WO2021197376A1 - 一种非布司他片 - Google Patents

一种非布司他片 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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WIPO (PCT)
Prior art keywords
febuxostat
cellulose
coating layer
chip
tablet
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PCT/CN2021/084422
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English (en)
French (fr)
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/zh

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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

一种缓释包芯片，包括含有活性药物非布司他的片芯，和包覆于片芯的包衣层，片芯位于包衣层内，Y轴方向片芯两侧的包衣层厚度至少有一侧小于X轴方向的包衣层厚度，包衣层外可含有非布司他的速释含药包衣层。该片剂可用于治疗痛风、高尿酸血症等疾病。

Description

一种非布司他片 技术领域
本公开涉及一种非布司他片，其为包芯片，该制剂包括含有药物的片芯及包覆于片芯上的包衣，属于药物制剂领域。
背景技术
口服给药是一种非常有利的药物递送途径，将口服施用的制剂置于口腔中并吞咽，给药简单、方便、无痛、不需要任何专门的设备或医护人员的参与，具有良好的患者依从性且正本低。
胃排空是人体正常消化过程的一部分，其导致经口服途径进入胃部的药物制剂通常在胃内仅停留较短的时间，短的胃停留时间限制了许多类型的口服施用的药物的生物利用度，特别是胃内局部作用、优先在上胃肠道吸收或在下胃肠道的环境中吸收的药物，及在中性或碱性pH下不稳定的或具有低溶解度的药物，这种类型的药物可以通过胃滞留制剂递送。
缓/控释片是指能够以预先确定的速率和/或在给药后预先确定的时间来释放药物从而在所需要的一段时间内保持所需要的药理学活性。这样的制剂在预先确定的时间段内或者在预先确定的吸收位点向机体提供药物，从而相对于常规的(例如速释)制剂来说，可以在较长的时间段内保持药物水平处于治疗范围内。包含核心的剂型是产生缓/控释片的形式，最常使用的材料为亲水性材料，其一旦与生理介质接触之后，即膨胀并成为胶体。当剂型暴露于生理介质时，***将开始水合并形成胶体基质，随着介质持续地渗透剂型，胶体基质的厚度增加。药物通过基质扩散和/或侵蚀基质从而被释放。
非布司他是一种由日本帝人制药开发的的口服非嘌呤黄嘌呤氧化酶(NP-SIXO)选择性抑制剂，其主要用于痛风患者高尿酸血症的慢性治疗、已发生尿酸盐沉积的慢性高尿酸血症的治疗以及与癌症化疗相关的高尿酸血症(肿瘤溶解综合症)的治疗。主要副反应是在治疗早期常伴随痛风急性发作，增加痛风发作频率，严重影响了患者的顺应性。
武田制药的专利申请CN103210084A公开了一种含有非布司他的新型组合物，包括含有非布司他的立即释放珠粒及缓释释放珠粒，通过膜控的方式达到缓释效果，该申请背景技术中指出，在延长的时间段内保持药物浓度高于100ng/mL的临界浓度的非布司他制剂被期望可以产生较高的药效，并且将会是控制高尿酸血症、痛风和许多其他疾病状态的期望的治疗选择。但涉及该申请的临床项目 TMX-67XR后因未公开的原因项目终止，充分证明了非布司他缓/控释片在开发上存在很大的难度。
发明内容
本公开提供一种包芯片，包括含有活性药物非布司他的片芯，和包覆于片芯的包衣层，片芯位于包衣层内，Y轴方向片芯两侧的包衣层厚度至少有一侧小于X轴方向的包衣层厚度(附图1为示意图，其中Y轴方向片芯两侧分别对应图中上下两个面)。
本公开中所述的沿着冲头运动方向的轴向(上述“Y”轴)包衣厚度是通过包衣原料在模片中的加入量以及片剂成形时所用的冲压力进行确定的。而沿“X”轴方向(与冲头运动方向垂直方向)的包衣厚度通过内核尺寸、内核在模片内的位置以及模片直径来确定。
本公开提供的非布司他的包芯片提供足以使其在进食状态下胃部滞留的初始直径，例如约12-18mm直径的片剂在进食状态下通常可以抵抗通过幽门***，具体的本公开的非布司他的包芯片的初始最大直径可以为12-16mm，可选13-15mm。
可选的实施方案中，本公开提供的包芯片为胃部滞留的包芯片。
可选的实施方案中，Y轴方向片芯两侧的包衣层厚度相同或者不相同，片芯的一侧的包衣层厚度可以为0.5-2.2mm，可选1.0-2.0mm，可选1.5-1.8mm，可选1.7-1.9mm；片芯另一侧的包衣层厚度可以为0.3-2.0mm，可选0.8-1.8mm，可选1.2-1.4mm，可选1.0-1.5mm。
本公开中提供的包芯片，由于特殊的沿Y轴方向包衣厚度的选择，使得活性物质非布司他在预定延缓时间段释放，达到控释效果，所述的包衣层能够在水性介质中浸泡至少1小时之后破裂，释放活性物质，可选1.5小时之后破裂，可选2小时以后破裂，本公开中提供的包芯片的包衣层在水性介质中的破裂时间不晚于4小时。本公开中所述的包衣层在水性介质中破裂时间的考察是指采用桨法50rpm，在pH4.5PBS-0.5％SDS介质500mL中考察的结果。
对于给定活性药物而言，如果能够用将药物可控地几乎完全输送至特定吸收窗口，或者在胃肠道中该活性药物的降解或代谢较高的区域优先地避免或降低释放速率，此外，将活性药物递送至吸收窗口可以增加药物的功效和/或减少或消除副作用。出于该方面考虑，包衣层破裂太晚则可能错过吸收窗，本公开中提供的包芯片，所述包衣层能够在粘性介质中浸泡时间≤6小时时发生破裂，释放活性物质，可选≤5小时破裂，可选≤4小时破裂。本公开中所述的包衣层在粘性介质中破裂时间的考察是指采用采用篮法75rpm，500mL pH4.5 PBS  -2.5％HPMC K100LV介质中实验2h，再更换至500ml 0.1MHCl-3％HPMC E5LV介质中继续实验，考察在粘性介质中破裂时间。
本公开中所述的包衣层按照溶出度与释放度测定法(中国药典2015年版四部通则0931第二法)，以2.5％HPMC K100LV-pH6.0磷酸盐缓冲液500ml为溶出介质，温度为37±0.5℃，转速为每分钟150转，4h后弃去上述各溶出杯中的介质，随即在各溶出杯中加入900ml预热至37±0.5℃的pH6.8磷酸盐缓冲液，转速不变，继续依法操作，3-5h破裂。
当包芯片的破裂位置在X轴方向时，由于开口太小，纵深比较长(如附图6所示)，导致药物释放缓慢，故Y轴方向片芯两侧的包衣层厚度至少有一侧小于X轴方向的包衣厚度，使得包衣破裂释放活性药物在Y轴方向发生，保证了片芯药物的快速释放(如附图2所示)。
本公开中，延缓时间段内片芯的释放量不大于片芯非布司他的总量的约10％应理解为片芯基本无药物释放，片芯在延缓时间届满后在很短的时间内释放全部或基本全部的非布司他，具体为包衣层破裂1小时内，片芯的非布司他释放量为片芯非布司他总量的65％以上，可选70％以上，可选75％以上。
本公开的包芯片采用压制包衣技术(compression-coated technology)成形，以下将详细说明。压包片剂通常是通过将一部分粉状或颗粒状包衣原料置于模片内，用冲压机将该部分包衣原料捣实成致密态，后将内核置于致密的包衣原料上，接着将剩余的包衣原料引入模片内，施加压力形成包衣片剂。随着压制技术的创新，也产生了一些一步干包衣来制备压包片的技术，例如
Figure PCTCN2021084422-appb-000001
具体可见Yuichi Ozeki等人的研究Evaluation of novel one-step dry-coated tablets as a platform for delayed-release tablets(Journal of Controlled Release 95(2004)51–60)。
本公开中片芯硬度相对较低，保证水介质接触到片芯后，片芯能够膨胀，使得外包层更好的破裂，片芯的硬度为10-120N，可选20-60N。为保证包芯片的机械稳定性，使得其足以抵抗胃部产生的压力，尤其是在有食物存在时，保证外包层的完整性不受破坏，片剂的硬度控制在120-300N，可选170-230N。本公开中，非布司他从片芯释放，不是药物通过膨胀的包衣材料而扩散的结果，是包衣物理破裂的结果。
本公开提供的包芯片，包衣层含有至少一种基质材料，至少一种疏水性的增塑剂和至少一种亲水凝胶骨架材料，所述的基质材料为不溶于水或难溶于水的赋形剂。
可选的实施方案中所述的疏水性的增塑剂可选液状石蜡、玉米油、蓖麻油、椰子油、甘油三醋酸酯、甘油单醋酸酯、二丁基癸二酸酯、邻苯二甲酸二丁酯、 长链脂肪醇、长链脂肪酸及其酯或其盐类、山嵛酸甘油酯，可选山嵛酸甘油酯，所述水不溶的增塑剂的含量为包衣层总重的0.1％-30％(质量百分比)，可选为0.5％-20％，可选1％-10％。
本公开中所述的增塑剂山嵛酸甘油酯是甘油与山嵛酸(一种C 22脂肪酸)形成的酯，山嵛酸甘油酯可以其单、双或三酯或它们的混合物的形式存在，其HLB值可选小于5，可选为约2。
申请人惊奇的发现不含疏水性的增塑剂的包衣层在水性介质中溶蚀严重，难以维持刚性及完整性，包衣层不能起到延缓时间段后释放的效果。
可选的实施方案中，所述不溶于水或难溶于水的赋形剂可选自任意已知的水不溶性纤维素衍生物、聚合物以及聚乙酸乙烯酯和聚维酮混合物等，所述水不溶性纤维素衍生物和聚合物包括烷基纤维素，如乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素以及它们的衍生物，聚甲基丙烯酸聚合物，聚乙酸乙烯酯以及纤维素乙酸酯聚合物，脂肪酸或其酯类或其盐类，长链脂肪醇，聚氧乙烯烷基醚，聚氧乙烯硬脂酸，糖酯，月桂酰聚乙二醇-32甘油，硬脂酰聚乙二醇-32甘油等。
Figure PCTCN2021084422-appb-000002
是聚醋酸乙烯酯与聚乙烯吡咯烷酮混合物，是一种可塑性非常好的材料，特别适用于直接压片。
可选的实施方案中，所述基质材料选自聚甲基丙烯酸聚合物、聚乙酸乙烯酯和聚维酮混合物的组合。
可选的，包衣层中聚甲基丙烯酸聚合物的含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，乙酸乙烯酯和聚维酮混合物的含量为包衣层总重的5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，所述基质材料选自尤特奇与聚乙酸乙烯酯和聚维酮混合物的组合。
可选的实施方案中，包衣层中尤特奇含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，聚乙酸乙烯酯和聚维酮混合物的含量为包衣层总重的5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，所述基质材料选自尤特奇RL、尤特奇RS与聚乙酸乙烯酯和聚维酮混合物的组合，尤特奇RL、尤特奇RS在水中不溶但是可以溶胀，从而在包衣中形成孔道，尤特奇RL的孔道直径为1-5μm，尤特奇RS的孔道直径为0.1-0.6μm。
可选的实施方案中，包衣层中尤特奇RL与尤特奇RS的含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，聚乙酸乙烯酯和聚维酮混合物的含量为包衣层总重5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，所述基质材料选自尤特奇RLPO与尤特奇RSPO与聚乙酸乙烯酯和聚维酮混合物的组合。
可选的实施方案中，包衣层中尤特奇RLPO与尤特奇RSPO的含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，聚乙酸乙烯酯和聚维酮混合物的含量为包衣层总重5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，所述基质材料选自尤特奇RLPO、尤特奇RSPO、
Figure PCTCN2021084422-appb-000003
的组合。
可选的实施方案中，包衣层中尤特奇RLPO与尤特奇RSPO的含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，
Figure PCTCN2021084422-appb-000004
的含量为包衣层总重5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，包衣层中尤特奇RSPO的含量占包衣层总重的5％-40％(质量百分比)，可选10％-30％，可选15％-25％。
可选的实施方案中，包衣层中尤特奇RLPO的含量占包衣层总重的20％-80％(质量百分比)，可选30％-70％，可选45％％-55％。
可选的实施方案中，包衣层中尤特奇RSPO的含量占包衣层总重的5％-40％(质量百分比)，尤特奇RLPO的含量占包衣层总重20％-80％(质量百分比)，
Figure PCTCN2021084422-appb-000005
的含量为包衣层总重5％-40％(质量百分比)。
可选的实施方案中，包衣层中尤特奇RSPO的含量占包衣层总重的10％-30％(质量百分比)，尤特奇RLPO的含量占包衣层总重的30％-70％(质量百分比)，
Figure PCTCN2021084422-appb-000006
的含量为包衣层总重的15％-25％(质量百分比)。
可选的实施方案中，包衣层中尤特奇RSPO的含量占包衣层总重的15％-25％(质量百分比)，尤特奇RLPO的含量占包衣层总重的45％-55％(质量百分比)，
Figure PCTCN2021084422-appb-000007
的含量为包衣层总重的15％-25％(质量百分比)。
本公开中所述亲水凝胶骨架材料选自甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素、羟甲基纤维素钠、壳多糖、脱乙酰壳多糖、半乳糖甘露聚糖、果胶、海藻酸钠、海藻酸钾、琼脂、角叉菜胶、刺槐豆胶等。
可选的实施方案中，所述亲水凝胶骨架材料为羟丙基甲基纤维素，所述羟丙基甲基纤维素材料选自重均分子量低、粘度低的材料，诸如E-型甲基纤维素。
本公开中亲水凝胶骨架材料的含量为包衣层总重的1％-30％(质量百分比)，可选5％-20％，可选8％-15％。
可选的实施方案中，所述亲水凝胶骨架材料为E-型羟丙基甲基纤维素，其含量为包衣层总重的1％-30％(质量百分比)，可选5％-20％，可选10％-15％。
本公开中，为适应制备工艺的需求，可选的亲水凝胶骨架材料也可以做为粘 合剂。
本公开提供的非布司他的包芯片，片芯中除含有活性物质非布司他外，还含有本领域公知的速释制剂的崩解剂，在本公开中崩解剂可以是在水介质存在时泡腾和/或膨胀的材料，从而可提供必要的力量使包衣材料发生机械性破裂，具体的，崩解剂可以选自交联羧甲基纤维素钠、干淀粉、低取代羟丙甲基纤维素、羧甲基淀粉钠及交联聚维酮等，可选交联羧甲基纤维素钠，崩解剂的用量可为片芯重量的2％-35％(质量百分比)，可选的可以是片芯重量的5％-25％，可选的可以是片芯重量的8％-15％。
本公开提供的非布司他的包芯片，片芯中还可以含有药学上可接受的水溶性填充剂和/或水不溶性填充剂，水溶性填充剂包括乳糖、甘露醇、蔗糖、山梨醇等，水不溶性填充剂包括淀粉、微晶纤维素、硫酸钙、磷酸氢钙等，稀释剂的含量可以是片芯重量的1％-99％，(质量百分比)可选的20％-85％，可选60％-80％。
可选的实施方案中，片芯的填充剂选自水溶性填充剂与水不溶性填充剂的组合，其中水溶性填充剂的含量可以是片芯重量的35％-75％(质量百分比)，可选45％-70％，可选50％-65％；水不溶性填充剂的含量可以是片芯重量的1％-25％(质量百分比)，可选10％-25％。
可选的实施方案中，片芯的填充剂为选自水溶性填充剂的乳糖和选自水不溶性填充剂的微晶纤维素的组合。
本公开提供的非布司他的包芯片，片芯中还可以含有药学上可接受的粘合剂，粘合剂可以选自例如羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、海藻糖和支链淀粉中的至少一种，但不限于此，粘合剂的含量可以为片芯总重量的1％-5％(质量百分比)。
可选的实施方案中，粘合剂为羟丙基纤维素。
片芯中可含有合适的润滑剂，例如胶态二氧化硅、滑石粉、硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酸富马酸钠、聚乙二醇或十二烷基硫酸钠，片芯中润滑剂的含量为片芯总重的0.5％-10％(质量百分比)，可选1％-5％。
可选的实施方案中，片芯的润滑剂为硬脂酸镁。
适当的，可以在片芯加入着色剂来保证片芯在包衣内准确定位以确保片剂具有合适的包衣厚度，使得延缓时间重现性好，从而避免患者内部(intra-subject)和患者之间的生物利用率差异，适当的着色剂可以是氧化铁、二氧化钛、氢氧化铁等，着色剂的选择并不限定本公开的范围，着色剂的含量是片芯总重的0.1％-3％，可选0.4％-1％。
可选的实施方案中，本公开提供的非布司他的包芯片，片芯中还可以含有亲水凝胶骨架材料，所述的亲水凝胶骨架材料选自纤维素衍生物、非纤维素多糖、 天然胶、乙烯基聚合物或丙烯酸聚合物等。所述的纤维素衍生物可选自甲基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素和羟甲基纤维素钠等；所述的非纤维素多糖选自葡萄糖、壳多糖、脱乙酰壳多糖和半乳糖甘露聚糖等；所述的天然胶选自果胶、海藻酸钠、海藻酸钾、琼脂、角叉等胶、刺槐豆胶、爪耳树胶等。
可选的实施方案中，本公开提供的非布司他的包芯片，片芯中的亲水凝胶骨架材料为纤维素衍生物。
可选的实施方案中，本公开提供的非布司他的包芯片，片芯中的亲水凝胶骨架材料选自羟乙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素。
可选的实施方案中，本公开提供的非布司他的包芯片，片芯中的亲水凝胶骨架材料为羟丙基甲基纤维素。
可选的实施方案中，本公开提供的非布司他的包芯片，片芯中的亲水凝胶骨架材料占片芯总重的1％-20％。
可选的实施方案中，本公开提供的非布司他的包芯片，片芯中的亲水凝胶骨架材料占片芯总重的2％-10％。
可选的实施方案中，本公开提供的非布司他的包芯片，片芯中的亲水凝胶骨架材料占片芯总重的3％-8％。
本公开提供一种非布司他片，除含有上述的包芯片，包衣层外还含有非布司他的速释部分，速释部分可以以任何本领域熟知的技术手段完成，例如双层片、速释包衣等。
可选的实施方案中，本公开提供的非布司他片具有缓释的效果。
本公开提供一种非布司他片，除含有上述的包芯片，所述包芯片的包衣层外含有非布司他的速释含药包衣层。
可选的实施方案中，非布司他的速释含药包衣层，含有活性药物非布司他及包衣材料，所述的包衣材料可选羟丙基甲基纤维素、羟丙基纤维素、聚乙烯醇、胃溶型欧巴代，可选胃溶型欧巴代，可选欧巴代(03K180007-CN)。
由于速释组分在介质或者体内迅速释放，故本公开中包芯片的释药特征与含有速释组分的非布司他片的释药特征相同。
可选的实施方案中，本公开提供的非布司他片的单位剂型中非布司他的含量为菲布力单位剂型中非布司他含量的1.1-1.8倍，可选1.2-1.6倍，可选1.5倍。具体的，例如市售非布司他的单片的含量为20mg，则本公开提供的非布司他的单位片剂含量为30mg，市售非布司他的单片的含量为40mg，则本公开提供的非布司他的单位片剂含量为60mg。增加的药物剂量使降尿酸达标率增加，从而降低痛风发作频率及保证疗效。
可选的实施方案中，本公开提供的非布司他片的单位剂型中非布司他的量为10mg-200mg，可选20mg-150mg，可选的非布司他的量为10mg、15mg、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，可选30mg和60mg，速释含药包衣层与片芯中活性物质的含量比为1:10-10:1，可选1:5-5:1。
可选的实施方案中，所述非布司他片含有以下成分：
片芯
非布司他
乳糖50％-65％(质量百分比)；
微晶纤维素10％-25％(质量百分比)；
交联羧甲基纤维素钠8％-15％(质量百分比)；
羟丙基纤维素1-5％(质量百分比)；
硬脂酸镁1％-5％(质量百分比)，以片芯总重计；
包衣层
尤特奇RSPO 15％-25％(质量百分比)；
尤特奇RLPO 45％％-55％(质量百分比)；
Figure PCTCN2021084422-appb-000008
15％-25％(质量百分比)；
羟丙基甲基纤维素8％-15％(质量百分比)，以包衣层总重计。
可选的实施方案中，所述非布司他片含有以下成分：
片芯
非布司他
乳糖50％-65％(质量百分比)；
微晶纤维素10％-25％(质量百分比)；
交联羧甲基纤维素钠8％-15％(质量百分比)；
羟丙基纤维素1-5％(质量百分比)；
硬脂酸镁1％-5％(质量百分比)；
羟丙基甲基纤维素3％-8％(质量百分比)，以片芯总重计；
包衣层
尤特奇RSPO 15％-25％(质量百分比)；
尤特奇RLPO 45％％-55％(质量百分比)；
Figure PCTCN2021084422-appb-000009
15％-25％(质量百分比)；
羟丙基甲基纤维素8％-15％(质量百分比)，以包衣层总重计。
可选的实施方案中，非布司他片中活性物质含量为30mg，其中速释含药包衣层与片芯中活性物质的含量比为1:10-10:1，可选1:5-5:1，可选1:2-1:1，可选2:3。
可选的实施方案中非布司他片中活性物质含量为60mg，其中速释含药包衣层与片芯中活性物质的含量比为1:10-10:1，可选1:5-5:1，可选1:3-1:1，可选3:7。
任选的，包衣层与非布司他速释层之间存在隔离层，所述的隔离层是一层薄薄的高分子材料，形成薄膜状的衣层，使得片重增加1％-50％(质量百分比)，可选2％-4％。
所述的隔离层的材料可选羟丙甲纤维素、聚维酮、共聚维酮、羟丙基纤维素和胃溶型欧巴代中的一种或多种，可选胃溶型欧巴代，可选胃溶型的欧巴(YS-1-7027-CN)。
可选的实施方式中，本公开提供的非布司他片，与菲布力AUC(几何均值)基本相当的基础上，明显延长有效血药浓度维持时间，有效性提高，其中基本相当是指AUC比值在85％-135％范围内。
本公开提供的非布司他片，在明显延长有效血药浓度维持时间的基础上降低了Cmax值，安全性更好。
本公开提供的非布司他片，受试者一日一次服用本公开提供的非布司他片体内血药浓度(几何均值)≥100ng/ml的维持时间是受试者一日一次服用菲布力的1-3倍，可选1.25-2.0倍。
本公开提供的非布司他片，受试者进食低脂低热量餐(脂肪提供食物中约10％的热量，总热量约300千卡)后，血药浓度≥100ng/ml的维持时间至少为10小时，可选至少为12小时，可选至少为15小时。
本公开提供的非布司他片，受试者进食标准餐后，血药浓度≥100ng/ml的维持时间至少为12小时，可选至少为15小时，可选至少为17小时。
本公开中所述的血药浓度指的是几何均值。
本公开提供的非布司他片在体内提供明显的双峰。
本公开提供的非布司他片，受试者服药后血药浓度复升时间为自服药后2-5小时，可选3-4小时。
本公开提供的非布司他片，在受试者体内破裂时间为自服药后2-5小时，可选3-4小时。
本公开提供一种上述的非布司他片在制备用于治疗痛风、高尿酸血症、***炎、炎性肠病、QT间期延长、心肌梗塞、心脏肥大、高血压、肾石病、慢性肾脏疾病、代谢综合征、糖尿病、糖尿病性肾病、充血性心力衰竭的疾病的药物中的用途。
本公开提供一种治疗治疗痛风、高尿酸血症、***炎、炎性肠病、QT间期延长、心肌梗塞、心脏肥大、高血压、肾石病、慢性肾脏疾病、代谢综合征、糖尿病、糖尿病性肾病、充血性心力衰竭的方法，给与患者上述本公开提供的非布司他片。
本公开提供一种制备上述非布司他片的方法，该方法包括以下步骤：将非布司他与任选的片芯赋形剂制粒成第一颗粒；使第一颗粒成片芯；将包衣层辅料制粒成第二颗粒；将第二颗粒压制包覆于片芯周围；速释层包衣。
可选的实施方案中，该方法包括以下步骤：将非布司他与填充剂、粘合剂、部分崩解剂制粒，与剩余的崩解剂、润滑剂混合后压制片芯；含有基质材料、水不溶的增塑剂和亲水凝胶骨架材料的包衣层辅料制粒；压制包芯片；速释层包衣。
可选的实施方案中，该方法包括以下步骤：将非布司他与乳糖、微晶纤维素、羟丙基纤维素及部分交联羧甲基纤维素钠制粒后与剩余的交联羧甲基纤维素钠、硬脂酸镁混合后压制片芯；将尤特奇RSPO、尤特奇RLPO、山嵛酸甘油酯及部分羟丙甲纤维素制粒后与Kollidon SR、剩余羟丙甲纤维素混合后压制包芯片；速释层包衣。
可选的实施方案中，该方法包括以下步骤：将非布司他与乳糖、微晶纤维素、羟丙基纤维素基及部分交联羧甲基纤维素钠制粒后与剩余的交联羧甲基纤维素钠、硬脂酸镁混合后压制片芯；将尤特奇RSPO、尤特奇RLPO、山嵛酸甘油酯及部分羟丙甲纤维素制粒后与Kollidon SR、剩余羟丙甲纤维素混合后压制包芯片；欧巴代隔离层包衣；欧巴代与非布司他速释层包衣。
任选的，非布司他片的制备方法，在完成包芯片的制备后有薄膜包衣的步骤。
本公开另一方面提供一种非布司他片，包括含有活性药物非布司他的片芯，和包覆于片芯的包衣层，片芯位于包衣层内，所述片芯还含有占片芯总重的1％-20％的亲水凝胶骨架材料；包衣层含有至少一种基质材料，至少一种疏水性的增塑剂和至少一种亲水凝胶骨架材料，另包括含有活性物质非布司他的速释组分。
可选的实施方案中，片芯的亲水凝胶骨架材料选自纤维素衍生物、非纤维素多糖、天然胶、乙烯基聚合物或丙烯酸聚合物等；所述的纤维素衍生物可选自甲基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素和羟甲基纤维素钠等；所述的非纤维素多糖选自葡萄糖、壳多糖、脱乙酰壳多糖和半乳糖甘露聚糖等；所述的天然胶选自果胶、海藻酸钠、海藻酸钾、琼脂、角叉等胶、刺槐豆胶、爪耳树胶等。
可选的实施方案中，本公开提供的非布司他片，片芯中的亲水凝胶骨架材料为纤维素衍生物。
可选的实施方案中，本公开提供的非布司他的包芯片，片芯中的亲水凝胶骨架材料选自羟乙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素。
可选的实施方案中，本公开提供的非布司他片，片芯中的亲水凝胶骨架材料为羟丙基甲基纤维素。
可选的实施方案中，本公开提供的非布司他片，片芯中的亲水凝胶骨架材料占片芯总重的2％-10％。
可选的实施方案中，本公开提供的非布司他片，片芯中的亲水凝胶骨架材料占片芯总重的3％-8％。
可选的实施方案中，所述的疏水性的增塑剂可选液状石蜡、玉米油、蓖麻油、椰子油、甘油三醋酸酯、甘油单醋酸酯、二丁基癸二酸酯、邻苯二甲酸二丁酯、长链脂肪醇、长链脂肪酸及其酯或其盐类、山嵛酸甘油酯，可选山嵛酸甘油酯，所述水不溶的增塑剂的含量为包衣层总重的0.1％-30％(质量百分比)，可选为0.5％-20％，可选1％-10％。
本公开中所述的增塑剂山嵛酸甘油酯是甘油与山嵛酸(一种C 22脂肪酸)形成的酯，山嵛酸甘油酯可以其单、双或三酯或它们的混合物的形式存在，其HLB值可选小于5，可选为约2。
申请人惊奇的发现不含疏水性的增塑剂的包衣层在水性介质中溶蚀严重，难以维持刚性及完整性，包衣层不能起到延缓时间段后释放的效果。
可选的实施方案中，所述不溶于水或难溶于水的赋形剂可选自任意已知的水不溶性纤维素衍生物、聚合物以及聚乙酸乙烯酯和聚维酮混合物等，所述水不溶性纤维素衍生物和聚合物包括烷基纤维素，如乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素以及它们的衍生物，聚甲基丙烯酸聚合物，聚乙酸乙烯酯以及纤维素乙酸酯聚合物，脂肪酸或其酯类或其盐类，长链脂肪醇，聚氧乙烯烷基醚，聚氧乙烯硬脂酸，糖酯，月桂酰聚乙二醇-32甘油，硬脂酰聚乙二醇-32甘油等。
可选的实施方案中，所述基质材料选自聚甲基丙烯酸聚合物、聚乙酸乙烯酯和聚维酮混合物的组合。
可选的实施方案中，包衣层中聚甲基丙烯酸聚合物的含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，乙酸乙烯酯和聚维酮混合物的含量为包衣层总重的5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，所述基质材料选自尤特奇与聚乙酸乙烯酯和聚维酮混合物的组合。
可选的实施方案中，包衣层中尤特奇含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，聚乙酸乙烯酯和聚维酮混合物的含量 为包衣层总重的5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，所述基质材料选自尤特奇RL、尤特奇RS与聚乙酸乙烯酯和聚维酮混合物的组合，尤特奇RL、尤特奇RS在水中不溶但是可以溶胀，从而在包衣中形成孔道，尤特奇RL的孔道直径为1-5μm，尤特奇RS的孔道直径为0.1-0.6μm。
可选的实施方案中，包衣层中尤特奇RL与尤特奇RS的含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，聚乙酸乙烯酯和聚维酮混合物的含量为包衣层总重5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，所述基质材料选自尤特奇RLPO与尤特奇RSPO与聚乙酸乙烯酯和聚维酮混合物的组合。
可选的实施方案中，包衣层中尤特奇RLPO与尤特奇RSPO的含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，聚乙酸乙烯酯和聚维酮混合物的含量为包衣层总重5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，所述基质材料选自尤特奇RLPO、尤特奇RSPO、
Figure PCTCN2021084422-appb-000010
的组合。
可选的实施方案中，包衣层中尤特奇RLPO与尤特奇RSPO的含量占包衣层总重的50％-90％(质量百分比)，可选60％-85％，可选65％-75％，
Figure PCTCN2021084422-appb-000011
的含量为包衣层总重5％-40％(质量百分比)，可选15％-25％。
可选的实施方案中，包衣层中尤特奇RSPO的含量占包衣层总重的5％-40％(质量百分比)，可选10％-30％，可选15％-25％。
可选的实施方案中，包衣层中尤特奇RLPO的含量占包衣层总重的20％-80％(质量百分比)，可选30％-70％，可选45％％-55％。
可选的实施方案中，包衣层中尤特奇RSPO的含量占包衣层总重的5％-40％(质量百分比)，尤特奇RLPO的含量占包衣层总重20％-80％(质量百分比)，
Figure PCTCN2021084422-appb-000012
的含量为包衣层总重5％-40％(质量百分比)。
可选的实施方案中，包衣层中尤特奇RSPO的含量占包衣层总重的10％-30％(质量百分比)，尤特奇RLPO的含量占包衣层总重的30％-70％(质量百分比)，
Figure PCTCN2021084422-appb-000013
的含量为包衣层总重的15％-25％(质量百分比)。
可选的实施方案中，包衣层中尤特奇RSPO的含量占包衣层总重的15％-25％(质量百分比)，尤特奇RLPO的含量占包衣层总重的45％-55％(质量百分比)，
Figure PCTCN2021084422-appb-000014
的含量为包衣层总重的15％-25％(质量百分比)。
可选的实施方案中，包衣层中的亲水凝胶骨架材料选自甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素、羟甲基纤维素钠、壳多糖、脱乙酰壳多糖、半乳糖甘露聚糖、果胶、海藻酸钠、海藻酸钾、琼脂、 角叉菜胶、刺槐豆胶等。
可选的实施方案中，包衣层中的亲水凝胶骨架材料为羟丙基甲基纤维素，所述羟丙基甲基纤维素材料选自重均分子量低、粘度低的材料，诸如E-型甲基纤维素。
可选的实施方案中，本公开包衣层中亲水凝胶骨架材料的含量为包衣层总重的1％-30％(质量百分比)，可选5％-20％，可选8％-15％。
可选的实施方案中，所述亲水凝胶骨架材料为E-型羟丙基甲基纤维素，其含量为包衣层总重的1％-30％(质量百分比)，可选5％-20％，可选8％-15％。
本公开中，为适应制备工艺的需求，可选的亲水凝胶骨架材料也可以做为粘合剂。
本公开提供的非布司他片，片芯中除含有活性物质非布司他外，还含有本领域公知的速释制剂的崩解剂，在本公开中崩解剂可以是在水介质存在时泡腾和/或膨胀的材料，从而可提供必要的力量使包衣材料发生机械性破裂，具体的，崩解剂可以选自交联羧甲基纤维素钠、干淀粉、低取代羟丙甲基纤维素、羧甲基淀粉钠及交联聚维酮等，可选交联羧甲基纤维素钠，崩解剂的用量可为片芯重量的2％-35％(质量百分比)，可选的可以是片芯重量的5％-25％，可选的，可以是片芯重量的8％-15％。
本公开提供的非布司他片，片芯中还可以含有药学上可接受的水溶性填充剂和/或水不溶性填充剂，水溶性填充剂包括乳糖、甘露醇、蔗糖、山梨醇等，水不溶性填充剂包括淀粉、微晶纤维素、硫酸钙、磷酸氢钙等，稀释剂的含量可以是片芯重量的1％-99％，(质量百分比)，可选20％-85％，可选60％-80％。
可选的实施方案中，片芯的填充剂选自水溶性填充剂与水不溶性填充剂的组合，其中水溶性填充剂的含量可以是片芯重量的35％-75％(质量百分比)，可选45％-70％，可选50％-65％；水不溶性填充剂的含量可以是片芯重量的1％-30％(质量百分比)，可选10％-25％。
可选的实施方案中，片芯的填充剂为选自水溶性填充剂的乳糖和选自水不溶性填充剂的微晶纤维素的组合。
本公开提供的非布司他片，片芯中还可以含有药学上可接受的粘合剂，粘合剂可以选自例如羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、海藻糖和支链淀粉中的至少一种，但不限于此，粘合剂的含量可以为片芯总重量的1％-5％(质量百分比)。
可选的实施方案中，粘合剂为羟丙基纤维素。
片芯中可含有合适的润滑剂，例如胶态二氧化硅、滑石粉、硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酸富马酸钠、聚乙二醇或十二烷基硫酸钠，片芯中润滑剂的 含量为片芯总重的0.5％-10％(质量百分比)，可选1％-5％。
可选的实施方案中，片芯的润滑剂为硬脂酸镁。
适当的，可以在片芯加入着色剂来保证片芯在包衣内准确定位以确保片剂具有合适的包衣厚度，使得延缓时间重现性好，从而避免患者内部(intra-subject)和患者之间的生物利用率差异，适当的着色剂可以是氧化铁、二氧化钛、氢氧化铁等，着色剂的选择并不限定本公开的范围，着色剂的含量是片芯总重的0.1％-3％，可选0.4％-1％。
本公开提供的非布司他片提供足以使其在进食状态下胃部滞留的初始直径，例如约12-18mm直径的片剂在进食状态下通常可以抵抗通过幽门***，具体的本公开的非布司他的包芯片的初始最大直径可以为12-16mm，可选13-15mm。
可选的实施方案中，本公开提供的非布司他片为胃部滞留片。
本公开中片芯硬度相对较低，保证水介质接触到片芯后，片芯能够膨胀，使得外包层更好的破裂，片芯的硬度为10-120N，可选20-60N。为保证包芯片的机械稳定性，使得其足以抵抗胃部产生的压力，尤其是在有食物存在时，保证外包层的完整性不受破坏，片剂的硬度控制在30-250N，可选70-180N。本公开中，非布司他从片芯释放，不是药物通过膨胀的包衣材料而扩散的结果，是包衣物理破裂的结果。
可选的实施方案中，本公开提供的非布司他片具有缓释的效果。
可选的实施方案中，本公开提供一种非布司他片的速释组分为速释含药包衣层。
可选的实施方案中，非布司他的速释含药包衣层，含有活性药物非布司他及包衣材料，所述的包衣材料可选羟丙基甲基纤维素、羟丙基纤维素、聚乙烯醇、胃溶型欧巴代，可选胃溶型欧巴代，可选欧巴代(03K180007-CN)。
可选的实施方案中，本公开提供的非布司他片的单位剂型中非布司他的含量为菲布力单位剂型中非布司他含量的1.1-1.8倍，可选1.2-1.6倍，可选1.5倍。具体的，例如市售非布司他的单片的含量为20mg，则本公开提供的非布司他的单位片剂含量为30mg，市售非布司他的单片的含量为40mg，则本公开提供的非布司他的单位片剂含量为60mg。增加的药物剂量使降尿酸达标率增加，从而降低痛风发作频率及保证疗效。
可选的实施方案中，本公开提供的非布司他片的单位剂型中非布司他的量为10mg-200mg，可选20mg-150mg，可选的非布司他的量为10mg、15mg、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，可选30mg和60mg，速释组分与片芯中活性物质的含量比为1:10-10:1，可选1:5-5:1。
可选的实施方案中，所述非布司他片含有以下成分：
片芯
非布司他
乳糖50％-65％(质量百分比)；
微晶纤维素10％-25％(质量百分比)；
交联羧甲基纤维素钠8％-15％(质量百分比)；
羟丙基纤维素1-5％(质量百分比)；
羟丙甲基纤维素3％-8％(质量百分比)；
硬脂酸镁1％-5％(质量百分比)，以片芯总重计；
包衣层
尤特奇RSPO 15％-25％(质量百分比)；
尤特奇RLPO 45％-55％(质量百分比)；
Figure PCTCN2021084422-appb-000015
15％-25％(质量百分比)；
羟丙基甲基纤维素8％-15％(质量百分比)，以包衣层总重计。
可选的实施方案中，非布司他片中活性物质含量为30mg，其中速释含药包衣层与片芯中活性物质的含量比为1:10-10:1，可选1:5-5:1，可选1:2-1:1，可选2:3。
可选的实施方案中非布司他片中活性物质含量为60mg，其中速释含药包衣层与片芯中活性物质的含量比为1:10-10:1，可选1:5-5:1，可选1:3-1:1，可选3:7。
任选的，包衣层与非布司他速释层之间存在隔离层，所述的隔离层是一层薄薄的高分子材料，形成薄膜状的衣层，使得片重增加1％-50％(质量百分比)，可选2％-4％。
所述的隔离层的材料可选羟丙甲纤维素、聚维酮、共聚维酮、羟丙基纤维素和胃溶型欧巴代中的一种或多种，可选胃溶型欧巴代，可选胃溶型的欧巴(YS-1-7027-CN)。
本公开提供的非布司他片，使得活性物质非布司他在预定延缓时间段释放，达到控释效果，所述的包衣层能够在水性介质中浸泡至少1小时之后破裂，释放活性物质，可选1.5小时之后破裂，可选2小时以后破裂，本公开中提供的包芯片的包衣层在水性介质中的破裂时间不晚于4小时。本公开中所述的包衣层在水性介质中破裂时间的考察是指采用桨法50rpm，在pH4.5PBS-0.5％SDS介质500mL中考察的结果。
对于给定活性药物而言，如果能够用将药物可控地几乎完全输送至特定吸收 窗口，或者在胃肠道中该活性药物的降解或代谢较高的区域优先地避免或降低释放速率，此外，将活性药物递送至吸收窗口可以增加药物的功效和/或减少或消除副作用。出于该方面考虑，包衣层破裂太晚则可能错过吸收窗，本公开中提供的包芯片，所述包衣层能够在粘性介质中浸泡时间≤6小时时发生破裂，释放活性物质，可选≤5小时破裂，可选的≤4小时破裂。本公开中所述的包衣层在粘性介质中破裂时间的考察是指采用采用篮法75rpm，500mL pH4.5 PBS -2.5％HPMC K100LV介质中实验2h，再更换至500ml 0.1MHCl-3％HPMC E5LV介质中继续实验，考察在粘性介质中破裂时间。
本公开中所述的包衣层按照溶出度与释放度测定法(中国药典2015年版四部通则0931第二法)，以2.5％HPMC K100LV-pH6.0磷酸盐缓冲液500ml为溶出介质，温度为37±0.5℃，转速为每分钟150转，4h后弃去上述各溶出杯中的介质，随即在各溶出杯中加入900ml预热至37±0.5℃的pH6.8磷酸盐缓冲液，转速不变，继续依法操作，3-5h破裂。
本公开中，延缓时间段内片芯的释放量不大于片芯非布司他的总量的约10％应理解为片芯基本无药物释放，片芯在延缓时间届满后在很短的时间内释放全部或基本全部的非布司他，具体为包衣层破裂1小时内，片芯的非布司他释放量为片芯非布司他总量的65％以上，可选70％以上，可选75％以上。
可选的实施方式中，本公开提供的非布司他片，与菲布力AUC(几何均值)基本相当的基础上，明显延长有效血药浓度维持时间，有效性提高，其中基本相当是指AUC比值在85％-135％范围内。
本公开提供的非布司他片，在明显延长有效血药浓度维持时间的基础上降低了Cmax值，安全性更好。
本公开提供的非布司他片，受试者一日一次服用本公开提供的非布司他片体内血药浓度(几何均值)≥100ng/ml的维持时间是受试者一日一次服用菲布力的1-3倍，可选1.25-2.0倍。
本公开提供的非布司他片，受试者进食中脂晚餐后，血药浓度≥100ng/ml的维持时间至少为10小时，可选至少为12小时，可选至少为15小时。
本公开提供的非布司他片，受试者服药后血药浓度复升时间为自服药后2-5小时，可选3-4小时。
本公开提供的非布司他片，在受试者体内破裂时间为自服药后2-5小时，可选3-4小时。
本公开提供一种上述的非布司他片在制备用于治疗痛风、高尿酸血症、***炎、炎性肠病、QT间期延长、心肌梗塞、心脏肥大、高血压、肾石病、慢性肾脏疾病、代谢综合征、糖尿病、糖尿病性肾病、充血性心力衰竭的疾病的药物 中的用途。
本公开提供一种治疗治疗痛风、高尿酸血症、***炎、炎性肠病、QT间期延长、心肌梗塞、心脏肥大、高血压、肾石病、慢性肾脏疾病、代谢综合征、糖尿病、糖尿病性肾病、充血性心力衰竭的方法，给与患者上述本公开提供的非布司他片。
本公开提供一种制备上述非布司他片的方法，该方法包括以下步骤：将非布司他与任选的片芯赋形剂制粒成第一颗粒；使第一颗粒成片芯；将包衣层辅料制粒成第二颗粒；将第二颗粒压制包覆于片芯周围；速释层包衣。
可选的实施方案中，该方法包括以下步骤：将非布司他与填充剂、粘合剂、部分崩解剂制粒，与片芯中的亲水凝胶骨架材料、剩余的崩解剂、润滑剂混合后压制片芯；含有基质材料、水不溶的增塑剂和亲水凝胶骨架材料的包衣层辅料制粒；压制包芯片；速释层包衣。
可选的实施方案中，该方法包括以下步骤：将非布司他与乳糖、微晶纤维素、羟丙基纤维素及部分交联羧甲基纤维素钠制粒后与羟丙甲基纤维素、剩余的交联羧甲基纤维素钠、硬脂酸镁混合后压制片芯；将尤特奇RSPO、尤特奇RLPO、山嵛酸甘油酯及部分羟丙甲纤维素制粒后与Kollidon SR、剩余羟丙甲纤维素混合后压制包芯片；速释层包衣。
可选的实施方案中，该方法包括以下步骤：将非布司他与乳糖、微晶纤维素、羟丙基纤维素基及部分交联羧甲基纤维素钠制粒后与羟丙甲基纤维素、剩余的交联羧甲基纤维素钠、硬脂酸镁混合后压制片芯；将尤特奇RSPO、尤特奇RLPO、山嵛酸甘油酯及部分羟丙甲纤维素制粒后与Kollidon SR、剩余羟丙甲纤维素混合后压制包芯片；欧巴代隔离层包衣；欧巴代与非布司他速释层包衣。
任选的，非布司他片的制备方法，在完成包芯片的制备后有薄膜包衣的步骤。
本公开提供一种治疗痛风、高尿酸血症、***炎、炎性肠病、QT间期延长、心肌梗塞、心脏肥大、高血压、肾石病、慢性肾脏疾病、代谢综合征、糖尿病、糖尿病性肾病、充血性心力衰竭的方法，中脂晚餐后给与患者包含30mg非布司他的非布司他片或给与患者包含60mg非布司他的非布司他片，一日一次给药。
本公开提供的治疗痛风、高尿酸血症、***炎、炎性肠病、QT间期延长、心肌梗塞、心脏肥大、高血压、肾石病、慢性肾脏疾病、代谢综合征、糖尿病、糖尿病性肾病、充血性心力衰竭的方法，中脂晚餐后给与患者包含30mg非布司他的非布司他片，平均血药浓度≥100ng/ml的维持时间至少为10小时。
本公开提供的治疗痛风、高尿酸血症、***炎、炎性肠病、QT间期延长、心肌梗塞、心脏肥大、高血压、肾石病、慢性肾脏疾病、代谢综合征、糖尿病、 糖尿病性肾病、充血性心力衰竭的方法，中脂晚餐后给与患者包含60mg非布司他的非布司他片，平均血药浓度≥100ng/ml的维持时间至少为15小时。
在一些实施方案中，中脂晚餐后给与患者包含60mg非布司他的非布司他片，平均血药浓度≥100ng/ml的维持时间至少为18小时。
附图说明
图1.包芯片以及X轴和Y轴的示意图；
图2.包芯片破裂示意图；
图3. 30mg规格两批样品体外溶出曲线；
图4. 60mg规格两批样品体外溶出曲线；
图5.Beagle犬单次灌胃给予60mg*4片非布司他缓释片或40mg*4片非布司他片后的平均药物浓度-时间对数图(饱腹，喂食后1h给药)。
图6.包芯片小开口示意图。
具体实施方式
以下通过具体实施例对本公开的内容作进一步的详细说明，但不应将此理解为本公开上述主题的范围仅局限于以下的实例。
实施例1、非布司他片(处方1)的制备
表1. 60mg及30mg规格的非布司他片的制备
Figure PCTCN2021084422-appb-000016
Figure PCTCN2021084422-appb-000017
1、制备方法：
1)片芯制备(2000片)
按处方规定量准确称取各种原辅料，称取处方量的粘合剂羟丙基纤维素(SL)搅拌下加入到已称好的纯化水中，配置成5％的水溶液，将处方量非布司他、微晶纤维素(MCC Type101)、乳糖、交联羧甲基纤维素钠(CC-Na)、黄氧化铁置于流化床中混合，以处方量羟丙基纤维素(SL)的5％溶液作为粘合剂，制粒，干燥。将整粒后的颗粒及按收率折算后的外加辅料交联羧甲基纤维素钠及硬脂酸镁加入混合罐中进行混合，使用STYL’One单冲压片机(冲模10.0mm浅凹冲，R＝24.75mm)进行压片，片剂硬度控制为20-60N。
2)外包层制备
称取处方量的羟丙甲纤维素E5LV搅拌下加入纯化水中，配置成5％的水溶液，将处方量尤特奇RSPO、尤特奇RLPO、山嵛酸甘油酯置于流化床中以HPMC E5LV的5％溶液作为粘合剂，制粒、干燥，按收率折算后将外加辅料Kollidon SR、HPMC E5LV加入混合罐中进行总混。
3)包芯片制备
使用STYL’One单冲压片机(冲模14.0mm浅凹冲，R＝24.75mm)按照理论下层填料305mg，上层填料205mg进行压片，包芯片理论总重为746mg，片重差异控制范围为±3％，片剂硬度控制为170-230N。
4)隔离层包衣
配置10％浓度的欧巴代(YS-1-7027-CN)水溶液作为包衣材料，作为隔离层包衣液。
5)速释层包衣
称取处方量的纯化水，在搅拌下缓慢加入欧巴代(03K180007-CN)搅拌45min，再加入非布司他，配置为固含量为12％的溶液，搅拌至分散均匀后，作为速释层包衣液。
2、包芯片素片(未包隔离层和速释层)体外开盖中控数据
为保证包芯片在体内在一定时间内开盖，进行体外开盖时间中控。包芯片开盖时间受片芯吸水速度影响，所以介质粘性对开盖时间影响较大，在水性介质中开盖较快，在粘性介质中开盖较慢。为防止包芯片过早开盖达不到延缓释放目的，考察在水性介质pH4.5PBS-0.5％SDS中开盖时间；为防止包芯片开盖太晚错过吸收窗，考察在粘性介质pH4.5PBS-2.5％HPMC K100LV(模拟饱腹胃液粘度和pH)+0.1MHCl-3％HPMC E5LV(模拟胃排空后胃液粘度和pH)中开盖时间。
2.1水性介质中溶出度测试
表2.采用桨法50rpm，在pH4.5PBS-0.5％SDS介质500ml中考察开盖时间。
Figure PCTCN2021084422-appb-000018
2.2粘性介质中溶出度测试
采用篮法75rpm，在500ml pH4.5PBS-2％HPMC K100LV介质中实验2h，再更换至500ml 0.1MHCl-3％HPMC E5LV介质中继续实验，考察在粘性介质中开盖时间，更换介质后每30min停机观察包芯片。
表3.
Figure PCTCN2021084422-appb-000019
2.3非布司他片成品体外溶出数据：
按照溶出度与释放度测定法(中国药典2015年版四部通则0931第二法)，以2.5％HPMC K100LV-pH6.0磷酸盐缓冲液500ml为溶出介质，温度为37±0.5℃，转速为每分钟150转，依法操作经1h、2h、3h、4h分别取溶出液5ml，滤过，取续滤液作为供试品溶液，1h、2h、3h同时补充相同温度相同体积的溶出介质。4h后弃去上述各溶出杯中的介质，随即在各溶出杯中加入900ml预热至37±0.5℃的pH6.8磷酸盐缓冲液，转速不变，继续依法操作，经0.5h、1h、1.5h、 2h分别取溶出液5ml，滤过，取续滤液作为供试品溶液，并同时补充相同温度相同体积的溶出介质，高效液相色谱法测定累积溶出量(％)。
表4.
Figure PCTCN2021084422-appb-000020
具体溶出曲线见附图3与附图4。
3、外包层厚度测量
经测量，Y轴外包层厚度一侧为1.2-1.4mm，另一侧为1.7-1.9mm；X轴方向外包层厚度约为2mm。
实施例2、动物PK结果
本实验采用双周期交叉实验设计，12只雄性Beagle犬分两组分别灌胃给药240mg(60mg*4片)非布司片和160mg(40mg*4片)非布司他片(菲布力)，对比研究Beagle犬体内药物浓度-时间变化过程，研究两者的药代动力学行为。
Beagle犬单次灌胃给予240mg剂量的供试品非布司他片后，血药浓度先在0.5h左右达到一个较低的峰值，浓度约为2180ng/mL，随后下降，在2.00h时血药浓度再次升高，在4h左右达到更高的血药浓度峰，浓度约为4490ng/mL，随后血药浓度随时间逐渐下降，总体的达峰浓度Cmax为5340±2350ng/mL，达峰时间Tmax为4.00[0.500,4.00]h。药物浓度-时间曲线下面积AUC INF_obs为19100±8960h*ng/mL，血药浓度高于100ng/mL的总时间Time High为12.3±4.88h
Beagle犬单次灌胃给予160mg剂量的对照品非布司他片(菲布力)后，血药浓度在1.00[0.250,1.00]h左右达峰，随后血药浓度随时间逐渐下降，达峰浓度Cmax为6930±3290ng/mL。药物浓度-时间曲线下面积AUC INF_obs为15700±7680h*ng/mL，血药浓度高于100ng/mL的总时间Time High为9.86±5.00h，具体见附图5。
Beagle犬经口灌胃给予240mg剂量的供试品非布司他片与经口灌胃给予160mg剂量的对照品非布司他片(菲布力)相比，在药物***暴露量相当的情况下，非布司他缓释片出现明显的双吸收峰，Cmax显著降低，平均血药浓度维持在有效血药浓度(＞100ng/mL)的总时间为对照品非布司他片的1.25倍，提示临床上非布司他片药效维持时间更长、安全性更好。
实施例3、非布司他片(处方2)的制备
表5.处方2组成
Figure PCTCN2021084422-appb-000021
制备工艺参考处方1。
实施例4、处方2在健康人体中的药动学研究
4.1研究目的
1)考察和比较中国健康成年受试者单剂量口服江苏恒瑞医药股份有限公司研制的非布司他片(大规格：60mg，N＝12，中脂晚餐后)与帝人制药有限公司生产的非布司他片(规格：40mg，N＝40，早上空腹)的药动学特征及相对生物利用度。
Figure PCTCN2021084422-appb-000022
结果提示，晚中脂餐后T制剂有效浓度(血药浓度≥100ng/ml)的维持时间均比早上空腹的R制剂显著延长。
对比例1.
按照实施例1制备方法制备表7中的处方，采用桨法50rpm，在pH4.5 PBS-0.5％SDS介质500ml中考察开盖时间。
表7.
Figure PCTCN2021084422-appb-000023
Figure PCTCN2021084422-appb-000024
上述处方制备的包芯片在水性介质中外包层溶蚀很严重，并在1h内破裂，难以维持刚性和完整性。

Claims (34)

  1. 一种包芯片，包括含有活性药物非布司他的片芯，和包覆于片芯的包衣层，片芯位于包衣层内，Y轴方向片芯两侧的包衣层厚度至少有一侧小于X轴方向的包衣层厚度。
  2. 根据权利要求1所述的包芯片，包芯片的最大直径为12-16mm，优选13-15mm。
  3. 根据权利要求1所述的包芯片，所述的包衣层能够在水性介质中浸泡至少1小时之后破裂，优选1.5小时之后破裂，最优选2小时以后破裂。
  4. 根据权利要求1所述的包芯片，所述包衣层在粘性介质中浸泡时间≤6小时时发生破裂，优选≤5小时破裂，最优选≤4小时破裂。
  5. 根据权利要求1所述的包芯片，包衣层破裂1小时内，片芯的非布司他释放量为片芯非布司他总量的65％以上，优选70％以上，最优选75％以上。
  6. 根据权利要求1-5任一项所述的包芯片，片芯的硬度为10-120N，优选为20-60N。
  7. 根据权利要求6所述的包芯片，包芯片的硬度为120-300N，优选为170-230N。
  8. 根据权利要求1所述的包芯片，包衣层含有至少一种基质材料，至少一种疏水的增塑剂和至少一种亲水凝胶骨架材料，所述的基质材料为不溶于水或难溶于水的赋形剂。
  9. 根据权利要求8所述的包芯片，所述的疏水性的增塑剂可选液状石蜡、玉米油、蓖麻油、椰子油、甘油三醋酸酯、甘油单醋酸酯、二丁基癸二酸酯、邻苯二甲酸二丁酯、长链脂肪醇、长链脂肪酸及其酯或其盐类、山嵛酸甘油酯，优选山嵛酸甘油酯。
  10. 根据权利要求9所述的包芯片，所述的疏水性的增塑剂的含量为包衣层总重的0.1％-30％(质量百分比)，优选为0.5％-20％，最优选1％-10％。
  11. 根据权利要求8所述的包芯片，所述不溶于水或难溶于水的赋形剂选自水不溶性纤维素衍生物、聚合物以及聚乙酸乙烯酯和聚维酮混合物，所述水不溶性纤维素衍生物和聚合物包括乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素以及它们的衍生物，聚甲基丙烯酸聚合物，聚乙酸乙烯酯以及纤维素乙酸酯聚合物，脂肪酸或其酯类或其盐类，长链脂肪醇，聚氧乙烯烷基醚，聚氧乙烯硬脂酸，糖酯，月桂酰聚乙二醇-32甘油，硬脂酰聚乙二醇-32甘油，优选聚甲基丙烯酸聚合物、聚乙酸乙烯酯和聚维酮混合物的组合。
  12. 根据权利要求11所述的包芯片，所述不溶于水或难溶于水的赋形剂选自尤特奇RLPO、尤特奇RSPO、
    Figure PCTCN2021084422-appb-100001
    的组合。
  13. 根据权利要求12所述的包芯片，包衣层中尤特奇RLPO与尤特奇RSPO的含量为包衣层总重的50％-90％(质量百分比)，优选60％-85％，最优选65％-75％，
    Figure PCTCN2021084422-appb-100002
    的含量为包衣层总重的5％-40％(质量百分比)，优选15％-25％。
  14. 根据权利要求13所述的包芯片，包衣层中尤特奇RSPO的含量为包衣层总重的5％-40％(质量百分比)，优选10％-30％，最优选15％-25％。
  15. 根据权利要求13所述的包芯片，包衣层中尤特奇RLPO的含量占包衣层总重的20％-80％(质量百分比)，优选30％-70％，最优选45％％-55％。
  16. 根据权利要求8所述的包芯片，所述的亲水凝胶骨架材料选自甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素、羟甲基纤维素钠、壳多糖、脱乙酰壳多糖、半乳糖甘露聚糖、果胶、海藻酸钠、海藻酸钾、琼脂、角叉菜胶、刺槐豆胶，优选羟丙基甲基纤维素，亲水凝胶骨架材料的含量为包衣层总重的1％-30％(质量百分比)，优选5％-20％，最优选8％-15％。
  17. 根据权利要求1-16任一项所述的包芯片，片芯还含有选自崩解剂、填充剂、粘合剂、润滑剂、着色剂的至少一种赋形剂，所述的崩解剂选自交联羧甲基纤维素钠、干淀粉、低取代羟丙甲基纤维素、羧甲基淀粉钠及交联聚维酮，优 选交联羧甲基纤维素钠；所述的填充剂选自水溶性填充剂和/或水不溶性填充剂，其中水溶性填充剂选自乳糖、甘露醇、蔗糖、山梨醇等，水不溶性填充剂选自淀粉、微晶纤维素、硫酸钙、磷酸氢钙，优选乳糖与微晶纤维素的组合；所述的粘合剂选自羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、海藻糖和支链淀粉，优选羟丙基纤维素；所述的润滑剂选自胶态二氧化硅、滑石粉、硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酸富马酸钠、聚乙二醇或十二烷基硫酸钠，优选硬脂酸镁，所述着色剂选自氧化铁、二氧化钛、氢氧化铁，优选氧化铁。
  18. 一种非布司他片，含有权利要求1-17任一项所述的包芯片，还含有非布司他的速释组分。
  19. 根据权利要求18所述的非布司他片，所述包芯片的包衣层外含有非布司他的速释含药包衣层。
  20. 根据权利要求19所述的非布司他片，所述的包衣材料选羟丙基甲基纤维素、羟丙基纤维素、聚乙烯醇、胃溶型欧巴代，优选胃溶型欧巴代，最优选欧巴代(03K180007-CN)。
  21. 根据权利要求19或20任一项所述的非布司他片，单位剂型中非布司他的含量为菲布力单位剂型中非布司他含量的1.1-1.8倍，优选1.2-1.6倍，最优选1.5倍。
  22. 根据权利要求19或20任一项所述的非布司他片，单位剂型中非布司他的量为10mg-200mg，优选20mg-150mg，可选的非布司他的量为10mg、15mg、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，优选30mg和60mg，速释含药包衣层与片芯中活性物质的含量比为1:10-10:1，优选1:5-5:1。
  23. 根据权利要求21或22任一项所述的非布司他片，所述缓/控释片含有以下成分：
    片芯
    非布司他
    乳糖50％-65％；
    微晶纤维素10％-25％；
    交联羧甲基纤维素钠8％-15％；
    羟丙基纤维素1-5％；
    硬脂酸镁1％-5％，以片芯总重计；
    包衣层
    尤特奇RSPO 15％-25％；
    尤特奇RLPO 45％％-55％；
    Figure PCTCN2021084422-appb-100003
    15％-25％；
    羟丙基甲基纤维素8％-15％，以包衣层总重计。
  24. 根据权利要求23所述的非布司他片，非布司他的含量为30mg，其中速释含药包衣层与片芯中活性物质的含量为2:3。
  25. 根据权利要求23所述的非布司他片，非布司他的含量为60mg，其中速释含药包衣层与片芯中活性物质的含量为3:7。
  26. 根据权利要求18-25任一项所述的非布司他片，受试者进食低脂低热量餐后，血药浓度≥100ng/ml的维持时间至少为10小时，优选至少为12小时，最优选至少为15小时。
  27. 根据权利要求18-25任一项所述的非布司他片，受试者进食标准餐后，血药浓度≥100ng/ml的维持时间至少为12小时，优选至少为15小时，最优选至少为17小时。
  28. 一种根据权利要求18-25任一项所述的非布司他片在制备用于治疗痛风、高尿酸血症、***炎、炎性肠病、QT间期延长、心肌梗塞、心脏肥大、高血压、肾石病、慢性肾脏疾病、代谢综合征、糖尿病、糖尿病性肾病、充血性心力衰竭的疾病的药物中的用途。
  29. 一种制备权利权利要求18-25任一项所述的非布司他片的方法，该方法包括以下步骤：将非布司他与任选的片芯赋形剂制粒成第一颗粒；使第一颗粒成片芯；将包衣层辅料制粒成第二颗粒；将第二颗粒压制包覆于片芯周围；速释层 包衣。
  30. 根据权利要求29所述的方法，该方法包括以下步骤：将非布司他与填充剂、粘合剂、部分崩解剂制粒，与剩余的崩解剂、润滑剂混合后压制片芯；将含有基质材料、水不溶的增塑剂和亲水凝胶骨架材料的包衣层辅料制粒；压制包芯片；速释层包衣。
  31. 根据权利要求30所述的方法，该方法包括以下步骤：将非布司他与乳糖、微晶纤维素、羟丙基纤维素及部分交联羧甲基纤维素钠制粒后与剩余的交联羧甲基纤维素钠、硬脂酸镁混合后压制片芯；将尤特奇RSPO、尤特奇RLPO、山嵛酸甘油酯及部分羟丙甲纤维素制粒后与Kollidon SR、剩余羟丙甲纤维素混合后压制包芯片；速释层包衣。
  32. 根据权利要求31所述的方法，该方法包括以下步骤：将非布司他与乳糖、微晶纤维素、羟丙基纤维素基及部分交联羧甲基纤维素钠制粒后与剩余的交联羧甲基纤维素钠、硬脂酸镁混合后压制片芯；将尤特奇RSPO、尤特奇RLPO、山嵛酸甘油酯及部分羟丙甲纤维素制粒后与Kollidon SR、剩余羟丙甲纤维素混合后压制包芯片；欧巴代隔离层包衣；欧巴代与非布司他速释层包衣。
  33. 根据权利要求1-17任一项所述的包芯片或根据权利要求18-27任一项所述的非布司他片，所述片芯还含有亲水凝胶骨架材料，含量占片芯总重的1％-20％；优选2％-10％；最优选3％-8％。
  34. 根据权利要求33所述的包芯片或者非布司他片，所述的亲水凝胶骨架材料选自纤维素衍生物、非纤维素多糖、天然胶、乙烯基聚合物或丙烯酸聚合物，所述的纤维素衍生物可选自甲基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素和羟甲基纤维素钠；所述的非纤维素多糖选自葡萄糖、壳多糖、脱乙酰壳多糖和半乳糖甘露聚糖；所述的天然胶选自果胶、海藻酸钠、海藻酸钾、琼脂、角叉等胶、刺槐豆胶、爪耳树胶；优选纤维素衍生物，最优选羟乙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素，特别优选羟丙基甲基纤维素。
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