TW201929839A - Controlled release pharmaceutical composition and preparation method thereof - Google Patents

Abstract

The present invention relates to a controlled release pharmaceutical composition and a preparation method thereof. In particular, the present invention relates to a controlled release pharmaceutical composition comprising (a) an active drug-containing core; (b) an outer layer comprising at least one matrix-forming agent. By means of the controlled release pharmaceutical composition of the present invention, the residence time of the drug in the stomach can be prolonged, thereby prolonging the transport of the drug throughout the gastrointestinal tract and increasing the absorption of the drug.

Description

Controlled release pharmaceutical composition and preparation method thereof

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

The present application claims priority from Chinese Patent Application No. CN201711484309.2, filed on Dec. 29, 2017. This application cites the entire text of the above-mentioned Chinese patent application.

In recent years, the development and research of oral drug delivery systems have made great breakthroughs, and the gastric drug retention drug delivery system (GRDDS) has been one of the research hotspots as a direction of controlled release or continuous drug delivery. Gastrointestinal drug delivery systems refer to drug delivery systems designed to maintain an extended and predictable period of time in the stomach, thereby extending the gastric residence time of the active drug and improving bioavailability. Gastric retention drug delivery systems typically include a buoyancy system, an expansion system, a bioadhesive system, and a high density system.

Gastrointestinal drug delivery systems are beneficial for a variety of drugs, such as topical pharmaceutical substances in the stomach and drugs that exhibit a narrow absorption window in the stomach or in the upper part of the small intestine (eg Davis, 2005 , Drug Dis Today 10249- Discussed in 257). In addition, drugs that degrade in the intestinal or colonic environment as well as pharmaceuticals that are poorly soluble at alkaline pH are candidates that benefit from GRDDS.

There are multiple ways of implementing a gastric retention drug delivery system. Specifically, CN103813787A discloses a swellable core/shell type tablet that achieves gastric retention by swelling, the drug delivery system having at least one drug-containing core and surrounding The outer skin of the core, and the outer skin comprising a swellable shell and an elastic coating surrounding the shell, the outer skin having at least one aperture.

WO0156544A discloses a core-shell dosage form having a drug release characteristic close to zero-order release, the core of the dosage form comprising a first polymer and a drug dispersed therein, the outer shell coated on the core, containing the drug and the second polymer, Upon swelling of the water, it swells to a size sufficient to remain in the stomach during the feeding mode, the shell and core being configured such that the drug contained in the core is released from the dosage form by diffusion of the shell. The shell is of sufficient thickness and strength that it is not substantially destroyed by swelling and remains intact throughout the period of drug release.

US20160000721A discloses an oral pharmaceutical dosage form having a plurality of layers, wherein the active drug layer contains lativavir and a first swellable polymer, the inactive drug layer contains a second swellable polymer, and the two are swellable The molecular weight of the polymer is close to or slightly higher in the molecular weight of the inactive drug layer.

Journal of Drug Delivery &Therapeutics; 2013 , 3(5), 58-61 discloses a sustained release comprising wet granulation from metformin hydrochloride and different swollen polymers such as HPMC E15, HPMC K100 and carbomer. A core tablet and a two-layer tablet of an immediate release layer prepared from pioglitazone hydrochloride, cross-linked polyvinylpyrrolidone and a superdisintegrant for the combined treatment of diabetic patients.

No. 4,207,890 A discloses a drug dispensing device and method for controlling and prolonging the internal administration of a drug to a warm-blooded animal, including an outer polymeric shell containing a blowing agent, a drug metering device and the drug itself. When the device is in contact with body fluids when the device is in a use environment (eg, the stomach), the outer polymeric outer shell is permeable and swellable to both the drug and body fluids. This expansion maintains the device in the environment of use while being administered by the metering device.

US20130315991A discloses a delayed or controlled release drug delivery system for gastrointestinal administration comprising one or more solid drugs and one or more polymers which hydrate and swell in the presence of gastric acid to form A degradable protective outer shell that reduces the rate of diffusion of drug particles.

CN1960711A discloses a gastric retention system in the form of a coated tablet comprising: (a) a core in the form of a tablet, an agent capable of generating an internal pressure on the coating, and (b) an expandable coating, said The swellable coating is formed by coating a coating core comprising a film forming polymer and one or more swellable components on a core of the tablet.

Sharma Shailesh et al. IJRPS 2012 , 2(4), 48-60 discloses a two-layered gastric retention of amisulpride, including both delayed and immediate release portions, both delayed and immediate release through wet The granulation is obtained.

WO2008027945A discloses a gastric retention preparation of valsartan, which comprises a release component of valsartan and a gastric retention swelling component, wherein the release component contains a hydrogel or an inert material, and further the preparation may contain Provide the second pulse of valsartan.

CN101022808A discloses a gastric retention matrix tablet-type pharmaceutical composition containing an active ingredient, characterized in that when contacted with a representative gastric fluid medium, the volume increases after 15 minutes, the degree of swelling is at least 200%, and the composition contains povidone and/or poly Vinyl acetate, crospovidone, carbomer, and other compositions may be prepared as a bilayer tablet or in one or more phase-wrapped nuclear dosage forms.

Although the gastric retention drug delivery system has been researched and developed for 20 to 30 years, the successfully marketed gastric retention preparations are only Roche's Madopar HBS (levodopa and benserazide) and Valrelease (Standing), and Squibb's Glucophage XR. (Metformin Hydrochloride) and Rifock's Cifran OD (ciprofloxacin), etc., in order to reduce the number of medications, improve patient compliance, and improve the bioavailability of drugs, there is still a need to develop a new gastric retention drug delivery system. .

The invention provides a controlled release composition of an active drug, which prolongs the drug retention in the gastrointestinal tract by prolonging the residence time of the drug in the stomach, increases the maintenance time of the effective blood drug concentration, and reduces side effects.

The present invention provides a controlled release pharmaceutical composition comprising a) a tablet-containing core comprising an active drug, b) an outer layer, the outer layer containing no active drug and comprising at least one water-swellable matrix forming agent, It remains intact for at least 4 hours in the environment of gastric fluid or simulated gastric fluid, followed by rupture release; the composition swells to a size sufficient to remain in the stomach in the feeding mode.

In one aspect of the present invention, the present invention provides a controlled release pharmaceutical composition, wherein the composition is immersed in a gastric juice or simulated gastric fluid environment for less than 4 hours, and the release amount is less than 10%, preferably less than 5%, most preferably Less than 2%; after soaking time is more than 4h, preferably more than 5h, specifically 5-16h, 5-15h, 6-12h, 7-11h, 8-10h release amount is more than 75%, preferably more than 85%, most preferably More than 95%.

The release amount of less than 10% when the soaking time is less than 4 hours in the present invention means that the controlled release composition is substantially non-released for at least 4 hours. The immersion time of the present invention is greater than 75%, and the release amount is greater than 75% at any time point after 4 hours, for example, 5h, 5.5h, and 6h, that is, the release drug requirement is satisfied; the immersion time is satisfied. The limitation is, for example, 5-12 h, which means that the release amount is greater than 75% at any time point in the interval, for example, 5h, 6h, and 7h.

The controlled release pharmaceutical composition provided by the present invention rapidly absorbs water in the environment of gastric juice or simulated gastric juice, and specifically swells to a maximum size at 5-120 min, preferably swells to a maximum size at 5-60 min.

The controlled release pharmaceutical composition provided by the present invention may further comprise at least one gelling agent. Specifically, the present invention provides a controlled release pharmaceutical composition comprising a) a tablet core comprising an active drug , b) an outer layer that is free of active drug and that contains at least one water-swellable matrix former.

Further, the outer layer of the controlled release pharmaceutical composition provided by the present invention may further contain at least one gelling agent.

The outer layer of the controlled release pharmaceutical composition provided by the present invention is insoluble in the digestive juice in the stomach, but can swell and maintain its integrity, and helps control the release rate of the drug. The specific matrix forming agent may be selected from the group consisting of ethyl acrylate-methyl methacrylate-trimethylaminoethyl 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, polyepoxy Ethane, polyvinyl alcohol, carbopol, glyceryl behenate, hydrogenated castor oil, cetyl alcohol, carnauba wax, preferably ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate Copolymer.

The controlled release pharmaceutical composition provided by the present invention, the matrix forming agent in the outer layer may account for 40%-95%, preferably 60%-90%, and most preferably 75%-85% of the total weight of the outer layer, as a specific value. 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85% (% of the content is a percentage by mass unless otherwise specified in the present invention).

The controlled release pharmaceutical composition provided by the present invention, the non-limiting examples of the ethyl acrylate-methyl methacrylate-methacrylic acid trimethylaminoethyl methacrylate copolymer include EUDRAGIT® RLPO, EUDRAGIT® RSPO, EUDRAGIT® RL100, EUDRAGIT® RS100.

The gelling agent in the outer layer of the controlled release pharmaceutical composition provided by the present invention refers to a water-soluble polymer which swells and gels upon contact with water, and the gel expands on water, thereby further increasing the volume of the tablet. Large, on the other hand, the gel-like substance further fills the pores generated by the matrix forming agent in the outer cladding by water swelling and is gradually eroded after being in contact with water for a period of time, and then the outer cladding is broken to make the core active. The drug is released to the desired release profile.

Specifically, the gelling agent in the outer layer may be selected from the group consisting of ethyl cellulose, methyl ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and hydroxymethyl cellulose. , hydroxyethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate butyrate, cellulose propionate, hypromellose Ester, hypromellose acetate succinate, hydroxypropyl methylcellulose acetate trimellitate, ethyl hydroxyethyl cellulose, preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl Cellulose sodium, most preferably hydroxypropylmethylcellulose.

In a preferred embodiment of the invention, the gelling agent of the outer layer is hydroxypropylmethylcellulose, and the commercially available hydroxypropylmethylcellulose has various types, such as E and K from the Dow Chemical Company of the United States, specifically It is selected from the group consisting of E3, E5, E6, E15, E50LV, E4M, E10M, K100LV, K4M, K15M, K100M, etc. The test method for the viscosity of hydroxypropylmethylcellulose in the present invention is 2% (w/w) aqueous solution 20 ° C It was tested that hydroxypropylmethylcellulose having a viscosity of from 5 mPa•s to 100000 mPa•s is within the scope of the present invention.

Other materials useful in the present invention for gelling agents include, but are not limited to, pregelatinized starch, vinyl acetate povidone polymer matrix, polyvinylpyrrolidone, sodium polyacrylate, and polyoxyethylene (160) polyoxypropylene (30). Copolymers of diols, polyethylene oxides, pullulans, polyvinyl alcohols, polyvinyl acetates, glyceryl fatty acid esters, polyacrylamides, polyacrylic acid, ethacrylic acid or methacrylic acid and other acrylic acids Derivatives such as butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate and (trimethylaminoethyl)methyl Homopolymers and copolymers of chloroacrylate.

The controlled release pharmaceutical composition provided by the present invention, the weight of the gelling agent in the outer layer may be from 1% to 30%, preferably from 5% to 20%, most preferably from 8% to 15%, based on the total weight of the outer layer, as a specific value. Optional 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 controlled release pharmaceutical composition provided by the present invention, the outer covering layer may further comprise a binder, and the binder may be selected from the group consisting of polyvinylpyrrolidone, a mixture of polyvinyl acetate and polyvinylpyrrolidone, preferably polyvinyl acetate. A formulated mixture of an ester and polyvinylpyrrolidone. Non-limiting examples include Kollidon® SR, Kollidon® V64, Kollidon® 25, Kollidon® 30, Kollidon® 90F, Kollidon® 17PF, Kollidon® 12PF.

The controlled release pharmaceutical composition provided by the present invention, the weight of the binder in the outer layer may be from 1% to 30%, preferably from 5% to 20%, most preferably from 8% to 15%, based on the total weight of the outer layer, as a specific value. Optional 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15.0%.

The outer layer of the controlled release pharmaceutical composition provided by the present invention optionally contains an enteric polymer, and the enteric polymer may be selected from the group consisting of hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose. Phthalate, hydroxymethylethylcellulose phthalate, methylcellulose phthalate, carboxymethyl ethyl ether cellulose, ethyl hydroxyethyl cellulose phthalate Formate, methyl hydroxyethyl cellulose, styrene-acrylic acid copolymer, methacrylic acid copolymer, methyl acrylate-acrylic acid copolymer, acrylic acid-methyl methacrylate copolymer, butyl acrylate-styrene- Acrylic copolymer, methyl acrylate-methacrylic acid-octyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, polyvinyl alcohol phthalate, At least one of polyvinyl acetal phthalate, polyvinyl butyral phthalate, and polyvinyl alcohol acetate acetal phthalate.

The controlled release pharmaceutical composition provided by the present invention may further comprise one or more of a disintegrating agent, a gelling agent and a floating auxiliary agent.

The controlled release pharmaceutical composition provided by the invention may be selected from the group consisting of sodium carboxymethyl cellulose, sodium croscarmellose, calcium carboxymethyl cellulose, and low substituted hydroxypropyl. Cellulose, sodium carboxymethyl starch, partially pregelatinized starch, pregelatinized starch, crospovidone, preferably sodium carboxymethyl starch, partially pregelatinized starch, croscarmellose sodium, most Preference is given to croscarmellose sodium.

The controlled release pharmaceutical composition provided by the invention may comprise a disintegrant in the tablet core in an amount of 5% to 70%, preferably 10% to 50%, based on the total weight of the core.

The present invention provides a controlled release pharmaceutical composition, wherein the gel containing the tablet core may be selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and Cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, pregelatinized starch, sodium alginate, gelatin, agar, tragacanth, xanthan gum, guar gum, gum arabic, carrageenan , carboxyvinyl polymer, polyethylene oxide, vinyl acetate povidone polymer matrix, polyvinyl alcohol, polyvinyl pyrrolidone, pullulan, sodium polyacrylate and polyoxyethylene (160) polyoxypropylene (30 ) diol.

The controlled release pharmaceutical composition provided by the present invention, wherein the floating agent in the tablet-containing core may be at least one acidic substance selected from the group consisting of citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, ascorbic acid, and malic acid, and at least A combination of basic substances selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, and calcium carbonate.

The controlled release pharmaceutical composition provided by the invention may comprise the active drug in the tablet core in an amount of 3% to 60%, preferably 10% to 50%, most preferably 20% to 40% by weight based on the total weight of the core.

In one embodiment, the controlled release composition provided by the present invention comprises: a) a tablet core, b) an outer layer, the tablet core containing a disintegrant; the outer layer containing no active material and containing at least one A water-swellable matrix former, at least one gel.

The controlled release pharmaceutical composition provided by the present invention may further comprise an immediate release component, which is rapidly released after oral administration to achieve an effective blood drug concentration.

The immediate release component of the controlled release pharmaceutical composition of the present invention may be added by means of a two-layer tablet, a chip, or a film coating, preferably in the form of a film coating.

In the present invention, the content of the core active drug and the content of the active drug in the immediate release component can be formulated by actual needs, thereby achieving a therapeutic effect.

Preferably, the present invention provides a controlled release pharmaceutical composition containing an immediate release component, wherein the immediate release component is released in the gastric juice or simulated gastric fluid environment for 1 hour, and the release amount is greater than 70% of the total amount of the immediate release component drug. Preferably 80%, most preferably 90%.

In one embodiment provided by the present invention, the controlled release pharmaceutical composition comprising the immediate release component is optionally in the form of a multilayer tablet such as a three layer tablet.

In one aspect of the present invention, the present invention provides a controlled release pharmaceutical composition comprising an immediate release component, wherein the immediate release component is greater than the immediate release component drug in the gastric juice or simulated gastric fluid environment for 1 hour. 70%, preferably 80%, most preferably 90% of the total amount; the delayed release component is not substantially released within 4 hours of immersion in gastric juice or simulated gastric fluid environment, specifically, when the soaking time is less than 4h, the delayed release component The release amount of the active drug is less than 10% (w/w) of the total amount of the drug of the delayed release component, preferably less than 5%, and most preferably less than 2%; after the soaking time is more than 4 hours, the outer layer is broken, and the core drug is released suddenly. The amount of active drug released in the release component is greater than greater than 75%, preferably greater than 85%, and most preferably greater than 95% of the total amount of delayed release component drug.

The controlled release pharmaceutical composition provided by the present invention, in a preferred embodiment, the immediate release component is coated on the outer cladding in a coating form.

In a preferred embodiment of the present invention, the controlled release pharmaceutical composition comprises the following components: a tablet core containing an active drug, a disintegrant; and ethyl acrylate-methyl methacrylate-methyl methacrylate An outer cladding of a formulated mixture of trimethylaminoethyl ester copolymer, hydroxypropylmethylcellulose, polyvinyl acetate and polyvinylpyrrolidone; an immediate release drug-containing coating.

In a preferred embodiment of the present invention, the controlled release pharmaceutical composition comprises the following components: a tablet core containing an active drug, croscarmellose sodium, containing EUDRAGIT® RLPO, EUDRAGIT® RSPO, hydroxypropylmethyl fiber An outer layer of Kollidon SR; an immediate release drug-containing coating.

The controlled release pharmaceutical composition provided by the present invention, the matrix forming agent in the outer layer may account for 40%-95%, preferably 60%-90%, and most preferably 75%-85% of the total weight of the outer layer, as a specific value. 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%.

The controlled release pharmaceutical composition provided by the present invention, the weight of the gelling agent in the outer layer may be from 1% to 30%, preferably from 5% to 20%, most preferably from 8% to 15%, based on the total weight of the outer layer, as a specific value. Optional 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8.0%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15.0%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20% (w/ w).

The controlled release pharmaceutical composition provided by the present invention, the weight of the binder in the outer layer may be from 1% to 30%, preferably from 5% to 20%, most preferably from 8% to 15%, based on the total weight of the outer layer, as a specific value. Optional 8.0%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15.0%.

The controlled release pharmaceutical composition provided by the present invention, in a preferred embodiment, further comprises an isolating layer between the outer cladding layer and the immediate release drug-containing coating layer.

In a preferred embodiment of the present invention, the material of the separator may be selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, methyl cellulose, and carboxymethyl fiber. One or more of sodium, povidone, acrylic resin, polyvinyl alcohol polyethylene glycol copolymer, preferably hydroxypropylmethylcellulose.

The controlled release pharmaceutical composition provided by the present invention, the release layer and the immediate release drug-containing coating layer may further comprise a plasticizer, and the plasticizer may be selected from the group consisting of paraffin wax, corn oil, refined coconut oil, and glycerin Acetate, 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 triacetin, preferably citric acid three Ethyl ester.

The controlled release composition provided by the present invention, the weight ratio of the separator material to the plasticizer in the separator may be selected from 50:1 to 1:50, preferably 20:1 to 1:20, and most preferably 15:1. -1:1.

In the controlled release composition provided by the present invention, the weight gain of the release layer may be from 0.5% to 10%, preferably from 1% to 5%, most preferably from 1.5% to 3%, based on the total weight of the tablet core and the outer cover.

The controlled release pharmaceutical composition provided by the present invention, the immediate release drug-containing coating layer may further comprise a binder, and the binder may be selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, and hydroxypropyl group. At least one of cellulose, sodium carboxymethylcellulose, povidone starch, sucrose, and dextrin is preferably hydroxypropylmethylcellulose.

The present invention provides a controlled release composition comprising an immediate release component, wherein the weight ratio of the binder to the plasticizer of the immediate release component in the composition may be selected from 50:1 to 1:50, preferably 20:1. -1:20, most preferably 15:1-1:1.

The controlled release composition containing the immediate release component provided by the present invention may have a weight gain of from 2% to 10%, preferably from 3% to 6%, based on the total weight of the tablet core, the outer layer and the separator.

The present invention provides a controlled release pharmaceutical composition which can be selected from the group consisting of drugs having a narrow absorption window.

The controlled release pharmaceutical composition provided by the present invention, the narrow absorption window drug may be selected from the group consisting of febuxostat, nefazodone hydrochloride, ibuprofen, ondansetron, ondansetron hydrochloride, metformin , midazolin hydrochloride, olanzapine, ofloxacin, ciprofloxacin, topiramate, atorvastatin, simvastatin, gatifloxacin, rosiglitazone, ranitidine, cimetidine Ding, famotidine, captopril, quinapril, acyclovir, fexofenadine, pseudoephedrine, bupropion, nizatidine, fluoxetine hydrochloride, nifedipine, nis Kaldipine, naproxen, amlodipine maleate, lovastatin, omeprazole, lansoprazole, pantoprazole, esomeprazole, clarithromycin, ranitidine hydrochloride, house Qulin hydrochloride, roppenem, bisphosphonate, furosemide, gabapentin, levodopa, carbidopa, baclofen, pregabalin, acyclovir, pabutrazil, valaciclo Wei, nitrofurantoin, lithium carbonate, calcium carbonate, citric acid, citric acid, ascorbic acid, folic acid, vitamin E, pravastatin, enalapril, cilazapril, Benazepril, fosinopril, ramipril, salbutamol, pirbutanol, allopurinol, atenolol, metoprolol, cimetidine, famotidine, misoprostol, 5-fluorouracil, doxorubicin, cisplatin, etoposide, semustine, methotrexate, clarithromycin, metronidazole, zaleplon, methylnaltrexone, tetracycline.

The active drug of the present invention may be selected from chronological pharmacological related drugs, including but not limited to drugs for treating angina pectoris, antihypertensive drugs, anti-hyperlipemia agents, and drugs for treating asthma.

The medicament for treating angina pectoris of the present invention includes, but not limited to, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, betaxolol, metoprolol succinate, ranolazine, nifedipine, ivabradine hydrochloride , atorvastatin, amlodipine, cilostazol, verapamil, diltiazem hydrochloride, donaperminogene, seltoplasmid, lercanidipine, carvedilol, nilvadipine, nicorandil, benidipine, rich Bisoprolol citrate, atenolol, felodipine, benidipine, irilappine, celrilol, trinitrate, astragaloside, progesterone, tirofiban hydrochloride, and effluentine hydrochloride.

The antihypertensive drugs of the present invention include, but are not limited to, sildenafil citrate, amlodipine, Trevyent, citrulline, carvedilol phosphate, clonidine, betatalol, Sacubitril, laksa Tantan, candesartan cilexetil, rosuvastatin calcium, treprostinil, methyl bardoxolone, olmesartan medoxomil, non-marsartan, metoprolol succinate, nifedipine, aubrey Cholic acid, tadalafil, irbesartan, atorvastatin, macitentan, aliskiren, sunitinib, nebivolol, losartan, umbrel, Esuberaprostsodium, aetna Carlin, leoxicillin, doxazosin, diltiazem hydrochloride, alisartan, ambrisentan, candesartan, Selexipag, levagionoid, lercanidipine, mecamylamine, esaxerenone, hydrochlorothiazide, Visartan, furosemide, spironolactone, ramipril, bosentan, Treprostinildiolamine, perindopril, bisoprolol fumarol, azilsartan, nilvadipine, azulolol, Udenafil, cilnidipine, lovastatin, treprostinil, irilappine, fosinopril, chlorothiazide , quinapril hydrochloride, iloprost, epoprostenol, aliskiren, midazolam, beraprost, adipine, indapamide, clevidipine, torsemide, benidipine , candesartan cilexetil, felodipine, terazosin, nicardipine, bainidipine, eplerenone, enalapril, quinapril hydrochloride, perfluoro-n-butane, urapidil, Prazosin, Elpaqu, Moxonidine, Nepolong, Manidipine, Ilapidine, Spiropril, Zofenopril, Benazepril, Bunazosin, Group Dopply, Epsich Tetan, dexamepril hydrochloride, moxipril, trichlorothiazide, nicilipine, fenoldopam, valpromine, nitrendipine, docarbaamine, naprodil, fosinopril, Ketochrome tartrate, adipine, propranolol, effluentil, and delalipril.

The anti-hyperlipidemic agent (lipophilic agent or "high-fat blood" agent) of the present invention includes, but is not limited to, Apabetalone, rosuvastatin, ezetimibe, simvastatin, vorapa, and colesevelam. , Pemafibrate, irbesartan, atorvastatin, Bempedoic acid, Volanesorsen, Lomestatin, Sarogrezide, Amlodipine, Losartan, Misoprostol, Pravastatin, Lovastatin, West Rivastatin, clofibrate, fenofibrate, gemfibrozil, tacrine, pitavastatin, olmesartan medoxomil, non-marsartan, fenofibrate, valsartan, metformin, dalcetrapib , telmisartan, hydrochloric acid, Acetylsalicylic acid, ramipril, bezafibrate, isradipine, acipimox, clopidogrel hydrogen sulfate, colestilan, lacidipine, ciprofibrate, Fenofibrate, glimepiride.

The medicament for treating asthma according to the invention includes, but is not limited to, theophylline, fluticasone furoate, vilantrol trifluorobenzoate, fluticasone propionate, citrulline, etanercept, abatacept, gron Ammonium bromide, budesonide, formoterol fumarate, salmeterol, Mitizax, dasatinib, beclomethasone propionate, montelukast sodium, imatinib, ipratropium bromide, Butro, roflumilast, indacaterol, mometasone furoate, methylprednisolone, triamcinolone acetonide, dexamethasone, salbutamol, terbutaline, procaterol, isopropionine, evipiprant, Salbutamol, mometasone, Qitong, Grazax, levocetirizine hydrochloride, timapiprant, ciclesonide, ozagrel, prednisolone, ebastine, mometasone furoate, emisone Ting, dexpramipexole, metformin, bislastine, plenbuter, doxofylline, flunisolide, sodium cromoglycate, zafirlukast, pyrimilast, flubutate hydrochloride, stopper Quist, Difcote, Bambuterol, Epilepsin Hydrochloride, Nydrolomid, Tolutrotroz, Mizolastine, Pru Patent, tranilast, sulfo heptyl methylprednisolone, Switzerland pyrazol montelukast.

The core of the controlled release pharmaceutical composition of the present invention may further contain a lubricant selected from the group consisting of talc, micronized gum, titanium dioxide, magnesium stearate, calcium stearate, zinc stearate, starch, and poly Any one or a combination of ethylene glycol 4000, polyethylene glycol 6000, and liquid paraffin, preferably magnesium stearate. The level of lubricant in the tablet-containing core of the controlled release composition of the present invention may range from 0.01% to 5%, preferably from 0.1% to 3%, most preferably from 1% to 2%, based on the total weight of the core. The lubricant reduces the friction between the particles and the mold wall during compression and discharge, prevents the particles from adhering to the tablet punches, facilitates their discharge from the tablet press, and the like.

The core of the controlled release pharmaceutical composition of the present invention may further comprise a filler including but not limited to calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, glucose, fructose, trehalose, kaolin , xylitol, maltitol, erythritol, sodium chloride, dried starch, sorbitol, wheat starch, corn starch, potato starch, partially pregelatinized starch, dextrin, preferably microcrystalline cellulose. The filler of the tablet-containing core of the controlled release composition of the present invention may be included in an amount of from 30% to 90%, preferably from 40% to 85% by weight based on the total weight of the core.

In a preferred embodiment of the present invention, the present invention provides a controlled release pharmaceutical composition of febuxostat, wherein the weight ratio of the active ingredient to the active ingredient in the core of the febuxostat immediate release component is 1:0.1 -1:20, preferably 1:0.5-1:15, most preferably 1:1 to 1:10.

In a preferred embodiment of the invention, the present invention provides a febuxostat controlled release composition comprising an immediate release component, wherein the total amount of febuxostat in a unit dosage form is from 10 to 120 mg, preferably from 20 to 100 mg, most preferably 30. -90 mg, specifically 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, preferably 30 mg, 60 mg.

The invention provides a controlled release pharmaceutical composition of febuxostat, the specific composition is as follows:

Wherein the weight ratio of hydroxypropylmethylcellulose to triethyl citrate is selected from 50:1 to 1:50, preferably from 20:1 to 1:20, most preferably from 15:1 to 1:1; The weight gain is from 0.5% to 10%, preferably from 1% to 5%, most preferably from 1.5% to 3%, based on the total weight of the tablet core and the outer layer; the immediate release component of the composition is hydroxypropylmethylcellulose and The weight ratio of triethyl citrate is selected from the group consisting of 50:1 to 1:50, preferably 20:1 to 1:20, and most preferably 15:1 to 1:1; the weight gain of the immediate release layer is a tablet core, an outer layer, The total weight of the barrier layer is from 2% to 10%, preferably from 3% to 6%.

The present invention provides a controlled release composition of febuxostat prepared for the treatment of gout, hyperuricemia, prostatitis, inflammatory bowel disease, prolongation of QT interval, myocardial infarction, cardiac hypertrophy, hypertension Use in medicines for diseases of nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes, diabetic nephropathy, and congestive heart failure.

Another aspect of the present invention provides a method for treating gout, hyperuricemia, prostatitis, inflammatory bowel disease, prolongation of QT interval, myocardial infarction, cardiac hypertrophy, hypertension, nephrolithiasis, chronic kidney disease, metabolic syndrome, diabetes A method of diabetic nephropathy, congestive heart failure comprising administering to a patient 30 mg or 60 mg of a controlled release composition of febuxostat according to the invention.

The core of the controlled release pharmaceutical composition of the present invention further optionally contains a binder including, but not limited to, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose Sodium, povidone starch, sucrose, dextrin.

The invention provides a method for preparing the controlled release pharmaceutical composition, comprising the steps of: 1) pressing a tablet core containing an active drug by a powder direct pressing method; 2) dry pressing a coating material containing a matrix forming agent into a core Coating.

The invention provides a preparation method of a controlled release composition containing an immediate release component, which comprises the following steps: 1) pressing a tablet core containing a drug by a direct pressure method; 2) drying a coating material containing a matrix forming agent into a dry process Core coating; 3) film coating into a barrier layer; 4) film coating into a release layer.

The invention provides a preparation method of a controlled release composition containing an immediate release component, which comprises the following steps: 1) pressing a tablet core by a direct pressure method; 2) dry pressing a coating material containing a matrix forming agent into a core Coating; 3) film coating into a release layer; 4) film coating into a release layer, wherein the weight gain of the spacer layer is 0.5%-10%, preferably 1%-5%, of the total weight of the core and the outer layer. Preferably, from 1.5% to 3%, the weight gain of the immediate release layer is from 2% to 10%, preferably from 3% to 6%, based on the total weight of the tablet core, the outer layer and the release layer.

Preferably, the method for preparing a controlled release composition comprising an immediate release component provided by the present invention, the step of coating the film into a release layer comprises the step of coating a film coating material, a plasticizer with water, ethanol or a mixture thereof.

Preferably, the method for preparing a controlled release composition comprising an immediate release component provided by the present invention, the step of coating the film into an immediate release layer comprises the step of mixing a binder, a plasticizer with water, ethanol or a mixture thereof.

The hardness of the core of the present invention is controlled to be 10 to 100 N, preferably 15 to 60 N, and most preferably about 20 to 40 N, and the outer cladding hardness of the present invention is controlled to be 100 to 400 N, 150 to 350 N.

The method for preparing a gastric retention sheet provided in the present invention optionally includes a drying step, and the coating method may be a method generally used in the art.

The present invention provides a controlled release pharmaceutical composition wherein the unit dosage form of the composition may be selected from 8-22 mm, preferably 10-14 mm.

The controlled release pharmaceutical composition provided by the present invention may be a tablet, and may be a circular piece or other anisotropic sheet, such as an ellipse, a triangle, a quadrangle, a pentagon, a hexagon, etc., and the diameter of the circular piece or the short diameter of the shaped piece is not Less than 8mm. Since the pylorus of an adult has an average diameter of about 9-14 mm and is moderately closed after eating, the pyloric diameter of the adult normal state generally does not exceed 10 mm, so the dosage form of the controlled release pharmaceutical composition unit dosage form provided by the present invention is about 11 mm to about. 22 mm, from about 13 mm to about 22 mm or more, or from about 17 mm to about 22 mm or more. The "size" described in the present invention corresponds to the longest linear dimension of the cross section of the dosage form having the smallest area.

The controlled release pharmaceutical composition provided by the invention can maintain a certain hardness in the gastric juice environment for 3-8h, preferably 4-6h, so that the preparation itself maintains a certain size and rigidity in the stomach, and therefore is not subjected to gastric juice during the gastric retention period. And the stomach is creeping, but it can't pass the pylorus.

The controlled release pharmaceutical composition provided by the invention comprises a tablet core and an outer layer of the active drug to form a delayed release layer, wherein the outer layer of the delayed release layer covering the core reaches the stomach and contacts the gastric juice to swell and expand, thereby realizing the stomach Retention; the immediate release layer does not contain a polymer having water swelling, the purpose of which is to release the active drug into the stomach of the patient immediately upon ingestion of the dosage form without the need to diffuse through the polymer layer.

The controlled release pharmaceutical composition provided by the present invention provides two pulse concentrations after being taken by the patient, and the active drug is substantially completely released in the 0.5-1 hour immediate release layer, but the drug of the delayed release layer is not substantially released, and the delayed release layer is in the stomach. The retention is about 3-8h, more specifically 4-6h after the outer layer ruptures, and the active drug of the core begins to release 4-16h, and the delayed release core active drug is completely released.

The double-pulse release method of the controlled release pharmaceutical composition of the invention is superior to the diffusion and dissolution release methods of other gastric retention tablets, and facilitates the release of highly soluble drugs in the intestinal environment due to insoluble and insoluble gastric juice, double pulse The drug release method can provide two drug peak concentrations, which is beneficial to improve bioavailability. The "active drug" as used in the present invention also includes pharmaceutically acceptable active derivatives of those active agents specifically mentioned herein, including but not limited to salts, esters, guanamines, prodrugs, active metabolites, analogs and the like. More specifically, the active drug is intended to include the poorly soluble drug of the present invention having a narrow gastrointestinal absorption window.

The term "about" as used herein is used synonymously with the term "about." Illustratively, the use of the term "about" means a value that is slightly outside the referenced value, ie plus or minus 10%. Such dosages are thus encompassed by reference to the scope of the claims of the terms "about" and "approximately".

The "absorption window" as used in the present invention refers to a specific gastrointestinal segment in which a particular drug is absorbed. The ability of a drug to be absorbed in a particular fragment is related to the solubility and stability of the drug in a particular microenvironment, depending on the pH, the lipophilicity of the drug and the permeability of the intima, the presence of a drug transport mechanism, and the like. The "narrow absorption window drug" as used in the present invention refers to a drug that is absorbed only in the pH environment of the stomach or upper intestine.

The "chronology pharmacology" described in the present invention is a subject which studies the dynamic changes and effects of the drug content in the body due to the difference in administration time, thereby elucidating these mechanisms of action.

By "polymer" to which the invention pertains is meant molecules 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 copolymers, block copolymers and graft copolymers, as well as uncrosslinked polymers and light to moderate to substantially crosslinked polymers.

The above and other objects, features and advantages of the present invention will become more <RTIgt;

The following is a specific embodiment of the present invention, and the embodiments are intended to further describe the present invention and not to limit the present invention, and all the technical solutions equivalent to the present invention belong to the protection scope of the present invention.

The sources of materials used in the tests were as follows: Evonik, Evonik, Evonik, Kollidon SR (BASF), Hypromellose K100 (Ashland), Hypromellose E5 (Ashland).

Example 1. Preparation of febuxostat gastric retention tablets (12 mm)
Table 1. Formulation and preparation method of febuxostat gastric retention tablets

Preparation:
1) Core preparation: take the prescription amount of microcrystalline cellulose, CC-Na, febuxostat into the TURBULA three-dimensional mixer mixing tank, premix and add magnesium stearate total mixing, using 8.0mm circular shallow concave The head is compressed, the theoretical tablet weight is 150mg, and the control hardness is 30-40N.
2) Preparation of packaged chip coating: Take the prescription Utech RSPO, Eudragit RLPO, Koliidon SR, HPMC K100, HPMC E5 into the mixing tank and mix it as the outer layer material, using a rotary package chip tablet press Package chip, the mold is a 12.0mm circular dimple punch, the theoretical weight of the outer cladding is 500mg, and the control hardness is 200N-300N;
3) Preparation of the isocoat: 5 g of triethyl citrate was added to 945 g of 95% medicinal ethanol, stirred uniformly, and 550 g of HPMC E was slowly added under stirring, and then thoroughly stirred, passed through a mesh of 80 mesh, and used as a coating liquid for the release layer. Coating with Xiaolun BGB-5F coating machine, the coating is stopped when the weight gain is 2.0%-3.0%;
4) Immediate release layer coating: 2g of triethyl citrate is added to 700g of purified water, stirred evenly, and 20g of HPMC E5 hypromellose (E5) is slowly added under stirring, stirred until completely dissolved, and then added to the cloth. He was 50 g, stirred until evenly dispersed, and passed through a 80 mesh sieve as a coating material for the immediate release layer. The coating was stopped with a Xiaolun BGB-5F coating machine, and the coating was stopped when the weight was increased to 4.0% (containing 18 mg of febuxostat).

Experimental Example 1. Dissolution effect and outbreak rupture time Determination of dissolution method: The second method of dissolution measurement was carried out by Chinese Pharmacopoeia 2015. The rotation speed was 50 rpm, the medium temperature was 37 ° C, and the pH was 4.5 phosphate buffer (0.5% SDS). 500ml is the dissolution medium, sampled for 5h, 0.5h, 1h, 2h, 3h, 4h, 5h, respectively, and replenished; add phosphate buffer solution 500ml to adjust the dissolution medium to pH6.8, continue the experiment, respectively at 5.5h Samples were taken at 6h, 7h, 8h, 9h, and 11h, and the liquid was refilled. The test sample was determined by high performance liquid phase method.
Formulated in pH 4.5 phosphate buffer (0.5% SDS): weigh NaH ₂ PO ₄ ·2H ₂ O 31.20g + SDS 20g, add 4L of pure water, mix and adjust the pH to 4.5 (using phosphoric acid or sodium hydroxide solution) )
Phosphate buffer rehydration: Weigh NaH ₂ PO ₄ · 2H ₂ O 31.20g + NaOH 7.17g + SDS 20g, add 4L of pure water, mix, adjust the pH to make the rehydration and pH 4.5 PBS (0.5% SDS) equivalent The pH was mixed at 6.8 (with phosphoric acid or sodium hydroxide solution).
RESULTS: The outer layer of the febuxostat gastric retention sheet prepared by Experiment 1 was ruptured at 4-6 h, and the amplitude was large.
Using the same preparation method as in Example 1, a gastric retentive sheet (6 pieces) of Batch 1 was obtained, and the outer layer rupture time and dissolution were measured as shown in Table 2 and FIG.
Table 2. Batch 1 dissolution data
Conclusion: The immediate release layer of the sample is completely released (30%) at 0.5-1h, and the burst release of the core drug is obvious after the outer layer is broken.

Example 2 Preparation of Nifedipine and Levofloxacin Gastric Retention Tablets (14 mm)
Table 3. Formulation and preparation method of nifedipine and levofloxacin gastric retention tablets

Preparation:
1) Core preparation: take the prescription amount of microcrystalline cellulose, CC-Na, raw material medicine into TURBULA three-dimensional mixer mixing tank, premix and add magnesium stearate total mixing, using 10.0mm circular dimple punch pressure The film has a theoretical weight of 235 mg and a hardness of 20-40 N.
2) Preparation of packaged chip coating: Take the prescription Utech RSPO, Eudragit RLPO, Koliidon SR, HPMC E5 into the mixing tank and mix it as the outer layer material, and use the rotary package chip tablet press to press the package chip. The mold is a 14.0mm circular dimple punch, the theoretical weight of the outer cladding is 650mg, and the control hardness is 150N-300N;
3) Preparation of the isocoat: 5 g of triethyl citrate was added to 945 g of 95% medicinal ethanol, stirred uniformly, and 50 g of HPMC E5 was slowly added under stirring, and then thoroughly stirred, passed through a mesh of 80 mesh, and used as a coating liquid for the release layer. Coating with Xiaolun BGB-5F coating machine, the coating is stopped when the weight gain is 2.0%-3.0%;
4) Immediate release layer coating: 3.2g of triethyl citrate was added to 560g of purified water, stirred evenly, and 32g of HPMC E5 hypromellose (E5) was slowly added under stirring, stirred until completely dissolved, and then the raw material was added. 40 g, stirred until evenly dispersed, passed through a mesh of 80 mesh, as a coating material for the immediate release layer. The coating was stopped by coating with a Xiaolun BGB-5F coater and increasing the weight to 3.6% (nifedipine or levofloxacin 18 mg).
The dissolution method of the above-mentioned nifedipine gastric retention tablets and levofloxacin gastric retention tablets was examined by the dissolution method of Experimental Example 1, as shown in Table 4, Figure 2 (nifedipine) and Figure 3 (levofloxacin).
Table 4. Dissolution data of nifedipine and levofloxacin stagnation tablets

Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention, and those skilled in the art can make some modifications and refinements without departing from the spirit and scope of the present invention. Therefore, the scope of the invention is defined by the scope of the appended claims.

no

Figure 1 is a dissolution profile of a febuxostat controlled release pharmaceutical composition.

Figure 2 is a dissolution curve of nifedipine gastric retention tablets.

Figure 3 is a dissolution curve of levofloxacin gastric retention tablets.

Claims (30)

A controlled release pharmaceutical composition, characterized in that the composition comprises a) a tablet-containing core comprising an active drug, b) an outer layer, the outer layer containing no active drug and containing at least one water-swellable matrix forming agent Maintaining intact in the environment of gastric juice or simulated gastric fluid for at least 4 hours, followed by rupture release; the composition swells to a size sufficient to remain in the stomach in the feeding mode. The controlled release pharmaceutical composition according to claim 1, wherein the composition is less than 10%, preferably less than 5%, when the soaking time is less than 4 hours in the environment of gastric juice or simulated gastric juice. Most preferably less than 2%; after soaking time is greater than 4 hours, preferably greater than 5 hours, the release amount is greater than 75%, preferably greater than 85%, and most preferably greater than 95%. The controlled release pharmaceutical composition according to claim 1 or 2, wherein the outer layer further comprises at least one gelling agent. The controlled release pharmaceutical composition according to claim 3, wherein the unit dosage form of the composition is selected from the group consisting of 8-22 mm, preferably 10-14 mm; and the size after swelling by water absorption is 11-22 mm. It is preferably 13-22 mm. A controlled release pharmaceutical composition comprising a) a tablet-containing core, b) an outer layer, said outer coating being free of active drug and comprising at least one water-swellable matrix forming agent. The controlled release pharmaceutical composition according to claim 5, wherein the outer layer further comprises at least one gelling agent. The controlled release pharmaceutical composition according to any one of claims 1 to 6, wherein the matrix forming agent in the outer cladding is selected from the group consisting of ethyl acrylate-methyl methacrylate-methyl methacrylate Trimethylaminoethyl ester 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, carbopol, glyceryl behenate, hydrogenated castor oil, cetyl alcohol, Carnauba wax, preferably ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate copolymer. The controlled release pharmaceutical composition according to claim 3, wherein the gelling agent in the outer layer is selected from the group consisting of ethyl cellulose, methyl ethyl cellulose, and hydroxypropyl cellulose. , hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylethylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, acetic acid Cellulose butyrate, cellulose propionate, hypromellose phthalate, hypromellose acetate succinate, hydroxypropyl methylcellulose acetate trimellitate, ethyl hydroxyethyl Cellulose, pregelatinized starch, vinyl povidone polymer matrix, polyvinylpyrrolidone, sodium polyacrylate and polyoxyethylene (160) polyoxypropylene (30) diol, polyethylene oxide, Pru Copolymer of blue polysaccharide, polyvinyl alcohol, polyvinyl acetate, glyceryl fatty acid ester, polypropylene decylamine, polyacrylic acid, ethacrylic acid or methacrylic acid, preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose Sodium carboxymethylcellulose, most preferably hydroxypropyl methylcellulose. The controlled release pharmaceutical composition according to any one of claims 1 to 8, wherein the outer covering further comprises a binder selected from the group consisting of polyvinylpyrrolidone and polyvinyl acetate. A formulated mixture of an ester and polyvinylpyrrolidone, preferably a formulated mixture of polyvinyl acetate and polyvinylpyrrolidone. The controlled release pharmaceutical composition according to claim 9, wherein the tablet-containing core contains one or more of a disintegrating agent, a gelling agent, and a floating aid. The controlled release pharmaceutical composition according to claim 10, characterized in that the content of the disintegrating agent, the gelling agent and the floating auxiliary agent in the tablet-containing core accounts for 5-70 of the total weight of the tablet core. %, preferably 10-50%. The controlled release pharmaceutical composition according to claim 10, wherein the tablet-containing core disintegrating agent is selected from the group consisting of sodium carboxymethylcellulose, croscarmellose sodium, and carboxymethyl Cellulose calcium, low substituted hydroxypropyl cellulose, sodium carboxymethyl starch, partially pregelatinized starch, pregelatinized starch, crospovidone, preferably sodium carboxymethyl starch, partially pregelatinized starch, cross Sodium carboxymethylcellulose, most preferably croscarmellose sodium. The controlled release pharmaceutical composition according to claim 10, wherein the gel containing the tablet core is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose. , sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, pregelatinized starch, sodium alginate, gelatin, agar, tragacanth, xanthan gum, guar Gum, gum arabic, carrageenan, carboxyvinyl polymer, polyethylene oxide, vinyl acetate povidone polymer matrix, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, sodium polyacrylate and polyoxygen Ethylene (160) polyoxypropylene (30) diol. The controlled release pharmaceutical composition according to claim 10, wherein the floating agent in the tablet-containing core is at least one selected from the group consisting of citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, A combination of an acidic substance of ascorbic acid and malic acid with at least one basic substance selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, and calcium carbonate. The controlled release pharmaceutical composition according to any one of claims 1 to 14, wherein the content of the active drug in the core of the tablet is from 3 to 60%, preferably from 10 to 50%, based on the total weight of the core. It is preferably 20-40%. The controlled release pharmaceutical composition according to claim 15, which further comprises an immediate release component. The controlled release pharmaceutical composition according to claim 16, wherein the immediate release component is in an environment of gastric juice or simulated gastric juice within 1 hour, and the release amount is greater than the total amount of the immediate release component drug. 70%, preferably 80%, most preferably 90%. The controlled release pharmaceutical composition according to claim 16 or 17, wherein the immediate release component is coated on the outer cladding in a coating form. The controlled release pharmaceutical composition according to claim 18, which comprises the following components: a tablet core containing an active drug and a disintegrating agent; and ethyl acrylate-methyl methacrylate-methacrylic acid. An outer cladding of a formulation mixture of trimethylaminoethyl chloride copolymer, hydroxypropylmethylcellulose, polyvinyl acetate and polyvinylpyrrolidone; an immediate release drug-containing coating. The controlled release pharmaceutical composition according to claim 18, wherein the outer layer and the immediate release drug-containing coating layer further comprise an isolating layer. The controlled release pharmaceutical composition according to claim 20, wherein the material of the separation layer is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and alginic acid. One or more of sodium, methylcellulose, sodium carboxymethylcellulose, povidone, acrylic resin, polyvinyl alcohol polyethylene glycol copolymer, preferably hydroxypropylmethylcellulose. The controlled release pharmaceutical composition according to any one of claims 1 to 21, wherein the matrix forming agent in the outer layer accounts for 40% to 95%, preferably 60% to 90%, of the total weight of the outer layer. Most preferably from 75% to 85%. The controlled release pharmaceutical composition according to any one of claims 3, 6, and 8 to 22, wherein the weight of the gelling agent in the outer layer accounts for 1% to 30% of the total weight of the outer layer, preferably 5%-20%, most preferably 8%-15%. The controlled release pharmaceutical composition according to any one of claims 9 to 23, wherein the weight of the binder in the outer layer is from 1% to 30%, preferably 5%, based on the total weight of the outer layer. %, most preferably 8%-15%. The controlled release pharmaceutical composition according to any one of claims 20 to 21, wherein the release layer and the immediate release component further comprise a plasticizer, and the plasticizer is selected from the group consisting of paraffin, Corn oil, refined coconut oil, glycerin monoacetate, triacetin, glycerin, triethyl citrate, tributyl citrate, polyethylene glycol, triethyl phthalate, tributyl phthalate Ester, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, glyceryl stearate, diethyl succinate, propylene glycol, castor oil and Triacetin, preferably triethyl citrate. The controlled release pharmaceutical composition according to any one of claims 16 to 21, wherein the immediate release component further comprises a binder selected from the group consisting of polyvinylpyrrolidone, Any one or a combination of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, povidone starch, sucrose, or dextrin is preferably hydroxypropylmethylcellulose. The controlled release pharmaceutical composition according to any one of claims 1 to 26, wherein the active drug is selected from the group consisting of drugs having a narrow absorption window. The controlled release pharmaceutical composition according to claim 27, wherein the drug of the narrow absorption window is selected from the group consisting of febuxostat, nefazodone hydrochloride, ibuprofen, and ondans Joan, ondansetron hydrochloride, metformin, midazolam hydrochloride, olanzapine, ofloxacin, ciprofloxacin, topiramate, atorvastatin, simvastatin, gatifloxacin, rosiglitazone , ranitidine, cimetidine, famotidine, captopril, quinapril, ramipril, acyclovir, fexofenadine, pseudoephedrine, bupropion, nevi Zalidine, fluoxetine hydrochloride, nifedipine, nicardipine, naproxen, amlodipine maleate, lovastatin, omeprazole, lansoprazole, pantoprazole, etoma Latrazole, clarithromycin, ranitidine hydrochloride, sertraline hydrochloride, ropenem, bisphosphonate, furosemide, gabapentin, levodopa, carbidopa, baclofen, pregabalin, Acyclovir, pabutrazil, metoprolol, valacyclovir, nitrofurantoin, lithium carbonate, calcium carbonate, citric acid, citric acid, ascorbic acid, leaves , vitamin E, pravastatin, enalapril, cilazapril, benazepril, fosinopril, salbutamol, pirinol, allopurinol, atenolol, cimetidine, famo Tetidine, misoprostol, 5-fluorouracil, doxorubicin, mitomycin, cisplatin, etoposide, semustine, methotrexate, clarithromycin, metronidazole, zaleplon, methyl Naltrexone, tetracycline. The controlled release pharmaceutical composition according to any one of claims 1 to 26, wherein the active drug is selected from the group consisting of a pharmacologically relevant drug, and the pharmacologically relevant drug includes, but is not limited to, The medicine for treating angina pectoris, the antihypertensive drug, the anti-hyperlipidemic drug, the medicine for treating asthma, the medicine for treating angina is selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, betaxolol, succinic acid Metoprolol, ranolazine, nifedipine, ivabradine hydrochloride, atorvastatin, amlodipine, cilostazol, verapamil, diltiazem hydrochloride, donaperminogene, seltoplasmid, lercanidipine, calvi Dullo, nilvadipine, nicorandil, benidipine, bisoprolol fumarol, atenolol, felodipine, bainidipine, iraradipine, celrilol, trinitrate, jaundice A glucoside, progesterone, tirofiban hydrochloride, and efodipine hydrochloride; the antihypertensive drug is selected from the group consisting of sildenafil citrate, amlodipine, Trevyent, citrulline, carvedilol phosphate Clonidine, betatalol Sacubitril, valsartan, candesartan cilexetil, rosuvastatin calcium, treprostinil, methyl bardoxolone, olmesartan medoxomil, non-marsartan, metoprolol succinate, nifedipine Dipine, olbecholic acid, tadalafil, irbesartan, atorvastatin, macitentan, aliskiren, sunitinib, nebivolol, losartan, umbramide, Esuberaprostsodium, iptakalim, leoxicillin, doxazosin, diltiazem hydrochloride, alisartan, ambrisentan, candesartan, Selexipag, gamma adenosine, lercanidipine, mecamylamine, Esaxerenone , hydrochlorothiazide, telmisartan, furosemide, spironolactone, ramipril, bosentan, Treprostinil diolamine, perindopril, bisoprolol fumarate, azilsartan, nilvadipine, Amisulfolol, udenafil, cilnidipine, lovastatin, treprostinil, elaradiide, fosinopril, chlorthalidone, quinapril hydrochloride, iloprost, epoprostenol , aliskiren, midazolam, beraprost, adipine, indapamide, clevidipine, torsemide, Nidipine, candesartan cilexetil, felodipine, terazosin, nicardipine, bainidipine, eplerenone, enalapril, quinapril hydrochloride, perfluoro-n-butane, uradia , prazosin, Elpaqu, Moxonidine, Nepolong, Manidipine, Ilapidine, Spiropril, Zofenopril, Benazepril, Bunazosin, Group Dopply, Dependent Prasalan, dexamepril hydrochloride, moxipril, trichlorothiazide, nicitipine, fenoldopam, valproate, nitrendipine, docarbaamine, naphtholidine, fosump , ketochrome tartrate, adipine, propranolol, effluentine, delaipril; the anti-hyperlipidemic agent is selected from the group consisting of Apabetalone, rosuvastatin, ezetimibe, simvastatin , Worapasha, Colesovalon, Pemafibrate, Irbesartan, Atorvastatin, Bempedoic acid, Volanesorsen, Lomestat, Sarogreza, Amlodipine, Losartan, Misoprostol, Pravastatin, lovastatin, cerivastatin, clofibrate, fenofibrate, gemfibrozil, tacrine, pitavastatin, olmesartan cilexetil, non Marsartan, fenofibrate, valsartan, metformin, dalcetrapib, telmisartan, hydrochloric acid, Acetylsalicylic acid, ramipril, bezafibrate, isradipine, acipimox, sulphuric acid Hydroclopidogrel, colestilline, lacidipine, ciprofibrate, fenofibrate, glimepiride; the drug for treating asthma is selected from the group consisting of theophylline, fluticasone furoate, and virantra Benzoate, fluticasone propionate, citrulline, etanercept, abatacept, glycopyrrolate, budesonide, formoterol fumarate, salmeterol, Mitizax, dasatinib , beclomethasone dipropionate, montelukast sodium, imatinib, ipratropium bromide, tobracilol, roflumilast, indacaterol, mometasone furoate, methylprednisolone, koji Anede, dexamethasone, salbutamol, terbutaline, procaterol, isoproterenol, evipiprant, salbutamol, mometasone, cisplatin, Grazax, levocetirizine hydrochloride, timapiprant, ciclesonide, Ozagray, prednisolone, ebastine, mometasone furoate, ezetine, dexpramipexole, methane Tebastine, pirenast, doxofylline, flunisolide, sodium cromoglycate, zafirlukast, pyrimilast, flubuterol hydrochloride, sertrastat, dextrovir Special, bambuterol, eplesine hydrochloride, nedocromil, toltoterol, mizolastine, prussit, tranilast, sulfonamide, and rispiride. A method for preparing a controlled release pharmaceutical composition according to any one of claims 1 to 29, which comprises the steps of: 1) a powder core containing an active drug; 2) a dry method The outer cladding material containing the matrix former is pressed into a core coating.