CN101166517A - 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 feature 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 may 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 by adopting the melt granulation technology.The innovation aspect of uniqueness of the present invention 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
Feature 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 mixed in extruder, for example twin (double) screw extruder or knead, simultaneously with this mixture heated to the temperature that is lower than therapeutic compound fusing point or melting range; And this mixture pushed by 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 feature 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 finished the therapeutic compound of poor compressibility.
Term " 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 as used herein.
As used herein term " 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 " therapeutic compound " expression has treatment or pharmacotoxicological effect and be suitable for any compound, material, medicine, medicament or the active component of using for mammal, for example people in being particularly suitable for Orally administered compositions as used herein.
The therapeutic compound of term " poor compressibility " refers to be difficult in conjunction with the chemical compound that forms tablet after the application of force as used herein.When the tablets that weight are about 10 grams (or at least 10 units) are tested fall 500 times immediately after compacting after, separately by weight for the therapeutic compound preparation of 1 gram and under the power of 5kN to 25kN scope, the friability that tablet provided suppressed in 30 seconds of the time of staying will be equal to or greater than acceptable limit 1.0% (w/w).These chemical compounds may need other processing and special preparation before compacting, for example wet granulation or cylinder compression.The therapeutic compound of high dose also may be because mobile differ from and poor compressibility makes therapeutic compound be unsuitable for direct compacting.
The therapeutic compound of term " wet quick property " refers to for example stand by the therapeutic compound hydrolysis of at least 1% weight the therapeutic compound of spontaneous degraded when therapeutic compound contacts with water as used herein.
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, the anticancer therapy chemical compound, caccagogue, Decongestant, vitamin, the gastrointestinal tranquilizer, antidiarrhea agent, the antianginal therapy chemical compound, vasodilation, anti-arrhythmic, the antihypertensive therapy 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 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 for the treatment of hypertensive therapeutic compound, for example propranolol hydrochloride, guanethidine monosulphate, methyldopa, oxprenolol hydrochloride, captopril and hydralazine; Be used for the treatment of migrainous therapeutic compound, for example Ergotamine; Influence the therapeutic compound of blood coagulation, for example episilon amino caproic acid and protamine sulfate; Analgesia therapy 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 for the treatment of the treatment of diabetes chemical compound, for example metformin, tolbutamide, diabenase glucagon and insulin; The therapeutic compound that is used for the treatment of dysthyreosis, for example 3, thyroxine and propylthiouracil; Diuretic therapy 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, for example pure and mild pseudoephedrine of amfetamine; Hypnotherapy 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.
As used herein term " rapid release " refer 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 to discharge in oral back 30 minutes at least or equal about 80% therapeutic compound.The concrete conditions for immediate-release of particular treatment chemical compound will be that those of ordinary skill in the art approves or known.
Term " 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 as used herein.Release will continue for some 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 " granulation excipient " refers to carry out with the therapeutic compound of poor compressibility any pharmaceutically useful material or the material of melt granulation as used herein, as described further 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 example of polymer includes but not limited to:
The homopolymer of N-vinyl lactam and copolymer, 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 polypropylene oxide 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, poly-(acrylic acid hydroxy alkyl ester), poly-(hydroxyalkyl methacrylate));
Polyacrylamide;
Vinyl acetate polymer, 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 " plasticizer " refers to join in the pharmaceutical composition to reduce the glass transition temperature of polymer and the material of melt viscosity by the free volume that increases between the polymer chain as used herein.Plasticizer for example includes but not limited to water, citron acid esters (for example triethyl citrate, triacetin), low-molecular-weight poly-(oxyalkylene) (for example poly-(ethylene glycol), poly-(propylene glycol), poly-(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 example 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 example 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 as CUTINA CP, magnesium stearate and calcium stearate from Cognis company (D ü sseldorf, Germany).
The example of hydrogenated oil and fat includes but not limited to castor oil hydrogenated, hydrogenated cottonseed oil, hydrogenated soybean oil and hydrogenated palm oil.An example of oil comprises Oleum sesami.
The example of wax includes but not limited to Brazil wax, Cera Flava and spermaceti.The example of hydrocarbon includes but not limited to microwax and paraffin.Aliphatic alcohol, promptly have about 14 examples and include but not limited to that spermol is as (Edison, CRODACOL C-70 NJ), stearyl alcohol are as 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 examples 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 " melt granulation " refers to the preparation method that may further comprise the steps as used herein:
(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 finish by 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 for preparing in wet-granulation process, 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 gained granule for example by the granulation excipient bag by or wrap the granule of the therapeutic compound of quilt basically, 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 by 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 form, for example solid oral dosage form, for example tablet, pill, lozenge, Caplet, capsule or sachet by 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 example 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 select one or more above-mentioned excipient without any inappropriate burden ground by 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 ﹠amp; Wilkins (2003).
Term " release retardant " refers to work as any materials or the material that oral administration time spent later treatment chemical compound discharges from pharmaceutical composition as used herein.Can finish as known in the art various slow-released systems, for example diffusion system, digestion series and/or osmosis system by 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 example 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 example 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 example 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 example 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 therapeutic compound and granulation excipient mixed with 99: 1 to 1: 1 (based on dry weight) scopes.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 plasticizer can 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, extrudate can be ground and sieves 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 (as the monolithic tablet) or seal with capsule by the V-type blender.
After obtaining tablet, can choose the functional or non-functional coating of using as known in the art wantonly they are carried out coating.The example 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 levels 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, this method comprise will the treatment effective dose pharmaceutical composition of the present invention be 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 example 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), mix about 200 and change in performance chamber mixer.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 by 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 by 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 in conjunction with its detailed description and described the present invention, above description is intended to explanation but not limits the scope of the invention, and scope of the present invention is limited by the scope of subsequently claim.Others, advantage and accommodation are within the scope of the claims.
Claims (21)
1. the method for pharmaceutical compositions, this method comprises the steps:
The therapeutic compound and at least a granulation components of poor compressibility are merged, form mixture;
Described mixture is kneaded in extruder, simultaneously with described mixture heated to the heating-up temperature that is lower than described therapeutic compound fusing point; With
Described mixture extruding is formed granule.
2. the method for claim 1, this method also comprise the step that described granule compacting is formed solid oral dosage form.
3. the process of claim 1 wherein that described granulation components is the polymer with the Tg that is lower than described fusing point.
4. the method for claim 3, wherein said polymer is selected from water-soluble polymer, water-swellable polymer and insoluble polymer.
5. the method for claim 4, wherein said heating-up temperature is more than or equal to described Tg.
6. the method for claim 3, wherein said mixture also comprises plasticizer.
7. the process of claim 1 wherein that described pharmaceutical composition is an immediate release composition.
8. the process of claim 1 wherein that described pharmaceutical composition is a slow releasing composition.
9. the method for claim 8, wherein said pharmaceutical composition comprises release retardant.
10. the process of claim 1 wherein that described extruding is by mould.
11. the process of claim 1 wherein that described extruder is a twin (double) screw extruder.
12. the method for pharmaceutical compositions, this method comprise the steps: wet quick property therapeutic compound and at least a granulation components are merged, and form mixture; Described mixture is kneaded in extruder, simultaneously with described mixture heated to the heating-up temperature that is lower than described therapeutic compound fusing point; With being pushed, described mixture forms granule.
13. improve the method for friability of the tablet of the therapeutic compound contain poor compressibility, this method comprises the steps:
The therapeutic compound and at least a granulation components of poor compressibility are merged, form mixture;
Described mixture is kneaded in extruder, simultaneously with described mixture heated to the heating-up temperature that is lower than described therapeutic compound fusing point;
Described mixture extruding is formed granule; With
Described granule is pressed into tablet.
14. drug particles by the preparation of the method for claim 1.
15. the drug particles of claim 14, wherein said therapeutic compound is a metformin hydrochloride.
16. comprise the drug particles of claim 13 and the pharmaceutical composition of other therapeutic compound.
17. the drug particles of claim 15, wherein said metformin hydrochloride exists with 250mg to 2000mg.
18. comprise the particulate pharmaceutical composition by the method preparation of claim 1, wherein said pharmaceutical composition has the hardness of 15kP to 35kP.
19. extruder improves the purposes of friability of the compositions of the therapeutic compound comprise poor compressibility.
20. extruder prepares the purposes of the pharmaceutical composition of the therapeutic compound that comprises poor compressibility.
21. the extruder preparation comprises the purposes of the pharmaceutical composition of wet quick property therapeutic compound.
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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| Application Number | Title | Priority Date | Filing Date |
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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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| Publication Number | Publication Date |
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| CN101166517A true CN101166517A (en) | 2008-04-23 |
| CN101166517B CN101166517B (en) | 2012-01-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200680014443XA Expired - Fee Related CN101166517B (en) | 2005-05-10 | 2006-05-08 | Extrusion process for making compositions with poorly compressible therapeutic compounds |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101166517B (en) |
| ZA (1) | ZA200708315B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102014846A (en) * | 2008-04-30 | 2011-04-13 | 诺瓦提斯公司 | Continuous process for making pharmaceutical compositions |
| CN102076329B (en) * | 2008-07-03 | 2013-03-06 | 诺瓦提斯公司 | Melt granulation process |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2571046B1 (en) * | 1984-10-03 | 1987-10-16 | Roquette Freres | PROCESS FOR THE PREPARATION OF DIRECTLY COMPRESSIBLE GRANULAR MANNITOL |
| US5965161A (en) * | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| DE19721467A1 (en) * | 1997-05-22 | 1998-11-26 | Basf Ag | Process for the preparation of small-scale preparations of biologically active substances |
| EP1322158B1 (en) * | 2000-10-02 | 2012-08-08 | USV Ltd. | Sustained release pharmaceutical compositions containing metformin and method of their 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
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102014846A (en) * | 2008-04-30 | 2011-04-13 | 诺瓦提斯公司 | Continuous process for making pharmaceutical compositions |
| CN102076329B (en) * | 2008-07-03 | 2013-03-06 | 诺瓦提斯公司 | Melt granulation process |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200708315B (en) | 2008-10-29 |
| CN101166517B (en) | 2012-01-04 |
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