CN115297848A

CN115297848A - Febuxostat tablet

Info

Publication number: CN115297848A
Application number: CN202180019661.7A
Authority: CN
Inventors: 马爱明; 王捷; 潘凯; 曹笑立; 陈爱玲; 潘彩云
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2020-03-31
Filing date: 2021-03-31
Publication date: 2022-11-04
Also published as: TW202143959A; WO2021197376A1

Abstract

A slow-release core-coated tablet comprises a tablet core containing the active drug febuxostat and a coating layer coated on the tablet core, wherein the tablet core is positioned in the coating layer, the thickness of the coating layer on at least one side of the tablet core in the Y-axis direction is smaller than that of the coating layer in the X-axis direction, and the coating layer can contain a quick-release drug-containing coating layer of febuxostat. The tablet can be used for treating gout and hyperuricemia.

Description

Febuxostat tablet

Technical Field

The invention relates to a febuxostat tablet which is a core-spun tablet, comprises a tablet core containing a medicament and a coating coated on the tablet core, and belongs to the field of medicinal preparations.

Background

Oral administration is a very advantageous drug delivery route, placing the orally administered formulation in the oral cavity and swallowing, is simple, convenient, painless, does not require any special equipment or the involvement of medical personnel, has good patient compliance and is cost-effective.

Gastric emptying is part of the normal digestive process of the human body, which results in that drug formulations entering the stomach by the oral route usually only stay in the stomach for a short time, which limits the bioavailability of many types of orally administered drugs, in particular 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 at neutral or alkaline pH or have low solubility, which can be delivered by gastroretentive formulations.

Sustained/controlled release tablets are those which release drug at a predetermined rate and/or for a predetermined time after administration so that the desired pharmacological activity is retained for a desired period of time. Such formulations provide the drug to the body over a predetermined period of time or at a predetermined site of absorption, thereby maintaining the drug level within the therapeutic range for an extended period of time relative to conventional (e.g., immediate release) formulations. The dosage form comprising a core is in a form that produces a sustained/controlled release tablet, the most commonly used material being a hydrophilic material that swells and becomes a gel upon contact with a physiological medium. When the dosage form is exposed to physiological media, the periphery will begin to hydrate and form a colloidal matrix that increases in thickness as the media continues to penetrate the dosage form. The drug is released by diffusion through and/or erosion of the matrix.

Febuxostat is an oral non-purine xanthine oxidase (NP-sigo) selective inhibitor developed by the drug of teijin japan, which is mainly used for the chronic treatment of hyperuricemia in gout patients, the treatment of chronic hyperuricemia in which urate deposition has occurred, and the treatment of hyperuricemia (tumor lysis syndrome) associated with cancer chemotherapy. The main side effect is that gout attack is often accompanied in the early treatment stage, the gout attack frequency is increased, and the compliance of patients is seriously influenced.

Patent application CN103210084A to wutian pharmacy discloses a novel composition containing febuxostat, comprising immediate release beads and sustained release beads containing febuxostat, achieving sustained release effect by means of membrane control, which background art indicates that febuxostat formulations that maintain drug concentrations above a critical concentration of 100ng/mL for extended periods of time are expected to produce higher drug efficacy and would be a desirable treatment option for controlling hyperuricemia, gout and many other disease states. However, the clinical item TMX-67XR related to the application is terminated by an unpublished reason item, and the great difficulty in developing the febuxostat sustained/controlled release tablet is fully proved.

Disclosure of Invention

The invention provides a core-spun tablet, which comprises a tablet core containing an active drug febuxostat and a coating layer coated on the tablet core, wherein the tablet core is positioned in the coating layer, the thickness of the coating layer on at least one side of the tablet core in the Y-axis direction is smaller than that of the coating layer in the X-axis direction (figure 1 is a schematic diagram, wherein the two sides of the tablet core in the Y-axis direction respectively correspond to the upper surface and the lower surface in the figure).

The axial (above "Y" axis) coating thickness along the direction of punch movement described in this disclosure is determined by the amount of coating material added to the die and the punch pressure used in tablet formation. While the thickness of the coating in the "X" direction (perpendicular to the direction of punch motion) is determined by the size of the core, the position of the core within the die, and the diameter of the die.

The core-coated tablet of febuxostat provided by the present disclosure provides an initial diameter sufficient for gastric retention in a fed state, e.g., a tablet of about 12-18mm diameter may generally resist passage through the pyloric sphincter in a fed state, and the initial maximum diameter of a particular core-coated tablet of febuxostat of the present disclosure may be 12-16mm, optionally 13-15mm.

In an alternative embodiment, the core-wrapped tablet provided by the present disclosure is a gastric retention core-wrapped tablet.

In an alternative embodiment, the thicknesses of the coating layers on the two sides of the tablet core in the Y-axis direction are 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, optionally 1.5-1.8mm, optionally 1.7-1.9mm; the thickness of the coating layer on the other side of the tablet core can be 0.3-2.0mm, optionally 0.8-1.8mm, optionally 1.2-1.4mm, optionally 1.0-1.5mm.

The core-coated tablet provided by the disclosure has the advantages that due to the selection of the special coating thickness along the Y-axis direction, the active substance febuxostat is released in a preset delay time period, the controlled release effect is achieved, the coating layer can be broken after being soaked in an aqueous medium for at least 1 hour, the active substance is released, the breaking can be carried out after 1.5 hours, the breaking can be carried out after 2 hours, and the breaking time of the coating layer of the core-coated tablet provided by the disclosure in the aqueous medium is not later than 4 hours. The examination of the breaking time of the coating layer in the aqueous medium described in the present disclosure means the results of the examination in the pH4.5PBS-0.5% SDS medium 500mL using the paddle method at 50 rpm.

For a given active agent, delivery of the active agent to the absorption window may increase the efficacy of the agent and/or reduce or eliminate side effects if the release rate can be preferentially avoided or reduced by controlled, almost complete delivery of the agent to a particular absorption window, or higher degradation or metabolism of the active agent in the gastrointestinal tract. Considering that, in this respect, the coating layer breaks too late and may miss the absorption window, the core-coated tablet provided in the present disclosure is capable of breaking upon immersion in a viscous medium for 6 hours or less, releasing the active substance, optionally 5 hours or less, optionally 4 hours or less. The examination of the burst time of the coating layer in viscous medium described in the present disclosure means that the examination was continued in the viscous medium using the basket method 75rpm,500mL pH4.5PBS-2.5% in HPMC K100LV medium for 2h, then replaced to 500mL 0.1MHCl-3% HPMC E5LV medium, and the burst time in viscous medium was examined.

The coating layer described in this disclosure is subjected to dissolution and release rate measurement (0931 second method of the general rule of the four parts of the chinese pharmacopoeia 2015 year edition), using 500ml of 2.5% hpmc k100lv-ph6.0 phosphate buffer as dissolution medium, at 37 ± 0.5 ℃, at 150 rpm, discarding the medium in each dissolution cup after 4h, adding 900ml of ph6.8 phosphate buffer preheated to 37 ± 0.5 ℃ into each dissolution cup, keeping the rotation speed constant, continuing the operation according to the method, and breaking for 3-5 h.

When the rupture position of the core-spun tablet is in the X-axis direction, the opening is too small, the depth is longer (as shown in figure 6), and the drug release is slow, so that the thickness of at least one side of the coating layer on the two sides of the tablet core in the Y-axis direction is smaller than that of the coating in the X-axis direction, the coating ruptures to release the active drug in the Y-axis direction, and the rapid release of the drug in the tablet core is ensured (as shown in figure 2).

In the disclosure, the release amount of the tablet core in the delay period is not more than about 10% of the total amount of the febuxostat in the tablet core, and it is understood that the tablet core has no drug release basically, and the tablet core releases all or substantially all of the febuxostat in a very short time after the delay period expires, specifically, the release amount of the febuxostat in the tablet core is more than 65%, optionally more than 70%, optionally more than 75% of the total amount of the febuxostat in the tablet core within 1 hour of breakage of the coating layer.

The core-coated tablets of the present disclosure are formed using compression-coated technology, as described in detail below. Compressed tablets are generally prepared by placing a portion of the powdered or granular coating material in a mold, tamping the portion of the coating material into a compacted state with a punch, placing the core over the compacted coating material,the remaining coating material is then introduced into a mold and pressure is applied to form a coated tablet. With the innovation of compression technology, several techniques for preparing compressed tablets by one-step dry coating have been developed, such as

Specifically, it can be seen from the Evaluation of novel one-step dry-coated tables as a platform for delayed-Release tables by Yuichi Ozeki et al (Journal of Controlled Release 95 (2004) 51-60).

The hardness of the tablet core in the method is relatively low, so that the tablet core can expand after the aqueous medium contacts the tablet core, the outer cladding layer can be better broken, and the hardness of the tablet core is 10-120N, optionally 20-60N. In order to ensure mechanical stability of the core tablet, so that it is sufficiently resistant to the stresses generated in the stomach, and in particular to ensure that the integrity of the envelope is not destroyed in the presence of food, the hardness of the tablet is controlled to be between 120 and 300N, optionally between 170 and 230N. In this disclosure, febuxostat is released from the tablet core, not as a result of diffusion of the drug through the expanding coating material, but as a result of physical rupture of the coating.

The present disclosure provides a core-coated tablet, wherein a coating layer comprises at least one matrix material, at least one hydrophobic plasticizer and at least one hydrophilic gel matrix material, and the matrix material is an excipient which is insoluble in water or insoluble in water.

In alternative embodiments, the hydrophobic plasticizer may be selected from liquid paraffin, corn oil, castor oil, coconut oil, triacetin, monoacetin, dibutyl sebacate, dibutyl phthalate, long-chain fatty alcohols, long-chain fatty acids, esters or salts thereof, glyceryl behenate, and the water-insoluble plasticizer may be present in an amount of 0.1-30% (by weight), optionally 0.5-20%, and optionally 1-10%, based on the total weight of the coating.

The plasticizer glyceryl behenate described in this disclosure is glycerol and behenic acid (a C) ₂₂ Fatty acids), glyceryl behenate, mono-, di-or triesters thereof or mixtures thereofOptionally, has an HLB value of less than 5, optionally about 2.

Applicants have surprisingly found that coating layers without hydrophobic plasticizers erode significantly in aqueous media, are difficult to maintain in rigidity and integrity, and do not provide the effect of delaying release over a period of time.

In alternative embodiments, the water insoluble or poorly soluble excipients may be selected from any known water insoluble cellulose derivatives and polymers including alkyl celluloses, such as ethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and their derivatives, polymethacrylic acid polymers, polyvinyl acetate and cellulose acetate polymers, fatty acids or esters or salts thereof, long chain fatty alcohols, polyoxyethylene alkyl ethers, polyoxyethylene stearic acid, sugar esters, lauroyl macrogol-32 glycerol, stearoyl macrogol-32 glycerol, and the like, as well as polyvinyl acetate and povidone blends and the like.

Is a mixture of polyvinyl acetate and polyvinylpyrrolidone, is a material with very good plasticity, and is particularly suitable for direct tabletting.

In an alternative embodiment, the matrix material is selected from the group consisting of polymethacrylic acid polymers, polyvinyl acetate, and combinations of povidone mixtures.

Optionally, the content of the polymethacrylic acid polymer in the coating layer accounts for 50-90% (by mass), optionally 60-85%, optionally 65-75%, and the content of the mixture of vinyl acetate and povidone accounts for 5-40% (by mass), optionally 15-25%, of the total weight of the coating layer.

In an alternative embodiment, the matrix material is selected from the group consisting of ewings in combination with polyvinyl acetate and povidone mixture.

In an alternative embodiment, the amount of ewt's in the coating layer is 50-90% (by mass), optionally 60-85%, optionally 65-75%, of the total weight of the coating layer, and the amount of the mixture of polyvinyl acetate and povidone is 5-40% (by mass), optionally 15-25%, of the total weight of the coating layer.

In an alternative embodiment, the matrix material is selected from the group consisting of ewtzing RL, ewtzing RS, which are insoluble but swellable in water to form pores in the coating, in combination with a mixture of polyvinyl acetate and povidone, the pore diameter of ewtzing RL is 1-5 μm and the pore diameter of ewtzing RS is 0.1-0.6 μm.

In an alternative embodiment, the amount of the ewter RL and the ewter RS in the coating layer is 50-90% (by mass), optionally 60-85%, optionally 65-75%, of the total weight of the coating layer, and the amount of the mixture of polyvinyl acetate and povidone is 5-40% (by mass), optionally 15-25%, of the total weight of the coating layer.

In an alternative embodiment, the matrix material is selected from the group consisting of ewing RLPO in combination with ewing RSPO in combination with polyvinyl acetate and povidone mixture.

In an alternative embodiment, the amount of ewt's RLPO and ewt's RSPO in the coating layer is between 50% and 90% (by mass), optionally between 60% and 85%, optionally between 65% and 75%, of the total weight of the coating layer, and the amount of the mixture of polyvinyl acetate and povidone is between 5% and 40% (by mass), optionally between 15% and 25%, of the total weight of the coating layer.

In alternative embodiments, the matrix material is selected from the group consisting of Ewing RLPO, ewing RSPO, and combinations thereof,

Combinations of (a) and (b).

In an alternative embodiment, the content of the eucalyptus RLPO and the eucalyptus RSPO in the coating layer is 50-90% (by mass), optionally 60-85%, optionally 65-75%,

in the content of5 to 40 percent (mass percentage) of the total weight of the coating layer, and 15 to 25 percent of the total weight of the coating layer can be selected.

In an alternative embodiment, the content of the ewt RSPO in the coating layer is 5-40% (mass%), optionally 10-30%, optionally 15-25% of the total weight of the coating layer.

In an alternative embodiment, the content of the eucalyptus RLPO in the coating layer is 20% to 80% (by mass), optionally 30% to 70%, optionally 45% to 55%, of the total weight of the coating layer.

In an alternative embodiment, the content of the ewing RSPO in the coating layer is 5-40% (mass%) of the total weight of the coating layer, the content of the ewing RLPO is 20-80% (mass%) of the total weight of the coating layer,

the content of (B) is 5-40% (mass percentage) of the total weight of the coating layer.

In an alternative embodiment, the amount of the ewt RSPO in the coating layer is between 10% and 30% (mass%) of the total weight of the coating layer, the amount of the ewt RLPO is between 30% and 70% (mass%) of the total weight of the coating layer,

the content of (A) is 15-25% (mass percentage) of the total weight of the coating layer.

In an alternative embodiment, the content of the ewing RSPO in the coating layer is 15-25% (mass%) of the total weight of the coating layer, the content of the ewing RLPO is 45-55% (mass%) of the total weight of the coating layer,

In the present disclosure, the hydrophilic gel matrix material is selected from methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose, chitin, chitosan, galactomannan, pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, and the like.

In an alternative embodiment, the hydrophilic gel matrix material is hydroxypropyl methylcellulose selected from low weight average molecular weight, low viscosity materials such as E-methylcellulose.

In the present disclosure, the content of the hydrophilic gel matrix material is 1-30% (by mass), optionally 5-20%, optionally 8-15% of the total weight of the coating layer.

In an alternative embodiment, the hydrophilic gel matrix material is E-hydroxypropyl methylcellulose in an amount of 1-30% (by weight), optionally 5-20%, optionally 10-15% of the total weight of the coating layer.

In the present disclosure, in order to meet the requirements of the preparation process, an optional hydrophilic gel matrix material may also be used as the adhesive.

The tablet core of the febuxostat provided by the disclosure contains a disintegrating agent of a quick release preparation known in the art besides an active substance of febuxostat, and in the disclosure, the disintegrating agent can be a material which effervesces and/or expands in the presence of an aqueous medium, so that necessary force can be provided to mechanically break a coating material, specifically, the disintegrating agent can be selected from croscarmellose sodium, dry starch, low-substituted hydroxypropyl methylcellulose, sodium carboxymethyl starch, crospovidone and the like, and can be selected from croscarmellose sodium, and the dosage of the disintegrating agent can be 2-35% (by mass) of the weight of the tablet core, optionally 5-25% of the weight of the tablet core, and optionally 8-15% of the weight of the tablet core.

The core-spun tablet of febuxostat provided by the disclosure can also contain pharmaceutically acceptable water-soluble filler and/or water-insoluble filler in the tablet core, wherein the water-soluble filler comprises lactose, mannitol, sucrose, sorbitol and the like, the water-insoluble filler comprises starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate and the like, the content of the diluent can be 1-99% of the weight of the tablet core, and the diluent can be 20-85% (by mass percentage) or 60-80%.

In an alternative embodiment, the filler of the tablet core is selected from the group consisting of water-soluble fillers and water-insoluble fillers, wherein the content of the water-soluble filler may be 35-75% (mass percentage), optionally 45-70%, optionally 50-65% of the weight of the tablet core; the content of the water-insoluble filler may be 1-25% (by mass), optionally 10-25% of the weight of the tablet core.

In an alternative embodiment, the filler of the tablet core is a combination of lactose selected from the group of water soluble fillers and microcrystalline cellulose selected from the group of water insoluble fillers.

The core-coated tablet of febuxostat provided by the present disclosure may further include a pharmaceutically acceptable binder in the core tablet, and the binder may be selected from at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, trehalose, and pullulan, but is not limited thereto, and the content of the binder may be 1% to 5% (by mass) of the total weight of the core tablet.

In an alternative embodiment, the binder is hydroxypropyl cellulose.

The core may contain a suitable lubricant, for example colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, sodium fumarate stearate, polyethylene glycol or sodium lauryl sulphate, in an amount of from 0.5% to 10% by weight, optionally from 1% to 5% by weight, of the total core weight.

In an alternative embodiment, the lubricant of the core is magnesium stearate.

Suitably, a colorant may be added to the core to ensure that the core is correctly positioned within the coating to ensure that the tablet has a suitable coating thickness and that the delay time reproducibility is good, thereby avoiding intra-patient and inter-patient bioavailability differences, the colorant may be iron oxide, titanium dioxide, iron hydroxide or the like, the choice of colorant is not limiting the scope of the disclosure, and the colorant may be present in an amount of 0.1% to 3%, optionally 0.4% to 1%, of the total weight of the core.

In an optional embodiment, the tablet core of the febuxostat core-coated tablet provided by the present disclosure may further include a hydrophilic gel matrix material, where the hydrophilic gel matrix material is selected from a cellulose derivative, a non-cellulose polysaccharide, a natural gum, a vinyl polymer or an acrylic acid polymer, and the like. The cellulose derivative can be selected from methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose, etc.; the non-cellulosic polysaccharide is selected from glucose, chitin, chitosan, galactomannan, etc.; the natural gum is selected from pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, and Tremella gum.

In an optional embodiment, in the febuxostat-containing core-spun tablet provided by the disclosure, the hydrophilic gel skeleton material in the tablet core is a cellulose derivative.

In an alternative embodiment, the febuxostat core-coated tablet provided by the present disclosure, the hydrophilic gel matrix material in the tablet core is selected from hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

In an optional embodiment, in the febuxostat-containing tablet provided by the present disclosure, the hydrophilic gel matrix material in the tablet core is hydroxypropyl methylcellulose.

In an optional embodiment, in the febuxostat-containing core-spun tablet provided by the disclosure, the hydrophilic gel framework material in the tablet core accounts for 1-20% of the total weight of the tablet core.

In an optional embodiment, in the febuxostat-containing core-spun tablet provided by the present disclosure, the hydrophilic gel matrix material in the tablet core accounts for 2% -10% of the total weight of the tablet core.

In an optional embodiment, in the febuxostat-containing core-spun tablet provided by the present disclosure, the hydrophilic gel matrix material in the tablet core accounts for 3% to 8% of the total weight of the tablet core.

The present disclosure provides a febuxostat tablet, which comprises the above-mentioned core-coated tablet and a coating layer, and also comprises an immediate-release part of febuxostat, wherein the immediate-release part can be completed by any technical means well known in the art, such as a double-layer tablet, an immediate-release coating and the like.

In an alternative embodiment, the febuxostat tablets provided by the present disclosure have a sustained release effect.

The present disclosure provides a febuxostat tablet, which comprises the above core-spun tablet, wherein a coating layer of the core-spun tablet comprises a quick-release drug-containing coating layer of febuxostat.

In an alternative embodiment, the fast release febuxostat-containing coating layer comprises the active drug febuxostat and a coating material, wherein the coating material can be hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol and gastric-soluble opadry, can be gastric-soluble opadry and can be 03K 180007-CN.

Since the quick release component is rapidly released in a medium or in vivo, the drug release characteristics of the chip in the present disclosure are the same as those of the febuxostat tablet containing the quick release component.

In an optional embodiment, the content of febuxostat in the unit dosage form of the febuxostat tablet provided by the present disclosure is 1.1-1.8 times, optionally 1.2-1.6 times, optionally 1.5 times of the content of febuxostat in the febuxostat unit dosage form. Specifically, for example, if the content of a single tablet of commercially available febuxostat is 20mg, the unit tablet content of febuxostat provided by the present disclosure is 30mg, and if the content of a single tablet of commercially available febuxostat is 40mg, the unit tablet content of febuxostat provided by the present disclosure is 60mg. The increased dosage of the medicine increases the uric acid standard-reaching rate, thereby reducing the gout attack frequency and ensuring the curative effect.

In an alternative embodiment, the amount of non-busulfan in the unit dosage form of the febuxostat tablet provided by the present disclosure is 10mg to 200mg, optionally 20mg to 150mg, and the amount of the optional febuxostat tablet is 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, optionally 30mg and 60mg, and the content ratio of the active substance in the immediate release drug-containing layer to the active substance in the tablet core is 1 to 10, optionally 1 to 5 1.

In an alternative embodiment, the febuxostat tablet contains the following components:

tablet core

Febuxostat

50-65% of lactose (mass percentage);

10-25% of microcrystalline cellulose (mass percent);

8-15% (mass percent) of croscarmellose sodium;

1-5% of hydroxypropyl cellulose (mass percent);

1-5 percent (mass percent) of magnesium stearate based on the total weight of the tablet core;

coating layer

15-25% of Ettqi RSPO (mass percent);

eudragit RLPO 45%% -55% (mass%);

15-25% (mass percentage);

8 to 15 percent of hydroxypropyl methyl cellulose (mass percent) based on the total weight of the coating layer.

tablet core

Febuxostat

50-65% of lactose (mass percentage);

10-25% of microcrystalline cellulose (mass percent);

8-15% (mass percent) of croscarmellose sodium;

1-5% of hydroxypropyl cellulose (mass percent);

1-5 percent (mass percentage) of magnesium stearate;

3-8 percent of hydroxypropyl methyl cellulose (mass percent) based on the total weight of the tablet core;

coating layer

15-25% of Ettqi RSPO (mass percent);

eudragit RLPO 45%% -55% (mass%);

15-25% (mass percentage);

In an optional embodiment, the content of active substances in the febuxostat tablet is 30mg, wherein the content ratio of the quick-release drug-containing coating layer to the active substances in the tablet core is (1).

In an alternative embodiment, the content of active substances in the febuxostat tablet is 60mg, wherein the content ratio of the quick-release drug-containing coating layer to the active substances in the tablet core is (1-10).

Optionally, an isolating layer is arranged between the coating layer and the febuxostat quick-release layer, and the isolating layer is a thin high polymer material and forms a film-shaped coating layer, so that the weight of the tablet is increased by 1-50% (by mass), and optionally 2-4%.

The material of the isolating layer can be one or more of hypromellose, povidone, copovidone, hydroxypropyl cellulose and gastric soluble opal, and can be gastric soluble opal or gastric soluble opal (YS-1-7027-CN).

In an alternative embodiment, the febuxostat tablet provided by the present disclosure significantly prolongs the effective blood concentration maintenance time and improves the effectiveness on the basis that the febuxostat tablets are substantially equivalent to the febuxostat AUC (geometric mean), wherein substantially equivalent means that the AUC ratio is in the range of 85% to 135%.

The febuxostat tablet provided by the disclosure reduces the Cmax value on the basis of obviously prolonging the effective blood concentration maintaining time, and has better safety.

The febuxostat tablet provided by the disclosure is taken by a subject once a day, and the maintenance time of the blood concentration (geometric mean) in the febuxostat tablet provided by the disclosure which is more than or equal to 100ng/ml is 1-3 times, optionally 1.25-2.0 times of the febuxostat tablet taken by the subject once a day.

The febuxostat tablets provided by the present disclosure have a maintenance time for a blood concentration of greater than or equal to 100ng/ml of at least 10 hours, optionally at least 12 hours, optionally at least 15 hours, after a subject eats a low-fat low-calorie meal (fat provides about 10% of the calories in the food, and the total calories are about 300 kcal).

The febuxostat tablet provided by the disclosure has the advantages that after a subject eats a standard meal, the maintaining time of the blood concentration of more than or equal to 100ng/ml is at least 12 hours, optionally at least 15 hours, optionally at least 17 hours.

The blood concentration in the present disclosure refers to the geometric mean.

The febuxostat tablets provided by the present disclosure provide significant double peaks in vivo.

According to the febuxostat tablet provided by the disclosure, after a subject takes the tablet, the blood concentration re-rising time is 2-5 hours, optionally 3-4 hours after the subject takes the tablet.

The febuxostat tablet provided by the disclosure has the rupture time in a subject body ranging from 2 to 5 hours after taking medicine, and can be selected from 3 to 4 hours.

The present disclosure provides an application of the febuxostat tablet in preparation of a medicament for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney diseases, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure.

The present disclosure provides a method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes, diabetic nephropathy, congestive heart failure, administering to a patient the febuxostat tablets provided by the present disclosure.

The present disclosure provides a method for preparing the febuxostat tablet, which comprises the following steps: granulating febuxostat with optional core excipients into first granules; tablet-core the first granules; granulating the coating auxiliary materials into second granules; compressing the second granules around the core; coating the quick release layer.

In an alternative embodiment, the method comprises the steps of: granulating febuxostat, a filling agent, an adhesive and a part of disintegrating agent, mixing with the rest disintegrating agent and a lubricant, and pressing a tablet core; granulating coating layer adjuvants comprising matrix material, water-insoluble plasticizer and hydrophilic gel skeleton material; pressing the core-spun sheets; and coating the quick release layer.

In an alternative embodiment, the method comprises the steps of: granulating febuxostat, lactose, microcrystalline cellulose, hydroxypropyl cellulose and part of croscarmellose sodium, mixing with the rest croscarmellose sodium and magnesium stearate, and pressing to obtain tablet core; granulating Eudragit RSPO, eudragit RLPO, glyceryl behenate and part of hydroxypropyl methylcellulose, mixing with Kollidon SR and rest hydroxypropyl methylcellulose, and making into core-coated tablet; and coating the quick release layer.

In an alternative embodiment, the method comprises the steps of: granulating febuxostat, lactose, microcrystalline cellulose, hydroxypropyl cellulose base and part of croscarmellose sodium, mixing with the rest croscarmellose sodium and magnesium stearate, and pressing into tablet cores; granulating Eudragit RSPO, eudragit RLPO, glyceryl behenate and part of hydroxypropyl methylcellulose, mixing with Kollidon SR and rest hydroxypropyl methylcellulose, and making into core-coated tablet; coating an Opadry isolation layer; coating the Opadry and the febuxostat quick-release layer.

Optionally, the preparation method of the febuxostat tablet comprises the step of film coating after the preparation of the tablet core is finished.

The febuxostat tablet comprises a tablet core containing an active drug febuxostat and a coating layer coated on the tablet core, wherein the tablet core is positioned in the coating layer, and the tablet core also contains a hydrophilic gel framework material accounting for 1-20% of the total weight of the tablet core; the coating layer contains at least one matrix material, at least one hydrophobic plasticizer and at least one hydrophilic gel framework material, and also comprises a quick-release component containing the active substance febuxostat.

In alternative embodiments, the hydrophilic gel matrix material of the core is selected from cellulose derivatives, non-cellulosic polysaccharides, natural gums, vinyl or acrylic polymers, and the like; the cellulose derivative can be selected from methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose, etc.; the non-cellulosic polysaccharide is selected from glucose, chitin, chitosan, galactomannan, etc.; the natural gum is selected from pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, and Tremella gum.

In an optional embodiment, in the febuxostat tablet provided by the present disclosure, the hydrophilic gel skeleton material in the tablet core is a cellulose derivative.

In an alternative embodiment, the febuxostat core-coated tablet provided by the present disclosure, the hydrophilic gel skeleton material in the tablet core is selected from hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

In an optional embodiment, in the febuxostat tablet provided by the present disclosure, the hydrophilic gel matrix material in the tablet core is hydroxypropyl methylcellulose.

In an optional embodiment, in the febuxostat tablet provided by the present disclosure, the hydrophilic gel matrix material in the tablet core accounts for 2% -10% of the total weight of the tablet core.

In an optional embodiment, in the febuxostat tablet provided by the present disclosure, the hydrophilic gel matrix material in the tablet core accounts for 3% to 8% of the total weight of the tablet core.

In an alternative embodiment, the hydrophobic plasticizer may be selected from liquid paraffin, corn oil, castor oil, coconut oil, triacetin, monoacetin, dibutyl sebacate, dibutyl phthalate, long-chain fatty alcohol, long-chain fatty acid and its ester or its salt, and glyceryl behenate, and the content of the water-insoluble plasticizer is 0.1-30% (by weight), optionally 0.5-20%, optionally 1-10% of the total weight of the coating layer.

The plasticizer glyceryl behenate described in this disclosure is glycerol and behenic acid (a C) ₂₂ Fatty acids) and glyceryl behenate may be present as mono-, di-or triesters thereof, or mixtures thereof, optionally having an HLB value of less than 5, optionally about 2.

In an alternative embodiment, the polymethacrylic acid polymer in the coating layer accounts for 50-90% (by mass), optionally 60-85%, optionally 65-75%, of the total weight of the coating layer, and the mixture of vinyl acetate and povidone accounts for 5-40% (by mass), optionally 15-25%, of the total weight of the coating layer.

In an alternative embodiment, the matrix material is selected from the group consisting of ewing in combination with a blend of polyvinyl acetate and povidone.

In an alternative embodiment, the matrix material is selected from the group consisting of ewtex RL, ewtex RS in combination with a polyvinyl acetate and povidone mixture, ewtex RL, ewtex RS being insoluble but swellable in water, thereby forming pores in the coating, the pore diameter of ewtex RL being between 1 and 5 μm and the pore diameter of ewtex RS being between 0.1 and 0.6 μm.

In an alternative embodiment, the amount of the ettringy RLPO and the ettringy RSPO in the coating layer is 50-90% (by mass), optionally 60-85%, optionally 65-75%, based on the total weight of the coating layer, and the amount of the mixture of polyvinyl acetate and povidone is 5-40% (by mass), optionally 15-25%, based on the total weight of the coating layer.

Combinations of (a) and (b).

In an alternative embodiment, the content of the ewing RLPO and the ewing RSPO in the coating layer is 50-90% (mass%), optionally 60-85%, optionally 65-75%,

the content of (B) is 5-40% (mass percentage) of the total weight of the coating layer, and optionally 15-25%.

In an alternative embodiment, the content of the ewing RSPO in the coating layer is 10-30% (mass%) of the total weight of the coating layer, the content of the ewing RLPO is 30-70% (mass%) of the total weight of the coating layer,

In alternative embodiments, the hydrophilic gel matrix material in the coating layer is selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, carboxymethylcellulose sodium, chitin, chitosan, galactomannan, pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, and the like.

In an alternative embodiment, the hydrophilic gel matrix material in the coating layer is hydroxypropyl methylcellulose selected from materials with low weight average molecular weight and low viscosity, such as E-type methylcellulose.

In alternative embodiments, the content of the hydrophilic gel matrix material in the coating layer of the present disclosure is 1% to 30% (by mass), optionally 5% to 20%, optionally 8% to 15% of the total weight of the coating layer.

In an alternative embodiment, the hydrophilic gel matrix material is E-hydroxypropyl methylcellulose in an amount of 1-30% (by weight), optionally 5-20%, optionally 8-15% of the total weight of the coating layer.

In the present disclosure, in order to meet the requirements of the preparation process, an optional hydrophilic gel matrix material may also be used as the binder.

In the febuxostat tablet provided by the disclosure, the tablet core contains an active substance febuxostat and a disintegrating agent of a quick release preparation known in the art, and in the disclosure, the disintegrating agent can be a material which effervesces and/or expands in the presence of an aqueous medium, so that a necessary force can be provided to mechanically break a coating material, specifically, the disintegrating agent can be selected from croscarmellose sodium, dry starch, low-substituted hydroxypropyl methylcellulose, sodium carboxymethyl starch, crospovidone and the like, and the amount of the disintegrating agent can be 2-35% (by mass) of the weight of the tablet core, optionally 5-25% of the weight of the tablet core, and optionally 8-15% of the weight of the tablet core.

The febuxostat tablet provided by the disclosure can further comprise a pharmaceutically acceptable water-soluble filler and/or a water-insoluble filler in the tablet core, wherein the water-soluble filler comprises lactose, mannitol, sucrose, sorbitol and the like, the water-insoluble filler comprises starch, microcrystalline cellulose, calcium sulfate, calcium hydrophosphate and the like, and the content of the diluent can be 1-99% (by mass) of the weight of the tablet core, optionally 20-85%, optionally 60-80%.

In an alternative embodiment, the filler of the tablet core is selected from the group consisting of water-soluble fillers and water-insoluble fillers, wherein the content of the water-soluble filler may be 35-75% (mass percentage), optionally 45-70%, optionally 50-65% of the weight of the tablet core; the content of the water-insoluble filler may be 1-30% (by mass), optionally 10-25% of the weight of the tablet core.

In an alternative embodiment, the filler of the core is a combination of lactose selected from the group of water-soluble fillers and microcrystalline cellulose selected from the group of water-insoluble fillers.

The febuxostat tablet provided by the present disclosure may further include a pharmaceutically acceptable binder in the tablet core, and the binder may be selected from at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, trehalose, and pullulan, but is not limited thereto, and the content of the binder may be 1% to 5% (by mass) of the total weight of the tablet core.

In an alternative embodiment, the binder is hydroxypropyl cellulose.

In an alternative embodiment, the lubricant of the core is magnesium stearate.

Suitably, a colouring agent may be added to the core to ensure that the core is correctly positioned within the coating to ensure that the tablet has a suitable coating thickness, such that the delay time reproducibility is good, thereby avoiding intra-patient (intra-subject) and inter-patient bioavailability differences, the colouring agent may be iron oxide, titanium dioxide, iron hydroxide or the like, the choice of colouring agent is not limiting the scope of the present disclosure, the content of colouring agent is 0.1% to 3%, optionally 0.4% to 1%, of the total weight of the core.

The febuxostat tablets provided by the present disclosure provide an initial diameter sufficient for gastric retention in the fed state, for example tablets of about 12-18mm diameter may generally resist passage through the pyloric sphincter in the fed state, and the initial maximum diameter of a particular coated tablet of febuxostat of the present disclosure may be 12-16mm, optionally 13-15mm.

In an alternative embodiment, the febuxostat tablet provided by the present disclosure is a gastric retention tablet.

The hardness of the tablet core in the method is relatively low, so that the tablet core can expand after the aqueous medium contacts the tablet core, the outer cladding layer can be better broken, and the hardness of the tablet core is 10-120N, optionally 20-60N. To ensure mechanical stability of the core-coated tablet, so that it is sufficiently resistant to the stresses generated in the stomach, and especially in the presence of food, to ensure that the integrity of the envelope is not destroyed, the hardness of the tablet is controlled to be between 30 and 250N, optionally between 70 and 180N. In this disclosure, febuxostat is released from the tablet core, not as a result of diffusion of the drug through the expanding coating material, but as a result of physical rupture of the coating.

In an alternative embodiment, the present disclosure provides that the immediate release component of the febuxostat tablet is an immediate release drug-containing coating layer.

In an optional embodiment, the content of febuxostat in the unit dosage form of the febuxostat tablet provided by the present disclosure is 1.1-1.8 times, optionally 1.2-1.6 times, optionally 1.5 times of the content of febuxostat in the febuxostat unit dosage form. Specifically, for example, if the content of the single tablet of commercially available febuxostat is 20mg, the unit tablet content of febuxostat provided by the present disclosure is 30mg, and if the content of the single tablet of commercially available febuxostat is 40mg, the unit tablet content of febuxostat provided by the present disclosure is 60mg. The increased medicine dosage increases the uric acid standard-reaching rate, thereby reducing the gout attack frequency and ensuring the curative effect.

In an alternative embodiment, the amount of non-busulfan in the unit dosage form of the febuxostat tablet provided by the present disclosure is 10mg to 200mg, optionally 20mg to 150mg, and the amount of optional febuxostat is 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, optionally 30mg and 60mg, and the content ratio of the immediate release component to the active substance in the tablet core is 1 to 10, optionally 1 to 5.

tablet core

Febuxostat

50-65% of lactose (mass percentage);

10-25% of microcrystalline cellulose (mass percent);

8-15% (mass percent) of croscarmellose sodium;

1-5% of hydroxypropyl cellulose (mass percent);

hydroxypropyl methylcellulose 3-8% (mass percent);

1-5 percent (mass percentage) of magnesium stearate based on the total weight of the tablet core;

coating layer

15 to 25 percent of Eudragit RSPO (mass percent);

45-55 percent of Eudragit RLPO (mass percent);

15-25% (mass percentage);

In an optional embodiment, the content of the active substance in the febuxostat tablet is 30mg, wherein the content ratio of the quick-release drug-containing coating layer to the active substance in the tablet core is 1.

The febuxostat tablet provided by the disclosure enables the active substance febuxostat to be released in a preset delay time period to achieve a controlled release effect, the coating layer can be broken after being soaked in an aqueous medium for at least 1 hour, the active substance is released, the coating layer can be broken after 1.5 hours, and the coating layer can be broken after 2 hours, and the breaking time of the coating layer of the core-spun tablet provided by the disclosure in the aqueous medium is not later than 4 hours. The examination of the breaking time of the coating layer in the aqueous medium described in the present disclosure means the results of the examination in a slurry method of 50rpm, pH4.5PBS-0.5% SDS medium of 500 mL.

For a given active agent, delivery of the active agent to the absorption window may increase the efficacy of the agent and/or reduce or eliminate side effects if the release rate can be preferentially avoided or reduced by controlled, almost complete delivery of the agent to a particular absorption window, or higher degradation or metabolism of the active agent in the gastrointestinal tract. Considering in this respect that a coating layer that ruptures too late may miss the absorption window, a cored tablet is provided in the present disclosure that is capable of rupturing upon immersion in a viscous medium for less than 6 hours, releasing the active substance, optionally rupturing for less than 5 hours, optionally rupturing for less than 4 hours. The examination of the rupture time of the coating layer in viscous medium described in this disclosure means that the rupture time in viscous medium was examined by conducting experiments in HPMC K100LV medium for 2h using basket 75rpm,500mL pH4.5PBS-2.5% and then continuing the experiments in 500mL 0.1MHCl-3% HPMC E5LV medium.

The coating layer described in the present disclosure is subjected to dissolution and release determination (second 0931 method of the general rules of the four kingdoms of the chinese pharmacopoeia 2015 year edition) using 500ml of 2.5% hpmc k100lv-ph6.0 phosphate buffer as dissolution medium at 37 ± 0.5 ℃ and 150 rpm, discarding the medium in each dissolution cup after 4 hours, adding 900ml of ph6.8 phosphate buffer preheated to 37 ± 0.5 ℃ into each dissolution cup, keeping the rotation speed constant, continuing the operation according to the method, and breaking for 3-5 hours.

In the disclosure, the fact that the release amount of the tablet core in the delay time period is not more than about 10% of the total amount of the tablet core febuxostat is understood that the tablet core basically has no drug release, and the tablet core releases all or substantially all febuxostat in a very short time after the delay time expires, specifically, within 1 hour of the rupture of the coating layer, the release amount of the febuxostat in the tablet core is more than 65%, optionally more than 70%, optionally more than 75% of the total amount of the tablet core febuxostat.

In an alternative embodiment, the febuxostat tablet provided by the present disclosure significantly prolongs the effective blood concentration maintenance time and improves the effectiveness on the basis that the febuxostat AUC (geometric mean) is substantially equivalent, wherein substantially equivalent means that the AUC ratio is in the range of 85% to 135%.

The febuxostat tablet provided by the disclosure has the advantages that after a subject eats a middle fat dinner, the maintaining time of the blood concentration of more than or equal to 100ng/ml is at least 10 hours, optionally at least 12 hours, optionally at least 15 hours.

According to the febuxostat tablet provided by the disclosure, after a subject takes the tablet, the blood concentration can be recovered for 2-5 hours, optionally 3-4 hours after the subject takes the tablet.

The disclosure provides an application of the febuxostat tablet in preparing a medicament for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney diseases, metabolic syndrome, diabetes, diabetic nephropathy and congestive heart failure.

The present disclosure provides a method for preparing the febuxostat tablet, which comprises the following steps: granulating febuxostat and optional tablet core excipients into first granules; tablet-core the first granules; granulating the coating auxiliary materials into second granules; compressing the second granules around the core; and coating the quick release layer.

In alternative embodiments, the method comprises the steps of: granulating febuxostat, a filling agent, an adhesive and a part of disintegrating agent, mixing the granulated febuxostat with a hydrophilic gel framework material, the rest disintegrating agent and a lubricant in the tablet core, and pressing the tablet core; granulating coating layer adjuvants comprising matrix material, water-insoluble plasticizer and hydrophilic gel skeleton material; pressing the core-spun sheets; and coating the quick release layer.

In alternative embodiments, the method comprises the steps of: mixing febuxostat, lactose, microcrystalline cellulose, hydroxypropyl cellulose and part of croscarmellose sodium after granulation with hydroxypropyl methylcellulose, the rest croscarmellose sodium and magnesium stearate, and pressing into tablet core; granulating Eudragit RSPO, eudragit RLPO, glyceryl behenate and part of hydroxypropyl methylcellulose, mixing with Kollidon SR and rest hydroxypropyl methylcellulose, and making into core-coated tablet; coating the quick release layer.

In alternative embodiments, the method comprises the steps of: mixing febuxostat, lactose, microcrystalline cellulose, hydroxypropyl cellulose base and part of croscarmellose sodium after granulation, hydroxypropyl methylcellulose, the rest croscarmellose sodium and magnesium stearate, and pressing the mixture into a tablet core; granulating Ewing RSPO, ewing RLPO, glyceryl behenate and part of hydroxypropyl methylcellulose, mixing with Kollidon SR and the rest hydroxypropyl methylcellulose, and pressing into core-coated tablet; coating an Opadry isolation layer; coating the Opadry and the febuxostat quick-release layer.

The present disclosure provides a method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes, diabetic nephropathy, congestive heart failure, wherein febuxostat tablets containing 30mg of febuxostat are administered to a patient or 60mg of febuxostat tablets containing 60mg of febuxostat are administered to a patient after a middle fat dinner once a day.

The method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney diseases, metabolic syndrome, diabetes, diabetic nephropathy and congestive heart failure, provided by the disclosure, the febuxostat tablet containing 30mg of febuxostat is given to a patient after middle fat dinner, and the maintaining time of the average blood concentration of more than or equal to 100ng/ml is at least 10 hours.

The method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney diseases, metabolic syndrome, diabetes, diabetic nephropathy and congestive heart failure, provided by the disclosure, the febuxostat tablet containing 60mg of febuxostat is given to a patient after middle fat dinner, and the maintenance time of the average blood concentration of more than or equal to 100ng/ml is at least 15 hours.

In some embodiments, the febuxostat tablet comprising 60mg febuxostat is administered to the patient after the middle fat dinner, and the maintenance time for the mean plasma concentration ≧ 100ng/ml is at least 18 hours.

Drawings

FIG. 1 is a schematic illustration of a core-spun sheet and X and Y axes;

FIG. 2 is a schematic view of a rupture of a core sheet;

FIG. 3.30 mg specification in vitro dissolution profiles of two batches of samples;

FIG. 4.60 mg specification in vitro dissolution profiles for two batches of samples;

figure 5 mean drug concentration versus time log plot after single gavage administration of 60mg x 4 febuxostat sustained release tablets or 40mg x 4 febuxostat tablets to beagle dogs (satiety, dosing 1h after feeding).

FIG. 6 is a schematic view of a small opening of a core-spun piece.

Detailed Description

The present disclosure is described in further detail below with reference to specific examples, but it should not be construed that the scope of the above-described subject matter of the present disclosure is limited to the following examples.

Example 1 preparation of febuxostat tablet (formulation 1)

TABLE 1.60 mg and 30mg preparation of febuxostat tablets

1. The preparation method comprises the following steps:

1) Preparation of tablet core (2000 tablets)

Accurately weighing various raw and auxiliary materials according to the prescribed amount of the prescription, weighing the adhesive hydroxypropyl cellulose (SL) of the prescription amount, adding the adhesive hydroxypropyl cellulose (SL) of the prescription amount into the weighed purified water under stirring to prepare a 5% aqueous solution, placing the febuxostat, the microcrystalline cellulose (MCC Type 101), the lactose, the cross-linked sodium carboxymethyl cellulose (CC-Na) and the ferric oxide of the prescription amount into a fluidized bed for mixing, taking the 5% solution of the hydroxypropyl cellulose (SL) of the prescription amount as the adhesive, granulating and drying. Adding the granules and the additional adjuvants including croscarmellose sodium and magnesium stearate into a mixing tank, mixing, and tabletting with STYL' One single punch tablet machine (punch die 10.0mm shallow concave punch, R =24.75 mm) to obtain tablet with hardness of 20-60N.

2) Preparation of the outer cover

Weighing hydroxypropyl methylcellulose E5LV with the prescription amount, adding the hydroxypropyl methylcellulose E5LV into purified water under stirring to prepare a 5% aqueous solution, placing the eucalyptus RSPO, the eucalyptus RLPO and the behenic acid glyceride with the prescription amount into a fluidized bed, taking the 5% solution of the HPMC E5LV as an adhesive, granulating, drying, adding additional auxiliary materials Kollidon SR and HPMC E5LV into a mixing tank for total mixing after the yield is reduced.

3) Preparation of core-wrapped tablet

Tabletting with a STYL' One single punch tablet press (14.0 mm punch, R =24.75 mm) with a theoretical lower layer of 305mg and an upper layer of 205mg, with a core tablet with a theoretical total weight of 746mg, a tablet weight variation control range of + -3% and a tablet hardness control of 170-230N.

4) Isolation layer coating

Preparing a 10% concentration Opadry (YS-1-7027-CN) aqueous solution as a coating material and an isolation layer coating solution.

5) Quick release layer coating

Weighing purified water according to the prescription amount, slowly adding opadry (03K 180007-CN) under stirring, stirring for 45min, adding febuxostat to prepare a solution with the solid content of 12%, and stirring until the solution is uniformly dispersed to obtain the quick-release layer coating solution.

2. Core-spun tablet plain tablet (without isolation layer and quick release layer) in-vitro uncapping center control data

In order to ensure that the core-spun sheet is uncapped in vivo within a certain time, the in vitro uncapping time is controlled. The uncapping time of the core-spun tablets is influenced by the water absorption speed of the tablet cores, so the influence of the viscosity of the medium on the uncapping time is large, the uncapping is fast in aqueous medium, and the uncapping is slow in viscous medium. In order to prevent the core-coated tablet from being uncapped prematurely and not achieving the purpose of delayed release, the uncapping time in aqueous medium pH4.5PBS-0.5% SDS is considered; to prevent the cover of the core tablet from missing the absorption window too late, the open cover time in viscous medium pH4.5PBS-2.5% HPMC K100LV (simulating gastric viscosity and pH at full stomach) +0.1MHCl-3% HPMC E5LV (simulating gastric viscosity and pH after gastric emptying) was examined.

2.1 dissolution test in aqueous Medium

TABLE 2 decap time was examined in SDS medium 500ml at pH4.5PBS-0.5% using paddle method 50 rpm.

2.2 dissolution test in viscous Medium

The experiment was continued in 500ml HPMC K100LV medium (pH4.5PBS-2%) for 2h at 75rpm by basket method, replaced by 500ml 0.1MHCl-3% HPMC E5LV medium, the capping time in viscous medium was examined, and the tablet was observed every 30min after replacement of medium.

Table 3.

2.3 in vitro dissolution data of finished febuxostat tablets:

according to the determination method of dissolution rate and release rate (second method of 0931 in the general rules of the four parts of the Chinese pharmacopoeia 2015 edition), using 500ml of 2.5% HPMC K100LV-pH6.0 phosphate buffer solution as dissolution medium, at 37 +/-0.5 deg.C and at 150 rpm, taking 5ml of dissolution solution respectively after 1h, 2h, 3h and 4h according to the method, filtering, taking the subsequent filtrate as test solution, and simultaneously supplementing dissolution medium with the same volume and temperature for 1h, 2h and 3 h. Discarding the medium in each dissolution cup after 4h, adding 900ml of phosphate buffer solution with pH6.8 preheated to 37 +/-0.5 ℃ into each dissolution cup, keeping the rotation speed unchanged, continuously operating according to the method, taking 5ml of dissolution liquid after 0.5h, 1h, 1.5h and 2h, respectively, filtering, taking the subsequent filtrate as a sample solution, simultaneously supplementing the dissolution medium with the same temperature and volume, and measuring the accumulated dissolution amount (%) by high performance liquid chromatography.

Table 4.

The specific dissolution curves are shown in figures 3 and 4.

3. Overcladding thickness measurement

The thickness of the Y-axis outer cladding layer is measured to be 1.2-1.4mm on one side and 1.7-1.9mm on the other side; the thickness of the cladding in the X-axis direction is about 2mm.

Example 2 animal PK results

The experiment adopts a double-cycle cross experimental design, 12 male Beagle dogs are respectively intragastrically administered with 240mg (60mg × 4 tablets) of non-bushy tablets and 160mg (40mg × 4 tablets) of non-bushy tablets (Fibrave), and the pharmacokinetic behaviors of the two dogs are researched by comparing and researching the in-vivo drug concentration-time change process of the Beagle dogs.

After 240mg test product febuxostat tablet is administrated to Beagle dogs through single gastric lavage, the blood concentration reaches a lower peak value at about 0.5h, the concentration is about 2180ng/mL and then decreases, the blood concentration rises again at 2.00h, a higher blood concentration peak is reached at about 4h, the concentration is about 4490ng/mL, the blood concentration gradually decreases with time, the overall peak reaching concentration Cmax is 5340 +/-2350 ng/mL, and the peak reaching time Tmax is 4.00[0.500 ], [ 4.00 ] Tmax]h. Area under drug concentration-time Curve AUC _{INF_obs} 19100 + -8960h ng/mL, total Time of blood concentration higher than 100ng/mL _High Is 12.3 +/-4.88 h

After the Beagle dog is administrated with the control febuxostat tablet (febuxostat tablet) with the dose of 160mg by single intragastric administration, the blood concentration is 1.00[ mu ] 0.250 [ mu ] 1.00]h reaches a peak, and then the blood concentration gradually decreases along with time, and the Cmax reaches the peak concentration of 6930 +/-3290 ng/mL. Area under drug concentration-time Curve AUC _{INF_obs} 15700 +/-7680h ng/mL, total Time of blood concentration higher than 100ng/mL _High Is 9.86 + -5.00 h, as shown in figure 5.

Compared with a reference febuxostat tablet (febuxostat) with the dose of 240mg administered by oral gavage to Beagle dogs, the febuxostat sustained-release tablet with the dose of 160mg administered by oral gavage has the advantages that under the condition that the exposure amount of a drug system is equivalent, an obvious double absorption peak appears, the Cmax is obviously reduced, the total time for maintaining the average blood concentration at the effective blood concentration (more than 100 ng/mL) is 1.25 times that of the reference febuxostat tablet, and the clinical application of the febuxostat tablet is longer in drug effect maintaining time and better in safety.

Example 3 preparation of febuxostat tablet (formula 2)

TABLE 5 formulation 2 composition

The preparation process refers to formula 1.

Example 4, prescription 2 pharmacokinetic Studies in healthy humans

4.1 purpose of study

1) Investigation and comparison of the single-dose oral administration of febuxostat tablets developed by jiangsu henri medicine gmbh (large format: 60mg, n =12, after dinner of medium fat) and febuxostat tablet manufactured by teijin pharmaceutical limited (specification: 40mg, n =40, fasting in the morning) and relative bioavailability.

The results indicate that the maintenance time of the effective concentration (blood concentration is more than or equal to 100 ng/ml) of the T preparation after the night and the middle fat is obviously prolonged compared with the R preparation with the fasting state in the morning.

Comparative example 1.

The formulations in Table 7 were prepared according to the preparation method of example 1, and the decap time was examined in 500ml SDS medium at pH4.5PBS-0.5% using paddle method 50 rpm.

Table 7.

The clad sheet prepared by the above formula has severe erosion of the outer clad layer in an aqueous medium, is broken within 1h, and is difficult to maintain rigidity and integrity.

Claims

A core-coated tablet comprises a tablet core containing an active drug febuxostat and a coating layer coated on the tablet core, wherein the tablet core is positioned in the coating layer, and at least one side of the thickness of the coating layer on two sides of the tablet core in the Y-axis direction is smaller than that of the coating layer in the X-axis direction.
Core-spun sheet according to claim 1, the maximum diameter of the sheet being 12-16mm, preferably 13-15mm.
The cored tablet of claim 1, said coating being capable of rupturing after immersion in an aqueous medium for at least 1 hour, preferably after 1.5 hours, most preferably after 2 hours.
The cored tablet of claim 1, wherein said coating layer ruptures upon immersion in a viscous medium for a time of 6 hours or less, preferably 5 hours or less, most preferably 4 hours or less.
The core-coated tablet according to claim 1, wherein the tablet core has a febuxostat release amount of more than 65%, preferably more than 70%, most preferably more than 75% of the total amount of the tablet core febuxostat within 1 hour of the coating layer rupture.
Core-spun tablet according to any of claims 1 to 5, the hardness of the core tablet being 10 to 120N, preferably 20 to 60N.
The core-spun sheet according to claim 6, the core-spun sheet having a hardness of 120-300N, preferably 170-230N.
The cored tablet of claim 1, wherein the coating layer comprises at least one matrix material, at least one hydrophobic plasticizer and at least one hydrophilic gel matrix material, wherein the matrix material is an excipient insoluble in water or poorly soluble in water.
The core-coated tablet according to claim 8, wherein the hydrophobic plasticizer is selected from liquid paraffin, corn oil, castor oil, coconut oil, triacetin, monoacetin, dibutyl sebacate, dibutyl phthalate, long-chain fatty alcohol, long-chain fatty acid ester or salt thereof, glyceryl behenate, preferably glyceryl behenate.
The core-coated tablet according to claim 9, wherein the hydrophobic plasticizer is present in an amount of 0.1% to 30% (by mass), preferably 0.5% to 20%, most preferably 1% to 10% of the total weight of the coating layer.
The core-coated tablet according to claim 8, wherein said water insoluble or poorly soluble excipients are selected from water insoluble cellulose derivatives and polymers including ethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and their derivatives, polymethacrylic acid polymers, polyvinyl acetate and cellulose acetate polymers, fatty acids or their esters or salts, long chain fatty alcohols, polyoxyethylene alkyl ethers, polyoxyethylene stearic acid, sugar esters, lauroyl polyethylene glycol-32 glycerol, stearoyl polyethylene glycol-32 glycerol, preferably a combination of polymethacrylic acid polymers, polyvinyl acetate and povidone mixture, and polyvinyl acetate and povidone mixture.
The cored tablet of claim 11, wherein the water insoluble or poorly soluble excipient is selected from the group consisting of Eudragit RLPO, eudragit RSPO, and,
A combination of (a) and (b).
The core-coated tablet according to claim 12, wherein the content of the Ewing RLPO and the Ewing RSPO in the coating layer is 50-90% (mass percentage) of the total weight of the coating layer, preferably 60-85%, most preferably 65-75%,
the content of (B) is 5-40% (mass percent) of the total weight of the coating layer, preferably 15-25%.
The core-coated tablet according to claim 13, wherein the content of ewt RSPO in the coating layer is 5-40% (mass percentage) of the total weight of the coating layer, preferably 10-30%, most preferably 15-25%.
The core-coated tablet according to claim 13, wherein the content of ewt RLPO in the coating layer is 20-80% (mass percentage) based on the total weight of the coating layer, preferably 30-70%, most preferably 45-55%.
The cored tablet of claim 8, wherein the hydrophilic gel matrix is selected from the group consisting of methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose, chitin, chitosan, galactomannan, pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, preferably hydroxypropyl methylcellulose, and the hydrophilic gel matrix is present in an amount of 1-30% (by weight), preferably 5-20%, most preferably 8-15%, based on the total weight of the coating layer.
The core-coated tablet according to any one of claims 1 to 16, wherein the tablet core further comprises at least one excipient selected from the group consisting of disintegrants, fillers, binders, lubricants, colorants, said disintegrants being selected from croscarmellose sodium, dry starch, low substituted hydroxypropylmethyl cellulose, sodium carboxymethyl starch, and crospovidone, preferably croscarmellose sodium; the filler is selected from water-soluble filler and/or water-insoluble filler, wherein the water-soluble filler is selected from lactose, mannitol, sucrose, sorbitol and the like, the water-insoluble filler is selected from starch, microcrystalline cellulose, calcium sulfate and calcium hydrophosphate, and the combination of lactose and microcrystalline cellulose is preferred; the adhesive is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, trehalose and amylopectin, preferably hydroxypropyl cellulose; the lubricant is selected from colloidal silicon dioxide, talcum powder, stearic acid, magnesium stearate, calcium stearate, sodium stearate fumarate, polyethylene glycol or sodium lauryl sulfate, preferably magnesium stearate, and the colorant is selected from ferric oxide, titanium dioxide, ferric hydroxide, preferably ferric oxide.
A febuxostat tablet comprising the cored tablet of any one of claims 1 to 17, and further comprising a quick release component of febuxostat.
The febuxostat tablet according to claim 18, wherein the coating layer of the core-coated tablet comprises an immediate release drug-containing coating layer of febuxostat outside the coating layer of the core-coated tablet.
The febuxostat tablet according to claim 19 wherein the coating material is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, gastric-soluble opadry, preferably gastric-soluble opadry, most preferably opadry (03K 180007-CN).
The febuxostat tablet according to any one of claims 19 or 20, wherein the content of febuxostat in the unit dosage form is 1.1-1.8 times, preferably 1.2-1.6 times, most preferably 1.5 times the content of febuxostat in the febuxostat unit dosage form.
The febuxostat tablet according to any one of claims 19 or 20, wherein the amount of non-bustat in the unit dosage form is 10mg to 200mg, preferably 20mg to 150mg, optionally the amount of febuxostat is 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, preferably 30mg and 60mg, the content ratio of immediate release drug containing layer to active substance in the core is 1.
The febuxostat tablet according to any one of claims 21 or 22, wherein the sustained/controlled release tablet comprises the following components:

tablet core

Febuxostat

50% -65% of lactose;

10% -25% of microcrystalline cellulose;

8% -15% of croscarmellose sodium;

1-5% of hydroxypropyl cellulose;

1% -5% of magnesium stearate based on the total weight of the tablet core;

coating layer

15% -25% of Eudragit RSPO;

eudragit RLPO 45% -55%;

15％-25％；

8% -15% of hydroxypropyl methyl cellulose based on the total weight of the coating layer.
The febuxostat tablet according to claim 23, wherein the content of febuxostat is 30mg, and the content of active substances in the quick release drug-containing coating layer and the tablet core is 2.
The febuxostat tablet according to claim 23, wherein the content of febuxostat is 60mg, and the content of active substances in the quick release drug-containing coating layer and the tablet core is 3.
The febuxostat tablet according to any one of claims 18-25, wherein the plasma concentration of the subject is maintained at or above 100ng/ml for at least 10 hours, preferably at least 12 hours, most preferably at least 15 hours after the subject eats a low-fat, low-calorie meal.
The febuxostat tablet according to any one of claims 18-25 wherein the plasma concentration of greater than or equal to 100ng/ml is maintained for a period of at least 12 hours, preferably at least 15 hours, most preferably at least 17 hours after the subject eats a standard meal.
Use of the febuxostat tablet according to any one of claims 18-25 for the preparation of a medicament for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes, diabetic nephropathy, congestive heart failure.
A process for preparing the febuxostat tablet according to any one of claims 18-25, comprising the steps of: granulating febuxostat with optional core excipients into first granules; tablet-core the first granules; granulating the coating layer excipients into second granules; compressing the second granules around the core; coating the quick release layer.
The method of claim 29, comprising the steps of: granulating febuxostat, a filling agent, an adhesive and a part of disintegrating agent, mixing with the rest disintegrating agent and a lubricant, and pressing a tablet core; granulating coating layer adjuvants comprising matrix material, water-insoluble plasticizer and hydrophilic gel skeleton material; pressing the core-spun sheet; and coating the quick release layer.
The method of claim 30, comprising the steps of: granulating febuxostat, lactose, microcrystalline cellulose, hydroxypropyl cellulose and part of croscarmellose sodium, mixing with the rest croscarmellose sodium and magnesium stearate, and pressing to obtain tablet core; granulating Eudragit RSPO, eudragit RLPO, glyceryl behenate and part of hydroxypropyl methylcellulose, mixing with Kollidon SR and rest hydroxypropyl methylcellulose, and making into core-coated tablet; and coating the quick release layer.
The method of claim 31, comprising the steps of: granulating febuxostat, lactose, microcrystalline cellulose, hydroxypropyl cellulose base and part of croscarmellose sodium, mixing with the rest croscarmellose sodium and magnesium stearate, and pressing into tablet cores; granulating Ewing RSPO, ewing RLPO, glyceryl behenate and part of hydroxypropyl methylcellulose, mixing with Kollidon SR and the rest hydroxypropyl methylcellulose, and pressing into core-coated tablet; coating an Opadry isolation layer; coating the Opadry and the febuxostat quick-release layer.
The core-coated tablet according to any one of claims 1 to 17 or the febuxostat tablet according to any one of claims 18 to 27, wherein the tablet core further comprises a hydrophilic gel matrix material in an amount of 1% to 20% of the total weight of the tablet core; preferably 2% -10%; most preferably 3% to 8%.
The cored sheet or febuxostat sheet according to claim 33, wherein the hydrophilic gel matrix material is selected from the group consisting of cellulose derivatives selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, and sodium hydroxymethylcellulose; said non-cellulosic polysaccharide is selected from the group consisting of glucose, chitin, chitosan and galactomannan; the natural gum is selected from pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, and Tremella gum; cellulose derivatives are preferred, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose are most preferred, and hydroxypropyl methylcellulose is particularly preferred.