TWI682789B - Controlled release pharmaceutical composition and preparation method thereof - Google Patents

Abstract

The present invention relates to a controlled release pharmaceutical composition comprising: a) an immediate release component containing an active drug, b) a delayed release floating component containing the active drug. The delayed release floating component was prepared by hot melt extrusion.

Description

Controlled release pharmaceutical composition and preparation method thereof

This application requires the priority of the Chinese patent application CN201710454301.5 on June 14, 2017. This application cites the entire text of the aforementioned Chinese patent application.

The invention relates to a controlled-release pharmaceutical composition, which belongs to the field of pharmacy.

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

Most compounds are poorly absorbed in the back end of the intestine, resulting in patients who take the preparation and the preparation is transported to the colon (generally considered to be 4-6 hours), the preparation cannot be effectively released and absorbed. It cannot be guaranteed that the blood concentration can be effectively maintained 6 hours after taking the drug through ordinary sustained release. The oral gastric retention preparation prolongs the residence time of the drug at the upper end of the gastrointestinal tract. Even if the drug is poorly absorbed at the rear end of the intestine and the clearance is fast, it can ensure the effective release and absorption after 6 hours of administration, reducing the The interval and dosage of medicines improve the patient's compliance. As one of the methods of gastric retention, the gastric floating preparation increases the residence time of the preparation in the stomach. In the past, it was absorbed in the upper end of the gastrointestinal tract but its solubility is very small or easily degradable in an alkaline environment. Local and persistent administration of drugs in the upper end of the small intestine for the treatment of specific conditions.

At present, a large number of existing technologies have disclosed the achievable methods of gastric floating preparations. For example, CN103037850A discloses a class of elongated gastric retention capsules. Tests have shown that it can prolong the gastric retention time. However, such a design has gastric obstruction or The danger of the system staying permanently, so its actual value is very small. In order to achieve a more reasonable drug effect, a large number of drugs have been made into a combination of immediate release and controlled release gastric floating drug delivery system, but most of them are double-layer tablets or capsules. For example, Yin Lifang et al. Bilayer tablet, the active ingredients are pioglitazone and metformin, the immediate release component is pioglitazone, the controlled release component is metformin, the bilayer tablet is achieved by using sodium carbonate that can generate carbon dioxide and low density floating aid stearyl alcohol The effect of floating, in which the most preferred formulation can float in the test solvent for at least 24h (International Journal of Pharmaceutics 476 (2014) 223-231). However, a single tablet has various deficiencies such as poor floating ability, long float time, and large individual differences. Indian patent application IN2009DE00792A discloses a dual-particle intragastric drug delivery system containing ofloxacin immediate-release particles and gastric floating controlled-release particles, wherein the controlled-release particles include hydrophobic materials and hydrophilic materials.

Hot melt extrusion (HME) is the process of pumping raw materials into a uniformly shaped product at high temperatures by rotating a screw through a die. Hot melt extrusion has many advantages over other drug processing technologies. The molten polymer during extrusion can be used as a thermal adhesive and as a drug depot and/or drug release blocker during cooling and solidification . Since this method does not require solvents and water, it reduces the number of processing steps and eliminates time-consuming drying steps. The matrix material can be assembled into larger units that are independent of compression characteristics. The intense mixing and stirring applied by the rotating screw causes the aggregation of suspended particles in the molten polymer, making the dispersion more uniform.

In recent years, hot-melt extrusion technology has been tried for the preparation of controlled-release gastric floating formulations. Nakamichi et al. disclosed the floating formulation of nicardipine hydrochloride prepared by a twin-screw extruder. The polymer material is hydroxypropyl methylcellulose acetate succinate (HPMCAS). It was found in the study that the use of drugs and polymers alone does not result in a swollen extrudate. A third substance, phosphoric acid dihydrate, must be added Calcium, when the amount of calcium phosphate dihydrate is 8%, can float in gastric juice for 6h (International Journal of Pharmace-Utics 218 (2001) 103-112). Nakamichi speculated about the role of calcium phosphate dihydrate. When the melt of the drug and the polymer was in the machine, it was subjected to the high pressure of the screw. When it was extruded from the head, the high pressure zone entered the normal pressure zone. According to the Clausius-Clapeyron relation, 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 to make the extrusion The object produced a large number of bubbles in an instant. With the rapid decrease in temperature, the air bubbles solidify again immediately, resulting in a swell.

US2016113906A discloses a hot melt extruded composition. By adding a polar organic solvent to the hot melt extruded composition, the decomposition of the active ingredient is reduced, the miscibility between the active ingredient and the polymer is increased, and the decrease The operating temperature of the hot melt extrusion reduces the torque. Nakamichi et al. investigated the effect of moisture on the solid dispersion prepared by the twin-screw hot melt extruder. The test results proved that the addition of water will reduce the flow temperature (Tfb) of the material, and prove that the material can be treated at a temperature below the melting point. Extrusion (International Journal of Pharmaceutics 241 (2002) 203-211).

Padma V. Devarajan et al. disclosed a gastric floating controlled-release multiparticulate formulation of metoprolol succinate prepared by hot-melt extrusion, and optimized hot-melt extruded material Eudragit® RSPO (Eudragit® RSPO) , Polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC) to balance the floating capacity and controlled release capacity, the generation of gas using sodium carbonate (International Journal of Pharmaceutics 491 (2015) 345-351) .

Mamoru Fukuda et al. disclosed a gastric retention floating tablet prepared by hot-melt extrusion method, using Eudragit® RSPO (Eudragit® RS PO) and or Eudragit® EPO (Eudragit® E PO.) matrix materials to investigate The effect of sodium carbonate on the physical and chemical properties of the composition (Journal of Controlled Release 115 (2006) 121-129).

Michael A. Repka et al. disclosed gastric floatation prepared by using the operation method of adding ethanol during hot-melt extrusion using Eutec RSPO (Eudragit® RSPO) or hydroxypropylmethyl cellulose K15M (HPMC K15M) as the matrix material Pellets (European Journal of Pharmaceutics and Biopharm-Aceutics 98 (2016) 108-121).

Michael A. Repka et al. disclosed an intragastric therapeutic drug delivery system containing a solid dispersion prepared by hot melt extrusion with a dual action mechanism, the drug delivery system taking felodipine as an active ingredient, hydroxypropyl Cellulose-based hydroxymethylcellulose is used as a matrix material to make the drug stay in the stomach longer by means of floating agent adhesion (European Journal of Pharmaceutical Sciences 102 (2017) 71-84). However, this dosage form is inherently The danger is that the adhesion of drugs in the esophagus may cause damage.

Since hot-melt extrusion technology and gastric floating preparations have shown irreplaceable advantages, and the advantages of controlled release preparations containing immediate-release and controlled-release components are obvious to all, therefore, a variety of technologies have been integrated to develop new The preparation of solutions to various technical barriers is self-evident for the pharmaceutical field.

The invention provides a controlled-release pharmaceutical composition prepared by hot melt extrusion, which effectively prolongs the front-end 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 number of medications and increasing Patient compliance with medication.

The present invention provides a controlled-release pharmaceutical composition, comprising: a) an immediate-release component containing an active drug, b) a delayed-release floating component containing an active drug, characterized in that the delayed-release floating component is extruded by hot melt The process of preparation.

The controlled release pharmaceutical composition provided by 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 according to the present invention releases the drug under the condition of pH ≥ 5.5.

The controlled release pharmaceutical composition provided by the present invention is characterized in that the enteric polymer is selected from polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, 1,2,4-benzenetricarboxylic acid acetic acid Cellulose, hydroxypropyl methylcellulose phthalate, 1,2,4-benzenetricarboxylic acid hydroxypropyl methylcellulose, cellulose acetate succinate, hypromellose acetate succinate, hydroxyl acetate Propyl methylcellulose phthalate, methacrylic acid-ethyl acrylate copolymer, methyl vinyl ether-maleic anhydride copolymer, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, methacrylic acid-methacrylate Methyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate copolymer, polyvinyl acetate, ethyl cellulose, polyvinyl acetate and polyvinyl pyrrolidone K30 mixture It is 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 l 100-55 or Kollicoat MAE100P.

In some embodiments, the methyl vinyl ether-maleic anhydride copolymer corresponds to the commercially available Gantrez® ES 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 of the present invention is a 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 methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose acetate succinate disclosed in the prior art US4226981B, CN104208713A and CN103153343A The element is included in the scope of the present invention.

HPMCAS sold by Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan) is divided into three grades, which have 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 granular) provide enteric protection at a pH of up to 5.5. AS-MF and AS-MG grades provide enteric protection at a pH of up to 6.0, while AS-HF and AS-HG grades provide enteric protection at a pH of up to 6.8.

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

In the controlled release pharmaceutical composition provided by the present invention, the hot-melt extrusion method optionally includes a solvent to participate in the hot-melt extrusion process, that is, in some schemes, a solvent is added, and in other schemes, no solvent is added. The solvent participation refers to adding a solvent before or during hot melt extrusion for the purpose of invention.

If the controlled release pharmaceutical composition provided by the present invention is added with a solvent during the preparation process, the solvent only needs to satisfy that it can be volatilized after the hot melt extrusion process is completed. Preferably, the present invention limits the boiling point of the solvent to 30 -110℃.

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, methylene chloride, and tetrahydrofuran. One is preferably water and ethanol.

The present invention provides a controlled release pharmaceutical composition. When a solvent is involved in the hot melt extrusion process, the density of the delayed release floating component in the controlled release pharmaceutical composition is 0.1-1.0 g/cm ³ , preferably 0.2-0.8 g/cm ^3, most preferably 0.3-0.7g / cm ^3, is shown as porous, and may be maintained from immediately float and float longer than 24h in a solution of pH5.0 FaSSGF in the electron microscope.

If the controlled release pharmaceutical composition provided by the present invention does not add a solvent during the preparation process, it contains an alkaline substance that generates gas when it encounters an acid. That is, the alkaline substance in the controlled release pharmaceutical composition of the present invention is not necessary. At this time, the alkaline substance is specifically alkali metal carbonate, alkali metal or alkaline earth metal bicarbonate, more specifically sodium bicarbonate, sodium carbonate, sodium glycinate carbonate, potassium bicarbonate, 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 added calcium phosphate dihydrate to the drug and matrix, and extruded by hot melt After out, the floating agent is prepared.

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

The controlled release pharmaceutical composition provided by the present invention is characterized in that the delayed release floating component is in the form of multiple units.

The controlled release pharmaceutical composition provided by the present invention is characterized in that the multi-unit form is microchips, micropellets, granules, preferably granules.

The immediate-release component in the controlled-release pharmaceutical composition provided by the present invention may be in the form of pellets, micro-tablets, granules, etc. Specifically, when the immediate-release component is a pellet, it may contain an active drug and a blank pellet core.

Generally, pharmaceutical preparations will reach the colon within 3 to 6 hours after oral administration in most cases. Therefore, the premise of successful sustained-release preparations is to increase the time of gastrointestinal absorption and increase absorption.

The Biopharmaceutical Classification System (BCS) introduced by the US Food and Drug Administration (FDA) has classified drugs according to their solubility and intestinal permeability. For details, see "The Biopharmaceutics Classification System (BCS) Guidance". Jennifer B. Dressman and Christos Reppas mentioned in page 273 of "Oral Drug Absorption: Prediction and Assessment" that drugs with high solubility and permeability when administered orally (Class I) usually have good absorption throughout the gastrointestinal tract. The most preferred drugs for sustained-release preparations. Such drugs are included in the range of active drugs for delaying the release of floating components according to the present invention.

The Class I drugs in the BCS classification of the present invention include, but are not limited to: Pabivestat, Cobimetinib, Patiromer, omarigliptin, bupropion, guanfacine, venlafaxine hydrochloride, methylphenidate hydrochloride, Tedizolid phosphate, flibanserin, eliglustat, alogliptin, dimethyl fumarate, pirenpanet, lometapine, lusotinib, clobazam, dalfampridine, Prolia, drone Dalon hydrochloride, Pralatrexate, lacosamide, fesoterodine fumarate, alprazolam, amitriptyline hydrochloride, amlodipine besylate, benazepril, amoxicillin, anastrozole, azezos Ting, bisoprolol, buspirone, caffeine, carbidopa, cetirizine, chloroquine phosphate, chlorpheniramine, clindamycin, clonidine, cyclobenzaprine, cyclophosphamide, go Oxypregnene, ethinylestradiol, diazepam, diphenhydramine, donepezil hydrochloride, doxazosin mesylate, doxycycline, emtricitabine, estradiol, ethosuximide, non- Solifenadine, finasteride, fluconazole, flucytosine, fluoxetine hydrochloride, fluvoxamine mesylate, imipramine, indipamide, isoniazid, lamivudine , Lidocaine, lorazepam, losartan, metoprolol succinate, mexiletine, midazolam, mirtazapine, montelukast sodium, norethisterone, norethisterone, Nortriptyline, olopatadine hydrochloride, oseltamivir, pramipexole, pravastatin sodium, prednisone, prednisolone, pregabalin, procainamide hydrochloride, isotopic Promazine hydrochloride, propranolol hydrochloride, pyrazinamide, pyridoxine hydrochloride, quinapril hydrochloride, quinidine, quinine hydrochloride, ramipril, serpentine Traline, sildenafil citrate, sotalol, stavudine, terbinafine hydrochloride, tolterodine, torasemide, tramadol hydrochloride, trazodone, valprodone Nickran, Zidovudine, Alfacalcidol, Bepprost, Biperiden, Brompheniramine, Brotazolam, Carbisamin, Clomiphene, Clomipramine, Cloxacillin, Diltiazem , Dolasetron, morpholine, eperisone hydrochloride, epilastine, calciferol, ergonovine, ergotamine, ethinyl estradiol, etifazolam, fluvastatin, granisetron, Tifen, levamisole, levonorgestrel, limaprost, loxoprofen, mefloquine, mexiletine hydrochloride, nicardipine, niclosamide, tobuterol, trimethoprim, trimethoprim Mebutine, toremifene, terbinafine, temopril, tamsulosin, sertraline, sagrete hydrochloride, saquinavir, rosiglitazone, reserpine, ramipril Li, propiverine hydrochloride, promethazine, pergolide, paroxetine.

Jennifer B. Dressman and Christos Reppas pointed out on pages 272-274 of "Oral Drug Absorption: Prediction and Assessment" that due to permeability and solubility problems, drugs in categories B to IV in the BCS classification show poor colon absorption or poor solubility. It is not suitable for the preparation of sustained-release preparations. The composition of the present invention uses hot-melt extrusion technology and gastric floating technology, especially enteric polymerization, which effectively prolongs the residence time of such drugs in the gastrointestinal tract and improves the drug In the absorption rate of the small intestine, the drugs for this class have a better effect.

The drugs of the BCS classification of the present invention belonging to Class II to IV include but are not limited to: febuxostat, ixazomib, Alectinib, Erismodegib, vandetanib, aprepitant, verapamil sulfate, aspirin, metformin, Engligliflozin, ritagliptin, naltrexone, dasabuvir, sofosbuvir, amphetamine, etravirine, everolimus, itraconazole, verofenib, and trapivir , Tacrolimus, posaconazole, ivacaftor, redipavir, Suvorexant, Ombitasvir, paritaprevir, daclatasvir, caliprazine, brexpiprazole, olpemifene, levetiracetam, ivacaftor, eluxadoline , Lumacaftor, ivacaftor, etrepopa, nidanib, meloxicam, morphine, macitentan, dutasteride, abiraterone, lumacaftor, dagligliflozin, tasmetron, yiru Tenib, paramivir, olaparib, ipagliflozin, idelalisib, belibastat, serritinib, aprost, pomalidomide, opimifene, cagliflozin, Dalafenib mesylate, Trimetinib, dolutegravir, vortioxetine, bazedoxifene, simeprevir, axitinib, Vismodegib, avanafil, lorcaserin, mirabelon, bosutinib, teritri Fluoramine, Regorafenib, tofacitinib, Cabozantinib, panatinib, apixaban, Bedaquiline, Crofelemer, Pocepvir, Trapvir, berasaip, verafinil, crizotinib , Roflumilast, verazolidone, azilsartan, gabapentin, vandetanib, nategliptin, ribivirin, fidaxomicin, ezogabine, ibibantyl acetate, lecithin Valsarban, ticagrelor, polidocanol, carglumic acid, temogrelin, vemurafenib, cabazitaxel, dabigatran etexilate, everolimus, tolvaptan, prasugrel, saxagliptin, telavancin, pazopanib, silodosin, rufinamide, Eltrombopag, acetazolamide, paracetamol, acyclovir, atorvastatin, atorvastatin calcium, amprenavir, aripiprazole, atenolol, ketamine, a Tolquinone, azathioprine, azithromycin, budesonide, calcitriol, isopropyl metformin, cefdinir, cefixime, cefuroxime acetate, celecoxib, cephalexin, chlorothiazide Azine, clarithromycin, clopidogrel bisulfate, clotrimazole, betamethasone, diaminodiphenol, diclofenac sodium, bicyclic amine, daroxoxine, trabenol, duloxetine, dutasteride, Etodolic acid, ezetimibe, simvastatin, filurate, fenofibrate, fluoride Carni, fosanavir, furananilide, xyloxyheptanoic acid, glimepiride, glibenclamide, griseofulvin, ibuprofen, hydroxychloroquine, hydroxyzine, indomethacin, eroxir Besartan, isoniazid, iradipine, ketoconazole, lamotrigine, lansoprazole, latanoprost, linezolid, loperamide, chlorcarbazone, loratadine, lorazidine Vastatin, mebendazole, chlorphenazine, mercaptopurine, ammonia salicylic acid, metaxalone, phenoperidine methyl acetate, methylprednisolone, modafinil, mycophenolic acid, mycophenolic acid Ester, Nabumetone, Naproxen, Nifedipine, Omeprazole, Carbamazepine, Oxycodone Hydrochloride, Finapyridine, Phenytoin Sodium, Pioglitazone Hydrochloride, Piroxicam, Deoxybenzene Barbiturate, prochlorperazine, progesterone, pyrimethamine, thiopine, raloxifene hydrochloride, rifabutin, rifampicin, risperidone, spironolactone, sulfamethoxazole, tadala Fe, telmisartan, telanavir, valsartan, vardenafil, ziprasidone, abacavir sulfate, codeine, albuterol, alendronate, allopurinol, clavulanate Potassium acid, benztropine, bimatoprost, buprenorphine, naloxone, captopril, levodopa, cefixime, cefadroxil, cetirizine hydrochloride, ciprofloxacin Star, Colchicine, Ergocalciferol, Famotidine, Pseudoephedrine, Folic Acid, Gabapentin, Hydralazine, Hydrochlorothiazide, Salbutamol, Levocetil, Levofloxacin, Levothyroxine Sodium, Lisinopril, Methotrexate, Methyldopa, nadolol, nystatin, pantoprazole, primaquine phosphate, pyrazinamide, ranitidine hydrochloride, ribavirin, risedronate sodium, soli Nashin, spironolactone, sumatriptan succinate, terazosin, tetracycline, thiamine, topiramate, valacyclovir hydrochloride, valganciclovir, acarbose, vinegar Clofenac, acetazolamide, acetylcarnitine, albendazole, allyl sulamine, amiloride, atropine, azathioprine, azithromycin, benidipine, benzhydrazine, benznidazole , Bicalutamide, bisacodyl, cabergoline, candesartan, capecitabine, carvedilol, cefditoren, cefmetazole, cefotiam, cefpodoxime, ceftazidime, cefuroxime Octyl ester, celecoxib, chloramphenicol, chlorpromazine, cilazapril, cilostazol, cimetidine, citalopram, chlorphenazine, cyclosporine, cyproterone, ammonia Phenylsulfone, ethamazine, digoxin, diclonet, deoxyfluorouridine, doxycycline, ebastine, efavirenz, epalrestat, prusartan, erythromycin, ethambutol Alcohol, ezetimibe, famciclovir, fenofibrate, fluconazole, flurbiprofen, diuretic sulfonamide, furosemide, gefitinib, gliclazide, glipizide, griseofulvin , Haloperidol, hydroxyzine hydrochloride, ibuprofen, imatinib, midapril, indinavir, irbesartan, isoniazid, ivermectin, ketoprofen, lamotrigine , Levofloxacin, lopina, lovastatin, manidipine, mebendazole, medroxyprogesterone, aminosalicylic acid, metaxalone, methotrexate, methyldopa, metronidazole, modafinil Nimes, mosapride, nabumetone, nalidixic acid, nelfinavir, neostigmine, nevirapine, nicorandil, nicotinamide, nifurtimox , Nilvadipine, nimesulide, zolpidem, zolmitriptan, zaltoprofen, warfarin, voglibose, verapamil, valproic acid, ursodeoxycholic acid, Trimetazidine, tosufloxacin, ticlopidine, theophylline, teprenone, tenofovir, tegafur, tamoxifen, tateriline, sumacillin, sulpiride, sulfasalazine Sulfapyridine, Sulfamethoxazole, Sulfadiazine, Stavudine, Roxithromycin, Rofecoxib, Rizatriptan, Ritunavir, Risedronic Acid, Rifampicin, Rifaximin , Rebamipide, ranitidine, rabeprazole, nizatidine, norethindrone, olanzapine, olopatadine, orlistat, oseltamivir, oxcarbazepine, quetiapine Ping, pyridoxine hydrochloride, bromopyridine, propylthiouracil, procaterol, praziquantel, primilast, phenytoin sodium, phenobarbital, benzotriazine, perindopril, oxycodone , Dexamethasone, furosemide.

The controlled release pharmaceutical composition provided by the present invention is characterized in that the delayed-release floating component may further include at least one plasticizer selected from triethyl citrate, 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 content of the plasticizer is 0.01%-50%, preferably 0.1-30%, most preferably 2.5%-15% (mass percentage, in solid group The total mass of points 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 by the present invention further include at least one pharmaceutically acceptable other excipient, and commonly used excipients in pharmacy include But not limited to fillers, lubricants, glidants, binders, disintegrants.

As is well known to those skilled in the art, pharmaceutical excipients are routinely mixed into solid dosage forms to facilitate the process and improve the performance of the dosage form. Common excipients include diluents or fillers, lubricants, glidants, binders, disintegrants, etc. The diluent or filler is used to increase the weight of a single 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 sticking to tablet punches, and promotes their discharge from the tablet punches. Examples of suitable lubricants that can be used include, but are not limited to, talc, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate, and the like.

Glidants are used to improve the flow characteristics of particles. Examples of suitable glidants include, but are not limited to, silicon dioxide, corn starch, micronized silicone rubber, 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 gums such as carboxymethyl cellulose, methyl cellulose , Hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy cellulose, gelatin, starch and pregelatinized starch.

Disintegrant refers to a substance that can quickly break the tablet into fine particles in the gastrointestinal fluid, so that the functional ingredients can be quickly dissolved and absorbed to play a role. The disintegrant in the present invention includes, but is not limited to, one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and crospovidone.

The controlled release pharmaceutical composition provided by the present invention may further include other excipients in the composition, including but not limited to preservatives, antioxidants, or any other excipients commonly used in the pharmaceutical industry.

The composition provided by the present invention is finally presented in a pharmaceutical form that is easy for patients to take, and may be selected as tablets or capsules.

The recommended administration method of the controlled release composition of the present invention is to take it after meals.

The controlled-release pharmaceutical composition provided by the present invention is characterized in that the active drug in the delayed-release floating composition optionally maintains a crystalline state or changes to an amorphous state after the hot melt extrusion process.

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

The invention also provides a method for preparing the above controlled-release drug combination.

The method for preparing a controlled-release pharmaceutical composition provided by the present invention includes the following steps: 1) Before hot-melt extrusion, at least one solvent, the active ingredient in the delayed-release floating component and at least one enteric polymer are mixed to obtain a pre-mixed crude product or During the hot-melt extrusion process, at least one solvent, the active ingredient in the delayed-release floating component and at least one enteric polymer are mixed online to obtain a pre-mixed crude product; 2) The pre-mixed crude product passes through the heated screw zone of the extruder and passes through the die The extrudate left.

The preparation method provided by the present invention is characterized in that the solvent only needs to be volatile after the hot melt extrusion process is completed. 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 water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, dichloromethane, tetrahydrofuran, preferably water, ethanol 、Isopropyl alcohol.

In the method provided by the present invention, the amount of the solvent is 0.1%-70%, preferably 1%-50%, and most preferably 10%-30% (mass percentage, calculated based on the total mass of the solid component is 100). In the method disclosed in the present invention, the temperature of the heating 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 70-200°C, preferably 90-180°C, more preferably 110-160°C.

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

Considering the nature of the active therapeutic agent itself, in some solutions of the present invention, if water is used as the solvent in the hot melt extrusion process, the esters (including lactones) and amides (including Internal amides) and substances that decompose easily at high temperatures are not considered as active drugs in this application.

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

In the method provided by the present invention, according to the nature of the solvent itself and the temperature of the die, the low boiling point volatile solvent can be substantially volatilized during the extrusion process. The low boiling point volatile solvent includes but is not limited to ethanol.

The term "substantially volatilized" in the present invention means that the residual amount of solvent in the extrudate is less than 15%, preferably less than 12%, and most preferably less than 10%.

In the method provided by the present invention, when a solvent with a higher boiling point is selected, the step of desolvating the extrudate can be followed immediately after the hot melt extrusion is completed.

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 liquid to gaseous state.

In some embodiments, the removal of the solvent in the extrudate is done under reduced pressure.

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

The method for preparing a controlled-release floating component in a controlled-release pharmaceutical composition provided by the present invention is characterized by further comprising the step of cutting the extrudate.

The preparation method of the instant release part of the present invention includes wet granulation, dry granulation, powder direct compression and the like.

The preparation method provided by the present invention is characterized in that the extruder is selected from 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 modified release in which a pharmaceutical dosage form exhibits a time delay between oral administration of the pharmaceutical dosage form and release of the drug from the dosage form. Generally, delayed-release release dosage forms release little or no active compound within a predetermined time or until a predetermined condition is 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 present invention refers to the type of extended-release preparations in which the gradual release of the drug is controlled or manipulated for a certain extended period of time.

The following are specific embodiments of the present invention. The examples are for further describing the present invention rather than limiting the present invention. Any technical solution equivalent to the present invention falls within the protection scope of the present invention.

The hydroxypropyl methyl cellulose acetate succinate (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 extruder.

Example 1. Febuxostat formulation 1 consisting of immediate release febuxostat (Febuxostat) microtablets and febuxostat floating particles A releasing drug above pH 6 1

A single capsule contains 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 granule A containing 32 mg of febuxostat active ingredient. Particle A is released above pH 6. The quick release febuxostat microtablets are prepared by the wet granulation process, and its prescription composition is listed in Table 1 below. Table 1. Prescription of immediate release febuxostat microtablets

Specific preparation process: wet granulation mechanism granulation, mixing raw materials and auxiliary materials, adding binder, stirring, 1500rpm cutter shearing and sieving, drying to less than 3% moisture, passing 30 mesh sieve, and then using Combo C&C600B single punching Tablet machine, 4.76mm punch tablet. Tablet weight: theory 61.5mg, actual control 59-65mg, hardness about 30N.

Febuxostat granules A are prepared by hot melt extrusion process, and its prescription composition is listed in Table 2 below. Table 2. Prescription of febuxostat floating particles A

Weigh febuxostat and HPMCAS MG in the mixer and mix them evenly. Hot melt extruder (Thermofei). The temperature setting is shown in Table 3. Table 3. Temperature of hot melt extruder (℃)

Specifically, add ethanol to Zone 4 at a speed of 700 ul/min, feed at Zone 2 at a speed of 4 g/min, set the screw speed to 100 rpm, cut the extrudate into segments, and then dry the extrudate at 60°C for 2 hours. The content is less than 0.5%, crushed to 2mm after drying.

Example 2. Febuxostat formulation 2 consisting of immediate-release febuxostat pellets and febuxostat delayed-release floating particles B that rapidly release 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 rest of the capsule contains a delayed-release febuxostat containing a total of 32 mg febuxostat. The floating particles B are released. This delayed release of the floating enteric particles B is quickly released at a pH above 6. The immediate release febuxostat pellets are prepared by the blank pill core dispensing process, and the prescription composition is shown in Table 4. Table 4. Composition of immediate release febuxostat pellets

Febuxostat controlled-release floating particles B are prepared by hot melt extrusion process, and their prescription composition is shown in Table 5. Table 5. Prescription of febuxostat floating particles B

Weigh 150g febuxostat, 90g HPMCAS MG and 360g hydroxypropyl methylcellulose in a blender and mix well. The temperature setting of the hot melt extruder is shown in Table 3. Add ethanol to Zone 4 of the hot melt extruder at a speed of 700ul/min, feed at Zone 2 at a speed of 4g/min, and set the screw speed to 100rpm to cut the extrudate. In sections, the extrudate was dried in an oven at 60°C for 2 hours, and the ethanol content was <0.5%. After drying, it was crushed to 4mm, and the obtained Febustat gastric floating controlled-release particles B were obtained.

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

A 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 remaining part of the capsule contains a total of 32 mg of febuxostat gastric floating particles C. This stomach floats Particle C is released above pH 5. The quick release febuxostat microtablets are prepared by the wet granulation process, and its prescription composition is listed in Table 1 above. Febuxostat controlled-release floating particles C are prepared by hot melt extrusion process, and their formulations are shown in Table 6. Table 6. Prescription of febuxostat floating particles C

After mixing 150g febuxostat and 450g HPMCAS LG uniformly, hot-melt extrusion was carried out, and the temperature parameters were set the same as the preparation of pellet A. The hot melt extruder's Zone4 is added with ethanol at a speed of 600ul/min, Zone2 is fed, the speed is 2g/min, the screw speed is 60rpm, the extrudate is cut into segments, and then the extrudate is oven dried at 60℃ for 2h , Ethanol content <0.5%, crushed to 4mm long particles after drying, to get the febuxostat floating particles C.

Example 4. Febuxostat formulation consisting of 40% immediate release febuxostat microchips and 60% febuxostat floating particles C releasing drug above pH 5 4

A single capsule contains an immediate-release component and a controlled-release floating component. The immediate-release component is a microtablet containing 16 mg of febuxostat. The remaining part of the capsule contains a total of 24 mg of febuxostat delayed-release floating particles C. This delay Release the floating controlled release particles C above pH5. The quick release febuxostat microtablets are prepared by the wet granulation process, the formulation of which is listed in Table 1 above, and the febuxostat controlled release floating particles C are the same as in Example 3.

Example 5. 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 rest of the capsule contains a febuxostat stomach containing a total of 32 mg febuxostat. Delayed release of floating particles D. This gastric floating delayed release particles D are slowly released while floating in gastric juice. The immediate-release febuxostat pellets are prepared by the blank pill core drug application process, and its prescription composition is listed in Table 4 above.

The febuxostat gastric floating controlled-release particles D were prepared by the hot melt extrusion process, and the prescription composition is shown in Table 7. Table 7. Prescription of febuxostat floating particles D

After mixing febuxostat with quaternary amino methacrylate copolymer type B and hypromellose, and then shearing in a wet granulator, triethyl citrate was slowly added dropwise. Hot melt extrusion of the mixed materials, the temperature parameter setting is the same as Table 3, add ethanol to Zone4, the speed is 1000ul/min, feed to Zone2, the speed is 4g/min, the screw speed is set to 100rpm, the extrudate Cut into sections, and then dry the extrudate at 60 ℃ for 2 hours, the ethanol content <0.5%. After drying, it was crushed to 4mm long particles, and the obtained Febustat gastric floating controlled-release particles D were obtained.

Example 6. Febuxostat formulation consisting of immediate release febuxostat microchips and the delayed release febuxostat floating particles E 6

A 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 remaining part of the capsule contains a total of 32 mg of febuxostat delayed-release floating particles E. This stomach The floating controlled-release particles E are slowly released while floating in the gastric juice. The quick release febuxostat microtablets are prepared by the wet granulation process, and the prescription composition is listed in Table 1. Febuxostat gastric floating delayed-release particles E were prepared by the hot melt extrusion process, and their formulations are shown in Table 8. Table 8. Prescription of febuxostat floating particles E

Mix the febuxostat with other excipients according to the prescribed amount and then perform hot-melt extrusion. The temperature parameter settings are shown in Table 3. Add ethanol to Zone4 at a speed of 300ul/min, feed at Zone2 at a speed of 4g/min, the screw speed is set to 100rpm, cut the extrudate into segments, and then dry the extrudate at 60℃ for 2h, ethanol content <0.5%, pulverized to 4mm long particles, and the existing Febustat gastric floating controlled-release particles E.

Example 7. Febuxostat preparation consisting of immediate-release febuxostat microtablets and floating particles F in controlled release febuxostat 7

A 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 remaining part of the capsule contains a total of 32 mg of febuxostat gastric floating particles F. This stomach floats The controlled-release particles E are slowly released while floating in the gastric juice. The quick release febuxostat microtablets are prepared by the wet granulation process, and its prescription composition is listed in Table 1. The febuxostat gastric floating controlled release particles F are prepared by the hot melt extrusion process, and its prescription composition is shown in Table 9. Table 9. Prescription of febuxostat floating particles F

Mix the febuxostat with other excipients according to the prescribed amount and then perform hot-melt extrusion. The temperature parameter settings are shown in Table 3. Add ethanol to Zone4 at a speed of 300ul/min, feed at Zone2 at a speed of 4g/min, the screw speed is set to 100rpm, cut the extrudate into segments, and then dry the extrudate at 60℃ for 2h, ethanol content ＜0.5%, crushed to 4mm long particles after drying, to obtain the febustat gastric floating controlled release particles F.

Example 8. Febuxostat formulation consisting of immediate release febuxostat microchips and febuxostat floating particles G that release the drug above pH 5.5 8

A single capsule contains 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 granule G containing 32 mg of febuxostat active ingredient. Particle A is released above pH 5.5. The quick release febuxostat microtablets are prepared by the wet granulation process, the formulation of which is shown in Table 1, the formulation of febuxostat delayed release floating particles G is shown in Table 10, and the hot melt extrusion and temperature settings are shown in Table 11. Table 10. Febuxostat delayed release of floating particles G

Pharma11 hot melt extruder (Thermofei), set the temperature as shown in Table 11. Table 11. Temperature setting of hot melt extruder (℃)

Specifically, feeding in Zone2, adding water in Zone4, the feeding speed is 5g/min, the adding water speed is 0.9ml/min, the screw speed is set to 100rpm, the extrudate is cut into sections, and then the extrudate is oven dried at 60℃ for 2h. Moisture<3%, crushed to 2mm after drying, test density is 0.5g/cm ³ , fill the capsules of the obtained febuxostat particles G and the febustat microplate obtained in Example 1 to obtain febuxostat preparation 8 .

Example 9. Human pharmacokinetic study

C_max ：最大血藥峰濃度 T_max ：最大血藥濃度時間 AUC_{0 →∞} ：藥時曲線面積 TC_≥100μg/mL ：有效血藥濃度C≥100μg/mL時間 Fr：相對生物利用度Using commercially available 40 mg febuxostat tablets as a reference preparation, human pharmacokinetic studies were conducted together with the preparations obtained in Example 3 and Example 4. The results of the studies are shown in Table 12 below. Table 12. Pharmacokinetic parameters of different preparations

C _max : maximum blood drug peak concentration T _max : maximum blood drug concentration time AUC _{0 →∞} : drug-time curve area TC _≥100μg/mL : effective blood drug concentration C ≥100μg/mL time Fr: relative bioavailability

The results of pharmacokinetic studies showed that compared with the commercially available febuxostat tablet reference formulations, Examples 3 and 4 can reduce the maximum peak drug concentration of the drug, greatly extend the action time, and exert the controlled release treatment of the drug Action, thereby reducing the side effects of the drug, the results are shown in Figure 1.

Experimental Example 1

Using 300mL of pH5.0 FaSSGF as the dissolution medium, observe the floating situation of gastric floating particles under simulated gastric juice. After observation, each particle floated immediately and floated for a long time. After 24 hours, the particles remained floating. Stop watching.

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

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

According to the dissolution testing method 1 (Basket method, 100 rpm, 37°C) of the appendix of the Chinese Pharmacopoeia 2015 edition, 900mL of pH 6.8 phosphate buffer is used as the dissolution medium, and the preparations 3 and 4 are obtained in Example 3. The dissolution profiles of Formulation 4 and the immediate-release microtablets are shown in Figure 4.

The dissolution rate can indicate the speed of release of the drug from the preparation in the gastrointestinal environment. The lower release rate reflects the lower Cmax and longer release time on the pharmacokinetic data. Compared with ordinary immediate-release tablets, the dissolution rate of the preparation prepared in the present invention is significantly reduced. It can be speculated that the formulations in the present invention (Examples 1-7) can achieve a reduction in Cmax value compared to immediate-release tablets. The purpose of extending the effective blood concentration time.

Observing the properties of the particles G with an electron microscope scan, it was found that the particles G were porous under the electron microscope, see Figure 5 for details.

The powder diffraction pattern of the crystalline state of febuxostat raw material and febuxostat after extrusion is shown in Figure 6. The febuxostat remains in crystalline form after hot melt extrusion.

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

Mix hydrochlorothiazide and HPMC AS LG uniformly for hot melt extrusion, and set the temperature parameters as shown in Table 13 (℃). Table 13.

Specifically, feed in Zone2, add water in Zone4, set the screw speed to 50 rpm, add water at 400ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

Phenomenon: The extrusion is smooth, the process is stable, the sample expands, and it can float quickly.

The powder diffraction pattern of the hydrochlorothiazide raw material and the crystal form of hydrochlorothiazide after extrusion in Example 10 was tested. After hot-melt extrusion, the hydrochlorothiazide remained in the crystal form as shown in FIG. 7; the dissolution curve of the prescription of Example 10 is shown in FIG. 8. As shown.

Example 11 Hydrochlorothiazide (30 mg prescription) Hydrochlorothiazide: HPMCP=1:3 Mix hydrochlorothiazide and HPMCP uniformly, perform hot melt extrusion, and set the temperature parameters as shown in Table 14 (℃). Table 14.

Specifically, feed in Zone2, add water in Zone4, set the screw speed to 50 rpm, add water speed to 500 ul/min, dry the extrudate at 60 ℃ for 2 hours, moisture <3%, and crush to 2 mm after drying.

Phenomenon: The sample is extruded smoothly and can float quickly.

The powder diffraction pattern of the hydrochlorothiazide raw material and the crystal form of the hydrochlorothiazide after extrusion in Example 11 was tested. After hot-melt extrusion, the hydrochlorothiazide remained in the crystalline state as shown in FIG. 9; the dissolution curve of the prescription of Example 11 is shown in FIG. 10. As shown.

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

Mix nifedipine and HPMC AS LG evenly and perform hot melt extrusion. The temperature parameters are set as shown in Table 15 (℃). Table 15.

Specifically, feed in Zone2, add water in Zone4, set the screw speed to 50 rpm, add water at a speed of 1200ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, crush to 2mm after drying.

Phenomenon: The sample is extruded smoothly and can float quickly.

For the nifedipine raw material and the powder diffraction pattern of the nifedipine crystal form after extrusion in Example 12, the nifedipine remained in the crystalline state after hot melt extrusion, as shown in FIG. 11; Example 12 prescription The dissolution curve is shown in Figure 12.

Example 13 Tadalafil (Tadalafil, 30 mg prescription) Tadalafil: HPMC AS LG=1:3 Mix tadalafil and HPMC AS LG uniformly, perform hot melt extrusion, and set the temperature parameters as shown in Table 16 ( ℃). Table 16.

Specifically, feed in Zone2, add water in Zone4, set screw speed to 50 rpm, add water at 900ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

Phenomenon: The extrusion is smooth, the process is stable, the sample expands, and it can float quickly.

The powder diffraction pattern of the tadalafil raw material and the crystal form of tadalafil after extrusion in Example 13 was tested. After hot melt extrusion, tadalafil remained in the crystalline state, as shown in FIG. 13; The dissolution curve of the prescription of Example 13 is shown in Figure 14.

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

Mix losartan and HPMC AS LG uniformly and perform hot melt extrusion. The temperature parameters are set as shown in Table 17 (℃). Table 17.

Specifically, feed in Zone2, add water in Zone4, set the screw speed to 50 rpm, add water at 600ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

Phenomenon: The extrusion is smooth, the sample expands, and it can float quickly.

The powder diffraction pattern of the losartan raw material and the crystal form of losartan after extrusion in Example 14 was tested. After hot-melt extrusion, losartan remained in the crystal state, as shown in FIG. 15; The dissolution curve is shown in Figure 16.

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

Mix dexamethasone and HPMC AS LG uniformly for hot melt extrusion, and set the temperature parameters as shown in Table 18 (℃). Table 18.

Specifically, feed in Zone2, add water in Zone4, set the screw speed to 50 rpm, add water at 400ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

Phenomenon: The extrusion is smooth, the sample expands, and it can float quickly.

The dissolution curve of the prescription of Example 15 is shown in FIG. 17.

Example 16 Dexamethasone (30 mg prescription) Dexamethasone: HPMCP=1:3 Mix dexamethasone and HPMCP uniformly, perform hot melt extrusion, and set the temperature parameters as shown in Table 19 (℃). Table 19.

Specifically, feed in Zone2, add water in Zone4, set the screw speed to 50 rpm, add water at 400ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

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

The dissolution curve of the prescription of Example 16 is shown in FIG. 18.

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

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

Specifically, feed in Zone2, add water in Zone4, set the screw speed to 50 rpm, add water at 600ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

Phenomenon: The extrusion is smooth, the sample expands, and it can float quickly.

The dissolution curve of the prescription of Example 17 is shown in FIG. 19.

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

Mix febuxostat and HPMCP uniformly, perform hot melt extrusion, and set the temperature parameters as shown in Table 21 (℃). Table 21.

Specifically, feed in Zone2, add water in Zone4, set the screw speed to 100 rpm, add water at a speed of 700-900ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

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

The dissolution curve of the prescription of Example 18 is shown in FIG. 20.

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

Mix hydrochlorothiazide and HPMC AS LG uniformly for hot melt extrusion, and set the temperature parameters as shown in Table 22 (℃). Table 22.

Specifically, feed in Zone2, add ethanol in Zone4, set the screw speed to 60 rpm, add ethanol at 700ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

Phenomenon: The extrusion is smooth, the process is stable, the sample expands, and it can float quickly.

The powder diffraction pattern of the hydrochlorothiazide raw material and the crystal form of hydrochlorothiazide after extrusion in Example 19 was tested. After hot melt extrusion, the hydrochlorothiazide remained in the crystalline state, as shown in FIG. 21; the dissolution curve of the prescription of Example 19 is shown in FIG. 22 As shown.

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

Mix hydrochlorothiazide and HPMCP uniformly and perform hot melt extrusion. The temperature parameters are set as shown in Table 23 (℃). Table 23.

Specifically, feed in Zone2, add ethanol to Zone4, set the screw speed to 50 rpm, add ethanol to 700ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

Phenomenon: The sample is extruded smoothly and can float quickly.

The powder diffraction pattern of the hydrochlorothiazide raw material and the crystal form of hydrochlorothiazide after extrusion in Example 20 was tested. After hot melt extrusion, the hydrochlorothiazide remained in the crystalline state, as shown in FIG. 23; the dissolution curve of the prescription of Example 20 is shown in FIG. 24. Show.

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

Mix losartan and HPMC AS LG evenly and perform hot melt extrusion. The temperature parameters are set as shown in Table 24 (℃). Table 24.

Specifically, feed in Zone2, add ethanol to Zone4, set the screw speed to 50 rpm, add ethanol to 700ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

Phenomenon: The sample is extruded smoothly and can float quickly.

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

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

Mix febuxostat and HPMCP uniformly and perform hot melt extrusion. The temperature parameters are set as shown in Table 25 (℃). Table 25.

Specifically, feed in Zone2, add ethanol to Zone4, set the screw speed to 50 rpm, add ethanol to 700 ul/min, dry the extrudate at 60℃ for 2h, moisture<3%, and pulverize to 2mm after drying.

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

The dissolution curve of the prescription of Example 22 is shown in FIG. 27.

Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention . Therefore, the scope of protection of the present invention shall be subject to the scope defined in the appended patent application.

no

Fig. 1 is the drug time curve of the preparation 3, preparation 4 and ordinary immediate-release tablets of the invention; Fig. 2 is the dissolution curve of the floating particles obtained in Examples 1-7 of the invention; Fig. 3 is the particles of the invention Dissolution curve diagram of G; FIG. 4 is a dissolution curve diagram of Formulation 3, Formulation 4 and ordinary immediate-release tablets of the invention; FIG. 5 is an electron microscope scanning diagram of the particle G of the invention; FIG. 6 is a particle G of the invention The powder diffraction pattern before and after the hot melt extrusion of bulastat. 7 is a powder diffraction pattern of hydrochlorothiazide before and after extrusion of Example 10 of the present invention; FIG. 8 is a dissolution curve of Example 10 of the present invention; FIG. 9 is a powder diffraction pattern of hydrochlorothiazide before and after extrusion of Example 11 of the present invention; 10 is the dissolution curve of Example 11 of the present invention; FIG. 11 is the powder diffraction pattern of nifedipine before and after extrusion of Example 12 of the present invention; FIG. 12 is the dissolution curve of Example 12 of the present invention; FIG. 13 is the present invention Example 13 powder diffraction pattern of tadalafil before and after extrusion; FIG. 14 is a dissolution profile of Example 13 of the present invention; FIG. 15 is powder diffraction pattern of losartan before and after extrusion of Example 14 of the present invention; 16 is the dissolution curve of Example 14 of the present invention; FIG. 17 is the dissolution curve of Example 15 of the present invention; FIG. 18 is the dissolution curve of Example 16 of the present invention; FIG. 19 is the dissolution curve of Example 17 of the present invention Figure 20 is the dissolution curve of Example 18 of the present invention; Figure 21 is the powder diffraction pattern of hydrochlorothiazide before and after extrusion of Example 19 of the present invention; Figure 22 is the dissolution curve of Example 19 of the present invention; Figure 23 is the present invention Example 20 is the powder diffraction pattern of hydrochlorothiazide before and after extrusion; FIG. 24 is the dissolution curve of Example 20 of the present invention; FIG. 25 is the powder diffraction pattern of losartan before and after extrusion of Example 21 of the present invention; FIG. 26 is the present Dissolution curve of Example 21 of the present invention; FIG. 27 is a dissolution curve of Example 22 of the present invention.

Claims (50)

A controlled release pharmaceutical composition, comprising: a) an immediate release component containing an active drug, b) a delayed release floating component containing an active drug, wherein the delayed release floating component is porous and contains at least one enteric Polymer, the delayed release floating component is prepared by hot melt extrusion. The controlled release pharmaceutical composition according to claim 1, wherein the enteric polymer is selected from polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, 1,2,4-benzenetricarboxylic acid acetic acid Cellulose, hydroxypropyl methylcellulose phthalate, 1,2,4-benzenetricarboxylic acid hydroxypropyl methylcellulose, cellulose acetate succinate, hypromellose acetate succinate, hydroxyl acetate Propyl methylcellulose phthalate, methacrylic acid-ethyl acrylate copolymer, methyl vinyl ether-maleic anhydride copolymer, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, methacrylic acid-methacrylate Methyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate copolymer, polyvinyl acetate, ethyl cellulose, polyvinyl acetate and polyvinyl pyrrolidone K30 mixture . The controlled release pharmaceutical composition according to claim 2, wherein the enteric polymer is selected from hypromellose acetate succinate, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate Copolymer, hydroxypropyl methyl cellulose phthalate. The controlled release pharmaceutical composition according to claim 1, wherein the ratio of active drug to enteric polymer in the delayed-release floating component is selected from 1:0.1-1:100. The controlled release pharmaceutical composition according to claim 4, wherein the ratio of active drug to enteric polymer in the delayed-release floating component is selected from 1:0.1-1:50. The controlled release pharmaceutical composition according to claim 5, wherein the ratio of active drug to enteric polymer in the delayed-release floating component is selected from 1:1 to 1:25. The controlled release pharmaceutical composition according to claim 1, wherein a solvent is added before the hot melt extrusion or during the hot melt extrusion. The controlled release pharmaceutical composition according to claim 7, wherein the boiling point of the solvent is selected from 30 to 110°C. The controlled release pharmaceutical composition according to claim 8, wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, methylene chloride, and tetrahydrofuran At least one. The controlled release pharmaceutical composition according to claim 9, wherein the solvent is selected from water or ethanol. The controlled release pharmaceutical composition according to claim 7, wherein the delayed-release floating component is in a multi-unit form. The controlled release pharmaceutical composition according to claim 11, wherein the multi-unit form is microchips, pellets, and granules. The controlled release pharmaceutical composition according to claim 12, wherein the multi-unit form is a particle. The controlled release pharmaceutical composition according to any one of claims 1 to 10, wherein the delayed-release floating component immediately floats in a FaSSGF solution at pH 5.0. The controlled release composition according to any one of claims 1-10, wherein the delayed release floating component floats in a FaSSGF solution at pH 5.0 for more than 24 hours. The controlled-release pharmaceutical composition according to any one of claims 1-10, wherein the density of the delayed-release floating component is 0.1-1.0 g/cm ³ . The controlled-release pharmaceutical composition according to claim 16, wherein the density of the delayed-release floating component is 0.2-0.8 g/cm ³ . The controlled release pharmaceutical composition according to claim 16, wherein the density of the delayed-release floating component is 0.3 to 0.7 g/cm ³ . The controlled release pharmaceutical composition according to any one of claims 1 to 10, wherein the delayed-release floating component is dissolved in 300 mL of FaSSGF dissolution medium of pH 5.0, basket method, 37° C., 100 rpm, cumulative dissolution of 5 h Less than 30%. The controlled-release pharmaceutical composition according to claim 19, wherein the delayed-release floating component is less than 20% in 300 mL of a FaSSGF dissolution medium of pH 5.0, basket method, 37° C., 100 rpm, and 5 hours of cumulative dissolution. The controlled-release pharmaceutical composition according to claim 19, wherein the delayed-release floating component is less than 10% in 300 mL of a FaSSGF dissolution medium of pH 5.0, basket method, 37° C., 100 rpm, and 5 h of cumulative dissolution. The controlled release pharmaceutical composition according to any one of claims 1 to 10, wherein the active drug in the delayed-release floating component is selected from BCS class I drugs. The controlled-release pharmaceutical composition according to claim 22, wherein the BCS class I drug is selected from the group consisting of pabital, cobimetinib, Patiromer, omarigliptin, bupropion, guanfacine, venlafaxine hydrochloride, Methylphenidate hydrochloride, tedizolid phosphate, flibanserin, eliglustat, alogliptin, dimethyl fumarate, pirenpanet, lometapine, lusotinib, clobazam, dalfampridine , Prolia, dronedarone hydrochloride, Pralatrexate, lacosamide, fesoterodine fumarate, alprazolam, amitriptyline hydrochloride, amlodipine besylate, benazepril, amoxicillin, anatrox Azole, azelastine, bisoprolol, buspirone, caffeine, carbidopa, cetirizine, chloroquine phosphate, chlorpheniramine, clindamycin, clonidine, cyclobenzaprine, cyclic Phosphatamide, desogestrel, ethinylestradiol, diazepam, diphenhydramine, donepezil hydrochloride, doxazosin mesylate, doxycycline, emtricitabine, estradiol, Ethosuximide, fexofenadine, finasteride, fluconazole, flucytosine, fluoxetine hydrochloride, fluvoxa mesylate, imipramine, indapamide, isoniazid , Lamivudine, lidocaine, lorazepam, losartan, metoprolol succinate, mexiletine, midazolam, mirtazapine, montelukast sodium, norethisterone, and Norethindrone, nortriptyline, olopatadine hydrochloride, oseltamivir, pramipexole, pravastatin sodium, Prednisone, prednisolone, pregabalin, procainamide hydrochloride, promethazine hydrochloride, propranolol hydrochloride, pyrazinamide, pyridoxine hydrochloride, quine Naplepril hydrochloride, quinidine, quinine hydrochloride, ramipril, sertraline, sildenafil citrate, sotalol, stavudine, terbinafine hydrochloride Salt, tolterodine, torasemide, tramadol hydrochloride, trazodone, varenicline, zidovudine, alfacalcidol, beraprost, biperiden, brompheniramine , Brometazolam, carbisamin, clomiphene, clomipramine, cloxacillin, diltiazem, dolasetron, morpholine, eperisone hydrochloride, epistatin, calciferol, ergonovine , Ergotamine, ethinyl estradiol, etazolam fluvastatin, granisetron, ketotifen, levamisole, levonorgestrel, riprost, loxoprofen, mefloquine, meclizine hydrochloride Celestine, nicardipine, niclosamide, tobrabutrol, trimethoprim, trimebutine, toremifene, terbinafine, temopril, tamsulosin, sertraline , Sagrete hydrochloride, saquinavir, rosiglitazone, reserpine, ramipril, propiverine hydrochloride, promethazine, pergolide, paroxetine. The controlled release pharmaceutical composition according to any one of claims 1 to 10, wherein the active drug in the delayed-release floating component is selected from BCS Classes II to IV drugs. The controlled-release pharmaceutical composition according to claim 24, wherein the BCS class II to IV drugs are selected from the group consisting of febuxostat, ixazomib, Alectinib, Erismodegib, vandetanib, aprepitant, and verapamil sulfate , Aspirin, metformin, englitazone, ritagliptin, naltrexone, dasabuvir, sofosbuvir, amphetamine, etravirine, everolimus, itraconazole, verofenib , Trapivir, tacrolimus, posaconazole, ivacaftor, redipavir, Suvorexant, Ombitasvir, paritaprevir, daclatasvir, caliprazine, brexpiprazole, obemifene, levetiracet Tan, ivacaftor, eluxadoline, lumacaftor, ivacaftor, etrepopa, nidanib, meloxicam, morphine, macitentan, dutasteride, abiraterone, lumacaftor, daglitazone, tasine Mejon, ibrutinib, paramivir, olaparib, iparetin, idelalisib, belistil, ceritinib, aprost, pomalidomide, operimifen, Cagliflozin, dabrafenib mesylate, trimetinib, dolutegravir, vortioxetine bazedoxifene, simeprevir, axitinib, Vismodegib, avanafil, chlorca Serin, Mirabello, Bosutinib, Teriflunomide, Regorafenib, Tofacitinib, Cabozantinib, Panatinib, Apixaban, Bedaquiline, Crofelemer, Pocepvir, Trapvir , Belazep, verafinil, crizotinib, roflumilast, verazodone, azilsartan, gabapentin, vandetanib, nategliptin, ribavirin, feda Amycin, ezogabine, etibantol acetate, rivaroxaban, ticagrelor, polidocanol, carglumic acid, temorelin, vemurafenib, cabazitaxel, dabigatran etexilate, everolimus, tolva Proptan, prasugrel, saxagliptin, telavancin, pazopanib, silodosin, rufinamide, eltrombopag, acetazolamide, paracetamol, acyclovir, atorvastatin, atorvastatin calcium, amprena Wei, aripiprazole, atenolol, ketamine, atoquinone, azathioprine, azithromycin, budesonide, calcitriol, isopropyl metformin, cefdinir, cefixime, Cephalosporin acetate, celecoxib, cephalexin, chlorothiazide, clarithromycin, clopidogrel bisulfate, clotrimazole, betamethasone, diaminodiphenol, diclofenac sodium, bicyclic amine, arrived at Nuoxin, Trabenol, duloxetine, dutasteride, etodolac, ezetimibe, simvastatin, fenflurate, fenofibrate, flecainide, fosanivir, furananilide , Xyloxyheptanoic acid, glimepiride, glibenclamide, griseofulvin, ibuprofen, hydroxychloroquine, hydroxyzine, indomethacin, irbesartan, isoniazid, iradipine , Ketoconazole, lamotrigine, lansoprazole, latanoprost, linezolid, loperamide, cephalosporin, loratadine, lovastatin, mebendazole, chlorphenazine, Mercaptopurine, ammonia salicylic acid, metaxalone, phenoperidine methyl acetate, methylprednisolone, modafinil, mycophenolic acid, mycophenolate mofetil, nabmetone, naproxen , Nifedipine, omeprazole, carbamazepine, oxycodone hydrochloride, phenazopyridine, phenytoin sodium, pioglitazone hydrochloride, piroxicam, deoxyphenobarbital, prochlorperazine, progesterone , Pyrimethamine, quetiapine, raloxifene hydrochloride, rifabutin, rifampicin, risperidone, spironolactone, sulfamethoxazole, tadalafil, telmisartan, tilana Wei, valsartan, vardenafil, ziprasidone, abacavir sulfate, codeine, salbutamol, alendronate, allopurinol, potassium clavulanate, benztropine, bima Prostaglandin, buprenorphine, naloxone, captopril, levodopa, cefixime, cefadroxil, cetirizine hydrochloride, ciprofloxacin, colchicine, ergocalciferol , Famotidine, pseudoephedrine, folic acid, gabapentin, hydralazine, hydrochlorothiazide, salbutamol, levocetil, levofloxacin, levothyroxine sodium, lisinopril, methotrexate, methyldopa, nadolol, prepared Mycotoxins, pantoprazole, primaquine phosphate, pyrazinamide, ranitidine hydrochloride, ribavirin, risedronate sodium, sorinasin, spironolactone, sumatra Proptan succinate, terazosin, tetracycline, thiamine, topiramate, valacyclovir hydrochloride, valganciclovir, carbose, aceclofenac, acetazolamide, acetyl meat Toxicine, albendazole, allyl sulamine, amiloride, atropine, azathioprine, azithromycin, benidipine, benzhydrazine, benznidazole, bicalutamide, bisacodyl, carbamazepine Kolin, candesartan, capecitabine, carvedilol, cefditoren, cefmetazole, cefotiam, cefpodoxime, ceftazidime, cefuroxime axetil, celecoxib, chloramphenicol, Chlorpromazine, Cilazapril, Cilostazol, cimetidine, citalopram, chlorphenazine, cyclosporine, cyproterone, dapsone, ethamazine, digoxin, dimethine Clonet, deoxyfluridine, doxycycline, ebastine, efavirenz, epalrestat, psartan, erythromycin, ethambutol, ezetimibe, famciclovir, fenofibrate Fibrate, fluconazole, flurbiprofen, diuretic sulfonamide, furanthiamine, gefitinib, gliclazide, glipizide, griseofulvin, haloperidol, hydroxyzine hydrochloride, bulo Fen, imatinib, midapril, indinavir, irbesartan, isoniazid, ivermectin, ketoprofen, lamotrigine, levofloxacin, lopinavir, lovastatin, horse Nidipine, mebendazole, medroxyprogesterone, aminosalicylic acid, metaxalone, methotrexate, methyldopa, metronidazole, modafinil, mosapride, nabumetone, Nalidixic acid, nelfinavir, neostigmine, nevirapine, nicorandil, nicotinamide, nifurtimox, nilvadipine, nimesulide, zolpidem, zolmitriptan, zap Tolofen, warfarin, voglibose, verapamil, valproic acid, ursodeoxycholic acid, trimetazidine, tosufloxacin, ticlopidine, theophylline, teprenil Ketone, tenofovir, tegafur, tamoxifen, tatirelin, sumacillin, 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, bromopyrus, propion Thiouracil, procaterol, praziquantel, proprimed, phenytoin sodium, phenobarbital, benzotriazine, perindopril, oxycodone, dexamethasone, furosemide. The controlled release pharmaceutical composition according to any one of claims 1-10, wherein the delayed-release floating component further comprises at least one plasticizer selected from triethyl citrate, citrate Tributyl citrate, polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl sebacate, diethyl sebacate, glyceryl stearate, succinic acid Diethyl ester, propylene glycol, castor oil, and triacetin. The controlled release pharmaceutical composition according to claim 26, wherein the plasticizer is triethyl citrate. The controlled release pharmaceutical composition according to claim 26, wherein the content of the plasticizer is 0.01%-50% (mass percentage, calculated based on the total mass of the solid component being 100). The controlled release pharmaceutical composition according to claim 28, wherein the content of the plasticizer is 0.1%-30%. The controlled release pharmaceutical composition according to claim 29, wherein the content of the plasticizer is 2.5%-15%. The controlled release pharmaceutical composition according to any one of claims 1-10, wherein the immediate release component and/or the delayed release floating component further comprise at least one pharmaceutically acceptable other excipient. The controlled release pharmaceutical composition according to claim 31, wherein the excipient is selected from a filler, a lubricant, a binder, and a disintegrant. The controlled release pharmaceutical composition according to any one of claims 1-10, which is a tablet or a capsule. The controlled release pharmaceutical composition according to any one of claims 1 to 10, wherein the active drug in the immediate release component is the same as or different from the active drug in the delayed release component. The controlled release pharmaceutical composition according to claim 34, wherein the active drug in the immediate release component is the same as the active drug in the delayed release component. The controlled release pharmaceutical composition according to any one of claims 1 to 10, wherein the active drug in the delayed-release floating component is optionally maintained in a crystalline state or transformed into an amorphous state after hot melt extrusion. A method for preparing a controlled-release pharmaceutical composition according to any one of claims 1-10, which includes the following steps: 1) Before hot-melt extrusion, at least one solvent, the active ingredient in the delayed-release floating component and At least one enteric polymer is mixed to obtain a pre-mixed crude product or at least one solvent, the active ingredient in the delayed-release floating component and at least one enteric polymer are mixed online during hot-melt extrusion to obtain a pre-mixed crude product; 2) pre-mixed crude product After passing through the heated screw zone of the extruder, the extrudate is obtained through the die. The production method according to claim 37, wherein the solvent is selected from solvents having a boiling point of 30-110°C. The production method according to claim 38, wherein the solvent is selected from water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, dichloromethane, and tetrahydrofuran. The production method according to claim 39, wherein the solvent is selected from water or ethanol. The preparation method according to claim 39, wherein the amount of the solvent is 0.1%-70% (mass percentage, calculated based on the total mass of the solid component is 100). The preparation method according to claim 41, wherein the amount of the solvent is 1%-50%. The preparation method according to claim 42, wherein the amount of the solvent is 10%-30%. The preparation method according to claim 37, wherein the die temperature is 70-200°C. The preparation method according to claim 44, wherein the die temperature is 90-180°C. The preparation method according to claim 45, wherein the die temperature is 110-160°C. The preparation method according to claim 44, wherein the temperature of the solvent injection screw zone is 10-90°C. The preparation method according to any one of claims 37 to 47, further comprising the following steps: 1) cooling the extrudate; 2) desolvating the extrudate; 3) cutting the extrudate. The production method according to any one of claims 37 to 47, wherein the extruder is selected from a single screw hot melt extruder, an intermeshing screw extruder, and a twin screw hot melt extruder. The production method according to claim 49, wherein the extruder is a twin-screw hot melt extruder.

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