WO2018228441A1 - Controlled release pharmaceutical composition and method for preparing same - Google Patents

Abstract

The present application relates to a controlled release pharmaceutical composition. The controlled release pharmaceutical composition comprises: a) an immediate release component containing an active drug; and b) a delayed release floating component containing an active drug, the delayed release floating component is prepared by means of hot melt extrusion.

Description

Controlled release pharmaceutical composition and preparation method thereof

The present application claims priority on Chinese Patent Application No. CN201710454301.5, filed on Jun. 14, 2017. This application cites the entire text of the above-mentioned Chinese patent application.

Technical field

The invention relates to a controlled release pharmaceutical composition, belonging to the field of pharmacy.

Background technique

In the pharmaceutical field, in order to effectively reduce the number of medications, increase the compliance of patients taking medication, improve the safety of medication and reduce side effects of the gastrointestinal tract, many drugs have been developed to contain immediate release components and sustained release components. A controlled release formulation, such as the cardro-dualopa modified release formulation disclosed in CN101910113A.

Most of the compounds absorb poorly at the back end of the intestine, causing the preparation to be released and absorbed into the colon (usually considered to be 4-6 hours) after the patient takes the preparation, and the preparation cannot be effectively released and absorbed. It is impossible to ensure the effective maintenance of blood concentration 6 hours after taking the medicine by means of ordinary sustained release. The oral gastric retention preparation prolongs the residence time of the drug at the upper end of the gastrointestinal tract, and even if the drug is poorly absorbed at the rear end of the intestinal tract, the drug can be effectively released and absorbed after 6 hours of administration. The dosing interval and dose increase patient compliance. The gastric floating preparation is one of the ways of gastric retention, which increases the residence time of the preparation in the stomach. It has been absorbed in the upper part of the gastrointestinal tract but has little solubility or is easily degraded in an alkaline environment, and is delivered to the stomach. Topical and long-lasting administration of the upper end of the small intestine for the treatment of certain specific conditions.

At present, a large number of prior art has disclosed a achievable manner of gastric floating preparations. For example, CN103037850A discloses a type of elongated intragastric retention capsule, which has been shown to prolong gastric retention time, however, such a design There is a risk of gastric obstruction or permanent retention of the system, so its actual value is small. In order to achieve a more reasonable drug effect, a large number of drugs have been made into a gastric floating drug delivery system combining immediate release and controlled release, but most of them are double-layer tablets or capsules. For example, Yin Lifang et al. disclose a gastric floating system. The bilayer tablet has active ingredients of pioglitazone and metformin, wherein the immediate release component is pioglitazone and the controlled release component is metformin. The bilayer tablet is obtained by adding sodium carbonate which can generate carbon dioxide and a low density floating aid stearyl alcohol. The effect of floating is achieved, with the most preferred formulation being able to float in the test solvent for at least 24 h (International Journal of Pharmaceutics 476 (2014) 223-231). However, single tablets have various disadvantages such as poor floating ability, long drift time, and large individual differences. Indian Patent Application No. 200900/00792 A discloses a dual particle intragastric delivery system comprising immediate release particles of ofloxacin and gastric floating controlled release particles, wherein the controlled release particles comprise a hydrophobic material and a hydrophilic material.

Hot melt extrusion (HME) is the process of pumping raw materials through a mold through a mold at a high temperature to a uniform shape product. HME has many advantages over other drug treatment techniques in that the molten polymer can be used as a thermal adhesive during extrusion and as a drug depot and/or drug release blocker upon cooling and solidification. Since the process does not require solvent and water, the number of processing steps is reduced and the time consuming drying step is eliminated. The matrix material can be assembled into larger units that are independent of the compression characteristics. The intense mixing and agitation exerted by the rotating screw causes the agglomeration of suspended particles in the molten polymer to make the dispersion more uniform.

In recent years, hot melt extrusion technology has been tried in the preparation of controlled release gastric floating preparations, and Nakamichi et al. disclose a floating preparation of nicardipine hydrochloride prepared by a twin-screw extruder, which is hot melt extruded. The polymer material was hydroxypropylmethylcellulose acetate succinate (HPMCAS). It was found that only the use of drugs and polymers did not result in a loose extrudate, and the third intermediate substance, dihydrate phosphoric acid, must be added. Calcium, when the amount of calcium phosphate dihydrate is 8%, floats in gastric juice for 6 hours (International Journal of Pharmace-Utics 218 (2001) 103-112). Nakamichi speculated that the action of calcium phosphate dihydrate, when the melt of the drug and the polymer is in the machine, is subjected to the high pressure of the screw, and the moment of extrusion from the machine head enters the atmospheric zone from the high pressure zone, according to The Lausius-Clapperon equation, the boiling point of the melt will have a downward trend. At this time, the solid calcium phosphate dihydrate is equivalent to zeolite, and a gasification center is introduced into the melt, so that the extrudate is instantaneously produced. A lot of bubbles. As the temperature rapidly decreases, the bubbles solidify immediately, giving a loose material.

US2016113906A discloses a hot melt extruded composition which, by adding a polar organic solvent to a hot melt extruded composition, reduces the decomposition of the active ingredient and increases the miscibility between the active ingredient and the polymer. Reduces the operating temperature and temperature of the hot melt extrusion and reduces the torque. Nakamichi et al. examined the effect of moisture on solid dispersions prepared by twin-screw hot melt extruders. The results of the tests demonstrate that the addition of water reduces the flow temperature (Tfb) of the material, demonstrating that the material can be at temperatures below the melting point. Extrusion (International Journal of Pharmaceutics 241 (2002) 203-211).

Padma V. Devarajan et al. disclose a gastric floating controlled release multiparticulate formulation of metoprolol succinate prepared by hot melt extrusion to optimize the hot melt extruded material Eudragit RSPO

The ratio between polyoxyethylene (PEO) and hydroxypropylmethylcellulose (HPMC) is used to balance the floating capacity and the controlled release ability, and the production of gas uses sodium carbonate (International Journal of Pharmaceutics 491 (2015) 345-351).

Mamoru Fukuda et al. disclose a gastric retention floating sheet prepared by hot melt extrusion using Eudragit RSPO (

RS PO) and or Eudragit EPO (

E PO.) Matrix material, the effect of sodium carbonate on the physicochemical properties of the composition was examined (Journal of Controlled Release 115 (2006) 121-129).

Michael A. Repka et al.

Or hydroxypropylmethylcellulose K15M (HPMC K15M) as a matrix material, using the method of adding ethanol in the hot melt extrusion process to prepare gastric floating pellets (European Journal of Pharmaceutics and Biopharm-

Aceutics 98 (2016) 108–121). Michael A. Repka et al. disclose a dual-effect intragastric therapeutic delivery system comprising a solid dispersion prepared by hot melt extrusion using felodipine as an active ingredient, hydroxypropyl Cellulose-based hydroxymethylcellulose is used as a matrix material, and the residence time of the drug in the stomach is made longer by the adhesion of the floating agent (European Journal of Pharmaceutical Sciences 102 (2017) 71-84), however, this The inherent danger of the dosage form is that adhesion of the drug to the esophagus may cause damage.

Because of the irreplaceable advantages of hot melt extrusion technology and gastric floating preparations, and the superiority of the controlled release preparations containing immediate release and controlled release components in terms of efficacy, it is obvious that a variety of technologies have been developed to develop new types. The formulation of various technical barriers is of great importance to the pharmaceutical industry.

Summary of the invention

The invention provides a controlled release pharmaceutical composition prepared by hot melt extrusion, which effectively prolongs the residence time in the gastrointestinal tract and increases the effective absorption time of the gastrointestinal tract to more than 10 hours, thereby effectively reducing the dosage. The number of times increases the compliance of patients taking medication.

The present invention provides a controlled release pharmaceutical composition comprising: a) an immediate release component comprising an active drug, b) a delayed release floating component comprising an active drug, characterized in that said delayed release floating component is passed through a heat fusion The extrusion process is prepared.

The controlled release pharmaceutical composition of the present invention is characterized in that the delayed release floating component contains at least one enteric polymer. The delayed release drug component containing the enteric polymer of the present invention releases the drug at a pH of ≥ 5.5.

The controlled release pharmaceutical composition provided by the present invention is characterized in that the enteric polymer is selected from the group consisting of polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, and 1,2,4-benzenetricarboxylic acid acetic acid. Cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose 1,2,4-benzenetricarboxylate, cellulose acetate succinate, hypromellose acetate succinate, hydroxyacetate Propylmethylcellulose phthalate, methacrylic acid-ethyl acrylate copolymer, methyl vinyl ether-maleic anhydride copolymer, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, methacrylic acid-A Methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate copolymer, polyvinyl acetate, ethyl cellulose, polyvinyl acetate and polyvinylpyrrolidone K30 mixture Preferably, hypromellose acetate succinate, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate.

In some embodiments, the methacrylic acid-ethyl acrylate copolymer is a 1:1 copolymer corresponding to commercially available Eudragit 100-55 or Kollicoat MAE 100P.

In some embodiments, the methyl vinyl ether-maleic anhydride copolymer is commercially available.

series.

In some embodiments, the methacrylic acid-methyl methacrylate copolymer is a 1:1 or 1:2 copolymer corresponding to Eudragit L100 and Eudragit S100, respectively.

In some embodiments, the mixture of polyvinyl acetate and polyvinylpyrrolidone K30 is Kollidon SR.

In some embodiments, the enteric polymer described herein is an Eudragit polymer, such as Eudragit L, Eudragit S or Eudragit L 100-55.

In some embodiments, the enteric polymer described in the present invention is hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl acetate succinate disclosed in the prior art US 4,266,981 B, CN 104208713 A, and CN 103153343 A. Cellulose is included within the scope of this application.

HPMCAS sold by Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan) is classified into three grades having different combinations of substituent levels to provide enteric protection at various pH levels. AS-LF and AS-LG grades ("F" means fine and "G" means granules) provide enteric protection at a pH of up to 5.5. The AS-MF and AS-MG grades provide enteric protection at pH values up to 6.0, while the AS-HF and AS-HG grades provide enteric protection at pHs up to 6.8.

The controlled release pharmaceutical composition provided by the present invention is characterized in that the ratio of the active drug to the enteric polymer in the delayed release floating component is selected from 1:0.1 to 1:100, preferably from 1:0.1 to 1:50, more preferably 1: 1-1:25.

The controlled release pharmaceutical composition provided by the present invention, wherein the hot melt extrusion method optionally participates in a hot melt extrusion process, that is, in some embodiments, a solvent is added, and in other embodiments, a solvent is not added, in the present invention The participation of the solvent means that the solvent is added before the hot melt extrusion or during the hot melt extrusion process for the needs of the invention.

In the controlled release pharmaceutical composition provided by the present invention, if a solvent is added during the preparation, the solvent only needs to be able to be volatilized after the end of the hot melt extrusion process. Preferably, the present invention limits the boiling point of the solvent to 30. -110 ° C.

The controlled release pharmaceutical composition provided by the present invention is characterized in that the solvent is at least selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, dichloromethane, tetrahydrofuran. One is preferably water and ethanol.

The present invention provides a controlled release pharmaceutical composition having a density of delayed release floating components in a controlled release pharmaceutical composition of from 0.1 to 1.0 g/cm3, preferably from 0.2 to 0.8 g/cm3, when a solvent is involved in the hot melt extrusion process. Most preferably, it is 0.3-0.7 g/cm3, which is porous under electron microscopy, and can be floated immediately in a solution of FaSSGF at pH 5.0 and maintained for a float time of more than 24 h.

The controlled release pharmaceutical composition provided by the present invention contains an alkaline substance which is exposed to an acid generating gas in the preparation process without adding a solvent, that is, the alkaline substance in the controlled release pharmaceutical composition of the present invention is not essential, and when the alkaline substance is contained The basic substance is specifically an alkali metal carbonate, an alkali metal or an alkaline earth metal hydrogencarbonate, more specifically sodium hydrogencarbonate, sodium carbonate, sodium aminoacetate carbonate, potassium hydrogencarbonate, magnesium carbonate and calcium carbonate. .

The controlled release pharmaceutical composition provided by the present invention does not contain calcium phosphate dihydrate, Nakamichi (International Journal of Pharmace-Utics 218 (2001) 103-112), and others add calcium phosphate dihydrate to the drug and the matrix, and by hot melt extrusion After that, a floatant was prepared.

The controlled release pharmaceutical composition provided by the present invention, the delayed release floating component in a 300 mL of FaSSGF dissolution medium at pH 5.0, the basket method, 37 ° C, 100 rpm, 5 h cumulative dissolution is less than 30%, more preferably less than 20% Most preferably less than 10%.

The controlled release pharmaceutical composition of the present invention is characterized in that the delayed release floating component is in a multi-unit form.

The controlled release pharmaceutical composition of the present invention is characterized in that the multi unit form is a microtablet, a pellet, a pellet, preferably a pellet.

The immediate release component of the controlled release pharmaceutical composition provided by the invention may be selected from the form of pellets, microtablets, granules and the like. Specifically, when the immediate release component is a pellet, the active drug and the blank pellet core may be contained. .

In general, pharmaceutical preparations reach the colon in most cases after oral administration in 3 to 6 hours. Therefore, the success of the sustained-release preparation is to increase the time of gastrointestinal absorption and increase absorption.

The Biopharmaceutical Classification System (BCS) introduced by the FDA has classified drugs according to their solubility and intestinal permeability, see "The Biopharmaceutics Classification System (BCS) Guidance". Jennifer B. Dressman and Christos Reppas, on page 273 of the Oral Drug Absorption: Prediction and Assessment, mention that drugs that have high solubility and permeability when administered orally (Class I) generally have good absorption throughout the gastrointestinal tract. It is the most preferred drug for the sustained release preparation, and such a drug is included in the range of the active drug of the delayed release floating component of the present invention.

Class I drugs in the BCS classification of the present invention include, but are not limited to, pabitatin, Cobimetinib, Patiromer, omarigliptin, bupropion, guanfacine, venlafaxine hydrochloride, methylphenidate hydrochloride, Tetrazolamide, flurbanin, eliglustat, alogliptin, dimethyl fumarate, pyrenoprene, lometanide, rosobinib, clozaban, dalfampridine, Prolia, drone Dalong hydrochloride, Pralatrexate, lacosamide, fesoterodine fumarate, alprazolam, amitriptyline hydrochloride, amlodipine besylate, benazepril, amoxicillin, anastrozole, azastroz Ting, bisoprolol, buspirone, caffeine, carbidopa, cetirizine, chloroquine phosphate, chlorpheniramine, clindamycin, clonidine, cyclobenzaprine, cyclophosphamide, deoxygenation Pregnene, ethinyl estradiol, diazepam, diphenhydramine, donepezil hydrochloride, doxazosin mesylate, doxycycline, emtricitabine, estradiol, ethosylamine, fensamine Phenazepine, finasteride, fluconazole, flucytosine, fluoxetine hydrochloride, fluvoxamine mesylate, imipramine, guanidine Pamine, isoniazid, lamivudine, lidocaine, lorazepam, losartan, metoprolol succinate, mexiletine, midazolam, mirtazapine, montelukast sodium , norethisterone, norgestrel, nortriptyline, olopatadine hydrochloride, oseltamivir, pramipexole, pravastatin sodium, prednisone, prednisolone, pregabalin , procainamide hydrochloride, promethazine hydrochloride, propranolol hydrochloride, pyrazinamide, pyridoxine hydrochloride, quinapril hydrochloride, quinidine, quinine Hydrochloride, ramipril, sertraline, sildenafil citrate, sotalol, stavudine, terbinafine hydrochloride, tolterodine, torasemide, ko Malone hydrochloride, trazodone, varenicline, zidovudine, alfacalcidol, beraprost, biperiden, brompheniramine, bromozolam, carbifamine, clomiphene , clomipramine, cloxacillin, diltiazem, dolasetron, morphine, eperisone hydrochloride, epilistin, calciferol, ergometrine, ergotamine, ethinyl estradiol, etidazolam , fluvastatin, granisetron, Tetfen, levamisole, levonorgestrel, erimaprost, loxoprofen, mefloquine, mexiletine hydrochloride, nicardipine, niclosamide, tobrexol, trimethoprim, koji Mebutin, toremifene, terbinafine, temocapril, tamsulosin, sertraline, sarpogrelate hydrochloride, saquinavir, rosiglitazone, reserpine, remept Lee, propiverine hydrochloride, promethazine, pergolide, paroxetine.

Jennifer B. Dressman and Christos Reppas on page 272-274 of Oral Drug Absorption: Prediction and Assessment indicate that Class II to IV drugs in the BCS classification show poor colonic absorption or poor solubility due to problems with permeability and solubility. Unsuitable for preparation into a sustained-release preparation, the composition of the present invention effectively uses the enteric polymerization to effectively prolong the residence time of the drug in the gastrointestinal tract due to the use of hot melt extrusion technology and gastric floating technology, especially the use of enteric polymerization. The absorption rate of the drug in the small intestine shows a better effect for the drug of this kind.

The BCS classification of the present invention belongs to the class II to IV drugs including, but not limited to, febuxostat, ixazomib, Alectinib, Erismodegib, vandetanib, aprepitant, worapsar sulfate, aspirin, metformin, Engliflozin, linagliptin, naltrexone, dasabuvir, sofosbuvir, amphetamine, etravirine, everolimus, itraconazole, vemurafenib, telaprevir , tacrolimus, posaconazole, isikato, redipavir, Suvorexant, Ombitasvir, paritaprevir, daclatasvir, cariprazine, brexpiprazole, omemiprofen, levetiracetam, ivacaftor, eluxadoline , lumacaftor, ivacaftor, atratropa, nidanib, meloxicam, morphine, macitentan, dutasteride, abiraterone, lumacaftor, dagley net, hesiqiong, yilu Tinidil, peramivir, olrapani, empaglifloz, itelalisib, balystatin, ceritinib, apster, pomamide, omemiprofen, calpamin, Dalafenib mesylate, trimetinib, dolutegravir, vortioxetine, bazedoxifene, simeprevir, ar Cetinib, Vismodegib, Avavira, lorcaserin, Mirabelon, Bosutinib, Triflurane, Regorafenib, Tofacitinib, Cabozantinib, Panatinib, Apixaban, Bedaquiline, Crofelemer, Poseprevir, Traverse, Bellasep, Vilafenib, Crizotinib, Roflumilast, Verazodone, Alzartan, Gabapentin, Van derani Nalagliptin, rivivirin, fidarimycin, ezitabine, icatibine acetate, rivaroxaban, ticagrelor, polidocanol, carglumic acid, temoline, vemurafenib, cabazitaxel, Dabigatran etexilate, everolimus, tolvaptan, prasugrel, saxagliptin, telavancin, pazopanib, silodosin, rufinamide, eltrombopag, acetazolamide, acetaminophen, acyclovir, atovava Statins, atorvastatin calcium, amprenavir, aripiprazole, atenolol, ketamine, attorikone, azathioprine, azithromycin, budesonide, calcitriol, isopropyl methacrylate Diurea, cefdinir, cefixime, cefuroxime acetate, celecoxib, cephalosporin Benzyl, chlorothiazide, clarithromycin, clopidogrel hydrogen sulphate, clotrimazole, betamethasone, diaminodiphenol, diclofenac sodium, bicyclic amine, arrived in Nuoxin, cannabinol, duloxetine, degree Otamin, etodolac, ezetimibe, simvastatin, felamine, fenofibrate, flecainide, phosphaviravir, furosemide, xyloxyheptanoic acid, glime Urea, glibenclamide, griseofulvin, ibuprofen, hydroxychloroquine, hydroxyzine, indomethacin, irbesartan, isoniazid, iraradipine, ketoconazole, lamotrigine, Lansoprazole, latanoprost, linezolid, loperamide, chlorocarbon cephalosporin, loratadine, lovastatin, mebendazole, meclizine, guanidine, salicylic acid, metha Ketone, piperidine acetate methyl ester, methylprednisolone, modafinil, mycophenolic acid, mycophenolate mofetil, nabumetone, naproxen, nifedipine, omeprazole, Carbamazepine, oxycodone hydrochloride, phenazopyridine, phenytoin, pioglitazone hydrochloride, piroxicam, deoxyphenobarbital, prochlorperazine, progesterone, pyrimethamine, Quetiapine, raloxifene hydrochloride, rifabutin, rifampicin, risperidone, spironolactone, sulfamethoxazole, tadalafil, telmisartan, telavanavir, valsartan , vardenafil, ziprasidone, abacavir sulfate, codeine, albuterol, alendronate, allopurinol, potassium clavulanate, benzotropine, bimatoprost, butylbenzene Normaine, naloxone, captopril, levodopa, cefixime, cefadroxil, cetirizine hydrochloride, ciprofloxacin, colchicine, ergocalciferol, famotidine, Pseudoephedrine, folic acid, gabapentin, hydralazine, hydrochlorothiazide, salbutamol, levocetirizine, levofloxacin, levothyroxine sodium, lisinopril, methotrexate, methyldopa, nadolol, nystatin, Latrazole, primaquine phosphate, pyrazinamide, ranitidine hydrochloride, ribavirin, risedronate sodium, solifenacin, spironolactone, sumatriptan succinate, Terazosin, tetracycline, thiamine, topiramate, valacyclovir hydrochloride, valganciclovir, acarbose, aceclofenac, Acylzolamine, acetylcarnitine, albendazole, allenamide, amiloride, atropine, azathioprine, azithromycin, benidipine, benserazide, benznidazole, bicalutamide, Bisacodidine, cabergoline, candesartan, capecitabine, carvedilol, cefditoren, cefmetazole, cefotiam, cefpodoxime, ceftazidime, cefuroxime axetil, celecoxib , chloramphenicol, chlorpromazine, cilazapril, cilostazol, cimetidine, citalopram, chlorpheniramine, cyclosporine, cyproterone, dapsone, ethamazine, Digoxin, diclofen, deoxyfluorouridine, doxycycline, ebastine, efavirenz, epalrestat, valsartan, erythromycin, ethambutol, ezetimibe , famciclovir, fenofibrate, fluconazole, flurbiprofen, diurea, furosemide, gefitinib, gliclazide, glipizide, griseofulvin, haloperidol, hydrochloric acid Hydroxyzine, ibuprofen, imatinib, midazolam, indinavir, irbesartan, isoniazid, ivermectin, ketoprofen, lamotrigine, levofloxacin, lopi Wei, lovastatin, manidipine, mebendazole, medroxyprogesterone, aminosalicylic acid, metaxalone, methotrexate, methyldopa, metronidazole, modafinil, mosapride , nabumetone, nalidixic acid, nelfinavir, neostigmine, nevirapine, nicorandil, nicotinamide, nifurolimus, nilvadipine, nimesulide, zolpidem, zo Mitreloptan, zaltoprofen, warfarin, voglibose, verapamil, valproic acid, ursodeoxycholic acid, trimetazidine, tosufloxacin, ticlopidine, Theophylline, teprenone, tenofovir, tegafur, tamoxifen, statin, sultasis, sulpiride, sulfasalazine, sulfamethoxazole, sulfadiazine, stavudine , roxithromycin, rofecoxib, rizatriptan, ritonavir, risedronate, rifampicin, rifaximin, rebamipide, ranitidine, rabeprazole , nizatidine, norethisterone, olanzapine, olopatadine, orlistat, oseltamivir, oxcarbazepine, quetiapine, pyridoxine hydrochloride, bromide, propylthio Pyrimidine, Procaterol, Praziquantel, Montelukast, phenytoin, phenobarbital, phendimetrazine, perindopril, oxycodone, dexamethasone, furosemide.

The controlled release pharmaceutical composition provided by the present invention is characterized in that the delayed release floating component further comprises at least one plasticizer selected from the group consisting of triethyl citrate and tributyl citrate. , polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl sebacate, diethyl sebacate, glyceryl stearate, diethyl succinate, propylene glycol , castor oil and triacetin, preferably triethyl citrate, the plasticizer is present in an amount of from 0.01% to 50%, preferably from 0.1% to 30%, most preferably from 2.5% to 15% (% by mass, by solids) The total mass of the components is calculated as 100).

In some embodiments, the immediate release component and/or the controlled release floating component of the controlled release pharmaceutical composition provided herein further comprises at least one pharmaceutically acceptable additional excipient, a pharmaceutically acceptable excipient These include, but are not limited to, fillers, lubricants, glidants, binders, disintegrants.

As is well known to those skilled in the art, pharmaceutical excipients are conventionally incorporated into solid dosage forms to facilitate ease of handling and to improve the performance of the dosage form. Common excipients include diluents or fillers, lubricants, glidants, binders, disintegrants, and the like. Wherein a diluent or filler is added to increase the weight of the individual dose to a size suitable for tablet compression. Suitable diluents include powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, sodium chloride, dried starch, sorbitol, and the like.

The lubricant reduces the friction between the particles and the mold wall during compression and discharge. This prevents the particles from adhering to the tablet punches, facilitating their discharge from the tablet press, and the like. Examples of suitable lubricants that may be used include, but are not limited to, talc, stearic acid, vegetable oils, calcium stearate, zinc stearate, magnesium stearate, and the like.

Glidants are used to improve the flow characteristics of the particles. Examples of suitable glidants include, but are not limited to, silica, corn starch, micronized silica gel, talc, polyethylene glycol.

If the preparation of the composition includes a granulation step, a binder is usually used, and examples of suitable binders include, but are not limited to, pyrrolidone, polyvinylpyrrolidone, xanthan gum, cellulose gum such as carboxymethylcellulose, methyl Cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy cellulose, gelatin, starch and pregelatinized starch.

The disintegrant refers to a substance which can rapidly break up a tablet into fine particles in a gastrointestinal fluid, so that the functional component dissolves and absorbs rapidly, and functions. The disintegrants described in the present invention include, but are not limited to, one or more of low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, and crospovidone.

The controlled release pharmaceutical compositions provided herein, other excipients that may also be included in the compositions include, but are not limited to, preservatives, antioxidants, or any other excipients commonly used in the pharmaceutical industry, and the like.

The compositions provided by the present invention are ultimately presented in a pharmaceutically acceptable form for administration to a patient, optionally as a tablet or capsule.

The recommended mode of administration of the controlled release compositions of the present invention is after meals.

The controlled release pharmaceutical composition of the present invention is characterized in that the active drug in the delayed release floating composition optionally remains in a crystalline state or is converted to an amorphous state after the hot melt extrusion process.

It may be desirable to use a single drug in the pharmaceutical compositions of the present invention for efficacy, safety, economy, convenience, and/or efficiency, but it should be understood that the compositions of the present invention may include more than one drug, ie, The immediate release component is the same as or different from the drug in the delayed release release component.

The present invention also provides a method of preparing the above controlled release drug combination.

The method for preparing a controlled release pharmaceutical composition provided by the present invention comprises the steps of: 1) premixing at least one solvent, an active ingredient in a delayed release floating component, and at least one enteric polymer before hot melt extrusion. In the crude or hot melt extrusion process, at least one solvent, the active ingredient in the delayed release floating component and the at least one enteric polymer are mixed in advance to obtain a premixed crude product; 2) the premixed crude product passes through the heating screw zone of the extruder. After the die exits the extrudate.

The preparation method provided by the present invention is characterized in that the solvent only needs to satisfy the fact that it can be volatilized after the end of the hot melt extrusion process. Preferably, the present invention limits the boiling point of the solvent to 30-110 °C.

The preparation method provided by the present invention is characterized in that the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, dichloromethane, tetrahydrofuran, preferably water, ethanol. , isopropanol.

In the process provided by the present invention, the solvent is used in an amount of from 0.1% to 70%, preferably from 1% to 50%, most preferably from 10% to 30% by mass based on the total mass of the solid component of 100.

In the method disclosed herein, the temperature of the heated zone at the front end of the die should be greater than the glass transition temperature (Tg) of the extruded mixture.

The preparation method provided by the present invention is characterized in that the die temperature is from 70 to 200 ° C, preferably from 90 to 180 ° C, more preferably from 110 to 160 ° C.

The preparation method provided by the present invention is characterized in that the solvent injection screw zone temperature is 10-90 °C.

In view of the nature of the active therapeutic agent, in some parts of the present invention, if water is used as a solvent in the hot melt extrusion process, the esters (including lactones) and amides (including lactones) which are easily degraded by water are included. The amide) and the substance which is easily decomposed at a high temperature are not used as the active drug of the present application.

The preparation method provided by the present invention is characterized by further comprising the steps of: 1) cooling the extrudate, 2) removing the extrudate from the solvent; 3) cutting the extrudate.

In the method provided by the present invention, the solvent having a low boiling point and being relatively volatile may be substantially volatilized during extrusion according to the nature of the solvent itself and the temperature of the die, and the solvent having a low boiling point and being volatile is included, but not limited to, ethanol.

Substantially volatilized as used herein means that the residual amount of solvent in the extrudate is less than 15%, preferably less than 12%, and most preferably less than 10%.

The method provided by the present invention, when a solvent having a higher boiling point is selected, may be followed by a step of desolvating the extrudate after the end of hot melt extrusion.

In some embodiments, the solvent in the extrudate is removed under elevated temperature and/or vacuum conditions.

In some embodiments, the elevated temperature is sufficient to convert the solvent from a liquid to a gaseous state.

In some embodiments, the solvent in the extrudate is removed under reduced pressure conditions.

In some embodiments, the method of preparation provided by the present invention further comprises the step of cooling the extrudate.

The present invention provides a method of preparing a controlled release floating component in a controlled release pharmaceutical composition, characterized by further comprising the step of cutting the extrudate.

The preparation method of the immediate release portion of the present invention includes wet granulation, dry granulation, powder direct pressing and the like.

The preparation method provided by the present invention is characterized in that the extruder is selected from the group consisting of a single screw hot melt extruder, an intermeshing screw extruder, a twin screw hot melt extruder, preferably a twin screw hot melt extruder.

The term "delayed release" as used in the present invention refers to a type of improved release wherein the pharmaceutical dosage form exhibits a time delay between oral administration of the pharmaceutical dosage form and release of the drug from the dosage form. Typically, the delayed release release dosage form will have little or no release of the active compound for a predetermined period of time or until predetermined conditions are met, such as exposure to a certain pH level, and then the release of the active compound occurs immediately thereafter.

The term "controlled release" in the context of the invention refers to a type of extended release formulation wherein the gradual release of the drug is controlled or manipulated for an extended period of time.

DRAWINGS

Figure 1. Drug time profile of Formulation 3, Formulation 4, and conventional immediate release tablets;

Figure 2. Dissolution profile of the floating particles obtained in Examples 1-7;

Figure 3. Dissolution profile of particle G;

Figure 4. Dissolution profiles of Formulation 3, Formulation 4, and conventional immediate release tablets;

Figure 5. Electron microscopic scan of particle G;

Figure 6. Powder diffraction pattern before and after non-clothes hot melt extrusion in granule G.

Figure 7. Powder diffraction pattern of hydrochlorothiazide before and after extrusion of Example 10;

Figure 8. Example 10 dissolution profile;

Figure 9. Powder diffraction pattern of hydrochlorothiazide before and after extrusion in Example 11;

Figure 10. Example 11 dissolution profile;

Figure 11. Powder diffraction pattern of nifedipine before and after extrusion in Example 12;

Figure 12. Example 12 dissolution profile;

Figure 13. Powder diffraction pattern of tadalafil before and after extrusion in Example 13;

Figure 14. Example 13 dissolution profile;

Figure 15. Powder diffraction pattern of losartan before and after extrusion of Example 14;

Figure 16. Example 14 dissolution profile;

Figure 17. Example 15 dissolution profile;

Figure 18. Example 16 dissolution profile;

Figure 19. Example 17 dissolution profile;

Figure 20. Example 18 dissolution profile;

Figure 21. Powder diffraction pattern of hydrochlorothiazide before and after extrusion in Example 19;

Figure 22. Example 19 dissolution profile;

Figure 23. Powder diffraction pattern of hydrochlorothiazide before and after extrusion of Example 20.

Figure 24. Example 20 dissolution profile;

Figure 25. Powder diffraction pattern of losartan before and after extrusion of Example 21;

Figure 26. Example 21 dissolution profile;

Figure 27. Example 22 dissolution profile.

detailed description

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 HPMCAS used in the examples of the present invention was purchased from Shin-Etsu Chemical Co., Ltd., and the hot melt extruder was Thermo Fisher's twin-screw hot melt extrusion instrument.

Example 1. Febuxostat 1 consisting of immediate release febuxostat microchips and febuxostat floating particles A which release the drug above pH 6

The single capsule comprises an immediate release component and a delayed release floating component, the immediate release component is a microtablet containing 8 mg of febuxostat active ingredient, and the delayed release floating component is a particulate A containing 32 mg of febuxostat active ingredient, granules A is released above pH 6. The immediate release febuxostat microtablets were prepared by a wet granulation process, the formulation of which is listed in Table 1 below.

Table 1. Immediate release of febuxostat microchip prescription

	effect	8mg tablets
Febuxostat	Main drug	13.3%
lactose	Filler	35.0%
MCC	Filler	27.3%
Cross-linked carboxymethyl cellulose	Disintegrator	10.8%
Microsilica gel	Glidant	2.2%
HPMC-E5	Adhesive	3.6%
water	Binder solvent
Carboxymethyl starch sodium	Disintegrator	8.3%
Magnesium stearate	Lubricant	1.2%

The specific preparation process: wet granulation mechanism granules, mixing raw materials and auxiliary materials, adding binder, stirring, 1500 rpm cutting, sieving, drying, to moisture <3%, passing through 30 mesh sieve, and then using Chuangbo C&C600B single Stamping machine, 4.76mm punch press. Tablet weight: theory 61.5mg, the actual control is 59-65mg, the hardness is about 30N.

The febuxostat bleaching granule A was prepared by a hot melt extrusion process, the formulation of which is listed in Table 2 below.

Table 2. Formulation of febuxostat floating particles A

	Content (g)	percentage
Febuxostat	150	25%
HPMCAS MG	450	75%

The febuxostat and HPMCAS MG were weighed and mixed uniformly in a blender, and the hot melt extruder (Simofly) was set as shown in Table 3.

Table 3. Hot melt extruder temperature (°C)

Die	Zone8	Zone7	Zone6	Zone5	Zone4	Zone3	Zone2
140	110	90	70	40	30	30	30

Specifically, adding ethanol to Zone 4, the speed is 700 ul/min, Zone 2 feeding, the speed is 4 g/min, the rotation speed of the screw is set to 100 rpm, the extrudate is cut into segments, and then the extrudate is oven-dried at 60 ° C for 2 h. The ethanol content is less than 0.5%, and is pulverized to 2 mm after drying.

Example 2. Febuxostat formulation consisting of immediate release febuxostat pellets and febuxostat delayed release floating particle B, which rapidly releases the drug above pH 6

A single capsule contains an immediate release component and a delayed release floating component, the immediate release component is a pellet containing 8 mg of febuxostat active ingredient, and the remainder of the capsule contains a delayed release of febuxostat containing 32 mg of febuxostat. Floating particles B, this delayed release of floating enteric particles B is rapidly released above pH 6. The immediate release febuxostat pellets were prepared by a blank pellet core drug preparation process, and the prescription composition is shown in Table 4.

Table 4. Composition of immediate release febuxostat pellets:

	8mg pellets
Febuxostat	32%
Sugar pill	52%
Hypromellose	18%

The febuxostat controlled release floating granules B were prepared by a hot melt extrusion process, and the formulation composition thereof is shown in Table 5.

Table 5. Formulation of febuxostat floating particles B

	content
Febuxostat	25%
Hydroxypropylmethylcellulose	60%
HPMCAS MG	15%

150 g of febuxostat and 90 g of HPMCAS MG and 360 g of hydroxypropylmethylcellulose were weighed and mixed uniformly in a blender. The temperature setting of the hot melt extruder was as shown in Table 3. The ethanol was added to the Zone 4 of the hot melt extruder at a speed of 700 ul/min, the Zone 2 was fed at a speed of 4 g/min, and the rotation speed of the screw was set to 100 rpm. After cutting into sections, the extrudate was oven-dried at 60 ° C for 2 h, and the ethanol content was <0.5%. After drying, it is pulverized to 4 mm, and the controlled release granule B of febuxostat is obtained.

Example 3. Febuxostat formulation consisting of 20% immediate release febuxostat microchip and 80% febuxostat floating particle C releasing drug above pH 5

The single capsule comprises an immediate release component and a controlled release floating component, the immediate release component is a microtablet containing 8 mg of febuxostat, and the remainder of the capsule comprises a total of 32 mg of febuxostat gastric floating particles C, the gastric floating particles C is released above pH 5. The immediate release febuxostat microtablets were prepared by a wet granulation process, the formulation of which is listed in Table 1 above. The febuxostat controlled release floating granule C was prepared by a hot melt extrusion process, and its prescription composition is shown in Table 6.

Table 6. Formulation of febuxostat floating particles C

	content
Febuxostat	25%
HPMCAS LG	75%

After 150 g of febuxostat and 450 g of HPMCAS LG were uniformly mixed, hot melt extrusion was carried out, and the temperature parameter setting was the same as that of the preparation of the pellet A. The hot melt extruder's Zone4 was added with ethanol at a speed of 600 ul/min, Zone 2 was fed at a speed of 2 g/min, the screw speed was 60 rpm, the extrudate was cut into segments, and the extrudate was oven dried at 60 ° C for 2 h. The ethanol content is <0.5%, and after pulverization, it is pulverized to 4 mm long particles, and the febuxostat floating particles C are obtained.

Example 4 is a febuxostat formulation consisting of 40% immediate release febuxostat microtablets and 60% febuxostat floating particles C which release the drug above pH 5

The single capsule contains an immediate release component and a controlled release floating component, the immediate release component is a microchip containing 16 mg of febuxostat, and the remainder of the capsule contains a total of 24 mg of febuxostat delayed release floating particle C, which is delayed release. The floating controlled release granule C is released above pH 5. The immediate release febuxostat microchip was prepared by a wet granulation process, the formulation of which is listed in Table 1 above, and the febuxostat controlled release floating granule C was the same as in Example 3.

Example 5: a febuxostat formulation consisting of immediate release febuxostat pellets and delayed release febuxostat floating particles D 5

A single capsule contains an immediate release component and a controlled release floating component. The immediate release component is a pellet containing 8 mg of febuxostat active ingredient, and the remainder of the capsule contains a delay of 32 mg of febuxostat containing 32 mg of febuxostat. The floating particles D are released, and the gastric floating delayed release particles D are slowly released while floating in the gastric juice. The immediate release febuxostat pellets were prepared by a blank pellet core drug preparation process, and the prescription compositions are listed in Table 4 above.

The febuxostat gastric floating controlled release granule D was prepared by a hot melt extrusion process, and the composition of the formulation is shown in Table 7.

Table 7. Formulation of febuxostat floating particles D

After blending the febuxostat with the quaternary amino methacrylate copolymer type B and hypromellose, it was sheared in a wet granulator while slowly adding triethyl citrate dropwise. The mixed materials were hot melt extruded, the temperature parameters were set as in Table 3, ethanol was added in Zone 4, the speed was 1000 ul/min, Zone 2 was fed, the speed was 4 g/min, the screw speed was set to 100 rpm, and the extrusion was performed. The material was cut into sections, and then the extrudate was oven-dried at 60 ° C for 2 h, and the ethanol content was <0.5%. After drying, it is pulverized to 4 mm long granules, and the controlled release granule D of febuxostat is obtained.

Example 6 is a non-busestat formulation consisting of an immediate release febuxostat microparticle and a delayed release of febuxostat floating particle E 6

The single capsule contains an immediate release component and a controlled release floating component. The immediate release component is a microtablet containing 8 mg of febuxostat. The remainder of the capsule contains a total of 32 mg of febuxostat delayed release floating particles E, which floats on the stomach. The controlled release granule E is slowly released while floating in the gastric juice. The immediate release febuxostat microchips were prepared by a wet granulation process, and the formulation of the compositions is shown in Table 1. The febuxostat gastric floating delayed release granule E was prepared by a hot melt extrusion process, and its prescription composition is shown in Table 8.

Table 8. Formulation of febuxostat floating particles E

The febuxostat was mixed with other excipients in a prescribed amount and then subjected to hot melt extrusion. The temperature parameters were set as shown in Table 3. Add ethanol to Zone4 at a rate of 300 ul/min, Zone2 feed at a speed of 4 g/min, set the screw speed to 100 rpm, cut the extrudate into sections, and then extrude the extrudate at 60 ° C for 2 h in ethanol. The content is <0.5%, pulverized to 4 mm long particles, and the obtained bupretaxer gastric floating controlled release granule E is obtained.

Example 7 is a non-busestat formulation consisting of an immediate release febuxostat microparticle and a controlled release febuxostat floating particle F

The single capsule contains the immediate release component and the controlled release floating component, and the immediate release component is a microchip containing 8 mg of febuxostat. The remainder of the capsule contains a total of 32 mg of febuxostat floating particles F, which is controlled by the stomach. The release granule E is slowly released while floating in the gastric juice. The immediate release febuxostat microtablets were prepared by a wet granulation process, the formulation of which is listed in Table 1. The febuxostat gastric floating controlled release granule F was prepared by a hot melt extrusion process, and its formulation composition is shown in Table 9.

Table 9. Formulation of febuxostat floating particles F

The febuxostat was mixed with other excipients in a prescribed amount and then subjected to hot melt extrusion. The temperature parameters were set as shown in Table 3. Add ethanol to Zone4 at a rate of 300 ul/min, Zone2 feed at a speed of 4 g/min, set the screw speed to 100 rpm, cut the extrudate into sections, and then extrude the extrudate at 60 ° C for 2 h in ethanol. The content is <0.5%, and after pulverization, it is pulverized to 4 mm long particles, and the controlled release granule F of febuxostat is obtained.

Example 8 is a febuxostat formulation consisting of an immediate release febuxostat microplatelet and a febuxostat floating particle G which releases the drug above pH 5.5.

The single capsule comprises an immediate release component and a delayed release floating component, the immediate release component is a microtablet containing 8 mg of febuxostat active ingredient, and the delayed release floating component is a particulate G containing 32 mg of febuxostat active ingredient, granules A is released above pH 5.5. The immediate release febuxostat microtablets were prepared by a wet granulation process, the formulation of which is shown in Table 1, and the formulation of febuxostat delayed release floating granules G is shown in Table 10. The hot melt extrusion and temperature settings are shown in Table 11.

Table 10. Febuxostat delayed release floating particles G

	proportion
Febuxostat	25%
HPMCAS LF	75%

Pharma11 hot melt extruder (Siomer), set the temperature as shown in Table 11.

Table 11. Hot melt extruder temperature setting (°C)

Die	Zone8	Zone7	Zone6	Zone5	Zone4	Zone3	Zone2
140	130	100	90	80	70	60	50

Specifically, in Zone2 feeding, Zone4 is added with water, the feeding speed is 5g/min, the watering speed is 0.9ml/min, the screw rotation speed is set to 100rpm, the extrudate is cut into segments, and the extrudate is dried in an oven at 60°C for 2 hours. Moisture <3%, pulverized to 2 mm after drying, test density was 0.5 g/cm ³ , and the obtained febuxostat granule G and the febuxostat microderage obtained in Example 1 were filled into capsules to obtain febuxostat preparation. 8.

Example 9 Human Pharmacokinetic Study

The human pharmacokinetic study was carried out together with the preparations obtained in Example 3 and Example 4 using a commercially available 40 mg-sized febuxostat as a reference preparation, and the results of the study are shown in Table 12 below.

Table 12. Pharmacokinetic parameters of different formulations

C _max : maximum peak plasma concentration

T _max : maximum blood concentration time

AUC _0→∞ : drug time curve area

T _{C≥100μg/mL} : effective blood concentration C≥100μg/mL time

Fr: relative bioavailability

The results of pharmacokinetic studies showed that Example 3 and Example 4 can reduce the maximum peak concentration of the drug compared with the commercially available febuxostat reference preparation, greatly prolong the duration of action, and exert controlled release of the drug. The effect, thereby reducing the side effects of the drug, the results are shown in Figure 1.

Experimental example 1

300mL of pH5.0FaSSGF was used as the dissolution medium to observe the floating condition of the gastric floating particles under simulated gastric fluid. After observation, all the particles immediately floated and floated for a long time. After 24 hours, the particles remained floating and stopped. Observed.

Detection of febuxostat delayed release floating particle A, particle B, particle C, particle D, particle E, particle F, particle G according to the Chinese Pharmacopoeia 2015 edition two appendix dissolution test method 1 (basket method, 100 rpm, 37 ° C) Dissolution.

300mL of pH5.0FaSSGF was used as the dissolution medium to detect the dissolution of gastric floating particles under simulated gastric juice, and then 900mL of pH6.5FaSSIF was used as the dissolution medium to detect the dissolution of gastric floating particles under simulated intestinal fluid. The results are shown in Fig. 2. Figure 3 (Particle G).

According to the Chinese Pharmacopoeia 2015 edition two appendix dissolution detection method 1 (basket method, 100 rpm, 37 ° C), 900 mL of phosphate buffer solution of pH 6.8 was used as the dissolution medium, and the preparations 3 and preparations obtained in Example 3 and Example 4 were tested. 4 and the dissolution profile of the immediate release microchip, the results are shown in Figure 4.

The rate of dissolution can indicate the rate at which the drug is released from the formulation in the gastrointestinal environment, and the lower rate of release response is a lower Cmax and longer release time on the pharmacokinetic data. Compared with the conventional immediate release tablets, the dissolution rate of the preparation prepared in the present invention is remarkably lowered, and it can be inferred that the preparations of the present invention (Examples 1 to 7) can achieve a lower Cmax value than the immediate release tablets. The purpose of extending the effective blood concentration time.

The traits of the particle G were observed by scanning electron microscopy, and it was found that the particle G was porous under the electron microscope, as shown in Fig. 5.

The powder diffraction pattern for the crystalline state of the febuxostat and the non-busestat after extrusion, as shown in Fig. 6, is maintained in a crystalline state after hot melt extrusion.

Example 10 Hydrochlorothiazide (30 mg prescription) Hydrochlorothiazide: HPMC AS LG = 1:3

The hydrochlorothiazide and HPMC AS LG were uniformly mixed and subjected to hot melt extrusion, and the temperature parameters were set as shown in Table 13 (° C.).

Table 13.

Zone2

Zone3

Zone4

Zone5

Zone6

Zone7

Zone8

Die

30

50

60

70

90

90

100

120

Specifically, in Zone2 feeding, Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water addition speed is 400 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is <3%, and the pulverization is 2 mm after drying.

Phenomenon: The extrusion is smooth, the process is stable, the sample is expanded, and it can be quickly floated.

The powder diffraction pattern of the hydrochlorothiazide starting material and the crystalline state of the hydrochlorothiazide after extrusion in Example 10, the hydrochlorothiazide remained in a crystalline state after hot melt extrusion, as shown in FIG. 7; the dissolution profile of the formulation of Example 10 is shown in FIG. Shown.

Example 11 Hydrochlorothiazide (30 mg prescription) Hydrochlorothiazide: HPMCP = 1:3

Hydrochlorothiazide and HPMCP were uniformly mixed and hot melt extruded. The temperature parameters were set as shown in Table 14 (°C).

Table 14.

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
40	50	60	70	80	80	100	130

Specifically, in Zone2 feeding, Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water addition speed is 500 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is <3%, and the pulverization is 2 mm after drying.

Phenomenon: The sample is extruded smoothly and can be quickly floated.

For the hydrochlorothiazide starting material and the crystal form test powder diffraction pattern of the hydrochlorothiazide after extrusion in Example 11, hydrochlorothiazide remained in a crystalline state after hot melt extrusion, as shown in FIG. 9; the dissolution profile of the formulation of Example 11 is shown in FIG. Shown.

Example 12 Nifedipine (30 mg prescription) Nifedipine: HPMC AS LG = 1:3

Nifedipine and HPMC AS LG were uniformly mixed and hot melt extruded. The temperature parameters were set as shown in Table 15 (°C).

Table 15.

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
40	50	60	80	80	80	110	130

Specifically, in Zone2 feeding, Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water adding speed is 1200 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is <3%, and the pulverization is 2 mm after drying.

Phenomenon: The sample is extruded smoothly and can be quickly floated.

The powder diffraction pattern of the nifedipine starting material and the crystalline state of the nifedipine after extrusion in Example 12, the nifedipine remained in a crystalline state after hot melt extrusion, as shown in FIG. 11; The dissolution profile is shown in Figure 12.

Example 13 Tadalafil (30 mg prescription) Tadalafil: HPMC AS LG = 1:3

The tadalafil and HPMC AS LG were mixed uniformly for hot melt extrusion, and the temperature parameters were set as shown in Table 16 (°C).

Table 16.

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
30	40	40	50	70	90	110	130

Specifically, in Zone2 feeding, Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water adding speed is 900 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is <3%, and the pulverization is 2 mm after drying.

Phenomenon: The extrusion is smooth, the process is stable, the sample is expanded, and it can be quickly floated.

The powder diffraction pattern of the tadalafil raw material and the crystalline state of the tadalafil after extrusion in Example 13 was maintained, and the tadalafil remained in a crystalline state after hot melt extrusion, as shown in FIG. 13; The dissolution profile of the formulation of Example 13 is shown in FIG.

Example 14 Losartan (30 mg prescription) Losartan: HPMC AS LG = 1:3

The losartan and HPMC AS LG were uniformly mixed and hot melt extruded. The temperature parameters were set as shown in Table 17 (°C).

Table 17

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
30	50	60	80	80	90	100	130

Specifically, in Zone2 feeding, Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water adding speed is 600 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is <3%, and the pulverization is 2 mm after drying.

Phenomenon: The extrusion is smooth, the sample is expanded, and it can be quickly floated.

The powder diffraction pattern of the losartan raw material and the crystalline state of losartan after extrusion in Example 14 was maintained, and the losartan remained in a crystalline state after hot melt extrusion, as shown in FIG. 15; The dissolution profile is shown in Figure 16.

Example 15 (dexamethasone 30 mg prescription) dexamethasone: HPMC AS LG = 1:3

The dexamethasone and HPMC AS LG were mixed uniformly and hot melt extruded. The temperature parameters were set as shown in Table 18 (°C).

Table 18

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
30	50	60	80	80	90	100	130

Specifically, in Zone2 feeding, Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water addition speed is 400 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is <3%, and the pulverization is 2 mm after drying.

Phenomenon: The extrusion is smooth, the sample is expanded, and it can be quickly floated.

The dissolution profile of the formulation of Example 15 is shown in FIG.

Example 16 Dexamethasone (30 mg Prescription) Dexamethasone: HPMCP = 1:3

The dexamethasone and HPMCP were uniformly mixed and hot melt extruded. The temperature parameters were set as shown in Table 19 (°C).

Table 19

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
40	50	60	70	80	80	100	140

Specifically, in Zone2 feeding, Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water addition speed is 400 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is <3%, and the pulverization is 2 mm after drying.

Phenomenon: The extrusion is smooth, the surface of the sample expands, and the bubbles rupture on the surface, but can quickly float.

The dissolution profile of the formulation of Example 16 is shown in FIG.

Example 17 Furosemide (30 mg prescription) furosemide: HPMC AS LG = 1:3

Furosemide and HPMC AS LG were uniformly mixed and hot melt extruded. The temperature parameters were set as shown in Table 20 (°C).

Table 20

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
30	50	60	80	80	90	100	130

Specifically, in Zone2 feeding, Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water adding speed is 600 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is <3%, and the pulverization is 2 mm after drying.

Phenomenon: The extrusion is smooth, the sample is expanded, and it can be quickly floated.

The dissolution profile of the formulation of Example 17 is shown in FIG.

Example 18 febuxostat (30 mg) febuxostat: HPMCP = 1:3

The febuxostat and HPMCP were uniformly mixed and hot melt extruded. The temperature parameters were set as shown in Table 21 (°C).

Table 21

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
40	50	60	70	80	80	100	130

Specifically, in Zone2 feeding, Zone4 is added with water, the screw rotation speed is set to 100 rpm, the water adding speed is 700-900 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is <3%, and the pulverization is 2 mm after drying.

Phenomenon: The sample can expand and the sample can float.

The dissolution profile of the formulation of Example 18 is shown in FIG.

Example 19 Hydrochlorothiazide (30 mg prescription) Hydrochlorothiazide: HPMC AS LG = 1:3

Hydrochlorothiazide and HPMC AS LG were uniformly mixed and hot melt extruded. The temperature parameters were set as shown in Table 22 (°C).

Table 22

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
30	30	40	50	80	90	110	130

Specifically, in Zone2 feeding, Zone4 plus ethanol, the screw rotation speed was set to 60 rpm, the ethanol speed was 700 ul/min, the extrudate was oven-dried at 60 ° C for 2 h, the moisture was <3%, and the pulverization was 2 mm after drying.

Phenomenon: The extrusion is smooth, the process is stable, the sample is expanded, and it can be quickly floated.

For the hydrochlorothiazide starting material and the crystal form test powder diffraction pattern of the hydrochlorothiazide after extrusion in Example 19, hydrochlorothiazide remained in a crystalline state after hot melt extrusion, as shown in FIG. 21; the dissolution profile of the formulation of Example 19 is shown in FIG. Shown.

Example 20 Hydrochlorothiazide (30 mg prescription) Hydrochlorothiazide: HPMCP = 1:3

The hydrochlorothiazide and HPMCP were uniformly mixed and subjected to hot melt extrusion, and the temperature parameters were set as shown in Table 23 (° C.).

Table 23

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
30	30	40	50	80	90	110	130

Specifically, in Zone2 feeding, Zone4 plus ethanol, the screw rotation speed was set to 50 rpm, the ethanol speed was 700 ul/min, the extrudate was oven-dried at 60 ° C for 2 h, the moisture was <3%, and the pulverization was 2 mm after drying.

Phenomenon: The sample is extruded smoothly and can be quickly floated.

The powder diffraction pattern of the hydrochlorothiazide starting material and the crystal form state of hydrochlorothiazide after extrusion in Example 20, the hydrochlorothiazide remained in a crystalline state after hot melt extrusion, as shown in FIG. 23; the dissolution profile of the formulation of Example 20 is shown in FIG. Show.

Example 21 Losartan (30 mg prescription) Losartan: HPMC AS LG = 1:3

The losartan and HPMC AS LG were mixed uniformly for hot melt extrusion, and the temperature parameters were set as shown in Table 24 (°C).

Table 24

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
30	30	40	50	80	90	110	130

Specifically, in Zone2 feeding, Zone4 plus ethanol, the screw rotation speed was set to 50 rpm, the ethanol speed was 700 ul/min, the extrudate was oven-dried at 60 ° C for 2 h, the moisture was <3%, and the pulverization was 2 mm after drying.

Phenomenon: The sample is extruded smoothly and can be quickly floated.

The powder diffraction pattern of the losartan raw material and the crystal form state of losartan after extrusion in Example 21 was maintained, and the losartan remained in a crystalline state after hot melt extrusion, as shown in FIG. 25; The dissolution profile is shown in Figure 26.

Example 22 febuxostat (30 mg prescription) febuxostat: HPMCP = 1:3

The febuxostat and HPMCP were uniformly mixed and hot melt extruded. The temperature parameters were set as shown in Table 25 (°C).

Table 25

Zone2	Zone3	Zone4	Zone5	Zone6	Zone7	Zone8		Die
30	30	40	50	80	90	110	130

Specifically, the Zone2 feed, Zone4 plus ethanol, the screw rotation speed was set to 50 rpm, the ethanol speed was 700/min, the extrudate was oven-dried at 60 ° C for 2 h, the moisture was <3%, and the pulverization was 2 mm after drying.

Phenomenon: The sample can expand and the sample can float.

The dissolution profile of the formulation of Example 22 is shown in FIG.

While the invention has been described with respect to the preferred embodiments of the embodiments of the embodiments of the invention modify. Accordingly, the scope of the invention is defined by the appended claims.

Claims (33)

1. A controlled release pharmaceutical composition comprising: a) an immediate release component comprising an active drug, b) a delayed release floating component comprising an active drug, characterized in that the delayed release floating component is extruded by hot melt preparation.
2. The controlled release pharmaceutical composition according to claim 1, wherein said delayed release floating component contains at least one enteric polymer.
3. The controlled release pharmaceutical composition according to claim 2, wherein said enteric polymer is selected from the group consisting of polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, 1,2,4-benzene Cellulose triacetate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose 1,2,4-benzenetricarboxylate, cellulose acetate succinate, hypromellose acetate succinate , hydroxypropyl methylcellulose phthalate acetate, methacrylic acid-ethyl acrylate copolymer, methyl vinyl ether-maleic anhydride copolymer, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, methyl Acrylic-methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate copolymer, polyvinyl acetate, ethyl cellulose, polyvinyl acetate and polyethylene A mixture of pyrrolidone K30, preferably hypromellose acetate succinate, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate.
4. The controlled release pharmaceutical composition according to claim 2 or 3, wherein the ratio of the active drug to the enteric polymer in the delayed release floating component is selected from 1:0.1 to 1:100, preferably 1:0.1-1 : 50, more preferably 1:1 to 1:25.
5. The controlled release pharmaceutical composition according to any one of claims 1 to 4, characterized in that a solvent is added before the hot melt extrusion or during the hot melt extrusion.
6. The controlled release pharmaceutical composition according to claim 5, wherein the solvent has a boiling point selected from the group consisting of 30 to 110 °C.
7. The controlled release pharmaceutical composition according to claim 6, wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, dichloromethane, At least one of tetrahydrofuran is preferably water or ethanol.
8. The controlled release pharmaceutical composition according to any one of claims 1 to 7, wherein the delayed release floating component contains an alkaline substance which is in contact with an acid generating gas, and the basic substance is selected from the group consisting of sodium hydrogencarbonate and carbonic acid. Sodium, sodium aminoacetate carbonate, potassium hydrogencarbonate, magnesium carbonate and calcium carbonate are preferably sodium carbonate or sodium hydrogencarbonate.
9. The controlled release pharmaceutical composition according to any one of claims 1 to 8, characterized in that the delayed release floating component is in a multi-unit form.
10. The controlled release pharmaceutical composition according to claim 9, wherein the multi unit form is a microtablet, a pellet, a granule, preferably a granule.
11. The controlled release pharmaceutical composition according to any one of claims 1 to 7, wherein the delayed release floating component is porous.
12. The controlled release pharmaceutical composition according to any one of claims 1 to 7, wherein the delayed release floating component is immediately floated in a FaSSGF solution at pH 5.0.
13. The controlled release composition according to any one of claims 1 to 7, wherein the delayed release floating component floats in a FaSSGF solution at pH 5.0 for more than 24 hours.
14. The controlled release pharmaceutical composition according to any one of claims 1 to 7, characterized in that the delayed release floating component has a density of from 0.1 to 1.0 g/cm ³ , preferably from 0.2 to 0.8 g/cm ³ , most preferably 0.3- 0.7 g/cm ³ .
15. The controlled release pharmaceutical composition according to any one of claims 1-8, characterized in that the delayed release floating component is accumulated in 300 mL of FaSSGF dissolution medium at pH 5.0, basket method, 37 ° C, 100 rpm, 5 h The dissolution is less than 30%, more preferably less than 20%, and most preferably less than 10%.
16. The controlled release pharmaceutical composition according to any one of claims 1 to 8, characterized in that the active drug in the delayed release floating component is selected from the group consisting of BCSI drugs.
17. The controlled release pharmaceutical composition according to claim 16, wherein the BCSI-based drug is selected from the group consisting of pabisstat, Cobimetinib, Patiromer, omarigliptin, bupropion, guanfacine, venlafaxine hydrochloride , methylphenidate hydrochloride, tertimazine phosphate, flurbanin, eliglustat, alogliptin, dimethyl fumarate, pyrenoprene, lometan, rosotinib, clozab, Dalfampridine, Prolia, dronedarone hydrochloride, Pralattrexate, lacosamide, fesoterodine fumarate, alprazolam, amitriptyline hydrochloride, amlodipine besylate, benazepril, amoxicillin, ar Natrozole, azelastine, bisoprolol, buspirone, caffeine, carbidopa, cetirizine, chloroquine phosphate, chlorpheniramine, clindamycin, clonidine, cyclobenzaprine, Cyclophosphamide, desogestrel, ethinyl estradiol, diazepam, diphenhydramine, donepezil hydrochloride, doxazosin mesylate, doxycycline, emtricitabine, estradiol, Ethyl succinate, fexofenadine, finasteride, fluconazole, flucytosine, fluoxetine hydrochloride, fluvoxamine Sulfonate, imipramine, indapamide, isoniazid, lamivudine, lidocaine, lorazepam, losartan, metoprolol succinate, mexiletine, midazolam , mirtazapine, montelukast sodium, norethisterone, norgestrel, nortriptyline, olopatadine hydrochloride, oseltamivir, pramipexole, pravastatin sodium, strong Pine, prednisolone, pregabalin, procainamide hydrochloride, promethazine hydrochloride, propranolol hydrochloride, pyrazinamide, pyridoxine hydrochloride, quinapril Hydrochloride, quinidine, quinine hydrochloride, ramipril, sertraline, sildenafil citrate, sotalol, stavudine, terbinafine hydrochloride, care Trojan, torasemide, tramadol hydrochloride, trazodone, varenicline, zidovudine, alfacalcidol, beraprost, biperiden, brompheniramine, bromine Tazolam, carbyzamine, clomiphene, clomipramine, cloxacillin, diltiazem, dolasetron, morphine, eperisone hydrochloride, eplestine, calciferol, ergometrine, ergotamine , ethinyl estradiol, etidazolam, fluoride Rutastatin, granisetron, ketotifen, levamisole, levonorgestrel, ermaspirin, loxoprofen, mefloquine, mexiletine hydrochloride, nicardipine, niclosamide, tobex Luo, trimethoprim, trimebutine, toremifene, terbinafine, temocapril, tamsulosin, sertraline, sarpogrelate hydrochloride, saquinavir, rosiglitazone , reserpine, ramipril, propiverine hydrochloride, promethazine, pergolide, paroxetine.
18. The controlled release pharmaceutical composition according to any one of claims 1 to 8, characterized in that the active drug in the delayed release floating component is selected from the group consisting of BCSII to IV drugs.
19. The controlled release pharmaceutical composition according to claim 18, wherein said BCSII to IV drugs are selected from the group consisting of febuxostat, ixazomib, Alectinib, Erismodegib, vandetanib, aprepitant, and volpa sulfate Sand, aspirin, metformin, nglipepsin, linagliptin, naltrexone, dasabuvir, sofosbuvir, amphetamine, etravirine, everolimus, itraconazole, verrofi Nitra, telaprevir, tacrolimus, posaconazole, isikato, radipavir, Suvorexant, Ombitasvir, paritaprevir, daclatasvir, cariprazine, brexpiprazole, olpemiprofen, leztra Seatan, ivacaftor, eluxadoline, lumacaftor, ivacaftor, ezeppa, nidanib, meloxicam, morphine, macitentan, dutasteride, abiraterone, lumacaftor, daglibine, he Simeiqiong, Ibrutinib, Paramivir, Olapani, Epalibene, Idelalisib, Bellistat, Coloritinib, Apster, Pomamide, Obepamine , calpagliflozin, darabifen mesylate, trimetinib, dolutegravir, vortioxetine, baz Edoxifene, simeprevir, axitinib, Vismodegib, avermectin, lorcaserin, mirabine, bosutinib, teriflamine, Regorafenib, tofacitinib, cabozantinib, panatinib, Apixaban, Bedaquiline, Crofelemer, Poseprevir, Trafivir, Bellacit, Verapamil, Crizotinib, Roflumilast, Verazodone, Azurtan, Gabapentin , vandetanib, nategliptin, rivivirin, fidarimycin, ezazobine, icatibine acetate, rivaroxaban, ticagrelor, polidocanol, carglumic acid, temoline , vemurafenib, cabazitaxel, dabigatran etexilate, everolimus, tolvaptan, prasugrel, saxagliptin, telavancin, pazopanib, silodosin, rufinamide, eltrombopag, acetazolamide, acetaminophen, acyclovir Wei, atorvastatin, atorvastatin calcium, amprenavir, aripiprazole, atenolol, ketamine, ataquinone, azathioprine, azithromycin, budesonide, calcitriol, Isopropyl methylbutazone, cefdinir, cefixime, cefofurate , celecoxib, cephalexin, chlorothiazide, clarithromycin, clopidogrel hydrogen sulphate, clotrimazole, betamethasone, diaminodiphenol, diclofenac sodium, bicyclic amine, arrived in Nuoxin, cannabinol , duloxetine, dutasteride, etodolac, ezetimibe, simvastatin, felamine, fenofibrate, flecainide, phosphaviravir, furosemide, xylene Oxyheptanoic acid, glimepiride, glibenclamide, griseofulvin, ibuprofen, hydroxychloroquine, hydroxyzine, indomethacin, irbesartan, isoniazid, irilappine, ketocon Azole, lamotrigine, lansoprazole, latanoprost, linezolid, loperamide, chlorocarbon cephalosporin, loratadine, lovastatin, mebendazole, meclizine, guanidine, Ammonia salicylic acid, metaxalone, methylphenidate methyl acetate, methylprednisolone, modafinil, mycophenolic acid, mycophenolate mofetil, nabumetone, naproxen, nifedipine Dipine, omeprazole, carbamazepine, oxycodone hydrochloride, phenazopyridine, phenytoin, pioglitazone hydrochloride, piroxicam, deoxyphenobarbital, prochlorperazine Progesterone, pyrimethamine, quetiapine, raloxifene hydrochloride, rifabutin, rifampicin, risperidone, spironolactone, sulfamethoxazole, tadalafil, telmisartan, Ranavir, valsartan, vardenafil, ziprasidone, abacavir sulfate, codeine, salbutamol, alendronate, allopurinol, potassium clavulanate, benzotropine, Bimatoprost, buprenorphine, naloxone, captopril, levodopa, cefixime, cefadroxil, cetirizine hydrochloride, ciprofloxacin, colchicine, ergot calcification Alcohol, famotidine, pseudoephedrine, folic acid, gabapentin, hydralazine, hydrochlorothiazide, albuterol, levocetirizine, levofloxacin, levothyroxine sodium, lisinopril, methotrexate, methyldopa, nadolol , nystatin, pantoprazole, primaquine phosphate, pyrazinamide, ranitidine hydrochloride, ribavirin, risedronate sodium, solifenacin, spironolactone, suma Triptan succinate, terazosin, tetracycline, thiamine, topiramate, valacyclovir hydrochloride, valganciclovir, ar Carbohydrate, aceclofenac, acetazolamide, acetylcarnitine, albendazole, allenamide, amiloride, atropine, azathioprine, azithromycin, benidipine, benserazide, Benzidazole, bicalutamide, bisacodyl, cabergoline, candesartan, capecitabine, carvedilol, cefditoren, cefmetazole, cefotiam, cefpodoxime, ceftazidime, Cefuroxime axetil, celecoxib, chloramphenicol, chlorpromazine, cilazapril, cilostazol, cimetidine, citalopram, chlorpheniramine, cyclosporine, cyproterone , dapsone, ethamazine, digoxin, dichlorit, deoxyfluorouridine, doxycycline, ebastine, efavirenz, epalrestat, valsartan, erythromycin, B Aminobutanol, ezetimibe, famciclovir, fenofibrate, fluconazole, flurbiprofen, diurea, furosemide, gefitinib, gliclazide, glipizide, gray yellow Neomycin, haloperidol, hydroxyzine hydrochloride, ibuprofen, imatinib, midazolam, indinavir, irbesartan, isoniazid, ivermectin, ketoprofen, pull Motriazine Levofloxacin, lopinavir, levastatin, manidipine, mebendazole, medroxyprogesterone, aminosalicylic acid, metaxalone, methotrexate, methyldopa, metronidazole, modafi Nis, mosapride, nabumetone, nalidixic acid, nelfinavir, neostigmine, nevirapine, nicorandil, nicotinamide, nifuroxime, nilvadipine, nimesulide, Zolpidem, zolmitriptan, zaltoprofen, warfarin, voglibose, verapamil, valproic acid, ursodeoxycholic acid, trimetazidine, tosufloxacin, Ticlopidine, theophylline, teprenone, tenofovir, tegafur, tamoxifen, statin, sultamicill, sulpiride, sulfasalazine, sulfamethoxazole, sulfadiazine , stavudine, roxithromycin, rofecoxib, rizatriptan, ritonavir, risedronate, rifampicin, rifaximin, rebamipide, ranitidine , rabeprazole, nizatidine, norethisterone, olanzapine, olopatadine, orlistat, oseltamivir, oxcarbazepine, quetiapine, pyridoxine hydrochloride, bromide Propyl thiouracil, Procaterol, praziquantel, pranlukast, phenytoin, phenobarbital, phendimetrazine, perindopril, oxycodone, dexamethasone, furosemide.
20. The controlled release pharmaceutical composition according to any one of claims 1 to 8, wherein the delayed release floating component further comprises at least one plasticizer selected from the group consisting of triethyl citrate Ester, tributyl phthalate, polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl sebacate, diethyl sebacate, glyceryl stearate, Diethyl succinate, propylene glycol, castor oil and triacetin, preferably triethyl citrate, the plasticizer is present in an amount of from 0.01% to 50%, preferably from 0.1% to 30%, most preferably 2.5%. 15% (mass percent, calculated as the total mass of the solid components is 100).
21. The controlled release pharmaceutical composition according to any one of claims 1 to 8, characterized in that the immediate release component and/or the delayed release floating component further comprises at least one pharmaceutically acceptable other excipient.
22. The controlled release pharmaceutical composition according to claim 21, wherein the excipient is selected from the group consisting of a filler, a lubricant, a binder, and a disintegrant.
23. A controlled release pharmaceutical composition according to any one of claims 1-8 which is a tablet or capsule.
24. The controlled release pharmaceutical composition according to any one of claims 1 to 8, characterized in that the active drug in the immediate release component is the same as or different from the active drug in the delayed release component, preferably the same.
25. The controlled release pharmaceutical composition according to any one of claims 1 to 8, characterized in that the active drug in the delayed release floating component is optionally maintained in a crystalline state or converted to an amorphous form after hot melt extrusion.
26. A method for preparing a controlled release pharmaceutical composition according to any one of claims 2 to 7, which comprises the steps of: 1) reacting at least one solvent, delayed release floating component before hot melt extrusion Mixing the ingredients with at least one enteric polymer to obtain a premixed crude product or mixing the at least one solvent, the active ingredient in the delayed release floating component, and the at least one enteric polymer in a hot melt extrusion process to obtain a premixed crude product; 2) The premixed crude product passes through the heating screw zone of the extruder and exits the extrudate through the die.
27. The production method according to claim 27, wherein the solvent is preferably a solvent having a boiling point between 30 and 110 °C.
28. The preparation method according to claim 28, wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, dichloromethane, tetrahydrofuran, preferably Water, ethanol.
29. The process according to claim 28, wherein the solvent is used in an amount of from 0.1% to 70%, preferably from 1% to 50%, most preferably from 10% to 30% by mass based on the total mass of the solid component. Calculated for 100).
30. The process according to claim 26, wherein the die temperature is from 70 to 200 ° C, preferably from 90 to 180 ° C, more preferably from 110 to 160 ° C.
31. The method according to claim 30, wherein the temperature of the solvent injection screw zone is from 10 to 90 °C.
32. The method of preparation according to claims 26-31, further comprising the step of: 1) cooling the extrudate; 2) removing the extrudate from the solvent; 3) cutting the extrudate.
33. The preparation method according to any one of claims 26 to 31, characterized in that the extruder is selected from the group consisting of a single screw hot melt extruder, an intermeshing screw extruder, a twin screw hot melt extruder, preferably a twin screw Hot melt extruder.

Images