Diclofenac sodium pellet and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a diclofenac sodium pellet and a preparation method thereof, and the diclofenac sodium pellet comprises a pellet core, a diclofenac sodium medicine layer and a coating layer from inside to outside; wherein the diclofenac sodium medicine layer comprises 35%-50% of diclofenac sodium, 15%-30% of microcrystalline cellulose, 0.2%-2% of PVP (Polyvinyl Pyrrolidone) and 0.2%-2% of colloidal silicon dioxide. According to the diclofenac sodium pellet disclosed by the invention, organic solvents such as isopropanol, ethanol and the like are abandoned in the preparation process, the formula is more environment-friendly, the process is simpler, and more importantly, the technical threshold and the process requirements in the production process are remarkably reduced.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to diclofenac sodium micropills and a preparation method thereof. Background Art

[0002] Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister in 1973. It was patented in Germany by Ciba-Geigy (now Novartis) in 1978 and first marketed in the United States in 1988. Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID), often provided in the form of diclofenac sodium, which has antipyretic, analgesic and anti-inflammatory effects and is used to treat inflammatory diseases such as pain and gout. Diclofenac sodium is irritating to the gastrointestinal tract to a certain extent, and ordinary dosage forms may release the drug in the stomach, causing gastrointestinal adverse reactions.

[0003] Enteric-coated pellets have an enteric coating on the outer layer, which can prevent the drug from being released in the acidic environment of the stomach, so that the drug begins to dissolve and release only after reaching the alkaline environment of the small intestine. This allows the drug to be released slowly over a long period of time, thereby maintaining a relatively stable blood drug concentration, prolonging the drug's duration of action, reducing the number of dosings, and improving patient compliance with medication. At present, the main processes for diclofenac sodium pellets are extrusion spheronization and centrifugal granulation. The extrusion spheronization process is complex and has a relatively low yield. Most diclofenac sodium pellets are made using a centrifugal granulation process.

[0004] For example, the publication number is CN101804030B, and the name is a diclofenac sodium micropill preparation and a preparation method thereof. The micropill is an enteric-coated sustained-release micropill, which is composed of a blank core, an active layer and an outer coating. The active layer includes diclofenac sodium, an adhesive sustained-release material and an adhesive enteric-coated material, and the outer layer includes a sustained-release material. Due to the unique process and prescription of the invention, its drug release mechanism becomes a unique dual sustained-release system, that is, through a skeleton-type dispersion system combined with a multi-layer semi-permeable membrane coating system, the main drug can be continuously and stably released in the complex internal environment of the human body. In addition, due to the use of unique excipients, the micropills of the present invention do not dissolve in the stomach, have almost no damage to the gastric mucosa, and ensure that the drug is continuously effective in the intestine for 24 hours, improve bioavailability, and ensure the use effect of the drug. Another example is the publication number: CN102188388B, the name: A diclofenac sodium sustained-release microcapsule preparation and its preparation method, wherein the diclofenac sodium sustained-release microcapsules are mainly composed of blank microcapsules and a drug sustained-release composite layer, and the weight ratio thereof is (1.0-5.0): (0.5-1.5). The preparation process only needs to be completed in one step of coating the drug sustained-release composite layer. The process is simple and has strong operability. The sustained-release microcapsules can release drugs continuously for 12 hours, greatly reducing the number of dosing times. Compared with ordinary tablets, it can greatly reduce the occurrence of burst release and improve the safety of the drug.

[0005] However, the sodium element in the molecular structure of diclofenac sodium is hygroscopic, which makes diclofenac sodium classified as a Class II drug in the Biopharmaceutics Classification System (BCS). In the actual production environment, when the humidity in the surrounding environment is high, sodium ions will actively attract water molecules by virtue of their own chemical properties, which will cause diclofenac sodium to show obvious hygroscopicity. In view of this situation, when diclofenac sodium is granulated, organic solvents such as isopropanol and ethanol are often used as solvents for adhesives. However, isopropanol and ethanol are both flammable solvents, and they have great safety hazards during use. Therefore, in the entire production process, the production workshop must take a series of rigorous and comprehensive preventive measures to prevent dangerous situations. For example, the working area must be well ventilated; the production equipment also needs to have explosion-proof functions; there are also special requirements for warehousing. Since it involves the storage of these flammable organic solvents, the corresponding storage area needs to be planned and managed in accordance with the standards of dangerous goods. These special requirements undoubtedly increase the cost of production to a great extent. In view of the many practical problems that may arise in the production process of diclofenac sodium microcapsules, such as safety issues, the difficulty of achieving good ventilation in GMP workshops, and special requirements for warehousing, there is no doubt that more and more complex requirements are put forward for the production management of enterprises. Summary of the invention

[0006] In view of the above technical problems existing in the prior art, the present invention proposes a new diclofenac sodium microcapsule and a preparation method thereof, which can accurately control the release of diclofenac sodium. More importantly, the process is simple and the requirements for production are reduced.

[0007] On the one hand, the present disclosure provides a method for preparing diclofenac sodium microcapsules, wherein the diclofenac sodium microcapsules include a pill core, a diclofenac sodium drug layer and a coating layer from the inside to the outside, wherein the diclofenac sodium drug layer includes the following components in percentage by mass: 35%-50% of diclofenac sodium, 15%-30% of microcrystalline cellulose, 0.2%-2% of PVP and 0.2%-2% of colloidal silicon dioxide, and the preparation method of the diclofenac sodium microcapsules includes the following steps: S1, preparing a pill core and a diclofenac sodium drug layer component; S2, sieving the diclofenac sodium drug layer component; S3, putting the pill core into a centrifugal granulating coating machine, and spraying binder water or an aqueous solution of PVP k25; S4, adding a mixed powder composed of the diclofenac sodium drug layer components; S5, drying; S6, taking the dried finished product with a diameter of 710-1250 μm as the upper pill core, and coating it with an enteric coating layer or a sustained-release coating layer.

[0008] Preferably, the diclofenac sodium is 40%-45%.

[0009] Preferably, the microcrystalline cellulose is 20%-25% microcrystalline cellulose PH105.

[0010] Preferably, the PVP is 0.5%-1.5% PVP k25.

[0011] Preferably, the colloidal silicon dioxide is 0.5%-1.5%.

[0012] Preferably, the pellet core is an MCC pellet core.

[0013] Preferably, when the binder is water, diclofenac sodium and colloidal silicon dioxide are weighed and passed through a 40-mesh sieve to obtain a mixed powder 1; microcrystalline cellulose powder is weighed and mixed with the mixed powder 1 and passed through a 40-mesh sieve to obtain a mixed powder 2; PVP k25 is weighed and mixed with the mixed powder 2 and passed through a 40-mesh sieve to obtain a mixed powder; the MCC pill cores are weighed and put into a centrifugal granulation coating machine, the binder water is sprayed, the mixed powder is added to coat the pill cores, and after coating, the pill cores are dried to a moisture content of <2%.

[0014] Preferably, when the binder is a PVP k25 aqueous solution, diclofenac sodium and colloidal silicon dioxide are weighed and passed through a 40-mesh sieve to obtain a mixed powder 1; microcrystalline cellulose powder is weighed and mixed with the mixed powder 1 and passed through a 40-mesh sieve to obtain a mixed powder; PVP k25 is weighed and added to purified water, stirred evenly and set aside; MCC pill cores are weighed and put into a centrifugal granulation coating machine, the binder PVP k25 aqueous solution is sprayed, the mixed powder is added to coat the pill cores, and after coating, the pill cores are dried to a moisture content of <2%.

[0015] In a second aspect, the present disclosure further proposes a diclofenac sodium enteric-coated microcapsule, wherein the microcapsule comprises, from the inside to the outside, an MCC core, a diclofenac sodium drug layer and an enteric coating layer, wherein the diclofenac sodium drug layer contains, by mass percentage, 40%-45% of diclofenac sodium, 20%-25% of microcrystalline cellulose PH105, 0.5%-1.5% of PVP k25 and 0.5%-1.5% of colloidal silicon dioxide.

[0016] In a third aspect, the present disclosure further proposes a diclofenac sodium sustained-release microcapsule, which comprises, from the inside to the outside, an MCC core, a diclofenac sodium drug layer and a sustained-release coating layer, wherein the diclofenac sodium drug layer contains, by mass percentage, 40%-45% of diclofenac sodium, 20%-25% of microcrystalline cellulose PH105, 0.5%-1.5% of PVP k25 and 0.5%-1.5% of colloidal silicon dioxide.

[0017] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present disclosure.

[0018] The above technical solution has the following advantages or beneficial effects: the diclofenac sodium microcapsules disclosed in the present invention abandon organic solvents such as isopropanol and ethanol in the production process, the formula is more environmentally friendly and the process is simpler, and more importantly, the technical threshold and process requirements in the production process are significantly reduced. Of course, any technical solution disclosed in the present invention does not necessarily achieve all the advantages described above at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present disclosure or the prior art, the drawings required for use in the embodiments or the prior art description are briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on the provided drawings without creative work.

[0020] Figure 1 It is a schematic diagram of the production process of MCC pellet core according to one embodiment of the present disclosure.

[0021] Figure 2 It is a schematic diagram of the production process of diclofenac sodium enteric-coated microcapsules according to an embodiment of the present disclosure.

[0022] Figure 3 It is a schematic diagram of the production process of diclofenac sodium enteric-coated microcapsules according to another embodiment of the present disclosure.

[0023] Figure 4 It is a schematic diagram of the production process of diclofenac sodium sustained-release microcapsules according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present disclosure are clearly and completely described below in conjunction with the drawings of the present disclosure. Obviously, the described embodiments are only part of the embodiments of the present disclosure and are intended to be used to explain the inventive concept. Based on the embodiments of the present disclosure, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present disclosure. Example 1

[0025] like Figure 1 As shown, this is the production process of microcrystalline cellulose (MCC) pellet cores, and the specific formula is shown in the following table.

[0026] Raw material name Feeding ratio (g) Quality Standards Microcrystalline Cellulose 100 Four volumes of the Chinese Pharmacopoeia (2020 Edition) Purified water 100 Company-made The specific operation process is as follows.

[0027] Material preparation: Prepare materials according to the recipe.

[0028] Start: Turn on the coating granulator host, blow air, control the host speed at 25HZ, and control the blast wind speed at 10-20HZ, and the air source pressure at 0.4-0.7MPa. Add the material into the granulator, spray purified water, and supply powder; control the host speed at 40-50HZ, and the peristaltic pump speed at 0-300r / min to spray, so that the material is moistened and supplied with powder. The manufacturer of the centrifugal granulation coating machine is Jiujiang Dongsheng, model LBLX-360.

[0029] Masterbatch enlargement: Turn on the coating granulator host, blow air, control the host speed at 25HZ, and the blast wind speed at 10-15HZ, and the air source pressure at 0.2-0.8MPa. Add an appropriate amount of masterbatch, control the peristaltic pump speed at 0-300r / min, spray purified water to moisten the material, and supply powder. When the pellets grow to the target specifications, stop supplying powder, stop spraying liquid, turn the host speed to 50HZ, polish for about 1 minute, and discharge.

[0030] Fluidized bed drying: The wet pellet cores prepared above were transported to the hopper of a fluidized bed dryer and placed in the fluidized bed dryer for fluidized bed drying for 60 minutes.

[0031] Sieving: Sieve according to target particle size (600-710μm).

[0032] like Figure 2 As shown, this is the production process of the first diclofenac sodium enteric-coated microcapsules, and the specific formula is shown in the following table.

[0033]

[0034] The specific operation process is as follows.

[0035] According to the above formula table, weigh the prescribed amount of active pharmaceutical ingredient (API) for use; API and the prescribed amount of colloidal silicon dioxide are sieved through a 40-mesh sieve to obtain mixed powder 1; weigh the prescribed amount of microcrystalline cellulose powder and mix it with mixed powder 1 and sieve it through a 40-mesh sieve to obtain mixed powder 2; weigh the prescribed amount of polyvinyl pyrrolidone (PVP) k25 and mix it evenly with mixed powder 2 and sieve it through a 40-mesh sieve to obtain mixed powder; weigh the MCC pill core and put it into a centrifugal granulation coating machine, spray the binder water, add the mixed powder in small amounts and multiple times to coat the pill core, the amount of water sprayed is based on completely wetting the material, the material can be formed into a mass and it will fall apart when touched, record the amount of binder after coating, and the amount of binder is controlled at 500g-1000g; put the diclofenac sodium pill core into a fluidized bed for drying, the initial drying temperature is 60℃, the air intake is 35m 3 / h, dry until the moisture content is <2%; after drying, sieve (710-1250 um) to obtain the finished product.

[0036] The finished product (710-1250 μm) was used as the upper pill core, and the enteric coating formula was shown in the following table.

[0037] Material Name Dosage / g Diclofenac Sodium Pills 200 Polyacrylic acid resin aqueous dispersion premix 142.86 Purified water 209.52 According to the above formula table, weigh the coating premix, add purified water and stir evenly to obtain the coating solution for use; weigh the diclofenac sodium pellets (710-1250μm) and put them into the fluidized bed, spray the coating solution, coating parameters: initial air volume 20-35m³ / h, air temperature 25-40℃, atomization pressure 0.1-0.2mpa, and send them for inspection after coating. Example 2

[0038] like Figure 3As shown in the figure, it is the production process of the second diclofenac sodium enteric-coated microcapsules. The formula table is the same as above, and the specific experimental operations are as follows: weigh the prescription amount of API for use; pass the API and the prescription amount of colloidal silicon dioxide through a 40-mesh sieve to obtain a mixed powder 1; weigh the prescription amount of microcrystalline cellulose powder and mix it with the mixed powder 1 and pass it through a 40-mesh sieve to obtain a mixed powder; weigh PVP k25 and add purified water, stir evenly to obtain an adhesive for use; weigh the MCC pill core as described above and put it into a centrifugal granulation coating machine, spray the adhesive PVPk25 aqueous solution, add the mixed powder in small amounts and multiple times to coat the pill core, the spraying amount is based on completely wetting the material, and the amount of adhesive is recorded after the coating is completed, and the amount of adhesive is controlled at 500-1000g; put the diclofenac sodium pill core into a fluidized bed for drying, with an initial drying temperature of 60°C and an air intake of 35 m 3 / h, drying to a moisture content of <2%; after drying, sieving (710-1250 um) to obtain the finished product. In this embodiment, spraying PVP k25 aqueous solution can further improve the roundness of the pellet core.

[0039] The finished product (710-1250 μm) was used as the upper pill core, and the enteric coating formula was shown in the following table.

[0040] Material Name Dosage / g Diclofenac Sodium Pills 200 Polyacrylic acid resin aqueous dispersion premix 171.43 Purified water 228.57 According to the above formula table, weigh the coating premix, add purified water and stir evenly to obtain the coating solution for use; weigh the diclofenac sodium pellets (710-1250μm) and put them into the fluidized bed, spray the coating solution, coating parameters: initial air volume 20-35m³ / h, air temperature 25-40℃, atomization pressure 0.1-0.2mpa, and send them for inspection after coating. Example 3

[0041] The production process of the third type of diclofenac sodium enteric-coated microcapsules and the specific formula are shown in the following table.

[0042]

[0043] According to the above formula table, weigh the prescription amount of API for use; pass the API and the prescription amount of colloidal silicon dioxide through a 40-mesh sieve to obtain mixed powder 1; weigh the prescription amount of microcrystalline cellulose powder and mix it with mixed powder 1 and pass it through a 40-mesh sieve to obtain a mixed powder; weigh PVP k25, add purified water, stir evenly to obtain a binder for use; weigh the MCC pill cores as described above, put them into a centrifugal granulation coating machine, spray the binder PVP k25 aqueous solution, and add the mixed powder in small amounts and multiple times to coat the pill cores; after coating, record the amount of binder, and control the amount of binder to be 500-1000g; put the diclofenac sodium pill cores into a fluidized bed for drying, with an initial drying temperature of 60°C and an air intake of 35 m³ / h, and dry until the moisture content is <2%; after drying, sieve (710-1250μm) to obtain the finished product.

[0044] The finished product (710-1250 μm) was used as the upper pill core, and the enteric coating formula was shown in the following table.

[0045] Material Name Dosage / g Diclofenac Sodium Pills 200 Polyacrylic acid resin aqueous dispersion premix 171.43 Purified water 228.57 According to the above formula table, weigh the coating premix, add purified water and stir evenly to obtain the coating solution for use; weigh the diclofenac sodium pellets (710-1250μm) and put them into the fluidized bed, spray the coating solution, coating parameters: initial air volume 20-35m³ / h, air temperature 25-40℃, atomization pressure 0.1-0.2mpa, and send them for inspection after coating. Example 4

[0046] The production process of the fourth type of diclofenac sodium enteric-coated microcapsules and the specific formula are shown in the following table.

[0047]

[0048] According to the above formula table, weigh the prescription amount of API for use; API and prescription amount of colloidal silicon dioxide are sieved through a 40-mesh sieve to obtain mixed powder 1; weigh the prescription amount of microcrystalline cellulose powder and mix it with mixed powder 1 and sieve through a 40-mesh sieve to obtain mixed powder 2; weigh the prescription amount of PVPk25 and mix it evenly with mixed powder 2 and sieve through a 40-mesh sieve to obtain mixed powder; weigh the MCC pill cores and put them into a centrifugal granulation coating machine, spray the binder water, and add the mixed powder in small amounts and multiple times to coat the pill cores; after coating, record the amount of binder, and control the amount of binder to be 500-1000g; put the diclofenac sodium pill cores into a fluidized bed for drying, with an initial drying temperature of 60°C and an air intake of 35 m³ / h, and dry until the moisture content is <2%; after drying, sieve (710-1250 um) to obtain the finished product.

[0049] The finished product (710-1250 μm) was used as the upper pill core, and the enteric coating formula was shown in the following table.

[0050] Material Name Dosage / g Diclofenac Sodium Pills 200 Polyacrylic acid resin aqueous dispersion premix 238.10 Purified water 161.90 According to the above formula table, weigh the coating premix, add purified water and stir evenly to obtain the coating solution for use; weigh the diclofenac sodium pellets (710-1250μm) and put them into the fluidized bed, spray the coating solution, coating parameters: initial air volume 20-35m³ / h, air temperature 25-40℃, atomization pressure 0.1-0.2mpa, and send them for inspection after coating. Comparative Example 1

[0051] The production process of diclofenac sodium enteric-coated microcapsules as a comparative example and the specific formula are shown in the following table.

[0052]

[0053] According to the above formula table, weigh the prescription amount of API for use; pass the API and the prescription amount of sodium dodecyl sulfate through a 40-mesh sieve to obtain a mixed powder; weigh PVP k30 and add purified water, stir evenly to obtain a binder for use; weigh the MCC pill core as described above and put it into a centrifugal granulation coating machine, spray the binder PVP k25 aqueous solution, and add the mixed powder in small amounts and multiple times to coat the pill core; record the amount of binder after coating, and control the amount of binder to 500-1000g; put the diclofenac sodium pill core into a fluidized bed for drying, with an initial drying temperature of 60°C and an air intake of 35 m³ / h, and dry to a moisture content of <2%; sieve (710-1250 um) after drying to obtain a finished product. Enteric coating is the same as in Example 1. Comparative Example 2

[0054] Another production process of diclofenac sodium enteric-coated microcapsules as a comparative example, and the specific formula are shown in the following table.

[0055]

[0056] According to the above formula table, weigh the prescription amount of API for use; pass the API and the prescription amount of sodium dodecyl sulfate through a 40-mesh sieve to obtain a mixed powder; weigh HPMC and add purified water, stir evenly to obtain a binder for use; weigh the MCC pill cores as described above and put them into a centrifugal granulation coating machine, spray the binder hydroxypropyl methylcellulose (HPMC) aqueous solution, and add the mixed powder in small amounts and multiple times to coat the pill cores; record the amount of binder after coating; put the diclofenac sodium pill cores into a fluidized bed for drying, with an initial drying temperature of 60°C and an air intake of 35 m³ / h, and dry until the moisture content is <2%; after drying, sieve (710-1250 um) to obtain the finished product. Enteric coating is the same as in Example 1. Comparative Example 3

[0057] Another production process of diclofenac sodium microcapsules as a comparative example, the specific formula is shown in the following table.

[0058] Material Name Dosage / g MCC pellets 500 Diclofenac Sodium 420.56 Sodium Lauryl Sulfate 4.67 PVP k30 9.35 According to the above formula table, weigh the prescription amount of API for use; pass the API and the prescription amount of sodium dodecyl sulfate through a 40-mesh sieve to obtain mixed powder 1; weigh the prescription amount of PVP K30 and mix it with mixed powder 1 and pass it through a 40-mesh sieve to obtain mixed powder 2; weigh the MCC pill core and put it into the centrifugal granulation coating machine, spray the adhesive 12% ethanol, and add the mixed powder in small amounts and multiple times to coat the pill core; record the amount of adhesive after coating; put the diclofenac sodium pill core into the fluidized bed for drying, with an initial drying temperature of 60°C and an air intake of 35 m 3 / h, and dried until the moisture content is less than 2%; after drying, the mixture is sieved (710-1250 um) to obtain the finished product. Enteric coating is the same as in Example 1. Test Example 1

[0059] Release rate and enteric coating test method refer to the first method 1 of the fourth general rule 0931 dissolution and release rate determination method of the 2020 edition of the Chinese Pharmacopoeia.

[0060] Dissolution in acid: Dissolution conditions: 750ml of 0.1mol / L hydrochloric acid solution is used as the dissolution medium, the speed is 100 revolutions per minute, operate according to the law, and take samples after 2 hours. For the test solution, take 10ml of the dissolution solution, filter, and take the filtrate. For the reference stock solution, take 10mg of diclofenac sodium reference substance, accurately weigh, place in a 50ml volumetric bottle, add water to dissolve and dilute to the scale, and shake well. For the reference solution, accurately measure 5ml of the reference stock solution, place in a 200ml volumetric bottle, dilute to the scale with 0.1mol / L hydrochloric acid solution, and shake well. Determination method: accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the dissolution amount of each particle by the peak area according to the external standard method.

[0061] Dissolution in buffer solution conditions: immediately add 250ml of 0.2mol / L sodium phosphate solution preheated to 37℃±0.5℃ to the solution after 2 hours under the item of dissolution in acid, mix well (adjust pH value to 6.8 with 2mol / L sodium hydroxide solution or 2mol / L hydrochloric acid solution if necessary), rotate at 100 rpm, operate according to the law, and take samples after 45 minutes. For the test solution, take an appropriate amount of dissolution solution, filter, and take the filtrate. For the reference solution, accurately measure 5ml of the reference stock solution under the item of dissolution in acid, place it in a 20ml volumetric flask, dilute to the scale with dissolution medium (0.1mol / L hydrochloric acid solution and 0.2mol / L sodium phosphate solution, mix evenly at a ratio of 3:1, and adjust pH value to 6.8 with 2mol / L sodium hydroxide solution or 2mol / L hydrochloric acid solution if necessary), and shake well. The determination method is the same as above.

[0062] Test results: Test Example 2

[0063] Stability test, experimental method: put the coated pellets of Examples 1-4 and Comparative Examples 1-3 into a stability test box (5°C), detect the drying loss before putting them in, and detect the drying loss after 3, 7, 15, and 30 days. Detection method: take about 1g or the weight specified under each variety, put it in a flat weighing bottle dried to constant weight under the same conditions as the test sample, accurately weigh it, and dry it at 105°C to constant weight unless otherwise specified. Calculate the drying loss of the test sample from the lost weight and the sample amount.

[0064] Test results:

[0065] It can be seen from the results of the test examples that the diclofenac sodium enteric-coated micropellets disclosed in the present invention have excellent stability, and their release in the intestine is better than the prior art. The diclofenac sodium enteric-coated micropellets disclosed in the present invention abandon organic solvents such as isopropanol and ethanol during the production process, and use purified water as a solvent. The mechanism of preventing moisture absorption is as follows: 1. Adsorption mechanism; colloidal silica has a huge specific surface area. The particles of colloidal silica are very fine, and these tiny particles provide a large amount of surface, so that it can adsorb water molecules around diclofenac sodium. When diclofenac sodium is mixed with colloidal silica, the silanol groups on the surface of the silica particles can form hydrogen bonds with water molecules. For example, a colloidal silica particle can interact with multiple water molecules through multiple silanol groups, thereby adsorbing water molecules that may have been absorbed by diclofenac sodium to its own surface. This adsorption is a physical adsorption process, which reduces the chance of diclofenac sodium contacting with water molecules to a certain extent, thereby reducing the hygroscopicity of diclofenac sodium. 2. Mechanism of forming a physical barrier: colloidal silica forms a physical barrier around diclofenac sodium particles. Silica particles fill the gaps between diclofenac sodium particles, preventing water molecules from entering, just like building a "wall" around diclofenac sodium. When external water molecules try to contact diclofenac sodium, they will first encounter the barrier composed of silica particles, which can effectively reduce the penetration of water and protect diclofenac sodium from the influence of humid environment. Moreover, this barrier effect of colloidal silica can also prevent diclofenac sodium from agglomerating due to moisture absorption, and maintain good fluidity and dispersibility of the drug. 3. Dispersion mechanism: colloidal silica can make diclofenac sodium disperse better. In the absence of colloidal silica, diclofenac sodium particles may gather together due to moisture absorption. Colloidal silica can be adsorbed on the surface of diclofenac sodium, and through electrostatic action, steric hindrance effect, etc., diclofenac sodium particles are isolated from each other and evenly dispersed. For example, in pharmaceutical preparations, a good dispersion state can reduce the hygroscopic phenomenon caused by excessive local concentration of diclofenac sodium. If diclofenac sodium aggregates together, the humidity in the aggregated area will be higher in a high humidity environment, making it easier to absorb moisture. The dispersing effect of colloidal silica can avoid this situation, thereby indirectly preventing diclofenac sodium from absorbing moisture. In addition, microcrystalline cellulose has a porous structure and a large specific surface area. It can absorb a certain amount of water and also disperse diclofenac sodium. When diclofenac sodium and microcrystalline cellulose are mixed, microcrystalline cellulose can absorb part of the water and prevent the close aggregation of diclofenac sodium particles, thereby reducing the hygroscopic phenomenon caused by the increase in local humidity caused by particle aggregation. The principle of its water absorption is related to physical adsorption, that is, it interacts with water molecules through functional groups such as hydroxyl groups on the surface. Example 5

[0066] like Figure 4As shown, it is the production process of the first diclofenac sodium sustained-release micro-pellets. The drug formulation is the same as that of Example 1 of enteric coating of diclofenac sodium after drug application. The finished product (710-1250 μm) is taken as the drug pellet core. The sustained-release coating formulation is as follows.

[0067]

[0068] According to the above formula table, weigh ethyl cellulose, add 95% ethanol to completely dissolve, then add triethyl citrate and talcum powder, stir evenly to obtain the coating solution for use; weigh diclofenac sodium pellets (710-1250μm) and put them into the fluidized bed, spray the coating solution, coating parameters: initial air volume 15-40m³ / h, air temperature 20-50℃, atomization pressure 0.1-0.3mpa, and send them for inspection after coating. Example 6

[0069] The second preparation process of diclofenac sodium sustained-release micropellets is as follows: the drug formulation is the same as that of Example 2 of diclofenac sodium enteric coating after drug application; the finished product (710-1250 μm) is used as the drug pellet core; and the sustained-release coating formulation is as follows.

[0070] Material Name Dosage / g Ethyl cellulose 0.5 95% ethanol 45.95 Triethyl citrate 0.075 talcum powder 0.1 Weight gain 4.5% According to the above formula table, weigh ethyl cellulose, add 95% ethanol to completely dissolve, then add triethyl citrate and talcum powder, stir evenly to obtain the coating solution for use; weigh diclofenac sodium pellets (710-1250μm) and put them into the fluidized bed, spray the coating solution, coating parameters: initial air volume 15-40m³ / h, air temperature 20-50℃, atomization pressure 0.1-0.3mpa, and send them for inspection after coating. Comparative Example 4

[0071] As a comparative example, the preparation process of diclofenac sodium sustained-release micropellets, the drug formulation is the same as that of Example 1 of diclofenac sodium enteric coating after drug application, the finished product (710-1250 μm) is taken as the drug pellet core, and the sustained-release coating formulation is as follows.

[0072] Material Name Dosage / g Ethyl cellulose 0.5 95% ethanol 45.95 Triethyl citrate 0.075 talcum powder 0.1 Weight gain 4% According to the above formula table, weigh ethyl cellulose, add 95% ethanol to completely dissolve, then add triethyl citrate and talcum powder, stir evenly to obtain the coating solution for use; weigh diclofenac sodium pellets (710-1250μm) and put them into the fluidized bed, spray the coating solution, coating parameters: initial air volume 15-40m³ / h, air temperature 20-50℃, atomization pressure 0.1-0.3mpa, and send them for inspection after coating. Comparative Example 5

[0073] As another comparative example, the production process of diclofenac sodium sustained-release micropellets, the drug formulation is the same as that of Example 2 of diclofenac sodium enteric coating after drug application, the finished product (710-1250 μm) is taken as the drug pellet core, and the sustained-release coating formulation is as follows.

[0074]

[0075] According to the above formula table, weigh ethyl cellulose, add 95% ethanol to completely dissolve, then add triethyl citrate and talcum powder, stir evenly to obtain the coating solution for use; weigh diclofenac sodium pellets (710-1250μm) and put them into the fluidized bed, spray the coating solution, coating parameters: initial air volume 15-40m³ / h, air temperature 20-50℃, atomization pressure 0.1-0.3mpa, and send them for inspection after coating. Test Example 3

[0076] The sustained release test method refers to the first method of Appendix XD of Part II of the 2010 edition of the Chinese Pharmacopoeia. The second dissolution method apparatus is used. First, 900 ml of 0.1 mol / L hydrochloric acid solution is used as the medium. The rotation speed is 75 revolutions per minute. The operation is carried out in accordance with the law. After 2 hours, 10 ml of the solution is taken, filtered, and the filtrate is taken as the test solution (1). Another sample is taken, and 900 ml of phosphate buffer (pH 6.8) [0.1 mol / L hydrochloric acid solution and 0.2 mol / L sodium phosphate solution are mixed in a ratio of 3:1. If necessary, the pH value is adjusted to 6.8 with 2 mol / L sodium hydroxide solution or 2 mol / L hydrochloric acid solution] is used as the release medium. The rotation speed is 75 revolutions per minute. The operation is carried out in accordance with the law. After 2 hours, 4 hours and 8 hours, 10 ml of the solution is taken respectively, filtered, and immediately supplemented with the same temperature and the same volume of release medium, accurately measure 2 ml (specification: 0.1 g) or 3 ml (specification: 50 mg) of the filtrate, place it in a 10 ml volumetric flask, dilute to the mark with the release medium, shake well, and use it as the test solution (2); separately take 10 mg of diclofenac sodium reference substance, accurately weigh it, place it in a 50 ml volumetric flask, add water to dissolve and dilute to the mark, and use it as the reference substance stock solution; accurately measure 10 ml (specification: 0.1 g) or 5 ml (specification: 50 mg) of the reference substance stock solution, place it in a 200 ml volumetric flask, dilute to the mark with 0.1 mol / L hydrochloric acid solution, shake well, and use it as the reference substance solution for the test solution (1); separately accurately measure 2 ml of the reference substance stock solution, place it in a 25 ml volumetric flask, dilute to the mark with the release medium, shake well, and use it as the reference substance solution for the test solution (2).

[0077] According to the UV-Vis spectrophotometry (Appendix IVA of Part II of the 2010 edition of the Chinese Pharmacopoeia), the absorbance is measured at a wavelength of 276nm, and the release amount of each capsule at different times is calculated. The release limit of this product in acid should not exceed 10% of the labeled amount; the release amount of each capsule in 2 hours, 4 hours and 8 hours should be 25%-50%, 45%-80% and more than 75% of the labeled amount, respectively, which should meet the requirements.

[0078] The test results are shown in the following table.

[0079]

[0080] Although the embodiments of the present disclosure have been shown and described above, it is to be understood that the above embodiments are exemplary and cannot be understood as limiting the present disclosure. Without departing from the spirit and scope of the present disclosure, the present disclosure may also have various changes and improvements, which all fall within the scope of the present disclosure claimed for protection.

Claims

1. A method for preparing diclofenac sodium microcapsules, wherein the diclofenac sodium microcapsules sequentially comprise a core, a diclofenac sodium drug layer and a coating layer from inside to outside, characterized in that: The diclofenac sodium drug layer comprises the following components in mass percentage: 35%-50% of diclofenac sodium, 15%-30% of microcrystalline cellulose, 0.2%-2% of PVP and 0.2%-2% of colloidal silicon dioxide; the preparation method of diclofenac sodium microcapsules comprises the following steps: S1, preparing pill cores and diclofenac sodium drug layer components; S2, sieving the diclofenac sodium drug layer components; S3, putting the pill cores into a centrifugal granulating coating machine, and spraying adhesive water or a PVP k25 aqueous solution; S4, adding a mixed powder composed of the diclofenac sodium drug layer components; S5, drying; S6, taking the dried pill cores with a diameter of 710 μm-1250 μm as the upper pill cores, and coating them with an enteric coating layer or a sustained-release coating layer.

2. A method for preparing diclofenac sodium pellets according to claim 1, characterized in that: The diclofenac sodium is 40%-45%.

3. A method for preparing diclofenac sodium pellets according to claim 1, characterized in that: The microcrystalline cellulose is 20%-25% microcrystalline cellulose PH105.

4. The method for preparing diclofenac sodium pellets according to claim 1, characterized in that: The PVP is 0.5%-1.5% PVP k25.

5. A method for preparing diclofenac sodium pellets according to claim 1, characterized in that: The colloidal silicon dioxide is 0.5%-1.5%.

6. A method for preparing diclofenac sodium pellets according to any one of claims 1 to 5, characterized in that: The pellet core is an MCC pellet core.

7. The method for preparing diclofenac sodium pellets according to claim 6, characterized in that: When the binder is water, diclofenac sodium and colloidal silicon dioxide are weighed and passed through a 40-mesh sieve to obtain mixed powder 1; microcrystalline cellulose powder is weighed and mixed with mixed powder 1 and passed through a 40-mesh sieve to obtain mixed powder 2; PVP k25 is weighed and mixed with mixed powder 2 and passed through a 40-mesh sieve to obtain mixed powder; MCC pill cores are weighed and put into a centrifugal granulation coating machine, the binder water is sprayed, the mixed powder is added to coat the pill cores, and after coating, the pellets are dried to a moisture content of <2%.

8. The method for preparing diclofenac sodium pellets according to claim 6, characterized in that: When the binder is a PVP k25 aqueous solution, diclofenac sodium and colloidal silicon dioxide are weighed and passed through a 40-mesh sieve to obtain a mixed powder 1; microcrystalline cellulose powder is weighed, mixed with the mixed powder 1 and passed through a 40-mesh sieve to obtain a mixed powder; PVP k25 is weighed, added to purified water, stirred evenly and set aside; MCC pill cores are weighed, put into a centrifugal granulation coating machine, the binder PVP k25 aqueous solution is sprayed, the mixed powder is added to coat the pill cores, and after coating, the pill cores are dried to a moisture content of <2%.

9. A diclofenac sodium enteric-coated micropellet, the micropellet comprising, from inside to outside, an MCC core, a diclofenac sodium drug layer and an enteric coating layer, characterized in that The diclofenac sodium drug layer contains 40%-45% of diclofenac sodium, 20%-25% of microcrystalline cellulose PH105, 0.5%-1.5% of PVP k25 and 0.5%-1.5% of colloidal silicon dioxide by mass percentage.

10. A diclofenac sodium sustained-release pellet, the pellet comprising an MCC pellet core, a diclofenac sodium drug layer and a sustained-release coating layer from the inside to the outside, characterized in that The diclofenac sodium drug layer contains 40%-45% of diclofenac sodium, 20%-25% of microcrystalline cellulose PH105, 0.5%-1.5% of PVP k25 and 0.5%-1.5% of colloidal silicon dioxide by mass percentage.

Images