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WO2025218797A1 - 一种胶囊或固体制剂及其应用 - Google Patents

一种胶囊或固体制剂及其应用

Info

Publication number
WO2025218797A1
WO2025218797A1 PCT/CN2025/089923 CN2025089923W WO2025218797A1 WO 2025218797 A1 WO2025218797 A1 WO 2025218797A1 CN 2025089923 W CN2025089923 W CN 2025089923W WO 2025218797 A1 WO2025218797 A1 WO 2025218797A1
Authority
WO
WIPO (PCT)
Prior art keywords
capsule
microcrystalline cellulose
lactose
disintegrant
filler
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/089923
Other languages
English (en)
French (fr)
Inventor
陈鹏
李晓朋
邱燕
杜治强
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dongbao Purple Star Hangzhou Biopharmaceutical Co Ltd
Original Assignee
Dongbao Purple Star Hangzhou Biopharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dongbao Purple Star Hangzhou Biopharmaceutical Co Ltd filed Critical Dongbao Purple Star Hangzhou Biopharmaceutical Co Ltd
Publication of WO2025218797A1 publication Critical patent/WO2025218797A1/zh
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a capsule or solid preparation and application thereof.
  • Uric acid is a decomposition metabolite of purine nucleotides in the human body.
  • Purines are oxidatively metabolized in the liver to uric acid, which is then excreted by the kidneys and intestines.
  • Hyperuricemia is usually caused by purine metabolism disorders and/or decreased uric acid excretion. Due to the low solubility of uric acid, gout can develop when its concentration in the body increases. In recent years, the number of patients with hyperuricemia and gout has increased significantly, becoming the most common chronic non-communicable disease, and the trend is showing a younger age. Complications caused by hyperuricemia, such as gouty arthritis, gouty kidney disease, gouty kidney stones, gouty heart disease, and gouty hypertension, seriously affect people's daily lives.
  • xanthine oxidase inhibitors include allopurinol, febuxostat, and topiroxetine, which reduce uric acid production by interfering with xanthine oxidase.
  • Uric acid excretion agents include benzbromarone, probenecid, and lecithinide, which increase uric acid excretion by reducing uric acid reabsorption. While existing marketed drugs can reduce uric acid levels in patients, they also have significant drawbacks.
  • Xanthine oxidase inhibitors are not sufficiently effective, and approximately half of hyperuricemia patients cannot be effectively treated.
  • Uric acid excretion drugs have significant side effects, such as liver and kidney toxicity, which can easily cause liver and kidney damage in patients. Long-term use can also lead to disorders in uric acid synthesis and metabolism in the body.
  • the present invention aims to solve the technical problem that 2-((5-bromo-4-(3-cyclopropyl-5,5-difluoro-4,5,6,7-tetrahydrobenzothiophen-1-yl)-1,2,4-triazol-3-yl)thio)-2-methylpropionic acid is easily degraded in the formulation, and a pharmaceutical composition with stable physical and chemical properties cannot be provided, thereby failing to exert the uric acid-lowering effect of URAT1 (Uric acid anion transporter 1) inhibitors.
  • URAT1 User acid anion transporter 1
  • the present invention provides a capsule or solid preparation and application thereof.
  • the capsule or solid preparation product provided by the present invention has stable properties; the capsule or solid preparation shows a low onset dose in clinical application of gout and hyperuricemia, and has a significant effect in lowering blood uric acid compared with commercial products.
  • the present invention provides a capsule comprising a substance Z and pharmaceutical excipients;
  • the substance Z is a compound represented by Formula I or a pharmaceutically acceptable salt thereof;
  • the content of the compound represented by Formula I accounts for at least 5% of the mass of the capsule;
  • the pharmaceutical excipients comprise a binder, a disintegrant, and a filler;
  • the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch, sucrose and pregelatinized starch.
  • the capsule further comprises a glidant and/or a lubricant.
  • the binder can be selected from one or more of povidone, hydroxypropyl cellulose, hypromellose and sodium carboxymethyl cellulose, such as hypromellose.
  • the hypromellose may be hypromellose E5.
  • the content of the binder may be 1-5% of the mass of the capsule, preferably 2-4.5%, for example 3%.
  • the filler is selected from one or two of lactose, microcrystalline cellulose, mannitol and pregelatinized starch, such as microcrystalline cellulose, lactose and microcrystalline cellulose, microcrystalline cellulose and pregelatinized starch lactose, or mannitol and pregelatinized starch.
  • the starch is corn starch.
  • the microcrystalline cellulose may be microcrystalline cellulose PH101.
  • the lactose may be lactose 200 mesh.
  • the content of the filler may be 40-90% of the mass of the capsule, preferably 60.5-87%, such as 68.5%, 70.5% or 73.8%.
  • the disintegrant can be selected from one or more of crospovidone, crospovidone sodium, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; for example, crospovidone or sodium carboxymethyl starch.
  • the cross-linked polyvinylpyrrolidone may be cross-linked polyvinylpyrrolidone XL.
  • the content of the disintegrant may be 2-10% of the mass of the capsule, preferably 2-8%, such as 3%, 5% or 7%.
  • the glidant can be selected from one or both of silicon dioxide and talc, such as colloidal silicon dioxide.
  • the content of the glidant may be 0-1% of the mass of the capsule, such as 0.5%, 0.3% or 0.1%.
  • the lubricant can be selected from one or more of magnesium stearate, sodium stearyl fumarate, calcium stearate and sodium lauryl sulfate, such as magnesium stearate.
  • the content of the lubricant may be 0-1% of the mass of the capsule, such as 0.1%, 0.5% or 1%.
  • the particle size D50 of the raw material of the capsule can be 1 ⁇ m to 45 ⁇ m, preferably 9.55 ⁇ m to 44.30 ⁇ m or 1.29 ⁇ m to 25.58 ⁇ m, more preferably 2-30 ⁇ m, further preferably 5-30 ⁇ m, and further preferably 9.55 ⁇ m to 25.58 ⁇ m, for example 10 ⁇ m to 25 ⁇ m.
  • the composition comprises 2.5-40 mg of the substance Z, for example, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg or 40 mg of the substance Z.
  • the capsule comprises the following components by weight: 1-5% binder, 40-90% filler, 2-10% disintegrant, 0-1% glidant and 0-1% lubricant; preferably, the binder is selected from one or more of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose; the filler is selected from one or two of lactose, microcrystalline cellulose, mannitol and pregelatinized starch; the disintegrant can be selected from one or more of cross-linked povidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; the glidant is selected from one or more of silicon dioxide and talc; the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, calcium stearate and sodium lauryl sulfate.
  • the binder is selected from one or more of povidone, hydroxypropyl cellulose,
  • the capsule comprises the following components by weight:
  • binder 60.5-87% filler, 2-8% disintegrant, 0-1% glidant and 0-1% lubricant;
  • the binder is hypromellose;
  • the filler is microcrystalline cellulose, lactose and microcrystalline cellulose, microcrystalline cellulose and pregelatinized starch lactose or mannitol and pregelatinized starch;
  • the disintegrant is cross-linked polyvinylpyrrolidone or sodium carboxymethyl starch;
  • the glidant is colloidal silicon dioxide; and the lubricant is magnesium stearate.
  • the capsule comprises any combination of the following components by weight:
  • Combination 1 16.67% of a compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% microcrystalline cellulose PH101, 24.5% lactose 200 mesh, 3% hypromellose E5, 5% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;
  • Combination 2 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% microcrystalline cellulose PH101, 24.5% pregelatinized starch, 3% hypromellose E5, 5% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;
  • Combination 3 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 73.83% of microcrystalline cellulose PH101, 3% of hypromellose E5, 5% of crospovidone XL, 0.5% of colloidal silicon dioxide, and 1% of magnesium stearate;
  • Combination 4 16.67% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 49.33% microcrystalline cellulose PH101, 24.5% lactose 200 mesh, 3% hypromellose E5, 5% sodium starch glycolate, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;
  • Combination 5 20% of a compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% microcrystalline cellulose PH101, 30% lactose 200 mesh, 3% hypromellose E5, 5% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;
  • Combination 6 20% of a compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% pregelatinized starch, 30% mannitol, 3% hypromellose E5, 5% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;
  • Combination 7 20% of a compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% microcrystalline cellulose PH101, 28% lactose 200 mesh, 7% hypromellose E5, 3% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;
  • Combination 8 5% of a compound of Formula I or a pharmaceutically acceptable salt thereof, 56% of microcrystalline cellulose PH101, 30% of lactose 200 mesh, 3% of hypromellose E5, 5% of crospovidone XL, 0.5% of colloidal silicon dioxide, and 0.5% of magnesium stearate;
  • Combination 9 20% of a compound of Formula I or a pharmaceutically acceptable salt thereof, 40.5% microcrystalline cellulose PH101, 28% lactose 200 mesh, 3% hypromellose E5, 7% crospovidone XL, 0.5% colloidal silicon dioxide, and 1% magnesium stearate;
  • Combination 10 20% of a compound of Formula I or a pharmaceutically acceptable salt thereof, 41.2% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 3% of hypromellose E5, 7% of crospovidone XL, 0.3% of colloidal silicon dioxide, and 0.5% of magnesium stearate;
  • Combination 11 20% of the compound of Formula I or a pharmaceutically acceptable salt thereof, 41.8% of microcrystalline cellulose PH101, 28% of lactose 200 mesh, 3% of hypromellose E5, 7% of crospovidone XL, 0.1% of colloidal silicon dioxide and 0.1% of magnesium stearate.
  • the pharmaceutical excipient consists of the binder, the disintegrant, the filler and the glidant, or the pharmaceutical excipient consists of the binder, the disintegrant, the filler and the lubricant, or the pharmaceutical excipient consists of the binder, the disintegrant, the filler, the glidant and the lubricant.
  • the "capsule" in which each excipient accounts for the content of the capsule or the content of each excipient is the mass of the capsule does not include the shell of the capsule.
  • the capsule is prepared by the following method:
  • step 2 (2) spraying the binder solution (5% aqueous solution) into the mixture in step 1, controlling the atomization pressure to be greater than 1 bar to uniformly atomize the solution;
  • step 2 Dry the material in step 2 (40°C to 50°C) and control the end point moisture to less than 3%; the dried granules are sieved (24 mesh);
  • step 3 (4) mixing the dry granules in step 3, the glidant, the glidant, and the remaining disintegrant for 10 min;
  • the present invention provides a solid preparation comprising a substance Z and a pharmaceutical excipient;
  • the substance Z is a compound represented by Formula I or a pharmaceutically acceptable salt thereof;
  • the pharmaceutical excipient comprises a binder, a disintegrant, and a filler;
  • the content of the compound represented by Formula I accounts for at least 5% by weight of the solid preparation;
  • the raw material particle size D50 of the solid preparation is 5-30 ⁇ m;
  • the content and definition of each component of the solid preparation are as described in the aforementioned capsule.
  • the solid preparation may be a tablet or a capsule.
  • the solid preparation is prepared by the following method: the preparation method is method A or method B;
  • the method A comprises the following steps:
  • Described method B comprises the following steps:
  • the components of the solid formulation were mixed, sieved and tableted as described above.
  • the present invention also provides a use of a substance W in preparing a URAT1 inhibitor, wherein the substance W is the aforementioned capsule or solid preparation.
  • the present invention also provides a use of a substance W in preparing a medicine, wherein the substance W is the aforementioned capsule or solid preparation; the medicine is used to treat and/or prevent hyperuricemia or gout.
  • the present invention also provides a method for treating and/or preventing hyperuricemia or gout, comprising administering an effective amount of substance W to a subject; the substance W is the aforementioned capsule or solid preparation; and the drug is used to treat and/or prevent hyperuricemia or gout.
  • the present invention also provides a substance W for treating and/or preventing hyperuricemia or gout, wherein the substance W is the aforementioned capsule or solid preparation.
  • the present invention also provides a method for preparing the capsule, which comprises the following steps:
  • step 2 spraying the binder solution into the mixture in step 1, controlling the atomization pressure to be greater than 1 bar to uniformly atomize the solution;
  • step 2 Dry the material in step 2 (40°C to 50°C) and control the end point moisture to less than 3%; the dried granules are sieved (24 mesh);
  • step 3 (4) mixing the dry granules in step 3, the glidant, the glidant, and the remaining disintegrant for 10 min;
  • the reagents and raw materials used in the present invention are commercially available.
  • the present invention offers a promising advancement in providing a URAT1-containing capsule or solid formulation, its preparation method, and its application.
  • the formulation comprises a URAT1 inhibitor and a pharmaceutically acceptable excipient.
  • the composition demonstrates a low onset dose, safety, and superior efficacy in clinical applications for gout and hyperuricemia.
  • FIG1 is the clinical study results of the safety and effectiveness of Example 9.
  • the detection methods for impurities or related substances in this application are as follows:
  • the detection and analysis methods are as follows:
  • Test solution Randomly take 10 samples, accurately weigh them, and grind them into a fine powder using an agate mortar. Accurately weigh the fine powder and place it into a volumetric flask. Add solvent and dilute to the mark. Ultrasonicate in an ultrasonic device for 30 minutes. After the sonication is complete, transfer an appropriate amount to a centrifuge tube and centrifuge at 8000 rpm for 10 minutes. Collect the supernatant.
  • Reference substance solution Take an appropriate amount of reference substance, weigh it accurately, add solvent to dissolve it and dilute it to make a solution of specific concentration.
  • Chromatographic conditions Use octadecylsilane bonded silica gel as the filler (Agilent Eclipse Plus C18 column, 4.6 mm ⁇ 150 mm, 3.5 ⁇ m or a chromatographic column of equivalent performance); use 0.1% trifluoroacetic acid aqueous solution as mobile phase A, acetonitrile as mobile phase B, and a flow rate of 0.8 ml per minute. Perform gradient elution as shown in the table below; detection wavelength is 250 nm; column temperature is 40°C; injection volume is 10 ⁇ l.
  • Determination method Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.
  • Limit Calculate the content of each impurity and the total impurity by peak area according to the external standard method.
  • the dosage of this product is planned to range from 2.5mg to 40mg.
  • the dosage form is tentatively proposed as a tablet or capsule.
  • the formulation process selection of the present invention is described using a 25mg dosage form as an example.
  • composition B Preparation methods of composition B, composition C, composition D and composition E:
  • composition A was prepared by wet granulation, and had good compressibility, stable tablet weight, and no sticking or punching occurred.
  • Raw material particle size investigation The particle size of raw materials in oral solid dosage forms influences the drug's in vitro dissolution, in vivo bioavailability, and product stability.
  • This example uses a single batch of raw materials, crushed to different particle sizes using a pulverizer to prepare compositions to investigate the effect of particle size on formulation properties.
  • Particle size measurements using a Malvern laser particle size analyzer yield the following results:
  • composition I composition I, composition J, composition K, and composition L are consistent with the preparation methods, and the prescription dosages are shown in the table below.
  • composition in this example was tested according to the dissolution and release rate determination method (Chinese Pharmacopoeia General Chapter 0931, Method 2).
  • Dissolution conditions 900 ml of phosphate buffer solution (pH 6.8) (8.96 g of sodium hydroxide and 68.05 g of potassium dihydrogen phosphate were dissolved completely in 10 L of pure water, mixed uniformly, and the pH was adjusted to 6.8 with phosphoric acid or sodium hydroxide) was used as the dissolution medium, the rotation speed was 50 rpm, and samples were taken at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, respectively.
  • the dissolution results are shown in the table below.
  • Stability The composition was exposed to the influence factor condition of 60°C/75%RH for 7 days.
  • the content of relevant substances is shown in the following table.
  • compositions G, H, and I had comparable bioavailability.
  • the raw material particle size D50 ranged from 1.29 ⁇ m to 25.58 ⁇ m, with bioavailability ranging from 44.0% to 48.7%.
  • Composition I had a D50 of 44.30 ⁇ m, but its bioavailability was significantly lower, reaching only 34.8%.
  • composition was exposed to the influencing factor condition of 60°C/75%RH for 7 days, and the content of the relevant substances is shown in the following table.
  • the composition of the URAT1 inhibitor, the excipient includes a prescription ratio of (a) 50-87 weight% lactose or microcrystalline cellulose or a combination of the two; (b) 2-8 weight% crospovidone; (c) 0-1 weight% colloidal silicon dioxide, (d) 2-5 weight% hydroxypropyl methylcellulose; (e) 0-1 weight% magnesium stearate; the excipient prescription ratio range and preferred range are shown in the table below.
  • step 2 Dry and granulate the material in step 2
  • step 4 Mix the dry granules from step 3, colloidal silicon dioxide, magnesium stearate and additional crospovidone.
  • step 5 Use the coating material of the desired color to coat the tablets in step 5
  • composition containing a URAT1 inhibitor described in this embodiment comprises (a) 50-87 weight percent lactose or microcrystalline cellulose, or a combination thereof; (b) 2-8 weight percent crospovidone; (c) 0-1 weight percent colloidal silicon dioxide; (d) 2-5 weight percent hypromellose; and (e) 0-1 weight percent magnesium stearate. Specific proportions are set forth in the table below.
  • step 3 Dry the material in step 2 at 40-50°C, and control the moisture content at the end point to be less than 3%. Use a 24-mesh sieve to sieve the dried particles.
  • step 4 Press the mixture in step 4 into tablets, and control the tablet hardness in the range of 30 to 120N;
  • step 6 Use the coating material of the desired color to coat the tablets in step 5, and control the coating weight gain to 2% to 5%.
  • compositions P, Q, R and S of Example 5 were tested according to the dissolution and release rate test method (Chinese Pharmacopoeia General Chapter 0931 Method 2).
  • Dissolution conditions 900 ml of phosphate buffer solution (pH 6.8) (8.96 g of sodium hydroxide and 68.05 g of potassium dihydrogen phosphate were dissolved completely in 10 L of pure water, mixed evenly, and the pH adjusted to 6.8 with phosphoric acid or sodium hydroxide) was used as the dissolution medium. The rotation speed was 50 rpm. Samples were taken at 5, 10, 15, 20, 30, 45, 60, and 90 minutes. Dissolution results are shown in the table below. Within the specific formulation ratio range, the composition dissolves rapidly, with a rate greater than 85% in 15 minutes.
  • step 2 Prepare a solution of hypromellose and spray it into the mixture in step 1. Control the atomization pressure to be greater than 1 bar to ensure uniform atomization of the solution.
  • step 3 Dry the material in step 2 at 40-50°C, and control the moisture content at the end point to be less than 3%. Use a 24-mesh sieve to sieve the dried particles.
  • step 4 Press the mixture in step 4 into tablets, and control the tablet hardness in the range of 30 to 120N;
  • step 6 Use the coating material of the desired color to coat the tablets in step 5, and control the coating weight gain to 2% to 5%.
  • compositions S, T, and U maintain impurity levels below the pre-set limit of 0.5% for 12 months, demonstrating excellent stability.
  • the dosage form of this composition is designed as a conventional solid dosage form. Based on the production conditions and clinical medication needs, this composition can be designed into tablets or capsules. Based on the preparation process of Composition V in Example 7, a capsule dosage form is prepared. The specific preparation process is as follows:
  • step 2 Prepare a 5% aqueous solution of hypromellose and spray it into the mixture in step 1. Control the atomization pressure to be greater than 1 bar to ensure uniform atomization of the solution.
  • step 3 Dry the material in step 2 at 40-50°C, and control the moisture content at the end point to be less than 3%. Use a 24-mesh sieve to sieve the dried particles.
  • Composition P of Example 6 was used to evaluate the safety and efficacy of this composition in adult patients with hyperuricemia and without gout.
  • a randomized, double-blind, parallel, active/placebo-controlled clinical study was conducted. Patients with hyperuricemia (with or without gout) were enrolled and dosed for four consecutive weeks. The results are shown in the following table and Figure 1.

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Abstract

一种胶囊或固体制剂及其应用。提供了一种胶囊，其包含物质Z和药用的辅料；物质Z为如式I所示化合物或其药学上可接受的盐；式I所示化合物的含量占胶囊质量的至少5％；药用的辅料包含粘合剂、崩解剂和填充剂。胶囊或固体制剂的药学性质稳定，具有在痛风和高尿酸血症临床应用上显示出起效剂量低，安全优效等特点。

Description

一种胶囊或固体制剂及其应用
本申请要求申请日为2024年4月19日的中国专利申请2024104778523的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种胶囊或固体制剂及其应用。
背景技术
尿酸是人体内嘌呤核苷酸的分解代谢产物。嘌呤经肝脏氧化代谢变成尿酸，然后由肾脏和肠道排出。高尿酸血症通常由嘌呤代谢紊乱和/或尿酸排泄减少所导致。由于尿酸的溶解度小，体内浓度升高时可形成痛风。近年来，高尿酸血症及痛风的患病人数明显上升，已经成为最常见的慢性非传染性疾病，并且呈现年轻化趋势。包括由高尿酸血症引起的并发症如痛风性关节炎、痛风性肾脏病变、痛风性肾结石、痛风性心脏病、痛风性高血压等，严重影响人们的日常生活。
目前市场上用于治疗高尿酸血症的药物分为两类：黄嘌呤氧化酶抑制剂和排尿酸剂。黄嘌呤氧化酶抑制剂包括别嘌醇、非布司他和托匹司他等，通过干扰黄嘌呤氧化酶来减少尿酸的产生。排尿酸剂包括苯溴马隆、丙磺舒和雷西纳德等，通过减少尿酸的重吸收来增加尿酸的排泄。现有上市药物虽可以降低患者体内的尿酸含量，但也存在明显缺点；黄嘌呤氧化酶抑制剂药效不够，约一半高尿酸血症患者得不到有效治；而排尿酸药物存在较明显的副作用，如肝、肾毒性，容易导致患者的肝肾损伤，长期服用还会导致体内尿酸合成与代谢紊乱。
在对本品组合物研究时发现，由于原料的分子结构特性及理化性质，原料在制剂处方中易降解，无法提供一个理化性质稳定的药用组合物，从而无法发挥URAT1(Uric acid anion transporter 1)抑制剂降尿酸的作用。
发明内容
本发明为了解决2-((5-溴-4-(3-环丙基-5,5-二氟-4,5,6,7-四氢苯并噻吩-1-基)-1,2,4-三氮唑-3-基)硫代)-2-甲基丙酸在制剂处方中易降解，无法提供一个理化性质稳定的药用组合物，从而无法发挥URAT1(Uric acid anion transporter 1)抑制剂降尿酸的作用的技术问题。本发明提供了一种胶囊或固体制剂及其应用。本发明提供的胶囊或固体制剂产品性质稳定；胶囊或固体制剂在痛风和高尿酸血症临床应用上显示出起效剂量低，与商业化产品相比降低血尿酸的效果明显。
本发明提供了一种胶囊，其包含物质Z和药用的辅料；所述物质Z为如式I所示化合物或其药学上可接受的盐；所述如式I所示化合物的含量占所述胶囊质量的至少5％；所述药用的辅料包含粘合剂、崩解剂和填充剂；
某一方案中，所述填充剂选自乳糖、微晶纤维素、甘露醇、淀粉、蔗糖和预胶化淀粉中的一种或多种。
某一方案中，所述胶囊还包括助流剂和/或润滑剂。
某一方案中，所述粘合剂可选自聚维酮、羟丙纤维素、羟丙甲纤维素和羧甲基纤维素钠中的一种或多种，例如羟丙甲纤维素。
某一方案中，所述羟丙甲纤维素可为羟丙甲纤维素E5。
某一方案中，所述粘合剂的含量可为所述胶囊质量的1-5％，优选2-4.5％，例如3％。
某一方案中，所述填充剂选自乳糖、微晶纤维素、甘露醇和预胶化淀粉中的一种或两种，例如微晶纤维素、乳糖和微晶纤维素、微晶纤维素和预胶化淀粉乳糖或甘露醇和预胶化淀粉。
某一方案中，所述淀粉为玉米淀粉。
某一方案中，所述微晶纤维素可为微晶纤维素PH101。
某一方案中，所述乳糖可为乳糖200目。
某一方案中，所述填充剂的含量可为所述胶囊质量的40-90％，优选60.5-87％，例如68.5％、70.5％或73.8％。
某一方案中，所述崩解剂可选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙纤维素和羧甲基淀粉钠中的一种或多种；例如交联聚维酮或羧甲基淀粉钠。
某一方案中，所述交联聚维酮可为交联聚维酮XL。
某一方案中，所述崩解剂的含量可为所述胶囊质量的2-10％，优选2-8％，例如3％、5％或7％。
某一方案中，所述助流剂可选自二氧化硅和滑石粉中的一种或两种，例如胶态二氧化硅。
某一方案中，所述助流剂的含量可为所述胶囊质量的0-1％，例如0.5％、0.3％或0.1％。
某一方案中，所述润滑剂可选自硬脂酸镁、硬脂富马酸钠、硬脂酸钙和十二烷基硫酸钠中的一种或多种，例如脂酸镁。
某一方案中，所述润滑剂的含量可为所述胶囊质量的0-1％，例如0.1％、0.5％或1％。
某一方案中，所述胶囊的原料粒径D50可为1μm～45μm，优选为9.55μm～44.30μm或1.29μm～25.58μm，更优选为2-30μm，进一步优选为5-30μm，还优选为9.55μm～25.58μm，例如10μm～25μm。
某一方案中，所述组合物包含2.5-40mg的所述物质Z，例如2.5mg、5mg、10mg、20mg、25mg或40mg的所述物质Z。
某一方案中，所述胶囊为包含以重量计的如下组分：1-5％的粘合剂、40-90％的填充剂、2-10％的崩解剂、0-1％的助流剂和0-1％润滑剂；较佳地，所述粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素和羧甲基纤维素钠中的一种或多种；所述填充剂选自乳糖、微晶纤维素、甘露醇和预胶化淀粉中的一种或两种；所述崩解剂可选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙纤维素和羧甲基淀粉钠中的一种或多种；所述助流剂选自二氧化硅和滑石粉中的一种或多种；所述润滑剂选自硬脂酸镁、硬脂富马酸钠、硬脂酸钙和十二烷基硫酸钠中的一种或多种。
某一方案中，所述胶囊为包含以重量计的如下组分：
2-4.5％的粘合剂、60.5-87％的填充剂、2-8％的崩解剂、0-1％的助流剂和0-1％润滑剂；较佳地，所述粘合剂为羟丙甲纤维素；所述填充剂为微晶纤维素、乳糖和微晶纤维素、微晶纤维素和预胶化淀粉乳糖或甘露醇和预胶化淀粉；所述崩解剂为交联聚维酮或羧甲基淀粉钠；所述助流剂为胶态二氧化硅；所述润滑剂为脂酸镁。
某一方案中，所述胶囊为包含以重量计的如下组分的任一组合：
组合1、16.67％的如式I所示化合物或其药学上可接受的盐、49.33％的微晶纤维素PH101、24.5％的乳糖200目、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
组合2、16.67％的如式I所示化合物或其药学上可接受的盐、49.33％的微晶纤维素PH101、24.5％的预胶化淀粉、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
组合3、16.67％的如式I所示化合物或其药学上可接受的盐、73.83的微晶纤维素PH101、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
组合4、16.67％的如式I所示化合物或其药学上可接受的盐、49.33％的微晶纤维素PH101、24.5％的乳糖200目、3％的羟丙甲纤维素E5、5％的羧甲基淀粉钠、0.5％的胶态二氧化硅和1％的硬脂酸镁；
组合5、20％的如式I所示化合物或其药学上可接受的盐、40.5％的微晶纤维素PH101、30％的乳糖200目、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
组合6、20％的如式I所示化合物或其药学上可接受的盐、40.5％的预胶化淀粉、30％的甘露醇、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
组合7、20％的如式I所示化合物或其药学上可接受的盐、40.5％的微晶纤维素PH101、28％的乳糖200目、7％的羟丙甲纤维素E5、3％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
组合8、5％的如式I所示化合物或其药学上可接受的盐、56％的微晶纤维素PH101、30％的乳糖200目、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和0.5％的硬脂酸镁；
组合9、20％的如式I所示化合物或其药学上可接受的盐、40.5％的微晶纤维素PH101、28％的乳糖200目、3％的羟丙甲纤维素E5、7％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
组合10、20％的如式I所示化合物或其药学上可接受的盐、41.2％的微晶纤维素PH101、28％的乳糖200目、3％的羟丙甲纤维素E5、7％的交联聚维酮XL、0.3％的胶态二氧化硅和0.5％的硬脂酸镁；
组合11、20％的如式I所示化合物或其药学上可接受的盐、41.8％的微晶纤维素PH101、28％的乳糖200目、3％的羟丙甲纤维素E5、7％的交联聚维酮XL、0.1％的胶态二氧化硅和0.1％的硬脂酸镁。
本发明中，所述药用的辅料由所述粘合剂、所述崩解剂、所述填充剂和所述助流剂组成，或者，所述药用的辅料由所述粘合剂、所述崩解剂、所述填充剂和所述润滑剂组成，或者所述药用的辅料由所述粘合剂、所述崩解剂、所述填充剂、所述助流剂和所述润滑剂组成。
本发明中，各个辅料占胶囊的含量的或各个辅料的含量为胶囊质量中的“胶囊”的含义为不包括胶囊的外壳。
某一方案中，所述胶囊由如下方法制备得到：
(1)将所述物质Z为如式I所示化合物或其药学上可接受的盐、所述填充剂和40％-60(例如50％)的所述解崩剂混合；
(2)将所述粘合剂溶液(5％的水溶液)喷雾加入至步骤1中的混合物，控制雾化压力大于1bar使溶液均匀雾化；
(3)将步骤2中的物料干燥(40℃～50℃)，终点水分控制低于3％；干燥颗粒采用整粒(24目筛网)；
(4)将步骤3中的干颗粒、所述助流剂、所述助流剂和剩余所述解崩剂混合10min；
(5)将步骤4中的混合物充填胶囊。
本发明提供了一种固体制剂，其包含物质Z和药用的辅料；所述物质Z为如式I所示化合物或其药学上可接受的盐；所述药用的辅料包含粘合剂、崩解剂和填充剂；所述如式I所示化合物的含量占所述固体制剂质量的至少5％；所述固体制剂的原料粒径D50为5-30μm；
某一方案中，所述固体制剂各组分的含量和定义如前述胶囊所述。
某一方案中，所述固体制剂可为片剂或胶囊。
某一方案中，所述固体制剂由如下方法制备得到：所述制备方法为方法A或方法B；
所述方法A包括如下步骤：
(1)将如前所述物质Z、粘合剂、崩解剂和填充剂混合，经湿法制粒得到颗粒(制粒完成后过24目筛进行湿整粒)；经干燥(40℃～50℃)得到干颗粒(过24目筛)；
(2)将前述助流剂和润滑剂与干颗粒进行混合；
(3)压片；
所述方法B包括如下步骤：
将如前所述固体制剂的各组分混合、过筛和压片。
本发明还提供了一种物质W在制备URAT1抑制剂中的应用，所述物质W为前述胶囊或固体制剂。
本发明还提供了一种物质W在制备药物中的应用，所述物质W为前述胶囊或固体制剂；所述药物用于治疗和/或预防高尿酸血症或痛风。
本发明还提供了一种治疗和/或预防高尿酸血症或痛风的方法，所述方法包括向受试者施加有效量的物质W；所述物质W为前述胶囊或固体制剂；所述药物用于治疗和/或预防高尿酸血症或痛风。
本发明还提供了一种治疗和/或预防高尿酸血症或痛风的物质W，所述物质W为前述胶囊或固体制剂。
本发明还提供了一种胶囊的制备方法，其包括如下步骤：
(1)将所述物质Z为如式I所示化合物或其药学上可接受的盐、所述填充剂和40％-60(例如50％)所述解崩剂混合；
(2)将所述粘合剂溶液喷雾加入至步骤1中的混合物，控制雾化压力大于1bar使溶液均匀雾化；
(3)将步骤2中的物料干燥(40℃～50℃)，终点水分控制低于3％；干燥颗粒采用整粒(24目筛网)；
(4)将步骤3中的干颗粒、所述助流剂、所述助流剂和剩余所述解崩剂混合10min；
(5)将步骤4中的混合物充填胶囊。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明提供了一种含URAT1胶囊或固体制剂及其制备方法和应用，该制剂包含URAT1抑制剂及可药用的赋形剂，通过控制URAT1抑制剂原料粒径、特定原辅料的用量及粘合剂加入工艺，确保了制剂药学性质稳定。与市售产品相比，本发明提供的组合物在痛风和高尿酸血症临床应用上显示出起效剂量低，安全优效等特点。
附图说明
图1为实施例9安全性、有效性的临床研究结果。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例中使用的URAT1抑制剂的结构为
本申请中杂质或有关物质检测方法如下：
检测分析方法如下：
有关物质  照高效液相色谱法(通则0512)测定。
溶剂  乙腈-水(50:50)。
供试品溶液  随机取样品10片，精密称定，用玛瑙研钵研细。取细粉精密称定，置量瓶中，加溶剂稀释至刻度，置超声仪中超声30分钟，超声完毕后取适量转移至离心管中于8000转每分钟离心10分钟，取上清液；
对照品溶液  取对照品适量，精密称定，加溶剂溶解并稀释制成特定浓度的溶液。
色谱条件  用十八烷基硅烷键合硅胶为填充剂(Agilent Eclipse Plus C18柱，4.6mm×150mm，3.5μm或效能相当的色谱柱)；以0.1％三氟乙酸水溶液为流动相A，以乙腈为流动相B，流速为每分钟0.8ml，按下表进行梯度洗脱；检测波长为250nm；柱温为40℃；进样体积10μl。
测定法  精密量取供试品溶液和对照品溶液，分别注入液相色谱仪，记录色谱图。限度  按外标法以峰面积计算各杂质的含量和总杂。
实施例1
根据本品API在多个动物模型中的起效剂量和毒理的安全剂量，拟定本品的规格在2.5mg～40mg范围，为便于剂量探索试验给药，初步拟定剂型为片剂或胶囊。为说明本发明的特点，以25mg规格制剂为例，说明本发明制剂工艺的选择。
组合物A制备方法：
a.原料药和辅料预混合；
b.将混合好的物料湿法制粒；
c.制粒完成后过24目筛进行湿整粒；
d对湿颗粒40℃～50℃下进行干燥，过24目筛整粒；
e将胶态二氧化硅、硬脂酸镁与干颗粒进行混合；
f压片；
组合物B、组合物C、组合物D、组合物E制备方法：
a.原料药和辅料预混合；
b.将混合好的物料过24目筛；
c压片；
在此实施例中，组合物A处方采用湿法制粒，可压性良好，片重稳定且没有粘冲等情况发生。
实施例2
原料粒径考察：口服固体制剂中原料的粒径影响药品的体外溶出、体内生物利用度以及产品本身的稳定性。本实施例采用同一批原料，使用粉碎机粉碎至不同粒径分别制备组合物，研究粒径对制剂属性的影响。马尔文激光粒度仪检出粒径结果如下：
组合物I、组合物J、组合物K、组合物L的处方与制备方法一致，处方用量见下表。

制备方法：
a.原料药和辅料预混合；
b.将混合好的物料湿法制粒；
c.制粒完成后进行湿整粒；
d对湿颗粒进行干燥，整粒；
e将胶态二氧化硅、硬脂酸镁与干颗粒进行混合；
f压片；
将本实施例中的组合物照溶出度与释放度测定法(中国药典通则0931第二法)测定。溶出条件：以磷酸盐缓冲溶液(pH6.8)(取氢氧化钠8.96g和磷酸二氢钾68.05g于10L纯水中，溶解完全，混合均匀，用磷酸或氢氧化钠调节pH至6.8，即得)900ml为溶出介质，转速为每分钟50转，分别在5、10、15、20、30、45、60、90分钟时取样，溶出结果见下表。
结果表明：由于原料的水溶性较好，原料粒径D50在1.29μm～44.30μm范围内溶出无明显差异，15min溶出大于85％，针对体外溶出，无需严格控制粒径；
稳定性：组合物采用影响因素条件60℃/75％RH敞口放置7天，有关物质情况如下表所示。
稳定性数据显示，组合物L中原料粒径D50为1.29μm时，杂质RRT0.84增长明显，基于对杂质的控制，原料粒径D50应控制在9.55μm～44.30μm。
生物利用度：将组合物分别进行犬(n＝6)的口服生物利用度研究。每只犬单次静脉注射给药1mg/kg，另外组合物F、组合物G、组合物H、组合物I依次分别给药一片(2mg/kg)，检测给药后24小时血药浓度。测定不同原料粒径的组合物口服生物利用度。
*口服生物利用度＝口服给药的AUC0-last/注射给药的AUC0-last*注射给药的剂量/口服给药的剂量*100％
不同原料粒径的生物利用度结果显示，组合物G、组合物H、组合物I生物利用度相当，原料粒径D50在1.29μm～25.58μm，生物利用度在44.0％～48.7％，结果相当。组合物I原料D50为44.30μm，生物生物利用度有显著下降仅为34.8％。
现有研究数据表明：当原料粒径D50在9.55μm～25.58μm，粒径不影响药品的体外溶出、体内生物利用度以及产品本身的稳定性。
实施例3
API处方占比考察：采用同一批次API，设计处方占比分别为2.5％、5％、20％，制备组合物M、组合物N、组合物O，制备方法与实施例3所述一致，处方信息见下表。
组合物采用影响因素条件60℃/75％RH敞口放置7天，有关物质情况如下表所示。
结果表明：相比于组合物M，组合物N、组合物O提高处方中原料占比后，杂质RRT0.83/0.84增加幅度有明显降低。结合实施例2原料粒径对杂质的影响，初步分析是API占比小，增加了与不相容辅料的接触从而导致API降解，初步通过控制原料处方占比≥5％，并控制处方中各赋形剂的比例，以及在合理的储存条件下保存，从而降低API的降解速度。
实施例4：
根据实施例1～实施例3的研究结论，已明确工艺、原料粒径以及原辅料处方比例对组合物的体外溶出、生物利用度及稳定性存在影响。在实施例1～实施例4较优选的范围内，为更进一步说明本品的特点，本实施例对组合物的处方工艺进行充分说明。所述URAT1抑制剂的组合物，赋形剂包含处方比例(a)50-87重量％的乳糖或微晶纤维素或两者的组合；(b)2-8重量％的交聚维酮；(c)0-1重量％的胶态二氧化硅，(d)2-5重量％的羟丙甲纤维素；(e)0-1重量％的硬脂酸镁；赋形剂处方比例范围及优选范围见下表。
本实施例制备方法如下：
1、将URAT1抑制剂、微晶纤维素、乳糖、交联聚维酮混合。
2、将羟丙甲纤维素配成溶液后喷雾加入至步骤1中的混合物
3、将步骤2中的物料干燥、整粒
4、将步骤3中的干颗粒、胶态二氧化硅、硬脂酸镁和外加的交联聚维酮混合。
5、将步骤4中的混合物压制合适硬度的片剂
6、使用期望颜色的包衣材料，对步骤5中的片剂包衣
7、可选地，将步骤4中的混合物填充到胶囊壳中。
实施例5：
本实施例所述一种含URAT1抑制剂的组合物，包含处方比例(a)50-87重量％的乳糖或微晶纤维素或两者的组合；(b)2-8重量％的交聚维酮；(c)0-1重量％的胶态二氧化硅，(d)2-5重量％的羟丙甲纤维素；(e)0-1重量％的硬脂酸镁；具体处方比例如下表。
本实施例制备方法如下：
1、将URAT1抑制剂、微晶纤维素、乳糖、部分交联聚维酮混合20min；
2、将羟丙甲纤维素配成溶液后喷雾加入至步骤1中的混合物，控制雾化压力大于1bar；
3、将步骤2中的物料在40℃～50℃下干燥，终点水分控制低于3％；干燥颗粒采用24目筛网整粒；
4、将步骤3中的干颗粒、胶态二氧化硅、硬脂酸镁及剩余交联聚维酮混合10min；
5、将步骤4中的混合物压制成片剂，片剂硬度控制在30～120N范围；
6、使用期望颜色的包衣材料，对步骤5中的片剂包衣，包衣增重控制在2％～5％。
实施例6：
将实施例5的组合物P、组合物Q、组合物R、组合物S照溶出度与释放度测定法(中国药典通则0931第二法)测定。
溶出条件：以磷酸盐缓冲溶液(pH6.8)(取氢氧化钠8.96g和磷酸二氢钾68.05g于10L纯水中，溶解完全，混合均匀，用磷酸或氢氧化钠调节pH至6.8，即得)900ml为溶出介质，转速为每分钟50转，分别在5、10、15、20、30、45、60、90分钟时取样，溶出结果见下表。在特定处方比例范围下，组合物溶出均为快速溶出，15min大于85％。
实施例7：
辅料考察
发明人对实施例2、3中主要增长的杂质(RRT约0.84)研究后确定其为水解杂质，通过机理分析，原料可能在偏酸/碱性的辅料环境下条件下更易发生杂质降解。发明人对本组合物处方中偏酸/碱性的物料二氧化硅、硬脂酸镁处方用量进行了充分的优化同时杂质增长得到控制。

上述组合物准备工艺如下：
1、将URAT1抑制剂、微晶纤维素、乳糖、部分交联聚维酮混合20min；
2、将羟丙甲纤维素配成溶液后喷雾加入至步骤1中的混合物，控制雾化压力大于1bar使溶液均匀雾化；
3、将步骤2中的物料在40℃～50℃下干燥，终点水分控制低于3％；干燥颗粒采用24目筛网整粒；
4、将步骤3中的干颗粒、胶态二氧化硅、硬脂酸镁及剩余交联聚维酮混合10min；
5、将步骤4中的混合物压制成片剂，片剂硬度控制在30～120N范围；
6、使用期望颜色的包衣材料，对步骤5中的片剂包衣，包衣增重控制在2％～5％。
长期试验是在接近药物的实际贮存条件下进行，其目的是为制定药物的有效期提供依据。现阶段研究结果显示，二氧化硅、硬脂酸镁用量少，增长速率慢；组合物S、T、U长期12月杂质水平均低于预设限度0.5％，具有良好的稳定性。
实施例8：
剂型考察
本组合物剂型设计为常规固体剂型，结合生产条件和临床用药需求，本组合物可设计成片剂或胶囊。在实施例7组合物V的制备工艺基础上，制备成胶囊剂型。具体制备工艺如下：
1、将URAT1抑制剂、微晶纤维素、乳糖、50％交联聚维酮混合20min；
2、将羟丙甲纤维素配成浓度5％的水溶液后喷雾加入至步骤1中的混合物，控制雾化压力大于1bar使溶液均匀雾化；
3、将步骤2中的物料在40℃～50℃下干燥，终点水分控制低于3％；干燥颗粒采用24目筛网整粒；
4、将步骤3中的干颗粒、胶态二氧化硅、硬脂酸镁及剩余交联聚维酮混合10min；
5.将步骤4中的混合物充填胶囊，控制胶囊装量差异小于7.5％。
对比组合物V片剂和胶囊不同剂型下杂质的增长情况，杂质水平均低于预设限度0.5％；根据片剂和胶囊长期12月的杂质水平推定，两种剂型均能够满足预设货架期24月内的稳定性要求。并且胶囊剂型杂质增长速率更慢，稳定性期间风险更小。
实施例9：
采用实施例6的组合物P，开展一项在成人高尿酸血症伴或不伴痛风患者中评价本组合物的安全性、有效性的临床研究，采用随机、双盲、平行、阳性药/安慰剂对照设计。研究入组高尿酸血症(伴或不伴痛风)患者，连续4周给药。研究结果如下表和图1。
安全性分析：在组合物(10mg BID)、苯溴马隆组及安慰剂组中研究发现，发生率最高的主要为肌酐增高以及痛风发作，其次包括尿检异常以及腹泻。除痛风外其它各项不良事件发生率与安慰剂、苯溴马隆相似。组合物痛风发生率仅为6.9％，较安慰剂、苯溴马隆更低。

有效性分析：痛风/高尿酸治疗中外指南均建议对于存在痛风石、慢性痛风性关节炎或痛风性关节炎频繁发作，降尿酸治疗目标为<5mg/dl，直至痛风石完全溶解且关节炎频繁发作症状改善。研究发现在基线血尿酸≥9mg/dL的受试者中，对于第4周血清尿酸苯溴马隆6mg/dl达标率约为25％，组合物达标率为53.3％，远高于苯溴马隆组；4/5mg/dl达标率，组合物较苯溴马隆组显示了明显的优势。4/5mg/dl达标率代表了更深度的缓解，深度缓解对于复杂/难治性痛风，或痛风合并基础疾病的患者的治疗具有极大的临床意义与优势。
以上所述，仅列举了本发明的几种具体实施方式，但并不意味着本发明的保护范围仅限于此。本发明可以扩展到任何在本发明中披露的新特征或任何新的组合，以及披露的任一新的方法或过程的步骤或新的组合。对于本领域的技术人员在本发明披露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都落入本发明的保护范围之内。

Claims (10)

  1. 一种胶囊，其包含物质Z和药用的辅料；所述物质Z为如式I所示化合物或其药学上可接受的盐；所述如式I所示化合物的含量占所述胶囊质量的至少5％；所述药用的辅料包含粘合剂、崩解剂和填充剂；
  2. 如权利要求1所述胶囊，其特征在于，所述胶囊满足如下条件中的一种或多种：
    (1)所述胶囊还包括助流剂和/或润滑剂；
    (2)所述粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素和羧甲基纤维素钠中的一种或多种；
    (3)所述粘合剂的含量为所述胶囊质量的1-5％；
    (4)所述填充剂选自乳糖、微晶纤维素、甘露醇、淀粉、蔗糖和预胶化淀粉中的一种或多种；较佳地，所述填充剂选自乳糖、微晶纤维素、甘露醇和预胶化淀粉中的一种或两种；
    (5)所述粘合剂为羟丙甲纤维素；
    (6)所述填充剂的含量为所述胶囊质量的40-90％；
    (7)所述胶囊的原料粒径D50为1μm～45μm；
    和(8)所述组合物包含2.5-40mg的所述物质Z。
  3. 如权利要求2所述胶囊，其特征在于，所述胶囊满足如下条件中的一种或多种：
    (1)所述粘合剂的含量为所述胶囊质量的2-4.5％；
    (2)所述崩解剂选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙纤维素和羧甲基淀粉钠中的一种或多种；
    (3)所述崩解剂的含量为所述胶囊质量的2-10％；
    (4)所述填充剂为微晶纤维素、乳糖和微晶纤维素、微晶纤维素和预胶化淀粉乳糖或甘露醇和预胶化淀粉；
    (5)所述填充剂的含量为60.5-87％；
    (6)所述崩解剂交联聚维酮或羧甲基淀粉钠；
    (7)所述崩解剂的含量为所述胶囊质量的2-8％；
    (8)所述助流剂选自二氧化硅和滑石粉中的一种或两种；
    (9)所述助流剂的含量为所述胶囊质量的0-1％；
    (10)所述润滑剂选自硬脂酸镁、硬脂富马酸钠、硬脂酸钙和十二烷基硫酸钠中的一种或多种；
    (11)所述润滑剂的含量为所述胶囊质量的0-1％；
    (12)所述胶囊的原料粒径D50为9.55μm～44.30μm或1.29μm～25.58μm；
    和(13)所述组合物包含2.5mg、5mg、10mg、20mg、25mg或40mg的所述物质Z。
  4. 如权利要求3所述胶囊，其特征在于，所述胶囊满足如下条件中的一种或多种：
    (1)所述羟丙甲纤维素为羟丙甲纤维素E5；
    (2)所述粘合剂的含量为3％；
    (3)所述微晶纤维素为微晶纤维素PH101；
    (4)所述乳糖为乳糖200目；
    (5)所述填充剂的含量为68.5％、70.5％或73.8％；
    (6)所述交联聚维酮为交联聚维酮XL；
    (7)所述崩解剂的含量为所述胶囊质量的3％、5％或7％；
    (8)所述助流剂为胶态二氧化硅；
    (9)所述助流剂的含量为所述胶囊质量的例如0.1％、0.5％或1％；
    (10)所述润滑剂为硬脂酸镁；
    (11)所述润滑剂的含量为所述胶囊质量的0.1％、0.5％或1％；
    (12)所述淀粉为玉米淀粉；
    (13)所述胶囊的原料粒径D50为5-30μm，优选为9.55μm～25.58μm，例如10μm～25μm；
    和(14)所述药用的辅料由所述粘合剂、所述崩解剂、所述填充剂和所述助流剂组成，或者，所述药用的辅料由所述粘合剂、所述崩解剂、所述填充剂和所述润滑剂组成，或者所述药用的辅料由所述粘合剂、所述崩解剂、所述填充剂、所述助流剂和所述润滑剂组成。
  5. 如权利要求1-4任一项所述胶囊，其特征在于，所述胶囊为包含以重量计的如下组分：1-5％的粘合剂、40-90％的填充剂、2-10％的崩解剂、0-1％的助流剂和0-1％润滑剂；较佳地，所述粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素和羧甲基纤维素钠中的一种或多种；所述填充剂选自乳糖、微晶纤维素、甘露醇和预胶化淀粉中的一种或两种；所述崩解剂选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙纤维素和羧甲基淀粉钠中的一种或多种；所述助流剂选自二氧化硅和滑石粉中的一种或多种；所述润滑剂选自硬脂酸镁、硬脂富马酸钠、硬脂酸钙和十二烷基硫酸钠中的一种或多种；优选地，所述胶囊为包含以重量计的如下组分：2-4.5％的粘合剂、60.5-87％的填充剂、2-8％的崩解剂、0-1％的助流剂和0-1％润滑剂；较佳地，所述粘合剂为羟丙甲纤维素；所述填充剂为微晶纤维素、乳糖和微晶纤维素、微晶纤维素和预胶化淀粉乳糖或甘露醇和预胶化淀粉；所述崩解剂为交联聚维酮或羧甲基淀粉钠；所述助流剂为胶态二氧化硅；所述润滑剂为硬脂酸镁。
  6. 如权利要求1所述胶囊，其特征在于，
    所述胶囊为包含以重量计的如下组分的任一组合：
    组合1、16.67％的如式I所示化合物或其药学上可接受的盐、49.33％的微晶纤维素PH101、24.5％的乳糖200目、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
    组合2、16.67％的如式I所示化合物或其药学上可接受的盐、49.33％的微晶纤维素PH101、24.5％的预胶化淀粉、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
    组合3、16.67％的如式I所示化合物或其药学上可接受的盐、73.83的微晶纤维素PH101、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
    组合4、16.67％的如式I所示化合物或其药学上可接受的盐、49.33％的微晶纤维素PH101、24.5％的乳糖200目、3％的羟丙甲纤维素E5、5％的羧甲基淀粉钠、0.5％的胶态二氧化硅和1％的硬脂酸镁；
    组合5、20％的如式I所示化合物或其药学上可接受的盐、40.5％的微晶纤维素PH101、30％的乳糖200目、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
    组合6、20％的如式I所示化合物或其药学上可接受的盐、40.5％的预胶化淀粉、30％的甘露醇、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
    组合7、20％的如式I所示化合物或其药学上可接受的盐、40.5％的微晶纤维素PH101、28％的乳糖200目、7％的羟丙甲纤维素E5、3％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
    组合8、5％的如式I所示化合物或其药学上可接受的盐、56％的微晶纤维素PH101、30％的乳糖200目、3％的羟丙甲纤维素E5、5％的交联聚维酮XL、0.5％的胶态二氧化硅和0.5％的硬脂酸镁；组合9、20％的如式I所示化合物或其药学上可接受的盐、40.5％的微晶纤维素PH101、28％的乳糖200目、3％的羟丙甲纤维素E5、7％的交联聚维酮XL、0.5％的胶态二氧化硅和1％的硬脂酸镁；
    组合10、20％的如式I所示化合物或其药学上可接受的盐、41.2％的微晶纤维素PH101、28％的乳糖200目、3％的羟丙甲纤维素E5、7％的交联聚维酮XL、0.3％的胶态二氧化硅和0.5％的硬脂酸镁；
    组合11、20％的如式I所示化合物或其药学上可接受的盐、41.8％的微晶纤维素PH101、28％的乳糖200目、3％的羟丙甲纤维素E5、7％的交联聚维酮XL、0.1％的胶态二氧化硅和0.1％的硬脂酸镁。
  7. 如权利要求1所述胶囊，其特征在于，所述胶囊由如下方法制备得到：
    (1)将所述物质Z为如式I所示化合物或其药学上可接受的盐、所述填充剂和40％-60(例如50％)的所述解崩剂混合；
    (2)将所述粘合剂溶液(5％的水溶液)喷雾加入至步骤1中的混合物，控制雾化压力大于1bar使溶液均匀雾化；
    (3)将步骤2中的物料干燥(40℃～50℃)，终点水分控制低于3％；干燥颗粒采用整粒(24目筛网)；
    (4)将步骤3中的干颗粒、所述助流剂、所述助流剂和剩余所述解崩剂混合10min；
    (5)将步骤4中的混合物充填胶囊。
  8. 一种固体制剂，其包含物质Z和药用的辅料；所述物质Z为如式I所示化合物或其药学上可接受的盐；所述药用的辅料包含粘合剂、崩解剂和填充剂；所述如式I所示化合物的含量占所述固体制剂质量的至少5％；所述固体制剂的原料粒径D50为5-30μm；
    较佳地，所述固体制剂各组分的含量和定义如权利要求1-7任一项胶囊所述；
    和/或，所述固体制剂为片剂或胶囊；
    更佳地，所述固体制剂由如下方法制备得到：所述制备方法为方法A或方法B；
    所述方法A包括如下步骤：
    (1)将所述物质Z、粘合剂、崩解剂和填充剂混合，经湿法制粒得到颗粒(制粒完成后过24目筛进行湿整粒)；经干燥(40℃～50℃)得到干颗粒(过24目筛)；
    (2)将所述助流剂和润滑剂与干颗粒进行混合；
    (3)压片；
    所述方法B包括如下步骤：
    将所述固体制剂的各组分混合、过筛和压片。
  9. 一种物质W在制备药物中的应用，所述物质W为如权利要求1-7任一项所述胶囊或如权利要求8所述固体制剂；所述药物用于治疗和/或预防高尿酸血症或痛风。
  10. 一种物质W在制备URAT1抑制剂中的应用，所述物质W为如权利要求1-7任一项所述胶囊或如权利要求8所述固体制剂。
PCT/CN2025/089923 2024-04-19 2025-04-18 一种胶囊或固体制剂及其应用 Pending WO2025218797A1 (zh)

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