Oral solid preparation for treating gout and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and provides an oral solid preparation for treating gout and a preparation method thereof. The preparation method comprises the following steps: sieving a filling agent, a disintegrating agent, an adhesive and dotenorad to obtain a sieved material; and mixing the sieved material and a lubricant, and tabletting to obtain the oral solid preparation for treating gout, the filling agent is lactose, mannitol and microcrystalline cellulose. By optimizing the prescription and the preparation process, the dissolution rate and bioavailability of the medicine are improved, so that the curative effect is improved; by selecting proper auxiliary materials and preparation types, the stimulation to gastrointestinal tracts is reduced, and the tolerance of patients is improved; the oral solid preparation is convenient to take, accurate in dosage, high in patient compliance and beneficial to long-term treatment; moreover, the preparation method provided by the invention is simple to operate, easy for industrial production and relatively low in cost.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an oral solid preparation for treating gout and a preparation method thereof. Background Art

[0002] Gout is a disease caused by purine metabolism disorders, which lead to elevated blood uric acid levels and the deposition of urate crystals in joints, soft tissues, bones, and kidneys. Clinical manifestations include hyperuricemia and recurrent arthritis, which can lead to joint deformities and renal impairment over the long term. With improvements in living standards and changes in dietary patterns, the incidence of gout has been increasing year by year, making it a common metabolic disease.

[0003] As a drug with application potential in the treatment of gout, Dotinorel's mechanism of action is to inhibit uric acid transporter, reduce the reabsorption of uric acid by the kidneys, and thus lower blood uric acid levels. It shows certain clinical value in the treatment of gout and hyperuricemia.

[0004] Oral solid dosage forms are one of the most commonly used drug delivery methods in clinical practice, offering advantages such as ease of administration, accurate dosage, and low production costs. However, some currently available oral solid dosage forms for treating edema suffer from low solubility and poor oral absorption, resulting in low bioavailability and impacting efficacy.

[0005] The prior art uses a wet granulation process to prepare polytinorel tablets. However, the quality of granules produced by this process is significantly affected by factors such as equipment performance and operator skills. The production process is complex, the process stability is poor, and it is difficult to ensure uniform product quality. This has limited the industrial production and clinical application of polytinorel preparations.

[0006] Therefore, developing an oral solid preparation for the treatment of edema with simple process, high dissolution rate and good bioavailability has important clinical significance and market value. Summary of the Invention

[0007] In view of this, the present invention provides an oral solid preparation for treating gout and a preparation method thereof. The preparation method provided by the present invention has simple process, stable product quality, high drug solubility and good bioavailability.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] A method for preparing an oral solid preparation for treating gout, comprising the following steps:

[0010] sieving the filler, disintegrant, binder and docinolone to obtain a sifted material;

[0011] mixing the sieved material and the lubricant and then tableting to obtain an oral solid preparation for treating gout;

[0012] The filler is lactose, mannitol and microcrystalline cellulose; based on the total mass of the filler, disintegrant, binder, polytinol and lubricant as 100%, the mass fraction of the filler is 85-95%;

[0013] The main pressure of the tablet pressing is 6 to 14 kN.

[0014] Preferably, the mass ratio of lactose, mannitol and microcrystalline cellulose is 3.0-5.3:1.0-3.0:1.0.

[0015] Preferably, the binder comprises one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and hypromellose.

[0016] Preferably, the lubricant includes one or more of stearic acid, magnesium stearate and calcium stearate; and the disintegrant is carboxymethylcellulose.

[0017] Preferably, based on the total mass of the filler, disintegrant, binder, polytinol and lubricant as 100%, the mass fraction of the lubricant is 0.5% to 5%, the mass fraction of the binder is 2 to 8%; the mass fraction of the disintegrant is 2 to 6%, and the mass fraction of polytinol is 0.5% to 2%.

[0018] Preferably, the whole granule screening is to directly screen the filler, disintegrant, binder and polytinol; or the filler, disintegrant, binder and polytinol are first mixed to obtain a mixture, and then the mixture is screened.

[0019] Preferably, the screening is performed using a pulverizer, the screening speed is 300-800 rpm, and the mesh size is 0.8-1.5 mm.

[0020] Preferably, the mixing of the sieved material and the lubricant comprises: first mixing the sieved material for 10 to 20 minutes, and then adding the lubricant and mixing for 3 to 10 minutes.

[0021] Preferably, the hardness of the tablet is 30-100N, and the speed of the feeder is 10-30 rpm.

[0022] The present invention also provides an oral solid preparation for treating gout prepared by the preparation method described in the above scheme.

[0023] The present invention provides a method for preparing an oral solid formulation for treating gout, comprising the following steps: sieving a filler, a disintegrant, a binder, and polytinol to obtain a sieved material; mixing the sieved material with a lubricant for a second time and then tableting the mixture to obtain an oral solid formulation for treating gout; the fillers are lactose, mannitol, and microcrystalline cellulose; the mass fraction of the fillers is 85-95% based on the total mass of the filler, disintegrant, binder, polytinol, and lubricant as 100%; and the tableting pressure is 6-14 kN. The present invention utilizes a powder direct compression process to prepare the oral solid formulation of polytinol. By optimizing the formulation and preparation process, the drug's solubility and bioavailability are improved, thereby enhancing efficacy. By selecting appropriate excipients and formulation types, gastrointestinal irritation is reduced, improving patient tolerance. The oral solid formulation is easy to administer, has accurate dosage, and high patient compliance, facilitating long-term treatment. Furthermore, the preparation method provided by the present invention is simple to operate, efficient, and cost-effective, requiring commonly used production equipment, making it amenable to industrial production.

[0024] The present invention also provides an oral solid preparation for treating gout, prepared by the method described in the above scheme. The oral solid preparation provided by the present invention has a simple preparation process, stable quality, and excellent pharmaceutical properties, high solubility, good bioavailability, minimal gastrointestinal irritation, and high patient compliance, effectively improving the therapeutic effect of gout and the quality of life of patients. DETAILED DESCRIPTION

[0025] The present invention provides a method for preparing an oral solid preparation for treating gout, comprising the following steps:

[0026] sieving the filler, disintegrant, binder and docinolone to obtain a sifted material;

[0027] The sieved material and the lubricant are mixed for a second time and then tabletted to obtain an oral solid preparation for treating gout;

[0028] The filler is lactose, mannitol and microcrystalline cellulose; based on the total mass of the filler, disintegrant, binder, polytinol and lubricant as 100%, the mass fraction of the filler is 80-95%;

[0029] The main pressure of the tablet pressing is 6 to 14 kN.

[0030] The present invention sieves a filler, a disintegrant, a binder, and polytinol to obtain a sieved material. In the present invention, the filler is lactose, mannitol, and microcrystalline cellulose, and the lactose is preferably lactose monohydrate; the mesh size of the lactose is preferably 200 mesh; the mass ratio of the lactose, mannitol, and microcrystalline cellulose is preferably 3 to 5.3:1 to 3:1, specifically 3.1:1.9:1, 3.2:1.9:1, 3.3:1.9:1, 4.2:1:1, or 5.3:3:1; the present invention uses lactose, mannitol, and microcrystalline cellulose as fillers, which can improve the solubility of the drug.

[0031] In the present invention, the binder preferably includes one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and hypromellose, more preferably hypromellose; and the disintegrant is preferably carboxymethyl cellulose.

[0032] In the present invention, the granulation screening is performed by a crushing and sizing machine, the screening rotation speed is preferably 300-800 rpm, more preferably 500 rpm, and the mesh size is preferably 0.8-1.5 mm, more preferably 1.2 mm.

[0033] In a specific embodiment of the present invention, the screening is preferably to directly screen the filler, disintegrant, binder and polytinol; when directly screening, it is preferably to put part of the lactose, mannitol, polytinol, microcrystalline cellulose, disintegrant, binder and the remaining part of the lactose into a crushing and granulating machine in sequence for screening, and the part of the lactose is preferably 1 / 2 of the total mass of the lactose; or, the screening is preferably to first mix the filler, disintegrant, binder and polytinol (referred to as the first mixing) to obtain a mixture, and then sieve the mixture; the first mixing is preferably carried out in a mixer, the time of the first mixing is preferably 10 to 20 minutes, more preferably 15 minutes, and the rotation speed of the first mixing is preferably 8 to 15 rpm, more preferably 10 rpm.

[0034] After obtaining the sieved material, the present invention mixes the sieved material and the lubricant (referred to as the second mixing) and then tablets are pressed to obtain an oral solid preparation for treating gout. In the present invention, the lubricant preferably includes one or more of stearic acid, magnesium stearate and calcium stearate, more preferably magnesium stearate; the second mixing preferably includes: first mixing the sieved material for 10 to 20 minutes, preferably 15 minutes, and then adding the lubricant and mixing for 3 to 10 minutes; the speed of the second mixing is preferably 8 to 15 rpm, more preferably 10 rpm; the tableting is carried out in a tablet press, and the main pressure of the tableting is 6 to 14 kN, specifically 6.5 kN, 7.2kN, 8.6kN, 9kN, 10.8kN, 12.7kN or 14kN, the tableting hardness is preferably 30-100N, specifically 34.1N, 39.6kN, 50N, 71.4N, 80.9N, 89.6N, or 100N, the tableting feeder speed is preferably 10-30rpm, specifically 15rpm, 20rpm or 25rpm; in a specific embodiment of the present invention, the main pressure and hardness are calculated as average values. The present invention controls the tableting conditions within the above range, which can improve the dissolution rate of the drug.

[0035] In the present invention, based on the total mass of the filler, disintegrant, binder, polytinol and lubricant as 100%, the mass fraction of the filler is 85-95%, specifically 90%, 90.5%, 91.4%, 92.5%, 93% or 94.4%; the mass fraction of the lubricant is preferably 0.5%-5%, specifically 0.5%, 1%, 3% or 5%, the mass fraction of the binder is preferably 2-8%, specifically 2%, 3% or 5%; the mass fraction of the disintegrant is preferably 2-6%, specifically 2%, 3% or 5%, the mass fraction of polytinol is preferably 0.5%-2%, specifically 1%.

[0036] The present invention also provides an oral solid preparation for treating gout prepared by the preparation method described in the above scheme; the oral solid preparation is specifically a tablet.

[0037] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0038] The sources of materials used in the following examples are as follows:

[0039] Reference preparation (URECE), licensed by Fuji Pharmaceutical Co., Ltd.

[0040] Lactose as a filler was purchased from Jiangsu Daoning Pharmaceutical Co., Ltd.; mannitol as a filler was purchased from Qingdao Mingyue Seaweed Group Co., Ltd.; microcrystalline cellulose as a filler was purchased from Jiangxi Xidian Pharmaceutical Excipients Co., Ltd.; hypromellose as a binder was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; carboxymethylcellulose as a disintegrant was purchased from NICHIRIN CHEMICAL INDUSTRIES, LTD.; magnesium stearate as a lubricant was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; and dotinol as an active ingredient was purchased from Shandong Jikun Biopharmaceutical Co., Ltd.

[0041] Example 1

[0042] prescription:

[0043]

[0044] Preparation method:

[0045] Lactose, mannitol, microcrystalline cellulose, carboxymethyl cellulose, hypromellose and polytinor are put into mixer, arranging mixing speed is 15rpm, mixing 10min, obtain compound.The compound is sieved using pulverizing granulator, and sieving speed is 500rpm, and screen aperture is 1.2mm.The material after sieving is put into mixer, arranging mixing speed is 15rpm, mixing 10min, afterwards adding magnesium stearate mixing 3min, tabletting, the parameter setting of tablet press is: main pressure mean value 8.2kN, hardness mean value 47.9N, feeder speed 15rpm.

[0046] Example 2

[0047] prescription

[0048]

[0049] Preparation method:

[0050] About 1 / 2 lactose, mannitol, polytinol, microcrystalline cellulose, carboxymethyl cellulose, hypromellose and remaining lactose are added to pulverizing granulator successively, pass through 1.0mm sieve successively at 500rpm rotating speed, after drop into mixer, arranging mixing speed is 15rpm, mixes 20min.Add magnesium stearate mixing 5min, tabletting, the parameter setting of tablet press is: main pressure mean value 7.2kN, hardness mean value 39.6N, feeder speed 10rpm.

[0051] Example 3

[0052] prescription

[0053]

[0054] Preparation method:

[0055] Lactose, mannitol, microcrystalline cellulose, carboxymethyl cellulose, hypromellose and polytinor are put into mixer, arranging mixing speed is 8rpm, mixes 20min, obtains compound. Compound is sieved using pulverizing granulator, and sieving speed is 300rpm, and sieve aperture is 1.5mm. Material after sieving is put into mixer, arranging mixing speed is 15rpm, mixes 10min, then adds magnesium stearate mixing 3min, tabletting, the parameter setting of tablet press is: main pressure mean value 12.7kN, hardness mean value 89.6N, feeder speed 25rpm.

[0056] Example 4

[0057] Dotinol tablets

[0058] prescription

[0059]

[0060] Preparation process:

[0061] About 1 / 2 lactose, mannitol, polytinol, microcrystalline cellulose, carboxymethyl cellulose, hypromellose and remaining lactose are added to pulverizing and granulating machine successively, pass through 1.2mm sieve cloth successively at 300rpm rotating speed, after drop into mixer, arranging mixing speed is 10rpm, mixes 20min.Add magnesium stearate mixing 10min, tabletting, the parameter setting of tablet press is: main pressure mean value 10.8kN, hardness mean value 71.4N, feeder speed 30rpm.

[0062] Example 5

[0063] prescription

[0064]

[0065] Preparation method:

[0066] About 1 / 2 lactose, mannitol, polytinol, microcrystalline cellulose, carboxymethyl cellulose, hypromellose and remaining lactose are added to pulverizing and granulating machine successively, pass through 1.2mm sieve cloth successively at 500rpm rotating speed, after drop into mixer, arranging mixing speed is 15rpm, mixes 20min.Add magnesium stearate mixing 5min, tabletting, the parameter setting of tablet press is: main pressure mean value 8.6kN, hardness mean value 80.9N, feeder speed 15rpm.

[0067] Example 6

[0068] prescription

[0069]

[0070] Preparation method:

[0071] Lactose, mannitol, microcrystalline cellulose, carboxymethyl cellulose, hypromellose and polytinor are put into mixer, arranging mixing speed is 10rpm, mixes 20min, obtains compound.Described compound is sieved using pulverizing granulator, and sieving speed is that 300rpm mesh aperture is 1.2mm.Material after sieving is put into mixer, arranging mixing speed is 15rpm, mixes 10min, adds magnesium stearate mixing 3min afterwards, tabletting, the parameter setting of tablet press is: main pressure mean value 6.5kN, hardness mean value 34.1N, feeder speed 20rpm.

[0072] Comparative Example 1

[0073] prescription

[0074]

[0075] Preparation method:

[0076] The preparation was performed using a wet granulation process: lactose, mannitol, microcrystalline cellulose, carboxymethylcellulose, hypromellose, and docinolone were placed in a wet granulator at a stirring speed of 150 rpm and a chopping speed of 500 rpm, and mixed for 15 minutes. The prescribed amount of purified water was atomized using a spray system at a low cutter speed to prepare the soft material. After complete addition, the material was granulated for 3 minutes. The granules were wet granulated using an oscillating granulator equipped with a 20-mesh screen and then dried in a fluidized bed at an inlet air temperature of 65°C and a fan frequency of 30 Hz. The granules were dry granulated using an oscillating granulator equipped with a 20-mesh screen, and magnesium stearate was added for final mixing. The tablets were then compressed using the following parameters: average main pressure of 8.7 kN, average hardness of 79.6 N, and feeder speed of 15 rpm.

[0077] Comparative Example 2

[0078] Dotinol tablets were obtained using the formulation and preparation method of Example 1, except that corn starch was used instead of mannitol.

[0079] Comparative Example 3

[0080] The preparation method of Example 1 was used to obtain polytinol tablets, except that the amount of filler was between 80% and 85%. The specific formula is as follows:

[0081]

[0082]

[0083] Comparative Example 4

[0084] Dotinol tablets were obtained using the formulation and preparation method of Example 1, except that the average main compression force during tableting was 15.7 kN.

[0085] Test Case

[0086] Dissolution curve determination of Dotinol tablets

[0087] Chromatographic conditions: octadecylsilane bonded silica gel was used as the filler (C18, 4.6 mm × 150 mm, 5 μm); triethylamine solution (5 mL of triethylamine was added to 1000 mL with water and the pH value was adjusted to 3.0 ± 0.5 with phosphoric acid)-acetonitrile (the volume ratio of triethylamine solution to acetonitrile was 50:50) was used as the mobile phase; the column temperature was 40°C; the flow rate was 1.2 mL / min, the detection wavelength was 275 nm, and the injection volume was 80 μL.

[0088] Take 12 tablets of this product and measure the dissolution and release rate according to the dissolution and release rate determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0931 Method 2).

[0089] Dissolution conditions: Use 1000 L of water as the dissolution medium, the rotation speed is 50 rpm, operate according to the law, and take samples at 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min.

[0090] Test solution: Take 10 mL of the eluate, discard 7 mL of the initial filtrate, and take the subsequent filtrate.

[0091] Reference solution: Take an appropriate amount of Dotinorel reference substance, accurately weigh it, dissolve it in the mobile phase and quantitatively dilute it to make a solution containing approximately 2 μg per 1 mL.

[0092] Determination method: Accurately measure the test solution and reference solution, and calculate the dissolution amount of each tablet.

[0093] The test results are shown in Table 1.

[0094] Table 1 Dissolution test results of polytinol tablets in various embodiments

[0095]

[0096]

[0097] As shown in the dissolution test results in Table 1, the present application can significantly improve drug dissolution by controlling the type, dosage, and preparation process of the filler. Comparative Example 1 uses a wet granulation process, and the resulting solid preparation has a slow dissolution rate and a low dissolution volume. Comparative Example 2 replaces mannitol with corn starch, and the resulting solid preparation has a slow dissolution rate and a low dissolution volume. In Comparative Example 3, the amount of filler used is 70% to 80%, and the dissolution volume is 10% to 20% lower than that of the example. In Comparative Example 4, the main tableting pressure is controlled to 15.7 kN, and the dissolution volume of the resulting solid preparation is reduced by 5% to 10%.

[0098] In summary, the polytinorel tablets prepared by the present invention have made great progress in terms of quality stability, dissolution rate, cost reduction and adaptability to industrial production. By optimizing the prescription process, the present invention can improve the stability and reliability of product quality, significantly increase the dissolution rate, and can exert drug efficacy more quickly to meet the treatment needs of patients. At the same time, the preparation method provided by the present invention uses commonly used equipment in the pharmaceutical industry, has a simple process flow, is easy to scale production, effectively reduces production costs, and improves production efficiency. Compared with the existing technology, the present invention has significant economic and social benefits, fully reflecting its creativity.

[0099] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing an oral solid preparation for treating gout, characterized in that: The following steps are involved: sieving the filler, disintegrant, binder and docinolone to obtain a sifted material; mixing the sieved material and the lubricant and then tableting to obtain an oral solid preparation for treating gout; The filler is lactose, mannitol and microcrystalline cellulose; based on the total mass of the filler, disintegrant, binder, polytinol and lubricant as 100%, the mass fraction of the filler is 85-95%; The main pressure of the tablet pressing is 6 to 14 kN.

2. The preparation method according to claim 1, characterized in that The mass ratio of the lactose, mannitol and microcrystalline cellulose is 3-5.3:1-3:

1.

3. The preparation method according to claim 1, characterized in that The binder includes one or more of polyvinyl pyrrolidone, hydroxypropyl cellulose and hypromellose.

4. The preparation method according to claim 1, characterized in that The lubricant includes one or more of stearic acid, magnesium stearate and calcium stearate; and the disintegrant is carboxymethyl cellulose.

5. The preparation method according to any one of claims 1 to 4, characterized in that Taking the total mass of the filler, disintegrant, binder, polytinol and lubricant as 100%, the mass fraction of the lubricant is 0.5% to 5%, the mass fraction of the binder is 2 to 8%, the mass fraction of the disintegrant is 2 to 6%, and the mass fraction of polytinol is 0.5% to 2.0%.

6. The preparation method according to claim 1, characterized in that The sieving is to directly sieve the filler, disintegrant, binder and polytinol; or first mix the filler, disintegrant, binder and polytinol to obtain a mixture, and then sieve the mixture.

7. The preparation method according to claim 1, characterized in that The sieving is performed by a crushing and granulating machine, the sieving rotation speed is 300-800 rpm, and the mesh size of the sieve is 0.8-1.5 mm.

8. The preparation method according to claim 1, characterized in that The mixing of the sieved material and the lubricant comprises: first mixing the sieved material for 10 to 20 minutes, and then adding the lubricant and mixing for 3 to 10 minutes.

9. The preparation method according to claim 1, characterized in that The hardness of the tablet is 30-100N, and the rotation speed of the feeder is 10-30rpm.

10. An oral solid preparation for treating gout prepared by the preparation method according to any one of claims 1 to 9.

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