WO2021197376A1 - Comprimé de fébuxostat - Google Patents

Comprimé de fébuxostat Download PDF

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Publication number
WO2021197376A1
WO2021197376A1 PCT/CN2021/084422 CN2021084422W WO2021197376A1 WO 2021197376 A1 WO2021197376 A1 WO 2021197376A1 CN 2021084422 W CN2021084422 W CN 2021084422W WO 2021197376 A1 WO2021197376 A1 WO 2021197376A1
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WO
WIPO (PCT)
Prior art keywords
febuxostat
cellulose
coating layer
chip
tablet
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PCT/CN2021/084422
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English (en)
Chinese (zh)
Inventor
马爱明
王捷
潘凯
曹笑立
陈爱玲
潘彩云
Original Assignee
江苏恒瑞医药股份有限公司
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Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN202180019661.7A priority Critical patent/CN115297848A/zh
Publication of WO2021197376A1 publication Critical patent/WO2021197376A1/fr

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    • 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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

Definitions

  • the present disclosure relates to a febuxostat tablet, which is a chip-coated chip.
  • the preparation includes a tablet core containing a drug and a coating coated on the tablet core, and belongs to the field of pharmaceutical preparations.
  • Oral administration is a very advantageous route of drug delivery. Orally administered preparations are placed in the oral cavity and swallowed. The administration is simple, convenient, painless, does not require any special equipment or the participation of medical staff, and has good patients Compliance and low originality.
  • Gastric emptying is part of the human body’s normal digestion process, which causes pharmaceutical preparations that enter the stomach via oral routes to stay in the stomach for only a short time.
  • the short gastric residence time limits the bioavailability of many types of orally administered drugs.
  • drugs that act locally in the stomach are preferentially absorbed in the upper gastrointestinal tract or in the environment of the lower gastrointestinal tract, and drugs that are unstable or have low solubility at neutral or alkaline pH, this type The drug can be delivered through gastric retention formulations.
  • Sustained/controlled release tablets refer to the ability to release drugs at a predetermined rate and/or a predetermined time after administration so as to maintain the required pharmacological activity for a required period of time.
  • Such preparations provide drugs to the body within a predetermined period of time or at a predetermined absorption site, so that compared to conventional (for example, immediate-release) preparations, the drug level can be maintained for a longer period of time.
  • the dosage form containing the core is a form that produces a sustained/controlled release tablet.
  • the most commonly used material is a hydrophilic material, which swells and becomes a colloid once it comes into contact with a physiological medium.
  • the periphery When the dosage form is exposed to a physiological medium, the periphery will begin to hydrate and form a colloidal matrix. As the medium continues to penetrate the dosage form, the thickness of the colloidal matrix increases. The drug diffuses through the matrix and/or erodes the matrix to be released.
  • Febuxostat is an oral non-purine xanthine oxidase (NP-SIXO) selective inhibitor developed by Japan's Teijin Pharmaceuticals. It is mainly used for the chronic treatment of hyperuricemia in patients with gout, and urate has occurred. Treatment of deposited chronic hyperuricemia and treatment of hyperuricemia (tumor lysis syndrome) associated with cancer chemotherapy. The main side effect is that it is often accompanied by acute attacks of gout in the early stage of treatment, which increases the frequency of gout attacks, which seriously affects the compliance of patients.
  • NP-SIXO oral non-purine xanthine oxidase
  • the patent application CN103210084A of Takeda Pharmaceuticals discloses a new type of composition containing febuxostat, including immediate release beads and sustained release beads containing febuxostat, which achieve a sustained release effect by means of membrane control.
  • the background art pointed out that a febuxostat preparation that maintains a drug concentration higher than a critical concentration of 100 ng/mL for an extended period of time is expected to produce higher efficacy, and will be the control of hyperuricemia, gout and The desired treatment options for many other disease states.
  • the clinical project TMX-67XR involved in the application was terminated due to undisclosed reasons, which fully proved that the development of febuxostat sustained/controlled release tablets is very difficult.
  • the present disclosure provides a chip-coated chip, comprising a tablet core containing the active drug febuxostat and a coating layer coated on the tablet core, the tablet core is located in the coating layer, and the coating layers on both sides of the tablet core in the Y-axis direction At least one side of the thickness is smaller than the thickness of the coating layer in the X-axis direction ( Figure 1 is a schematic diagram, in which the two sides of the Y-axis direction of the tablet core correspond to the upper and lower surfaces in the figure).
  • the coating thickness along the axial direction of the punch movement (the "Y" axis) described in the present disclosure is determined by the amount of coating raw materials added to the die and the punching force used when the tablet is formed.
  • the coating thickness along the "X" axis (perpendicular to the direction of movement of the punch) is determined by the size of the inner core, the position of the inner core in the die, and the die diameter.
  • the febuxostat chip-on-chip provided in the present disclosure provides an initial diameter sufficient to make it stay in the stomach in the fed state.
  • a tablet with a diameter of about 12-18 mm can generally resist passing through the pyloric sphincter in the fed state.
  • the initial maximum diameter of the febuxostat package chip can be 12-16mm, and 13-15mm is optional.
  • the chip-on-chip provided in the present disclosure is a chip-on-chip retained in the stomach.
  • the thickness of the coating layer on both sides of the tablet core in the Y-axis direction is the same or different, and the thickness of the coating layer on one side of the tablet core can be 0.5-2.2mm, optionally 1.0-2.0mm, optional 1.5-1.8mm, optional 1.7-1.9mm; the thickness of the coating layer on the other side of the tablet core can be 0.3-2.0mm, optional 0.8-1.8mm, optional 1.2-1.4mm, optional 1.0-1.5mm.
  • the chip-coated chip provided in the present disclosure due to the selection of the coating thickness along the Y-axis direction, enables the active substance febuxostat to be released in a predetermined delay time period to achieve a controlled release effect.
  • the coating layer can be used in an aqueous medium. It ruptures after being soaked in the medium for at least 1 hour and releases the active substance, optionally 1.5 hours later, optionally 2 hours later, the rupture time of the coating layer of the chip-covered chip provided in the present disclosure in the aqueous medium is no later than 4 hours.
  • the investigation of the rupture time of the coating layer in the aqueous medium described in the present disclosure refers to the result of the investigation in 500 mL of pH 4.5PBS-0.5% SDS medium using the paddle method at 50 rpm.
  • the release rate is preferentially avoided or reduced.
  • Delivering the active drug to the absorption window can increase the efficacy of the drug and/or reduce or eliminate side effects.
  • the coating layer breaks too late, the absorption window may be missed.
  • the coating layer can break when immersed in a viscous medium for less than 6 hours, releasing the active substance, Choose ⁇ 5 hours to rupture, and choose ⁇ 4 hours to rupture.
  • the investigation of the rupture time of the coating layer in the viscous medium in this disclosure refers to the use of the basket method at 75rpm, 500mL pH4.5 PBS -2.5%HPMC K100LV medium for 2h, and then change to 500ml 0.1MHCl-3%HPMC Continue the experiment in E5LV medium to investigate the rupture time in viscous medium.
  • the coating layer described in this disclosure is in accordance with the dissolution and release determination method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0931 Method 2), with 2.5% HPMC K100LV-pH6.0 phosphate buffer 500ml as the dissolution medium, and the temperature is 37 ⁇ 0.5°C, the rotation speed is 150 revolutions per minute. After 4 hours, discard the medium in each dissolution cup, and then add 900ml of pH6.8 phosphate buffer preheated to 37 ⁇ 0.5°C in each dissolution cup. Change, continue to operate in accordance with the law, 3-5h rupture.
  • the thickness of the coating layer on both sides of the Y-axis core is at least one side
  • the thickness of the coating in the X-axis direction is smaller than that, so that the coating ruptures and releases the active drug in the Y-axis direction, which ensures the rapid release of the tablet core drug (as shown in Figure 2).
  • the release amount of the tablet core within the delay time period is not more than about 10% of the total amount of febuxostat in the tablet core. Release all or almost all of the febuxostat internally, specifically, within 1 hour of the coating layer rupture, the febuxostat release amount of the tablet core is more than 65% of the total amount of febuxostat in the core tablet, optionally more than 70% , Optional 75% or more.
  • the chip-in-package of the present disclosure is formed by compression-coated technology, which will be described in detail below.
  • Compression tablets are usually made by placing a part of the powdered or granular coating material in a die, tamping the part of the coating material into a compact state with a punching machine, and then placing the inner core on the dense coating material. Then, the remaining coating material is introduced into the die, and pressure is applied to form the coated tablet.
  • some one-step dry coating technology to prepare compressed tablets has also been produced, such as Specifically, see Evaluation of novel one-step dry-coated tablets as a platform for delayed-release tablets (Journal of Controlled Release 95 (2004) 51-60) by Yuichi Ozeki et al.
  • the hardness of the tablet core is relatively low, which ensures that after the aqueous medium contacts the tablet core, the tablet core can expand, so that the outer coating layer is better broken, and the hardness of the tablet core is 10-120N, optionally 20-60N.
  • the hardness of the tablet is controlled at 120-300N, 170 is optional -230N.
  • the release of febuxostat from the tablet core is not the result of the diffusion of the drug through the swollen coating material, but the result of the physical rupture of the coating.
  • the coating layer contains at least one matrix material, at least one hydrophobic plasticizer and at least one hydrophilic gel matrix material, and the matrix material is insoluble in water or hardly soluble in water. Excipients for water.
  • the hydrophobic plasticizer described in the optional embodiment can be selected from liquid paraffin, corn oil, castor oil, coconut oil, glycerol triacetate, glycerol monoacetate, dibutyl sebacate, and phthalate.
  • the plasticizer glyceryl behenate described in the present disclosure is an ester formed of glycerol and behenic acid (a C22 fatty acid), and glyceryl behenate can be in the form of its mono-, di-, or tri-ester or a mixture thereof Exist, the HLB value can be less than 5, and can be about 2.
  • the coating layer without a hydrophobic plasticizer dissolves severely in an aqueous medium, and it is difficult to maintain rigidity and integrity, and the coating layer cannot have the effect of delaying the release after a period of time.
  • the water-insoluble or poorly water-soluble excipient can be selected from any known water-insoluble cellulose derivatives, polymers, and mixtures of polyvinyl acetate and povidone, etc.
  • the water-insoluble cellulose derivatives and polymers include alkyl cellulose, such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and their derivatives, polymethyl cellulose Acrylic polymers, polyvinyl acetate and cellulose acetate polymers, fatty acids or their esters or their salts, long-chain fatty alcohols, polyoxyethylene alkyl ethers, polyoxyethylene stearic acid, sugar esters, laurel Acyl polyethylene glycol-32 glycerin, stearoyl polyethylene glycol-32 glycerin, etc.
  • the matrix material is selected from a combination of polymethacrylic acid polymer, polyvinyl acetate and a mixture of povidone.
  • the content of polymethacrylic acid polymer in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65%-75%, acetic acid
  • the content of the mixture of vinyl ester and povidone is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.
  • the matrix material is selected from the combination of Eudragit and a mixture of polyvinyl acetate and povidone.
  • the content of Eudragit in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65%-75%, polyacetic acid
  • the content of the mixture of vinyl ester and povidone is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.
  • the host material is selected from the group consisting of Eudragit RL, Eudragit RS and a combination of polyvinyl acetate and povidone.
  • Eudragit RL and Eudragit RS are insoluble in water but swellable. , So as to form pores in the coating, the diameter of the pores of Eudragit RL is 1-5 ⁇ m, and the diameter of the pores of Eudragit RS is 0.1-0.6 ⁇ m.
  • the content of Youditch RL and Youditch RS in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65 %-75%, the content of the mixture of polyvinyl acetate and povidone is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.
  • the matrix material is selected from the combination of Eudragit RLPO and Eudragit RSPO, and a mixture of polyvinyl acetate and povidone.
  • the content of Eudragit RLPO and Eudragit RSPO in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65 %-75%, the content of the mixture of polyvinyl acetate and povidone is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.
  • the host material is selected from Youditch RLPO, Youditch RSPO, The combination.
  • the content of Eudragit RLPO and Eudragit RSPO in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65 %-75%, The content is 5%-40% (mass percentage) of the total weight of the coating layer, and 15%-25% is optional.
  • the content of Eudragit RSPO in the coating layer accounts for 5%-40% (mass percentage) of the total weight of the coating layer, optionally 10%-30%, and optionally 15%-25%.
  • the content of Utraki RLPO in the coating layer accounts for 20%-80% (mass percentage) of the total weight of the coating layer, optional 30%-70%, optional 45%-55% .
  • the content of Eudragit RSPO in the coating layer accounts for 5%-40% (mass percentage) of the total weight of the coating layer, and the content of Eudragit RLPO accounts for 20%-80% of the total weight of the coating layer. % (Mass percentage), The content is 5%-40% (mass percentage) of the total weight of the coating layer.
  • the content of Eudragit RSPO in the coating layer accounts for 10%-30% (mass percentage) of the total weight of the coating layer, and the content of Eudragit RLPO accounts for 30% of the total weight of the coating layer. 70% (mass percentage), The content is 15%-25% (mass percentage) of the total weight of the coating layer.
  • the content of Eudragit RSPO in the coating layer accounts for 15%-25% (mass percentage) of the total weight of the coating layer, and the content of Eudragit RLPO accounts for 45% of the total weight of the coating layer. 55% (mass percentage), The content is 15%-25% (mass percentage) of the total weight of the coating layer.
  • the hydrophilic gel skeleton material in the present disclosure is selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose , Chitin, Chitosan, Galactomannan, Pectin, Sodium Alginate, Potassium Alginate, Agar, Carrageenan, Locust Bean Gum, etc.
  • the hydrophilic gel backbone material is hydroxypropyl methyl cellulose
  • the hydroxypropyl methyl cellulose material is selected from materials with low weight average molecular weight and low viscosity, such as E-formaldehyde. Base cellulose.
  • the content of the hydrophilic gel matrix material in the present disclosure is 1%-30% (mass percentage) of the total weight of the coating layer, optionally 5%-20%, and optionally 8%-15%.
  • the hydrophilic gel matrix material is E-hydroxypropyl methylcellulose, and its content is 1%-30% (mass percentage) of the total weight of the coating layer, optionally 5% -20%, optional 10%-15%.
  • the optional hydrophilic gel framework material can also be used as a binder.
  • the tablet core in addition to the active substance febuxostat, the tablet core also contains a disintegrant of an immediate-release preparation known in the art.
  • the disintegrant may be in water.
  • the effervescent and/or swelling material in the presence of the medium can provide the necessary strength to mechanically rupture the coating material.
  • the disintegrant can be selected from croscarmellose sodium, dry starch, and low substitution.
  • Hypromellose, sodium carboxymethyl starch and crospovidone, etc., croscarmellose sodium is optional, the amount of disintegrant can be 2%-35% of the weight of the tablet core (mass percentage ), optionally can be 5%-25% of the weight of the tablet core, and optionally can be 8%-15% of the weight of the tablet core.
  • the core of the febuxostat provided by the present disclosure may also contain pharmaceutically acceptable water-soluble fillers and/or water-insoluble fillers.
  • the water-soluble fillers include lactose, mannitol, sucrose, sorbitol, etc.
  • Water-insoluble fillers include starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, etc.
  • the content of diluent can be 1%-99% of the weight of the tablet core, (mass percentage) optional 20%-85%, Optional 60%-80%.
  • the filler of the tablet core is selected from a combination of a water-soluble filler and a water-insoluble filler, and the content of the water-soluble filler can be 35%-75% (mass percentage) of the weight of the tablet core. Choose 45%-70%, choose 50%-65%; the content of the water-insoluble filler can be 1%-25% (mass percentage) of the tablet core weight, and can choose 10%-25%.
  • the filler of the tablet core is a combination of lactose selected from water-soluble fillers and microcrystalline cellulose selected from water-insoluble fillers.
  • the core may also contain a pharmaceutically acceptable binder, and the binder may be selected from, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyethylene. At least one of pyrrolidone, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, trehalose and pullulan, but not limited thereto, the content of the binder may be 1% of the total weight of the tablet core %-5% (mass percentage).
  • the binder is hydroxypropyl cellulose.
  • the tablet core may contain suitable lubricants, such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearate fumarate, polyethylene glycol or dodecane Sodium sulfate, the content of lubricant in the tablet core is 0.5%-10% (mass percentage) of the total weight of the tablet core, and 1%-5% is optional.
  • suitable lubricants such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearate fumarate, polyethylene glycol or dodecane Sodium sulfate, the content of lubricant in the tablet core is 0.5%-10% (mass percentage) of the total weight of the tablet core, and 1%-5% is optional.
  • the lubricant of the tablet core is magnesium stearate.
  • coloring agents can be added to the tablet core to ensure accurate positioning of the tablet core in the coating to ensure that the tablet has an appropriate coating thickness, so that the delay time is reproducible, so as to avoid intra-subject and patient
  • the appropriate colorant can be iron oxide, titanium dioxide, iron hydroxide, etc.
  • the choice of colorant does not limit the scope of the present disclosure, and the content of the colorant is 0.1%-3 of the total weight of the core. %, 0.4%-1% is optional.
  • the core of the febuxostat chip provided in the present disclosure may also contain a hydrophilic gel skeleton material, and the hydrophilic gel skeleton material is selected from cellulose derivatives and non-fibers.
  • the cellulose derivative can be selected from methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose and hydroxymethyl cellulose.
  • the non-cellulosic polysaccharide is selected from glucose, chitin, chitosan and galactomannan, etc.
  • the natural gum is selected from pectin, sodium alginate, potassium alginate , Agar, carrageenan, locust bean gum, claw ear gum, etc.
  • the hydrophilic gel matrix material in the core is a cellulose derivative.
  • the hydrophilic gel matrix material in the core is selected from the group consisting of hydroxyethyl methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Cellulose.
  • the hydrophilic gel matrix material in the core is hydroxypropyl methylcellulose.
  • the hydrophilic gel matrix material in the core is 1%-20% of the total weight of the core.
  • the hydrophilic gel matrix material in the tablet core accounts for 2%-10% of the total weight of the tablet core.
  • the hydrophilic gel matrix material in the core is 3%-8% of the total weight of the core.
  • the coating layer also contains an immediate-release part of febuxostat.
  • the immediate-release part can be completed by any technical means well known in the art, such as a double layer. Tablets, immediate release coatings, etc.
  • the febuxostat tablet provided in the present disclosure has a sustained-release effect.
  • the present disclosure provides a febuxostat tablet, in addition to containing the aforementioned chip-coated chip, the coating layer of the chip-coated chip contains an immediate-release drug-containing coating layer of febuxostat.
  • the immediate-release drug-containing coating layer of febuxostat contains the active drug febuxostat and a coating material, and the coating material may be hydroxypropyl methylcellulose or hydroxypropyl methylcellulose.
  • Base cellulose polyvinyl alcohol, gastric-soluble Opadry, optional gastric-soluble Opadry, optional Opadry (03K180007-CN).
  • the release characteristics of the chip-coated chip in the present disclosure are the same as that of the febuxostat tablet containing the immediate-release component.
  • the content of febuxostat in the unit dosage form of the febuxostat tablet provided in the present disclosure is 1.1-1.8 times, optionally 1.2-1.6 times, of the content of febuxostat in the unit dosage form of febrex , Optional 1.5 times.
  • the content of a single tablet of commercially available febuxostat is 20 mg
  • the content of a unit tablet of febuxostat provided in the present disclosure is 30 mg
  • the content of a single tablet of commercially available febuxostat is 40 mg
  • the unit tablet content of febuxostat provided in the present disclosure is 60 mg.
  • the increased dosage of the drug increases the rate of uric acid lowering standards, thereby reducing the frequency of gout attacks and ensuring the efficacy.
  • the amount of febuxostat in the unit dosage form of the febuxostat tablet provided in the present disclosure is 10 mg-200 mg, optionally 20 mg-150 mg, and the optional amount of febuxostat is 10 mg, 15 mg , 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg , 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 30mg and 60mg are optional, the content ratio of the active substance in the immediate-release drug-
  • the febuxostat tablet contains the following ingredients:
  • the febuxostat tablet contains the following ingredients:
  • the active substance content in the febuxostat tablet is 30 mg
  • the content ratio of the immediate-release drug-containing coating layer to the active substance in the tablet core is 1:10-10:1, and 1:5 is optional. -5:1, optional 1:2-1:1, optional 2:3.
  • the content of the active substance in the febuxostat tablet is 60 mg
  • the ratio of the content of the active substance in the immediate-release drug-containing coating layer to the tablet core is 1:10-10:1, optionally 1:5- 5:1, optional 1:3-1:1, optional 3:7.
  • the isolation layer is a thin layer of polymer material to form a film-like coating layer, which increases the tablet weight by 1%- 50% (mass percentage), optional 2%-4%.
  • the material of the isolation layer can be selected from one or more of hypromellose, povidone, copovidone, hydroxypropyl cellulose and gastric-soluble Opadry, and gastric-soluble Opadry can be selected.
  • Generation optional gastro-soluble Ouba (YS-1-7027-CN).
  • the febuxostat tablet provided in the present disclosure is basically equivalent to the AUC (geometric mean) of phenibrol, significantly prolongs the effective blood concentration maintenance time and improves the effectiveness, wherein the substantially equivalent refers to The AUC ratio is in the range of 85%-135%.
  • the febuxostat tablet provided in the present disclosure reduces the Cmax value on the basis of significantly prolonging the effective blood concentration maintenance time, and has better safety.
  • the subject takes the febuxostat tablets provided in the present disclosure once a day.
  • the maintenance time of the blood concentration (geometric mean) ⁇ 100 ng/ml is that the subjects take phenbuxostat once a day. 1-3 times of cloth force, optional 1.25-2.0 times.
  • the blood concentration ⁇ 100ng/ml is maintained for at least It is 10 hours, optionally at least 12 hours, optionally at least 15 hours.
  • the maintenance time of the blood concentration ⁇ 100ng/ml is at least 12 hours, optionally at least 15 hours, and optionally at least 17 hours.
  • the blood drug concentration mentioned in the present disclosure refers to the geometric mean value.
  • the febuxostat tablets provided in the present disclosure provide obvious double peaks in the body.
  • the recovery time of the blood concentration of the subject after taking the drug is 2-5 hours after taking the drug, and 3-4 hours can be selected.
  • the rupture time in the subject's body is 2-5 hours after self-administration, optionally 3-4 hours.
  • the present disclosure provides a febuxostat tablet as described above in preparation for the treatment of gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, Use in medicine for diseases such as chronic kidney disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure.
  • the present disclosure provides a treatment and treatment of gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes,
  • the method for diabetic nephropathy and congestive heart failure is to administer the febuxostat tablets provided in the present disclosure to the patient.
  • the present disclosure provides a method for preparing the above-mentioned febuxostat tablet, which comprises the following steps: granulating febuxostat and optional tablet core excipients into first particles; making the first particles into tablet cores; Granulating the auxiliary material of the coating layer into second granules; compressing and coating the second granules around the tablet core; and coating the quick-release layer.
  • the method includes the following steps: granulating febuxostat with fillers, binders, and partial disintegrants, mixing with the remaining disintegrants and lubricants, and then compressing tablet cores; containing a matrix Granulation of materials, water-insoluble plasticizers, and auxiliary materials of the coating layer of hydrophilic gel matrix materials; compression-packed chips; rapid-release layer coating.
  • the method includes the following steps: granulating febuxostat with lactose, microcrystalline cellulose, hydroxypropyl cellulose and partially croscarmellose sodium and then with the remaining croscarmellose Sodium methylcellulose and magnesium stearate are mixed and compressed into tablet cores; Eudragit RSPO, Eudragit RLPO, glyceryl behenate and part of hypromellose are granulated with Kollidon SR, remaining hypromellose After cellulose is mixed, the chip is compressed; the quick-release layer is coated.
  • the method includes the following steps: granulating febuxostat with lactose, microcrystalline cellulose, hydroxypropyl cellulose base and partially cross-linked sodium carboxymethyl cellulose and cross-linking the remaining Sodium carboxymethyl cellulose and magnesium stearate are mixed and then compressed into tablet cores; Eudragit RSPO, Eudragit RLPO, glyceryl behenate and part of hypromellose are granulated with Kollidon SR, remaining hypromellose After the methylcellulose is mixed, the chip is compressed; the Opadry isolation layer is coated; the Opadry and febuxostat immediate release layer is coated.
  • the preparation method of febuxostat tablets includes a step of film coating after the preparation of the chip-coated chips is completed.
  • a febuxostat tablet comprising a core containing the active drug febuxostat, and a coating layer coated on the core.
  • the core is located in the coating layer, and the core is also Containing 1%-20% of the total weight of the tablet core hydrophilic gel matrix material;
  • the coating layer contains at least one matrix material, at least one hydrophobic plasticizer and at least one hydrophilic gel matrix material, It also includes an immediate-release component containing the active substance febuxostat.
  • the hydrophilic gel backbone material of the tablet core is selected from cellulose derivatives, non-cellulosic polysaccharides, natural gums, vinyl polymers or acrylic polymers, etc.; the cellulose derivatives are optional From methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose and sodium hydroxymethyl cellulose, etc.;
  • the non-cellulosic polysaccharide is selected from glucose, chitin, chitosan and galactomannan, etc.; the natural gum is selected from pectin, sodium alginate, potassium alginate, agar, carrageenan, etc. Soybean gum, claw ear gum, etc.
  • the hydrophilic gel matrix material in the tablet core is a cellulose derivative.
  • the hydrophilic gel matrix material in the core is selected from the group consisting of hydroxyethyl methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Cellulose.
  • the hydrophilic gel matrix material in the tablet core is hydroxypropyl methylcellulose.
  • the hydrophilic gel matrix material in the tablet core accounts for 2%-10% of the total weight of the tablet core.
  • the hydrophilic gel matrix material in the tablet core accounts for 3%-8% of the total weight of the tablet core.
  • the hydrophobic plasticizer can be selected from liquid paraffin, corn oil, castor oil, coconut oil, glycerol triacetate, glycerol monoacetate, dibutyl sebacate, o-benzene Dibutyl dicarboxylate, long-chain fatty alcohols, long-chain fatty acids and their esters or their salts, glyceryl behenate, optionally glyceryl behenate, the content of the water-insoluble plasticizer is the coating layer 0.1%-30% of the total weight (mass percentage), optional 0.5%-20%, optional 1%-10%.
  • the plasticizer glyceryl behenate described in the present disclosure is an ester formed of glycerol and behenic acid (a C22 fatty acid), and glyceryl behenate can be in the form of its mono-, di-, or tri-ester or a mixture thereof Exist, the HLB value can be less than 5, and can be about 2.
  • the coating layer without a hydrophobic plasticizer dissolves severely in an aqueous medium, and it is difficult to maintain rigidity and integrity, and the coating layer cannot have the effect of delaying the release after a period of time.
  • the water-insoluble or poorly water-soluble excipient can be selected from any known water-insoluble cellulose derivatives, polymers, and mixtures of polyvinyl acetate and povidone, etc.
  • the water-insoluble cellulose derivatives and polymers include alkyl cellulose, such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and their derivatives, polymethyl cellulose Acrylic polymers, polyvinyl acetate and cellulose acetate polymers, fatty acids or their esters or their salts, long-chain fatty alcohols, polyoxyethylene alkyl ethers, polyoxyethylene stearic acid, sugar esters, laurel Acyl polyethylene glycol-32 glycerin, stearoyl polyethylene glycol-32 glycerin, etc.
  • the matrix material is selected from a combination of polymethacrylic acid polymer, polyvinyl acetate and a mixture of povidone.
  • the content of the polymethacrylic acid polymer in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65%-75 %, the content of the mixture of vinyl acetate and povidone is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.
  • the matrix material is selected from the combination of Eudragit and a mixture of polyvinyl acetate and povidone.
  • the content of Eudragit in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65%-75%, polyacetic acid
  • the content of the mixture of vinyl ester and povidone is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.
  • the host material is selected from the group consisting of Eudragit RL, Eudragit RS and a combination of polyvinyl acetate and povidone.
  • Eudragit RL and Eudragit RS are insoluble in water but swellable. , So as to form pores in the coating, the diameter of the pores of Eudragit RL is 1-5 ⁇ m, and the diameter of the pores of Eudragit RS is 0.1-0.6 ⁇ m.
  • the content of Youditch RL and Youditch RS in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65 %-75%, the content of the mixture of polyvinyl acetate and povidone is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.
  • the matrix material is selected from the combination of Eudragit RLPO and Eudragit RSPO, and a mixture of polyvinyl acetate and povidone.
  • the content of Eudragit RLPO and Eudragit RSPO in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65 %-75%, the content of the mixture of polyvinyl acetate and povidone is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.
  • the host material is selected from Youditch RLPO, Youditch RSPO, The combination.
  • the content of Eudragit RLPO and Eudragit RSPO in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, optional 60%-85%, optional 65 %-75%, The content is 5%-40% (mass percentage) of the total weight of the coating layer, and 15%-25% is optional.
  • the content of Eudragit RSPO in the coating layer accounts for 5%-40% (mass percentage) of the total weight of the coating layer, optionally 10%-30%, and optionally 15%-25%.
  • the content of Utraki RLPO in the coating layer accounts for 20%-80% (mass percentage) of the total weight of the coating layer, optional 30%-70%, optional 45%-55% .
  • the content of Eudragit RSPO in the coating layer accounts for 5%-40% (mass percentage) of the total weight of the coating layer, and the content of Eudragit RLPO accounts for 20%-80% of the total weight of the coating layer. % (Mass percentage), The content is 5%-40% (mass percentage) of the total weight of the coating layer.
  • the content of Eudragit RSPO in the coating layer accounts for 10%-30% (mass percentage) of the total weight of the coating layer, and the content of Eudragit RLPO accounts for 30% of the total weight of the coating layer. 70% (mass percentage), The content is 15%-25% (mass percentage) of the total weight of the coating layer.
  • the content of Eudragit RSPO in the coating layer accounts for 15%-25% (mass percentage) of the total weight of the coating layer, and the content of Eudragit RLPO accounts for 45% of the total weight of the coating layer. 55% (mass percentage), The content is 15%-25% (mass percentage) of the total weight of the coating layer.
  • the hydrophilic gel matrix material in the coating layer is selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose , Sodium hydroxymethyl cellulose, chitin, chitosan, galactomannan, pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, etc.
  • the hydrophilic gel matrix material in the coating layer is hydroxypropyl methyl cellulose
  • the hydroxypropyl methyl cellulose material is selected from materials with low weight average molecular weight and low viscosity, such as E -Type methyl cellulose.
  • the content of the hydrophilic gel matrix material in the coating layer of the present disclosure is 1%-30% (mass percentage) of the total weight of the coating layer, optional 5%-20%, optional 8% -15%.
  • the hydrophilic gel matrix material is E-hydroxypropyl methylcellulose, and its content is 1%-30% (mass percentage) of the total weight of the coating layer, optionally 5% -20%, optional 8%-15%.
  • the optional hydrophilic gel skeleton material can also be used as a binder.
  • the tablet core in addition to the active substance febuxostat, the tablet core also contains a disintegrant of an immediate-release formulation known in the art.
  • the disintegrant may exist in an aqueous medium. Time effervescent and/or swelling material, which can provide the necessary strength to mechanically rupture the coating material.
  • the disintegrant can be selected from croscarmellose sodium, dry starch, and low-substituted hydroxypropyl.
  • Methyl cellulose, sodium carboxymethyl starch and crospovidone, etc., optional sodium croscarmellose, the amount of disintegrant can be 2%-35% (mass percentage) of the core weight, Optionally, it can be 5%-25% of the weight of the tablet core, and optionally, it can be 8%-15% of the weight of the tablet core.
  • the core of the tablet may also contain pharmaceutically acceptable water-soluble fillers and/or water-insoluble fillers.
  • the water-soluble fillers include lactose, mannitol, sucrose, sorbitol, etc.
  • Insoluble fillers include starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, etc.
  • the content of the diluent can be 1%-99% of the weight of the tablet core (mass percentage), optional 20%-85%, optional 60%-80%.
  • the filler of the tablet core is selected from a combination of a water-soluble filler and a water-insoluble filler, and the content of the water-soluble filler can be 35%-75% (mass percentage) of the weight of the tablet core. Choose 45%-70%, choose 50%-65%; the content of the water-insoluble filler can be 1%-30% (mass percentage) of the tablet core weight, and can choose 10%-25%.
  • the filler of the tablet core is a combination of lactose selected from water-soluble fillers and microcrystalline cellulose selected from water-insoluble fillers.
  • the febuxostat tablet provided in the present disclosure may also contain a pharmaceutically acceptable binder in the core of the tablet.
  • the binder can be selected from, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, At least one of methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, trehalose and pullulan, but not limited thereto, the content of the binder may be 1% of the total weight of the tablet core- 5% (mass percentage).
  • the binder is hydroxypropyl cellulose.
  • the tablet core may contain suitable lubricants, such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearate fumarate, polyethylene glycol or dodecane Sodium sulfate, the content of lubricant in the tablet core is 0.5%-10% (mass percentage) of the total weight of the tablet core, and 1%-5% is optional.
  • suitable lubricants such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearate fumarate, polyethylene glycol or dodecane Sodium sulfate, the content of lubricant in the tablet core is 0.5%-10% (mass percentage) of the total weight of the tablet core, and 1%-5% is optional.
  • the lubricant of the tablet core is magnesium stearate.
  • coloring agents can be added to the tablet core to ensure accurate positioning of the tablet core in the coating to ensure that the tablet has an appropriate coating thickness, so that the delay time is reproducible, so as to avoid intra-subject and patient
  • the appropriate colorant can be iron oxide, titanium dioxide, iron hydroxide, etc.
  • the choice of colorant does not limit the scope of the present disclosure, and the content of the colorant is 0.1%-3 of the total weight of the core. %, 0.4%-1% is optional.
  • the febuxostat tablet provided in the present disclosure provides an initial diameter sufficient to make it stay in the stomach in the fed state.
  • a tablet with a diameter of about 12-18 mm can generally resist passing through the pyloric sphincter in the fed state.
  • the initial maximum diameter of the chip of busstat can be 12-16mm, and 13-15mm is optional.
  • the febuxostat tablets provided in the present disclosure are gastric retention tablets.
  • the hardness of the tablet core is relatively low, which ensures that after the aqueous medium contacts the tablet core, the tablet core can expand, so that the outer coating layer is better broken, and the hardness of the tablet core is 10-120N, optionally 20-60N.
  • the hardness of the tablet is controlled at 30-250N, and 70 is optional. -180N.
  • the release of febuxostat from the tablet core is not the result of the diffusion of the drug through the swollen coating material, but the result of the physical rupture of the coating.
  • the febuxostat tablet provided in the present disclosure has a sustained-release effect.
  • the present disclosure provides an immediate-release component of febuxostat tablets as an immediate-release drug-containing coating layer.
  • the immediate-release drug-containing coating layer of febuxostat contains the active drug febuxostat and a coating material, and the coating material may be hydroxypropyl methylcellulose or hydroxypropyl methylcellulose.
  • Base cellulose polyvinyl alcohol, gastric-soluble Opadry, optional gastric-soluble Opadry, optional Opadry (03K180007-CN).
  • the content of febuxostat in the unit dosage form of the febuxostat tablet provided in the present disclosure is 1.1-1.8 times, optionally 1.2-1.6 times, of the content of febuxostat in the unit dosage form of febrex , Optional 1.5 times.
  • the content of a single tablet of commercially available febuxostat is 20 mg
  • the content of a unit tablet of febuxostat provided in the present disclosure is 30 mg
  • the content of a single tablet of commercially available febuxostat is 40 mg
  • the unit tablet content of febuxostat provided in the present disclosure is 60 mg.
  • the increased dosage of the drug increases the rate of uric acid lowering standards, thereby reducing the frequency of gout attacks and ensuring the efficacy.
  • the amount of febuxostat in the unit dosage form of the febuxostat tablet provided in the present disclosure is 10 mg-200 mg, optionally 20 mg-150 mg, and the optional amount of febuxostat is 10 mg, 15 mg , 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg , 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, optional 30mg and 60mg, the content ratio of the immediate-release component to the active substance in the
  • the febuxostat tablet contains the following ingredients:
  • the active substance content in the febuxostat tablet is 30 mg
  • the content ratio of the immediate-release drug-containing coating layer to the active substance in the tablet core is 1:10-10:1, and 1:5 is optional. -5:1, optional 1:2-1:1, optional 2:3.
  • the content of the active substance in the febuxostat tablet is 60 mg
  • the ratio of the content of the active substance in the immediate-release drug-containing coating layer to the tablet core is 1:10-10:1, optionally 1:5- 5:1, optional 1:3-1:1, optional 3:7.
  • the isolation layer is a thin layer of polymer material to form a film-like coating layer, which increases the tablet weight by 1%- 50% (mass percentage), optional 2%-4%.
  • the material of the isolation layer can be selected from one or more of hypromellose, povidone, copovidone, hydroxypropyl cellulose and gastric-soluble Opadry, and gastric-soluble Opadry can be selected.
  • Generation optional gastro-soluble Ouba (YS-1-7027-CN).
  • the febuxostat tablet provided in the present disclosure enables the active substance febuxostat to be released within a predetermined delay time period to achieve a controlled release effect.
  • the coating layer can be ruptured after being immersed in an aqueous medium for at least 1 hour to release the active substance , Optionally rupture after 1.5 hours, optionally rupture after 2 hours, the rupture time of the coating layer of the chip-covered chip provided in the present disclosure in the aqueous medium is no later than 4 hours.
  • the investigation of the rupture time of the coating layer in the aqueous medium described in the present disclosure refers to the result of the investigation in 500 mL of pH 4.5PBS-0.5% SDS medium using the paddle method at 50 rpm.
  • the release rate is preferentially avoided or reduced.
  • Delivering the active drug to the absorption window can increase the efficacy of the drug and/or reduce or eliminate side effects.
  • the coating layer can break when immersed in a viscous medium for less than 6 hours, releasing the active substance, Choose ⁇ 5 hours to rupture, optional ⁇ 4 hours to rupture.
  • the investigation of the rupture time of the coating layer in the viscous medium in this disclosure refers to the use of the basket method at 75rpm, 500mL pH4.5 PBS 2.5% HPMC K100LV medium for 2 hours, and then change to 500ml 0.1MHCl-3% HPMC Continue the experiment in E5LV medium to investigate the rupture time in viscous medium.
  • the coating layer described in this disclosure is in accordance with the dissolution and release determination method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0931 Method 2), with 2.5% HPMC K100LV-pH6.0 phosphate buffer 500ml as the dissolution medium, and the temperature is 37 ⁇ 0.5°C, the rotation speed is 150 revolutions per minute. After 4 hours, discard the medium in each dissolution cup, and then add 900ml of pH6.8 phosphate buffer preheated to 37 ⁇ 0.5°C in each dissolution cup. Change, continue to operate in accordance with the law, 3-5h rupture.
  • the release amount of the tablet core within the delay time period is not more than about 10% of the total amount of febuxostat in the tablet core. Release all or almost all of the febuxostat internally, specifically, within 1 hour of the coating layer rupture, the febuxostat release amount of the tablet core is more than 65% of the total amount of febuxostat in the core tablet, optionally more than 70% , Optional 75% or more.
  • the febuxostat tablet provided in the present disclosure is basically equivalent to the AUC (geometric mean) of phenibrol, significantly prolongs the effective blood concentration maintenance time and improves the effectiveness, wherein the substantially equivalent refers to The AUC ratio is in the range of 85%-135%.
  • the febuxostat tablet provided in the present disclosure reduces the Cmax value on the basis of significantly prolonging the effective blood concentration maintenance time, and has better safety.
  • the subject takes the febuxostat tablets provided in the present disclosure once a day.
  • the maintenance time of the blood concentration (geometric mean) ⁇ 100 ng/ml is that the subjects take phenbuxostat once a day. 1-3 times of cloth force, optional 1.25-2.0 times.
  • the maintenance time of the blood concentration ⁇ 100ng/ml is at least 10 hours, optionally at least 12 hours, and optionally at least 15 hours.
  • the recovery time of the blood concentration of the subject after taking the drug is 2-5 hours after taking the drug, and 3-4 hours can be selected.
  • the rupture time in the subject's body is 2-5 hours after self-administration, optionally 3-4 hours.
  • the present disclosure provides a febuxostat tablet as described above in preparation for the treatment of gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, Use in medicine for diseases such as chronic kidney disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure.
  • the present disclosure provides a treatment and treatment of gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes,
  • the method for diabetic nephropathy and congestive heart failure is to administer the febuxostat tablets provided in the present disclosure to the patient.
  • the present disclosure provides a method for preparing the above-mentioned febuxostat tablet, which comprises the following steps: granulating febuxostat and optional tablet core excipients into first particles; making the first particles into tablet cores; Granulating the auxiliary material of the coating layer into second granules; compressing and coating the second granules around the tablet core; and coating the quick-release layer.
  • the method includes the following steps: granulating febuxostat with filler, binder, and partial disintegrant, and the hydrophilic gel matrix material in the tablet core, and the remaining disintegrant. , After the lubricant is mixed, the tablet core is compressed; the auxiliary material of the coating layer containing the matrix material, the water-insoluble plasticizer and the hydrophilic gel matrix material is granulated; the chip is compressed; the quick-release layer is coated.
  • the method includes the following steps: granulating febuxostat with lactose, microcrystalline cellulose, hydroxypropyl cellulose and partially cross-linked sodium carboxymethyl cellulose and then mixing with hydroxypropyl methyl cellulose And the remaining croscarmellose sodium and magnesium stearate are mixed and compressed into the tablet core; the Eudragit RSPO, Eudragit RLPO, glyceryl behenate and part of hypromellose are granulated with Kollidon SR and the remaining hypromellose are mixed to compress the chip; the immediate release layer is coated.
  • the method includes the following steps: granulating febuxostat with lactose, microcrystalline cellulose, hydroxypropyl cellulose base and partially cross-linked sodium carboxymethyl cellulose and then granulating with hydroxypropyl methyl cellulose.
  • Cellulose, the remaining croscarmellose sodium, and magnesium stearate are mixed and then compressed into the tablet core; after Eudragit RSPO, Eudragit RLPO, glyceryl behenate and part of hypromellose are granulated It is mixed with Kollidon SR and the remaining hypromellose to compress the packaged chip; Opadry isolation layer coating; Opadry and febuxostat immediate release layer coating.
  • the preparation method of febuxostat tablets includes a step of film coating after the preparation of the chip-coated chips is completed.
  • the present disclosure provides a treatment for gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes, diabetes
  • the method of nephropathy and congestive heart failure is to give the patient a febuxostat tablet containing 30 mg of febuxostat or give the patient a febuxostat tablet containing 60 mg of febuxostat after a medium-fat dinner, once a day medicine.
  • the present disclosure provides treatments for gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes, diabetic For nephropathy and congestive heart failure, febuxostat tablets containing 30 mg febuxostat are given to patients after a medium-fat dinner, and the average blood concentration ⁇ 100ng/ml should be maintained for at least 10 hours.
  • the present disclosure provides treatments for gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes, diabetic For nephropathy and congestive heart failure, febuxostat tablets containing 60mg febuxostat are given to patients after a medium-fat dinner, and the average blood concentration ⁇ 100ng/ml is maintained for at least 15 hours.
  • a febuxostat tablet containing 60 mg of febuxostat is administered to a patient after a medium-fat dinner, and the maintenance time for an average blood concentration of ⁇ 100 ng/ml is at least 18 hours.
  • Figure 1 Schematic diagram of package chip and X-axis and Y-axis
  • Figure 5 The average drug concentration-time log graph after single intragastric administration of 60mg*4 febuxostat sustained-release tablets or 40mg*4 febuxostat tablets to Beagle dogs (full stomach, 1h after feeding ).
  • Figure 6 Schematic diagram of the small opening of the package chip.
  • a 10% concentration of Opadry (YS-1-7027-CN) aqueous solution was used as a coating material and used as a coating liquid for the isolation layer.
  • the time of in vitro opening of the lid is centrally controlled.
  • the opening time of the packaged chip is affected by the water absorption speed of the core, so the viscosity of the medium has a greater influence on the opening time.
  • the opening of the lid is faster in an aqueous medium, and the opening is slower in a viscous medium.
  • dissolution and release determination method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0931 Method 2), 500ml of 2.5% HPMC K100LV-pH6.0 phosphate buffer is used as the dissolution medium, the temperature is 37 ⁇ 0.5°C, and the rotation speed is per minute.
  • the thickness of the outer cover on the Y axis is 1.2-1.4mm on one side and 1.7-1.9mm on the other side; the thickness of the outer cover on the X axis is about 2mm.
  • This experiment adopts a two-period crossover experimental design. 12 male Beagle dogs were divided into two groups to give 240mg (60mg*4 tablets) febuxostat tablets and 160mg (40mg*4 tablets) febuxostat tablets (febrex). ), to compare the drug concentration-time change process in the body of Beagle dogs, and to study the pharmacokinetic behavior of the two.
  • the blood concentration After a single intragastric administration of a 240 mg dose of the test product febuxostat tablets to a Beagle dog, the blood concentration first reached a lower peak at about 0.5 h, the concentration was about 2180 ng/mL, and then decreased, and the blood concentration at 2.00 h The drug concentration increased again, reaching a higher plasma concentration peak in about 4 hours, the concentration was about 4490ng/mL, then the plasma concentration gradually decreased with time, the overall peak concentration Cmax was 5340 ⁇ 2350ng/mL, and the peak time Tmax is 4.00[0.500,4.00]h.
  • the area under the drug concentration-time curve AUC INF_obs is 19100 ⁇ 8960h*ng/mL, and the total time when the blood concentration is higher than 100ng/mL Time High is 12.3 ⁇ 4.88h
  • the blood concentration reached a peak at about 1.00[0.250,1.00]h, and then the blood concentration gradually decreased over time, reaching the peak
  • the concentration Cmax is 6930 ⁇ 3290ng/mL.
  • the area under the drug concentration-time curve AUC INF_obs is 15700 ⁇ 7680h*ng/mL, and the total time when the blood concentration is higher than 100ng/mL Time High is 9.86 ⁇ 5.00h, see Figure 5 for details.
  • the exposure of the drug system is comparable to that of the reference product febuxostat tablet at a dose of 160 mg orally.
  • Febuxostat sustained-release tablets showed obvious double absorption peaks, Cmax was significantly reduced, and the average blood concentration was maintained at the effective blood concentration (>100ng/mL) for a total time of 1.25 times that of the reference febuxostat tablets. , Suggesting that febuxostat tablets clinically maintain longer efficacy and better safety.
  • T preparation blood concentration ⁇ 100ng/ml
  • the prescription in Table 7 was prepared according to the preparation method of Example 1, using the paddle method at 50 rpm, and the opening time was investigated in 500 ml of pH 4.5 PBS-0.5% SDS medium.
  • the package chip prepared by the above prescription has severe erosion of the outer cover in an aqueous medium, and ruptures within 1 hour, making it difficult to maintain rigidity and integrity.

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Abstract

L'invention concerne une chips revêtue à libération prolongée, qui comprend un coeur de comprimé contenant le médicament actif fébuxostat et une couche d'enrobage recouvrant le coeur du comprimé. Le coeur du comprimé se situe dans la couche d'enrobage. Au moins une des couches d'enrobage sur les deux faces dans la direction d'axe Y du coeur de comprimé présente une épaisseur inférieure à l'épaisseur de la couche d'enrobage dans la direction d'axe X. La couche d'enrobage peut contenir une couche d'enrobage de fébuxostat contenant un médicament à libération immédiate. Le comprimé peut être utilisé pour traiter des maladies telles que la goutte et l'hyperuricémie.
PCT/CN2021/084422 2020-03-31 2021-03-31 Comprimé de fébuxostat WO2021197376A1 (fr)

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CN109985016A (zh) * 2017-12-29 2019-07-09 江苏恒瑞医药股份有限公司 一种非布司他的控释组合物及其制备方法

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CN115770226A (zh) * 2022-10-31 2023-03-10 修正药业集团股份有限公司 一种非布司他片及其制备方法

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