Anti-hyperuricemia drug and preparation method thereof

Abstract

The present invention discloses an anti-hyperuricemia drug and a preparation method thereof. The drug comprises the following components in parts by mass: 200 parts of allopurinol; 10 to 35 parts of lactose; 15 to 50 parts of component A; 1 to 5 parts of component B; 20 to 60 parts of component C; 0.6 to 2.4 parts of lubricant; component A is selected from at least one of microcrystalline cellulose, lactose, mannitol, sorbitol, calcium hydrogen phosphate and starch; component B is selected from at least one of povidone, copovidone, poloxamer 188, carbomer, sodium alginate and deacetylated chitosan; component C is selected from glyceryl behenate and / or glyceryl monostearate. Its preparation method is as follows: sieving the raw materials; adding water to component B to prepare a binder; adding allopurinol, component A and component C to a granulator, adding a binder for wet granulation, and adding a lubricant to tablet after drying to obtain the drug. The drug of the present invention has a sustained release effect and is simple to prepare.

Description

Technical Field

[0001] The invention relates to an anti-hyperuricemia drug and a preparation method thereof, and belongs to the field of medicine. Background Art

[0002] Allopurinol was first discovered by Roland K. Robins of Wellcome Research Laboratories (now GlaxoSmithKline) in the UK in 1956. It was first approved by the United States in 1966, and in 1967 Burroughs Wellcome (now GlaxoSmithKline) marketed it under the trade name Commercial sales. Allopurinol tablets are indicated for: ① primary and secondary hyperuricemia, especially hyperuricemia caused by excessive uric acid production; ② recurrent or chronic gout; ③ tophi; ④ uric acid kidney stones and (or) uric acid nephropathy; ⑤ hyperuricemia with renal insufficiency.

[0003] With the improvement of modern living standards, people's lifestyles and diets have also improved, which has led to an increase in the incidence of hyperuricemia. Hyperuricemia is a disease caused by a disorder in the metabolism of purine substances in the body. Persistent high uric acid may cause uric acid crystals and urate crystals to deposit in the renal pelvis, ureter or renal tubules and renal interstitium, causing kidney damage and kidney stones, becoming an invisible killer that endangers human health.

[0004] Allopurinol tablets are a uric acid synthesis inhibitor. Allopurinol and its metabolite oxypurinol can inhibit xanthine oxidase, prevent hypoxanthine and xanthine from being metabolized into uric acid, and thus reduce the production of uric acid. It reduces the uric acid content in blood and urine to a level below solubility, prevents uric acid from forming crystals and depositing in joints and other tissues, and also helps to redissolve uric acid crystals in the tissues of gout patients. Allopurinol also inhibits the synthesis of new purines in the body by acting on hypoxanthine-guanine phosphate nucleic acid transferase. Therefore, allopurinol is a drug with a more definite effect in preventing acute attacks of gout. It is also the only drug that can effectively reduce uric acid production and lower uric acid levels in the human body. As a first-line drug for the clinical treatment of gout, allopurinol is completely absorbed through the gastrointestinal tract after oral administration, reaches peak blood drug concentration in 2 to 6 hours, has a half-life of 14 to 28 hours, and is metabolized into active oxypurinol by the liver with a half-life of 15 to 18 hours.

[0005] According to the instructions for use and dosage of allopurinol tablets in the "Second Batch of Chemical Drug Instructions Published by the State Drug Administration": Common dosage for adults: Initial dose 50 mg once, 1 to 2 times a day, can be increased by 50 to 100 mg per week to 200 to 300 mg a day, divided into 2 to 3 times. Measure blood and urine uric acid levels every 2 weeks. If they have reached normal levels, no more increments will be made. If they are still high, they can be increased again. However, the maximum daily dose shall not exceed 600 mg.

[0006] If 600 mg is taken per day, it must be taken in multiple doses, and the patient is at risk of forgetting. In addition, the adverse reactions of allopurinol tablets in the "Second Batch of Chemical Drug Instructions Published by the State Food and Drug Administration" are as follows: (1) Rash: It may appear as pruritic papules or urticaria. If the rash is widespread and persistent, and symptomatic treatment is ineffective and there is a tendency to worsen, the drug must be discontinued.

[0007] (2) Gastrointestinal reactions: including diarrhea, nausea, vomiting and abdominal pain.

[0008] (3) If leukopenia, thrombocytopenia, anemia, or bone marrow suppression occurs, drug discontinuation should be considered.

[0009] (4) Other symptoms include hair loss, fever, lymphadenopathy, hepatotoxicity, interstitial nephritis and allergic vasculitis.

[0010] (5) There have been reports abroad of several patients suffering sudden death of unknown cause while taking this drug.

[0011] If the condition is serious and multiple medications are required, the adverse reactions will inevitably be more serious. Therefore, if allopurinol is prepared into sustained-release tablets, reducing the number of medications, reducing adverse reactions, and increasing patient compliance are the main issues that need to be solved urgently by medical technology personnel. Summary of the invention

[0012] The purpose of the present invention is to provide an anti-hyperuricemia drug and a preparation method thereof.

[0013] The present invention provides an anti-hyperuricemia drug, which comprises the following components in parts by weight: 200 parts of allopurinol; 25-85 parts of component A; 1-5 parts of component B; 20-60 parts of component C; and 0.6-2.4 parts of a lubricant.

[0014] The component A is selected from at least one of microcrystalline cellulose, lactose, mannitol, sorbitol, calcium hydrogen phosphate and starch;

[0015] The component B is selected from at least one of povidone, copovidone, poloxamer 188, carbomer, sodium alginate and deacetylated chitosan;

[0016] The component C is selected from glyceryl behenate and / or glyceryl monostearate.

[0017] In the present invention, the povidone may specifically be povidone K25, povidone K30 or povidone K90.

[0018] In the above anti-hyperuricemia drug, the lubricant is selected from at least one of magnesium stearate, differential silica gel and talc.

[0019] In the above anti-hyperuricemia drug, the anti-hyperuricemia drug includes the following components in parts by weight: 200 parts of allopurinol; 39.5-70 parts of component A; 1.25-5 parts of component B; 30-50 parts of component C; and 0.6-1.6 parts of lubricant.

[0020] In the above anti-hyperuricemia drug, the anti-hyperuricemia drug includes the following components in parts by weight: 200 parts of allopurinol; 50-60 parts of component A; 1.25-5 parts of component B; 35-45 parts of component C; and 1.6 parts of lubricant.

[0021] In the above anti-hyperuricemia drug, the component A is lactose and microcrystalline cellulose; wherein, lactose is 12.5 to 30 parts and microcrystalline cellulose is 27 to 40 parts; or lactose is 23 parts and microcrystalline cellulose is 27 to 37 parts;

[0022] The component B is povidone, specifically povidone K30;

[0023] The component C is glyceryl behenate or glyceryl monostearate;

[0024] The lubricant is magnesium stearate.

[0025] In the above-mentioned anti-hyperuricemia drug, the anti-hyperuricemia drug is made of the following components in parts by mass: 200 parts of allopurinol; 12.5-30 parts of lactose; 32-40 parts of microcrystalline cellulose; 1.5-5 parts of povidone (specifically povidone K30); 30-50 parts of behenic acid glyceryl ester or monostearate glyceryl ester; and 0.6-1.6 parts of lubricant.

[0026] In the present invention, specifically, the anti-hyperuricemia drug is prepared from the following components in parts by weight: 200 parts of allopurinol, 23 parts of lactose, 32 parts of microcrystalline cellulose, 2.5 parts of povidone, 40 parts of glyceryl behenate, and 1.6 parts of magnesium stearate;

[0027] Or the anti-hyperuricemia drug, whose raw materials and auxiliary materials include the following substances in parts by mass: 200 parts of allopurinol, 23 parts of lactose, 27 parts of microcrystalline cellulose, 2.5 parts of povidone, 45 parts of glyceryl behenate, and 1.6 parts of magnesium stearate:

[0028] Or the anti-hyperuricemia drug, whose raw materials and auxiliary materials include the following substances in parts by weight: 200 parts of allopurinol, 23 parts of lactose, 37 parts of microcrystalline cellulose, 2.5 parts of povidone, 36 parts of glyceryl behenate, and 1.6 parts of magnesium stearate:

[0029] Or the anti-hyperuricemia drug, whose raw materials and auxiliary materials include the following substances in parts by mass: 200 parts of allopurinol, 23 parts of lactose, 29.5 parts of microcrystalline cellulose, 5 parts of povidone, 40 parts of glyceryl behenate, and 1.6 parts of magnesium stearate:

[0030] Or the anti-hyperuricemia drug, whose raw materials and auxiliary materials include the following substances in parts by mass: 200 parts of allopurinol, 23 parts of lactose, 33.25 parts of microcrystalline cellulose, 1.25 parts of povidone, 40 parts of glyceryl monostearate, and 1.6 parts of magnesium stearate:

[0031] Or the anti-hyperuricemia drug, whose raw materials and auxiliary materials include the following substances in parts by mass: 200 parts of allopurinol, 20 parts of lactose, 32 parts of microcrystalline cellulose, 2.5 parts of povidone, 50 parts of glyceryl behenate, and 1.6 parts of magnesium stearate:

[0032] Or the anti-hyperuricemia drug, whose raw materials and auxiliary materials include the following substances in parts by weight: 200 parts of allopurinol, 30 parts of lactose, 35 parts of microcrystalline cellulose, 3.5 parts of povidone, 30 parts of glyceryl behenate, and 0.6 parts of magnesium stearate:

[0033] Or the anti-hyperuricemia drug, whose raw materials and auxiliary materials include the following substances in parts by mass: 200 parts of allopurinol, 20 parts of lactose, 25 parts of microcrystalline cellulose, 1.5 parts of povidone, 50 parts of glyceryl behenate, and 2.6 parts of magnesium stearate:

[0034] The present invention provides a method for preparing the above-mentioned anti-hyperuricemia drug, comprising the following steps:

[0035] 1) passing the allopurinol, component A, component B and lubricant through a 60-mesh sieve respectively for later use;

[0036] 2) Weighing the component B, adding it into purified water to dissolve it, and preparing an adhesive for later use;

[0037] 3) adding the allopurinol, component A and component C to a wet mixing granulator in order, mixing, then adding the binder in step 2) for wet granulation, then performing fluidized bed drying, adding the lubricant, mixing evenly and tableting to obtain the anti-hyperuricemia drug.

[0038] In the above preparation method, the working parameters of the wet mixing granulator are set as follows:

[0039] Stirring speed 150~500rpm, shear speed 800~1500rpm;

[0040] The mixing time may be 3 to 6 minutes;

[0041] The granulation time may be 2.5 to 5 minutes.

[0042] In the present invention, the working parameters of the wet mixing granulator are as follows: stirring speed 200 rpm, shear speed 1000 rpm;

[0043] The mixing time is 5 min;

[0044] The granulation time is 3 min.

[0045] The present invention has the following advantages:

[0046] 1. The anti-hyperuricemia drug of the present invention is a sustained-release preparation containing allopurinol, which can effectively improve the blood drug concentration, make it more stable, reduce the number of dosing times, and ensure the safety of medication;

[0047] 2. The anti-hyperuricemia drug of the present invention has a sustained release effect, which is beneficial to improving patient compliance, reducing adverse reactions, and has broad market prospects;

[0048] 3. The preparation process of the present invention is simple, which increases the stability of the drug and ensures the safety of the anti-hyperuricemia drug. DETAILED DESCRIPTION

[0049] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0050] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0051] Embodiment 1,

[0052] 1000 200 mg allopurinol sustained-release tablets were prepared.

[0053] Prescription 1 is as follows:

[0054] 200 parts of allopurinol, 23 parts of lactose, 32 parts of microcrystalline cellulose, 2.5 parts of povidone K30, 40 parts of glyceryl behenate, and 1.6 parts of magnesium stearate;

[0055] The preparation process is as follows:

[0056] 1) Pass allopurinol, lactose, microcrystalline cellulose, glyceryl behenate and magnesium stearate through a 60-mesh sieve respectively for later use;

[0057] 2) Weigh povidone and add it into purified water, stir to dissolve, and prepare an adhesive for later use.

[0058] 3) Allopurinol, lactose, microcrystalline cellulose, and glyceryl behenate are added to a wet mixer granulator in order, the stirring speed is set to 200 rpm, the shear speed is set to 1000 rpm, and the mixture is mixed for 5 minutes. The prepared binder is then added for wet granulation for 3 minutes, and then fluidized bed drying is performed. Magnesium stearate is added, the mixture is mixed evenly, and tableting is performed to obtain the product.

[0059] Embodiment 2,

[0060] The components and contents are basically the same as those in Example 1 of the present invention, except that glyceryl behenate is increased and microcrystalline cellulose is reduced. The preparation method is the same as that in Example 1 of the present invention.

[0061] Prescription 2 is as follows:

[0062] 200 parts of allopurinol, 23 parts of lactose, 27 parts of microcrystalline cellulose, 2.5 parts of povidone K30, 45 parts of glyceryl behenate, and 1.6 parts of magnesium stearate;

[0063] Embodiment 3,

[0064] The components and contents are substantially the same as those in Example 1 of the present invention, except that the amount of behenic acid glyceryl in Example 1 is reduced and the amount of microcrystalline cellulose is increased accordingly; the preparation method is the same as that in Example 1 of the present invention.

[0065] Prescription 3 is as follows:

[0066] 200 parts of allopurinol, 23 parts of lactose, 37 parts of microcrystalline cellulose, 2.5 parts of povidone K30, 35 parts of glyceryl behenate, and 1.6 parts of magnesium stearate;

[0067] Embodiment 4,

[0068] The components and contents are basically the same as those in Example 1 of the present invention, except that the amount of povidone K30 in Example 1 is doubled and the amount of microcrystalline cellulose is reduced accordingly; the preparation method is the same as that in Example 1 of the present invention.

[0069] Prescription 4 is as follows:

[0070] 200 parts of allopurinol, 23 parts of lactose, 29.5 parts of microcrystalline cellulose, 5 parts of povidone K30, 40 parts of glyceryl behenate, and 1.6 parts of magnesium stearate;

[0071] Embodiment 5,

[0072] The components and contents are basically the same as those in Example 1 of the present invention, except that the amount of povidone is reduced by half and the amount of microcrystalline cellulose is increased by 1.25 parts. The preparation method is the same as that in Example 1 of the present invention.

[0073] The prescription is as follows:

[0074] 200 parts of allopurinol, 23 parts of lactose, 33.25 parts of microcrystalline cellulose, 1.25 parts of povidone K30, 40 parts of glyceryl behenate, and 1.6 parts of magnesium stearate;

[0075] Embodiment 6,

[0076] The behenic acid glyceryl in Example 1 was replaced by glyceryl monostearate, and the other components and preparation methods were the same.

[0077] Allopurinol 200 parts, lactose 23 parts, microcrystalline cellulose 32 parts, povidone K30 2.5 parts, glyceryl monostearate 40 parts, magnesium stearate 1.6 parts;

[0078] The preparation process is as follows:

[0079] 1) Pass allopurinol, lactose, microcrystalline cellulose, glyceryl monostearate and magnesium stearate through a 60-mesh sieve respectively for later use;

[0080] 2) Weigh povidone K30 and add it into purified water, stir to dissolve, and prepare an adhesive for later use.

[0081] 3) Allopurinol, lactose, microcrystalline cellulose, and glyceryl monostearate are added to a wet mixing granulator in order, the stirring speed is set to 200 rpm, the shear speed is set to 1000 rpm, and the mixture is mixed for 5 min. Then, the prepared binder is added for wet granulation, the mixture is granulated for 3 min, and then fluidized bed drying is performed. Magnesium stearate is added, the mixture is mixed evenly, and tableting is performed to obtain the product.

[0082] The prescriptions of the above embodiments 1 to 6 are summarized as follows:

[0083] Table 1 Prescription summary

[0084]

[0085]

[0086] The dissolution curves of the above examples were investigated to determine the effects of various formulation changes on the in vitro dissolution of the product. The specific results are shown in Table 2:

[0087] Table 2 Summary of dissolution test results

[0088]

[0089] Prescription 1 is the optimal prescription: its dissolution curve is relatively smooth, ensuring efficacy without causing toxic side effects to patients; Prescription 2 will result in poor efficacy; Prescription 3 may cause toxic side effects.

[0090] Embodiment 7,

[0091] The components and contents are the same as those in Example 1 of the present invention, and the preparation method is as follows:

[0092] The preparation process is as follows:

[0093] 1) Pass allopurinol, lactose, microcrystalline cellulose, glyceryl behenate and magnesium stearate through a 60-mesh sieve respectively for later use;

[0094] 2) Weigh povidone K30 and add it into purified water, stir to dissolve, and prepare an adhesive for later use.

[0095] 3) Allopurinol, lactose, microcrystalline cellulose, and glyceryl behenate are added to a wet mixer granulator in order, the stirring speed is set to 250 rpm, the shear speed is set to 800 rpm, and the mixture is mixed for 4.5 min. Then, the prepared binder is added for wet granulation, the mixture is granulated for 3 min, and then fluidized bed drying is performed. Magnesium stearate is added, the mixture is mixed evenly, and tableting is performed to obtain the product.

[0096] Embodiment 8,

[0097] The components and contents are the same as those in Example 1 of the present invention, and the preparation method is as follows:

[0098] The preparation process is as follows:

[0099] 1) Pass allopurinol, lactose, microcrystalline cellulose, glyceryl behenate and magnesium stearate through a 60-mesh sieve respectively for later use;

[0100] 2) Weigh povidone K30 and add it into purified water, stir to dissolve, and prepare an adhesive for later use.

[0101] 3) Allopurinol, lactose, microcrystalline cellulose, and glyceryl behenate are added to a wet mixer granulator in order, the stirring speed is set to 300 rpm, the shear speed is set to 1500 rpm, and the mixture is mixed for 4 minutes. The prepared binder is then added for wet granulation for 3 minutes, and then fluidized bed drying is performed. Magnesium stearate is added, the mixture is mixed evenly, and tableting is performed to obtain the product.

Claims

1. An anti-hyperuricemia drug, characterized in that: The anti-hyperuricemia drug is prepared from the following components in parts by weight: 200 parts of allopurinol, 23 parts of lactose, 32 parts of microcrystalline cellulose, 2.5 parts of povidone K30, 40 parts of glyceryl behenate and 1.6 parts of magnesium stearate.

2. The method for preparing the anti-hyperuricemia drug according to claim 1, comprising the following steps: 1) Passing the allopurinol, lactose, microcrystalline cellulose, glyceryl behenate and magnesium stearate through a 60-mesh sieve respectively for later use; 2) Weigh the povidone K30, add it into purified water, stir and dissolve it, and prepare an adhesive for later use; 3) adding the allopurinol, lactose, microcrystalline cellulose, and glyceryl behenate to a wet mixing granulator in order, mixing, then adding the binder in step 2) for wet granulation, then performing fluidized bed drying, adding the magnesium stearate, mixing evenly, and tableting to obtain the anti-hyperuricemia drug.

3. The preparation method according to claim 2, characterized in that: The operating parameters of the wet mixing granulator are as follows: Stirring speed 150~500rpm, shear speed 800~1500rpm; Mixing time is 3 to 6 minutes; The granulation time is 2.5~5min.

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