Hydroxychloroquine sulfate medicament and method of preparation thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a hydroxychloroquine sulfate medicament and a preparation method thereof. The hydroxychloroquine sulfate or / and a filler is granulated by using a granulating liquid with a specific composition, a thin film is covered on the surface of the raw material, and the granule particle size is controlled, so that the moisture absorption and sticking and collision problems which are prone to occur in the hydroxychloroquine sulfate tablet are effectively solved, and the hydroxychloroquine sulfate tablet has consistent dissolution effect with the raw material.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a hydroxychloroquine sulfate preparation and its preparation method. Background Technology

[0002] Hydroxychloroquine (HCQ) is a 4-aminoquinoline derivative antimalarial drug available in both phosphate and sulfate forms. Due to its better solubility and fewer side effects, the sulfate form is primarily used clinically. Developed by Sanofi-Aventis, hydroxychloroquine sulfate tablets were first approved in the United States in 1955 under the brand name Plaquenil (200mg). It has since been marketed in many countries and regions worldwide and is currently used clinically primarily to treat rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus, and skin lesions triggered or exacerbated by sunlight. The structural formula of hydroxychloroquine sulfate is:

[0003]

[0004] Hydroxychloroquine sulfate is a white or off-white crystalline powder, easily hygroscopic, readily soluble in water, and practically insoluble in ethanol, chloroform, and ether. Upon absorbing water, hydroxychloroquine sulfate dissociates into hydroxychloroquine and sulfuric acid, both of which are highly corrosive to metals. During pharmaceutical production, due to the high proportion of hydroxychloroquine sulfate in the formulation (66.67%), it easily dissociates into sulfuric acid when the relative humidity of the production environment is high or when wet granulation is used. This sulfuric acid corrodes production equipment and accessories, especially tableting molds, causing rust and sticking, resulting in surface defects and unclear markings on the drug, posing significant challenges to the industrial production of pharmaceuticals.

[0005] Patent CN102525969B discloses a solid dosage form of hydroxychloroquine sulfate, which improves the solubility and stability of the hydroxychloroquine sulfate preparation through a pH buffer. However, this technical solution still suffers from sticking and punching problems caused by the hygroscopicity of the active pharmaceutical ingredient (API) during the drug production process. Patent CN102920674B uses anhydrous ethanol for wet granulation pretreatment of the API, which reduces the hygroscopicity of the API. However, the granulated API has poor flowability and is insufficient for subsequent processes, requiring secondary wet granulation with excipients, which greatly reduces production efficiency. Patent CN114224890B discloses a hydroxychloroquine sulfate drug composition and preparation method, using pregelatinized starch and other substances as disintegrants, combined with lubricants, which greatly improves the adsorption of water molecules and can solve the problem of tablet sticking and punching caused by the hygroscopicity of hydroxychloroquine sulfate particles. However, the tableting humidity needs to be controlled to ≤40% during tableting. Summary of the Invention

[0006] (a) Technical problems to be solved

[0007] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a hydroxychloroquine sulfate preparation, which solves the problems of moisture absorption and sticking that are very likely to occur in the hydroxychloroquine sulfate dosage form by adding granulation liquid.

[0008] The method for preparing hydroxychloroquine sulfate provided by this invention forms a thin film on the surface of the raw drug by granulation solution, thus solving the problems of moisture absorption and sticking.

[0009] (II) Technical Solution

[0010] To achieve the above objectives, the main technical solutions adopted by the present invention include:

[0011] In a first aspect, the present invention provides a hydroxychloroquine sulfate preparation comprising: hydroxychloroquine sulfate, a granulation solution, and a pharmaceutically acceptable excipient.

[0012] Optionally, the granulation solution consists of granules and a dispersant, wherein the granules include one or more of the following: polyvinylpyrrolidone, methacrylic acid copolymer, methylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxyethylcellulose, lactose, starch, polyethylene glycol, talc, and silica.

[0013] The present invention, through the combination of the above-mentioned granules, when applied to the hydroxychloroquine sulfate preparation of the present invention, can solve the problems of moisture absorption and sticking during the preparation process.

[0014] Optionally, the dispersant may be one or both of purified water and ethanol. Purified water and ethanol are essential dispersants.

[0015] Preferably, the granules include one or more of the following: polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica.

[0016] Optionally, the components in the granulation solution are as follows by weight: 1-5 parts polyvinylpyrrolidone, 0.5-3 parts polyethylene glycol, 5-10 parts lactose, 1-5 parts talc, 0.5-3 parts silica, and 80-90 parts dispersant.

[0017] Optionally, the granulation solution forms a thin film on the surface of particles made from hydroxychloroquine sulfate.

[0018] Optionally, the solid content of the granulation solution is 10% to 20%.

[0019] Optionally, hydroxychloroquine sulfate is made into granules.

[0020] The particles include: large particles with a particle size greater than 40 mesh and small particles with a particle size less than 80 mesh;

[0021] The number of large particles is more than 35% of the total number of particles, and the number of small particles is less than 40% of the total number of particles.

[0022] Optionally, hydroxychloroquine sulfate and granulation solution are used in a weight ratio of 65-70:10-92.

[0023] Optionally, the ratio of each group is: hydroxychloroquine sulfate: filler: lubricant = 65-70: 20-35: 0.5-1.5.

[0024] Alternatively, the excipients may include fillers and lubricants.

[0025] Optionally, the filler is one or more of the following: lactose, corn starch, pregelatinized starch, dextrin, dicalcium phosphate, mannitol, microcrystalline cellulose, and silica microcrystalline cellulose.

[0026] Optionally, the lubricant is one or more of magnesium stearate, sodium stearate fumarate, glyceryl behenate, magnesium trisilicate, talc, and silica.

[0027] Optionally, the pharmaceutical preparation includes, but is not limited to: tablets, capsules, oral liquids, emulsions, suppositories, and patches.

[0028] Secondly, the present invention also provides a method for preparing the hydroxychloroquine sulfate preparation described in any of the above embodiments, comprising the following steps:

[0029] S1 is used to prepare the granulation solution;

[0030] S2. Add hydroxychloroquine sulfate to a wet granulator or fluidized bed and mix thoroughly.

[0031] S3 sprays the granulation solution into a wet granulator or fluidized bed in an atomized state for granulation, and then dries and granulates to obtain granules;

[0032] S4 mixes the granules and excipients and then compresses them into tablets to prepare hydroxychloroquine sulfate.

[0033] Optionally, in step S1, the method for preparing the granulation solution includes: adding the granules to a dispersant and dispersing them evenly using a stirrer, a high-shear emulsifier, or a colloid mill to obtain the granulation solution.

[0034] Optionally, in step S2, hydroxychloroquine sulfate and the filler are added to a wet granulator or fluidized bed and mixed evenly;

[0035] Optionally, step S3 is more specifically as follows: the granulation solution is atomized and sprayed into a wet granulator or fluidized bed at a pressure of 0.15–0.2 MPa for granulation. After granulation, the granules are placed in an oven or fluidized bed for drying at a temperature of 60°C. The granules are discharged when the drying loss is ≤2.0%. Then, a granulator is used for granulation, with a screen aperture of 1.5 mm. The number of particles larger than 40 mesh is controlled to be no less than 35% of the total number of particles, and the number of particles smaller than 80 mesh is controlled to be no more than 40% of the total number of particles.

[0036] Optionally, in step S4, the granulated particles are mixed with filler and lubricant and stirred for 5 minutes before being compressed into tablets to obtain hydroxychloroquine sulfate preparation.

[0037] (III) Beneficial Effects

[0038] The beneficial effects of this invention are:

[0039] The granulation solution of this invention is used to prepare hydroxychloroquine sulfate. Polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica are used as the granulation solution, which can effectively enhance the hygroscopic resistance and reduce adhesion. On this basis, controlling the particle size further enhances the hygroscopic resistance and reduces adhesion, and also has good dissolution performance, thus improving the quality and stability of the drug.

[0040] Among its benefits, the invention enhances the drug's resistance to moisture by coating the surface of the active pharmaceutical ingredient (API) with a thin film. This prevents moisture absorption, reduces changes in drug quality, and thus enhances the stability of hydroxychloroquine sulfate preparations.

[0041] Among the benefits, reduced adhesion occurs because the combined effects of polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica in the granulation solution effectively reduce adhesion between hydroxychloroquine sulfate particles and between particles and equipment surfaces. This helps maintain particle independence, promotes smooth granulation, and reduces blockages and equipment maintenance requirements during production.

[0042] Among its features, controlling particle size: By controlling the granulation process, this invention can precisely adjust the particle size of hydroxychloroquine sulfate particles. A consistent particle size distribution is beneficial for drug uniformity and stability, improves dissolution performance, and reduces dose variability.

[0043] The invention features a streamlined preparation process: It defines a specific combination of five components in the granulation solution—polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica—that facilitates a smoother preparation process. This particular solution composition provides suitable viscosity and flowability, enabling efficient spraying and coating processes, thereby improving production efficiency and product quality stability. Detailed Implementation

[0044] To better explain and facilitate understanding of the present invention, the present invention will be described in detail below through specific embodiments.

[0045] In the following examples and comparative examples, the amount of each component is based on 1000 tablets.

[0046] Example 1 and Example 2

[0047] Example 1 and Example 2 each provide a method for preparing hydroxychloroquine sulfate, the steps of which are as follows:

[0048] S1. Polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica are added to purified water and stirred evenly with a stirrer to obtain a granulation solution.

[0049] S2 adds hydroxychloroquine sulfate, lactose 1, and corn starch to a wet granulator and mixes them evenly.

[0050] S3 The granulation liquid is atomized and sprayed into the wet granulator of step S2 at a pressure of 0.2MPa for granulation. After granulation, it is placed in a fluidized bed for drying. The drying temperature is set at 60℃. When the drying weight loss of the particles is ≤2.0%, the particles are discharged and granulated by a granulator with a granulation screen particle size of 1.5mm.

[0051] S4 involves adding the granulated granules and magnesium stearate to a mixer and mixing for 5 minutes before compressing into tablets to obtain hydroxychloroquine sulfate.

[0052] The amounts of each component in Examples 1 and 2 are shown in Table 1:

[0053] Table 1

[0054]

[0055]

[0056] Hydroxychloroquine sulfate 65-70 parts, granulation solution 10-20 parts. Optionally, by weight, filler 20-25 parts, lubricant 0.5-1.5 parts.

[0057] Example 3

[0058] In this embodiment, the purified water in Example 1 is replaced with a mixture of purified water and anhydrous ethanol, compared to Example 1.

[0059] The preparation method of hydroxychloroquine sulfate provided in this embodiment includes the following steps:

[0060] S1. Polyvinylpyrrolidone, polyethylene glycol, lactose, talc and silica are added to a 40% ethanol solution and stirred evenly with a stirrer to obtain the granulation solution.

[0061] S2 adds hydroxychloroquine sulfate, lactose 1, and corn starch to a wet granulator and mixes them evenly.

[0062] S3 sprays the granulation liquid into the wet granulator at a pressure of 0.2MPa for granulation. After granulation, it is placed in a fluidized bed for drying. The drying temperature is set at 60℃. The material is discharged when the drying weight loss of the particles is ≤2.0%. The particles are then granulated using a granulator with a granulation screen particle size of 1.5mm.

[0063] S4 involves adding the granulated granules and magnesium stearate to a mixer and mixing for 5 minutes before compressing into tablets to obtain hydroxychloroquine sulfate.

[0064] The dosage of each component in this embodiment is shown in Table 2:

[0065] Table 2

[0066]

[0067]

[0068] Example 4

[0069] This embodiment provides a method for preparing hydroxychloroquine sulfate, the steps of which are as follows:

[0070] Preparation method:

[0071] S1 involves adding ethyl cellulose, polyethylene glycol, lactose, talc, and silica to purified water and dispersing them evenly using a high-shear emulsifier to obtain the granulation solution.

[0072] S2 adds hydroxychloroquine sulfate and lactose 1 to the fluidized bed and mixes them evenly;

[0073] S3 atomizes the granulation liquid into the fluidized bed at a pressure of 0.2MPa for granulation, sets the inlet air temperature to 60℃, and controls the material temperature to 35℃-45℃; after granulation, drying begins, setting the drying temperature to 60℃, and discharges the material when the drying weight loss of the granules is ≤2.0%, and granulates them using a granulator with a granulation screen particle size of 1.5mm.

[0074] S4 involves adding the granulated particles and magnesium stearate to a mixer, mixing for 5 minutes, then compressing and coating to obtain the final product.

[0075] The dosage of each component in this embodiment is shown in Table 3:

[0076] Table 3

[0077] composition Dosage (g) Hydroxychloroquine sulfate 200.0 First lactose 66.0 Ethyl cellulose 6.6 polyethylene glycol 3.2 Second lactose 14.6 talcum powder 4.6 silicon dioxide 3.0 Purified water 228.0 magnesium stearate 2.0

[0078] Example 5

[0079] This embodiment provides a method for preparing hydroxychloroquine sulfate, the steps of which are as follows:

[0080] S1. Polyvinylpyrrolidone, talc, and silica are added to purified water and stirred evenly with a stirrer to obtain the granulation solution.

[0081] S2 adds hydroxychloroquine sulfate, lactose, and corn starch to a wet granulator and mixes them evenly.

[0082] S3 sprays the granulation liquid into the wet granulator at a pressure of 0.2MPa for granulation. After granulation, it is placed in a fluidized bed for drying. The drying temperature is set at 60℃. The material is discharged when the drying weight loss of the particles is ≤2.0%. The particles are then granulated using a granulator with a granulation screen particle size of 1.5mm.

[0083] S4 involves adding the granulated particles and magnesium stearate to a mixer, mixing for 5 minutes, then compressing and coating to obtain the final product.

[0084] The dosage of each component in this embodiment is shown in Table 4:

[0085] Table 4

[0086] Prescription composition Dosage (g) Hydroxychloroquine sulfate 200.0 lactose 28.5 corn starch 60.0 Polyvinylpyrrolidone 2.0 talcum powder 1.5 silicon dioxide 0.5 Purified water 40.5 magnesium stearate 2.0

[0087] Example 6

[0088] This embodiment provides a method for preparing hydroxychloroquine sulfate, the steps of which are as follows:

[0089] S1. Polyvinylpyrrolidone, polyethylene glycol, talc and silica are added to purified water and stirred evenly with a stirrer to obtain the granulation solution.

[0090] S2 adds hydroxychloroquine sulfate, lactose, and corn starch to a wet granulator and mixes them evenly.

[0091] S3 sprays the granulation liquid into the wet granulator at a pressure of 0.2MPa for granulation. After granulation, it is placed in a fluidized bed for drying. The drying temperature is set at 60℃. The material is discharged when the drying weight loss of the particles is ≤2.0%. The particles are then granulated using a granulator with a granulation screen particle size of 1.5mm.

[0092] S4 involves adding the granulated particles and magnesium stearate to a mixer, mixing for 5 minutes, then compressing and coating to obtain the final product.

[0093] The dosage of each component in this embodiment is shown in Table 5:

[0094] Table 5

[0095] Prescription composition Dosage (g) Hydroxychloroquine sulfate 200.0 lactose 28.5 corn starch 60.0 Polyvinylpyrrolidone 2.0 polyethylene glycol 0.5 talcum powder 1.5 silicon dioxide 0.5 Purified water 40.5 magnesium stearate 2.0

[0096] Example 7

[0097] This embodiment provides a method for preparing hydroxychloroquine sulfate, the steps of which are as follows:

[0098] S1. Polyvinylpyrrolidone, lactose, polyethylene glycol and talc are added to purified water and stirred evenly with a stirrer to obtain the granulation solution.

[0099] S2 adds hydroxychloroquine sulfate, lactose, and corn starch to a wet granulator and mixes them evenly.

[0100] S3 sprays the granulation liquid into the wet granulator at a pressure of 0.2MPa for granulation. After granulation, it is placed in a fluidized bed for drying. The drying temperature is set at 60℃. The material is discharged when the drying weight loss of the particles is ≤2.0%. The particles are then granulated using a granulator with a granulation screen particle size of 1.5mm.

[0101] S4 involves adding the granulated particles and magnesium stearate to a mixer, mixing for 5 minutes, then compressing and coating to obtain the final product.

[0102] The amounts of each component in this embodiment are shown in Table 6:

[0103] Table 6

[0104] Prescription composition Dosage (g) Hydroxychloroquine sulfate 200.0 First lactose 28.5 corn starch 60.0 Polyvinylpyrrolidone 2.0 polyethylene glycol 0.5 Second lactose 5.0 talcum powder 1.5 Purified water 40.5 magnesium stearate 2.0

[0105] Example 8

[0106] This embodiment provides a method for preparing hydroxychloroquine sulfate, the steps of which are as follows:

[0107] S1. Polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica are added to purified water and stirred evenly with a stirrer to obtain a granulation solution.

[0108] S2 adds hydroxychloroquine sulfate, lactose 1, and corn starch to a wet granulator and mixes them evenly.

[0109] S3 The granulation liquid is atomized and sprayed into the wet granulator of step S2 at a pressure of 0.2MPa for granulation. After granulation, it is placed in a fluidized bed for drying. The drying temperature is set at 60℃. When the drying weight loss of the particles is ≤2.0%, the particles are discharged and granulated by a granulator with a granulation screen particle size of 1.5mm.

[0110] S4 involves adding the granulated granules and magnesium stearate to a mixer and mixing for 5 minutes before compressing into tablets to obtain hydroxychloroquine sulfate.

[0111] In this embodiment,

[0112] The ratio of hydroxychloroquine sulfate: granulation solution: lactose: corn starch: magnesium stearate is 65:8:10:10:0.5.

[0113] The granulation solution contains the following components by weight: 3 parts polyvinylpyrrolidone, 0.5 parts polyethylene glycol, 10 parts lactose, 3.5 parts talc, 3 parts silica, and 80 parts purified water.

[0114] Example 9

[0115] This embodiment provides a method for preparing hydroxychloroquine sulfate, which is the same as in Example 8, except that:

[0116] The ratio of hydroxychloroquine sulfate: granulation solution: lactose: corn starch: magnesium stearate is 70:10:5:20:1.

[0117] The granulation solution contains the following components by weight: 1 part polyvinylpyrrolidone, 3 parts polyethylene glycol, 7 parts lactose, 1 part talc, 0.5 parts silica, and 85 parts purified water.

[0118] Example 10

[0119] This embodiment provides a method for preparing hydroxychloroquine sulfate, which is the same as in Example 8, except that:

[0120] The ratio of hydroxychloroquine sulfate: granulation solution: lactose: corn starch: magnesium stearate is 68:5:10:25:1.5.

[0121] The granulation solution contains, by weight, 5 parts polyvinylpyrrolidone, 2.5 parts polyethylene glycol, 5 parts lactose, 5 parts talc, 2 parts silica, and 90 parts purified water.

[0122] Comparative Example 1

[0123] Comparative Example 1 provides a method for preparing hydroxychloroquine sulfate, the steps of which are as follows:

[0124] S1. Polyvinylpyrrolidone is added to purified water and stirred to dissolve, resulting in a polyvinylpyrrolidone solution;

[0125] S2 adds hydroxychloroquine sulfate, lactose, and corn starch to a wet granulator and mixes them evenly.

[0126] S3 Atomizes the polyvinylpyrrolidone solution into a wet granulator at a pressure of 0.2 MPa for granulation. After granulation, it is placed in a fluidized bed for drying. The drying temperature is set at 60℃. When the drying weight loss of the granules is ≤2.0%, the granules are discharged and granulated using a granulator with a granulation screen of 1.5 mm.

[0127] After sizing,

[0128] The particles include: large particles with a particle size greater than 40 mesh and small particles with a particle size less than 80 mesh;

[0129] The number of large particles is 25.9% of the total number of particles, and the number of small particles is 45.8% of the total number of particles.

[0130] S4 involves adding the granulated particles and magnesium stearate to a mixer, mixing for 5 minutes, then compressing and coating to obtain the final product.

[0131] The amounts of each component in this comparative example are shown in Table 7:

[0132] Table 7

[0133]

[0134]

[0135] Comparative Example 2

[0136] Comparative Example 2 provides a method for preparing hydroxychloroquine sulfate, the steps of which are as follows:

[0137] S1. Polyvinylpyrrolidone is added to purified water and stirred to dissolve, thus obtaining a polyvinylpyrrolidone solution.

[0138] S2 adds hydroxychloroquine sulfate, lactose, and corn starch to a wet granulator and mixes them evenly.

[0139] S3 Atomizes the polyvinylpyrrolidone solution into a wet granulator at a pressure of 0.2 MPa for granulation. After granulation, it is placed in a fluidized bed for drying. The drying temperature is set at 60℃. When the drying weight loss of the granules is ≤2.0%, the granules are discharged and granulated using a granulator with a granulation screen of 1.5 mm.

[0140] After sizing,

[0141] The particles include: large particles with a particle size greater than 40 mesh and small particles with a particle size less than 80 mesh;

[0142] The number of large particles accounts for 44.1% of the total number of particles, and the number of small particles accounts for 27.4% of the total number of particles.

[0143] S4 involves adding the granulated particles and magnesium stearate to a mixer, mixing for 5 minutes, then compressing and coating to obtain the final product.

[0144] The amounts of each component in this comparative example are shown in Table 8:

[0145] Table 8

[0146] composition Dosage (g) Hydroxychloroquine sulfate 200.0 lactose 28.5 corn starch 60.0 Polyvinylpyrrolidone 2.0 Purified water 40.5 magnesium stearate 2.0

[0147] Comparative Example 3

[0148] Comparative Example 3 provides a method for preparing hydroxychloroquine sulfate, which is the same as Comparative Example 2, except that:

[0149] After sizing,

[0150] The particles include: large particles with a particle size greater than 40 mesh and small particles with a particle size less than 80 mesh;

[0151] The number of large particles is 32.3% of the total number of particles, and the number of small particles is 46.9% of the total number of particles.

[0152] Comparative Example 4

[0153] Comparative Example 4 provides a method for preparing hydroxychloroquine sulfate, which is the same as in Example 1, except that:

[0154] The particles include: large particles with a particle size greater than 40 mesh and small particles with a particle size less than 80 mesh;

[0155] The number of large particles is 32.9% of the total number of particles, and the number of small particles is 47.2% of the total number of particles.

[0156] Implementation results:

[0157] 1. Particle size detection and tableting effect:

[0158] The granulated particles from Examples 1-5 and Comparative Examples 1-4 were subjected to particle size sieving and testing.

[0159] Table 1. Particle size distribution and tableting effect after granulation.

[0160]

[0161] From the data in Table 1, we can obtain:

[0162] In Examples 1-5 of this invention, the film is made by granulation solution of polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica, and the sticking phenomenon can be prevented by controlling the particle size.

[0163] In Comparative Examples 1 and 3, since the granulation solution contained only polyvinylpyrrolidone and the particle size was not within the range described in this invention (the number of large particles was more than 35% of the total number of particles and the number of small particles was less than 40% of the total number of particles), sticking and colliding occurred.

[0164] Although the particles in Comparative Example 2 were within the specified range, the granulation solution contained only polyvinylpyrrolidone, which still resulted in sticking and bubbling.

[0165] In Comparative Example 4, although the granulation solution was composed of polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica, sticking and colliding still occurred due to the unqualified particle size.

[0166] Therefore, only by using a granulation solution of polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica to form a film, and by controlling the particle size, can the sticking phenomenon be completely avoided.

[0167] 2. Dissolution test:

[0168] Take the hydroxychloroquine sulfate tablets prepared in Examples 1-7 and Comparative Examples 1-4 and the original formulation ( The leaching of the sample (batch number OR498) was detected in water, pH 1.0 medium, pH 4.5 medium, and pH 6.8 medium, respectively.

[0169] Table 2. Results of leaching in aqueous medium

[0170]

[0171]

[0172] Table 3. Dissolution results in hydrochloric acid medium at pH 1.0

[0173]

[0174] Table 4. Dissolution results in acetate medium at pH 4.5

[0175]

[0176] Table 5. Dissolution results in phosphate medium at pH 6.8

[0177]

[0178]

[0179] In Examples 1-5, granulation solution was used to granulate hydroxychloroquine sulfate and filler. After granulation, the particle size of the prepared particles was greater than 40 mesh, not less than 35%, and less than 80 mesh, not more than 40%. No sticking was found during tableting. However, in Comparative Examples 1-4, no granulation solution was used, and the prepared particles, regardless of particle size, all showed sticking during tableting.

[0180] By comparing the dissolution of Examples 1-7 and Comparative Examples 3-4, the dissolution of Examples 1-7 all fit the original reagent. The dissolution of Examples 1-3 fits the original reagent best. The dissolution of Examples 4 and Comparative Example 3 is slower than the original reagent. The dissolution of Example 5 is faster than the original reagent. This indicates that the granulation solution containing the five components of polyvinylpyrrolidone, polyethylene glycol, lactose, talc, and silica has the best dissolution performance.

[0181] Among them, the dissolution effect of Comparative Example 2 (not shown in the table) is comparable to that of Comparative Example 3, indicating that the particle size has no effect on the dissolution effect; however, the comparison of the dissolution effects of Example 1 and Comparative Example 4 shows that the particle size has a certain influence on the dissolution effect. Therefore, under the premise of the thin film in this invention, the particle size has a certain promoting effect on the dissolution effect.

[0182] The results show that the present invention uses a granulation solution with a specific composition to granulate hydroxychloroquine sulfate and / or a filler, covering the surface of the active pharmaceutical ingredient with a thin film. By controlling the particle size of the prepared particles, the problems of moisture absorption and sticking that are very likely to occur in hydroxychloroquine sulfate tablets can be effectively solved.

[0183] In addition, Examples 8-10 can also effectively solve the problems of moisture absorption and sticking that are very easy to occur in hydroxychloroquine sulfate tablets, and have a dissolution rate close to that of the original formulation, which will not be elaborated here.

[0184] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A hydroxychloroquine sulfate preparation, characterized in that, It includes: Hydroxychloroquine sulfate, granulation solution, and pharmaceutically acceptable excipients; The components in the granulation solution are as follows by weight: 1-5 parts polyvinylpyrrolidone, 0.5-3 parts polyethylene glycol, 5-10 parts lactose, 1-5 parts talc, 0.5-3 parts silica, and 80-90 parts dispersant; The granulation solution forms a thin film on the surface of particles made from hydroxychloroquine sulfate. The hydroxychloroquine sulfate was prepared into granules. The particles include: large particles with a particle size greater than 40 mesh and small particles with a particle size less than 80 mesh; The number of large particles is more than 35% of the total number of particles, and the number of small particles is less than 40% of the total number of particles.

2. The hydroxychloroquine sulfate preparation as described in claim 1, characterized in that: The solid content of the granulation solution is 10% to 20%.

3. The hydroxychloroquine sulfate preparation as described in claim 1, characterized in that: The hydroxychloroquine sulfate and the granulation solution are in a weight ratio of 65-70:10-92.

4. The hydroxychloroquine sulfate preparation according to any one of claims 1-3, characterized in that: The pharmaceutical preparations include tablets and capsules.

5. A method for preparing the hydroxychloroquine sulfate preparation as described in claim 1, characterized in that, It includes the following steps: Preparation of S1 granulation solution; S2. Place hydroxychloroquine sulfate in a wet granulator or fluidized bed and mix thoroughly. S3 sprays the granulation solution into a wet granulator or fluidized bed in an atomized state for granulation, and then dries and granulates to obtain granules. S4 mixes the granules and excipients and then compresses them into tablets to obtain the hydroxychloroquine sulfate preparation.

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