CN110214007A

CN110214007A - A kind of controlled release pharmaceutical compositions and preparation method thereof

Info

Publication number: CN110214007A
Application number: CN201880008336.9A
Authority: CN
Inventors: 王捷; 王立坤; 顾国祥; 张凤娥
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2017-06-14
Filing date: 2018-06-13
Publication date: 2019-09-06
Also published as: WO2018228441A1; TW201904565A; TWI682789B

Abstract

This application involves a kind of controlled release pharmaceutical compositions, which includes: a) containing the immediate release component of active medicine, b) the sustained release floating component containing active medicine, wherein sustained release floating component is prepared by the method for hot-melt extruded.

Description

A kind of controlled release pharmaceutical compositions and preparation method thereof

This application claims the priority for the Chinese patent application CN201710454301.5 that the applying date is on June 14th, 2017.The application quotes the full text of above-mentioned Chinese patent application.

Technical field

The present invention relates to a kind of controlled release pharmaceutical compositions, belong to pharmaceutical field.

Background technique

In pharmaceutical field, to effectively reduce times for spraying, increase the compliance of patient's medication, the purpose of improving drug safety and reducing the side reaction of gastrointestinal tract, there are many drugs to be developed as the controlled release preparation containing immediate release component and release sustaining component, such as carbidopa/levodopa controlled release preparation disclosed in CN101910113A at present.

Rear end absorption difference of the majority of compounds in enteron aisle, after causing patient to take preparation, preparation is after being transported to colonic segment (being commonly considered as 4-6 hours), preparation effectively can not be discharged and be absorbed, for removing fast drug, can not guarantee effectively maintain blood concentration within 6 hours after the tablet has been ingested by way of being commonly sustained.Oral stomach is detained preparation and extends the residence time of drug in the upper end of gastrointestinal tract, even if removing fast drug in enteron aisle rear end absorption difference, also can guarantee effectively can discharge and absorb after medication 6 hours, dosing interval and dosage are reduced, the compliance of patient is improved.Mode one of of the stomach floating preparation as gastric retention, preparation is increased in the residence time of stomach, in the past in end absorption but its solubility very little or degradable drug in alkaline environment on the gastrointestinal tract, and it is transferred to the part of stomach and upper small intestine and is persistently administered for treating the drug of some specific situations.

At present, it is existing that largely prior art discloses the achievable modes of stomach floating preparation, such as, CN103037850A discloses a kind of leptosomatic Entogastric lingering capsule, experiments have shown that it goes out to extend the gastric retention time, however there are the danger of stomach block or system permanent retention for such design, therefore its real value very little.To realize more reasonable drug effect, have a large amount of drug and has been made into the stomach floating drug delivery system that quick-release is combined with controlled release, but mostly double-layer tablets or capsule, such as Yin Lifang et al. discloses a kind of double-layer tablets of stomach floating, active constituent is Pioglitazone and melbine, wherein immediate release component is Pioglitazone, controlled release component is melbine, the double-layer tablets are by using the floating auxiliary agent stearyl alcohol that the sodium carbonate and low-density that can produce carbon dioxide is added, to achieve the effect that floating, wherein most preferred preparation can float (International Journal of Pharmaceutics 476 (2014) 223-231) at least for 24 hours in test solvent.But single tablet is poor in the presence of there are floating capacities, plays the various deficiencies such as the drift time is long, individual difference is big.Indian patent application IN2009DE00792A discloses a kind of intragastric administration system of double particles, and the immediate-release granules containing Ofloxacin and stomach float controlled release granule, and wherein controlled release granule includes hydrophobic material and hydrophilic material.

Hot-melt extruded (HME) is the process that raw material are pumped into the product of uniform shapes at high temperature by rotary screw by mold.HME has many advantages better than other drugs processing technique, and the molten polymer in extrusion process can be used as heat adhesive, and is used as drug depot and/or drug release retarding agent in cooling and solidification.Since this method does not need solvent and water, to reduce the quantity of procedure of processing and eliminate time-consuming drying steps.Host material can be assembled to the larger unit independently of compression property.The strong mixing and stirring that rotary screw applies causes aggregation of the suspended particulate in molten polymer, so that dispersion is more evenly.

In recent years, torching mark has been attempted in the preparation of controlled release stomach floating preparation, Nakamichi et al. discloses the floating preparation of the nicardipine hydrochloride using double screw extruder preparation, the polymer material of hot-melt extruded is acetic acid hypromellose succinate (HPMCAS), it is found in research, the swollen extrudate of pine can not be obtained using only drug and high polymer, it must be added to substance i.e. calcium phosphate dihydrate in third, when the dosage of calcium phosphate dihydrate is 8%, floatability 6h (the International Journal of Pharmace-Utics 218 (2001) 103-112) in gastric juice.Nakamichi has speculated the effect of Calcium Phosphate, Dibasic Dihydrate, when the fusant of drug and high polymer is in machine letter, high pressure by screw rod acts on, and from the instantaneous of head extrusion, enters atmospheric area by higher-pressure region, according to one Clapeyron equation of Clausius, the boiling point of melt will have a declining tendency, and at this moment, solid Calcium Phosphate, Dibasic Dihydrate is equivalent to zeolite, gasification center is introduced in the melt, and extrudate is made to produce a large amount of bubbles in moment.With the quick reduction of temperature, bubble solidifies immediately again, obtains the swollen object of pine.

US2016113906A discloses a kind of composition of hot-melt extruded, polar organic solvent is added in the composition squeezed out by hot melt, so that the decomposition of active constituent is reduced, increase the compatibility between active constituent and polymer, the operation temperature temperature for reducing hot-melt extruded, reduces torque.Nakamichi et al. has investigated moisture for the influence by the standby solid dispersions of twin screw hot melt extrusion mechanism, the addition of experiment results proved water can reduce the flowing temperature (Tfb) of material, it was demonstrated that material can lower than fusing point at a temperature of be extruded (International Journal of Pharmaceutics 241 (2002) 203-211).

Padma V.Devarajan et al. discloses a kind of stomach floating more granular preparations of controlled release of metoprolol succinate prepared by hot-melt extruded mode, optimizes the material Utech RSPO of hot-melt extruded Proportion between polyethylene glycol oxide (PEO), hypromellose (HPMC) balances floating capacity and controlled release ability, and the generation of gas uses sodium carbonate (International Journal of Pharmaceutics 491 (2015) 345-351).

Mamoru Fukuda et al. discloses a kind of gastric retention floating tablet that the method using hot-melt extruded is prepared, using Utech RSPO ( RS PO) and/or Utech EPO ( E PO.) host material, sodium carbonate has been investigated to the shadow (Journal of Controlled Release 115 (2006) 121-129) of the physicochemical property of composition.

Michael A.Repka etc. is disclosed with Utech RSPO Or hypromellose K15M (HPMC K15M) is host material, floats pellet (European Journal of Pharmaceutics and Biopharm- using the stomach that the operating method that ethyl alcohol is added during hot-melt extruded is prepared

Aceutics 98(2016)108–121).Michael A.Repka et al. discloses therapeutic administratp system in a kind of stomach with double action mechanism containing the solid dispersions being prepared by hot-melt extruded method, the drug delivery system is using felodipine as effective component, hydroxypropyl cellulose base hydroxymethyl cellulose is as host material, in such a way that leafing agent adheres to, so that residence time of the drug in stomach is longer (European Journal of Pharmaceutical Sciences 102 (2017) 71-84), however, the intrinsic danger of this dosage form is that drug may cause to damage in esophagus adherency.

Since torching mark and stomach floating preparation embody irreplaceable advantage, and superiority of the controlled release preparation containing quick-release and release components in drug effect is obvious to all, therefore, comprehensive multiple technologies, the preparation of the novel various technical barriers of solution is developed, importance is self-evident for pharmaceutical field.

Summary of the invention

The present invention provides a kind of controlled release pharmaceutical compositions prepared using hot-melt extruded, the composition effectively extends the front end residence time in the gastrointestinal tract, the effective soak time of gastrointestinal tract is improved to 10 hours or more, to effectively reduce times for spraying, increases the compliance of patient's medication.

The present invention provides a kind of controlled release pharmaceutical compositions, include: a) containing the immediate release component of active medicine, b) the sustained release floating component containing active medicine, it is characterised in that the sustained release floating component is prepared by the process of hot-melt extruded.

Controlled release pharmaceutical compositions provided by the invention, it is characterised in that the sustained release floating component contains at least one enteric polymer.Delayed release medicine component of the present invention containing enteric polymer discharges drug under conditions of pH >=5.5.

Controlled release pharmaceutical compositions provided by the invention, it is characterized in that the enteric polymer is selected from polyvinyl alcohol phthalate, cellulose acetate phthalate, 1, 2, 4- benzenetricarboxylic acid cellulose acetate, Hydroxypropyl Methylcellulose Phathalate, 1, 2, 4- benzenetricarboxylic acid hydroxypropyl methyl cellulose, acetate succinate cellulose, acetic acid hydroxypropyl methylcellulose succinate, hydroxypropylmethylcellulose acetate methylcellulose phthalate ester, EUDRAGIT L100-55, methyl vinyl ether-maleic acid copolymer, EUDRAGIT L100-55 aqueous dispersion, EUDRAGIT L100, ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride base methacrylate copolymers, polyvinyl acetate, ethyl cellulose, polyvinyl acetate and poly- Vinylpyrrolidone K30 mixture, preferably acetic acid hydroxypropyl methylcellulose succinate, EUDRAGIT L100, EUDRAGIT L100-55, Hydroxypropyl Methylcellulose Phathalate.

In some embodiments, EUDRAGIT L100-55 is 1:1 copolymer, corresponding commercially available Eudragit l 100-55 or Kollicoat MAE100P.

In some embodiments, methyl vinyl ether-maleic acid copolymer corresponds to commercially available Series.

In some embodiments, EUDRAGIT L100 is 1:1 1:2 copolymer, respectively corresponds Eudragit L100 and Eudragit S100.

In some embodiments, polyvinyl acetate and PVP K30 mixture are Kollidon SR.

In some embodiments, heretofore described enteric polymer is Eudragit polymer, such as Eudragit L, Eudragit S or EudragitL 100-55.

In some embodiments, heretofore described enteric polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS), and hydroxypropylmethylcellulose acetate succinate disclosed in prior art US4226981B, CN104208713A and CN103153343A includes within the scope of application.

HPMCAS points of three kinds of grades of Shin-Etsu Chemical Co., Ltd. (Tokyo) sale, with the horizontal different combination of substituent group, to provide enteric protection in the case where various difference pH are horizontal.AS-LF and AS-LG grades (" F " indicates that thin and " G " indicates graininess) provides enteric protection at the pH of highest 5.5.AS-MF and AS-MG grades provides enteric protection at the pH of highest 6.0, and AS-HF and AS-HG grades provides enteric protection at the pH of highest 6.8.

Controlled release pharmaceutical compositions provided by the invention are characterized in that in the sustained release floating component that active medicine and enteric polymer ratio are selected from 1:0.1-1:100, preferably 1:0.1-1:50, more preferable 1:1-1:25.

Controlled release pharmaceutical compositions provided by the invention, the hot-melt extruded method optional solvents participate in hot-melt extruded process, i.e. in certain schemes, solvent is added, solvent is added without in other schemes, heretofore described solvent participation refers to invent needs, and solvent is added before hot-melt extruded or during hot-melt extruded.

If solvent is added in controlled release pharmaceutical compositions provided by the invention during the preparation process, the solvent is only needed to meet and can be volatilized after hot-melt extruded process, it is preferred that the boiling point of solvent is limited to 30-110 DEG C by the present invention.

Controlled release pharmaceutical compositions provided by the invention, it is characterised in that the solvent is selected from at least one of water, methanol, ethyl alcohol, isopropanol, acetone, pentane, hexane, heptane, hexamethylene, methylene chloride, tetrahydrofuran, preferably water and ethyl alcohol.

The present invention provides a kind of controlled release pharmaceutical compositions, when there is solvent to participate in hot-melt extruded process, sustained release floating density of fraction in controlled release pharmaceutical compositions is 0.1-1.0g/cm3, it is preferred that 0.2-0.8g/cm3, most preferably 0.3-0.7g/cm3, it is shown as cellular under Electronic Speculum, and drift can be played immediately in the solution of the FaSSGF of pH5.0 and the flotation time is maintained to be greater than for 24 hours.

If controlled release pharmaceutical compositions provided by the invention not solubilizer during the preparation process, contain the alkaline matter for meeting acid generation gas, i.e. controlled release pharmaceutical compositions neutral and alkali substance is not required in the present invention, when containing alkaline matter, the alkaline matter is specially alkali carbonate, alkali metal or alkali metal bicarbonates, more specifically sodium bicarbonate, sodium carbonate, sodium glycine carbonate, saleratus, magnesium carbonate and calcium carbonate.

Controlled release pharmaceutical compositions provided by the invention are free of calcium phosphate dihydrate, Nakamichi (International Journal of Pharmace-Utics 218 (2001) 103-112), et al. drug and matrix is added in calcium phosphate dihydrate, and by the way that leafing agent is prepared after hot-melt extruded.

Controlled release pharmaceutical compositions provided by the invention, the sustained release float in the FaSSGF dissolution medium of pH5.0 of the component in 300mL, basket method, and 37 DEG C, the accumulation of 100rpm, 5h are dissolved out less than 30%, and more preferably less than 20%, more preferably less than 10%.

Controlled release pharmaceutical compositions provided by the invention, it is characterised in that sustained release floating group is divided into multiple-unit form.

Controlled release pharmaceutical compositions provided by the invention, it is characterised in that the multiple-unit form is microplate, pellet, particle, preferably particle.

Immediate release component is chosen as the diversified forms such as pellet, microplate, particle in controlled release pharmaceutical compositions provided by the invention, specifically, can contain active medicine and blank capsule core when immediate release component is pellet.

In general, pharmaceutical preparation can reach colons 3 to 6h under most of situation after taking orally, therefore, sustained release preparation is successful on condition that improving the time of gastrointestinal absorption and increasing absorption.

Drug is classified according to their dissolubility and intestinal permeability by the bio-pharmaceuticals categorizing system (BCS) that FDA is introduced, referring specifically to " The Biopharmaceutics Classification System (BCS) Guidance ".Jennifer B.Dressman and Christos Reppas are in " Oral Drug Absorption:Prediction and Assessment " traps usually having had in entire gastrointestinal tract when mentioning in oral administration with high dissolubility and infiltrative drug (I class) of page 273, it is the most preferred drug of sustained release preparation, this kind of drug is included in the range of the active medicine of sustained release of the present invention floating component.

The drug of I class includes but is not limited in BCS classification of the present invention: pabishta, Cobimetinib, Patiromer, omarigliptin, Bupropion, guanfacine, venlafaxine hydrochloride, methylphenidate hydrochloride, phosphoric acid safe ground azoles amine, flibanserin, eliglustat, Egelieting, dimethyl fumarate, pyrrole Lun Panai, Lome Tapai, Lu Suo replaces Buddhist nun, Clobazam, dalfampridine, Prolia, dronedarone hydrochloride, Pralatrexate, lacosamide, fesoterodine fumarate, alprazolam, amitriptyline hydrochloride, amlodipine benzenesulphonate, benazepil, Amoxicillin, Anastrozole, nitrogen Zhuo Si Spit of fland, bisoprolol, buspirone, caffeine, carbidopa, cetirizine, chloroquine diphosphate, chlorpheniramine, clindamycin, clonidine, cyclobenzaprine, cyclophosphamide, Desogestrel, ethinyloestradiol, diazepam, diphenhydramine, donepezil hydrochloride, doxazosin mesylate, Doxycycline, emtricitabine, estradiol, ethymal, fexofenadine, Finasteride, Fluconazole, Flucytosine, fluoxetine hydrochloride, Fluvoxamine mesylate, imipramine, indapamide, isoniazid, Lamivudine, lidocaine, Lorazepam, Losartan, metroprolol succinate, mexiletine, midazolam, Mirtazapine, Montelukast Sodium, norethindrone, methylnorethindron, nortriptyline, olopatadine hydrochloride, Oseltamivir, Pramipexole, pravastatin sodium, prednisone, prednisolone, Pregabalin, it is general Shandong cacaine amine hydrochlorate, promethazine hydrochloride, propranolol hydrochloride, pyrazinamide, pyridoxine hydrochloride, quinapril hydrochloride, quinindium, quinine hydrochloride, Ramipril, Sertraline, sildenafil citrate, Sotalol, stavudine, Terbinafine hydrochloride, Tolterodine, Torasemide, Tramadol hydrochloride, Trazodone, varenicline, Zidovudine, Alfacalcidol, beraprost, Biperiden, Brompheniramine, brotizolam, carbinoxamine, clomiphene, clomipramine, Cloxacillin, diltiazem, Dolasetron, Domperidone, E-0646, epinastine, calciferol, ergometrine, ergotamine, ethinylestradiol, Etizolam, Fluvastatin, Granisetron, Ketotifen, levamisol, Levonorgestrel, vertical Bimatoprost, loxoprofen, Mefloquine, Mexiletine hydrochloride, nicardipine, niclosamidum, Tulobuterol, trimethoprim, Trimebutine, Toremifene, Terbinafine, Temocapril, Tamsulosin, Sertraline, sarpogrelate hydrochloride, inverase, Rosiglitazone, reserpine, Ramipril, propiverine hydrochloride, fenazil, pergolide, Paxil.

Jennifer B.Dressman and Christos Reppas are pointed out 272-274 pages of " Oral Drug Absorption:Prediction and Assessment " due to permeability and deliquescent problem, the drug of II to IV class in BCS classification shows poor colonic absorption or poor solubility, be not suitable for being prepared into sustained release preparation, composition of the invention is due to having used torching mark and stomach flotation technique, especially with enteric solubility polymerization, such drug is effectively extended in the residence time of gastrointestinal tract, drug is improved in the absorptivity of small intestine, more preferably effect has been embodied for such drug.

The drug that BCS classification of the present invention belongs to II to IV class includes but is not limited to: Febustat, ixazomib, Alectinib, Erismodegib, Vande Thani, Aprepitant, sulfuric acid Walla pa is husky, aspirin, melbine, En Gelie is net, Li Gelieting, naltrexone, dasabuvir, Suo Feibuwei, amphetamine, etravirine, everolimus, Itraconazole, Wei Luofeini, telavi, tacrolimus, posaconazole, according to cutting down Kato, Lei Dipawei, Suvorexant, Ombitasvir, paritaprevir, daclatasvir, Cariliprazine, brexpiprazole, Ao Pei meter Fen, Levetiracetam, ivacaftor, Eluxadoline, lumacaftor, ivacaftor, Ai Qubo pa, Nintedanib, Meloxicam, morphine, macitentan, dutasteride, abiraterone, lumacaftor, Dapagliflozin, Ta Simeiqiong, Buddhist nun is replaced according to Shandong, Peramivir, olaparib, Yi Palie is net, idelalisib, Baily department he, Ceritinib, Apremilast, pomalidomide, Ao Pei meter Fen, canagliflozin, methanesulfonic acid darafinib, Trimetinib, dolutegravir, vortioxetine, bazedoxifene, simeprevir, Axitinib, Vismodegib, avanaphil, lorcaserin, Mirabegron, bosutinib, teriflunomide, Rego Rafenib, tropsch imatinib, Cabozantinib, Pa Na replaces Buddhist nun, Eliquis, Bedaquiline, Crofelemer, Bo Saipuwei, Te Lapuwei, Bei Lasaipu, Wella Pfennig, gram azoles replaces Buddhist nun, roflumilast, vilazodone, A Zi sand is smooth, Gabapentin, Fan Detani, Na Gelieting, rilpivirine, feldamycin, ezogabine, icatibant acetate, razaxaban, Ticagrelor, polidocanol, carglumic acid, Tesamorelin, vemurafenib, cabazitaxel, dabigatran etcxilate, everolimus, tolvaptan, prasugrel, saxagliptin, telavancin, pazop Anib, silodosin, rufinamide, eltrombopag olamine, acetazolamide, paracetamol, acyclovir, Atorvastatin, Atorvastatin calcium, anpunave, Aripiprazole, atenolol, ketamine, atovaquone, imuran, azithromycin, budesonide, calcitriol, carisoprodol, Cefdinir, Cefixime, acetic acid cefuroxime, celecoxib, cefalexin, chlorothiazide, clarithromycin, clopidogrel hydrogenesulphate, clotrimazole, betamethasone, diamino biphenol, C14H10Cl2NNaO2, bentyl, it is new to arrive at promise, bent cannabinol, Duloxetine, dutasteride, Etodolac, ezetimibe, Simvastatin, Felbamate, fenofibrate, Flecainide, fosamprenavir, furosemide, gemfibrozil, Ge Liemei Urea, glibenclamide, griseofulvin, brufen, hydroxychloroquine, hydroxyzine, Indomethacin, Irbesartan, isoniazid, Isradipine, ketoconazole, Lamotrigine, Lansoprazole, Latanoprost, Linezolid, loperamide, Loracarbef, Loratadine, Lovastatin, mebendazole, meclizine, mercaptopurine, aminosalicylic acid, metaxalone, phenylphenidate acetate, methylprednisolone, modafinil, Mycophenolic Acid, Mycophenolate Mofetil, Nabumetone, naproxen, nifedipine, Omeprazole, carbamazepine, oxycodone hydrochloride, phenazopyridine, dilantin sodium, pioglitazone HCI salt, piroxicam, desoxyphenobarbital, prochlorperazine, progesterone, pyrimethamine, kui gentle ziprasidone, raloxifene hydrochloride, Rifabutin, rifampin, Risperidone, spirolactone, sulfamethoxazole, Tadalafei , Telmisartan, tipranavir, Valsartan, Vardenafil, Ziprasidone, abacavir sulfate, codeine, salbutamol, Alendronate sodium, Allopurinol, potassium clavulanate, benzatropine, bimatoprost, butylbenzene promise coffee, naloxone, captopril, levodopa, Cefixime, cefadroxil, citirizine dihydrochloride, Ciprofloxacin, colchicin, ergocalciferol, famotidine, pseudoephedrine, folic acid, Gabapentin, hydralazine, Hydrochioro, salbutamol, left west is for benefit, lavo-ofloxacin, levothyroxine sodium, lisinopril, methotrexate, ethyldopa, Nadolol, nystatin, Pantoprazole, primaquine phosphate, pyrazinamide, ranitidine hydrochloride, Ribavirin, risedronate sodium, Solifenacin, antisterone, sumatriptan succinate, spy draws azoles Piperazine, tetracycline, thiamine, Topiramate, Valaciclovir hydrochloride, valganciclovir, acarbose, Aceclofenac, acetazolamide, acetylcarnitine, albendazole, Alibendol, amiloride, atropine, imuran, azithromycin, Benidipine, benserazide, benznidazole, Bicalutamide, Bisacody, Cabergoline, Candesartan, capecitabine, Carvedilol, Cefditoren, cefmetazole, Cefotiam, Cefpodoxime, cefotaxime, CEFUROXIME AXETIL, celecoxib, chloramphenicol, chlorpromazine, Cilazapril, Cilostazol, Cimetidine, Citalopram, clofazimine, cyclosporine, cyproterone, dapsone, diethylcarbamazine, digoxin, diloxanide, deoxyfluorouridine, fortimicin, Ebastine, efavirenz, Epalrestat, Pu Shatan, erythromycin, ethambutol, Ezetimibe, famciclovir, fenofibrate, Fluconazole, Flurbiprofen, furosemide, thiamine tetrahydrofuryl disfulfide, Gefitinib, gliclazide, Glipizide, griseofulvin, haloperidol, hydroxyzine hydrochloride, brufen, Imatinib, Imidapril, indinavir, Irbesartan, isoniazid, ivermectin, Ketoprofen, Lamotrigine, lavo-ofloxacin, Lopinavir, pleasure cuts down statin, Manidipine, mebendazole, Medroxyprogesterone, aminosalicylic acid, metaxalone, methotrexate (MTX), ethyldopa, metronidazole, modafinil, Mosapride, Nabumetone, acidum nalidixicum, Nai Feinawei, neostigmine, nevirapine, nicorandil, niacinamide, nifurtimox, Nilvadipine, aulin, zolpidem, zolmitriptan, Zaltoprofen, warfarin, voglibose, Verapamil, valproic acid, Ursodesoxycholic acid, Trimetazidine, tosufloxacin, ticlopidine, theophylline, Teprenone, tenofovir, Tegafur, tamoxifen, Taltirelin, Sultamicillin, Sulpiride, salicylazosulfapyridine, sulfamethoxazole, sulphadiazine, stavudine, roxithromycin, rofecoxib, rizatriptan, Ritonavir, Risedronic Acid, rifampin, rifaximin, Rebamipide, ranitidine, Rabeprazole, nizatidine, norethindrone, Olanzapine, olopatadine, orlistat, Oseltamivir, Oxcarbazepine, Quetiapine, puridoxine hydrochloride, bromine pyrrole this, propylthiouracil, Procaterol, praziquantel, pranlukast, dilantin sodium, phenobarbital, phendimetrazine, Perindopril, Oxycodone, dexamethasone, frusemide.

Controlled release pharmaceutical compositions provided by the invention, it is characterized in that the sustained release floating component also may include at least one plasticiser, the plasticiser is selected from triethyl citrate, tributyl citrate, polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl sebacate, diethyl sebacate, tristerin, diethyl succinate, propylene glycol, castor oil and glyceryl triacetate, preferably citric acid triethyl, the content of the plasticizer is 0.01%-50%, it is preferred that 0.1-30%, most preferably 2.5%-15% (mass percent, it is 100 calculating with the gross mass of solid component).

In some embodiments, immediate release component and/or controlled release floating component also include other at least one pharmaceutically acceptable excipient in controlled release pharmaceutical compositions provided by the invention, and pharmaceutically common excipient includes but is not limited to filler, lubricant, glidant, adhesive, disintegrating agent.

As it is well known to the skilled in the art, routinely drug excipient is mixed into solid dosage forms operating process is made to be easy to carry out and improve the performance of dosage form.Common excipient includes diluent or filler, lubricant, glidant, adhesive, disintegrating agent etc..Wherein diluent or filler are to increase the weight of single dosage to the size for being suitable for tablet press.Diluent appropriate includes Icing Sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, sodium chloride, dry starch, sorbierite etc..

Lubricant reduces the frictional force during compression and discharge between particle and mold wall.This prevents particle to be adhered to tablet press (tablet punches), it is promoted to be discharged from tablet press etc..The example of workable lubricant appropriate includes but is not limited to talcum, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate etc..

Glidant is used to improve the flow characteristics of particle.The example of glidant appropriate includes but is not limited to silica, cornstarch, superfine silica gel powder, talcum powder, polyethylene glycol.

If the preparation of composition includes granulation step, then usually using adhesive, the example of adhesive appropriate includes but is not limited to pyrrolidones, polyvinylpyrrolidone, xanthan gum, cellulose gum such as carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxylated cellulose, gelatin, starch and pregelatinized starch.

Disintegrating agent, which refers to, can make tablet split the substance for being broken into fine particle rapidly in gastro-intestinal Fluid, so that functional component be made to dissolve and absorb rapidly, play a role.Heretofore described disintegrating agent includes but is not limited to one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch and crospovidone.

Controlled release pharmaceutical compositions provided by the invention, the other excipient that can be additionally included in the composition include but is not limited to preservative, antioxidant or any commonly used in other excipient of pharmaceuticals industry etc..

Composition provided by the invention is ultimately present as being easy to the medicinal forms that patient takes, optional tablet or capsule.

The administration mode that controlled release composition of the present invention is recommended is one after each meal.

Controlled release pharmaceutical compositions provided by the invention, it is characterised in that active medicine optionally keeps crystal form state after hot-melt extruded process or is changed into unformed state in the sustained release floating composition.

For drug effect, safety, economy, convenience and/or efficiency, it the use of single medicine may be desirable in pharmaceutical composition of the invention, it should be understood that the present composition may include the drug of more than one, i.e., it is same or different to release the drug floated in component with sustained release for immediate release component.

The present invention also provides a kind of methods for preparing above-mentioned controlled release drug combination.

1) method provided by the invention for preparing controlled release pharmaceutical compositions, which comprises the steps of:, will mix by active constituent and at least one enteric polymer at least one solvent, sustained release floating component online during active constituent and at least one enteric polymer mix to premix crude product or hot-melt extruded at least one solvent, sustained release floating component before hot-melt extruded and to obtain premix crude product；2) premix crude product leaves to obtain extrudate by the heating spiral rod Qu Houjing mouth mold of extruder.

Preparation method provided by the invention, it is characterised in that the solvent is only needed to meet and can be volatilized after hot-melt extruded process, it is preferred that the boiling point of solvent is limited to 30-110 DEG C by the present invention.

Preparation method provided by the invention, it is characterised in that the solvent is selected from water, methanol, ethyl alcohol, isopropanol, acetone, pentane, hexane, heptane, hexamethylene, methylene chloride, tetrahydrofuran, preferably water, ethyl alcohol, isopropanol.

In method provided by the invention, the dosage of the solvent is 0.1%-70%, preferably 1%-50%, most preferably 10%-30% (mass percent is 100 calculating with the gross mass of solid component).

In method disclosed by the invention, the temperature of mouth mold front end heating zone should be greater than the glass transition temperature (Tg) of extrusioning mixture.

Preparation method provided by the invention, it is characterised in that die temperature is 70-200 DEG C, preferably 90-180 DEG C, more preferable 110-160 DEG C.

Preparation method provided by the invention, it is characterised in that it is 10-90 DEG C that solvent, which injects screw rod area temperature,.

In view of the property of active therapeutic agent itself, in segmentation scheme of the invention, if select water to make solvent during hot-melt extruded, the active medicine of esters (including lactone), amides (including lactams) and the labile substance of high temperature not as the application of the incident degradation of water is met.

Preparation method provided by the invention, it is characterised in that also comprising optionally following step: 1) extrudate is cooled down, 2) extrudate is removed into solvent；3) extrudate is cut.

In method provided by the invention, according to the property of solvent itself and the temperature of mouth mold, the volatile solvent of low boiling point can substantially be volatilized in extrusion process, and the volatile solvent of low boiling point includes but is not limited to ethyl alcohol.

Heretofore described substantially refers to that solvent residual amount is less than 15% in extrudate by volatilization, preferably smaller than 12%, more preferably less than 10%.

Method provided by the invention can be after hot-melt extruded immediately following the step of extrudate is removed solvent when the higher solvent of selection boiling point.

In some embodiments, remove extrudate in solvent under heating and/or vacuum condition.

In some embodiments, raised temperature is enough that solvent is made to be converted into gaseous state by liquid.

In some embodiments, solvent in extrudate is removed to complete at reduced pressure conditions.

In some embodiments, preparation method provided by the invention also includes the step that extrudate is cooling.

The method provided by the invention for preparing controlled release floating component in controlled release pharmaceutical compositions, it is characterised in that further include the step of extrudate is cut.

The preparation method of immediate release section of the present invention includes wet granulation, dry granulation, powder vertical compression etc..

Preparation method provided by the invention, it is characterised in that the extruder is selected from single screw rod hot-melt extruded machine, engagement screws extruder, twin screw hot melt extruder, preferably twin screw hot melt extruder.

Term used in the present invention " sustained release " refers to the type for improving release, and wherein pharmaceutical dosage form shows time delay in oral administration pharmaceutical dosage form and between dosage form release drug.It puts dosage form in general, prolonging sustained release in the given time or is for example exposed to certain pH level until meeting predetermined condition, then the release of reactive compound occurs immediately hereafter for release of active compounds almost no or no.

Term " controlled release " refers to the type of extended release dosage system in the present invention, and wherein gradually discharging for drug is controlled within some extended period or is operated.

Detailed description of the invention

The Drug-time curve figure of Fig. 1 preparation 3, preparation 4 and common quick release piece；

The dissolution curve of floating particle obtained in Fig. 2 embodiment 1-7；

The dissolution curve of Fig. 3 particle G；

The dissolution curve of Fig. 4 preparation 3, preparation 4 and common quick release piece；

The electron-microscope scanning figure of Fig. 5 particle G；

Powder diagram before and after Febustat hot-melt extruded in Fig. 6 particle G.

Fig. 7 embodiment 10 squeezes out the powder diffraction spectrum of front and back Hydrochioro；

10 dissolution curve of Fig. 8 embodiment；

Fig. 9 embodiment 11 squeezes out the powder diffraction spectrum of front and back Hydrochioro；

11 dissolution curve of Figure 10 embodiment；

Figure 11 embodiment 12 squeezes out the powder diffraction spectrum of front and back nifedipine；

12 dissolution curve of Figure 12 embodiment；

Figure 13 embodiment 13 squeezes out the powder diffraction spectrum of front and back Tadalafei；

13 dissolution curve of Figure 14 embodiment；

Figure 15 embodiment 14 squeezes out the powder diffraction spectrum of front and back Losartan；

14 dissolution curve of Figure 16 embodiment；

15 dissolution curve of Figure 17 embodiment；

16 dissolution curve of Figure 18 embodiment；

17 dissolution curve of Figure 19 embodiment；

18 dissolution curve of Figure 20 embodiment；

Figure 21 embodiment 19 squeezes out the powder diffraction spectrum of front and back Hydrochioro；

19 dissolution curve of Figure 22 embodiment；

Figure 23 embodiment 20 squeezes out the powder diffraction spectrum of front and back Hydrochioro；

20 dissolution curve of Figure 24 embodiment；

Figure 25 embodiment 21 squeezes out the powder diffraction spectrum of front and back Losartan；

21 dissolution curve of Figure 26 embodiment；

22 dissolution curve of Figure 27 embodiment.

Specific embodiment

The following are a specific embodiment of the invention, embodiment is to further describe the present invention rather than the limitation present invention, all technical solutions equivalent with the present invention all belong to the scope of protection of the present invention.

The certainly Japanese SHIN-ETSU HANTOTAI's Chemical Co., Ltd. of HPMCAS purchase used, hot-melt extruded instrument are the twin screw hot melt extrusion instrument that match is write from memory winged in the embodiment of the present invention.

Embodiment 1. is by quick-release Febustat microplate and the Febustat preparation 1 formed in the Febustat floating particle A of pH6 or more release drug

Single capsule includes immediate release component and sustained release floats component, and immediate release component is the microplate of the active constituent of Febustat containing 8mg, and sustained release floating group is divided into the particle A of the active constituent of Febustat containing 32mg, and particle A is discharged in pH6 or more.Quick-release Febustat microplate is prepared by wet granulation technology, and composition arranges in table 1 below.

1. quick-release Febustat microplate prescription of table

	Effect	8mg piece
Febustat	Main ingredient	13.3%
Lactose	Filler	35.0%
MCC	Filler	27.3%
Cross-linked carboxymethyl cellulose is received	Disintegrating agent	10.8%
Superfine silica gel powder	Glidant	2.2%
HPMC-E5	Binder	3.6%
Water	Binder solvent
Sodium carboxymethyl starch	Disintegrating agent	8.3%
Magnesium stearate	Lubricant	1.2%

Specific preparation process: supplementary material is mixed, adhesive is added, stirred by wet granulator granulation, is sieved after the shearing of 1500rpm cutter, is dried to moisture < 3%, crosses 30 meshes, rear using the rich C&C600B single-punch tablet press of wound, 4.76mm formed punch tabletting.Slice weight: theoretical 61.5mg, practical control is in 59-65mg, hardness about 30N.

Febustat drift particle A is prepared by hot-melt extrusion process, and composition is listed in the following table 2.

2. Febustat floating particle A prescription of table

	Content (g)	Percentage
Febustat	150	25%
HPMCAS MG	450	75%

It weighs Febustat and HPMCAS MG to be uniformly mixed in batch mixer, hot-melt extruded instrument (match is silent to fly), temperature setting such as table 3.

3. hot-melt extruded machine temperature (DEG C) of table

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

Specifically add ethyl alcohol, speed 700ul/min, Zone2 feeding in Zone4, the revolving speed of speed 4g/min, screw rod are set as 100rpm, extrudate are cut into chunks, after 60 DEG C of baking ovens of extrudate are dried into 2h, ethanol content is crushed to 2mm after drying less than 0.5%.

Embodiment 2. is by quick-release Febustat pellet and the Febustat preparation 2 formed in the Febustat sustained release floating particle B of pH6 or more rapid delivery of pharmaceuticals

Single capsule includes that immediate release component and sustained release float component, immediate release component is the pellet of the active constituent of Febustat containing 8mg, the remainder of capsule includes the Febustat sustained release floating particle B of the Febustat containing 32mg altogether, this sustained release floats enteric coated particles B in pH6 or more quick release.Quick-release Febustat pellet is prepared by blank capsule core drug layering, composition such as table 4.

4. quick-release Febustat pellet composition of table:

	8mg pellet
Febustat	32%
Sugar-pill	52%
Hydroxypropyl methylcellulose	18%

Febustat controlled release floating particle B is prepared by hot-melt extrusion process, composition such as table 5.

5. Febustat floating particle B prescription of table

	Content
Febustat	25%
Hypromellose	60%
HPMCAS MG	15%

150g Febustat and 90g HPMCAS MG and 360g hypromellose is weighed to be uniformly mixed in batch mixer.Hot-melt extruded machine temperature setting such as table 3 adds ethyl alcohol, speed 700ul/min in the Zone4 of hot-melt extruded machine, the revolving speed of Zone2 feeding, speed 4g/min, screw rod is set as 100rpm, extrudate is cut into chunks, after 60 DEG C of baking ovens of extrudate are dried into 2h, ethanol content < 0.5%.It is crushed to 4mm after drying, has both obtained Febustat stomach and has floated controlled release granule B.

The Febustat preparation 3 that embodiment 3. is made of 20% quick-release Febustat microplate and 80% in the Febustat floating particle C of pH5 or more release drug

Single capsule includes immediate release component and controlled release floats component, and immediate release component is the microplate of the Febustat containing 8mg, and the remainder of capsule includes that the stomach of Febustat containing 32mg floating particle C, this stomach floating particle C are discharged in pH5 or more altogether.Quick-release Febustat microplate is prepared by wet granulation technology, and composition is listed in table 1.Febustat controlled release floating particle C is prepared by hot-melt extrusion process, composition such as table 6.

6. Febustat floating particle C prescription of table

	Content
Febustat	25%
HPMCAS LG	75%

After mixing by 150g Febustat and 450g HPMCAS LG, hot-melt extruded is carried out, temperature parameter setting is same to prepare particle A.The Zone4 of hot-melt extruded machine adds ethyl alcohol, speed 600ul/min, Zone2 feeding, speed 2g/min, screw speed is 60rpm, and extrudate is cut into pieces, after 60 DEG C of baking ovens of extrudate are dried into 2h, ethanol content < 0.5% is crushed to 4mm long grain after drying, both obtain Febustat floating particle C.

The Febustat preparation 4 that embodiment 4 is made of 40% quick-release Febustat microplate and 60% in the Febustat floating particle C of pH5 or more release drug

Single capsule includes immediate release component and controlled release floats component, and immediate release component is the microplate of the Febustat containing 16mg, and the remainder of capsule includes that the sustained release of Febustat containing 24mg floating particle C, this sustained release floating controlled release granule C are discharged in pH5 or more altogether.Quick-release Febustat microplate is prepared by wet granulation technology, and composition is listed in table 1, and Febustat controlled release floating particle C is the same as embodiment 3.

The Febustat preparation 5 that embodiment 5 is made of quick-release Febustat pellet and sustained release Febustat floating particle D

Single capsule includes that immediate release component and controlled release float component, immediate release component is the pellet of the active constituent of Febustat containing 8mg, the remainder of capsule includes the Febustat stomach sustained release floating particle D of the Febustat containing 32mg altogether, slow release while this stomach floating delayed release granule D is floated in gastric juice.Quick-release Febustat pellet is prepared by blank capsule core drug layering, and composition is listed in table 4.

Febustat stomach floating controlled release granule D is prepared by hot-melt extrusion process, composition such as table 7.

7. Febustat floating particle D prescription of table

After mixing by Febustat and ammonio methacrylate copolymer Type B and hydroxypropyl methylcellulose, it is sheared in wet granulator, while triethyl citrate is slowly added dropwise.The material mixed is subjected to hot-melt extruded, temperature parameter is arranged with table 3, in Zone4 plus ethyl alcohol, speed 1000ul/min, the revolving speed of Zone2 feeding, speed 4g/min, screw rod is set as 100rpm, extrudate is cut into chunks, after 60 DEG C of baking ovens of extrudate are dried into 2h, ethanol content < 0.5%.It is crushed to 4mm long grain after drying, has both obtained Febustat stomach and has floated controlled release granule D.

Embodiment 6 is by quick-release Febustat microplate and the Febustat preparation 6 formed in sustained release Febustat floating particle E

Single capsule includes that immediate release component and controlled release float component, immediate release component is the microplate of the Febustat containing 8mg, the remainder of capsule includes that the sustained release of Febustat containing 32mg floating particle E, this stomach float slow release while controlled release granule E is floated in gastric juice altogether.Quick-release Febustat microplate is prepared by wet granulation technology, composition column such as table 1.Febustat stomach floating delayed release granule E is prepared by hot-melt extrusion process, composition such as table 8.

8. Febustat floating particle E prescription of table

Febustat and other excipient are subjected to hot-melt extruded, temperature parameter setting such as table 3 by recipe quantity after mixing.In Zone4 plus ethyl alcohol, speed 300ul/min, Zone2 feeding, speed 4g/min, the revolving speed of screw rod is set as 100rpm, and extrudate is cut into chunks, after 60 DEG C of baking ovens of extrudate are dried into 2h, ethanol content < 0.5% is crushed to 4mm long grain, has both obtained Febustat stomach and has floated controlled release granule E.

Embodiment 7 is by quick-release Febustat microplate and the Febustat preparation 7 formed in controlled release Febustat floating particle F

Single capsule includes immediate release component and controlled release floats component, and immediate release component is the microplate of the Febustat containing 8mg, and the remainder of capsule includes the stomach of Febustat containing 32mg floating particle F altogether, slow release while this stomach floating controlled release granule E is floated in gastric juice.Quick-release Febustat microplate is prepared by wet granulation technology, and composition is listed in Table 1.Febustat stomach floating controlled release granule F is prepared by hot-melt extrusion process, composition such as table 9.

9. Febustat floating particle F prescription of table

Febustat and other excipient are subjected to hot-melt extruded, temperature parameter setting such as table 3 by recipe quantity after mixing.In Zone4 plus ethyl alcohol, speed is 300ul/min, Zone2 feeding, speed is 4g/min, and the revolving speed of screw rod is set as 100rpm, extrudate is cut into chunks, 60 DEG C of baking ovens of extrudate are dried into 2h afterwards, ethanol content < 0.5% is crushed to 4mm long grain after drying, both obtained Febustat stomach and floated controlled release granule F.

Embodiment 8 is by quick-release Febustat microplate and the Febustat preparation 8 formed in the Febustat floating particle G of pH5.5 or more release drug

Single capsule includes immediate release component and sustained release floats component, and immediate release component is the microplate of the active constituent of Febustat containing 8mg, and sustained release floating group is divided into the particle G of the active constituent of Febustat containing 32mg, and particle A is discharged in pH5.5 or more.Quick-release Febustat microplate is prepared by wet granulation technology, composition such as table 1, and Febustat sustained release floating particle G composition such as table 10, hot-melt extruded and temperature setting are as shown in table 11.

10. Febustat sustained release floating particle G of table

	Ratio
Febustat	25%
HPMCAS LF	75%

Pharma11 hot-melt extruded instrument (match is silent to fly), set temperature such as table 11.

11. hot-melt extruded machine temperature setting (DEG C) of table

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

Specifically in Zone2 feeding, Zone4 adds water, and rate of feeding 5g/min, adding water speed is 0.9ml/min, screw speed is set as 100rpm, and extrudate is cut into chunks, after 60 DEG C of baking ovens of extrudate are dried into 2h, moisture < 3% is crushed to 2mm, test density 0.5g/cm after drying ³, by gained Febustat particle G and the resulting Febustat microplate encapsulating capsule of embodiment 1, obtain Febustat preparation 8.

The research of 9 human pharmacokinetics of embodiment

Using commercially available 40mg specification Febustat piece as reference preparation, human pharmacokinetics research is carried out together with embodiment 3 and the preparation obtained of embodiment 4, result of study see the table below 12.

The different preparation pharmacokinetic parameters of table 12.

C _max: maximum blood peak concentration of drug

T _max: the maximum plasma concentration time

AUC _0→∞: Drug-time curve area

T _{C≥100μg/mL}: the μ g/mL time of effective blood drug concentration C >=100

Fr: relative bioavailability

Pharmacokinetic study results show compared with commercially available Febustat piece reference preparation, and embodiment 3 and embodiment 4 can reduce the maximum blood peak concentration of drug of drug, substantially extend action time, the controlled release treatment effect for playing drug, to reduce side effects of pharmaceutical drugs, as a result as shown in Figure 1.

Experimental example 1

PH5.0FaSSGF using 300mL is dissolution medium, observes floating situation of the stomach floating particle under simulate the gastric juice, it is observed that each particle plays drift immediately, and floats, is observed to after 24 hours for a long time, each particle still maintains to float, and stops observation.

According to 2015 editions two annex elution test methods 1 of Chinese Pharmacopoeia (basket method, 100rpm, 37 DEG C), the dissolution situation of Febustat sustained release floating particle A, particle B, particle C, particle D, particle E, particle F, particle G are detected.

PH5.0FaSSGF using 300mL is dissolution medium, detect dissolution situation of the stomach floating particle under simulate the gastric juice, the pH6.5FaSSIF for using 900mL instead again is dissolution medium, dissolution situation of the stomach floating particle under simulated intestinal fluid is detected, as a result as shown in Fig. 2, Fig. 3 (particle G).

According to 2015 editions two (basket methods of annex elution test method 1 of Chinese Pharmacopoeia, 100rpm, 37 DEG C), phosphate buffer using the pH 6.8 of 900mL is dissolution medium, the dissolution curve of preparation 3, preparation 4 and quick-release microplate is obtained in detection embodiment 3 and embodiment 4, as a result as shown in Figure 4.

Dissolution rate can prompt preparation drug under gastrointestinal tract environment to go out the speed discharged from preparation, and lower rate of release reaction is lower Cmax and longer release time in pharmacokinetic data available.Compared with common quick release piece, prepared preparation dissolution rate is substantially reduced in the present invention, can be deduced compared with fast-release tablet, and the preparation (embodiment 1-7) in the present invention can be achieved to reduce cmax value, extends the purpose of effective blood drug concentration time.

With the character of electron-microscope scanning observation particle G, discovery particle G under Electronic Speculum is cellular, is specifically shown in Fig. 5.

It is specific as shown in fig. 6, Febustat still remains crystal form state after hot-melt extruded for the crystal form state test powders diffracting spectrum of Febustat after Febustat raw material and extrusion.

10 Hydrochioro of embodiment (30mg prescription) Hydrochioro: HPMC AS LG=1:3

Hydrochioro and HPMC AS LG are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 13 (DEG C) are carried out.

Table 13.

Zone2

Zone3

Zone4

Zone5

Zone6

Zone7

Zone8

Die

30

50

60

70

90

100

120

Specifically in Zone2 feeding, Zone4 adds water, and screw speed is set as 50rpm, and adding water speed is 400ul/min, 60 DEG C of baking ovens of extrudate is dried 2h, moisture < 3% is crushed to 2mm after drying.

Phenomenon: squeezing out smoothly, process stabilizing, and sample expansion can play rapidly drift.

For the crystal form state test powders diffracting spectrum of Hydrochioro after squeezing out in Hydrochioro raw material and embodiment 10, Hydrochioro still remains crystal form state after hot-melt extruded, as shown in Figure 7；The dissolution curve of 10 prescription of embodiment is as shown in Figure 8.

11 Hydrochioro of embodiment (30mg prescription) Hydrochioro: HPMCP=1:3

Hydrochioro and HPMCP are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 14 (DEG C) are carried out.

Table 14.

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

Specifically in Zone2 feeding, Zone4 adds water, and screw speed is set as 50rpm, and adding water speed is 500ul/min, 60 DEG C of baking ovens of extrudate is dried 2h, moisture < 3% is crushed to 2mm after drying.

Phenomenon: sample squeezes out smoothly, and can play drift rapidly.

For the crystal form state test powders diffracting spectrum of Hydrochioro after squeezing out in Hydrochioro raw material and embodiment 11, Hydrochioro still remains crystal form state after hot-melt extruded, as shown in Figure 9；The dissolution curve of 11 prescription of embodiment is as shown in Figure 10.

12 nifedipine of embodiment (30mg prescription) nifedipine: HPMC AS LG=1:3

Nifedipine and HPMC AS LG are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 15 (DEG C) are carried out.

Table 15.

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

Specifically in Zone2 feeding, Zone4 adds water, and screw speed is set as 50rpm, and adding water speed is 1200ul/min, 60 DEG C of baking ovens of extrudate is dried 2h, moisture < 3% is crushed to 2mm after drying.

Phenomenon: sample squeezes out smoothly, and can play drift rapidly.

For the crystal form state test powders diffracting spectrum of nifedipine after squeezing out in nifedipine raw material and embodiment 12, nifedipine still remains crystal form state after hot-melt extruded, as shown in figure 11；The dissolution curve of 12 prescription of embodiment is as shown in figure 12.

13 Tadalafei of embodiment (30mg prescription) Tadalafei: HPMC AS LG=1:3

Tadalafei and HPMC AS LG are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 16 (DEG C) are carried out.

Table 16.

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

Specifically in Zone2 feeding, Zone4 adds water, and screw speed is set as 50rpm, and adding water speed is 900ul/min, 60 DEG C of baking ovens of extrudate is dried 2h, moisture < 3% is crushed to 2mm after drying.

For the crystal form state test powders diffracting spectrum of Tadalafei after squeezing out in Tadalafei raw material and embodiment 13, Tadalafei still remains crystal form state after hot-melt extruded, as shown in figure 13；The dissolution curve of 13 prescription of embodiment is as shown in figure 14.

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

Losartan and HPMC AS LG are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 17 (DEG C) are carried out.

Table 17

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

Specifically in Zone2 feeding, Zone4 adds water, and screw speed is set as 50rpm, and adding water speed is 600ul/min, 60 DEG C of baking ovens of extrudate is dried 2h, moisture < 3% is crushed to 2mm after drying.

Phenomenon: squeezing out smoothly, and sample expansion can play rapidly drift.

For the crystal form state test powders diffracting spectrum of Losartan after squeezing out in Losartan raw material and embodiment 14, Losartan still remains crystal form state after hot-melt extruded, as shown in figure 15；The dissolution curve of 14 prescription of embodiment is as shown in figure 16.

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

Dexamethasone and HPMC AS LG are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 18 (DEG C) are carried out.

Table 18

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

The dissolution curve of 15 prescription of embodiment is as shown in figure 17.

16 dexamethasone of embodiment (30mg prescription) dexamethasone: HPMCP=1:3

Dexamethasone and HPMCP are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 19 (DEG C) are carried out.

Table 19

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

Phenomenon: squeezing out smoothly, and sample surfaces expansion, bubble can play rapidly drift in skin breakage.

The dissolution curve of 16 prescription of embodiment is as shown in figure 18.

17 frusemide of embodiment (30mg prescription) frusemide: HPMC AS LG=1:3

Frusemide and HPMC AS LG are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 20 (DEG C) are carried out.

Table 20

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

The dissolution curve of 17 prescription of embodiment is as shown in figure 19.

18 Febustat of embodiment (30mg) Febustat: HPMCP=1:3

Febustat and HPMCP are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 21 (DEG C) are carried out.

Table 21

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

Specifically in Zone2 feeding, Zone4 adds water, and screw speed is set as 100rpm, and adding water speed is 700-900ul/min, 60 DEG C of baking ovens of extrudate is dried 2h, moisture < 3% is crushed to 2mm after drying.

Phenomenon: sample can expand, and sample can float.

The dissolution curve of 18 prescription of embodiment is as shown in figure 20.

19 Hydrochioro of embodiment (30mg prescription) Hydrochioro: HPMC AS LG=1:3

Hydrochioro and HPMC AS LG are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 22 (DEG C) are carried out.

Table 22

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

Specifically in Zone2 feeding, Zone4 adds ethyl alcohol, and screw speed is set as 60rpm, and adding ethyl alcohol speed is 700ul/min, 60 DEG C of baking ovens of extrudate is dried 2h, moisture < 3% is crushed to 2mm after drying.

For the crystal form state test powders diffracting spectrum of Hydrochioro after squeezing out in Hydrochioro raw material and embodiment 19, Hydrochioro still remains crystal form state after hot-melt extruded, as shown in figure 21；The dissolution curve of 19 prescription of embodiment is as shown in figure 22.

20 Hydrochioro of embodiment (30mg prescription) Hydrochioro: HPMCP=1:3

Hydrochioro and HPMCP are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 23 (DEG C) are carried out.

Table 23

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

Specifically in Zone2 feeding, Zone4 adds ethyl alcohol, and screw speed is set as 50rpm, and adding ethyl alcohol speed is 700ul/min, 60 DEG C of baking ovens of extrudate is dried 2h, moisture < 3% is crushed to 2mm after drying.

Phenomenon: sample squeezes out smoothly, and can play drift rapidly.

For the crystal form state test powders diffracting spectrum of Hydrochioro after Hydrochioro raw material and the extrusion of embodiment 20, Hydrochioro still remains crystal form state after hot-melt extruded, as shown in figure 23；The dissolution curve of 20 prescription of embodiment is as shown in figure 24.

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

Losartan and HPMC AS LG are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 24 (DEG C) are carried out.

Table 24

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

Phenomenon: sample squeezes out smoothly, and can play drift rapidly.

For the crystal form state test powders diffracting spectrum of Losartan after Losartan raw material and the extrusion of embodiment 21, Losartan still remains crystal form state after hot-melt extruded, as shown in figure 25；The dissolution curve of 21 prescription of embodiment is as shown in figure 26.

22 Febustat of embodiment (30mg prescription) Febustat: HPMCP=1:3

Febustat and HPMCP are uniformly mixed, hot-melt extruded, temperature parameter setting such as table 25 (DEG C) are carried out.

Table 25

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

Specifically in Zone2 feeding, Zone4 adds ethyl alcohol, and screw speed is set as 50rpm, and adding ethyl alcohol speed is 700/min, 60 DEG C of baking ovens of extrudate is dried 2h, moisture < 3% is crushed to 2mm after drying.

Phenomenon: sample can expand and sample can float.

The dissolution curve of 22 prescription of embodiment is as shown in figure 27.

Although specific embodiments of the present invention have been described above, it will be appreciated by those of skill in the art that these are merely examples, without departing from the principle and essence of the present invention, many changes and modifications may be made.Therefore, protection scope of the present invention is defined by the appended claims.

Claims

A kind of controlled release pharmaceutical compositions include: a) containing the immediate release component of active medicine, b) the sustained release floating component containing active medicine, it is characterised in that the sustained release floating component is prepared by the method for hot-melt extruded.
Controlled release pharmaceutical compositions according to claim 1, it is characterised in that the sustained release floating component contains at least one enteric polymer.
Controlled release pharmaceutical compositions according to claim 2, it is characterized in that the enteric polymer is selected from polyvinyl alcohol phthalate, cellulose acetate phthalate, 1, 2, 4- benzenetricarboxylic acid cellulose acetate, Hydroxypropyl Methylcellulose Phathalate, 1, 2, 4- benzenetricarboxylic acid hydroxypropyl methyl cellulose, acetate succinate cellulose, acetic acid hydroxypropyl methylcellulose succinate, hydroxypropylmethylcellulose acetate methylcellulose phthalate ester, EUDRAGIT L100-55, methyl vinyl ether-maleic acid copolymer, EUDRAGIT L100-55 aqueous dispersion, EUDRAGIT L100, ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride base methacrylate copolymers, polyvinyl acetate, ethyl cellulose, poly-vinegar acid second Enester and PVP K30 mixture, preferably acetic acid hydroxypropyl methylcellulose succinate, EUDRAGIT L100, EUDRAGIT L100-55, Hydroxypropyl Methylcellulose Phathalate.
Controlled release pharmaceutical compositions according to claim 2 or 3, it is characterised in that active medicine and enteric polymer ratio are selected from 1:0.1-1:100, preferably 1:0.1-1:50, more preferable 1:1-1:25 in the sustained release floating component.
Controlled release pharmaceutical compositions according to claim 1-4, it is characterised in that solvent is added before the hot-melt extruded or during hot-melt extruded.
Controlled release pharmaceutical compositions according to claim 5, it is characterised in that the solvent boiling point is selected from 30-110 DEG C.
Controlled release pharmaceutical compositions according to claim 6, it is characterised in that the solvent is selected from at least one of water, methanol, ethyl alcohol, isopropanol, acetone, pentane, hexane, heptane, hexamethylene, methylene chloride, tetrahydrofuran, preferably water, ethyl alcohol.
Controlled release pharmaceutical compositions according to claim 1-7, it is characterized in that the sustained release floating component, which contains, meets the alkaline matter that acid generates gas, the alkaline matter is selected from sodium bicarbonate, sodium carbonate, sodium glycine carbonate, saleratus, magnesium carbonate and calcium carbonate, preferably sodium carbonate, sodium bicarbonate.
Controlled release pharmaceutical compositions according to claim 1-8, it is characterised in that the sustained release floating group is divided into multiple-unit form.
Controlled release pharmaceutical compositions according to claim 9, it is characterised in that the multiple-unit form is microplate, pellet, particle, preferably particle.
Controlled release pharmaceutical compositions according to claim 1-7, it is characterised in that the sustained release floating group is divided into cellular.
Controlled release pharmaceutical compositions according to claim 1-7, it is characterised in that the sustained release floating component plays drift in the FaSSGF solution of pH5.0 immediately.
Controlled release composition according to claim 1-7, it is characterised in that sustained release floating component flotation time in the FaSSGF solution of pH5.0 is greater than for 24 hours.
Any one of -7 controlled release pharmaceutical compositions according to claim 1, it is characterised in that the sustained release floating density of fraction is 0.1-1.0g/cm ³, preferably 0.2-0.8g/cm ³, most preferably 0.3-0.7g/cm ³。
Any one of -8 controlled release pharmaceutical compositions according to claim 1, it is characterised in that in the FaSSGF dissolution medium of pH5.0 of the sustained release floating component in 300mL, basket method, 37 DEG C, the accumulation of 100rpm, 5h are dissolved out less than 30%, more preferably less than 20%, more preferably less than 10%.
Controlled release pharmaceutical compositions according to claim 1-8, it is characterised in that active medicine is selected from I class drug of BCS in the sustained release floating component.
Controlled release pharmaceutical compositions according to claim 16, it is characterized in that the I class drug of BCS is selected from pabishta, Cobimetinib, Patiromer, omarigliptin, Bupropion, guanfacine, venlafaxine hydrochloride, methylphenidate hydrochloride, phosphoric acid safe ground azoles amine, flibanserin, eliglustat, Egelieting, dimethyl fumarate, pyrrole Lun Panai, Lome Tapai, Lu Suo replaces Buddhist nun, Clobazam, dalfampridine, Prolia, dronedarone hydrochloride, Pralatrexate, lacosamide, fesoterodine fumarate, alprazolam, amitriptyline hydrochloride, amlodipine benzenesulphonate, benazepil, A Mo XiLin, Anastrozole, azelastine, bisoprolol, buspirone, caffeine, carbidopa, cetirizine, chloroquine diphosphate, chlorpheniramine, clindamycin, clonidine, cyclobenzaprine, cyclophosphamide, Desogestrel, ethinyloestradiol, diazepam, diphenhydramine, donepezil hydrochloride, doxazosin mesylate, Doxycycline, emtricitabine, estradiol, ethymal, fexofenadine, Finasteride, Fluconazole, Flucytosine, fluoxetine hydrochloride, Fluvoxamine mesylate, imipramine, indapamide, isoniazid, Lamivudine, lidocaine, Lorazepam, Losartan, metroprolol succinate, mexiletine, midazolam, Mirtazapine, Montelukast Sodium, norethindrone, methylnorethindron, nortriptyline, olopatadine hydrochloride, Oseltamivir, Pramipexole, pravastatin sodium, prednisone, Prednisolone, Pregabalin, procaine amide hydrochloride, promethazine hydrochloride, propranolol hydrochloride, pyrazinamide, pyridoxine hydrochloride, quinapril hydrochloride, quinindium, quinine hydrochloride, Ramipril, Sertraline, sildenafil citrate, Sotalol, stavudine, Terbinafine hydrochloride, Tolterodine, Torasemide, Tramadol hydrochloride, Trazodone, varenicline, Zidovudine, Alfacalcidol, beraprost, Biperiden, Brompheniramine, brotizolam, carbinoxamine, clomiphene, clomipramine, Cloxacillin, diltiazem, Dolasetron, Domperidone, E-0646, epinastine, calciferol, ergometrine, ergotamine, ethinylestradiol, Etizolam, Fluvastatin, Granisetron, Ketotifen, levamisol, Levonorgestrel, vertical Bimatoprost , loxoprofen, Mefloquine, mexiletine hydrochloride, nicardipine, niclosamidum, Tulobuterol, trimethoprim, Trimebutine, Toremifene, Terbinafine, Temocapril, Tamsulosin, Sertraline, sarpogrelate hydrochloride, inverase, Rosiglitazone, reserpine, Ramipril, propiverine hydrochloride, fenazil, pergolide, Paxil.
Controlled release pharmaceutical compositions described in -8 according to claim 1, it is characterised in that active medicine is selected from II to IV class drug of BCS in the sustained release floating component.
Controlled release pharmaceutical compositions according to claim 18, it is characterized in that II to the IV class drug of BCS is selected from Febustat, ixazomib, Alectinib, Erismodegib, Vande Thani, Aprepitant, sulfuric acid Walla pa is husky, aspirin, melbine, En Gelie is net, Li Gelieting, naltrexone, dasabuvir, Suo Feibuwei, amphetamine, etravirine, everolimus, Itraconazole, Wei Luofeini, telavi, tacrolimus, posaconazole, according to cutting down Kato, Lei Dipawei, Suvorexant, Ombitasvir, paritaprevir, daclatasvir, Cariliprazine, brexpiprazole, Ao Pei meter Fen, Levetiracetam, Ivacaftor, eluxadoline, lumacaftor, ivacaftor, Ai Qubo pa, Nintedanib, Meloxicam, morphine, macitentan, dutasteride, abiraterone, lumacaftor, Dapagliflozin, Ta Simeiqiong, Buddhist nun is replaced according to Shandong, Peramivir, olaparib, Yi Palie is net, idelalisib, Baily department he, Ceritinib, Apremilast, pomalidomide, Ao Pei meter Fen, canagliflozin, methanesulfonic acid darafinib, Trimetinib, dolutegravir, vortioxetine, bazedoxifene, simeprevir, Axitinib, Vismodegib, avanaphil, lorcaserin, Mirabegron, bosutinib , teriflunomide, Regorafenib, tropsch imatinib, Cabozantinib, Pa Na replaces Buddhist nun, Eliquis, Bedaquiline, Crofelemer, Bo Saipuwei, Te Lapuwei, Bei Lasaipu, Wella Pfennig, gram azoles replaces Buddhist nun, roflumilast, vilazodone, A Zi sand is smooth, Gabapentin, Fan Detani, Na Gelieting, rilpivirine, feldamycin, ezogabine, icatibant acetate, razaxaban, Ticagrelor, polidocanol, carglumic acid, Tesamorelin, vemurafenib, cabazitaxel, dabigatran etcxilate, everolimus, tolvaptan, prasugrel, saxagliptin, telava Ncin, pazopanib, silodosin, rufinamide, eltrombopag olamine, acetazolamide, paracetamol, acyclovir, Atorvastatin, Atorvastatin calcium, anpunave, Aripiprazole, atenolol, ketamine, atovaquone, imuran, azithromycin, budesonide, calcitriol, carisoprodol, Cefdinir, Cefixime, acetic acid cefuroxime, celecoxib, cefalexin, chlorothiazide, clarithromycin, clopidogrel hydrogenesulphate, clotrimazole, betamethasone, diamino biphenol, C14H10Cl2NNaO2, bentyl, it is new to arrive at promise, bent cannabinol, Duloxetine, dutasteride, Etodolac, ezetimibe, Simvastatin, Felbamate, fenofibrate, Flecainide, fosamprenavir, furosemide, two Gemfibrozil, Glimepiride, glibenclamide, griseofulvin, brufen, hydroxychloroquine, hydroxyzine, Indomethacin, Irbesartan, isoniazid, Isradipine, ketoconazole, Lamotrigine, Lansoprazole, Latanoprost, Linezolid, loperamide, Loracarbef, Loratadine, Lovastatin, mebendazole, meclizine, mercaptopurine, aminosalicylic acid, metaxalone, phenylphenidate acetate, methylprednisolone, modafinil, Mycophenolic Acid, Mycophenolate Mofetil, Nabumetone, naproxen, nifedipine, Omeprazole, carbamazepine, oxycodone hydrochloride, phenazopyridine, dilantin sodium, pioglitazone HCI salt, piroxicam, desoxyphenobarbital, prochlorperazine, progesterone, pyrimethamine, kui gentle ziprasidone, raloxifene hydrochloride, Rifabutin, rifampin, Risperidone, spirolactone, Sulfamethoxazole, Tadalafei, Telmisartan, tipranavir, Valsartan, Vardenafil, Ziprasidone, abacavir sulfate, codeine, salbutamol, Alendronate sodium, Allopurinol, potassium clavulanate, benzatropine, bimatoprost, butylbenzene promise coffee, naloxone, captopril, levodopa, Cefixime, cefadroxil, citirizine dihydrochloride, Ciprofloxacin, colchicin, ergocalciferol, famotidine, pseudoephedrine, folic acid, Gabapentin, hydralazine, Hydrochioro, salbutamol, left west is for benefit, lavo-ofloxacin, levothyroxine sodium, lisinopril, methotrexate, ethyldopa, Nadolol, nystatin, Pantoprazole, primaquine phosphate, pyrazinamide, ranitidine hydrochloride, Ribavirin, risedronate sodium, Solifenacin, antisterone, relax Ma Qu General smooth succinate, Terazosin, tetracycline, thiamine, Topiramate, Valaciclovir hydrochloride, valganciclovir, acarbose, Aceclofenac, acetazolamide, acetylcarnitine, albendazole, Alibendol, amiloride, atropine, imuran, azithromycin, Benidipine, benserazide, benznidazole, Bicalutamide, Bisacody, Cabergoline, Candesartan, capecitabine, Carvedilol, Cefditoren, cefmetazole, Cefotiam, Cefpodoxime, cefotaxime, CEFUROXIME AXETIL, celecoxib, chloramphenicol, chlorpromazine, Cilazapril, Cilostazol, Cimetidine, Citalopram, clofazimine, cyclosporine, cyproterone, dapsone, diethylcarbamazine, digoxin, diloxanide, deoxyfluorouridine, fortimicin, Ebastine, efavirenz, Epalrestat, Pu Shatan , erythromycin, ethambutol, ezetimibe, famciclovir, fenofibrate, Fluconazole, Flurbiprofen, furosemide, thiamine tetrahydrofuryl disfulfide, Gefitinib, gliclazide, Glipizide, griseofulvin, haloperidol, hydroxyzine hydrochloride, brufen, Imatinib, Imidapril, indinavir, Irbesartan, isoniazid, ivermectin, Ketoprofen, Lamotrigine, lavo-ofloxacin, Lopinavir, pleasure cuts down statin, Manidipine, mebendazole, Medroxyprogesterone, aminosalicylic acid, metaxalone, methotrexate (MTX), ethyldopa, metronidazole, modafinil, Mosapride, Nabumetone, acidum nalidixicum, Nai Feinawei, neostigmine, nevirapine, nicorandil, niacinamide, nifurtimox, Nilvadipine, aulin, zolpidem, zolmitriptan, Zaltoprofen, warfarin, voglibose, Verapamil, valproic acid, ursodesoxycholic acid, Trimetazidine, tosufloxacin, ticlopidine, theophylline, Teprenone, tenofovir, Tegafur, tamoxifen, Taltirelin, Sultamicillin, Sulpiride, salicylazosulfapyridine, sulfamethoxazole, sulphadiazine, stavudine, roxithromycin, rofecoxib, rizatriptan, Ritonavir, Risedronic Acid, rifampin, rifaximin, Rebamipide, ranitidine, Rabeprazole, nizatidine, norethindrone, Olanzapine, olopatadine, orlistat, Oseltamivir, Oxcarbazepine, Quetiapine, puridoxine hydrochloride, bromine pyrrole this, propylthiouracil, Procaterol, praziquantel, pranlukast, dilantin sodium, phenobarbital, phendimetrazine, Perindopril, Oxycodone, dexamethasone, frusemide.
Controlled release pharmaceutical compositions according to claim 1-8, it is characterized in that the sustained release floating component is also comprising at least one plasticiser, the plasticiser is selected from triethyl citrate, tributyl citrate, polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl sebacate, diethyl sebacate, tristerin, diethyl succinate, propylene glycol, castor oil and glyceryl triacetate, preferably citric acid triethyl, the content of the plasticizer is 0.01%-50%, it is preferred that 0.1-30%, most preferably 2.5%-15% (mass percent, it is 100 calculating with the gross mass of solid component).
Controlled release pharmaceutical compositions according to claim 1-8, it is characterised in that the immediate release component and/or sustained release floating component also include other at least one pharmaceutically acceptable excipient.
Controlled release pharmaceutical compositions according to claim 21, it is characterised in that the excipient is selected from filler, lubricant, adhesive, disintegrating agent.
Controlled release pharmaceutical compositions according to claim 1-8 are tablet or capsule.
Controlled release pharmaceutical compositions according to claim 1-8, it is characterised in that the active medicine in the immediate release component and the active medicine in sustained release component are same or different, preferably identical.
Controlled release pharmaceutical compositions according to claim 1-8, it is characterised in that the active medicine in the sustained release floating component optionally keeps crystal form state after hot-melt extruded or is changed into unformed.
A kind of preparation method of the described in any item controlled release pharmaceutical compositions of claim 2-7, it is characterized in that comprising the steps of, 1) active constituent and at least one enteric polymer at least one solvent, sustained release floating component will be mixed before hot-melt extruded and to obtain premix crude product online during active constituent and at least one enteric polymer mix to premix crude product or hot-melt extruded at least one solvent, sustained release floating component；2) premix crude product leaves to obtain extrudate by the heating spiral rod Qu Houjing mouth mold of extruder.
Preparation method according to claim 27, it is characterised in that solvent of the preferred boiling point of solvent between 30-110 DEG C.
Preparation method according to claim 28, it is characterised in that the solvent is selected from water, methanol, ethyl alcohol, isopropanol, acetone, pentane, hexane, heptane, hexamethylene, methylene chloride, tetrahydrofuran, preferably water, ethyl alcohol.
Preparation method according to claim 28, it is characterised in that the dosage of the solvent is 0.1%-70%, preferably 1%-50%, most preferably 10%-30% (mass percent is 100 calculating with the gross mass of solid component).
Preparation method according to claim 26, it is characterised in that die temperature is 70-200 DEG C, preferably 90-180 DEG C, more preferable 110-160 DEG C.
Preparation method according to claim 30, it is characterised in that it is 10-90 DEG C that solvent, which injects screw rod area temperature,.
According to preparation method described in claim 26-31, it is characterised in that also comprising optionally following step: 1) extrudate is cooling；2) extrudate is removed into solvent；3) extrudate is cut.
According to the described in any item preparation methods of claim 26-31, it is characterised in that the extruder is selected from single screw rod hot-melt extruded machine, engagement screws extruder, twin screw hot melt extruder, preferably twin screw hot melt extruder.