone, 40% to 90% (w / w) of fillers, 2% to 4% (w / w) of disintegrants, 1% to 4% (w / w) of binders, 0.05% to 0.3% (w / w) of surfactants, and 0.5% to 2.0% (w / w) of lubricants.

4. The method for preparing domperidone tablets by fluidized bed spraying process according to claim 3, characterized in that: The filler is one or more of lactose, sucrose, corn starch, pregelatinized starch, microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate dihydrate.

5. The method for preparing domperidone tablets by fluidized bed spraying process according to claim 3, characterized in that: The disintegrant is one or more of pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinyl pyrrolidone.

6. The method for preparing domperidone tablets by fluidized bed spraying process according to claim 3, characterized in that: The binder is one or more of povidone K90, povidone K30, sodium alginate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and starch.

7. The method for preparing domperidone tablets by fluidized bed spraying process according to claim 3, characterized in that: The surfactant is sodium lauryl sulfate or polysorbate 80.

8. The method for preparing domperidone tablets by fluidized bed spraying process according to claim 3, characterized in that: The lubricant is one or more of polyethylene glycol, magnesium lauryl sulfate, micro powder silica gel, talcum powder, hydrogenated vegetable oil, and magnesium stearate.

9. The method for preparing domperidone tablets by fluidized bed spraying process according to claim 1, characterized in that: The following steps are included: S1, crushing domperidone; S2, placing the domperidone treated in step S1 and the filler in a fluidized bed and mixing them evenly, spraying granulation with a binder solution and drying; S3, after granulating the granules dried in step S2, adding an additional auxiliary material and mixing evenly, then adding a lubricant and mixing evenly to obtain granules containing domperidone; S4. Compressing the granules containing domperidone into tablets to obtain domperidone tablets.

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