Magnesium citrate sustained-release pellets and a method for preparing the same

Abstract

The present application discloses a kind of magnesium citrate sustained-release pellets and a preparation method thereof, the magnesium citrate sustained-release pellets can control the release degree of magnesium in the stomach, and improve the bioavailability.Single magnesium citrate sustained-release pellets are developed, and compound magnesium citrate and magnesium oxide sustained-release pellets are a combination of multiple units, have the function of controlling release in the stomach, are not affected by food rhythm, are suitable for old people and children, improve compliance, overcome the adverse reactions caused by granules and tablets.The magnesium citrate and magnesium oxide pellet dosage form has not been seen at home and abroad, and is the first at home and abroad.

Description

TECHNICAL FIELD

[0001] The present application relates to the health food, pharmaceutical technology field, specifically relates to a single compound magnesium citrate sustained-release pellet or compound magnesium citrate magnesium oxide sustained-release pellet and a preparation method thereof. BACKGROUND

[0002] Magnesium citrate is also called magnesium citrate nonahydrate, and its molecular formula is C 12 H 28 Mg3O 23 It is white granules or crystalline powder, soluble in dilute acid, slightly soluble in water and alcohol. The magnesium content in magnesium citrate is very low, and the magnesium content is only 11.89%; Magnesium oxide is a white solid at room temperature, almost insoluble in water or ethanol, and soluble in dilute acid, which is a non-chelated ionic compound, so it is not easy to be absorbed and metabolized by the human body. The absorption rate of pure magnesium oxide in the human body is only 4%, but the magnesium content is as high as 60.31%.

[0003] According to the results published in the journal BMC Bioinformatics, researchers have detected 3751 magnesium binding sites on human proteins. Although the magnesium content in magnesium citrate is low, its absorption rate is significantly higher than that of magnesium oxide, and its water-soluble rate is as high as 55%, and its bioavailability is high. Its function and effect have the prevention of kidney stones, the treatment of osteoporosis, children's picky eating, and developmental retardation. There are many types of magnesium oxide, mainly food grade, medical grade, and feed grade. Although the magnesium content in the above magnesium oxide sources is high, it is not easy to be absorbed by the human body, and the bioavailability is low. The function and effect of magnesium oxide in the human body are ① treatment of constipation - the low absorption rate of magnesium oxide makes it have strong laxative properties, which helps to promote defecation. ② Treatment of gastric acid reflux - magnesium oxide can be used as an antacid to help alleviate the symptoms of gastric acid reflux. ③ Solve indigestion - like gastric acid reflux, indigestion is also caused by excessive stomach acid, and magnesium oxide can neutralize excess acid. The compound pellet of magnesium citrate and magnesium oxide has a coordinating effect in terms of efficacy, not only can it have some of the effects of pure magnesium oxide, but also can improve the absorption rate of magnesium elements in the human body, and play a magnesium element supplementing effect.

[0004] The common magnesium citrate dosage form in the market is powder and granule; the magnesium oxide preparation is magnesium milk, magnesium cover tablet and antacid agent. However, there is no sustained-release pellet preparation containing magnesium citrate and magnesium oxide in the market. The tablet disintegrates in half an hour, has low bioavailability in the stomach, and has a large volume, which is not easy to be swallowed by children and coma patients. The pellet has the characteristics of small volume and large surface area, can be rapidly and uniformly dispersed in the gastrointestinal tract after being taken, can rapidly increase the concentration of magnesium element in the gastrointestinal tract to the target concentration, has high bioavailability, and can reduce local irritation. Since the magnesium citrate pellets are uniformly distributed in the human body, the influence of food rhythm can be greatly reduced. Moreover, the product is a sustained-release pellet, which can reduce the frequency of taking medicine for patients, can make the blood magnesium concentration stable and continuous, and has small side effects. Magnesium citrate can be simply decomposed into magnesium carbonate and citric acid, and magnesium oxide can react with magnesium carbonate, and the two are complementary. The formula of magnesium citrate and magnesium oxide has a synergistic effect. Therefore, the bioavailability of magnesium can be increased when the two coexist, and the physiological needs of the human body can be met.

[0005] Most of the magnesium supplement products on the market at home and abroad are injections or ordinary tablets. Magnesium is mainly absorbed in the jejunum and ileum in the human body, and part of it is also absorbed in the colon. Therefore, the best absorption of magnesium is in the jejunum and ileum. The sustained-release magnesium citrate pellets developed by the patent can maximize the transportation of magnesium citrate to the jejunum for release, which is beneficial to the absorption of magnesium element. The sustained-release magnesium citrate and magnesium oxide compound pellets have the advantages of small gastric irritation, better absorption and long-term stable maintenance of blood magnesium concentration. The sustained-release magnesium citrate pellets are internationally innovative. SUMMARY

[0006] The object of the present application is to provide a sustained-release magnesium citrate pellet which can maximize the transportation of magnesium citrate to the jejunum for release.

[0007] To achieve the above object, the present application adopts the following technical solutions:

[0008] In the first aspect, the present application provides a sustained-release magnesium citrate pellet, which comprises a magnesium citrate core and a coating, and the mass of the coating is 2-4% of the mass of the magnesium citrate core.

[0009] Based on the magnesium citrate core, the magnesium citrate core is mainly made of the following mass parts of raw materials: 65-90 mass parts of magnesium citrate and 10-35 mass parts of microcrystalline cellulose.

[0010] The coating is a polyacrylic resin coating or is made of the following mass parts of each raw material: 2-6 mass parts of a sustained-release coating material, 0.06-0.15 mass parts of triethyl citrate and 0.08-0.15 mass parts of talc; the sustained-release coating material is ethyl cellulose or shellac (preferably ethyl cellulose).

[0011] The coating is a polyacrylic resin coating, which is made of a polyacrylic resin water dispersion coating premix, and the polyacrylic resin water dispersion coating premix is from Lianyungang Wanta Pharmaceutical Auxiliary Material Co., Ltd.

[0012] Preferably, the mass of the coating is 3% of the mass of the magnesium citrate inner core.

[0013] Further, the magnesium citrate sustained-release pellet is composed of a magnesium citrate inner core and a coating, and the mass of the coating is 3-4% of the mass of the magnesium citrate inner core.

[0014] Based on the magnesium citrate inner core, the magnesium citrate inner core is made of the following mass parts of each raw material: 65-90 mass parts of magnesium citrate and 10-35 mass parts of microcrystalline cellulose.

[0015] The coating is a polyacrylic resin coating or is made of the following mass parts of each raw material: 2-7 mass parts of a sustained-release coating material, 0.06-0.15 mass parts of triethyl citrate and 0.08-0.15 mass parts of talc; the sustained-release coating material is ethyl cellulose or shellac.

[0016] Further, the magnesium citrate inner core further includes a magnesium oxide layer, which is in contact with the coating, and the magnesium oxide layer is 0.01-36% of the total mass of the magnesium citrate inner core; based on the magnesium oxide layer, the magnesium oxide layer is made of the following mass parts of each raw material: 8-18 mass parts of magnesium oxide, 9.2-11 mass parts of microcrystalline cellulose, 0.5-10 mass parts of a binder.

[0017] In an embodiment of the present application, the binder is polyvinylpyrrolidone-K30.

[0018] In an embodiment of the present application, the magnesium oxide layer is 18-36% of the total mass of the magnesium citrate inner core and the intermediate layer of magnesium oxide. However, it should be understood that the intermediate layer can be 0, and as long as it is less than 36%, it does not affect the sustained-release effect.

[0019] Further, in the above-mentioned single (magnesium citrate) or compound (magnesium citrate) prescription, the magnesium citrate inner core further includes 1-4 mass parts of a pellet core with a particle size of 0.106-0.35 mm, which is one of microcrystalline cellulose pellet core, starch pellet core, sugar pellet, silicon dioxide pellet core or a mixture of two of them.

[0020] Still further, the magnesium citrate inner core not only has a core, but also comprises a magnesium oxide layer, the magnesium oxide layer is in contact with the coating, the magnesium oxide layer is 0.01-36% of the total mass of the magnesium citrate inner core; based on the magnesium oxide layer, the magnesium oxide intermediate layer is made of the following mass parts of each raw material: 8-18 mass parts of magnesium oxide, 9.2-11 mass parts of microcrystalline cellulose, 0.5-10 binder.

[0021] In a second aspect, the present application provides a preparation method of the above-mentioned magnesium citrate sustained-release pellet, the method comprising the following steps:

[0022] S1: Preparation of the magnesium citrate inner core:

[0023] Mix the magnesium citrate and the microcrystalline cellulose in the formula amount uniformly to obtain a mixed powder A; put the mixed powder A into a centrifugal granulator to granulate with water as a binder to obtain the magnesium citrate inner core A;

[0024] When the magnesium citrate inner core further comprises a core, it is prepared by the following method: mix the magnesium citrate and the microcrystalline cellulose in the formula amount uniformly to obtain a mixed powder B; put the core in the formula amount into a centrifugal granulator, wet it with purified water as a wetting agent, and granulate it with the mixed powder B to obtain the magnesium citrate inner core B;

[0025] If the magnesium citrate inner core further comprises a magnesium oxide layer, it is further prepared by the following method: take the magnesium oxide and the microcrystalline cellulose in the formula amount, mix them uniformly to obtain a mixed powder C; put the magnesium citrate inner core A or the magnesium citrate inner core B in the formula amount into a centrifugal granulator, add the binder in the formula amount to the magnesium citrate inner core A or the magnesium citrate inner core B by atomization with a spray gun, and add the mixed powder C to obtain the magnesium citrate inner core C; the binder is added in the form of an ethanol solution of the binder;

[0026] S2: uniformly disperse the polyacrylic acid resin water dispersion coating premix in water to obtain a coating liquid A;

[0027] Disperse the sustained-release coating material, triethyl citrate and talc powder in the formula amount uniformly in ethanol to obtain a coating liquid B;

[0028] Put the magnesium citrate inner core A, the magnesium citrate inner core B or the magnesium citrate inner core C in step S1 into a multifunctional coating machine, perform atomization coating with the coating liquid A or the coating liquid B, and discharge to obtain the magnesium citrate sustained-release pellet.

[0029] Specifically, the method comprises the following steps:

[0030] S1: Preparation of the magnesium citrate inner core:

[0031] Mixing the magnesium citrate and microcrystalline cellulose in a uniform manner to obtain a mixed powder A; put 1 / 4 of the mixed powder A into a centrifugal granulator, open the air blower, control the air volume at 10-15 HZ, control the air pressure at 0.2-0.7 MPa, use purified water as the binder to prepare the master batch, control the spraying speed at 20-150 r / min; when the 100-250 μm particles appear, continue to supply 1 / 4 of the mixed powder A, stop spraying, discharge, sieve to obtain the magnesium citrate master batch; put the magnesium citrate master batch into the centrifugal granulator, use purified water as the binder, control the spraying speed at 50-200 r / min, add the remaining mixed powder A (2 / 4), close the spraying system, discharge, dry, sieve to obtain the magnesium citrate inner core A;

[0032] When the magnesium citrate inner core further comprises a pellet core, it is prepared in the following manner: mix the magnesium citrate and microcrystalline cellulose in a uniform manner to obtain a mixed powder B; open the air blower, control the air volume at 10-20 HZ, control the air pressure at 0.2-0.7 MPa, put the pellet core of the formula amount, use purified water as the wetting agent, use a peristaltic pump to atomize the purified water through a spray gun to make the surface of the pellet core granulated, then add the mixed powder B, control the spraying speed at 50-200 r / min, after the addition of the mixed powder B is completed, close the liquid spraying system, discharge, dry, sieve to obtain the magnesium citrate inner core B;

[0033] The above sieving can set the screen size according to the requirements to sieve the inner core of the required particle size. Generally, in the preparation of the inner core A, the particle size of the master batch is 0.2-0.355 mm, and the particle size of the magnesium citrate inner core A is 0.8-0.9 mm. The particle size of the magnesium citrate inner core B is also 0.8-0.9 mm.

[0034] If the magnesium citrate inner core further comprises a magnesium oxide layer, it is further prepared in the following manner: take the magnesium oxide and microcrystalline cellulose of the formula amount, mix them uniformly to obtain a mixed powder C; put the magnesium citrate inner core A or the magnesium citrate inner core B of the formula amount into a centrifugal granulator, use a peristaltic pump to atomize the binder of the formula amount through a spray gun and add it to the magnesium citrate inner core A or the magnesium citrate inner core B, add the mixed powder C to obtain the magnesium citrate inner core C; the binder is added in the form of an ethanol solution of the binder;

[0035] Those skilled in the art know that if the ethanol does not evaporate in time, it can be further dried by using a boiling dryer.

[0036] Disperse the sustained-release coating material, triethyl citrate and talc powder of the formula amount uniformly in ethanol to obtain a coating liquid B;

[0037] Put the magnesium citrate inner core A, magnesium citrate inner core B or magnesium citrate inner core C in step S1 into a multifunctional coating machine, and the coating liquid A or coating liquid B is atomized and coated by a spray gun through a peristaltic pump, the air inlet temperature is 90℃, the material temperature is 45±5℃, the spraying speed is controlled at 5-140r / min, when the coating weight increases by 3%, the material is discharged, and the magnesium citrate sustained-release pellets are obtained.

[0038] The person skilled in the art knows that further drying can be carried out if ethanol or water does not evaporate in time.

[0039] In the embodiments of the present application, the concentration of the ethanol solution of the adhesive in step S1 is 1wt%.

[0040] The above letters A, B are only used to distinguish the materials at different stages and have no special meaning.

[0041] Through in-depth analysis of the physical and chemical properties of magnesium citrate and the absorption characteristics of magnesium in the human body, and taking dissolution as an index, scientific formula design is carried out: 1. Single magnesium citrate is made into sustained-release pellets, 2. Magnesium citrate and magnesium oxide are compounded to make sustained-release pellets. The pellets are made by centrifugal granulator, and the single magnesium citrate sustained-release pellets are obtained by coating. Magnesium citrate and magnesium oxide are combined to make magnesium citrate magnesium oxide compound sustained-release pellets. The invention team researched starch, compressible starch, pregelatinized starch, dextrin, hydroxypropyl methyl cellulose, microcrystalline cellulose, lactose, sucrose, silicon dioxide and other excipients. The formula optimization research was carried out on ethyl cellulose, gelatin, carrageenan, xanthan gum, povidone, polyvinyl pyrrolidone-K30, cross-linked povidone and other adhesives. And the starch pellet core, sugar pellet, microcrystalline cellulose pellet core, silicon dioxide pellet core were researched, and the compatibility test research was carried out on the above excipients and adhesives. Further, the release material; hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose, polyacrylic acid resin, shellac, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, polyacrylic acid resin water dispersion, triethyl citrate, talc, silicon dioxide and other coating materials were optimized, and the release rate was detected. The detection results optimize the weight percentage of excipients, adhesives and coating materials, among which the weight percentage of magnesium citrate is 65-90%, the weight percentage of magnesium oxide is 8-18%, the weight percentage of microcrystalline cellulose is 5-40%, the weight percentage of polyvinyl pyrrolidone-K30 is 0.5-10%, the weight percentage of ethyl cellulose is 2-5.5%, the weight percentage of triethyl citrate is 0.06-0.1%, the weight percentage of talc is 0.12-0.15%. The weight percentage of the pellet core is 1-5%. The weight percentage of purified water is 8-18%.

[0042] Preparation of single magnesium citrate pill; magnesium citrate, microcrystalline cellulose are weighed according to the formula, and then uniformly mixed after superfine crushing (mixed powder). The mixed powder is placed in a centrifugal granulator, purified water is used as a binder to make a master batch, and the master batch is continuously granulated with purified water as a binder in a centrifugal granulator to make magnesium citrate pills;

[0043] Preparation of compound magnesium citrate; magnesium citrate pills are added in a centrifugal granulator, magnesium oxide and microcrystalline cellulose are weighed according to the formula, and then uniformly mixed after superfine crushing (mixed powder). Polyvinylpyrrolidone-K30 is used as a binder to make compound magnesium citrate and magnesium oxide pills.

[0044] Starch pill cores, sugar pills, microcrystalline cellulose pill cores, and silicon dioxide pill cores can also be used as master batches to make magnesium citrate pills by adding mixed powder. Magnesium citrate pills are obtained,

[0045] Single magnesium citrate pills and compound magnesium citrate pills are dried using a fluidized bed dryer at a temperature of 100°C for 1-2 hours to obtain magnesium citrate and magnesium oxide pills, which are then tested for content and moisture.

[0046] Single magnesium citrate pills are coated; ethyl cellulose, triethyl citrate, and talc are weighed according to the proportion, and an ethanol solution is prepared as a coating solution. Magnesium citrate pills are coated in a multifunctional fluidized bed, and the coating solution is delivered by a peristaltic pump and atomized by a spray gun for sustained-release coating with a weight gain of 3%. After coating, the pills are dried at 45°C for 1 hour. The magnesium citrate sustained-release pills are obtained, and the content, moisture, and release rate are tested.

[0047] The coating process of compound magnesium citrate and magnesium oxide pills refers to the process of single magnesium citrate sustained-release pills to produce compound magnesium citrate and magnesium oxide sustained-release pills.

[0048] Magnesium citrate pills and compound magnesium citrate and magnesium oxide pills can use sugar pills, starch pill cores, microcrystalline cellulose pill cores, and silicon dioxide pill cores instead of magnesium citrate master batches. The process of making magnesium citrate master batches is omitted, making the production of magnesium citrate pills simple, time-saving, and labor-saving. The specific method is as follows: magnesium citrate and microcrystalline cellulose are weighed according to the proportion, and then uniformly mixed after superfine crushing (mixed powder). Starch pill cores are added as master batches in a centrifugal granulator, and purified water is used as a binder to granulate by adding mixed powder. The granules are dried using a fluidized bed dryer at a temperature of 100°C for 1-2 hours. After sieving, single magnesium citrate pills are obtained.

[0049] The preparation of compound magnesium citrate and magnesium oxide pills can refer to the process of single magnesium citrate pills. The pill cores can be starch pill cores, sugar pills, microcrystalline cellulose pill cores, and silicon dioxide pill cores. This simplifies the process of making single and compound magnesium citrate pills.

[0050] Single magnesium citrate pills, compound magnesium citrate and magnesium oxide pills are coated; ethyl cellulose, triethyl citrate and talc are weighed according to the proportion, and an alcohol solution is prepared to form a coating solution. The compound magnesium citrate and magnesium oxide pills are coated in a multifunctional fluidized bed, and the coating liquid is delivered by a peristaltic pump and atomized by a spray gun to perform sustained-release coating. The coating weight is increased by 3%; the compound magnesium citrate and magnesium oxide sustained-release pills are obtained after coating, and the content, moisture and release rate are detected;

[0051] The single and compound magnesium citrate master granules can be prepared by using sugar pill cores, microcrystalline cellulose pill cores, starch pill cores, silicon dioxide pill cores or a combination of the two.

[0052] The single and compound magnesium citrate and magnesium oxide sustained-release coating materials are ethyl cellulose, shellac, polyacrylic acid resin water dispersion coating premix, and the single and compound magnesium citrate and magnesium oxide sustained-release coating is performed. The alcohol-soluble ethyl cellulose coating solution is used for the single and compound magnesium citrate and magnesium oxide sustained-release coating. The polyacrylic acid resin water dispersion coating premix or shellac can also be used for the single and compound magnesium citrate and magnesium oxide sustained-release coating.

[0053] Compared with the prior art, the beneficial effects of the present application are as follows:

[0054] The magnesium supplement at home and abroad is in the form of injections, granules and tablets. The injections bring inconvenience to patients, and need to be injected by doctors in a specific environment. The granules are dissolved in the stomach to cause adverse reactions such as bloating, stomachache, nausea, acid reflux, vomiting and reflux, especially for patients with stomach diseases. The tablets are disintegrated into granules in the stomach, and most of the magnesium citrate is dissolved in the stomach to cause adverse reactions. In order to overcome the above shortcomings, the present application is a magnesium citrate sustained-release pill, which controls the release in the stomach and improves the bioavailability. The single magnesium citrate sustained-release pill and the compound magnesium citrate and magnesium oxide sustained-release pill are a combination of multiple units, have the function of controlling the release in the stomach, are not affected by food rhythm, are suitable for the elderly and children, improve compliance, and overcome the adverse reactions caused by granules and tablets. The present application will bring good news to patients, and the magnesium citrate and magnesium oxide pill dosage form has not been seen at home and abroad, and is the first of its kind in the world. DETAILED DESCRIPTION

[0055] The following examples, the various raw materials source: magnesium citrate, Jiangsu Kelun food ingredients Co. Ltd 21041701 magnesium oxide Shanxi Dongda biochemical Co. Ltd 210228 ethanol Jilin province new Tianlong industry Co. Ltd 2021061706. Microcrystalline cellulose: Shandong Liujia pharmaceutical excipients Co. Ltd batch number: 20211160, ethyl cellulose: Shanghai Heli chemical Co. Ltd batch number: 20210908, talc: Changzhou Changjiang talc factory batch number: 2021051301, polyvinylpyrrolidone-K30 Anhui shanhe pharmaceutical excipients Co. Ltd batch number 201120, microcrystalline cellulose pill core: Hangzhou Gaocheng biological nutrition technology Co. Ltd batch number: 20210801, starch pill core: Hangzhou Gaocheng biological nutrition technology Co. Ltd 20210801, sugar pill: Hangzhou Gaocheng biological nutrition technology Co. Ltd batch number: 20210109, silicon dioxide pill core: Hangzhou Gaocheng biological nutrition technology Co. Ltd batch number: 20211201, shellac: Shuangjiang Lahu, Va and Blang nationalities and Dai autonomous county forestry chemical factory batch number: 210413, polyacrylic acid resin water dispersion coating premix: Lianyungang Wantai pharmaceutical excipients Co. Ltd batch number: KF20211116-1, povidone: Anhui shanhe pharmaceutical excipients Co. Ltd batch number: 210201, hydroxypropyl methyl cellulose; Huzhou Zhanwang pharmaceutical Co. Ltd batch number: sp20221001 silicon dioxide: Zhejiang Zhongwei pharmaceutical Co. Ltd batch number: 210503; Purified water Hangzhou Gaocheng biological nutrition technology Co. Ltd 20210109

[0056] In the following examples, the various magnesium citrate, compound magnesium citrate sustained-release pellet release is tested as follows:

[0057] Take the product, according to the release determination method (Chinese pharmacopoeia general 0931 dissolution and release determination method first method), using dissolution determination method basket method device, with purified water 250ml as release medium. The speed is (100±2) r / min, the temperature is (37±0.5) ℃, according to the operation, respectively in 1h, 2h, 3h, take the dissolution liquid for detection. Add ammonia-ammonium chloride buffer (PH=10.0) 10ml and a little with chrome black T indicator, titrate with EDTA titration liquid (0.05mol / L), until the solution changes from purple red to pure blue. Every 1ml EDTA titration liquid (0.05mol / L) is equivalent to 1.214mg of magnesium ion content.

[0058] Content:

[0059] Take the product, finely ground, and accurately weigh about 0.4 g, add water 50 ml to dissolve, then add ammonia-ammonium chloride buffer (PH = 10.0) 10 ml and a little chromium black T indicator, titrate with EDTA titration solution (0.05 mol / L) until the solution changes from purple red to pure blue. Each 1 ml EDTA titration solution (0.05 mol / L) corresponds to 0.001214 g of magnesium ion.

[0060] Content (%) = V * F * 0.001214 / (m * w)

[0061] V - the volume of EDTA consumed (ml)

[0062] F - the correction coefficient of EDTA concentration (F = C / 0.05)

[0063] 0.001214 - the titration degree of magnesium

[0064] m - the sample weight (g)

[0065] w - the content of magnesium in the raw material (%)

[0066] Example 1 Preparation of single magnesium citrate sustained-release pellets

[0067] The formula of magnesium citrate pellets, magnesium citrate: microcrystalline cellulose = 90:10

[0068] The formula of magnesium citrate pellets:

[0069] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 90 900 microcrystalline cellulose 10 100 Purified water 15 150

[0070] II. Sustained-release coating liquid formula

[0071] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 5 50 ethanol 94.75 947.5 Triethyl citrate 0.1 1 talcum powder 0.15 1.5

[0072] I. Preparation of magnesium citrate pellets; Ultrafine grinding of magnesium citrate: Weigh magnesium citrate and microcrystalline cellulose according to the formula, mix them evenly (weigh the mixed powder). 1. Magnesium citrate mother; Start the centrifugal granulator main machine, turn on the air blast, control the air volume at 10-15 HZ, and control the air pressure at 0.2-0.7 MPa. Weigh 1 / 4 of the mixed powder and put it into the centrifugal granulator, use purified water as the binder to prepare the master batch, control the spraying speed at 20-150 r / min. When the mixed powder in the centrifugal granulator has small particles (100-250 μm), start supplying the mixed powder. Add 1 / 4 of the mixed powder, turn off the spraying system, discharge, and sieve to get magnesium citrate master batch; 2. Magnesium citrate master batch enlargement: Put the magnesium citrate master batch into the centrifugal granulator, use purified water as the binder, control the spraying speed at 50-200 r / min, and spray. At the same time, add 2 / 4 of the mixed powder, stop supplying the powder, and turn off the spraying system. Discharge to get magnesium citrate pellets, and dry. Use a boiling dryer to dry at a temperature of 100°C for 2 hours; discharge when the moisture content meets the requirements. Sieve according to the particle size requirements of the finished product.

[0073] II. Coating of magnesium citrate pellets;

[0074] Weigh according to the coating ratio, stir evenly with ethyl cellulose, triethyl citrate, talc, and ethanol to get the coating liquid.

[0075] Put the magnesium citrate pellets into the multifunctional coating machine, use the peristaltic pump to atomize the coating liquid through the spray gun for coating, the inlet air temperature is 90°C, the material temperature is 45±5°C, the spraying speed is controlled at 5-140 r / min, and the coating weight gain is 3%; coating is completed. Discharge. If the ethanol has not been volatilized in time due to too fast coating, dry at 40±5°C for 1 hour before discharging.

[0076] Magnesium citrate sustained-release pellets: test the content, moisture content, and release rate, the results are shown in Table 1;

[0077] Example 2: Preparation of single magnesium citrate sustained-release pellets

[0078] Formula of magnesium citrate pellets: Magnesium citrate: microcrystalline cellulose = 65:35

[0079] I. Formula of magnesium citrate pellets:

[0080] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 65 650 microcrystalline cellulose 35 350 Purified water 19 190

[0081] II. Formula of sustained-release coating liquid

[0082]

[0083]

[0084] Preparation method is the same as example 1, the results are shown in Table 1;

[0085] Preparation of single magnesium citrate sustained release pellets

[0086] The formula of magnesium citrate pellets, magnesium citrate: microcrystalline cellulose = 80:20

[0087] I. The formula of magnesium citrate pellets:

[0088] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 80 800 microcrystalline cellulose 20 200 Purified water 20 200

[0089] II. The formula of sustained release coating solution

[0090] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 4 40 ethanol 95.8 958 Triethyl citrate 0.08 0.8 talcum powder 0.12 1.2

[0091] The preparation method is the same as that in Example 1, and the results are shown in Table 1

[0092] Example 4 Preparation of compound magnesium citrate magnesium oxide sustained release pellets

[0093] The formula of magnesium citrate pellets, magnesium citrate: microcrystalline cellulose = 90:10

[0094] I. The formula of magnesium citrate pellets:

[0095] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 90 900 microcrystalline cellulose 10 100 Purified water 15 150

[0096] II. The formula of magnesium citrate magnesium oxide pellets:

[0097]

[0098] III. The formula of sustained release coating solution

[0099] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 5 50 ethanol 94.75 947.5 Triethyl citrate 0.1 1 talcum powder 0.15 1.5

[0100] I. The preparation of magnesium citrate pellets is the same as that in Example 1

[0101] II. The preparation of magnesium citrate pellets with magnesium oxide

[0102] Magnesium oxide, microcrystalline cellulose is weighed according to the proportion, mixed uniformly (mixed powder), magnesium citrate pellets are placed in a centrifugal granulator, the centrifugal granulator is started, and 1% polyvinylpyrrolidone-K30 (binder) ethanol solution is atomized by a spray gun and added to the magnesium citrate pellets through a peristaltic pump, then the mixed powder is added, and magnesium citrate magnesium oxide pellets are prepared, which are dried by a fluidized bed dryer at a temperature of 115°C for 1 hour; screen the magnesium citrate magnesium oxide pellets; III. Coating of magnesium citrate magnesium oxide pellets; the same as in Example 1

[0103] Magnesium citrate magnesium oxide sustained release pellets: detection of content, moisture, and release rate, and the results are shown in Table 2

[0104] Example 5 Compound magnesium citrate magnesium oxide sustained release pellets

[0105] Formulation of magnesium citrate pellets, magnesium citrate: microcrystalline cellulose = 65:35

[0106] I. Formulation of magnesium citrate pellets:

[0107] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 65 650 microcrystalline cellulose 35 350 Purified water 19 190

[0108] II. Formulation of magnesium citrate + magnesium oxide pellets:

[0109]

[0110] III. Formulation of sustained release coating solution

[0111] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 3 30 ethanol 96.77 967.7 Triethyl citrate 0.08 0.8 talcum powder 0.15 1.5

[0112] Preparation method same as Example 4, results shown in Table 2;

[0113] Example 6 Preparation of compound magnesium citrate magnesium oxide sustained release pellets

[0114] Formulation of magnesium citrate pellets, magnesium citrate: microcrystalline cellulose = 75:25

[0115] I. Formulation of magnesium citrate pellets:

[0116] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 75 750 microcrystalline cellulose 25 250 Purified water 20 200

[0117] II. Formulation of magnesium citrate + magnesium oxide pellets:

[0118]

[0119] III. Formulation of sustained release coating solution

[0120]

[0121]

[0122] Preparation method same as Example 4, results shown in Table 2;

[0123] Example 7 Preparation of magnesium citrate sustained release pellets

[0124] Microcrystalline cellulose pellet core is mother granules instead of magnesium citrate mixed with microcrystalline cellulose powder as mother, magnesium citrate sustained release pellets are prepared.

[0125] I. Formulation of magnesium citrate pellets:

[0126] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 86 860 microcrystalline cellulose 10 100 Purified water 15 150 Microcrystalline cellulose pellet core 4 (0.106-0.255mm) 40

[0127] II. Formulation of sustained release coating solution

[0128] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 3 30 ethanol 96.82 968.2 Triethyl citrate 0.06 0.6 talcum powder 0.12 1.2

[0129] I. Preparation of magnesium citrate pellets

[0130] Magnesium citrate superfine grinding: Magnesium citrate is weighed according to the proportion: microcrystalline cellulose is mixed uniformly (mixed powder is weighed), the main machine of the centrifugal granulator is opened, the air volume is controlled at 10-20 HZ, and the air pressure is controlled at 0.2-0.7 MPa. The microcrystalline cellulose pellet core is weighed and put into the semi-centrifugal granulator, purified water is used as a wetting agent, and the purified water is atomized by a spray gun to make the surface of the magnesium citrate pellet core granulated. The mixed powder is added at a speed of 50-200 r / min, and the spray liquid system is closed after the addition of the mixed powder. The magnesium citrate pellets are obtained, dried by a boiling dryer at a temperature of 100°C for 2 hours, and sieved.

[0131] II. Magnesium citrate pellet coating;

[0132] The same as Example 1

[0133] Magnesium citrate sustained-release pellets: content, moisture, and release rate are detected, and the results are shown in Table 1.

[0134] Example 8 Preparation of compound magnesium citrate magnesium oxide sustained-release pellets

[0135] Microcrystalline cellulose pellet core is used as a mother granule to replace magnesium citrate and microcrystalline cellulose mixed powder to make magnesium citrate magnesium oxide sustained-release pellets

[0136] I. Magnesium citrate pellet formula:

[0137] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 86 860 microcrystalline cellulose 10 100 Purified water 15 150 Microcrystalline cellulose pellet core 4 (0.106-0.255mm) 40

[0138] II. Magnesium citrate and magnesium oxide pellet formula:

[0139]

[0140]

[0141] III. Sustained-release coating liquid formula

[0142] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 5 50 ethanol 94.82 948.2 Triethyl citrate 0.06 0.6 talcum powder 0.12 1.2

[0143] I. Preparation of magnesium citrate pellets

[0144] The operation is the same as Example 7.

[0145] II. Preparation of magnesium citrate pellets with magnesium oxide

[0146] The operation is the same as Example 4

[0147] III. Coating of magnesium citrate magnesium oxide pellets

[0148] The operation is the same as Example 1, and the results are shown in Table 2.

[0149] Example 9 Preparation of magnesium citrate sustained-release pellets

[0150] Starch pellet core as mother granules instead of magnesium citrate mixed with microcrystalline cellulose powder as mother, magnesium citrate sustained-release pellets are prepared

[0151] I. Magnesium citrate pellet formula:

[0152] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 82 820 microcrystalline cellulose 15 150 Purified water 16 160 Starch pellet core 3 (0.106-0.255mm) 30

[0153] II. Sustained-release coating liquid formula

[0154] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 5 50 ethanol 94.8 948 Triethyl citrate 0.07 0.7 talcum powder 0.13 1.3

[0155] I. Preparation of magnesium citrate pellets

[0156] The operation is the same as Example 7, the only difference is that starch pellet core is used instead of microcrystalline cellulose pellet core.

[0157] II. Preparation of magnesium citrate pellets with magnesium oxide

[0158] The operation is the same as Example 1, and the results are shown in Table 1.

[0159] Example 10 Preparation of compound magnesium citrate magnesium oxide sustained-release pellets

[0160] Starch pellet core as mother granules instead of magnesium citrate mixed with microcrystalline cellulose powder as mother, magnesium citrate magnesium oxide sustained-release pellets are prepared

[0161] I. Magnesium citrate pellet formula:

[0162]

[0163]

[0164] II. Magnesium citrate and magnesium oxide pellet formula:

[0165]

[0166] III. Sustained-release coating liquid formula

[0167] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 5 50 ethanol 94.8 948 Triethyl citrate 0.07 0.7 talcum powder 0.13 1.3

[0168] I. Preparation of magnesium citrate pellets

[0169] The operation is the same as Example 7, the only difference is that starch pellet core is used instead of microcrystalline cellulose pellet core.

[0170] II. Preparation of magnesium citrate pellets with magnesium oxide

[0171] The operation is the same as Example 4

[0172] III. Coating of magnesium citrate magnesium oxide pellets

[0173] The operation is the same as Example 1, and the results are shown in Table 2.

[0174] Example 11 Preparation of Magnesium Citrate Sustained Release Pellets

[0175] The sugar pellets are used as the mother granules instead of mixing magnesium citrate with microcrystalline cellulose powder to form the mother granules, and magnesium citrate and magnesium oxide sustained release pellets are prepared.

[0176] I. Magnesium Citrate Pellet Formulation:

[0177] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 73 730 microcrystalline cellulose 25 250 Purified water 18 180 Sugar pills 2 (0.106-0.25mm) 20

[0178] II. Sustained Release Coating Liquid Formulation

[0179] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 6 60 ethanol 93.78 937.8 Triethyl citrate 0.08 0.8 talcum powder 0.14 1.4

[0180] I. Preparation of Magnesium Citrate Pellets

[0181] The operation is the same as Example 7, with the only difference being that sugar pellets are used instead of microcrystalline cellulose pellet cores.

[0182] II. Preparation of Magnesium Citrate Pellets with Magnesium Oxide

[0183] The operation is the same as Example 1, and the results are shown in Table 1.

[0184] Example 12 Preparation of Compound Magnesium Citrate and Magnesium Oxide Sustained Release Pellets

[0185] The sugar pellets are used as the mother granules instead of mixing magnesium citrate with microcrystalline cellulose powder to form the mother granules, and magnesium citrate and magnesium oxide sustained release pellets are prepared.

[0186] I. Magnesium Citrate Pellet Formulation:

[0187] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 73 730 microcrystalline cellulose 25 250 Purified water 18 180 Sugar pills 2 20

[0188] II. Magnesium Citrate and Magnesium Oxide Pellet Formulation:

[0189]

[0190] III. Sustained Release Coating Liquid Formulation

[0191] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 5 50 ethanol 94.78 947.8 Triethyl citrate 0.08 0.8 talcum powder 0.14 1.4

[0192] I. Preparation of Magnesium Citrate Pellets

[0193] The operation is the same as Example 7, with the only difference being that sugar pellets are used instead of microcrystalline cellulose pellet cores.

[0194] II. Preparation of Magnesium Citrate Pellets with Magnesium Oxide

[0195] The operation is the same as Example 4

[0196] III. Coating of Magnesium Citrate and Magnesium Oxide Pellets

[0197] Operation same as Example 1 moisture, results are shown in Table 2;

[0198] Example 13 Preparation of Magnesium Citrate Sustained Release Pellets

[0199] Silica pellet cores are used as the mother granules instead of mixing magnesium citrate with microcrystalline cellulose powder as the mother, to make magnesium citrate sustained release pellets.

[0200] I. Magnesium Citrate Pellet Formulation:

[0201] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 69 690 microcrystalline cellulose 30 300 Purified water 20 200 Silica pellet core 1 (0.106-0.255mm) 10

[0202] II. Sustained Release Coating Liquid Formulation

[0203]

[0204]

[0205] I. Preparation of Magnesium Citrate Pellets

[0206] Operation same as Example 7, the only difference is that silica pellet cores are used instead of microcrystalline cellulose pellet cores.

[0207] II. Preparation of Magnesium Citrate Pellets with Magnesium Oxide

[0208] Operation same as Example 1, results are shown in Table 1;

[0209] Example 14 Preparation of Compound Magnesium Citrate Magnesium Oxide Sustained Release Pellets

[0210] Silica pellet cores are used as the mother granules instead of mixing magnesium citrate with microcrystalline cellulose powder as the mother, to make magnesium citrate magnesium oxide sustained release pellets.

[0211] I. Magnesium Citrate Pellet Formulation:

[0212] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 69 690 microcrystalline cellulose 30 300 Purified water 20 200 Silica pellet core 1 10

[0213] II. Magnesium Citrate Pellet Formulation with Magnesium Oxide:

[0214]

[0215] III. Sustained Release Coating Liquid Formulation

[0216] Material Name Weight percentage (%) Feed amount / g Ethyl cellulose 5 50 ethanol 94.76 947.6 Triethyl citrate 0.09 0.9 talcum powder 0.15 1.5

[0217] I. Preparation of Magnesium Citrate Pellets

[0218] Operation same as Example 7, the only difference is that silica pellet cores are used instead of microcrystalline cellulose pellet cores.

[0219] II. Preparation of Magnesium Citrate Pellets with Magnesium Oxide

[0220] The operation is the same as Example 4

[0221] III. Magnesium Citrate Magnesium Oxide Pellet Coating

[0222] The operation is the same as Example 1, and the results are shown in Table 2.

[0223] Example 15 Preparation of Single-ingredient Magnesium Citrate Sustained-release Pellets

[0224] Use polyacrylic acid resin water dispersion coating premix instead of ethyl cellulose alcohol solution to make magnesium citrate sustained-release pellets.

[0225] I. Magnesium Citrate Pellet Formulation:

[0226]

[0227]

[0228] II. Sustained-release coating liquid formulation

[0229]

[0230] I. Preparation of Magnesium Citrate Pellets

[0231] The operation is the same as Example 7, with the only difference being that the starch pellet core is replaced with microcrystalline cellulose pellet core.

[0232] II. Magnesium Citrate Pellet Coating

[0233] According to the coating ratio, weigh the polyacrylic acid resin water dispersion coating premix, add purified water and stir until uniform to obtain the coating liquid.

[0234] Place the magnesium citrate pellets in a multifunctional coating machine, and use a peristaltic pump to atomize the coating liquid through a spray gun for coating. The inlet air temperature is 90°C, the material temperature is 45±5°C, the spray speed is controlled at 15-140 r / min, and the coating weight gain is 3%. After coating, magnesium citrate sustained-release pellets are obtained.

[0235] Magnesium citrate sustained-release pellets: test content, moisture, and release rate, and the results are shown in Table 1.

[0236] Example 16 Preparation of Compound Magnesium Citrate Magnesium Oxide Sustained-release Pellets

[0237] Use polyacrylic acid resin water dispersion coating premix instead of ethyl cellulose alcohol solution to make magnesium citrate magnesium oxide sustained-release pellets.

[0238] I. Magnesium Citrate Pellet Formulation:

[0239] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 90 900 microcrystalline cellulose 9 90 Purified water 15 150 Starch pellet core 1 10

[0240] II. Magnesium Citrate and Magnesium Oxide Pellet Formulation:

[0241]

[0242] III. Formulation of sustained release coating solution

[0243]

[0244] I. Preparation of magnesium citrate pellets

[0245] The operation is the same as that of Example 7, with the only difference being that the starch pellet core is replaced by the microcrystalline cellulose pellet core.

[0246] II. Preparation of magnesium citrate pellets with magnesium oxide

[0247] The operation is the same as that of Example 4

[0248] III. Coating of magnesium citrate magnesium oxide pellets

[0249] The operation is the same as that of Example 15

[0250] Determination of content, moisture, and release rate, with the results shown in Table 2

[0251] Example 17 Preparation of single-component magnesium citrate sustained release pellets

[0252] The preparation of magnesium citrate sustained release pellets is replaced by using shellac alcohol solution instead of ethyl cellulose alcohol solution.

[0253] I. Formulation of magnesium citrate pellets:

[0254] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 90 900 microcrystalline cellulose 9 90 Silica pellet core 1 10 Purified water 15 150

[0255] II. Formulation of sustained release coating solution

[0256] Material Name Weight percentage (%) Feed amount / g shellac 5 50 ethanol 94.75 947.5 Triethyl citrate 0.1 1 talcum powder 0.15 1.5

[0257] I. Preparation of magnesium citrate pellets

[0258] The operation is the same as that of Example 7, with the only difference being that the microcrystalline cellulose pellet core is replaced by the silicon dioxide pellet core.

[0259] II. Coating of magnesium citrate pellets

[0260] According to the coating proportion, weigh shellac, triethyl citrate, talc, and ethanol, and stir them uniformly to obtain the coating solution.

[0261] Place the magnesium citrate pellets in a multifunctional coating machine, and use a peristaltic pump to atomize the coating solution through a spray gun for coating. The inlet air temperature is 90°C, the material temperature is 45±5°C, the spray speed is controlled at 15-140 r / min, and the coating weight gain is 3%. After coating, magnesium citrate magnesium oxide sustained release pellets are obtained.

[0262] Determination of content, moisture, and release rate of magnesium citrate sustained release pellets, with the results shown in Table 1

[0263] Preparation of compound magnesium citrate and magnesium oxide sustained-release pellets

[0264] Preparation of compound magnesium citrate and magnesium oxide sustained-release pellets by replacing ethyl cellulose alcohol solution with shellac alcohol solution

[0265] I. Magnesium citrate pellet formula:

[0266] Material Name Weight percentage (%) Feed amount / g Magnesium citrate 90 900 microcrystalline cellulose 9 90 Purified water 15 150 Silica pellet core 1 10

[0267] II. Magnesium citrate and magnesium oxide pellet formula:

[0268]

[0269]

[0270] III. Sustained-release coating solution formula

[0271] Material Name Weight percentage (%) Amount of material / g Shellac 5 5 Ethanol 94.75 947.5 Triethyl citrate 0.1 1 Talc 0.15 1.5

[0272] I. Preparation of magnesium citrate pellets

[0273] The operation is the same as that in Example 7.

[0274] II. Preparation of magnesium citrate pellets and magnesium oxide

[0275] The operation is the same as that in Example 4

[0276] III. Coating of magnesium citrate and magnesium oxide pellets

[0277] According to the coating ratio, weigh shellac, triethyl citrate, talc, and ethanol, stir uniformly to obtain the coating solution.

[0278] The operation is the same as that in Example 17, with the only difference being that shellac is used to replace ethyl cellulose.

[0279] Magnesium citrate and magnesium oxide sustained-release pellets: detection of content, moisture, and release rate, and the results are shown in Table 2;

[0280] Example 19 Preparation of single magnesium citrate pellets

[0281] Preparation of magnesium citrate pellets by using povidone as an excipient to replace microcrystalline cellulose

[0282] I. Magnesium citrate pellet formula:

[0283] Name of material Weight percentage (%) Amount of material / g Magnesium citrate 90 900 Polyvidone 10 100 Purified water 15 150

[0284] II. Sustained-release coating solution formula

[0285] Name of material Weight percentage (%) Amount of material / g Ethyl cellulose 5 50 Ethanol 94.75 947.5 Triethyl citrate 0.1 1 Talc 0.15 1.5

[0286] I. Preparation of magnesium citrate pellets

[0287] The operation is the same as Example 1, the only difference is that povidone is used to replace microcrystalline cellulose.

[0288] III. Magnesium citrate pellets coating

[0289] The operation is the same as Example 1

[0290] Magnesium citrate sustained-release pellets: test content, moisture, release rate, the results are shown in Table 1;

[0291] When preparing magnesium citrate pellets, povidone is used as an excipient to replace microcrystalline cellulose. The solubility of povidone is larger, which makes the release of magnesium citrate faster, more than 75% in 2 hours, which does not meet the release requirements.

[0292] Example 20 Preparation of compound magnesium citrate magnesium oxide pellets

[0293] Use povidone as an excipient to replace microcrystalline cellulose to prepare magnesium citrate pellets

[0294] I. Magnesium citrate pellet formula:

[0295]

[0296]

[0297] II. Magnesium citrate and magnesium oxide pellets formula:

[0298]

[0299] III. Sustained-release coating liquid formula

[0300] Name of material Weight percentage (%) Amount of material / g Ethyl cellulose 5 5 Ethanol 94.75 947.5 Triethyl citrate 0.1 1 Talc 0.15 1.5

[0301] I. Preparation of magnesium citrate pellets

[0302] The operation is the same as Example 4, the only difference is that povidone is used to replace microcrystalline cellulose.

[0303] II. Preparation of magnesium citrate pellets and magnesium oxide

[0304] The operation is the same as Example 4

[0305] III. Magnesium citrate pellet coating

[0306] The operation is the same as Example 4

[0307] Magnesium citrate and magnesium oxide sustained-release pellets: test content, moisture, release rate, the results are shown in Table 2;

[0308] When preparing magnesium citrate pellets, povidone is used as an excipient to replace microcrystalline cellulose. The solubility of povidone is relatively large, which makes the release of magnesium citrate faster, more than 75% in 2 hours, which does not meet the release requirements.

[0309] Example 21 Magnesium citrate sustained-release pellets

[0310] When preparing magnesium citrate pellets, hydroxypropyl methyl cellulose is used as an excipient to replace microcrystalline cellulose.

[0311] I. Magnesium citrate pellet formula:

[0312] Name of material Weight percentage (%) Amount of material / g Magnesium citrate 90 900 Hydroxypropyl methyl cellulose 10 100 Purified water 15 150

[0313] II. Sustained-release coating liquid formula

[0314] Name of material Weight percentage (%) Amount of material / g Ethyl cellulose 5 5 Ethanol 94.75 947.5 Triethyl citrate 0.1 1 Talc 0.15 1.5

[0315] I. Preparation of magnesium citrate pellets

[0316] The operation is the same as that of Example 1, the only difference being that hydroxypropyl methyl cellulose is used to replace microcrystalline cellulose.

[0317] II. Coating of magnesium citrate pellets

[0318] The operation is the same as that of Example 1

[0319] Magnesium citrate sustained-release pellets: detection of content, moisture, and release rate, the results are shown in Table 1.

[0320] When preparing magnesium oxide pellets, hydroxypropyl methyl cellulose is used as an excipient to replace microcrystalline cellulose in the formula, which has a large viscosity and hinders the release of magnesium citrate, resulting in a slower dissolution rate, which does not meet the release rate requirements.

[0321] Example 22 Preparation of compound magnesium citrate magnesium oxide pellets

[0322] When preparing magnesium citrate pellets, hydroxypropyl methyl cellulose is used as an excipient to replace microcrystalline cellulose.

[0323] I. Magnesium citrate pellet formula:

[0324] Name of material Weight percentage (%) Amount of material / g Magnesium citrate 90 900 Hydroxypropyl methyl cellulose 10 100 Purified water 15 150

[0325] II. Magnesium citrate and magnesium oxide pellet formula:

[0326]

[0327] III. Sustained-release coating liquid formula

[0328] Name of material Weight percentage (%) Amount of material / g Ethyl cellulose 5 50 Ethanol 94.75 947.5 Triethyl citrate 0.1 1 Talc 0.15 1.5

[0329] I. Preparation of magnesium citrate pellets

[0330] The procedure was the same as in Example 21, with the only difference being that the hydroxypropyl methylcellulose was used instead of the microcrystalline cellulose.

[0331] II. Preparation of Magnesium Citrate Pellets with Magnesium Oxide

[0332] The procedure was the same as in Example 4

[0333] III. Coating of Magnesium Citrate Magnesium Oxide Pellets

[0334] The procedure was the same as in Example 4

[0335] Magnesium Citrate Magnesium Oxide Sustained Release Pellets: Assay, Moisture, Release, Results in Table 2

[0336] When preparing the magnesium oxide pellets, the hydroxypropyl methylcellulose in the formula was replaced with microcrystalline cellulose as an excipient. The viscosity of the hydroxypropyl methylcellulose greatly hinders the release of the magnesium citrate, and the dissolution rate is slow, which does not meet the release requirements.

[0337] Example 23 Preparation of Single-Ingredient Magnesium Citrate Pellets

[0338] In the formula of the magnesium citrate pellets, the magnesium citrate: microcrystalline cellulose = 50:50. The magnesium citrate pellets prepared in this way are as follows.

[0339] Name of material Weight percentage (%) Amount of material / g Magnesium citrate 50 500 Hydroxypropyl methyl cellulose 50 500 Purified water 15 150

[0340] II. Formula of Sustained Release Coating Liquid

[0341]

[0342]

[0343] I. Preparation of Magnesium Citrate Pellets

[0344] The procedure was the same as in Example 1, with the only difference being that the ratio of magnesium citrate to microcrystalline cellulose was changed.

[0345] II. Coating of Magnesium Citrate Pellets

[0346] The procedure was the same as in Example 1

[0347] Magnesium Citrate Sustained Release Pellets: Assay, Moisture, Release, Results in Table 1

[0348] When preparing the magnesium citrate pellets, the ratio of magnesium citrate to microcrystalline cellulose was 1:1. Because the amount of microcrystalline cellulose was large, it blocked the release of the magnesium citrate, so the release at 1 hour was slow, and it took 2 hours to reach the release at 1 hour, and the release at 3 hours was less than half. This formula does not meet the release requirements.

[0349] Example 24 Preparation of Compound Magnesium Citrate Magnesium Oxide Sustained Release Pellets

[0350] Magnesium Citrate Pellets Formula Magnesium Citrate: Microcrystalline Cellulose = 50:50 Magnesium Citrate Pellets I. Magnesium Citrate Pellets Formula:

[0351] Name of material Weight percentage (%) Amount of material / g Ethyl cellulose 50 500 Ethanol 50 500 Triethyl citrate 15 150

[0352] II. Magnesium Citrate Pellets with Magnesium Oxide Pellets Formula:

[0353]

[0354] III. Sustained Release Coating Solution Formula

[0355] Talc Name of material Weight percentage (%) Amount of material / g 5 50 Magnesium citrate 94.75 947.5 Microcrystalline cellulose 0.1 1 Purified water 0.15 1.5

[0356] I. Preparation of Magnesium Citrate Pellets

[0357] The procedure was the same as Example 23, except that the ratio of magnesium citrate to microcrystalline cellulose was changed.

[0358] II. Preparation of Magnesium Citrate Pellets with Magnesium Oxide

[0359] The procedure was the same as Example 4

[0360] III. Coating of Magnesium Citrate Pellets

[0361] The procedure was the same as Example 1

[0362] Magnesium Citrate Magnesium Oxide Sustained Release Pellets: Assay, Moisture, Release, Results in Table 2

[0363] When the ratio of magnesium citrate to microcrystalline cellulose in the formula for Compound Magnesium Citrate Magnesium Oxide Pellets was 1:1, the amount of microcrystalline cellulose was too much, which blocked the release of the Compound Magnesium Citrate Magnesium Oxide Pellets, so that the release at 1 hour, 2 hours was slow, and the release at 3 hours did not reach more than 75%, which could not meet the release requirements.

[0364] Example 25 Preparation of Single Magnesium Citrate Pellets

[0365] Magnesium Citrate Pellets Formula Magnesium Citrate: Microcrystalline Cellulose = 95:5 Magnesium Citrate Pellets I. Magnesium Citrate Pellets Formula:

[0366] Name of material Weight percentage (%) Amount of material / g Magnesium citrate 95 950 Microcrystalline cellulose 5 50 Purified water 15 150

[0367] II. Sustained Release Coating Solution Formula

[0368] Name of material Weight percentage (%) Amount of material / g Ethyl cellulose 8 80 Ethanol 91.75 917.5 Triethyl citrate 0.1 1 Talc 0.15 1.5

[0369] I. Preparation of Magnesium Citrate Pellets

[0370] The procedure was the same as Example 1, except that the ratio of magnesium citrate to microcrystalline cellulose was changed.

[0371] II. Magnesium citrate pellets coating

[0372] The operation is the same as Example 1

[0373] Magnesium citrate sustained-release pellets: test content, moisture, release rate, results are shown in Table 1;

[0374] Prepare magnesium citrate pellets; magnesium citrate and microcrystalline cellulose ratio is 95:5, because the amount of microcrystalline cellulose is less, so the release is faster in 1 hour, 2 hours, 3 hours are faster than the standard, this formula can not meet the release requirements.

[0375] Example 26 preparation of compound magnesium citrate magnesium oxide sustained-release pellets

[0376] In the formula of magnesium citrate pellets, magnesium citrate: microcrystalline cellulose = 95:5 magnesium citrate pellets are prepared

[0377] Name of material Weight percentage (%) Amount of material / g Magnesium citrate 95 950 Microcrystalline cellulose 5 50 Purified water 15 150

[0378] II. Magnesium citrate and magnesium oxide pellets formula:

[0379]

[0380] III. Sustained-release coating liquid formula

[0381]

[0382]

[0383] I. Preparation of magnesium citrate pellets

[0384] The operation is the same as Example 25, the only difference is the ratio of magnesium citrate and microcrystalline cellulose II. Preparation of magnesium citrate pellets with magnesium oxide

[0385] The operation is the same as Example 4

[0386] III. Magnesium citrate pellets coating

[0387] The operation is the same as Example 4

[0388] Magnesium citrate magnesium oxide sustained-release pellets: test content, moisture, release rate, results are shown in Table 2;

[0389] Prepare compound magnesium citrate magnesium oxide sustained-release pellets; magnesium citrate and microcrystalline cellulose ratio is 95:5, because the amount of microcrystalline cellulose is less, so the release is faster in 1 hour, 2 hours, 3 hours are faster than the standard, this formula can not meet the release requirements.

[0390] Example 27 preparation of single magnesium citrate pellets

[0391] When the magnesium citrate pellets are coated, the ethyl cellulose coating is increased by 5%, and the magnesium citrate pellets have a slow release curve.

[0392] I. Preparation of magnesium citrate pellets

[0393] Name of material Weight percentage (%) Amount of material / g Ethyl cellulose 90 900 Ethanol 10 100 Triethyl citrate 15 150

[0394] II. Preparation of slow release coating solution

[0395] Talc Name of material Weight percentage (%) Amount of material / g 8 80 Magnesium citrate 91.75 917.5 Microcrystalline cellulose 0.1 1 Purified water 0.15 1.5

[0396] I. Preparation of magnesium citrate pellets

[0397] The operation is the same as in Example 1

[0398] II. Coating of magnesium citrate pellets

[0399] The operation is the same as in Example 1, except that the concentration of the ethyl cellulose coating solution is increased

[0400] Release of magnesium citrate pellets: detection of content, moisture, and release, and the results are shown in Table 1.

[0401] For comparison of the ethyl cellulose coating weight gain, when the ethyl cellulose coating weight gain is 5%, the detection results show that the release is slow, which does not meet the release requirements.

[0402] Example 28 Preparation of compound magnesium citrate and magnesium oxide slow release pellets

[0403] When the magnesium citrate pellets are coated, the ethyl cellulose coating is increased by 5%, and the magnesium citrate and magnesium oxide slow release pellets have a slow release curve.

[0404] I. Preparation of magnesium citrate pellets

[0405] Name of material Weight percentage (%) Amount of material / g Ethyl cellulose 90 900 Ethanol 10 100 Triethyl citrate 15 150

[0406] II. Preparation of magnesium citrate and magnesium oxide pellets

[0407]

[0408] III. Preparation of slow release coating solution

[0409] Talc Name of material Weight percentage (%) Amount of material / g 9 90 Magnesium citrate 90.75 907.5 Microcrystalline cellulose 0.1 1 Purified water 0.15 1.5

[0410] I. Preparation of magnesium citrate pellets

[0411] The operation is the same as in Example 27

[0412] II. Preparation of magnesium citrate and magnesium oxide pellets

[0413] The operation is the same as in Example 4

[0414] III. Magnesium Citrate Coating

[0415] The only difference between the operation and Example 1 is that the concentration of ethyl cellulose coating solution is increased

[0416] The magnesium citrate and magnesium oxide sustained-release pellets were tested for content, moisture, and release rate, and the results are shown in Table 2.

[0417] The ethyl cellulose coating weight was compared, and when the ethyl cellulose coating weight was 5%, the test results showed that the release was slow, which did not meet the release requirements.

[0418] Example 29 Preparation of single magnesium citrate pellets

[0419] The ethyl cellulose coating material of the magnesium citrate pellets was replaced with hydroxypropyl methyl cellulose, and the release rate of the magnesium citrate pellets was tested.

[0420] I. Magnesium citrate pellet formula:

[0421] Name of material Weight percentage (%) Amount of material / g Hydroxypropyl methyl cellulose 90 900 Ethanol 10 100 Triethyl citrate 15 150

[0422] II. Sustained-release coating solution formula

[0423] Talc Name of material Weight percentage (%) Amount of material / g 5 50 Magnesium citrate 94.75 947.5 Microcrystalline cellulose 0.1 1 Purified water 0.15 1.5

[0424] I. Preparation of magnesium citrate pellets;

[0425] The operation is the same as Example 1

[0426] II. Coating of magnesium citrate pellets;

[0427] The only difference between the operation and Example 1 is that the hydroxypropyl cellulose is replaced with ethyl cellulose

[0428] The magnesium citrate and magnesium oxide sustained-release pellets were tested for content, moisture, and release rate, and the results are shown in Table 1.

[0429] When the coating material is replaced with hydroxypropyl methyl cellulose instead of ethyl cellulose, the release at 1 hour is faster, and the release at 2 hours exceeds the standard of 3 hours, which does not meet the release requirements.

[0430] Example 30 Preparation of compound magnesium citrate and magnesium oxide sustained-release pellets

[0431] The ethyl cellulose coating material of the magnesium citrate pellets was replaced with hydroxypropyl methyl cellulose, and the release rate of the magnesium citrate and magnesium oxide pellets was tested.

[0432] I. Magnesium citrate pellet formula:

[0433] Name of material Weight percentage (%) Amount of material / g Hydroxypropyl methyl cellulose 90 900 Ethanol 10 100 Triethyl citrate 15 150

[0434] II. Magnesium citrate and magnesium oxide pellet formula:

[0435]

[0436] III. Sustained release coating solution formulation

[0437] Talc Magnesium citrate Microcrystalline cellulose Purified water 5 50 Microcrystalline cellulose pellet core 94.75 947.5 Name of material 0.1 1 Weight percentage (%) 0.15 1.5

[0438] I. Preparation of magnesium citrate pellets

[0439] Procedure same as Example 1

[0440] II. Preparation of magnesium citrate pellets with magnesium oxide

[0441] Procedure same as Example 4

[0442] III. Coating of magnesium citrate pellets; (hydroxypropyl methylcellulose instead of ethyl cellulose)

[0443] Procedure same as Example 29, except that hydroxypropyl methylcellulose was used instead of ethyl cellulose

[0444] Magnesium citrate magnesium oxide sustained release pellets: Assay, moisture, release, results in Table 2.

[0445] When the coating material was hydroxypropyl methylcellulose instead of ethyl cellulose, the 1 hour release was too fast, and the 2 hour release was too fast to meet the 3 hour release requirement.

[0446] Example 31 Coating solution formulation using dodecyl sulfate instead of triethyl citrate in ethyl cellulose alcoholic solution to make magnesium citrate sustained release pellets.

[0447] Amount of material / g 90 900 Magnesium citrate 9 90 Microcrystalline cellulose 15 150 Purified water 1 10

[0448] II. Sustained release coating solution formulation

[0449]

[0450]

[0451] Magnesium citrate pellets were prepared as in Example 7

[0452] Coating solution formulation using dodecyl sulfate instead of triethyl citrate in ethyl cellulose alcoholic solution to make magnesium citrate sustained release pellets. The 1 hour release was too fast, over 40%, and the 2 hour release was also too fast to meet the requirements.

[0453] Example 32 Preparation of magnesium citrate sustained release pellets

[0454] I. Magnesium citrate pellet formulation:

[0455] Microcrystalline cellulose pellet core Name of material Weight percentage (%) Amount of material / g 90 900 Ethyl cellulose 9 90 Ethanol 15 150 Triethyl citrate 1 10

[0456] III. Sustained release coating solution formulation

[0457] Microfine silica gel Name of material Weight percentage (%) Amount of material / g 5 50 Magnesium citrate 94.82 948.2 Microcrystalline cellulose 0.06 0.6 Purified water Microcrystalline cellulose pellet core Name of material Weight percentage (%) Amount of material / g 0.12 1.2

[0458] The preparation method is same as example 7, the only difference is that the coating liquid formula is replaced by talc with micro-powder silica gel. The 1 hour release is too fast to exceed 40%, and the 2 hour release does not meet the release requirements.

[0459] Table 1. Single magnesium citrate pellet release test results

[0460]

[0461]

[0462] Table 2. Compound magnesium citrate pellet release test results

[0463]

[0464] The technical scheme of the present application and the release degree table of examples 19-30 show that the type of excipient and binder and the ratio of the same excipient, binder and magnesium citrate have an influence on the release degree, and the selection of suitable excipient, binder and appropriate ratio is the key. Different coating materials and the amount of the same coating material are important factors affecting the release degree.

Claims

1. A magnesium citrate sustained-release pellet, characterized in that: The magnesium citrate sustained-release pellets comprise a magnesium citrate core and a coating, wherein the mass of the coating is 2-4% of the mass of the magnesium citrate core. Based on the magnesium citrate core, the magnesium citrate core is mainly made of the following raw materials in parts by weight: 65-90 parts by weight of magnesium citrate and 10-35 parts by weight of microcrystalline cellulose; Based on the coating, the coating is a polyacrylic acid resin coating or is made from the following raw materials in parts by weight: 2-6 parts by weight of slow-release coating material, 0.06-0.15 parts by weight of triethyl citrate and 0.08-0.15 parts by weight of talc; the slow-release coating material is ethyl cellulose or shellac.

2. The magnesium citrate sustained-release pellets as described in claim 1, characterized in that: When the coating is a polyacrylic acid resin coating, the coating is made from a polyacrylic acid resin water-dispersible coating premix, which is sourced from Lianyungang Wantai Pharmaceutical Excipients Co., Ltd.

3. The magnesium citrate sustained-release pellets as described in claim 1, characterized in that: The mass of the coating is 3% of the mass of the magnesium citrate core.

4. The magnesium citrate sustained-release pellets as described in claim 1, characterized in that: The magnesium citrate sustained-release pellets consist of a magnesium citrate core and a coating, wherein the mass of the coating is 3-4% of the mass of the magnesium citrate core. Based on the magnesium citrate core, the magnesium citrate core is made from the following raw materials in parts by weight: 65-90 parts by weight of magnesium citrate and 10-35 parts by weight of microcrystalline cellulose; Based on the coating, the coating is a polyacrylic acid resin coating or is made from the following raw materials in parts by weight: 2-6 parts by weight of slow-release coating material, 0.06-0.15 parts by weight of triethyl citrate and 0.08-0.15 parts by weight of talc; the slow-release coating material is ethyl cellulose or shellac.

5. The magnesium citrate sustained-release pellets as described in claim 1, characterized in that: The magnesium citrate core further includes a magnesium oxide layer, which is in contact with the coating. The magnesium oxide layer accounts for 0.01-36% of the total mass of the magnesium citrate core. Based on the magnesium oxide layer, the magnesium oxide layer is made from the following raw materials in parts by mass: 8-18 parts by mass of magnesium oxide, 9.2-11 parts by mass of microcrystalline cellulose, and 0.5-10 parts by mass of binder. The binder is polyvinylpyrrolidone-K30.

6. The magnesium citrate sustained-release pellets as described in claim 1, characterized in that: The magnesium citrate core also includes 1-4 parts by weight of pellet cores with a particle size of 0.106-0.35 mm, wherein the pellet cores are one or a mixture of two of the following: microcrystalline cellulose pellet cores, starch pellet cores, sugar pellets, and silica pellet cores.

7. The magnesium citrate sustained-release pellets as described in claim 6, characterized in that: The magnesium citrate core further includes a magnesium oxide layer, which is in contact with the coating. The magnesium oxide layer comprises 0.01-36% of the total mass of the magnesium citrate core. Based on the magnesium oxide layer, the magnesium oxide layer is made from the following raw materials in parts by weight: 8-18 parts by weight of magnesium oxide, 9.2-11 parts by weight of microcrystalline cellulose, and 0.5-10 parts by weight of binder. The binder is polyvinylpyrrolidone-K30.

8. The method for preparing magnesium citrate sustained-release pellets according to any one of claims 1-7, characterized in that... The method includes the following steps: S1: Preparation of magnesium citrate core: The magnesium citrate and microcrystalline cellulose in the formulation are mixed evenly to obtain mixed powder A; mixed powder A is put into a centrifugal granulator and granulated with water as a binder to obtain magnesium citrate core A; When the magnesium citrate core also includes pellet cores, it is prepared as follows: the amount of magnesium citrate and microcrystalline cellulose in the formulation are mixed evenly to obtain mixed powder B; the amount of pellet cores in the formulation is put into a centrifugal granulator, purified water is used as a wetting agent, and mixed powder B is added to granulate to obtain magnesium citrate core B. If the magnesium citrate core also includes a magnesium oxide layer, then the preparation is continued as follows: Take the formulation amount of magnesium oxide and microcrystalline cellulose, mix them evenly to obtain mixed powder C; put the formulation amount of the magnesium citrate core A or magnesium citrate core B into a centrifugal granulator, atomize the formulation amount of binder and add it to the magnesium citrate core A or magnesium citrate core B through a spray gun, add the mixed powder C, and obtain magnesium citrate core C; The adhesive is added in the form of an ethanol solution of the adhesive; S2: Disperse the polyacrylic acid resin water-dispersible coating premix evenly in water to obtain coating solution A; The sustained-release coating material, triethyl citrate and talc were uniformly dispersed in ethanol to obtain coating solution B. The magnesium citrate core A, magnesium citrate core B, or magnesium citrate core C from step S1 is placed in a multi-functional coating machine, and coated by atomization with coating liquid A or coating liquid B. The product is then discharged to obtain the magnesium citrate sustained-release pellets.

9. The method for preparing magnesium citrate sustained-release pellets as described in claim 8, characterized in that: The concentration of the ethanol solution of the adhesive in step S1 is 1 wt%.

Images