CN113476421B

CN113476421B - Controlled release composition of febuxostat and preparation method thereof

Info

Publication number: CN113476421B
Application number: CN202110747579.8A
Authority: CN
Inventors: 王立坤; 王捷; 马爱明; 钱雯
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2017-12-29
Filing date: 2018-12-28
Publication date: 2023-04-07
Anticipated expiration: 2038-12-28
Also published as: CN109985016A; CN109985016B; CN113476421A

Abstract

The invention provides a febuxostat controlled release composition and a preparation method thereof. Specifically, the febuxostat controlled-release composition contains at least one outer coating layer of a matrix forming agent which swells when meeting water, and after the composition is retained in the stomach for at least 4 hours, a tablet core expands to ensure that the outer coating layer is broken to release medicine. The composition provided by the invention can effectively reduce the peak value of the drug concentration in blood plasma, prolong the effective drug action time, reduce side effects and improve the compliance of patients.

Description

Controlled release composition of febuxostat and preparation method thereof

The application is a divisional application of Chinese patent application with the application number of 201811616607.7, the application date of 2018, 12 and 28 months, and the invention is named as 'a controlled release composition of febuxostat and a preparation method thereof'.

Technical Field

The invention relates to a controlled release composition of febuxostat and a preparation method thereof, belonging to the field of pharmacy.

Background

The chemical name of Febuxostat (Febuxostat) is 2- [ (3-cyano-4-isobutoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid of the formula C ₁₆ H ₁₆ N ₂ O ₃ S, the molecular weight is 316.374, and the structural formula is as follows:

the febuxostat common tablet is marketed in the Japanese application 2004 by the company of Kitiu in Japan as a new generation of effective non-purine selective inhibitor of xanthine oxidase, can selectively inhibit Xanthine Oxidase (XO), reduces the uric acid level in the blood of patients with hyperuricemia gout, treats gout, has the plasma protein binding rate of 99.3 percent, vd of 33-66L, is mainly metabolized into glucuronide in the liver, is partially oxidized and metabolized in the form of prototype drug, and t is _1/2 The CL is 10 to 20L/h for 5 to 8 hours.

Febuxostat has the major side effect of gout attacks during treatment, with associated liver dysfunction, nausea, arthralgia, and rash. Clinical data show that febuxostat is associated with a higher probability of cardiovascular thromboembolic events, even death, during treatment. According to the related research results, the febuxostat concentration is more than 100ng/ml, the uric acid inhibition level of more than 80% can be maintained, and the febuxostat is mainly absorbed in the small intestine, the bioavailability of the proximal small intestine is 96.63%, the bioavailability of the distal small intestine is 84.05%, and the bioavailability of the colon is 34.75%, so that the bioavailability of the common sustained-release preparation is low. However, currently marketed febuxostat is a common quick-release tablet, which can be rapidly disintegrated and absorbed after being taken, and the blood concentration can be rapidly increased, but febuxostat can be rapidly cleared and the effective blood concentration (> 100 ng/ml) can be quickly maintained, so that the compliance of a patient is poor, the incidence rate of adverse reactions is increased, and the clinical use of febuxostat is limited.

CN103210084A discloses a modified release pharmaceutical composition comprising immediate release febuxostat (febuxostat) beads and delayed release febuxostat beads, wherein the inert core and the drug containing layer of the delayed release fraction are coated by an enteric polymer layer, the delayed release fraction having a solubility at a pH level greater than or equal to 6.8 and providing febuxostat over a period of 4-6 hours. CN102641255A discloses an osmotic pump controlled release tablet of febuxostat, which achieves the purpose of prolonged release. CN101773498B discloses a method for preparing an oral sustained and controlled release preparation containing febuxostat, wherein the sustained and controlled release preparation is a skeleton type tablet or capsule, and the sustained and controlled release skeleton is one or a mixture of several of hypromellose, polyoxyethylene and alginate. CN101658505A discloses a sustained release preparation of febuxostat, which comprises a quick release part and a sustained release part, and the in vitro dissolution of the preparation is 12h and the release is more than 90% when the preparation is measured in 900ml pure water at 37 ℃ at 100rpm by adopting a rotating basket method.

The oral gastric retention preparation prolongs the retention time of the drug at the upper ends of the stomach and the small intestine, thereby generating higher bioavailability, improving the treatment effect, reducing the administration frequency and dosage and improving the compliance of patients, therefore, the oral gastric retention preparation is widely used in the pharmaceutical field.

US8968779B discloses a controlled release core-coated tablet of febuxostat, the controlled release layer is a mixture of gel material and non-febuxostat, the tablet core is a quick release part of febuxostat, the controlled release layer is eroded in digestive juice to release drug, but the controlled release core-coated tablet is not a gastric retention preparation.

World Journal of Pharmaceutical Research, 2015,4 (1): 1063-1082 discloses a gastric retentive tablet of febuxostat, which is obtained by tabletting a preparation using hydroxypropyl methyl cellulose (HPMC) K4M of a hydrophilic gel matrix and sodium carbonate as an effervescent agent and other auxiliary materials, wherein the drug release rate of the febuxostat tablet obtained by the method does not change with time, i.e., the release rate is kept constant during the drug release period, and studies have shown that febuxostat needs to maintain a blood concentration of 100ng/ml to provide a xanthine oxidase inhibitor of 95% or more, and therefore it is not known whether the tablet prepared by the method can provide a blood concentration of more than 100ng/ml immediately after a patient takes a drug to achieve a therapeutic effect.

Since the existing immediate release preparation of febuxostat cannot meet the requirement of medication, and the sustained release preparation has not been developed in a breakthrough manner, the field is eager for a new dosage form of febuxostat with improved release rate.

Disclosure of Invention

The invention provides a controlled release composition of febuxostat, which prolongs the retention time of a medicament in the stomach, thereby prolonging the transportation of the medicament in the whole gastrointestinal tract, improving the maintenance time of effective blood concentration and reducing side effects.

The invention provides a controlled release composition of febuxostat, which comprises a) a drug-containing tablet core; b) An outer cover, characterized in that the outer cover does not contain active substances and contains at least one matrix forming agent which swells when encountering water, and the outer cover is kept intact for at least 4 hours in a gastric juice or simulated gastric juice environment and then is broken to release the drug; the composition is swellable to a size sufficient for gastric retention in the fed mode.

The controlled release composition of febuxostat is characterized in that when the soaking time of the composition in gastric juice or simulated gastric juice is less than 4h, the drug release amount is less than 10%, preferably less than 5%, and most preferably less than 2%; the soaking time is more than 4h, preferably more than 5h, specifically 5-12h, 6-10h, 7-11h, 8-10h, the drug release amount is more than 75%, preferably more than 85%, most preferably more than 95%.

In the invention, when the soaking time is less than 4 hours, the release amount is less than 10 percent, which means that the controlled release composition does not release drug basically for at least 4 hours. The soaking time is more than 4 hours, the medicine release amount is more than 75%, and the medicine release requirement can be met as long as the soaking time is more than 75% at any time point after 4 hours, such as 5 hours, 5.5 hours and 6 hours; the soaking time is defined as an interval, such as 5-12h, and means that the drug release amount is greater than 75% at any time point, such as 5h, 6h and 7h, in the interval.

The febuxostat controlled-release composition provided by the invention can rapidly absorb water in gastric juice or simulated gastric juice environment, and is specifically characterized in that the controlled-release composition swells to the maximum size within 5-120min, preferably swells to the maximum size within 5-60 min.

The controlled release composition of febuxostat is characterized in that the outer coating layer further contains at least one gel.

The invention provides a controlled release composition of febuxostat, which comprises a) a drug-containing tablet core and b) an outer coating layer, and is characterized in that the outer coating layer does not contain active substances and contains at least one matrix forming agent capable of swelling in water.

Further, the outer coating layer of the controlled release composition of febuxostat provided by the invention also contains at least one gel.

The outer coating of the controlled release composition of febuxostat provided by the invention is insoluble in digestive fluid in the stomach, but can swell by absorbing water and maintain the integrity of the composition, and is helpful for controlling the release rate of the drug. The matrix forming agent is selected from ethyl acrylate-methyl methacrylate-trimethyl aminoethyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethyl cellulose, cellulose acetate, chitosan, galactomannan, sodium alginate, agar, tragacanth, xanthan gum, pectin, guar gum, gelatin, gum arabic, carrageenan, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, carboxyvinyl polymer, glyceryl behenate, hydrogenated castor oil, cetyl alcohol, carnauba wax, preferably ethyl acrylate-methyl methacrylate-trimethyl aminoethyl methacrylate copolymer.

The controlled release composition of febuxostat is characterized in that the matrix forming agent in the outer coating layer accounts for 40-95%, preferably 60-90%, most preferably 75-85% of the total weight of the outer coating layer, and specific values can be 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84% and 85% (except for special description in the invention, the percentage contents are mass percentages).

The controlled release composition of febuxostat provided by the invention is characterized in that a non-limiting example of the copolymer of ethyl acrylate-methyl methacrylate-trimethylammoniochloride methacrylate comprises

RLPO、

RSPO、/>

RL100、/>

RS100。

The gel in the outer coating layer of the controlled release febuxostat composition provided by the invention is a water-soluble polymer which swells and gels when contacting with water, on one hand, the gel expands when contacting with water, on the other hand, the gel fills the pore diameter generated by the expansion of the matrix forming agent in the outer coating layer when contacting with water, and is gradually eroded after contacting with water and maintaining for a period of time, and then the outer coating layer is broken, so that the febuxostat in the tablet core is released, and an expected release curve is achieved.

In particular, the gelling agent in the outer wrapper is selected from ethyl cellulose, methyl ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate butyrate, cellulose propionate, hypromellose phthalate, hypromellose acetate succinate, hydroxypropyl methyl cellulose acetate trimellitate, ethyl hydroxyethyl cellulose, preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, most preferably hydroxypropyl methyl cellulose.

In a preferred embodiment of the invention, the outer-coating gelling agent is hydroxypropylmethylcellulose, which is commercially available in a variety of forms, for example from Dow chemical company, USA

The E and the K of the hydroxypropyl methylcellulose can be selected from E3, E5, E6, E15, E50LV, E4M, E10M, K100LV, K4M, K15M, K100M and the like, different types correspond to different viscosities, and the test method of the viscosity of the hydroxypropyl methylcellulose in the invention is 2 percent

(w/w) hydroxypropyl methylcellulose having a viscosity of from 5 mPa.s to 100000 mPa.s, as measured in an aqueous solution at 20 ℃, is within the scope of the present invention.

Other materials useful in the gelling agent of the present invention include, but are not limited to, pregelatinized starch, vinyl acetate povidone polymer matrix, polyvinyl pyrrolidone, sodium polyacrylate and polyoxyethylene (160) polyoxypropylene (30) glycol, polyethylene oxide, pullulan, polyvinyl alcohol, polyvinyl acetate, glyceryl fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid, and other acrylic acid derivatives such as butyl methacrylate, methyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) chloride methacrylate homopolymers and copolymers.

The controlled release composition of febuxostat is characterized in that the weight of the gel in the outer coating accounts for 1-30%, preferably 5-20%, most preferably 8-15% of the total weight of the outer coating, and specific values can be 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%.

The invention provides a controlled release group of febuxostatCompound, characterized in that the envelope further contains a binder selected from polyvinylpyrrolidone, a formulated mixture of polyvinyl acetate and polyvinylpyrrolidone, preferably a formulated mixture of polyvinyl acetate and polyvinylpyrrolidone. Non-limiting examples include

SR、

V64、/>

25、/>

30、/>

90F、/>

17PF、/>

12PF。

The controlled release composition of febuxostat is characterized in that the weight of the binder in the outer coating layer accounts for 1-30%, preferably 5-20%, most preferably 8-15% of the total weight of the outer coating layer, and specific values can be 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5% and 15.0%.

The outer coating layer of the controlled release composition of febuxostat optionally contains an enteric polymer, wherein the enteric polymer is selected from at least one of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, methyl cellulose phthalate, carboxymethyl ethyl ether cellulose, ethyl hydroxyethyl cellulose phthalate, methyl hydroxyethyl cellulose, styrene-acrylic acid copolymer, methacrylic acid copolymer, methyl acrylate-acrylic acid copolymer, acrylic acid-methyl methacrylate copolymer, butyl acrylate-styrene-acrylic acid copolymer, methyl acrylate-methacrylic acid-octyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyraldehyde phthalate and polyvinyl acetate acetal phthalate.

The controlled release composition of febuxostat is characterized in that the drug-containing tablet core contains one or more of disintegrant, gelling agent and floating auxiliary agent.

The controlled release composition of febuxostat is characterized in that a disintegrating agent in a drug-containing tablet core is selected from sodium carboxymethyl cellulose, croscarmellose sodium, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, partially pregelatinized starch, pregelatinized starch and crospovidone, preferably sodium carboxymethyl starch, partially pregelatinized starch, croscarmellose sodium and most preferably croscarmellose sodium.

The controlled release composition of febuxostat provided by the invention is characterized in that the content of the disintegrant in the drug-containing tablet core accounts for 5-70% of the total weight of the tablet core, and preferably 10-50%.

The controlled release composition of febuxostat is characterized in that the gel in the drug-containing tablet core is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, pregelatinized starch, sodium alginate, gelatin, agar, tragacanth gum, xanthan gum, guar gum, gum arabic, carrageenan, carboxyvinyl polymer, polyethylene oxide, vinyl acetate povidone polymer matrix, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, sodium polyacrylate and polyoxyethylene (160) polyoxypropylene (30) glycol.

The controlled release composition of febuxostat is characterized in that the floating auxiliary agent in the drug-containing tablet core is a combination of at least one acidic substance selected from citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, ascorbic acid and malic acid and at least one alkaline substance selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and calcium carbonate.

The controlled release composition of febuxostat is characterized in that the content of the non-butstat in the drug-containing tablet core accounts for 5-60%, preferably 10-45% and most preferably 15-35% of the total weight of the tablet core.

In one embodiment, the controlled release composition of febuxostat provided by the present invention comprises: a) A drug-containing core, b) an outer coating, said drug-containing core comprising a disintegrant; the outer coating does not contain active substances and contains at least one matrix forming agent capable of swelling in water and at least one gelling agent.

The invention also provides a controlled release composition of febuxostat, which further comprises a quick release component of febuxostat on the basis of the composition.

The controlled release composition of febuxostat is characterized in that a drug-containing tablet core and an outer cladding layer form a delayed release component.

The quick release component of the febuxostat controlled release composition can be added in a double-layer tablet tabletting mode, a core-spun tablet mode and a film coating mode, and the film coating mode is preferred.

The controlled release composition of febuxostat containing quick release component provided by the invention is characterized in that the release amount of the quick release component is more than 70%, preferably 80% and most preferably 90% of the total amount of the quick release component in the gastric juice or simulated gastric juice environment within 1 h.

In one embodiment of the invention, the controlled release composition containing the immediate release component is a multilayer tablet such as a trilayer tablet.

The controlled release composition of febuxostat containing quick release component is characterized in that the drug-containing tablet core and the outer cladding layer form a delayed release layer, and the febuxostat quick release component forms a quick release layer, so that the gastric retention double-layer tablet of febuxostat is formed.

The febuxostat controlled-release composition containing the quick-release component is characterized in that the release amount of the quick-release component is more than 70%, preferably 80% and most preferably 90% of the total amount of the quick-release component in a gastric juice or simulated gastric juice environment within 1 h; the delayed-release component is not released basically in 4 hours of immersion in gastric juice or simulated gastric juice, specifically, when the immersion time is less than 4 hours, the non-bestatin release amount in the delayed-release component is less than 10% (w/w), preferably less than 5%, and most preferably less than 2% of the total amount of the delayed-release component; after the soaking time is more than 4h, the outer coating is broken, the tablet core medicament is released suddenly, and the release amount of the non-bestatin in the delayed release component is more than 75 percent of the total amount of the release component medicament, preferably more than 85 percent, and most preferably more than 95 percent.

In the controlled release febuxostat composition containing the quick release component, the preferred embodiment of the controlled release febuxostat containing the quick release component is that the quick release component of febuxostat is coated on an outer coating layer in a coating form.

In a preferred embodiment of the present invention, the controlled release composition of febuxostat comprises the following components: a tablet core containing febuxostat and a disintegrating agent; an outer coating containing a mixture of ethyl acrylate-methyl methacrylate-chlorinated trimethanylethyl methacrylate copolymer, hydroxypropyl methylcellulose, polyvinyl acetate and polyvinylpyrrolidone; quick-release coating containing medicine.

In a preferred embodiment of the present invention, the controlled release composition of febuxostat comprises the following components: tablet core containing febuxostat and croscarmellose sodium

RLPO、/>

An outer cladding of RSPO, hydroxypropyl methylcellulose, kollidon SR; quick-release coating containing medicine.

The febuxostat controlled-release composition containing the quick-release component is characterized in that the weight ratio of active ingredients in the quick-release component to active ingredients in a tablet core is (1) 0.1-1, preferably 1.5-1.

The febuxostat controlled release composition containing the quick release component provided by the invention has the advantages that the total amount of febuxostat in a unit dosage form is 10-120mg, preferably 20-100mg, and most preferably 30-90mg. In a preferred embodiment of the invention, the content of febuxostat in the unit dosage form of the controlled release febuxostat composition containing the quick release component is 30mg, 40mg, 50mg, 60mg, 70mg, 80mg or 90mg, preferably 30mg or 60mg.

In a preferred embodiment of the invention, when the febuxostat immediate release component is coated on the outer coating layer in the form of a coating, the outer coating layer and the immediate release drug-containing layer further comprise an isolation layer therebetween.

The febuxostat controlled-release composition containing the quick-release component is characterized in that the material of the isolation layer is selected from one or more of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, povidone, acrylic resin and polyvinyl alcohol polyethylene glycol copolymer, and the hydroxypropyl methyl cellulose is preferred.

The controlled release febuxostat composition containing the quick release component is characterized in that the isolating layer and the quick release medicine-containing layer further comprise a plasticizer, and the plasticizer is selected from paraffin, corn oil, refined coconut oil, monoacetin, triacetin, glycerin, triethyl citrate, tributyl citrate, polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, glyceryl stearate, diethyl succinate, propylene glycol, castor oil and glyceryl triacetate, preferably triethyl citrate.

The controlled release composition of febuxostat is characterized in that the weight ratio of the isolation layer material to the plasticizer in the isolation layer is selected from the following components in parts by weight, namely 50-1.

The controlled release composition of febuxostat is characterized in that the weight gain of the isolation layer is 0.5-10%, preferably 1-5% and most preferably 1.5-3% of the total weight of the drug-containing tablet core and the outer wrapping layer. The febuxostat controlled release composition containing the quick release component is characterized in that when the quick release component of febuxostat is coated on an outer coating layer in a coating form, the quick release medicine-containing layer further comprises a binding agent, wherein the binding agent is selected from at least one of polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone starch, sucrose and dextrin, and is preferably hydroxypropyl methylcellulose.

The febuxostat controlled-release composition containing the quick-release component is characterized in that the weight ratio of the binder and the plasticizer of the quick-release component in the composition is selected from the following components in a ratio of 50.

The febuxostat controlled-release composition containing the quick-release component is characterized in that the weight of the quick-release layer is 2-10% of the total weight of a medicine-containing tablet core, an outer cladding layer and an isolation layer, and the weight is preferably 3-6%.

The controlled release febuxostat composition containing the quick release component is characterized in that the time for maintaining the plasma concentration of the febuxostat of more than 100ng/ml in vivo is 10h-24h, specifically about 10h, about 11h, about 12h, about 13h, about 14h, about 15h, about 16h, about 17h, about 18h, about 19h, about 20h, about 21h, about 22h, about 23h, about 24h, preferably 13-24h.

The drug-containing tablet core of the febuxostat controlled release composition provided by the invention further comprises a lubricant, wherein the lubricant is selected from any one or a combination of talcum powder, superfine silica powder, titanium dioxide, magnesium stearate, calcium stearate, zinc stearate, starch, polyethylene glycol 4000, polyethylene glycol 6000 and liquid paraffin, and magnesium stearate is preferred. The lubricant reduces friction between the granules and the die walls during compression and ejection, prevents the granules from sticking to tablet punches (tablets), facilitates their ejection from tablet punches, and the like. The content of the lubricant in the drug-containing tablet core of the febuxostat controlled-release composition is 0.01-5%, preferably 0.1-3%, and most preferably 1-2% of the total weight of the tablet core.

The drug-containing tablet core of the febuxostat controlled-release composition further contains a filler, wherein the filler comprises but is not limited to calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, glucose, fructose, trehalose, kaolin, xylitol, maltitol, erythritol, sodium chloride, dry starch, sorbitol, wheat starch, corn starch, potato starch, partial pregelatinized starch and dextrin, and preferably microcrystalline cellulose.

The content of the filler in the drug-containing tablet core of the febuxostat controlled release composition is 30-90 percent of the total weight of the tablet core, and preferably 40-85 percent.

The drug-containing tablet core of the febuxostat controlled release composition provided by the invention further optionally contains a binding agent, wherein the binding agent comprises but is not limited to polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, povidone starch, sucrose and dextrin.

A most preferred embodiment of the invention comprises the following active substances and excipients:

wherein the weight ratio of hydroxypropylmethylcellulose to triethyl citrate is selected from the group consisting of 50; the weight of the isolation layer is 0.5-10%, preferably 1-5%, most preferably 1.5-3% of the total weight of the drug-containing tablet core and the outer wrapping layer; the weight ratio of hydroxypropyl methylcellulose to triethyl citrate of the immediate release component in the composition is selected from the group consisting of 50; the weight of the quick release layer is 2-10%, preferably 3-6% of the total weight of the drug-containing tablet core, the outer cladding and the isolation layer.

The invention provides an application of a controlled release composition of febuxostat 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 invention provides a method for preparing a controlled release composition of febuxostat, which is characterized by comprising the following steps: 1) Pressing a tablet core containing febuxostat by a powder direct pressing method; 2) Dry compressing the coating material containing the matrix forming agent into a tablet core coating.

The invention provides a preparation method of a controlled release composition of febuxostat containing a quick release component, which is characterized by comprising the following steps of 1) pressing a tablet core containing febuxostat by a powder direct compression method; 2) Dry-pressing the coating material containing the matrix forming agent into a tablet core coating; 3) Coating with film to form an isolating layer; 4) Film coating to form quick release layer. The invention provides a preparation method of a controlled release composition of febuxostat containing a quick release component, which is characterized by comprising the following steps of 1) pressing a tablet core containing febuxostat by a powder direct compression method; 2) Dry-pressing the coating material containing the matrix forming agent into a tablet core coating; 3) Coating with film to form an isolating layer; 4) The weight of the isolating layer is 0.5-10 percent of the total weight of the medicine-containing tablet core and the outer cladding, preferably 1-5 percent, most preferably 1.5-3 percent, and the weight of the quick-release layer is 2-10 percent of the total weight of the medicine-containing tablet core, the outer cladding and the isolating layer, preferably 3-6 percent.

The invention provides a preparation method of a controlled release composition of febuxostat containing a quick release component, which is characterized in that the step of coating a film to form an isolation layer comprises the step of mixing a film coating material, a plasticizer, water, ethanol or a mixture of the plasticizer and the water, the ethanol or the mixture of the plasticizer and the ethanol.

The invention provides a preparation method of a controlled release composition of febuxostat containing quick release components, which is characterized in that a step of coating a film to form a quick release layer comprises a step of mixing a binder, a plasticizer, water, ethanol or a mixture of the water and the ethanol.

The hardness of the drug-containing tablet core is controlled to be 10-100N, preferably 15-60N, most preferably 20-40N, and the hardness of the outer cladding is controlled to be 100-400N, preferably 150-350N.

The method for preparing the controlled release febuxostat composition provided by the invention optionally comprises a drying step, and the coating method can be selected from methods commonly used in the field.

The controlled release composition of febuxostat is characterized in that the unit dosage form size of the composition is selected from 8-22mm, preferably 10-14mm.

The febuxostat controlled-release composition provided by the invention can be a tablet, and can be a circular tablet or other anisotropic tablets, such as an ellipse, a triangle, a quadrangle, a pentagon, a hexagon and the like, wherein the diameter of the circular tablet or the short diameter of the special-shaped tablet is not less than 8mm. Since the average diameter of the pylorus in an adult human is about 9 to 14mm, and the pylorus diameter is normally not more than 10mm in a normal state of an adult human after feeding with a moderate closure, the unit dosage form of the controlled-release composition of febuxostat provided by the present invention may have a size ranging from about 11mm to about 22mm or more, from about 13mm to about 22mm or more, or from about 17mm to about 22mm or more after swelling. The "dimension" as referred to in the present invention corresponds to the longest linear dimension of the cross-section of the dosage form having the smallest area.

The febuxostat controlled-release composition provided by the invention can maintain a certain hardness within 3-8h, preferably 4-6h in a gastric juice environment in vivo, so that the preparation per se can maintain a certain size and rigidity in the stomach, and therefore, the preparation is not damaged by gastric juice and gastric peristalsis in a gastric retention period, but the tablet expands and cannot pass through pylorus.

The tablet core containing febuxostat and the outer cladding layer in the controlled release composition form a delayed release layer, and the outer cladding layer covering the tablet core in the delayed release layer contacts with gastric juice to absorb water and swell after reaching the stomach, so that gastric retention is realized; the immediate release layer is free of polymers having a water-swellable property, which is intended to release the active agent into the stomach of the patient immediately upon ingestion of the dosage form, without the need for diffusion through the polymer layer.

The controlled release composition provided by the invention provides two pulse concentrations after being taken by a patient, active substances in a quick release layer are basically and completely released within 0.5-1h, but the medicines in a delayed release layer are basically not released, the outer covering layer is broken after the delayed release layer is retained in the stomach for about 3-8h, more specifically 4-6h, the active medicines in a tablet core begin to be released, and the active substances in the tablet core are completely released within 4-12 h.

The febuxostat controlled release composition further improves the bioavailability by increasing the absorption amount of the medicament, and reduces the medicament dosage and administration frequency, thereby reducing toxic and side effects and reducing the medicament cost.

The term "about" as used herein is used synonymously with the term "about". Illustratively, use of the term "about" indicates a value slightly outside the referenced value, i.e., plus or minus 10%. Such dosages are therefore encompassed by the scope of the claims referring to the terms "about" and "approximately".

"Polymer" as referred to herein refers to a molecule comprising a plurality of covalently linked monomer units and may include branched, dendritic and star polymers as well as linear polymers. The term also includes homopolymers and copolymers such as random, block and graft copolymers, as well as uncrosslinked and slightly to moderately to substantially crosslinked polymers.

Drawings

Figure 1 is a dissolution profile of the febuxostat controlled release composition provided in batch 1.

Detailed Description

The following is a detailed description of the invention, which is provided for the purpose of further illustration and is not intended to limit the invention, and equivalents thereof are intended to fall within the scope of the invention.

The sources of materials used in the tests were as follows: ewing RSPO (Evonik), ewing RLPO (Evonik), kollidon SR (BASF), hypromellose K100 (Ashland), hypromellose E5 (Ashland).

Example 1 preparation of febuxostat gastric retentive tablets (12 mm)

TABLE 1 febuxostat gastric retention tablet prescription

The preparation method comprises the following steps:

1) Preparation of a tablet core: taking microcrystalline cellulose, CC-Na and febuxostat according to the prescription amount, adding the microcrystalline cellulose, the CC-Na and the febuxostat into a mixing tank of a TURBULA three-dimensional mixer, adding the febuxostat into the mixing tank after premixing, tabletting by adopting a circular shallow concave punch with the diameter of 8.0mm, controlling the theoretical weight of the tablet to be 150mg and the hardness to be 30-40N;

2) Coating preparation of the core-spun tablets: taking the formula amount of Ewing RSPO, ewing RLPO, koliidon SR, HPMC K100 and HPMC E5, adding into a mixing tank, mixing uniformly to serve as an outer coating material, adopting a rotary core-spun tablet tabletting machine to press core-spun tablets, wherein a die is a 12.0mm round shallow concave punch, the theoretical weight of the outer coating is 500mg, and the hardness is controlled to be 200N300N;

3) Preparing the isolation clothes: adding 5g triethyl citrate into 945g 95% medicinal ethanol, stirring, slowly adding 550g HPMC E under stirring, and sieving with 80 mesh sieve to obtain coating solution for the isolating layer. Coating by using a Torontis BGB-5F coating machine, and stopping coating when the weight of the coating is increased to 2.0% -3.0%;

4) Coating the quick release layer: adding triethyl citrate 2g into purified water 700g, stirring well, slowly adding HPMC E520g under stirring, stirring to dissolve completely, adding febuxostat 50g, stirring to disperse well, and sieving with 80 mesh sieve to obtain the coating material for the quick release layer. Coating with a Torontis BGB-5F coating machine, and stopping coating when the weight of the coating is increased to 4.0% (containing febuxostat 18 mg).

Experimental example 1 measurement of dissolution Effect and outer cladding cracking time

Dissolution test method: adopting a second dissolution determination method of Chinese pharmacopoeia 2015 edition, wherein the rotation speed is 50rpm, the medium temperature is 37 ℃, 500ml of pH4.5 phosphate buffer (0.5% SDS) is used as a dissolution medium, the experiment is carried out for 5h, samples are respectively taken at 0.5h, 1h, 2h, 3h, 4h and 5h, and the solution is supplemented; adding 500ml of phosphate buffer solution for supplementing, adjusting the pH value of the dissolution medium to 6.8, continuing the experiment, sampling at 5.5h, 6h, 7h, 8h, 9h and 11h respectively, supplementing the solution, and determining the sample by adopting a high performance liquid chromatography.

pH4.5 phosphate buffer (0.5% SDS) preparation: weighing NaH ₂ PO ₄ ·2H ₂ O31.20g + SDS 20g, adding pure water 4L, mixing, adjusting pH to 4.5 (with phosphoric acid or sodium hydroxide solution)

Phosphate buffer solution replenishing: weighing NaH ₂ PO ₄ ·2H ₂ O31.20g + NaOH 7.17g + SDS 20g, and pure water 4L, followed by mixing, and adjusting pH to make the supplemented solution mix with PBS (pH 4.5. Sup. SDS) at pH6.8 (using phosphoric acid or sodium hydroxide solution) in equal amounts.

As a result: the outer cover of the febuxostat-containing tablet prepared in experiment 1 was broken at 4-6h and was large in amplitude.

Using the same production method as in example 1, batch 1 of gastric retentive tablets (6 tablets) was obtained, and the outer cover burst time and dissolution data were measured as shown in Table 2.

TABLE 2 batch 1 dissolution data

And (4) conclusion: the quick release layer of the sample is basically completely released (30%) within 30min-1h, and the burst release phenomenon of the tablet core medicament is obvious after the outer cladding layer is broken.

Claims

1. A controlled release composition of febuxostat, comprising a) a drug-containing core, b) an outer coating, characterized in that the outer coating does not contain active substances and contains at least one matrix former swelling in water and at least one gelling agent, the outer coating remains intact for at least 4h in gastric juice or simulated gastric juice and then breaks to release the drug, the size of the unit dosage form of the composition is selected from 8-22mm, and the size after swelling in water can reach 11-22mm, c) a fast release component of febuxostat;

the drug-containing tablet core comprises one or more of a disintegrating agent, a gelling agent and a floating auxiliary agent, the matrix forming agent in the outer cladding is an ethyl acrylate-methyl methacrylate-trimethyl aminoethyl chloride methacrylate copolymer, the gelling agent in the outer cladding is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose, the outer cladding further comprises an adhesive, and the adhesive is selected from a preparation mixture of polyvinylpyrrolidone, polyvinyl acetate and polyvinylpyrrolidone.

2. The controlled release composition of febuxostat according to claim 1, wherein the size of the unit dosage form of the composition is selected from 10-14mm, and the size can reach 13-22mm after swelling with water.

3. The controlled release composition of febuxostat according to claim 1, characterized in that the gelling agent in the outer coating is hydroxypropylmethylcellulose.

4. The controlled release composition of febuxostat according to claim 1, characterized in that the binder in the outer coating is a formulated mixture of polyvinyl acetate and polyvinylpyrrolidone.

5. The controlled release composition of febuxostat according to claim 1, characterized in that the content of the disintegrant in the drug-containing tablet core is 5-70% of the total weight of the tablet core.

6. The controlled release composition of febuxostat according to claim 5, characterized in that the content of the disintegrant in the drug-containing tablet core is 10-50% of the total weight of the tablet core.

7. The controlled release composition of febuxostat according to claim 1, characterized in that the disintegrant in the drug-containing core is selected from the group consisting of sodium carboxymethylcellulose, croscarmellose sodium, calcium carboxymethylcellulose, low substituted hydroxypropylcellulose, sodium carboxymethyl starch, partially pregelatinized starch, crospovidone.

8. The controlled release composition of febuxostat according to claim 7, characterized in that the disintegrant in the drug-containing core is selected from sodium carboxymethyl starch, partially pregelatinized starch, croscarmellose sodium.

9. The controlled release composition of febuxostat according to claim 8, characterized in that the disintegrant in the drug-containing core is selected from croscarmellose sodium.

10. The controlled release composition of febuxostat according to claim 1, characterized in that the gel agent in the drug-containing core is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, pregelatinized starch, sodium alginate, gelatin, agar, tragacanth, xanthan gum, guar gum, gum arabic, carrageenan, carboxyvinyl polymer, polyethylene oxide, polyvinyl acetate povidone polymer matrix, polyvinyl alcohol, polyvinyl pyrrolidone, pullulan, sodium polyacrylate and polyoxyethylene (160) polyoxypropylene (30) glycol.

11. The controlled release composition of febuxostat according to claim 1, characterized in that the floating aid in the drug-containing core is a combination of at least one acidic substance selected from citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, ascorbic acid, malic acid and at least one basic substance selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate.

12. The controlled release composition of febuxostat according to claim 1, characterized in that the non-butstat content of the drug-containing tablet core is 5-60% of the total weight of the tablet core.

13. The controlled release composition of febuxostat according to claim 12 characterized in that the non-butstat content of the drug containing core comprises 10% to 45% of the total core weight.

14. The controlled release composition of febuxostat according to claim 13, characterized in that the non-butstat content of the drug-containing tablet core is 20-35% of the total weight of the tablet core.

15. The controlled release composition of febuxostat according to claim 1 characterized in that the immediate release component of febuxostat is coated over a coating.

16. The controlled release composition of febuxostat according to claim 15, characterized by comprising the following components: a tablet core containing febuxostat and a disintegrating agent; an outer coating containing a mixture of ethyl acrylate-methyl methacrylate-chlorinated trimethanylethyl methacrylate copolymer, hydroxypropyl methylcellulose, polyvinyl acetate and polyvinylpyrrolidone; quick-release coating containing medicine.

17. The controlled release composition of febuxostat according to claim 15, wherein the outer coating layer further comprises an isolation layer intermediate the immediate release drug-containing coating layer.

18. The controlled release composition of febuxostat according to claim 17, wherein the material of the isolation layer is selected from one or more of hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, methylcellulose, sodium carboxymethylcellulose, povidone, polyvinyl alcohol polyethylene glycol copolymer.

19. The controlled release composition of febuxostat according to claim 18, wherein the material of the isolation layer is selected from hydroxypropyl methylcellulose.

20. The controlled release composition of febuxostat according to claim 1, wherein the weight ratio of the active ingredients in the fast release febuxostat component to the active ingredients in the tablet core is 1.

21. The controlled release composition of febuxostat according to claim 20, wherein the weight ratio of the active ingredients in the fast release febuxostat component to the active ingredients in the tablet core is 1.

22. The controlled release composition of febuxostat according to claim 21, wherein the weight ratio of the active ingredients in the fast release febuxostat component to the active ingredients in the tablet core is 1-1.

23. The controlled release composition of febuxostat according to claim 1, characterized in that the total amount of febuxostat in a unit dosage form of the controlled release composition is 10-120mg.

24. The controlled release composition of febuxostat according to claim 23, characterized in that the total amount of febuxostat in a unit dosage form of the controlled release composition is 20-100mg.

25. The controlled release composition of febuxostat according to claim 24, characterized in that the total amount of febuxostat in a unit dosage form of the controlled release composition is 30-90mg.

26. The controlled release composition of febuxostat according to claim 23 which maintains a plasma concentration of febuxostat greater than 100ng/ml in a patient for a period of 10h to 24h.

27. The controlled release composition of febuxostat according to claim 26 maintaining a plasma concentration of febuxostat greater than 100ng/ml in a patient for a period of 13-24h.

28. The controlled release composition of febuxostat according to claim 1, wherein the matrix forming agent in the outer envelope comprises 40% to 95% of the total weight of the outer envelope.

29. The controlled release composition of febuxostat according to claim 28 characterized in that the matrix forming agent in the outer envelope comprises 60% to 90% of the total weight of the outer envelope.

30. The controlled release composition of febuxostat according to claim 29 wherein the matrix forming agent in the outer covering comprises 75% to 85% of the total weight of the outer covering.

31. The controlled release composition of febuxostat according to claim 1, wherein the weight of the gel in the outer sheath comprises 1% to 30% of the total weight of the outer sheath.

32. The controlled release composition of febuxostat according to claim 31 wherein the weight of the gel in the outer sheath comprises 5% to 20% of the total weight of the outer sheath.

33. The controlled release composition of febuxostat according to claim 32 wherein the weight of the gel in the outer sheath comprises 8% to 15% of the total weight of the outer sheath.

34. The controlled release composition of febuxostat according to claim 1, wherein the weight of the binder in the outer cover layer accounts for 1-30% of the total weight of the outer cover layer.

35. The controlled release composition of febuxostat according to claim 34, wherein the weight of the binder in the outer covering layer accounts for 5-20% of the total weight of the outer covering layer.

36. The controlled release composition of febuxostat according to claim 35 wherein the weight of the binder in the outer envelope comprises 8% to 15% of the total weight of the outer envelope.

37. The controlled release composition of febuxostat according to claim 17, wherein the barrier layer and the immediate release component further comprise a plasticizer selected from the group consisting of paraffin, corn oil, refined coconut oil, monoacetin, triacetin, glycerin, triethyl citrate, tributyl citrate, polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, glyceryl stearate, diethyl succinate, propylene glycol, castor oil, and glyceryl triacetate.

38. The controlled release composition of febuxostat according to claim 37 characterized in that the plasticizer is selected from triethyl citrate.

39. The controlled release composition of febuxostat according to claim 1, characterized in that the immediate release component further comprises a binder selected from any one of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, povidone starch, sucrose, dextrin, and a combination thereof.

40. The controlled release composition of febuxostat according to claim 39 characterized in that the binder is selected from hydroxypropyl methylcellulose.

41. Use of the controlled release composition of febuxostat according to any one of claims 1-40 in the preparation of a medicament for the treatment of gout, hyperuricemia, prostatitis, inflammatory bowel disease, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes, congestive heart failure.

42. A process for preparing the controlled release composition of febuxostat according to any one of claims 1-40, characterized by comprising the steps of: 1) Pressing a tablet core containing febuxostat by a powder direct pressing method; 2) Dry compressing the outer coating material containing the matrix forming agent into a core coating.