Dotenorad orally disintegrating tablet and preparation method thereof

Abstract

The invention relates to a dotenorad orally disintegrating tablet which is prepared from the following raw materials: dotenorad, a filling agent, an antistatic agent and a disintegrating agent. The dotenorad orally disintegrating tablet is prepared by adopting a powder direct compression process, the problems of more material loss, reduced finished product content and the like in a wet granulation process are solved by screening the variety and the dosage of the antistatic agent, and the patient compliance is better based on the dosage form of the orally disintegrating tablet.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a polytinoreplast orally disintegrating tablet and a preparation method thereof. Background Art

[0002] Dotinorab is a highly selective urate transporter 1 (URAT1) inhibitor. It effectively inhibits URAT1 in the proximal renal tubules, promoting renal excretion of uric acid and thereby lowering serum uric acid levels. Compared with traditional non-selective URAT1 inhibitors, dotinorab does not affect the function of the uric acid excretion factors ABCG2 and OAT1 / 3, resulting in a higher serum uric acid-lowering efficacy, reduced hepatotoxicity, and improved safety and tolerability.

[0003] Dotinorel tablets were developed by Fuji Pharma Co., Ltd. and launched in Japan in 2020 for the treatment of hyperuricemia and gout. On December 6, 2024, the 1mg and 2mg strengths of Dotinorel tablets received NMPA approval for the treatment of patients with gout and hyperuricemia.

[0004] The CAS registration number of dotinorel is 1285572-51-1 and the molecular formula is C 14 H9C l2 NO4S, with a molecular weight of 358.20, is a white or pale yellowish-white crystalline powder that is poorly soluble in ethanol (99.5) or methanol and virtually insoluble in water. Dotinol is stable under high temperature, high humidity, and light conditions.

[0005] The original patent EP4074313A1 uses wet granulation for sample preparation. During the preparation process, the material is easily adsorbed on the surface of the equipment, which reduces the content of the finished product. This patent ensures the qualified content of the finished product by adjusting the ratio of three fillers: lactose, D-mannitol and microcrystalline cellulose. The prescription is relatively complex and there is a certain amount of material loss.

[0006] Therefore, there is an urgent need for an improved formulation of polyols and a process thereof. Summary of the Invention

[0007] The main purpose of the present invention is to provide a polytinol orally disintegrating tablet and a preparation method thereof. The polytinol orally disintegrating tablet is prepared by a powder direct compression process, and the problems of large material loss and reduced finished product content in the wet granulation process are overcome by screening the type and dosage of antistatic agents.

[0008] In a first aspect, the present invention provides a polytinol orally disintegrating tablet, which is made from the following raw materials: polytinol, a filler, an antistatic agent, and a disintegrant.

[0009] In some embodiments, the filler is selected from cellulose lactose, microcrystalline cellulose lactose, or spray-dried lactose, preferably microcrystalline cellulose lactose.

[0010] In some embodiments, the antistatic agent is selected from magnesium stearate, micronized silica gel and talc, preferably micronized silica gel.

[0011] In some embodiments, the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate and croscarmellose sodium, preferably sodium starch glycolate.

[0012] In some embodiments, the orally disintegrating tablet of dotinorex is made of 1-3 parts of dotinorex, 90-95.5 parts of filler, 3-6 parts of disintegrant, and 0.5-2 parts of antistatic agent.

[0013] Preferably, the orally disintegrating tablet of dotinoreplast is made of 2 parts of dotinoreplast, 90-95.5 parts of filler, 3-6 parts of disintegrant, and 0.5-2 parts of antistatic agent.

[0014] In some embodiments, the polytinol tablet is made of polytinol, microcrystalline cellulose lactose, sodium starch glycolate and micropowdered silica gel.

[0015] Preferably, the polytinol tablets are made of 1-3 parts of polytinol, 90-95.5 parts of microcrystalline cellulose lactose, 3-6 parts of sodium starch glycolate and 0.5-2 parts of micropowdered silica gel.

[0016] Preferably, the polytinol tablets are made of 2 parts of polytinol, 90-95.5 parts of microcrystalline cellulose lactose, 3-6 parts of sodium starch glycolate, and 0.5-2 parts of micropowdered silica gel.

[0017] Preferably, the polytinol tablets are made of 2 parts of polytinol, 92 parts of microcrystalline cellulose lactose, 5 parts of sodium starch glycolate, and 1 part of micropowdered silica gel.

[0018] Preferably, the polytinol tablets are made of 1 part of polytinol, 91-96.5 parts of microcrystalline cellulose lactose, 3-6 parts of sodium starch glycolate, and 0.5-2 parts of micropowdered silica gel.

[0019] Preferably, the polytinol tablets are made of 1 part of polytinol, 93 parts of microcrystalline cellulose lactose, 5 parts of sodium starch glycolate, and 1 part of micropowdered silica gel.

[0020] In a second aspect, the present invention provides a method for preparing the orally disintegrating tablets of dotinorex described in the first aspect, comprising the following steps:

[0021] 1) Weigh the prescribed amount of polytinol, filler, and disintegrant and pass through a 60-mesh sieve for later use;

[0022] 2) Mix the above materials in a hopper for 10-30 minutes;

[0023] 3) Add the prescribed amount of antistatic agent to the hopper and mix for 3-5 minutes to obtain the total mixed powder;

[0024] 4) The powder is compressed into tablets by a high-speed tablet press to obtain the finished product.

[0025] In a third aspect, the present invention provides use of the orally disintegrating dotinorate tablets described in the first aspect and the orally disintegrating dotinorate tablets prepared by the preparation method described in the second aspect in the preparation of drugs for treating hyperuricemia and gout.

[0026] Beneficial effects of the present invention:

[0027] ① The present invention adopts a powder direct compression process to replace a wet granulation process, which saves time and process and has obvious economic advantages.

[0028] ② The present invention investigates the effects of different antistatic agents on suppressing possible electrostatic adsorption of materials, determines the optimal type and dosage of antistatic agents, ensures qualified and stable content of the finished product, and improves the material yield.

[0029] ③ The present invention designs the dosage form as an orally disintegrating tablet, which is convenient to take (no water required) and quickly disintegrates or dissolves in the mouth compared to tablets. It can solve the swallowing difficulties of some patients (such as the elderly and children, patients with stroke, bedridden patients, esophageal problems, mental disorders, etc.), thereby improving patients' medication compliance.

[0030] In summary, the polytinol tablets prepared by the present invention have a simple preparation process, high yield, low cost, stable finished product content, are suitable for large-scale production, and have better medication compliance. DETAILED DESCRIPTION

[0031] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0032] The specific material ratios, process conditions and results described in the present invention are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0033] Detection method (applied to the following embodiments)

[0034] content

[0035] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512).

[0036] Solvent mobile phase.

[0037] Test solution: Take 10 tablets of this product, accurately weigh them, calculate the average tablet weight, take 5 tablets, accurately weigh them, place them in a 100ml volumetric flask, add an appropriate amount of solvent, sonicate and shake to dissolve, dilute to the scale with solvent, shake well, centrifuge, accurately measure 1ml (2mg specification) or 2ml (1mg specification) of supernatant, place it in a 10ml volumetric flask, dilute to the scale with solvent, and shake well.

[0038] Reference solution: Take an appropriate amount of polytinorel reference substance, accurately weigh it, add an appropriate amount of solvent, dissolve it by ultrasonication, and dilute it with solvent to make a solution containing approximately 10 μg of polytinorel per 1 ml.

[0039] The chromatographic conditions were as follows: octadecylsilane bonded silica gel was used as the filler; 0.1% phosphoric acid water-acetonitrile (60:40) was used as the mobile phase; the flow rate was 1.0 ml per minute; the column temperature was 40° C.; the detection wavelength was 275 nm; the injection temperature was 25° C.; and the injection volume was 20 μl.

[0040] Determination Method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph, record the chromatogram, and calculate the peak area according to the external standard method.

[0041] Disintegration time

[0042] Determined according to the disintegration time test method (Chinese Pharmacopoeia 2025 Edition Part IV General Chapter 0921).

[0043] The instrument mainly consists of a lifting bracket and a stainless steel tube with a screen at the bottom. The lifting bracket moves up and down a distance of 10mm ± 1mm, and the reciprocating frequency is 30 times per minute.

[0044] Disintegration basket stainless steel tube, tube length 30mm, inner diameter 13.0mm, stainless steel screen (set at the bottom of the stainless steel tube) with mesh inner diameter 710μm

[0045] Inspection method: Secure a stainless steel tube to a bracket and immerse it in a 1000ml cup filled with approximately 900ml of water at 37°C ± 1°C. Adjust the water level so that the screen is 15mm ± 1mm ​​below the water surface when the tube is at its lowest point. Start the instrument. Place one tablet of this product in the aforementioned stainless steel tube for inspection. It should completely disintegrate and pass through the screen within 60 seconds. If a small amount of light material floats up or adheres to the inner wall of the tube or screen, but there is no hard core, it can be considered to meet the requirements. Repeat the test on 6 tablets, and all should meet the requirements. If 1 tablet does not meet the requirements, retest 6 more tablets, and all should meet the requirements.

[0046] Example 1 Comparison of the present invention's prescription with the original prescription

[0047] Comparative preparations

[0048] A comparative preparation was prepared with reference to the prescription of Example 9 in the original patent EP4074313A1, with a prescription quantity of 2000 tablets (specification 2 mg), and the prescription is as follows:

[0049] composition Single tablet amount / mg Feeding amount / g Dotinor 2 4 lactose 49.5 99 microcrystalline cellulose 15 30 D-Mannitol 25 50 Carboxymethylcellulose 5 10 Hydroxypropyl methylcellulose 3 6 magnesium stearate 0.5 1

[0050] Preparation method: Weigh docinol, lactose, microcrystalline cellulose and D-mannitol and transfer them to a wet granulation pot, set the stirring speed to 200-300 rpm, the shear speed to 1000-1500 rpm, and premix for 10-30 minutes. Keep the speed unchanged and spray the binder solution (10% aqueous solution of hydroxypropyl methylcellulose) into the mixture within 2-5 minutes. After the liquid is added, keep the speed unchanged and continue granulation for 2-5 minutes. Pass the wet granules through a 6*6mm sieve to granulate. Set the fluidized bed inlet air temperature to 60-80℃, dry until the granule moisture content is ≤3%, and pass the dry granules through a 1.2mm sieve to granulate. Transfer the dry granules and carboxymethyl cellulose to a hopper, mix for 10-30 minutes, add magnesium stearate and mix for 3-5 minutes to obtain the total mixed granules. The total mixed granules are pressed into 8mm round tablets by a high-speed tablet press.

[0051] Preparation 1

[0052] The prescription quantity is 2000 tablets (specification 2 mg), and the prescription is as follows:

[0053] composition Single tablet amount / mg Feeding amount / g Dotinor 2 4 Microcrystalline cellulose lactose 92 184 Sodium starch glycolate 5 10 Micro-powder silica gel 1 2

[0054] Preparation: Pass the above materials through a 60-mesh sieve for later use. Weigh all materials except the silica gel powder and transfer them to a hopper. Set the speed to 15 rpm and mix for 10 minutes. Add the silica gel powder and continue mixing for 3 minutes to obtain the final mixed powder. Press the mixture into 8 mm round tablets using a high-speed tablet press.

[0055] The material adsorption, yield (yield = total mixed powder or granule amount / feed amount * 100%) and finished product content during the preparation process of the comparative preparation and preparation 1 were characterized:

[0056]

[0057]

[0058] The results in the above table show that compared with the comparative preparation, Preparation 1 significantly improved the problem of easy adsorption of materials on the surface of the equipment during the preparation process, thereby improving the product yield while also ensuring a good finished product content.

[0059] Example 2 Screening of antistatic agent types

[0060] The formulations for Formulations 2 and 3 are essentially identical to Formulation 1, with only the type of antistatic agent being changed. The antistatic agent dosage was fixed at 1%, and the effectiveness of magnesium stearate, micronized silica gel, and talc in suppressing material adsorption was screened. The results are as follows:

[0061] Comparison Item Preparation 1 Preparation 2 Preparation 3 antistatic agent Micro-powder silica gel magnesium stearate talcum powder Adsorption The material is basically not adsorbed in the hopper A very small amount of material is adsorbed in the hopper The material is basically not adsorbed in the hopper Feeding amount / g 200.79 200.04 199.85 Total mixed powder or granule amount / g 199.59 194.25 196.70 Yield / % 99.4 97.1 98.4 content / % 99.2 98.5 98.4 RSD / % 1.4 3.1 1.0

[0062] The results in the above table show that the three different types of antistatic agents can effectively inhibit the material adsorption of the equipment. Among them, micro-powder silica gel has the best effect, and micro-powder silica gel is the preferred type of antistatic agent.

[0063] Example 3 Screening of the amount of micropowder silica gel

[0064] The formulations of Formulations 4 and 5 are essentially the same as Formulation 1, with only the amount of antistatic agent changed, with the change being due to the increase or decrease in filler. The antistatic agent was fixed as micropowdered silica gel, and the effect of different amounts on inhibiting material adsorption on the equipment was investigated. The results are as follows:

[0065]

[0066] The results in the table above show that the amount of micro powder silica gel in the range of 0.5-1.5% has a significant effect on inhibiting material adsorption equipment, and the preferred amount is 1%.

[0067] Example 4 Screening of filler types

[0068] The formulations of Formulations 6 and 7 are essentially identical to Formulation 1, with only the filler type changing. The effects of cellulose-lactose, microcrystalline cellulose-lactose, and spray-dried lactose on the final product content and disintegration time were investigated, with the following results:

[0069]

[0070]

[0071] The results in the table above demonstrate that the powder mixes corresponding to the three fillers exhibited minimal hopper adsorption, resulting in virtually no material loss during the preparation process. The final product content for all three fillers was excellent. Formulations 6 and 1 exhibited faster disintegration times than Formulation 7, likely due to the microcrystalline cellulose in the filler contributing to the disintegration of the finished product. Considering overall cost, microcrystalline cellulose lactose is the preferred filler.

[0072] Example 5 Screening of disintegrant types

[0073] The formulations for Formulations 8 and 9 are essentially identical to Formulation 1, with only the type of disintegrant changed. The disintegrant dosage was fixed at 5%, and the effects of three superdisintegrants, sodium starch glycolate, croscarmellose sodium, and crospovidone, on the disintegration time of this product were investigated. The results are as follows:

[0074] Comparison Item Preparation 8 Preparation 1 Preparation 9 Disintegrant type Croscarmellose sodium Sodium starch glycolate Cross-linked polyvinylpyrrolidone Disintegration time 51s-58s 32s-41s 2min-2min14s

[0075] The results in the table above show that Formulation 1 disintegrated the fastest, followed by croscarmellose sodium, and finally crospovidone. Sodium starch glycolate is the preferred disintegrant.

[0076] The orally disintegrating tablets of dotinorex described in the present invention are prepared by direct compression of powder, and have the advantages of low material cost, high finished product yield, uniform finished product content, and rapid disintegration. Compared with the original tablets, they have achieved comprehensive improvements in preparation cost, quality control, patient compliance, etc.

Claims

1. A polytinol orally disintegrating tablet, characterized in that: Made from the following raw materials: dotinorel, filler, antistatic agent, disintegrant.

2. The orally disintegrating tablet of dotinorex according to claim 1, characterized in that The filler is selected from cellulose lactose, microcrystalline cellulose lactose or spray-dried lactose, preferably microcrystalline cellulose lactose.

3. The orally disintegrating tablet of dotinorex according to claim 1 or 2, characterized in that The antistatic agent is selected from magnesium stearate, micro-powder silica gel and talc, preferably micro-powder silica gel.

4. The orally disintegrating tablet of dotinorex according to any one of claims 1 to 3, characterized in that The disintegrant is selected from cross-linked polyvinylpyrrolidone, sodium starch glycolate and cross-linked sodium carboxymethylcellulose, preferably sodium starch glycolate.

5. The orally disintegrating tablets of any one of claims 1 to 4, characterized in that: The orodisintegrating tablets of polytinol are prepared from 1-3 parts of polytinol, 90-95.5 parts of filler, 3-6 parts of disintegrant, and 0.5-2 parts of antistatic agent. Preferably, the orodisintegrating tablets of polytinol are prepared from 2 parts of polytinol, 90-95.5 parts of filler, 3-6 parts of disintegrant, and 0.5-2 parts of antistatic agent.

6. The orally disintegrating tablets of any one of claims 1 to 5, characterized in that: The polytinol tablets are made of polytinol, microcrystalline cellulose lactose, sodium starch glycolate and micropowdered silica gel.

7. The orally disintegrating tablets of any one of claims 1 to 6, characterized in that: The polytinol tablets are made of 1-3 parts of polytinol, 90-95.5 parts of microcrystalline cellulose lactose, 3-6 parts of sodium starch glycolate, and 0.5-2 parts of micropowdered silica gel; or The polytinol tablets are prepared from 2 parts of polytinol, 90-95.5 parts of microcrystalline cellulose lactose, 3-6 parts of sodium starch glycolate, and 0.5-2 parts of micropowdered silica gel; or The polytinol tablet is prepared from 1 part of polytinol, 91-96.5 parts of microcrystalline cellulose lactose, 3-6 parts of sodium starch glycolate, and 0.5-2 parts of micropowdered silica gel.

8. The orally disintegrating tablets of any one of claims 1 to 7, characterized in that: The polytinol tablets are made of 2 parts of polytinol, 92 parts of microcrystalline cellulose lactose, 5 parts of sodium starch glycolate, and 1 part of micropowdered silica gel; or The polytinol tablets are prepared from 1 part of polytinol, 93 parts of microcrystalline cellulose lactose, 5 parts of sodium starch glycolate, and 1 part of micropowdered silica gel.

9. The method for preparing the orally disintegrating tablets of dotinorex according to any one of claims 1 to 8, comprising the following steps: 1) Weigh the prescribed amount of polytinol, filler, and disintegrant and pass through a 60-mesh sieve for later use; 2) Mix the above materials in a hopper for 10-30 minutes; 3) Add the prescribed amount of antistatic agent to the hopper and mix for 3-5 minutes to obtain the total mixed powder; 4) The powder is compressed into tablets by a high-speed tablet press to obtain the finished product.

10. Use of the orally disintegrating tablets of dotinorex according to any one of claims 1 to 8 or the orally disintegrating tablets of dotinorex prepared by the preparation method according to claim 9 in the preparation of drugs for treating hyperuricemia and gout.

Images