CN101166517B - Extrusion process for making compositions with poorly compressible therapeutic compounds - Google Patents
Extrusion process for making compositions with poorly compressible therapeutic compounds Download PDFInfo
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Abstract
A process for preparing solid dosage forms that contain poorly compressible therapeutic compound. The process, for example, provides for the inventive use of an extruder, especially a twin screw extruder, to melt granulate a therapeutic compound(s) with a granulation excipient.
Description
Invention field
The present invention relates to prepare the method for solid oral dosage form poor compressibility and/or moisture-sensitive therapeutic compound.The characteristic of this method is to use extruder to carry out melt granulation.
Background of invention
Poor compressibility can influence the ability that therapeutic compound is prepared into solid oral dosage form such as tablet.The conventional tablet that contains the therapeutic compound of poor compressibility often lacks enough hardness and frangible.Therefore, can use special preparation technique that the therapeutic compound of poor compressibility is prepared into solid oral dosage form, particularly tablet in viable commercial.
A kind of method that overcomes the poor compressibility of therapeutic compound is to adopt wet granulation technique to prepare tablet.This technology comprises extra unit operations: wet grinding, drying and dry granulation grind.But can demonstrate hardness by the tablet of wet method preparation increases with storage temperature in time.Therefore, the tablet by the wet method preparation can demonstrate variable properties of product.In addition, when some therapeutic compound contacted with water, they were easy to degraded, and therefore, it possibly be unfavorable making water carry out wet granulation.
Therefore, need the method for the pharmaceutical composition of the therapeutic compound for preparing poor compressibility with enough hardness and good reproducibility.The present invention has solved this needs through adopting the melt granulation technology.The innovation aspect that the present invention is unique is to use extruder that the melt granulation preparation is provided.
Usually, the high-temperature extruder in the pharmacy scope has been used to prepare solid dispersion and/or solid solution, and these solid dispersion and/or solid solution have needed therapeutic compound partial melting at least.Beat allly be that it is useful that the use that has been found that extruder need not aspect the therapeutic compound fusion in the solid dosage forms of preparation melt granulation.
Summary of the invention
Characteristic of the present invention is the method for pharmaceutical compositions, and this method comprises the steps: therapeutic compound poor compressibility and/or moisture-sensitive and at least a granulation excipient are merged and the formation mixture; This mixture is mixed in extruder, for example twin (double) screw extruder or kneads, simultaneously with this mixture heated to the temperature that is lower than therapeutic compound fusing point or melting range; And this mixture pushed through optional mould (die) form extrudate.
One special aspect in, can choose wantonly extrudate is ground to form granule, use conventional method that it is pressed into solid oral dosage form then.In another aspect of this invention, granulation excipient is the polymer with the glass transition temperature that is lower than the therapeutic compound fusing point.Useful especially polymer comprises water solublity, water-swellable and insoluble polymer.
Inventive process of the present invention both can be used to prepare quick-release medicinal composition, also can be used to prepare sustained release pharmaceutical composition.
Detailed Description Of The Invention
The present invention relates to prepare the method for pharmaceutical composition poor compressibility and/or moisture-sensitive therapeutic compound.The characteristic of this inventive process is to use extruder that the therapeutic compound and the granulation excipient of poor compressibility are carried out melt granulation.Need not therapeutic compound is carried out the melt granulation that any fusion just can be accomplished the therapeutic compound of poor compressibility.
Term as used herein " pharmaceutical composition " expression is applied to mammal, for example people attack mammiferous specified disease or disease with prevention, treatment or control the mixture that contains therapeutic compound.
Term as used herein " pharmaceutically acceptable " refer in reliable medical judgment scope, to be suitable for contact with mammal, particularly people's tissue and do not have excessive toxicity, zest, allergic response and match with rational income/risk-ratio other cause those chemical compounds, material, compositions and/or the dosage form of the complication of problem.
Term as used herein " therapeutic compound " expression has treatment or pharmacotoxicological effect and is suitable for any compound, material, medicine, medicament or the active component of in being particularly suitable for Orally administered compositions, using for mammal, for example people.
The therapeutic compound of term as used herein " poor compressibility " refers to be difficult for the chemical compound that combination forms tablet after the application of force.When the tablet that weight is about 10 grams (or at least 10 units) makes an experiment after after compacting, falling 500 times immediately, separately by weight be 1 gram the therapeutic compound preparation and under the power of 5kN to 25kN scope, the friability that tablet provided in 30 seconds, suppressed of the time of staying will be equal to or greater than acceptable limit 1.0% (w/w).These chemical compounds possibly need other processing and special preparation before compacting, for example wet granulation or cylinder compression.The therapeutic compound of high dose also maybe be because mobile differ from and poor compressibility makes therapeutic compound be inappropriate for direct compacting.
The therapeutic compound of term as used herein " wet quick property " refers to when therapeutic compound contacts with water, for example stand through the therapeutic compound hydrolysis of at least 1% weight the therapeutic compound of spontaneous degraded.
The treatment examples of types of therapeutic compound includes but not limited to antiacid; Anti-inflammatory substance; Coronary vasodilator; Cerebral vasodilator; Peripheral vasodilator; Anti-infective; Psychotropic; Antimanic drugs; Beta stimulant; Antihistaminic; Anticancer therapy property chemical compound; Caccagogue; Decongestant; Vitamin; The gastrointestinal tranquilizer; Antidiarrhea agent; Antianginal therapy property chemical compound; Vasodilation; Anti-arrhythmic; Antihypertensive therapy property chemical compound; Vasoconstrictor and migraine treatment; Anticoagulant and antithrombotic therapeutic compound; Analgesic; Antipyretic; Hypnotic; Tranquilizer; Bendectin; Antinauseant; Anticonvulsant; The neuromuscular therapeutic compound; Glucose elevating agent and blood sugar lowering; Thyroid and antithyroid preparation; Diuretic; Spasmolytic; Uterorelaxant; Mineral and nourishing additive agent; The obesity therapeutic compound; The anabolism therapeutic compound; The erythropoiesis therapeutic compound; Antiasthmatic drug; Expectorant; Cough medicine; Mucolytic; The anti-uricemic therapeutic compound and act locally on mouthful in a therapeutic compound or a material.
Exemplary therapeutic compound includes but not limited to: gastrointestinal tranquilizer, for example metoclopramide and propantheline bromide; Antiacid, for example three aluminium silicate, aluminium hydroxide and cimetidine; Anti-inflammatory treatment property chemical compound, for example Phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone; Coronary vasodilator therapeutic compound, for example nitroglycerin, sorbide nitrate and pentaerithrityl tetranitrate; Periphery and cerebral vasodilator, for example soloctidilum, vincamine, naftidrofuryl oxalate, Dihydroergotoxine Mesylate, cyclandelate, papaverine and nicotinic acid; Anti-infective therapy's property chemical compound, for example erythromycin octadecanoate, cefalexin, nalidixan, quadracycline, ampicillin, flucolaxacillin sodium, hexamine mandelate and methenamine hippu; Ataraxy therapeutic compound, for example fluazepam, diazepam, temazepam, amitriptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluoperazine, fluphenazine, piperothiazine, haloperidol, aueural, imipramine and Desipramine; Central nervous excitation agent, for example methylphenidate, ephedrine, epinephrine, isoproterenol, amfetamine sulfate and hydrochloric acid amfetamine; Antihistamine therapeutic compound, for example diphenhydramine, diphenylpyraline, chlorphenamine and brompheniramine; Antidiarrheal therapeutic compound, for example bisacodyl and magnesium hydroxide; Cathartic therapeutic compound, for example docusate sodium; Supplementary, for example ascorbic acid, alpha tocopherol, vitamin B1 and vitamin B6; Spasmolytic therapeutic compound, for example Neoquess and diphenoxylate; Influence the therapeutic compound of the rhythm of the heart, for example verapamil, nifedipine (nifedepine), diltiazem
, procainamide, disopyramide, bretylium tosilate, quinidine sulfate and gluconic acid quinidine; Be used to treat hypertensive therapeutic compound, for example propranolol hydrochloride, guanethidine monosulphate, methyldopa, oxprenolol hydrochloride, captopril and hydralazine; Be used to treat migrainous therapeutic compound, for example Ergotamine; Influence the therapeutic compound of blood coagulation, for example EACA and protamine sulfate; Analgesia therapy property chemical compound, for example aspirin, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine bitartrate, oxycodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, cyclazocine (cyclazacine), Pethidine, buprenorphine, scopolamine and mefenamic acid; Epilepsy therapeutic compound, for example phenytoin Sodium and sodium valproate; Neuromuscular therapeutic compound, for example dantamacrin; Be used to treat treatment of diabetes property chemical compound, for example metformin, tolbutamide, diabenase glucagon and insulin; Be used to treat the therapeutic compound of dysthyreosis, for example 3, thyroxine and propylthiouracil; Diuretic therapy property chemical compound, for example furosemide, chlortalidone, hydrochlorothiazide, spironolactone and triamterene (triampterene); Hysteranesis therapeutic compound, for example ritodrine; Appetite suppressant, for example fenfluramine hydrochloride, phentermine and amfepramone hydrochloride; Zhichuan therapeutic compound, for example aminophylline, theophylline, albuterol, orciprenaline sulfate and terbutaline sulphate; Therapeutic compound, for example guaifenesin eliminate the phlegm; Cough medicine, for example dextromethorphan and narcotine; Mucolysis therapeutic compound, for example carbocisteine; Disinfectant, for example cetylpyridinium chloride, Tyrothricin and chlorhexidine; Congestion therapeutic compound, the for example pure and mild pseudoephedrine of amfetamine; Hypnotherapy property chemical compound, for example dichloralphenazone and nitrazepam; End feel sick therapeutic compound, for example promethazine teoclate; Hemopoietic therapeutic compound, for example ferrous sulfate, folic acid and calcium gluconate; Urate excretion therapeutic compound, for example sulfinpyrazone, allopurinol and probenecid etc.
The therapeutic compound of poor compressibility is present in the pharmaceutical composition of the present invention with treatment effective dose or concentration.This treatment effective dose or concentration are that those of ordinary skill in the art is known, change with employed therapeutic compound and the indication that is solved.For example, according to the present invention, therapeutic compound can exist with about 0.05% to about 99% amount of pharmaceutical composition weight.In one embodiment, therapeutic compound can exist with about 10% to about 95% amount of pharmaceutical composition weight.
Term as used herein " rapid release " refers to after oral in the short relatively time, for example in 1 hour, 40 minutes, 30 minutes or 20 minutes, can discharge rapidly most of therapeutic compound, for example greater than about 50%, about 60%, about therapeutic compound of 70%, about 80% or about 90%.Useful especially conditions for immediate-release is in oral back 30 minutes, to discharge at least or equal about 80% therapeutic compound.The concrete conditions for immediate-release of particular treatment property chemical compound will be that those of ordinary skill in the art approves or known.
Term as used herein " slow release " or " (modified relese) that release slows down " refer to that time that the amount of oral back therapeutic compound goes through relative prolongation gradually but discharge continuously or constantly.Release will continue a period of time, and can continue to arrive intestinal and afterwards until pharmaceutical composition.Slow release can also refer to postpone to discharge; Wherein therapeutic compound can not begin to discharge when pharmaceutical composition arrives stomach immediately, but postpones a period of time, for example; Until when pharmaceutical composition arrives intestinal, when the pH that raises is used for causing therapeutic compound when pharmaceutical composition discharges.
Term as used herein " granulation excipient " refers to carry out any pharmaceutically useful material or the material of melt granulation with the therapeutic compound of poor compressibility, as is discussed in further detail below.Granulation excipient for example can be polymer or non-polymer material.
Term " polymer " as used herein " refer to self or in combination, have the polymer or the polymeric blends of glass transition temperature, softening temperature or fusion temperature of the fusing point (melting range) of the therapeutic compound of the poor compressibility of being no more than.Glass transition temperature (" Tg ") is the temperature that the character of this polymer changes to relatively low stickum from high viscosity.The type of polymer includes but not limited to water solublity, water-swellable, insoluble polymer and above-mentioned combination.
The instance of polymer includes but not limited to:
The homopolymer of N-vinyl lactam and copolymer, the for example copolymer of the homopolymer of N-vinyl pyrrolidone and copolymer (for example polyvinylpyrrolidone), N-vinyl pyrrolidone and vinyl acetate or propionate;
Cellulose esters and cellulose ether (for example methylcellulose and ethyl cellulose), hydroxy alkyl cellulose (for example hydroxypropyl cellulose), hydroxyalkyl alkylcellulose (for example hydroxypropyl emthylcellulose), cellulose phthalate ester (for example CAP and hydroxypropyl methyl cellulose phthalate) and cellulose hemisuccinate ester (for example hydroxypropyl methyl cellulose succinate or hydroxypropyl methylcellulose acetate succinate);
Polyphosphazene polymer oxyalkylene, for example polyethylene glycol oxide and PPOX and oxirane and epoxy propane copolymer;
Polyacrylate and polymethacrylates (for example methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methylmethacrylate copolymer, butyl methacrylate/methacrylic acid 2-dimethylaminoethyl ester copolymer, gather (acrylic acid hydroxy alkyl ester), gather (hydroxyalkyl methacrylate));
Polyacrylamide;
Vinyl acetate polymer, the for example polyvinyl acetate of vinyl acetate and .beta.-methylacrylic acid copolymer, partial hydrolysis;
Polyvinyl alcohol; With
Oligosaccharide and polysaccharide, for example carrageenin, galactomannan and xanthan gum, perhaps its one or more mixture.
Term as used herein " plasticizer " refers to join in the pharmaceutical composition to reduce the glass transition temperature of polymer and the material of melt viscosity through the free volume that increases between the polymer chain.Plasticizer for example includes but not limited to that water, citron acid esters (for example triethyl citrate, triacetin), low-molecular-weight gather (oxyalkylene) (for example gather (ethylene glycol), gather (propylene glycol), gather (ethylene glycol/propylene glycol)), glycerol, tetramethylolmethane, glyceryl monoacetate, diacetate esters or triacetate, propylene glycol, sodium sulfo-succinate diethylester and therapeutic compound itself.Plasticizer can with pharmaceutical composition weight about 0% to 15%, for example 0.5% to 5% concentration exists.The instance of plasticizer can also find in auxiliary pharmaceutical adjuvant handbook (The Handbook of Pharmaceutical Additives) (people such as Ash, Gower publishes (2000)).
Non-polymeric granulation excipients includes but not limited to ester, hydrogenated oil and fat, oil, native paraffin, synthetic wax, hydrocarbon, aliphatic alcohol, fatty acid, monoglyceride, diglyceride, triglyceride and composition thereof.
The instance of ester, for example glyceride includes but not limited to that glyceryl monostearate is as from (the Columbus of Abitec company; OH) CAPMUL GMS, glyceryl palmitostearate, acetylation glyceryl monostearate, Arlacel-60 are as from Uniqema (New Castle; DE) ARLACEL 60 and hexadecyl palmitate are like CUTINA CP, magnesium stearate and calcium stearate from Cognis company (D ü sseldorf, Germany).
The instance of hydrogenated oil and fat includes but not limited to castor oil hydrogenated, hydrogenated cottonseed oil, hydrogenated soybean oil and HPO.An instance of oil comprises Oleum sesami.
The instance of wax includes but not limited to Brazil wax, Cera Flava and spermaceti.The instance of hydrocarbon includes but not limited to microwax and paraffin.Aliphatic alcohol, promptly have about 14 instances and include but not limited to that spermol is as (Edison, CRODACOL C-70 NJ), stearyl alcohol are like CRODACOL S-95, lauryl alcohol and myristyl alcohol from Croda company from Croda company to the fixedness alcohol of the higher molecular weight of about 31 carbon atoms.Can have about 10 instances and include but not limited to that stearic acid is as from Crompton company (Middlebury, CT) HYSTRENE 5016, capric acid, Palmic acid, lauric acid and myristic acid to the fatty acid of about 22 carbon atoms.
Term as used herein " melt granulation " refers to the method for preparing that may further comprise the steps:
(a) form the therapeutic compound of poor compressibility and the mixture of at least a granulation excipient;
(b) use extruder with this granulating mixture, simultaneously with the temperature of this mixture heated to the fusing point that is lower than or approximates the therapeutic compound of poor compressibility (or melting range); With
(c) extrudate is cooled to room temperature, for example is cooled to room temperature with controlled velocity.
Forming granule (promptly from the extrudate) therapeutic compound of inner phase and the heating of granulation excipient and mixing can accomplish through using extruder.Granulation excipient for example can exist with about 1% to about 50% amount of composition weight.In one embodiment, granulation excipient can exist with about 3% to about 25% amount of composition weight.Therapeutic compound can exist with about 50% to about 99% amount of composition weight.In one embodiment, therapeutic compound can exist with about 60% to about 97% amount.Different with the granule that in wet-granulation process, prepares, melt granulation process of the present invention is not to need granulation liquid in pelletization, for example water, methanol, ethanol, isopropyl alcohol or acetone.
The granule of the therapeutic compound that the gained granule is for example encapsulated or encapsulates basically by granulation excipient, or by granulation excipient embedding or embedding or embedding or be embedded in the granule of the therapeutic compound in the granulation excipient basically basically.
Usually, extruder is included in the rotary screw in the stationary magazine creel, and stationary magazine creel has the optional mould that is positioned at tube one end.Along the total length of screw rod, screw rod can be material (for example therapeutic compound, the material that delays to discharge and other required excipient arbitrarily) at the tube internal rotation distributed kneading (distributivekneading) is provided.Conceptive saying, extruder can be divided at least three parts: feeding part, heating part and metering section (metering section).In feeding part, raw material is for example joined the extruder from loading hopper.In heating part, raw material is heated to the temperature of the fusion temperature of the therapeutic compound that is lower than poor compressibility.Be metering section behind the heating part, wherein blended material be squeezed into specific shape, for example graininess or strip through optional mould.The type that can be used in particular for extruder of the present invention has the optional single, double and multiscrew extrusion machine that is equipped with the kneading oar.
After obtaining granule, just can particle formulation be become oral forms, for example solid oral dosage form, for example tablet, pill, lozenge, Caplet, capsule or sachet through adding the other conventional excipients of forming the pharmaceutical composition foreign minister.The foreign minister of pharmaceutical composition can also comprise other therapeutic compound.These solid oral dosage forms for example are unit oral dosage forms.The instance of these excipient includes but not limited to release retardant, plasticizer, disintegrating agent, binding agent, lubricant, fluidizer, stabilizing agent, filler and diluent.According to the concrete required character of solid oral dosage form, those of ordinary skill in the art can have no inappropriate burden ground to select one or more above-mentioned excipient through normal experiment.The amount of each used excipient can change in the normal ranges of this area.What all be incorporated herein by reference discloses technology and the excipient that is used for formulate oral dosage forms below with reference to document.Referring to " handbook of pharmaceutical excipients " (The Handbook of Pharmaceutical Excipients), the 4th edition, people editors such as Rowe, American Pharmaceutical Association (2003); With Remington:the Science andPractice of Pharmacy, the 20th edition, Gennaro editor, Lippincott Williams &Wilkins (2003).
Term as used herein " release retardant " refers to work as any material or the material that oral administration time spent later treatment property chemical compound discharges from pharmaceutical composition.Can accomplish like various slow-released systems known in the art, for example diffusion system, digestion series and/or osmosis system through using hangover property component.Release retardant can be polymer or non-polymer in nature.Pharmaceutical composition of the present invention can for example comprise the release retardant in the weight at least 5% of compositions, the words of slow releasing composition if desired.
The instance of pharmaceutically acceptable disintegrating agent includes but not limited to: starch; Clay; Cellulose; Alginate; Natural gum; Cross linked polymer, for example crospolyvinylpyrrolidone or crospovidone are for example from International Specialty Products (Wayne, POLYPLASDONE XL NJ); Cross-linking sodium carboxymethyl cellulose is for example from the AC-DI-SOL of FMC; With cross-linked carboxymethyl cellulose calcium; Soybean polysaccharide and guar gum.Disintegrating agent can exist with about 0% to about 10% amount of composition weight.In one embodiment, disintegrating agent exists with about 0.1% to about 1.5% amount of composition weight.
The instance of pharmaceutically acceptable binding agent includes but not limited to: starch; Cellulose and derivant thereof, for example microcrystalline Cellulose is as from FMC (Philadelphia, AVICEL PH, hydroxypropyl cellulose, hydroxyethyl-cellulose and hydroxypropyl emthylcellulose PA), from Dow chemical company (Midland, METHOCEL MI); Sucrose; Glucose; Corn syrup; Polysaccharide and gelatin.Binding agent can exist to amount about 50%, for example 10-40% with about 0% of composition weight.
The instance of pharmaceutically acceptable lubricant and pharmaceutically acceptable fluidizer includes but not limited to silica sol, magnesium trisilicate, starch, Pulvis Talci, calcium phosphate, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, magnesium oxide, Polyethylene Glycol, Powderd cellulose and microcrystalline Cellulose.Lubricant can exist with about 0% to about 10% amount of composition weight.In one embodiment, lubricant can exist with about 0.1% to about 1.5% amount of composition weight.Fluidizer can exist with about 0.1% amount to about 10% weight.
The instance of pharmaceutically acceptable filler and pharmaceutically acceptable diluent includes but not limited to Icing Sugar (confectioner ' s sugar), sompressible sugar, dextrates, dextrin, glucose, lactose, mannitol, microcrystalline Cellulose, Powderd cellulose, sorbitol, sucrose and Pulvis Talci.Filler and/or diluent for example can exist with about 15% to about 40% amount of composition weight.
In order to prepare pharmaceutical composition of the present invention, in joining the loading hopper of extruder before or add fashionable ratio with 99: 1 to 1: 1 (based on dry weight) scopes with therapeutic compound and granulation excipient mixing.In an exemplary embodiment, this ratio between therapeutic compound and granulation excipient can be in the scope of 97: 3 to 60: 40 (based on dry weight).In another alternative embodiment, this ratio can be in the scope of 97: 3 to 75: 25 (based on dry weight).Optional can plasticizer being joined in the inner phase.
Mixture is heated to the temperature that is lower than the therapeutic compound fusion temperature.When mixture was heated, it also was extruded the screw rod kneading of machine.Mixture is remained on the temperature of rising and the time that mixing is enough to form granular product.Mixture obtains granular product (being extrudate) after the total length transmission of tube, granular mixture is cooled off.
After the cooling, can extrudate be ground also and sieve subsequently.Then, with the granule inner phase of pharmaceutical composition (constitute) with solid oral dosage form excipient (foreign minister of pharmaceutical composition), be merging such as filler, binding agent, disintegrating agent, lubricant.Can be for example the mixture that merges be further mixed, subsequently with its compacting or be molded as tablet (like the monolithic tablet) or seal with capsule through the V-type blender.
After obtaining tablet, can choose wantonly with as functional or non-functional coating known in the art they are carried out coating.The instance of packaging technique includes but not limited to sweet tablet, film coating, microencapsulation and pressed coated.The type of coating includes but not limited to enteric coating, sustained release coating, controlled release coat.
The effect of all pharmaceutical compositions of the present invention can be in standard clinical tests in the known indications of the drug dose of the effective blood level of treatment that therapeutic compound for example is provided, for example adopt and in standard animal model, observe the dosage in 75kg mammal such as adults 2.5-1000mg therapeutic compound/sky.
The invention provides that treatment suffers from can be with the disease of therapeutic compound treatment, disease or disorderly curee's method, and this method comprises that the pharmaceutical composition of the present invention with the treatment effective dose is applied to the curee who needs this treatment.
Following examples are illustrative, and are not to be used to limit scope of invention as herein described.Embodiment only is used for prompting and puts into practice method of the present invention.
An instance that is suitable for therapeutic compound of the present invention is a metformin hydrochloride.The unit dosage forms of metformin hydrochloride, for example single tablet or capsule can comprise 250mg to 2000mg metformin hydrochloride, for example 250mg, 500mg, 750mg, 850mg or 1000mg metformin.In the present invention, metformin hydrochloride may reside in the inner phase of final solid oral dosage form.
Embodiment
| Composition | Percentage ratio (w/w) | Amount/sheet (mg) |
| Inner phase | ||
| Metformin hydrochloride | 91％ | 1000 |
| Hydroxypropyl cellulose | 9％ | 99 |
| The foreign minister | ||
| Magnesium stearate | 1％ | 11 |
| Total amount | 1110 | |
With interior phase constituent, be that metformin hydrochloride and hydroxypropyl cellulose (can be merged by Hercules chemical company (Wilmington Delaware) obtains with KLUCEL EXF), in performance chamber mixer, mix about 200 and change.Mixture is joined in the feeding part or loading hopper of twin (double) screw extruder.Suitable twin (double) screw extruder is that the medicinal twin (double) screw extruder of PRISM 16mm (can be by Thermo Electron company (Waltham Massachusetts) obtains).
What be positioned at the twin (double) screw extruder end is the mould with about 3mm aperture.Twin (double) screw extruder is equipped with 5 independent tube district or parts, and these districts or part can be adjusted to different parameters independently.Begin to mould from loading hopper, the tube district is heated to following temperature respectively: 40 ℃, 110 ℃, 130 ℃, 170 ℃ and 185 ℃.The temperature of the thermal treatment zone is no more than the fusion temperature (about 232 ℃) of metformin hydrochloride.Screw speed is set to 150rpm, but can the volume charging rate be adjusted to per minute can transmit about 30 to 45 gram raw materials up to 400rpm.Speed of production can be adjusted to 4g/min to 80g/min.
Then, extrudate through self compaction in future machine or granule are placed and were made it be cooled to room temperature in about 15 to 20 minutes.Subsequently, refrigerative granule is crossed 18 mesh sieves (being the 1mm sieve aperture).
For the foreign minister, at first make magnesium stearate cross 18 mesh sieves.Then, using suitable performance chamber mixer that magnesium stearate is mixed about 60 with the granule that obtains changes.The pressure of the rotary tablet machine (ManestyBeta Press) of use routine, use 6kN to 25kN scope is pressed into tablet with the final mixture of gained.The gained tablet is that monolithic and its hardness range are 5kP to 35kP.Hardness range is that the tablet of 15kP to 35kP can produce the acceptable friability that is lower than 1.0%w/w falling after 500 times.In addition, 37 ℃, in the dish of 0.1N HCl, the disintegration time of these tablets was smaller or equal to 20 minutes.
Compare with it, when through wet granulation or direct compression process the prescription of embodiment 1 being prepared into tablet, when between the 6kN to 26kN during tabletting, the hardness range of gained tablet is 3kP to 7kP.In addition, these tablets are falling after 500 times the friability that produces greater than 1% (w/w).Therefore, the result shows that melt granulation process has improved the compressibility of the therapeutic compound of poor compressibility.
Though be appreciated that to combine its detailed description to describe the present invention, above description is intended to explanation and unrestricted scope of the present invention, and scope of the present invention is limited the scope of subsequently claim.Others, advantage and accommodation are within the scope of the claims.
Claims (10)
1. prepare the method for the pharmaceutical composition of rapid release, this method comprises the steps:
The therapeutic compound metformin hydrochloride and at least a granulation components of poor compressibility are merged, form mixture, wherein said granulation components is the polymer with the glass transition temperature that is lower than said therapeutic compound fusing point;
Described mixture is kneaded in extruder, simultaneously with described mixture heated to more than or equal to the glass transition temperature of said polymer and be lower than the heating-up temperature of said therapeutic compound fusing point;
Described mixture extruding is formed granule; And
Said granule compacting is formed solid oral dosage form;
Wherein this solid oral dosage form has the hardness of 15kP to 35kP and is lower than 1% friability.
2. the process of claim 1 wherein that described polymer is selected from water-soluble polymer, water-swellable polymer and insoluble polymer.
3. the process of claim 1 wherein that described mixture also comprises plasticizer.
4. the process of claim 1 wherein that described extruding is through mould.
5. the process of claim 1 wherein that described extruder is a twin (double) screw extruder.
6. improve the method for friability of the tablet of the therapeutic compound metformin hydrochloride contain poor compressibility, this method comprises the steps:
The therapeutic compound metformin hydrochloride and at least a granulation components of poor compressibility are merged, form mixture, wherein said granulation components is the polymer with the glass transition temperature that is lower than said therapeutic compound fusing point;
Described mixture is kneaded in extruder, simultaneously with described mixture heated to more than or equal to the glass transition temperature of said polymer and be lower than the heating-up temperature of said therapeutic compound fusing point;
Described mixture extruding is formed granule; With
Described granule is pressed into tablet, and wherein this tablet has the hardness of 15kP to 35kP and is lower than 1% friability.
7. by the pharmaceutical composition of the method for claim 1 or 6 preparation.
8. the pharmaceutical composition of claim 7, it also comprises other therapeutic compound.
9. the pharmaceutical composition of claim 7, wherein said metformin hydrochloride exists with 250mg to 2000mg.
10. the extruder preparation is like the purposes of each described pharmaceutical composition among the claim 7-9.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67958705P | 2005-05-10 | 2005-05-10 | |
| US60/679,587 | 2005-05-10 | ||
| US69315505P | 2005-06-23 | 2005-06-23 | |
| US60/693,155 | 2005-06-23 | ||
| PCT/US2006/017708 WO2006122021A1 (en) | 2005-05-10 | 2006-05-08 | Extrusion process for making compositions with poorly compressible therapeutic compounds |
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| CN2011103445944A Division CN102552162A (en) | 2005-05-10 | 2006-05-08 | Extrusion process for making compositions with poorly compressible therapeutic compounds |
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| CN101166517B true CN101166517B (en) | 2012-01-04 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2723053A1 (en) * | 2008-04-30 | 2009-11-05 | Novartis Ag | Continuous process for making pharmaceutical compositions |
| US20110092515A1 (en) * | 2008-07-03 | 2011-04-21 | Zhihui Qiu | Melt granulation process |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5160680A (en) * | 1984-10-03 | 1992-11-03 | Roquette Freres | Method for the preparation of directly compressible granular manitol |
| US5965161A (en) * | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| CN1255877A (en) * | 1997-05-22 | 2000-06-07 | Basf公司 | Method for producing small-particle prepns. of biologically active substances |
| WO2002028181A1 (en) * | 2000-10-02 | 2002-04-11 | Usv Limited | Sustained release pharmaceutical compositions containing metformin and method of its production |
-
2006
- 2006-05-08 CN CN200680014443XA patent/CN101166517B/en not_active Expired - Fee Related
-
2007
- 2007-09-28 ZA ZA200708315A patent/ZA200708315B/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5160680A (en) * | 1984-10-03 | 1992-11-03 | Roquette Freres | Method for the preparation of directly compressible granular manitol |
| US5965161A (en) * | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| CN1255877A (en) * | 1997-05-22 | 2000-06-07 | Basf公司 | Method for producing small-particle prepns. of biologically active substances |
| WO2002028181A1 (en) * | 2000-10-02 | 2002-04-11 | Usv Limited | Sustained release pharmaceutical compositions containing metformin and method of its production |
Non-Patent Citations (2)
| Title |
|---|
| KELEB EI ET AL.Extrusion Granulation and High Shear Granulation of DifferentGrades of Lactose and Highly Dosed Drugs：A ComparativeStudy.DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY30 6.2004,30(6),摘要. |
| KELEB EI ET AL.Extrusion Granulation and High Shear Granulation of DifferentGrades of Lactose and Highly Dosed Drugs:A ComparativeStudy.DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY30 6.2004,30(6),摘要. * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200708315B (en) | 2008-10-29 |
| CN101166517A (en) | 2008-04-23 |
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