TWI883162B - A febuxostat tablet - Google Patents

Abstract

The present disclosure relates to a febuxostat tablet. Specifically, the febuxostat tablet in the present disclosure is a package chip, including a core containing active drug non cloth, and a coating layer coated on the core. The core is located in the coating layer, and the coating layer thickness on both sides of the y-axis direction core is at least one side less than that of the x-axis direction, so as to ensure the complete drug release.

Description

A febuxostat tablet

The present disclosure relates to a Febuxostat tablet, which is a core-coated tablet. 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 mouth and swallowed. Administration is simple, convenient, painless, does not require any specialized equipment or medical staff, has good patient compliance, and is low cost.

Gastric emptying is part of the normal digestive process of the human body, which results in that drug formulations that enter the stomach via the oral route usually only stay in the stomach for a short time. The short gastric residence time limits the bioavailability of many types of orally administered drugs, especially drugs that act locally in the stomach, are preferentially absorbed in the upper gastrointestinal tract or absorbed in the environment of the lower gastrointestinal tract, and are unstable at neutral or alkaline pH or have low solubility. This type of drug can be delivered by gastric retentive formulations.

A sustained/controlled release tablet is one that is capable of releasing the drug at a predetermined rate and/or at a predetermined time after administration to maintain the desired pharmacological activity for a desired period of time. Such a formulation provides the drug to the body within a predetermined time period or at a predetermined absorption site, thereby maintaining the drug level within the therapeutic range for a longer period of time compared to a general (e.g., immediate release) formulation. The dosage form containing the core is the form in which a sustained/controlled release tablet is produced. The most commonly used material is a hydrophilic material, which swells and becomes a colloid once it comes into contact with the physiological medium. When the dosage form is exposed to the 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 is released by diffusion through the matrix and/or erosion of the matrix.

Febuxostat is an oral non-purine xanthine oxidase (NP-SIXO) selective inhibitor developed by Teijin Pharma. It is mainly used for the chronic treatment of hyperuricemia in gout patients, the treatment of chronic hyperuricemia with urate deposition, and the treatment of hyperuricemia associated with cancer chemotherapy (tumor lysis syndrome). The main side effect is that it is often accompanied by acute gout attacks in the early stages of treatment, which increases the frequency of gout attacks and seriously affects the patient's compliance.

Takeda Pharmaceutical's patent application CN103210084A discloses a novel composition containing febuxostat, including immediate-release beads and sustained-release beads containing febuxostat, which achieve a sustained-release effect by membrane control. The background technology of the application points out that febuxostat preparations that maintain a critical concentration of drug concentration higher than 100ng/mL for an extended period of time are expected to produce higher efficacy and will be a desired treatment option for controlling hyperuricemia, gout and many other disease states. However, the clinical project TMX-67XR involved in the application was terminated for undisclosed reasons, which fully proves that there are great difficulties in the development of febuxostat sustained/controlled-release tablets.

The present disclosure provides a coated tablet, including a tablet core containing an active drug, febuxostat, and a coating layer coated on the tablet core, wherein the tablet core is located in the coating layer, and the thickness of the coating layer on both sides of the tablet core in the Y-axis direction is at least one side less 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 tablet core in the Y-axis direction correspond to the upper and lower surfaces in the figure respectively).

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

The febuxostat tablets disclosed in the present invention provide an initial diameter sufficient to allow the tablets to be retained in the stomach when fed. For example, tablets with a diameter of about 12-18 mm can usually resist passing through the pyloric sphincter when fed. Specifically, the initial maximum diameter of the febuxostat tablets disclosed in the present invention can be 12-16 mm, or can be 13-15 mm.

In an optional embodiment, the chip package provided by the present disclosure is a chip package for gastric retention.

In an optional embodiment, the coating layer thickness on both sides of the tablet core in the Y-axis direction is the same or different. The coating layer thickness on one side of the tablet core can be 0.5-2.2mm, optionally 1.0-2.0mm, optionally 1.5-1.8mm, or optionally 1.7-1.9mm; the coating layer thickness on the other side of the tablet core can be 0.3-2.0mm, optionally 0.8-1.8mm, optionally 1.2-1.4mm, or optionally 1.0-1.5mm.

The coated core provided in this disclosure, due to the special choice of coating thickness along the Y-axis direction, allows the active substance Febuxostat to be released in a predetermined delayed time period to achieve a controlled release effect. The coating layer can be broken after being immersed in an aqueous medium for at least 1 hour to release the active substance. It can be broken after 1.5 hours or after 2 hours. The coating layer of the core provided in this disclosure breaks in an aqueous medium for no later than 4 hours. The investigation of the coating layer breaking time in an aqueous medium described in this disclosure refers to the results of the investigation in 500 mL of pH4.5 PBS-0.5% SDS medium using a paddle method at 50 rpm.

6小時時發生破裂，釋放活性物質，可選為

5小時破裂，亦可選為

4小時破裂。本揭露中所述的包衣層在黏性介質中破裂時間的考察是指採用籃法75rpm，500mL pH4.5 PBS-2.5% HPMC K100LV介質中實驗2h，再更換至500ml 0.1MHCl-3%HPMC E5LV介質中繼續實驗，考察在黏性介質中破裂時間。 For a given active drug, if the drug can be delivered almost completely to a specific absorption window in a controllable manner, or the release rate can be preferentially avoided or reduced in areas of the gastrointestinal tract where the degradation or metabolism of the active drug is high, in addition, delivering the active drug to the absorption window can increase the efficacy of the drug and/or reduce or eliminate side effects. Considering this aspect, if the coating layer breaks too late, the absorption window may be missed. The coated core provided in the present disclosure has a coating layer that can be immersed in a viscous medium for a period of time.

6 hours after the rupture occurs, releasing the active substance, optional

5 hours to rupture, also available

The investigation of the coating layer rupture time in a viscous medium described in this disclosure refers to the use of a basket method at 75 rpm, 500 mL pH 4.5 PBS-2.5% HPMC K100LV medium for 2 hours, and then changing to 500 ml 0.1 M HCl-3% HPMC E5LV medium to continue the experiment, and investigate the rupture time in the viscous medium.

The coating layer described in this disclosure is subjected to the dissolution and release test method (Chinese Pharmacopoeia 2015 Edition Part Four General Rules 0931 Second Method), using 500ml of 2.5% HPMC K100LV-pH6.0 phosphate buffer as the dissolution medium, the temperature is 37±0.5℃, the rotation speed is 150 revolutions per minute, and after 4 hours, the medium in each dissolution cup is discarded, and 900ml of pH6.8 phosphate buffer preheated to 37±0.5℃ is added to each dissolution cup, the rotation speed remains unchanged, and the operation is continued according to the law, and it ruptures in 3-5 hours.

When the rupture position of the tablet core is in the X-axis direction, the opening is too small and the depth is relatively long (as shown in Figure 6), resulting in slow drug release. Therefore, the coating thickness on both sides of the tablet core in the Y-axis direction is at least one side less than the coating thickness in the X-axis direction, so that the coating ruptures and releases the active drug in the Y-axis direction, ensuring the rapid release of the tablet core drug (as shown in Figure 2).

In this disclosure, the amount of the core tablet released during the extended time period is no more than about 10% of the total amount of febuxostat in the core tablet, which should be understood as the core tablet releasing substantially no drug, and the core tablet releases all or substantially all of the febuxostat in a very short time after the extended time expires, specifically, within 1 hour after the coating layer is ruptured, the amount of febuxostat released from the core tablet is more than 65% of the total amount of febuxostat in the core tablet, and can be selected as more than 70%, or more than 75%.

The core tablet disclosed herein is formed by compression-coating technology, which will be described in detail below. Compression-coated tablets are usually prepared by placing a portion of powdered or granular coating materials in a die, compacting the portion of coating materials with a punch press, placing the core on the dense coating materials, and then introducing the remaining coating materials into the die, applying pressure to form a coated tablet. With the innovation of compression technology, some one-step dry-coating technologies for preparing compression-coated tablets have also been developed, such as OSDrC®, as shown in the study 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.

In this disclosure, the tablet core has a relatively low hardness, which ensures that the tablet core can expand after the water medium contacts the tablet core, so that the outer coating layer can be better broken. The hardness of the tablet core is 10-120N, and 20-60N can be selected. In order to ensure the mechanical stability of the tablet core, so that it is sufficient to resist the pressure generated by the stomach, especially when there is food, to ensure that the integrity of the outer coating layer is not destroyed, the hardness of the tablet is controlled at 120-300N, and 170-230N can also be selected. In this disclosure, the release of febuxostat from the tablet core is not the result of the drug diffusing through the expanded coating material, but the result of physical rupture of the coating.

The core tablet provided by the present disclosure has a coating layer containing at least one base material, at least one hydrophobic plasticizer and at least one hydrophilic gel skeleton material, wherein the base material is a plasticizer that is insoluble or poorly soluble in water.

The hydrophobic plasticizer described in the optional implementation scheme can be selected from liquid wax, corn oil, castor oil, coconut oil, triacetin, monoacetin, dibutyl sebacate, dibutyl phthalate, long-chain fatty alcohols, long-chain fatty acids and their esters or salts, behenic acid glyceryl ester, and behenic acid glyceryl ester can be selected. The content of the water-insoluble plasticizer is 0.1%-30% (mass percentage) of the total weight of the coating layer, and can be selected as 0.5%-20%, or can be selected as 1%-10%.

The plasticizer behenic acid glyceryl described in the present disclosure is an ester formed by glycerol and behenic acid (a _C22 fatty acid). Behenic acid glyceryl can exist in the form of its mono-, di- or tri-ester or a mixture thereof, and its HLB value is preferably less than 5, and may be preferably about 2.

The applicant was surprised to find that the coating layer without hydrophobic plasticizer was severely eroded in aqueous media, making it difficult to maintain rigidity and integrity, and the coating layer could not achieve the effect of delaying release after a period of time.

In an optional embodiment, the water-insoluble or poorly soluble shaping agent can be selected from any known water-insoluble cellulose derivatives, polymers, and mixtures of polyvinyl acetate and polyvidone, etc. The water-insoluble cellulose derivatives and polymers include alkyl celluloses, such as ethyl cellulose, hydroxypropyl 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, lauryl polyethylene glycol-32 glycerol, stearyl polyethylene glycol-32 glycerol, etc.

Kollidon ^® SR is a mixture of polyvinyl acetate and polyvinyl pyrrolidone. It is a very plastic material and is particularly suitable for direct tableting.

In an optional embodiment, the matrix material is selected from a combination of polymethacrylic acid polymer, polyvinyl acetate and a polyvidone mixture.

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

In an optional embodiment, the matrix material is selected from a combination of Eudragit and a mixture of polyvinyl acetate and povidone.

In an optional implementation scheme, the content of Eudragit in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, and can be selected as 60%-85%, or 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, and can be selected as 15%-25%.

In an optional embodiment, the matrix material is selected from a combination of Eudragit RL, Eudragit RS and a mixture of polyvinyl acetate and povidone. Eudragit RL and Eudragit RS are insoluble in water but can swell, thereby forming channels in the coating. The channel diameter of Eudragit RL is 1-5μm, and the channel diameter of Eudragit RS is 0.1-0.6μm.

In an optional embodiment, the content of Eudragit RL and Eudragit RS in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, and can be selected as 60%-85%, or 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, and can be selected as 15%-25%.

In an optional embodiment, the matrix material is selected from a combination of Eudragit RLPO and Eudragit RSPO with a mixture of polyvinyl acetate and povidone.

In an optional embodiment, 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, and can be selected as 60%-85%, or can be selected as 65%-75%, and the content of the mixture of polyvinyl acetate and povidone is 5%-40% (mass percentage) of the total weight of the coating layer, and can be selected as 15%-25%.

In an optional embodiment, the matrix material is selected from the combination of Eudragit RLPO, Eudragit RSPO, and ^Kollidon® SR.

In an optional embodiment, the content of Eudragit RLPO and Eudragit RSPO in the coating layer is 50%-90% (mass percentage) of the total weight of the coating layer, optionally 60%-85%, or alternatively 65%-75%, and the content of ^Kollidon® SR is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.

In an optional implementation scheme, the content of Eudragit RSPO in the coating layer accounts for 5%-40% (mass percentage) of the total weight of the coating layer, which can be 10%-30%, or 15%-25%.

In an optional implementation scheme, the content of Eudragit RLPO in the coating layer accounts for 20%-80% (mass percentage) of the total weight of the coating layer, and can be selected as 30%-70%, or 45%-55%.

In an optional embodiment, the content of Eudragit RSPO in the coating layer is 5%-40% (mass percentage) of the total weight of the coating layer, the content of Eudragit RLPO is 20%-80% (mass percentage) of the total weight of the coating layer, and the content of Kollidon ^® SR is 5%-40% (mass percentage) of the total weight of the coating layer.

In an optional embodiment, the content of Eudragit RSPO in the coating layer is 10%-30% (mass percentage) of the total weight of the coating layer, the content of Eudragit RLPO is 30%-70% (mass percentage) of the total weight of the coating layer, and the content of Kollidon ^® SR is 15%-25% (mass percentage) of the total weight of the coating layer.

In an optional embodiment, the content of Eudragit RSPO in the coating layer is 15%-25% (mass percentage) of the total weight of the coating layer, the content of Eudragit RLPO is 45%-55% (mass percentage) of the total weight of the coating layer, and the content of Kollidon ^® SR is 15%-25% (mass percentage) of the total weight of the coating layer.

The hydrophilic gel skeleton material described in the present disclosure is selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, sodium hydroxymethylcellulose, chitosan, deacetylated chitosan, galactomannan, pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, etc.

In an optional embodiment, the hydrophilic gel skeleton material is hydroxypropyl methyl cellulose, and 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 skeleton material in this disclosure is 1%-30% (mass percentage) of the total weight of the coating layer, and can be selected as 5%-20%, or 8%-15%.

In an optional embodiment, the hydrophilic gel skeleton material is E-type hydroxypropyl methylcellulose, and its content is 1%-30% (mass percentage) of the total weight of the coating layer, and can be selected as 5%-20%, or 10%-15%.

In this disclosure, in order to meet the needs of the preparation process, the optional hydrophilic gel skeleton material can also be used as an adhesive.

The febuxostat coated core provided by the present disclosure contains, in addition to the active substance febuxostat, a disintegrant of a fast-release preparation known in the art. In the present disclosure, the disintegrant may be a material that effervesces and/or swells in the presence of an aqueous medium, thereby providing the necessary force to mechanically rupture the coating material. Specifically, the disintegrant may be selected from cross-linked sodium carboxymethyl cellulose, dry starch, low-substituted hydroxypropylmethyl cellulose, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone, etc., and may be cross-linked sodium carboxymethyl cellulose. The amount of the disintegrant may be 2%-35% (mass percentage) of the weight of the core, optionally 5%-25% of the weight of the core, and optionally 8%-15% of the weight of the core.

The febuxostat coated chip provided in the present disclosure may also contain a pharmaceutically acceptable water-soluble filler and/or a water-insoluble filler in the core. The water-soluble filler includes lactose, mannitol, sucrose, sorbitol, etc., and the water-insoluble filler includes starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, etc. The content of the diluent may be 1%-99% (mass percentage) of the core weight, and may be selected as 20%-85%, or may be selected as 60%-80%.

In an optional embodiment, the filler of the tablet core is selected from a combination of a water-soluble filler and a water-insoluble filler, wherein the content of the water-soluble filler can be 35%-75% (mass percentage) of the tablet core weight, optionally 45%-70%, or optionally 50%-65%; the content of the water-insoluble filler can be 1%-25% (mass percentage) of the tablet core weight, optionally 10%-25%.

In an optional embodiment, 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 coated core provided by the present disclosure may also contain a pharmaceutically acceptable binder in the core, and the binder may be selected from at least one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, trehalose and branched starch, but is not limited thereto. The content of the binder may be 1%-5% (mass percentage) of the total weight of the core.

In an optional embodiment, the binder is hydroxypropyl cellulose.

The tablet core may contain a suitable lubricant, such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol or sodium lauryl sulfate. The content of the lubricant in the tablet core is 0.5%-10% (mass percentage) of the total weight of the tablet core, and can be selected as 1%-5%.

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

Appropriately, a colorant can be added to the tablet core to ensure that the tablet core is accurately positioned in the coating to ensure that the tablet has an appropriate coating thickness, so that the delay time is reproducible, thereby avoiding intra-subject and inter-patient differences in bioavailability. Appropriate colorants can be iron oxide, titanium dioxide, iron hydroxide, etc. The selection of colorants is not limited to the scope of this disclosure. The content of the colorant is 0.1%-3% of the total weight of the tablet core, and can be selected as 0.4%-1%.

In an optional embodiment, the febuxostat-coated core chip provided by the present disclosure may further contain a hydrophilic gel skeleton material, and the hydrophilic gel skeleton material is selected from cellulose derivatives, non-cellulose polysaccharides, natural gums, vinyl polymers or acrylic polymers, etc. The cellulose derivative can be selected from methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and sodium hydroxymethylcellulose; the non-cellulose polysaccharide can be selected from glucose, chitosan, deacetylated chitosan and galactomannan; the natural gum can be selected from pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, schizonepeta gum and the like.

In an optional embodiment, the febuxostat coated chip provided by the present disclosure has a hydrophilic gel skeleton material in the core of the chip being a cellulose derivative.

In an optional embodiment, the febuxostat coated chip provided by the present disclosure has a hydrophilic gel skeleton material in the core selected from hydroxyethyl methylcellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

In an optional embodiment, the febuxostat coated chip provided by the present disclosure has a hydrophilic gel skeleton material in the core of the chip being hydroxypropyl methylcellulose.

In an optional embodiment, the febuxostat coated chip provided by the present disclosure has a hydrophilic gel skeleton material in the core accounting for 1%-20% of the total weight of the core.

In an optional embodiment, the febuxostat coated chip provided by the present disclosure has a hydrophilic gel skeleton material in the core accounting for 2%-10% of the total weight of the core.

In an optional embodiment, the febuxostat coated chip provided by the present disclosure has a hydrophilic gel skeleton material in the core accounting for 3%-8% of the total weight of the core.

The present disclosure provides a febuxostat tablet, which contains not only the core tablet and coating layer mentioned above, but also a febuxostat immediate-release portion. The immediate-release portion can be completed by any technical means known in the art, such as a double-layer tablet, an immediate-release coating, etc.

In an optional embodiment, the febuxostat tablets provided in the present disclosure have a sustained-release effect.

The present disclosure provides a febuxostat tablet, which contains not only the core tablet mentioned above, but also a coating layer of the core tablet and a fast-release drug-containing coating layer of febuxostat.

In an optional embodiment, the fast-release drug-containing coating layer of febuxostat contains the active drug febuxostat and a coating material, and the coating material can be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, gastric soluble opadyl, gastric soluble opadyl, or opadyl (03K180007-CN).

Since the rapid-release component is rapidly released in the medium or in the body, the drug release characteristics of the chip packaged in the present disclosure are the same as those of the febuxostat tablet containing the rapid-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 the content of febuxostat in the unit dosage form of Fibril, which can be 1.2-1.6 times, or 1.5 times. Specifically, for example, the content of a single tablet of commercially available febuxostat is 20 mg, and the content of a single tablet of febuxostat provided by the present disclosure is 30 mg. The content of a single tablet of commercially available febuxostat is 40 mg, and the content of a unit tablet of febuxostat provided by the present disclosure is 60 mg. The increased drug dosage increases the rate of achieving the target of uric acid reduction, thereby reducing the frequency of gout attacks and ensuring the efficacy.

In an optional embodiment, the amount of febuxostat in the unit dosage form of the febuxostat tablet provided by the present disclosure is 10 mg-200 mg, optionally 20 mg-150 mg, and the optional amount of febuxostat is 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg , 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 quick-release drug-containing coating layer to the active substance in the tablet core is 1:10-10:1, and 1:5-5:1 is optional.

In an optional embodiment, the Febuxostat tablet contains the following ingredients:

Chip

Febuxostat

Lactose 50%-65% (mass percentage);

Microcrystalline cellulose 10%-25% (mass percentage);

Cross-linked sodium carboxymethyl cellulose 8%-15% (mass percentage);

Hydroxypropyl cellulose 1-5% (mass percentage);

Magnesium stearate 1%-5% (mass percentage), based on the total weight of the tablet core;

Coating layer

Eudragit RSPO 15%-25% (mass percentage);

Eudragit RLPO 45%%-55% (mass percentage);

Kollidon ^® SR 15%-25% (mass percentage);

Hydroxypropyl methylcellulose 8%-15% (mass percentage), based on the total weight of the coating layer.

In an optional embodiment, the Febuxostat tablet contains the following ingredients:

Chip

Febuxostat

Lactose 50%-65% (mass percentage);

Microcrystalline cellulose 10%-25% (mass percentage);

Cross-linked sodium carboxymethyl cellulose 8%-15% (mass percentage);

Hydroxypropyl cellulose 1-5% (mass percentage);

Magnesium stearate 1%-5% (mass percentage);

Hydroxypropyl methylcellulose 3%-8% (mass percentage), based on the total weight of the tablet core;

Coating layer

Eudragit RSPO 15%-25% (mass percentage);

Eudragit RLPO 45%%-55% (mass percentage);

Kollidon ^® SR 15%-25% (mass percentage);

Hydroxypropyl methylcellulose 8%-15% (mass percentage), based on the total weight of the coating layer.

In an optional implementation scheme, the active substance content in the Febuxostat tablet is 30 mg, wherein the content ratio of the immediate-release drug-containing coating layer to the active substance in the tablet core is 1:10-10:1, optionally 1:5-5:1, optionally 1:2-1:1, or optionally 2:3.

In the optional implementation scheme, the active substance content in the Febuxostat tablet is 60 mg, wherein the content ratio of the immediate-release drug-containing coating layer to the active substance in the tablet core is 1:10-10:1, optionally 1:5-5:1, optionally 1:3-1:1, or optionally 3:7.

Optionally, there is a separation layer between the coating layer and the febuxostat immediate-release layer. The separation layer is a thin layer of polymer material, forming a film-like coating layer, which increases the tablet weight by 1%-50% (mass percentage), and can be selected by 2%-4%.

The material of the isolation layer can be selected from one or more of hydroxypropyl methylcellulose, povidone, copovidone, hydroxypropyl cellulose and gastric soluble opadyl, gastric soluble opadyl or gastric soluble opadyl (YS-1-7027-CN).

In an optional implementation, the Febuxostat tablets provided by the present disclosure have a substantially equivalent AUC (geometric mean) to that of Febuxostat, and significantly prolong the maintenance time of effective blood drug concentration and improve effectiveness, wherein substantially equivalent means that the AUC ratio is in the range of 85%-135%.

The Febuxostat tablets provided in this disclosure significantly prolong the maintenance time of effective blood drug concentration and reduce the Cmax value, which is safer.

100ng/ml的維持時間是受試者一日一次服用菲布力的1-3倍，可選為1.25-2.0倍。 Febuxostat tablets provided in this disclosure, blood drug concentration (geometric mean) of subjects taking Febuxostat tablets provided in this disclosure once a day

The maintenance time of 100ng/ml is 1-3 times that of the subjects taking Februa once a day, and can be 1.25-2.0 times.

100ng/ml的維持時間至少為10小時，可選至少為12小時，可選至少為15小時。 The febuxostat tablets provided in this disclosure, after the subjects ate a low-fat, low-calorie meal (fat provided about 10% of the calories in the food, the total calories were about 300 kcal), the blood drug concentration

The maintenance time of 100 ng/ml is at least 10 hours, optionally at least 12 hours, and optionally at least 15 hours.

100ng/ml的維持時間至少為12小時，可選至少為15小時，可選至少為17小時。 The febuxostat tablets provided in this disclosure, after the subjects took a standard meal, the blood drug concentration

The maintenance time of 100 ng/ml is at least 12 hours, optionally at least 15 hours, and optionally at least 17 hours.

The blood drug concentrations described in this disclosure refer to geometric means.

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

For the Febuxostat tablets provided in this disclosure, the time for the blood drug concentration of the subjects to recover after taking the drug is 2-5 hours, and 3-4 hours is optional.

The febuxostat tablets provided in this disclosure have a break-down time in the subject's body of 2-5 hours after taking the drug, and can be optionally 3-4 hours.

The present disclosure provides a use of the above-mentioned febuxostat tablets in the preparation of drugs for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure.

This disclosure provides a method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiomegaly, hypertension, nephrolithiasis, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure, by administering the Febuxostat tablets provided by this disclosure to the patient.

The present disclosure provides a method for preparing the above-mentioned Febuxostat tablets, which comprises the following steps: granulating Febuxostat and an optional tablet core excipient into first granules; forming the first granules into tablet cores; granulating the coating layer excipients into second granules; compressing the second granules to coat the tablet cores; and coating the immediate release layer.

In an optional embodiment, the method comprises the following steps: granulating Febuxostat with a filler, a binder, and a portion of a disintegrant, and pressing the tablet core after mixing with the remaining disintegrant and lubricant; granulating a coating layer excipient containing a base material, a water-insoluble plasticizer, and a hydrophilic gel matrix material; pressing a core tablet; and coating a quick-release layer.

In an optional embodiment, the method comprises the following steps: granulating febuxostat with lactose, microcrystalline cellulose, hydroxypropyl cellulose and part of cross-linked sodium carboxymethyl cellulose, mixing with the remaining cross-linked sodium carboxymethyl cellulose and magnesium stearate, and then pressing the tablet core; granulating Eudragit RSPO, Eudragit RLPO, behenic acid glyceride and part of hydroxypropyl methyl cellulose, mixing with Kollidon SR and the remaining hydroxypropyl methyl cellulose, and then pressing the tablet core; coating the quick-release layer.

In an optional embodiment, the method comprises the following steps: granulating febuxostat with lactose, microcrystalline cellulose, hydroxypropyl cellulose base and part of cross-linked carboxymethyl cellulose sodium, mixing with the remaining cross-linked carboxymethyl cellulose sodium and magnesium stearate, and then pressing the tablet core; granulating Eudragit RSPO, Eudragit RLPO, behenic acid glyceride and part of hydroxypropyl methylcellulose, mixing with Kollidon SR and the remaining hydroxypropyl methylcellulose, and then pressing the tablet core; coating with omega-3 isolation layer; coating with omega-3 and febuxostat immediate release layer.

Optionally, the method for preparing febuxostat tablets includes a film coating step after completing the preparation of the core tablets.

On the other hand, the present disclosure provides a febuxostat tablet, comprising a tablet core containing the active drug febuxostat, and a coating layer coated on the tablet core, wherein the tablet core is located in the coating layer, and the tablet core also contains a hydrophilic gel matrix material accounting for 1%-20% of the total weight of the tablet core; the coating layer contains at least one base material, at least one hydrophobic plasticizer and at least one hydrophilic gel matrix material, and further includes a rapid-release component containing the active substance febuxostat.

In an optional embodiment, the hydrophilic gel skeleton material of the tablet core is selected from cellulose derivatives, non-cellulose polysaccharides, natural gums, vinyl polymers or acrylic polymers, etc.; the cellulose derivatives can be selected from methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and sodium hydroxymethylcellulose, etc.; the non-cellulose polysaccharide is selected from glucose, chitosan, deacetylated chitosan and galactomannan, etc.; the natural gum is selected from pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, schizonepeta gum, etc.

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

In an optional embodiment, the febuxostat coated chip provided by the present disclosure has a hydrophilic gel skeleton material in the core selected from hydroxyethyl methylcellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

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

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

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

In the optional implementation scheme, the hydrophobic plasticizer can be selected from liquid wax, corn oil, castor oil, coconut oil, triacetin, monoacetin, dibutyl sebacate, dibutyl phthalate, long-chain fatty alcohols, long-chain fatty acids and their esters or salts, behenic acid glyceryl ester, and behenic acid glyceryl ester can be selected. The content of the water-insoluble plasticizer is 0.1%-30% (mass percentage) of the total weight of the coating layer, and can be selected as 0.5%-20%, or can be selected as 1%-10%.

The plasticizer behenic acid glyceryl described in the present disclosure is an ester formed by glycerol and behenic acid (a _C22 fatty acid). Behenic acid glyceryl can exist in the form of its mono-, di- or tri-ester or a mixture thereof, and its HLB value is preferably less than 5, and may be preferably about 2.

The applicant was surprised to find that the coating layer without hydrophobic plasticizer was severely eroded in aqueous media, making it difficult to maintain rigidity and integrity, and the coating layer could not achieve the effect of delaying release after a period of time.

In an optional embodiment, the water-insoluble or poorly soluble shaping agent can be selected from any known water-insoluble cellulose derivatives, polymers, and mixtures of polyvinyl acetate and polyvidone, etc. The water-insoluble cellulose derivatives and polymers include alkyl celluloses, such as ethyl cellulose, hydroxypropyl 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, lauryl polyethylene glycol-32 glycerol, stearyl polyethylene glycol-32 glycerol, etc.

In an optional embodiment, the matrix material is selected from a combination of polymethacrylic acid polymer, polyvinyl acetate and a polyvidone mixture.

In an optional embodiment, 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, and can be selected as 60%-85%, or 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, and can be selected as 15%-25%.

In an optional embodiment, the matrix material is selected from a combination of Eudragit and a mixture of polyvinyl acetate and povidone.

In an optional implementation scheme, the content of Eudragit in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, and can be selected as 60%-85%, or 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, and can be selected as 15%-25%.

In an optional embodiment, the matrix material is selected from a combination of Eudragit RL, Eudragit RS and a mixture of polyvinyl acetate and povidone. Eudragit RL and Eudragit RS are insoluble in water but can swell, thereby forming channels in the coating. The channel diameter of Eudragit RL is 1-5μm, and the channel diameter of Eudragit RS is 0.1-0.6μm.

In an optional embodiment, the content of Eudragit RL and Eudragit RS in the coating layer accounts for 50%-90% (mass percentage) of the total weight of the coating layer, and can be selected as 60%-85%, or 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, and can be selected as 15%-25%.

In an optional embodiment, the matrix material is selected from a combination of Eudragit RLPO and Eudragit RSPO with a mixture of polyvinyl acetate and povidone.

In an optional implementation scheme, 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, and can be selected as 60%-85%, or 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, and can be selected as 15%-25%.

In an optional embodiment, the matrix material is selected from the combination of Eudragit RLPO, Eudragit RSPO, and ^Kollidon® SR.

In an optional embodiment, the content of Eudragit RLPO and Eudragit RSPO in the coating layer is 50%-90% (mass percentage) of the total weight of the coating layer, optionally 60%-85%, or alternatively 65%-75%, and the content of ^Kollidon® SR is 5%-40% (mass percentage) of the total weight of the coating layer, optionally 15%-25%.

In an optional implementation scheme, the content of Eudragit RSPO in the coating layer accounts for 5%-40% (mass percentage) of the total weight of the coating layer, which can be 10%-30%, or 15%-25%.

In an optional implementation scheme, the content of Eudragit RLPO in the coating layer accounts for 20%-80% (mass percentage) of the total weight of the coating layer, and can be selected as 30%-70%, or 45%-55%.

In an optional embodiment, the content of Eudragit RSPO in the coating layer is 5%-40% (mass percentage) of the total weight of the coating layer, the content of Eudragit RLPO is 20%-80% (mass percentage) of the total weight of the coating layer, and the content of Kollidon ^® SR is 5%-40% (mass percentage) of the total weight of the coating layer.

In an optional embodiment, the content of Eudragit RSPO in the coating layer is 10%-30% (mass percentage) of the total weight of the coating layer, the content of Eudragit RLPO is 30%-70% (mass percentage) of the total weight of the coating layer, and the content of Kollidon ^® SR is 15%-25% (mass percentage) of the total weight of the coating layer.

In an optional embodiment, the content of Eudragit RSPO in the coating layer is 15%-25% (mass percentage) of the total weight of the coating layer, the content of Eudragit RLPO is 45%-55% (mass percentage) of the total weight of the coating layer, and the content of Kollidon ^® SR is 15%-25% (mass percentage) of the total weight of the coating layer.

In an optional embodiment, the hydrophilic gel skeleton material in the coating layer is selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, sodium hydroxymethylcellulose, chitosan, deacetylated chitosan, galactomannan, pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, etc.

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

In an optional embodiment, the content of the hydrophilic gel skeleton material in the coating layer disclosed herein is 1%-30% (mass percentage) of the total weight of the coating layer, which can be 5%-20%, or 8%-15%.

In an optional embodiment, the hydrophilic gel skeleton material is E-type hydroxypropyl methylcellulose, and its content is 1%-30% (mass percentage) of the total weight of the coating layer, and can be selected as 5%-20%, or 8%-15%.

In this disclosure, in order to meet the needs of the preparation process, the optional hydrophilic gel skeleton material can also be used as an adhesive.

The febuxostat tablets provided in the present disclosure contain, in addition to the active substance febuxostat, a disintegrant of a fast-release preparation known in the art in the tablet core. In the present disclosure, the disintegrant may be a material that effervesces and/or swells in the presence of an aqueous medium, thereby providing the necessary force to mechanically rupture the coating material. Specifically, the disintegrant may be selected from cross-linked sodium carboxymethyl cellulose, dry starch, low-substituted hydroxypropylmethyl cellulose, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone, etc., and cross-linked sodium carboxymethyl cellulose may be selected. The amount of the disintegrant may be 2%-35% (mass percentage) of the tablet core weight, optionally 5%-25% of the tablet core weight, and optionally 8%-15% of the tablet core weight.

The febuxostat tablets provided in the present disclosure may also contain pharmaceutically acceptable water-soluble fillers and/or water-insoluble fillers in the tablet core. The water-soluble fillers include lactose, mannitol, sucrose, sorbitol, etc., and the water-insoluble fillers include starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, etc. The content of the diluent may be 1%-99% (mass percentage) of the tablet core weight, and may be selected as 20%-85%, or may be selected as 60%-80%.

In an optional embodiment, the filler of the tablet core is selected from a combination of a water-soluble filler and a water-insoluble filler, wherein the content of the water-soluble filler can be 35%-75% of the tablet core weight (mass percentage), optionally 45%-70%, or 50%-65%; the content of the water-insoluble filler can be 1%-30% of the tablet core weight (mass percentage), optionally 10%-25%.

In an optional embodiment, 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 tablets provided in the present disclosure may also contain a pharmaceutically acceptable binder in the tablet core. The binder may be selected from, for example, at least one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, trehalose and branched starch, but is not limited thereto. The content of the binder may be 1%-5% (mass percentage) of the total weight of the tablet core.

In an optional embodiment, the binder is hydroxypropyl cellulose.

The tablet core may contain a suitable lubricant, such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol or sodium lauryl sulfate. The content of the lubricant in the tablet core is 0.5%-10% (mass percentage) of the total weight of the tablet core, and can be selected as 1%-5%.

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

Appropriately, a colorant can be added to the tablet core to ensure that the tablet core is accurately positioned in the coating to ensure that the tablet has an appropriate coating thickness, so that the delay time is reproducible, thereby avoiding intra-subject and inter-patient differences in bioavailability. Appropriate colorants can be iron oxide, titanium dioxide, iron hydroxide, etc. The selection of colorants is not limited to the scope of this disclosure. The content of the colorant is 0.1%-3% of the total weight of the tablet core, and can be selected as 0.4%-1%.

The febuxostat tablets provided in the present disclosure provide an initial diameter sufficient to prevent gastric retention in the fed state, for example, tablets with a diameter of about 12-18 mm can generally resist through the pyloric sphincter in the fed state. Specifically, the initial maximum diameter of the febuxostat package core of the present disclosure can be 12-16 mm, and can be 13-15 mm.

In an optional embodiment, the Febuxostat tablets provided in the present disclosure are gastric retention tablets.

In the disclosure, the tablet core has a relatively low hardness, which ensures that the tablet core can expand after the water medium contacts the tablet core, so that the outer coating layer can be better broken. The hardness of the tablet core is 10-120N, and 20-60N can be selected. In order to ensure the mechanical stability of the tablet core, so that it is sufficient to resist the pressure generated by the stomach, especially when there is food, to ensure that the integrity of the outer coating layer is not destroyed, the hardness of the tablet is controlled at 30-250N, and 70-180N can be selected. In the disclosure, the release of febuxostat from the tablet core is not the result of the drug diffusing through the expanded coating material, but the result of the physical rupture of the coating.

In an optional embodiment, the febuxostat tablets provided in the present disclosure have a sustained-release effect.

In an optional embodiment, the present disclosure provides a fast-release component of a Febuxostat tablet as a fast-release drug-containing coating layer.

In an optional embodiment, the fast-release drug-containing coating layer of febuxostat contains the active drug febuxostat and a coating material, and the coating material can be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, gastric soluble opadyl, gastric soluble opadyl, or opadyl (03K180007-CN).

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 the content of febuxostat in the unit dosage form of Fibril, which can be 1.2-1.6 times, or 1.5 times. Specifically, for example, if the content of a single tablet of commercially available febuxostat is 20 mg, the content of the unit tablet of febuxostat provided by the present disclosure is 30 mg, and if the content of a single tablet of commercially available febuxostat is 40 mg, the content of the unit tablet of febuxostat provided by the present disclosure is 60 mg. The increased drug dosage increases the rate of achieving the target of uric acid reduction, thereby reducing the frequency of gout attacks and ensuring the efficacy.

In an optional embodiment, the amount of febuxostat in the unit dosage form of the febuxostat tablet provided by the present disclosure is 10 mg-200 mg, optionally 20 mg-150 mg, and the optional amount of febuxostat is 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 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 immediate release component to the active substance in the tablet core is 1:10-10:1, and 1:5-5:1 is optional.

In an optional embodiment, the Febuxostat tablet contains the following ingredients:

Chip

Febuxostat

Lactose 50%-65% (mass percentage);

Microcrystalline cellulose 10%-25% (mass percentage);

Cross-linked sodium carboxymethyl cellulose 8%-15% (mass percentage);

Hydroxypropyl cellulose 1-5% (mass percentage);

Hydroxypropyl methylcellulose 3%-8% (mass percentage);

Magnesium stearate 1%-5% (mass percentage), based on the total weight of the tablet core;

Coating layer

Eudragit RSPO 15%-25% (mass percentage);

Eudragit RLPO 45%-55% (mass percentage);

Kollidon ^® SR 15%-25% (mass percentage);

Hydroxypropyl methylcellulose 8%-15% (mass percentage), based on the total weight of the coating layer.

In an optional implementation scheme, the active substance content in the Febuxostat tablet is 30 mg, wherein the content ratio of the immediate-release drug-containing coating layer to the active substance in the tablet core is 1:10-10:1, optionally 1:5-5:1, optionally 1:2-1:1, or optionally 2:3.

In the optional implementation scheme, the active substance content in the Febuxostat tablet is 60 mg, wherein the content ratio of the immediate-release drug-containing coating layer to the active substance in the tablet core is 1:10-10:1, optionally 1:5-5:1, optionally 1:3-1:1, or optionally 3:7.

Optionally, there is a separation layer between the coating layer and the febuxostat immediate-release layer. The separation layer is a thin layer of polymer material, forming a film-like coating layer, which increases the tablet weight by 1%-50% (mass percentage), and can be selected as 2%-4%.

The material of the isolation layer can be selected from one or more of hydroxypropyl methylcellulose, povidone, copovidone, hydroxypropyl cellulose and gastric soluble opadyl, gastric soluble opadyl or gastric soluble opadyl (YS-1-7027-CN).

The Febuxostat tablets provided in this disclosure can release the active substance Febuxostat in a predetermined delayed time period to achieve a controlled release effect. The coating layer can be broken after being immersed in an aqueous medium for at least 1 hour to release the active substance. It can be broken after 1.5 hours or after 2 hours. The coating layer of the tablet provided in this disclosure can break in an aqueous medium for no later than 4 hours. The investigation of the coating layer's breaking time in an aqueous medium in this disclosure refers to the results of the investigation in 500 mL of pH 4.5 PBS-0.5% SDS medium using a paddle method at 50 rpm.

6小時時發生破裂，釋放活性物質，可選為

5小時破裂，可選的

4小時破裂。本揭露中所述的包衣層在黏性介質中破裂時間的考察是指採用籃法75rpm，500mL pH4.5 PBS-2.5% HPMC K100LV介質中實驗2h，再更換至500ml 0.1MHCl-3%HPMC E5LV介質中繼續實驗，考察在黏性介質中破裂時間。 For a given active drug, if the drug can be delivered almost completely to a specific absorption window in a controllable manner, or the release rate can be preferentially avoided or reduced in areas of the gastrointestinal tract where the degradation or metabolism of the active drug is high, in addition, delivering the active drug to the absorption window can increase the efficacy of the drug and/or reduce or eliminate side effects. Considering this aspect, if the coating layer breaks too late, the absorption window may be missed. The coated core provided in the present disclosure has a coating layer that can be immersed in a viscous medium for a period of time.

6 hours after the rupture occurs, releasing the active substance, optional

5 hours rupture, optional

The investigation of the coating layer rupture time in a viscous medium described in this disclosure refers to the use of a basket method at 75 rpm, 500 mL pH 4.5 PBS-2.5% HPMC K100LV medium for 2 hours, and then changing to 500 ml 0.1 M HCl-3% HPMC E5LV medium to continue the experiment, and investigate the rupture time in the viscous medium.

The coating layer described in this disclosure is subjected to the dissolution and release test method (Chinese Pharmacopoeia 2015 Edition Part Four General Rules 0931 Second Method), using 500ml of 2.5% HPMC K100LV-pH6.0 phosphate buffer as the dissolution medium, the temperature is 37±0.5℃, the rotation speed is 150 revolutions per minute, and after 4 hours, the medium in each dissolution cup is discarded, and 900ml of pH6.8 phosphate buffer preheated to 37±0.5℃ is added to each dissolution cup, the rotation speed remains unchanged, and the operation is continued according to the law, and it ruptures in 3-5 hours.

In this disclosure, the amount of the core tablet released during the extended time period is no more than about 10% of the total amount of febuxostat in the core tablet, which should be understood as the core tablet releasing substantially no drug, and the core tablet releases all or substantially all of the febuxostat in a very short time after the extended time expires, specifically, within 1 hour after the coating layer is ruptured, the amount of febuxostat released from the core tablet is more than 65% of the total amount of febuxostat in the core tablet, and can be selected as more than 70%, or more than 75%.

In an optional implementation, the Febuxostat tablets provided by the present disclosure have a substantially equivalent AUC (geometric mean) to that of Febuxostat, and significantly prolong the maintenance time of effective blood drug concentration and improve effectiveness, wherein substantially equivalent means that the AUC ratio is in the range of 85%-135%.

The Febuxostat tablets provided in this disclosure significantly prolong the maintenance time of effective blood drug concentration and reduce the Cmax value, which is safer.

100ng/ml的維持時間是受試者一日一次服用菲布力的1-3倍，可選為1.25-2.0倍。 Febuxostat tablets provided in this disclosure, blood drug concentration (geometric mean) of subjects taking Febuxostat tablets provided in this disclosure once a day

The maintenance time of 100ng/ml is 1-3 times that of the subjects taking Februa once a day, and can be 1.25-2.0 times.

100ng/ml的維持時間至少為10小時，可選至少為12小時，可選至少為15小時。 The febuxostat tablets provided in this disclosure, after the subjects ate a medium-fat dinner, the blood drug concentration

The maintenance time of 100 ng/ml is at least 10 hours, optionally at least 12 hours, and optionally at least 15 hours.

For the Febuxostat tablets provided in this disclosure, the time for the blood drug concentration of the subjects to recover after taking the drug is 2-5 hours after taking the drug, and 3-4 hours is optional.

The febuxostat tablets provided in this disclosure have a break-down time in the subject's body of 2-5 hours after taking the drug, and can be optionally 3-4 hours.

The present disclosure provides a use of the above-mentioned febuxostat tablets in the preparation of drugs for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure.

This disclosure provides a method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiomegaly, hypertension, nephrolithiasis, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure, by administering the Febuxostat tablets provided by this disclosure to the patient.

The present disclosure provides a method for preparing the above-mentioned Febuxostat tablets, which comprises the following steps: granulating Febuxostat and an optional tablet core excipient into first granules; making the first granules into tablet cores; granulating the coating layer excipients into second granules; compressing the second granules to coat the tablet cores; and coating the immediate release layer.

In an optional embodiment, the method comprises the following steps: granulating Febuxostat with a filler, a binder, and a portion of a disintegrant, and mixing the mixture with the hydrophilic gel matrix material, the remaining disintegrant, and the lubricant in the tablet core to form a tablet core; granulating a coating layer auxiliary material containing a base material, a water-insoluble plasticizer, and a hydrophilic gel matrix material; pressing a core tablet; and coating a quick-release layer.

In an optional embodiment, the method comprises the following steps: granulating febuxostat with lactose, microcrystalline cellulose, hydroxypropyl cellulose and part of cross-linked sodium carboxymethyl cellulose, and then mixing with hydroxypropyl methyl cellulose, the remaining cross-linked sodium carboxymethyl cellulose and magnesium stearate to form tablet cores; granulating Eudragit RSPO, Eudragit RLPO, behenic acid glyceride and part of hydroxypropyl methyl cellulose, and then mixing with ^Kollidon® SR and the remaining hydroxypropyl methyl cellulose to form core tablets; and coating the quick-release layer.

In an optional embodiment, the method comprises the following steps: granulating febuxostat with lactose, microcrystalline cellulose, hydroxypropyl cellulose and part of cross-linked sodium carboxymethyl cellulose, and then mixing with hydroxypropyl methyl cellulose, remaining sodium cross-linked carboxymethyl cellulose and magnesium stearate to form tablet cores; granulating Eudragit RSPO, Eudragit RLPO, behenic acid glyceride and part of hydroxypropyl methyl cellulose, and then mixing with ^Kollidon® SR and remaining hydroxypropyl methyl cellulose to form tablet cores; coating with an omega-3 isolation layer; and coating with an omega-3 immediate-release layer.

Optionally, the method for preparing febuxostat tablets includes a film coating step after completing the preparation of the core tablets.

The present disclosure provides a method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiomegaly, hypertension, nephrolithiasis, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure, wherein a febuxostat tablet containing 30 mg of febuxostat or a febuxostat tablet containing 60 mg of febuxostat is administered to the patient after a medium-fat dinner, once a day.

100ng/ml的維持時間至少為10小時。 The present disclosure provides a method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiomegaly, hypertension, nephrolithiasis, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure. After a medium-fat dinner, a febuxostat tablet containing 30 mg of febuxostat is given to the patient, and the average blood drug concentration is

The maintenance time of 100ng/ml is at least 10 hours.

100ng/ml的維持時間至少為15小時。 The present disclosure provides a method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiomegaly, hypertension, nephrolithiasis, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure. After a medium-fat dinner, a febuxostat tablet containing 60 mg of febuxostat is given to the patient, and the average blood drug concentration is

The maintenance time of 100ng/ml is at least 15 hours.

100ng/ml的維持時間至少為18小時。 In some embodiments, a febuxostat tablet containing 60 mg of febuxostat is administered to a patient after a moderate-fat meal, and the mean blood concentration is

100 ng/ml is maintained for at least 18 hours.

X, Y: axis

Figure 1 is a schematic diagram of the package chip and the X-axis and Y-axis;

Figure 2 is a schematic diagram of the chip package rupture;

Figure 3 shows the in vitro dissolution curves of two batches of 30mg samples;

Figure 4 shows the in vitro dissolution curves of two batches of 60mg samples;

Figure 5 is the average drug concentration-time logarithmic graph of Beagle dogs after a single oral administration of 60mg*4 febuxostat sustained-release tablets or 40mg*4 febuxostat tablets (full stomach, drug administration 1 hour after feeding).

Figure 6 is a schematic diagram of the small opening for chip packaging.

The following is a further detailed description of the contents of this disclosure through specific examples, but this should not be understood as the scope of the above-mentioned subject matter of this disclosure being limited to the following examples.

Example 1, Preparation of Febuxostat Tablets (Prescription 1)

1. Preparation method:

1) Chip preparation (2000 pieces)

Accurately weigh various raw materials and auxiliary materials according to the prescribed amount, weigh the prescribed amount of binder hydroxypropyl cellulose (SL), add it to the weighed purified water under stirring to prepare a 5% aqueous solution, mix the prescribed amount of febuxostat, microcrystalline cellulose (MCC Type 101), lactose, cross-linked carboxymethyl cellulose sodium (CC-Na), and yellow ferric oxide in a fluidized bed, use the prescribed amount of hydroxypropyl cellulose (SL) 5% solution as a binder, granulate, and dry. Add the granules after granulation and the excipients calculated according to the yield, cross-linked carboxymethyl cellulose sodium and magnesium stearate, into a mixing tank for mixing, and use a STYL’One single punch tablet press (10.0mm shallow concave punch, R=24.75mm) for tableting. The tablet hardness is controlled to be 20-60N.

2) Preparation of outer layer

Weigh the prescribed amount of Hydroxypropyl Methylcellulose E5LV and add it to purified water under stirring to prepare a 5% aqueous solution. Place the prescribed amount of Eudragit RSPO, Eudragit RLPO, and Behenic Acid Glyceryl in a fluidized bed and use a 5% solution of HPMC E5LV as a binder. Granulate and dry. After converting the yield, add the additional excipients Kollidon ^® SR and HPMC E5LV into a mixing tank for total mixing.

3) Package chip preparation

The tablets were pressed using a STYL’One single punch tablet press (14.0mm shallow concave punch, R=24.75mm) with a theoretical lower filler of 305mg and an upper filler of 205mg. The theoretical total weight of the tablets was 746mg, the tablet weight variation was controlled within ±3%, and the tablet hardness was controlled at 170-230N.

4) Isolation layer coating

Prepare a 10% concentration of Opadry (YS-1-7027-CN) aqueous solution as the coating material and as the isolation layer coating liquid.

5) Quick-release coating

Weigh the prescribed amount of purified water, slowly add Opadry (03K180007-CN) and stir for 45 minutes, then add Febuxostat to prepare a solution with a solid content of 12%. Stir until evenly dispersed and use it as the coating solution for the immediate release layer.

2. Data of central control after opening the cover of the chip-wrapped plain tablet (without isolation layer and quick-release layer)

In order to ensure that the chip is opened within a certain time in vivo, the in vitro opening time is controlled. The opening time of the chip is affected by the water absorption rate of the core, so the viscosity of the medium has a greater impact on the opening time. The opening time is faster in aqueous media and slower in viscous media. In order to prevent the chip from opening too early and failing to delay release, the opening time in the aqueous medium pH4.5PBS-0.5%SDS was investigated; in order to prevent the chip from opening too late and missing the absorption window, the opening time in the viscous medium pH4.5PBS-2.5%HPMC K100LV (simulating the viscosity and pH of saturated gastric juice) + 0.1MHCl-3%HPMC E5LV (simulating the viscosity and pH of gastric juice after gastric emptying) was investigated.

2.1 Dissolution test in aqueous media

2.2 Dissolution test in viscous media

The experiment was conducted in 500ml pH4.5PBS-2%HPMC K100LV medium at 75rpm using the basket method for 2h, and then changed to 500ml 0.1MHCl-3%HPMC E5LV medium to continue the experiment. The opening time in the viscous medium was investigated, and the chip package was stopped every 30min after the medium was changed to observe the package.

2.3 In vitro dissolution data of finished Febuxostat tablets:

According to the dissolution and release test method (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 0931 Second Method), use 500 ml of 2.5% HPMC K100LV-pH6.0 phosphate buffer as the dissolution medium, the temperature is 37±0.5℃, the rotation speed is 150 revolutions per minute, and operate according to the law. Take 5 ml of the dissolution solution after 1h, 2h, 3h, and 4h respectively, filter, and take the filtered solution as the test solution. At the same time, add the same volume of dissolution medium at the same temperature for 1h, 2h, and 3h. After 4 hours, discard the medium in each dissolution cup, and then add 900 ml of pH 6.8 phosphate buffer preheated to 37±0.5℃ to each dissolution cup. Keep the rotation speed unchanged and continue to operate according to the law. Take 5 ml of dissolution solution after 0.5h, 1h, 1.5h, and 2h, filter, and take the filtered solution as the test solution. At the same time, add the same volume of dissolution medium at the same temperature, and determine the cumulative dissolution amount (%) by high performance liquid chromatography.

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

3. Measurement of outer layer thickness

After measurement, the thickness of the outer layer of 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 layer in the X-axis direction is about 2mm.

Example 2, Animal Drug Metabolism Kinetics (PK) Results

This experiment adopted a two-cycle crossover experimental design. Twelve male Beagle dogs were divided into two groups and gavaged with 240mg (60mg*4 tablets) of Febuxostat tablets and 160mg (40mg*4 tablets) of Febuxostat tablets (Febuxostat) respectively. The drug concentration-time variation process in Beagle dogs was compared to study the pharmacokinetic behavior of the two.

After a single oral administration of 240 mg of the test article febuxostat tablets to Beagle dogs, the blood drug concentration first reached a lower peak value of about 2180 ng/mL at about 0.5 h, then decreased, and increased again at 2.00 h, reaching a higher blood drug concentration peak of about 4490 ng/mL at about 4 h, and then the blood drug concentration gradually decreased with time. The overall peak concentration Cmax was 5340±2350 ng/mL, and the peak time Tmax was 4.00[0.500,4.00] h. The area under the drug concentration-time curve AUC _{INF_obs} was 19100±8960h*ng/mL, and the total time when the blood drug concentration was higher than 100ng/mL (Time _High) was 12.3±4.88h

After a single oral administration of 160 mg of the control substance Febuxostat tablets (Febuxostat) to Beagle dogs, the blood drug concentration peaked at around 1.00 [0.250, 1.00] h, and then the blood drug concentration gradually decreased with time, reaching a peak concentration Cmax of 6930 ± 3290 ng/mL. The area under the drug concentration-time curve AUC _{INF_obs} was 15700 ± 7680 h*ng/mL, and the total time Time _High when the blood drug concentration was higher than 100 ng/mL was 9.86 ± 5.00 h, as shown in Figure 5.

When Beagle dogs were given 240 mg of the test substance Febuxostat tablets by oral gavage, compared with 160 mg of the control substance Febuxostat tablets (Febuli) by oral gavage, under the condition of equivalent drug system exposure, the Febuxostat sustained-release tablets showed obvious double absorption peaks, Cmax was significantly reduced, and the total time that the average blood drug concentration was maintained at the effective blood drug concentration (>100ng/mL) was 1.25 times that of the control substance Febuxostat tablets, indicating that the Febuxostat tablets have a longer duration of efficacy and better safety in clinical practice.

Example 3, Preparation of Febuxostat Tablets (Prescription 2)

製備工藝參考處方1。

Preparation process reference recipe 1.

Example 4: Drug Metabolism Kinetics Study of Prescription 2 in Healthy Human Body

4.1 Research Purpose

1) To investigate and compare the pharmacokinetic characteristics and relative bioavailability of a single oral dose of febuxostat tablets (large size: 60 mg, N=12, after a medium-fat dinner) developed by Jiangsu Hengrui Pharmaceutical Co., Ltd. and febuxostat tablets (size: 40 mg, N=40, in the morning on an empty stomach) produced by Teijin Pharma Co., Ltd. in healthy Chinese adult subjects.

100ng/ml)的維持時間均比早上空腹的R製劑顯著延長。 The results suggest that the effective concentration of T preparation (blood concentration) after a medium-fat dinner

100ng/ml) was maintained for a significantly longer time than that of the R preparation taken on an empty stomach in the morning.

Comparative Example 1.

The prescription in Table 7 was prepared according to the preparation method of Example 1, and the opening time was observed in 500 ml of pH 4.5 PBS-0.5% SDS medium using a paddle at 50 rpm.

The outer coating of the chip prepared by the above prescription was severely eroded in an aqueous medium and broke within 1 hour, making it difficult to maintain rigidity and integrity.

X, Y: axis

Claims (30)

A tablet core comprises a tablet core containing the active drug febuxostat, and a coating layer coated on the tablet core, wherein the tablet core is located in the coating layer, and the thickness of the coating layer on both sides of the tablet core in the Y-axis direction is at least one side less than the thickness of the coating layer in the X-axis direction, wherein the coating layer contains at least one base material, at least one hydrophilic gel skeleton material and 1% to 10% behenic acid glyceryl ester, wherein the base material is a combination of polymethacrylic acid polymer, polyvinyl acetate and a mixture of polyvidone, and the hydrophilic gel skeleton material is selected from hydroxypropyl methylcellulose, and the coating layer is prepared by a method of compression coating after granulation. The chip package as described in claim 1, wherein the maximum diameter of the chip package is 12-16 mm. The chip package as described in claim 1, wherein the maximum diameter of the chip package is 13-15 mm. A chip package as described in claim 1, wherein the polymethacrylic acid polymer is selected from Eudragit RLPO and Eudragit RSPO, and the polyvinyl acetate and polyvidone mixture is selected from Kollidon ^® SR. The coated core tablet as described in claim 4, wherein the content of Eudragit RLPO and Eudragit RSPO in the coating layer is 50%-90% of the total weight of the coating layer, and the content of Kollidon ^® SR is 5%-40% of the total weight of the coating layer. The coated core tablet as described in claim 5, wherein the content of Eudragit RLPO and Eudragit RSPO in the coating layer is 60%-85% of the total weight of the coating layer. The coated core tablet as described in claim 6, wherein the content of Eudragit RLPO and Eudragit RSPO in the coating layer is 65%-75% of the total weight of the coating layer. The core tablet as described in claim 5, wherein the content of ^Kollidon® SR in the coating layer is 15%-25% of the total weight of the coating layer. The coated core tablet as described in claim 5, wherein the content of Eudragit RSPO in the coating layer is 5%-40% of the total weight of the coating layer. The coated core tablet as described in claim 9, wherein the content of Eudragit RSPO in the coating layer is 10%-30% of the total weight of the coating layer. The coated core tablet as described in claim 10, wherein the content of Eudragit RSPO in the coating layer is 15%-25% of the total weight of the coating layer. The coated core tablet as described in claim 5, wherein the content of Eudragit RLPO in the coating layer accounts for 20%-80% of the total weight of the coating layer. The coated core tablet as described in claim 12, wherein the content of Eudragit RLPO in the coating layer accounts for 30%-70% of the total weight of the coating layer. The coated core tablet as described in claim 13, wherein the content of Eudragit RLPO in the coating layer accounts for 45%-55% of the total weight of the coating layer. The core tablet as claimed in any one of claims 1 to 14, wherein the core tablet further contains at least one forming agent selected from a disintegrant, a filler, a binder, a lubricant, and a colorant; the disintegrant is selected from cross-linked sodium carboxymethyl cellulose, dry starch, low-substituted hydroxypropylmethyl cellulose, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone; the filler is selected from a water-soluble filler and/or a water-insoluble filler, wherein the water-soluble filler is selected from lactose, mannitol, sucrose, and sorbitol, and the water-insoluble The filler is selected from starch, microcrystalline cellulose, calcium sulfate, and calcium hydrogen phosphate; the binder is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, trehalose, and branched starch; the lubricant is selected from colloidal silica, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearate fumarate, polyethylene glycol, or sodium lauryl sulfate; the colorant is selected from iron oxide, titanium dioxide, and iron hydroxide. The core tablet as described in claim 15, wherein the disintegrant is selected from cross-linked sodium carboxymethyl cellulose; the filler is selected from a combination of lactose and microcrystalline cellulose; the binder is selected from hydroxypropyl cellulose; the lubricant is selected from magnesium stearate; and the colorant is selected from iron oxide. A febuxostat tablet, comprising a core package as described in any one of claims 1 to 16, and also comprising an immediate-release component of febuxostat. As described in claim 17, the Febuxostat tablets contain a fast-release drug-containing coating layer of Febuxostat outside the coating layer of the core tablet. As described in claim 18, the coating material of the rapid-release drug-containing coating layer is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and gastric-soluble opadyl. As described in claim 19, the coating material of the rapid-release drug-containing coating layer is selected from gastric-soluble Opadry. As described in claim 20, the coating material of the rapid-release drug-containing coating layer is selected from Opadry (03K180007-CN). The febuxostat tablets as described in claim 17, wherein the sustained/controlled release tablets contain the following ingredients: a core of febuxostat lactose 50%-65%; microcrystalline cellulose 10%-25%; cross-linked sodium carboxymethyl cellulose 8%-15%; hydroxypropyl cellulose 1-5%; magnesium stearate 1%-5%, based on the total weight of the core; a coating layer of Eudragit RSPO 15%-25%; Eudragit RLPO 45%%-55%; Kollidon ^® SR 15%-25%; and hydroxypropyl methylcellulose 8%-15%, based on the total weight of the coating layer. A use of the febuxostat tablets as described in any one of claims 17 to 22 in the preparation of a drug for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, QT interval prolongation, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic renal disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure. The packaged core as described in claim 1, wherein the core also contains a hydrophilic gel skeleton material, the content of which accounts for 1%-20% of the total weight of the core. The packaged core as described in claim 24, wherein the content of the hydrophilic gel skeleton material of the core accounts for 2%-10% of the total weight of the core. As described in claim 25, the core chip contains a hydrophilic gel skeleton material that accounts for 3%-8% of the total weight of the core. The core chip as described in claim 24, wherein the hydrophilic gel skeleton material of the core is selected from cellulose derivatives, non-cellulose polysaccharides, natural gums, vinyl polymers or acrylic polymers; the cellulose derivatives can be selected from methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and sodium hydroxymethylcellulose; the non-cellulose polysaccharide is selected from glucose, chitosan, deacetylated chitosan and galactomannan; the natural gum is selected from pectin, sodium alginate, potassium alginate, agar, carrageenan, locust bean gum, and safflower gum. The chip package as described in claim 27, wherein the hydrophilic gel skeleton material of the chip core is selected from cellulose derivatives. The chip package as described in claim 27, wherein the hydrophilic gel skeleton material of the chip core is selected from hydroxyethyl methylcellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. The chip package as described in claim 27, wherein the hydrophilic gel skeleton material of the chip core is selected from hydroxypropyl methylcellulose.

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