CN1942174A - Particulates - Google Patents
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- CN1942174A CN1942174A CNA2005800110496A CN200580011049A CN1942174A CN 1942174 A CN1942174 A CN 1942174A CN A2005800110496 A CNA2005800110496 A CN A2005800110496A CN 200580011049 A CN200580011049 A CN 200580011049A CN 1942174 A CN1942174 A CN 1942174A
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Abstract
A neutral poly(ethyl acrylate, methyl methacrylate) copolymer is employed as a carrier in the manufacture of pharmaceutical formulations containing an active ingredient. The formulations are preferably made by melt extrusion, and can have rubbery characteristics and can exhibit tamper resistance.
Description
The present invention relates to microgranule, and relate to the multiparticulates (multiparticulates) of melt extruded especially, it provides the controllable release of active component.
Background of invention
Multiparticulates with unified size of improved drug release characteristics can be easily by the preparation of melt extruded technology.Melt extruded is the single stage method of exempting to use solvent that is used to prepare multiparticulates, and improves effective especially for drug release.By selecting suitable thermoplastic polymer and additive, the melt extruded technology can be used to improve the dissolubility of few water miscible medicine, and improve its bioavailability thus, and the drug release of high water soluble medicine by the time that delays to be used for the product that may command discharges.
The key of melt extruded technology is to use thermoplastic, and it is used for pharmaceutical pack is contained at inner solution or the dispersion liquid that forms of described substrate as binding agent.The thermoplastic polymer that preferably will have lower glass transition temperatures (Tg) is used for melt extruded and handles.Consider the stability of heat sensitivity medicine and other necessary additional excipient, also preferred lower treatment temperature.The polymer glass transition temperature further can also be reduced, to promote using the optional plasticizer that adds to handle in lower temperature.
WO 9614058 provides a kind of pharmaceutical formulation that continues constant release illustratively, it comprises the therapeutic activity medicament, the melt extruded mixture of one or more materials and one or more hydrophobic fusile carriers, described one or more materials are selected from the group of being made up of following material: alkylcellulose, acrylic acid and methacrylic acid polymer and copolymer, lac, zein, castor oil hydrogenated, hydrogenated vegetable oil, and their mixture; Described carrier provides further retarding action, and it is selected from the group of being made up of following material: natural or synthetic paraffin, and fatty acid, aliphatic alcohol, and their mixture, described meltable carrier has 30-200 ℃ fusing point.The therapeutic activity medicament of described melt extruded is divided into unit dose, and its described therapeutic activity medicament that comprises effective dose to be giving the therapeutical effect of needs, and it provides described therapeutic activity medicament sustained release, continues about 24 hours time period of about 8-.
In addition, WO 9614058 describes the method that a kind of preparation is suitable for the medicinal extrudate of Orally administered lasting constant release.Described method comprises:
Therapeutic activity medicament and following material are mixed together: (1) is selected from the material of the group of being made up of following material: alkylcellulose, acrylic acid and methacrylic acid polymer and copolymer, lac, zein, castor oil hydrogenated, hydrogenated vegetable oil, and their mixture and (2) meltable carrier, it is selected from the group of being made up of following material: natural or synthetic paraffin, fatty acid, aliphatic alcohol, and their mixture; Described delayer material has 30-200 ℃ fusing point, and in being included in sufficient amount, being enough to further delay the release of described therapeutic activity medicament,
Described mixture heated to enough temperature, to be enough to softening described mixture, is enough to push described mixture;
The band of mixture extruding becoming with described heating with 0.1-3mm diameter;
With described band cooling; With
Described band is divided into the non-spheroid multiparticulates of described extrudate, and it has the length of 0.1-5mm; With
Described non-spheroid multiparticulates is divided into the unit dose of the described therapeutic activity medicament that contains effective dose, and described unit dose provides the sustained release of described therapeutic activity medicament, continues about 24 hours time period of about 8-.
In the specific preferred embodiment of WO 9614058, described hydrophobic substance is medicinal acrylic acid polymer, it includes but not limited to, acrylic acid and methacrylic acid copolymer, methyl methacrylate, methylmethacrylate copolymer, the methacrylic acid ethoxy ethyl ester, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly-(acrylic acid), poly-(methacrylic acid), methacrylic acid alkylamine copolymer, poly-(methyl methacrylate), poly-(methacrylic acid) (acid anhydride), polymethacrylates, polyacrylamide, poly-(methacrylic anhydride), and glycidyl methacrylate copolymer.Therefore, in many examples, described hydrophobic substance is an Eudragit RS PO (poly-(ethyl acrylate, methyl methacrylate, trimethylamine chloro methacrylic acid)), randomly under the existence of EudragitL100 (poly-(methacrylic acid, methyl methacrylate)).
Summary of the invention
The invention provides and use the preparation of neutral poly-(ethyl acrylate, methyl methacrylate) copolymer as pharmaceutical carrier.Such copolymer can give described preparation controllable release characteristics.And, use the present invention, by using melt extruded, we can provide (rubbery) preparation of rubbery.
Poly-(ethyl acrylate, the methyl methacrylate) copolymer of the neutrality of aqueous liquid dispersion form can be purchased.Two kinds of such products, Eudragit NE 30D and Eudragit NE 40D comprise 30% and 40% described polymer respectively.Especially, Eudragit NE 30D forms the water-insoluble thin film, and is suitable for not adding any plasticizer and prepares the substrate tablet and continue granulated processed in the coating of constant release.The information for preparing tablet and coating about application Eudragit NE can obtain from following network address: http://www.roehm.de/en/pharmapolymers.html.
For example, described network address has one piece of technical papers, and how its description is by using Eudragit NE 30D to prepare the lasting constant release matrix tablet of ibuprofen as the wet granulation of binding agent and DIFFUSION CONTROLLED agent.Granule uses filter screen (sieve) to mill by ibuprofen is mixed with the Eudragit dispersion liquid, and dry preparation.Granule is milled, mix, be compressed into tablet then with disintegrating agent and other component.The amount of Eudragit NE is low relatively.
In WO 03004009, Eudragit NE is in suggestion in the hydrophobic ingredient tabulation that hydrophilic easy erosion composition and difficult compression medicinal reagent are used.Because Eudragit NE is wet dispersion liquid, and the purpose of WO 03004009 is to form compressible preparation by the method outside the dehumidifying granulation, relates to another kind of Eudragit so the present invention is gone up on the surface.
At Pharmaceutical Technology 2004 (April): among the 62-85, descriptions such as Sood use extruding spherical turn into the preparation diltiazem hydrochloride _ may command discharge dosage form.Comprising wet granulation, wet granule extruding, and spheroidizing is assessed a series of candidate substances that forms agent as particle matrix with in the method that forms the wet granular that is dried then.Detect Eudragit NE 30D in preparation D19 and D20, it does not improve in control drug release.
In the present invention, we can use neutral poly-(ethyl acrylate, methyl methacrylate) copolymer as the carrier in the preparation.Typically, preparation of the present invention is used neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and is provided at the wherein substrate of dispersed activity component.Therefore, for example, the invention provides the multiparticulates that has such substrate respectively.
Preparation of the present invention can adopt the form of unit dose, and such as the capsule that is full of multiparticulates, it uses neutral poly-(ethyl acrylate, methyl methacrylate) copolymer as carrier.Described multiparticulates can be by the extruding drying composite, the extrudate that the mixture of the dry granule that wets especially forms, and it comprises neutral poly-(ethyl acrylate, methyl methacrylate) copolymer.
By using squeezing action, the invention provides the multiparticulates that may command discharges especially, it adopts the cylinder form, perhaps is generally spheroid, ellipsoid or disc-shape.
For this purpose, the present invention also provides the drying composite as uncompleted compositions, and described uncompleted compositions comprises neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and active component.Such compositions is anhydrous basically, and is applicable to extruding, and it is as the part that the method for preparation of the present invention is provided.Typically, described uncompleted compositions is dry granule, and can be the granule that squeezes out.
Especially, we provide the dry granule of neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and active component, and in order to give the characteristic that needs, wherein the level of neutral poly-(ethyl acrylate, methyl methacrylate) copolymer is higher relatively.Typically, in dry granule, use poly-(ethyl acrylate, methyl methacrylate) copolymer of neutrality of the amount of 20-60 weight %.
According to the present invention, we also are provided for preparing the method for the medicinal extrudate that may command discharges, and the wherein said mixture that is used for squeezing action comprises neutral poly-(ethyl acrylate, methyl methacrylate) copolymer.
Another aspect of the present invention belongs to the application process of active component, and wherein said active component is used as using the preparation that the may command of neutral poly-(ethyl acrylate, methyl methacrylate) copolymer as pharmaceutical carrier discharge.
Related fields of the present invention are to use neutral poly-(ethyl acrylate, methyl methacrylate) copolymer so that destruction (tamper) resistance to be provided in the preparation pharmaceutical formulation, and it is in the situation of infringement in described active component is important.The invention provides the method for giving the pharmaceutical formulation anti-destructive, it is included in the preparation poly-(ethyl acrylate, the methyl methacrylate) copolymer of neutrality is combined with active component.
Preferred embodiment is discussed
We find that by using neutral poly-(ethyl acrylate, methyl methacrylate) copolymer in the medicinal extrudate that discharges in the preparation may command, we can obtain to show the melt extruded multiparticulates of rubber like feature.Such rubber like extrudate can show enhanced to destructive resistance.Especially, seem that described rubber like feature given by the melt extruded step.
On the one hand, the invention provides the pharmaceutical formulation that may command discharges, it obtains or can obtain by melt extruded, and comprises neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and active component.
In related fields, the invention provides the preparation of the multiparticulates that comprises rubber like.
The feature of described rubber like provides typically flexible and compressible and can not rupture, and multiparticulates preferably with resilience.
As the demonstration of described rubber like feature, in a kind of preferred form, described multiparticulates can for example, between coin and the desktop or between two spoons, compress and can not rupture with hands between two rigid planes.Described multiparticulates usually can torsional deformation, but can not rupture or broken, and can recover its original shape ideally more or less again.
Described rubber like feature can help to give destructive resistance.For other active component that contains the opioid analgesic and often abused, anti-destructive is a particular importance.The anti-destructive of the preferred multiparticulates of the present invention can be by in water and/or ethanol, 40% ethanol for example, and the multiparticulates that shakes dosage amounts proves.
For example, in glass flask, the multiparticulates of dosage amounts can be mixed with 10ml liquid (water and/or ethanol), use Stuart Scientific Shaker then, Model SF1 randomly after placing 5 minutes, shook 15 minutes with 500-600 swing of per minute.Can determine the amount of the active agents of extraction by HPLC then, and, for example, detect at the 210nm wavelength by UV.
When detecting by this way, show the release characteristic of at least a following active agents according to the preferred multiparticulates of the present invention:
At room temperature shook in water 15 minutes: be less than 10% active agents release, preferably be less than 7.5% active agents release, more preferably be less than 5% active agents release, for example, the active agents of 1.5-4% discharges.
Placed 5 minutes in water at 50 ℃, then shook 15 minutes: be less than 20% active agents release, preferably be less than 15% active agents release, more preferably be less than 12% active agents release in identical temperature, for example, the active agents of 4-12% discharges.
Placed 5 minutes in water at 75 ℃, then shook 15 minutes: be less than 25% active agents release, preferably be less than 20% active agents release, more preferably be less than 15% active agents release in identical temperature, for example, the active agents of 10-15% discharges.
Placed 5 minutes in water at 100 ℃, then shook 15 minutes: be less than 30% active agents release, preferably be less than 25% active agents release, more preferably be less than 20% active agents release in identical temperature, for example, the active agents of 12-20% discharges.
Shook in 40% ethanol 15 minutes in room temperature: be less than 35% active agents release, preferably be less than 30% active agents release, more preferably be less than 25% active agents release, for example, the active agents of 15-25% discharges.
Alternatively, the anti-destructive of the preferred multiparticulates of the present invention can prove by following manner, promptly, make the multiparticulates of dosage amounts in mortar and pestle, stand to mill, pestle rotates 24 times, and described product is placed 900ml water, places 45 minutes at 37 ℃.Can determine the amount of the active agents of extraction by HPLC then, and, for example, detect at the 210nm wavelength by UV.
When detecting by this way, show the release characteristic of following active agents according to the preferred multiparticulates of the present invention: be less than 12.5% active agents release, preferably be less than 10% active agents release, more preferably be less than 7.5% active agents release, for example, the active agents of 2-7.5% discharges.
In another approach, the anti-destructive of the preferred multiparticulates of the present invention can prove by following manner, promptly, the multiparticulates of dosage amounts is being pulverized between two spoons or in the pill pulverizer, such as the Pill Pulverizer that sells by Apex Healthcare Products, be heated to extraction and filtration in the ebullient water at 2ml on the spoon then.Can determine the amount of the active agents of extraction by HPLC then, and, for example, detect at the 210nm wavelength by UV.
When detecting by this way, show the release characteristic of following active agents according to the preferred multiparticulates of the present invention: be less than 27.5% active agents release, preferably be less than 15% active agents release, more preferably be less than 5% active agents release, for example, the active agents of 1-5% discharges.
In order to give such anti-destructive, the invention provides and in the preparation pharmaceutical formulation, use neutral poly-(ethyl acrylate, methyl methacrylate) copolymer, to provide to destructive resistance.Neutral poly-(ethyl acrylate, methyl methacrylate) copolymer combines in preparation with active component.
On the one hand, the invention provides the method for in pharmaceutical formulation, giving anti-destructive, it comprises active component and neutral poly-(ethyl acrylate, methyl methacrylate) copolymer mixes, and form pharmaceutical formulation in conjunction with described active component and poly-(ethyl acrylate, the methyl methacrylate) copolymer of described neutrality.
Described neutrality is gathered (ethyl acrylate, methyl methacrylate) copolymer is suitable for being applied in the amount of 66 weight % nearly and is used for mixture for extrusion, such as the 20-66% of extruding mixture, the 20-50% of extruding mixture more typically is such as the 30-40% of extruding mixture.In dry granule of the present invention, these percentage ratios also are applied to the amount of neutral poly-(ethyl acrylate, methyl methacrylate) copolymer.
Poly-(ethyl acrylate, the methyl methacrylate) copolymer of described neutrality can with other component, comprise medicine or other active component, use together.Reading matter is with reference to WO 9614058, and it is incorporated into this fully by concrete reference.The release control material of using in the pressing method that the described patent that can form poly-(ethyl acrylate, the methyl methacrylate) copolymer of described neutrality describes in detail whole or part more preferably.
In this respect, our preferred compositions comprises other polymer that at least a improvement discharges.Especially, the application that seems ethyl cellulose or similar polymer can be assisted and be given destructive resistance, especially to the resistance with alcohol extraction.For example, alkylcellulose, such as ethyl cellulose, preferably with the 5-60%w/w of described preparation, the 10-50%w/w of described preparation preferably, most preferably the amount of the 20-45%w/w of described preparation is used.Other suitable polymer comprises the water-insoluble ammonio methacrylate copolymer.Described insoluble ammonio methacrylate copolymer can be Eudragit RSPO and Eudragit RL PO, and it is an ammonio methacrylate copolymer.Especially, at least a other polymer typically is and is difficult to the thermoplastic polymer of water permeability, perhaps relative altitude water permeability thermoplastic polymer, and it can improve release significantly, but uses not slacken resilience force or elastic amount.
When use has the extruder of low relatively torsional performance, such as Leistritz Micro 18 machines, preferred plasticizer and/or lubricant.Use bigger extruder,, can process not or have the similar preparation of low-level relatively plasticizer and/or lubricant such as Leistritz Micro 27.
Described plasticizer is selected from water insoluble solid usually, such as hexadecanol, and octadecanol and cetostearyl alcohol; Water-soluble solid, such as Sorbitol and sucrose and high molecular weight polyethylene glycol, water-insoluble liquid, such as dibutyl sebacate and tributyl citrate and water-soluble liquid, such as triethyl citrate, propylene glycol and low molecular poly.Tributyl citrate is a preferred plasticizer.Octadecanol also is a preferred plasticizer.Another kind of plasticizer is the high molecular weight polyethylene glycol of MW 1000-20000, such as PEG 6000.
Can comprise lubricant.Described lubricant is a solid in room temperature usually, and suitably is selected from stearic acid, two Glyceryl Behenates, magnesium stearate, calcium stearate, Talcum and titanium dioxide silica alkane (vitreous silica).The existence of lubricant in melt extruded thing preparation improves mixing, mediates and transportation, and reduces cohesion and adhesive force.Improve a collection of reproduction being low to moderate the smooth extruding of moderate temperature, and reduce the tension force on product and equipment.Stearic acid may be preferred lubricant with the form of salt.Another kind of preferred lubricant is two Glyceryl Behenates.
Medicine is present in the preparation of the present invention as active agents usually.For example, reading matter is with reference to WO9614058.Oxycodone is the typical medicaments that is applied to product of the present invention and method.For example, other opioid is a hydromorphone, hydrocodone, fentanyl and analog thereof, buprenorphine, diamorphine, pethidine, dextropropoxyphene and diphenoxylate.Can comprise analeptic according to other active agents of the present invention's preparation, such as dexamfetamine, amfetamine, metamfetamine, sibutamine, methylphenidate; The barbital acids is such as U.S. rope barbital (methobarbitol) and pentobarbital; Antidepressant, all diazepams, bromazepam, chlorine nitrogen _, oxazepam, malprazolam, triazolam and etazolam, flunitrazepam and methaqualone; With the anesthetis that dissociates, such as ketamine; And salt, acid addition salt, and ester.
Therefore, the preferred multiparticulates of the present invention can comprise neutral poly-(ethyl acrylate, methyl methacrylate) copolymer; Active component, other polymer that at least a improvement discharges it typically is alkylcellulose; Plasticizer randomly; And lubricant randomly.
Provide the suitable percentage of preferred ingredient in the following table, it is based on the gross weight of concrete component.
| Typical range | Preferable range | Preferred scope | Most preferred scope | |
| Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble | 5-66 | 15-50 | 20-45 | 25-45 |
| Active agents * | Reach 60 | 5-55 | 5-50 | 10-45 |
| Other improves the polymer that discharges | 0-85 | 5-75 | 5-60 | 5-45 |
| Plasticizer | 0-30 | 0-25 | 3-25 | 3-20 |
| Lubricant | 0-25 | 0-25 | 0-20 | 0-15 |
*Be used for testing or the placebo preparation of R﹠D work, the amount of active agents can be 0%.
For example, typical formulation can also comprise nearly active agents or the placebo of 60%w/w, and the neutrality of 15-50%w/w is gathered (ethyl acrylate, methyl methacrylate) copolymer; 5-60%w/w, 15-50%w/w aptly, the alkylcellulose of 15-25% or 25-45% for example, preferred, ethyl; And 0-25%, one or more plasticizers of preferred 7.5-20%, for example stearyl alcohol and tributyl citrate.For example, nearly 50% oxycodone can be used as the active agents existence.These components can be proprietary composition, and perhaps if desired, described preparation can contain the composition of interpolation, such as the insoluble ammonio methacrylate copolymer of 5-60%.Illustrative ground, described preparation can contain 10-60%, the insoluble ammonio methacrylate copolymer of the hypotonicity of preferred 35-50%, such as Eudragit RS PO, and/or it can contain 5-40%, 5-30% for example, the ammonio methacrylate copolymer of the high osmosis of 5-25% for example preferably is such as Eudragit RL PO.
Can also use other additive and prepare multiparticulates within a series of predetermined specifications.Extender (bulking agents), lactose for example, microcrystalline Cellulose and calcium phosphate are widely used as pharmaceutical excipient, and can be used for the present invention to improve rate of release and/or to discharge fully.It is also conceivable that other release regulator discharges to adjust rate of release and/or to strengthen fully.
The preferably preparation of the melt extruded by granule of described multiparticulates, and wet granulation and the dry described granule by comprising described component in particular, and the method for the melt extruded of described granule.
Described granulation step can be used conventional method and carries out, for example, the blender that uses high shearing force, such as the Gral blender, perhaps fluid bed granulator or have the fluid bed granulator that rotation is inserted.
When using high shearing force blender, described method can comprise the steps:
A) granulation, preferably wet granulation;
B) randomly push described granule;
C) with the granule drying of described granule or extruding, the mode by moving-bed dryer preferably;
D) randomly screen and/or exsiccant granule of the step c) of milling and exsiccant extruding granule; And
E) melt extruded step c) or d) product.
When application had or do not have the fluid bed granulator of rotation insertion, described method can comprise the steps:
A) granulation;
B) randomly push described granule;
C) with the granule drying of described granule or extruding, the mode by moving-bed dryer preferably;
D) randomly screen and/or the product of the step c) of milling; And
E) melt extruded step c) or d) dry granule or the screening or the product of milling.
Step (c) or (d) the product of last sample to the melt extruded machine, it is the described dry granule of randomly milling or screening, this is as novel product of the present invention.
Granulation step can be used conventional method and carries out, and for example, the agitator that uses high shearing force is such as Gral.Typically, at first add dried ingredients; By handling the high shear force agitator these are mixed,, and continue to mix then by spraying or dropwise add the dispersion liquid of polymer.
Alternatively, for example, liquid plasticizer can be added in the dried ingredients, and mix,, and continue to mix then by spraying or dropwise add the dispersion liquid of polymer by handling the high shear force agitator.
Can in optional step (b), push described granule then, for example use the Alexanderwerk extruder.Preferably use moving-bed dryer then with described extrudate drying.Described extrudate can directly produce and be applicable to the exsiccant size of thermopnore, and it uses suitable extruder, all Alexanderwerk as previously mentioned, and wherein small blade shreds described tablet, perhaps can resolve into suitable size.Alternatively, the granule of mix producing by high shear force can be the size that suits or resolve into and be applicable to dry size of then carrying out melt extruded.
Described dry matter typically comprises the water that is less than 5%w/w, the water of 2-3%w/w for example, perhaps still less, such as trace.
Described melt extruded can be to carry out to the similar mode described in the WO 9614058.
For the present invention, a kind of double-screw extrusion machine of our advantageous applications (twin screw extruder).Basically, preferably at low relatively temperature (for example 10-20 ℃), the described dry granule or the product of milling flow into the first of extruder barrel (barrel) by feeder, to guarantee the constant flow of material to the high temperature bucket.Described feeder provides isostatic flow of material to extruder.Because turnover rate irregular and variation may produce the have different physical characteristics multiparticulates of (such as density and porous), so concordance is necessary.
For transportation, the task of mixing and compressing described mixture and mechanical energy is provided, preferred extruder is designed to have Double helix, and it can have the spiral of synchronous rotation or reverse rotation.Described extruder should be equipped the mode of heating and the type of cooling that needs.The spiral of the signal portion of this melt extrusion methods of described implementation is made by different littler elements.By changing the type of described screw element, length and configuration can change described mixing and kneading method significantly.Short hold stay the time and in by the time low-shearing force help safety processing and stable even have a product of thermo-responsive medicine.
The spiral rotary speed may work in the quality of the multiparticulates of producing.There is not the high rotation speed of suitable rate of influx compensation can produce highly porous multiparticulates with variable drug release rate.On the other hand, low spiral rotation will induce unnecessary length to hold the time of staying.The depurator that is connected on the extruder barrel is necessary, with air and the residual moisture of holding back in the removal plastic material, and therefore makes low ideally porous intensive multiparticulates.
Extrusion head typically is designed to produce the multiply band of fixed diameter, for example 1.0mm.The number in hole, shape and diameter can change to be fit to predetermined specification.
Except described helix speed, the parameter that influences that other is main is the spiral moment of torsion, single barrel temperature, and extrusion head pressure and temperature.
According to a kind of cutting method of the present invention, described extruding band is transported from the die head (die-head) on the vehicle.
The diameter of band is subjected to the initial substance rate of influx, helix speed, bucket temperature, die head bore dia and travelling speed and the influence of force feed Kun speed.Transport suitably described extruding band is transported to laser scale or other measuring device.Transport in the processing procedure this, described band little by little cools down, but keeps pliability basically.On the laser scale device, flow between the force feed Kun and entering in the pelletizer process flexible being kept perfectly property of band at pelletizer (pelletiser).Quick refrigerative band depends on preparation, may lose its integrity, and is broken into the inhomogenous and irregular multiparticulates of shape in by force feed Kun and pelletizer process.
The laser scale can be used to provide the successive measurement of ferret diameter, for example 1.0mm.
The band of described measurement flows into pelletizer by force feed Kun.The band that described pelletizer cutting flows into is for example used the swivel knife cutting machine, cuts into predetermined length, for example 1.0mm.The length of the inflow velocity of band and pelletizer cutting machine speed decision multiparticulates.
In a word, feeder, extruder, the coordination/interaction between transveyer and the pelletizer is the quantity of the final multiparticulates product of influence, the important parameter of quality and repeatability.
The multiparticulates of producing by this cutting method typically adopts cylindrical shape, and the extruding band is transported from die head in the wherein said method.Preferably described cylinder has the length of diameter and the about 1mm of about 1mm.
In the preferred cutting method of another kind, when extruding mixture under the pressure and still for molten state when the hole of die occurs, cutting machine cuts described extruding mixture.Described cutting machine is suitably the rotary knife cutter with one or more blades, described insert ring around the surface of die head up to passing the hole.Preferred two direct relative blades.Ideally, not adhesive material bag quilt, for example polytetrafluoroethylene (PTFE) of the outer surface of described die head.Because the extruding multiparticulates of described cutting expands and cooling, they trend towards forming circular surface.By the speed of suitable adjusting extruding rate and cutter, and common cylindrical multiparticulates, for example, may arrange to obtain spheric or spheric basically, the multiparticulates of ellipsoidal or disc-shape.In one embodiment, with the lead surf zone of die head of air-flow, under the temperature that reduces, described extrudate of described air cooling and accelerated solidification.
The spherical multiparticulates of Sheng Chaning provides many advantages by this method:
Better a collection of repeatability.
Easier bag quilt and lower needs bag are by weight.
Better capsule is filled and higher output.
More stable under a high position.
Stronger anti-destructive.
Reduce or eliminate transport with the described band process of granulation in some problems of producing, be fragmented into the tablet of different length and possible electrostatic charge such as band.
Described multiparticulates can be divided into unit dose, is administered to mammal so that each individual unit dosage comprises, preferably the potion medicine of human patients.For preferred medicine, oxycodone or its salt, hydrochloride preferably, the suitable dosage of described active agents is 5-400mg, especially 5mg, 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, 120mg or 160mg dosage.In this respect, unit dose contains the therapeutic activity medicament of effective dose, the patient is produced pain relief and/or analgesia.The dosage that is administered to patient's oxycodone will be owing to many factors vary, and it comprises patient's weight, tolerance, the sensitivity of pain, the character of metabolism status and other healing potion of using.
Thus obtained multiparticulates can be applied as the filler in the capsule.Therefore, the invention provides the capsule that is applicable to dosage every day once or twice.The may command delivery formulations of other dosage form can be provided.
In a preferred embodiment, described multiparticulates is filled in the gelatin capsule, its each contain unit dose.Filling weight in the capsule preferably in the 80-500mg scope, 120-500mg more preferably.In variation of the present invention, the unit dose of multiparticulates can be combined in other solid medicinal and make up a prescription in the preparation, and for example applied compression or typing or make tablet is perhaps by making extruded product the form of suppository.
Preferred capsule of the present invention or other unit dosage form are preferably designed so that and are used for using every about 12 hours or 24 hours.
The preferred agents that is used to be included in the multiparticulates is oxycodone or its salt, preferably its hydrochloride.When at 37 ℃ of 900ml aqueous buffer solutions (pH 1.6-7.2) 100rpm, when testing by USP PaddleMethod (referring to U.S.Pharmacopoeia XXII 1990), be applicable to that so the unit dosage form every administration in 12 hours suitably has following external oxycodone disintegration rate, promptly, discharge the oxycodone of 12.5-42.5 weight % after 1 hour, discharge the oxycodone of 25-56 weight % after 2 hours, discharge the oxycodone of 45-75 weight % after 4 hours, and the oxycodone that discharges 55-85 weight % after 6 hours.
Contain oxycodone or its salt, its hydrochloride preferably, be applicable to unit dosage form every administration in 12 hours, as aqueous buffer solution (simulated gastric fluid that does not have enzyme) 100rpm at 37 ℃ of 900ml pH 1.2, detect by HPLC with 206nm wavelength UV, use USP BasketMethod＜＜711〉when Apparatus 1 tests, can also suitably have following external disintegration rate, that is, at 1 hour 0-40%, preferably 25-35%; At 2 hours 20-70%, preferably 40-60%; At 3 hours 40-80%, preferably 55-75%; At 4 hours 60-95%, preferably 65-90%; And at 5 hours greater than 70%.
And the maximum plasma level of the oxycodone that obtains in our preferred body is taking place between 2-4.5 hour after the administration of unit doses form.
More information about the feature of necessity of described oxycodone preparation provides in WO 9310765, and it is incorporated into this fully by concrete reference.
As alternative, oxycodone capsule of the present invention or other unit dosage form are designed to use every about 24 hours.For this purpose, 100rpm in the aqueous buffer solution between 37 ℃ of 900ml pH 1.6-7.2, when testing by USP Basket Method, described unit dosage form suitably has following external oxycodone disintegration rate, promptly, at 1 hour 0%-about 40%, about 70% at 4 hours about 8%-, about 80% at 8 hours about 20%-, at 12 hours about 30%-about 95%, about 95% at 18 hours about 35%-, and at 24 hours greater than about 50%.
And the maximum plasma level of the oxycodone that obtains in our preferred body reached using the back with the steady state dosage form in about 2 hours-about 17 hours.
Contain oxycodone or its salt, its hydrochloride preferably, be applicable to unit dosage form every administration in 24 hours, as aqueous buffer solution (simulated gastric fluid that does not have enzyme) 100rpm at 37 ℃ of 900ml pH 1.2, detect by HPLC with 206nm wavelength UV, use USP BasketMethod＜＜711〉when Apparatus 1 tests, can also suitably have following external disintegration rate, that is, at 1 hour 10-30%, preferably 17-23%; At 2 hours 20-35%, preferably 24-32%; At 8 hours 35-75%, preferably 48-66%; And 16 hours greater than 50%, 68-92% preferably.
More information about the feature of necessity of described oxycodone preparation provides in WO 02087512, and it is incorporated into this fully by concrete reference.
In variation, the invention provides and contain the unit dose that effectively prevents to destroy opioid and opioid antagonists.In this respect, with reference to WO 0313433, it is incorporated into this fully by concrete reference.Especially, described unit dose can contain oxycodone and naltrexone.
For this purpose, the invention provides opioid, such as the melt extruded multiparticulates of oxycodone, and opioid antagonists, such as the melt extruded multiparticulates of naltrexone.In preferred formulation, when routine was used, the antagonist multiparticulates did not discharge described antagonist, and, for example, have the bag quilt that does not discharge.Preferably visually (physically) is identical to two kinds of opioids with physically with opioid antagonists.
Importance of the present invention is to have the capsule of filling less than the 500mg unit dose, and it comprises the oxycodone multiparticulates that reaches about 350mg, and the anti-destruction oxycodone antagonist multiparticulates that reaches about 200mg.For example, can there be the oxycodone multiparticulates of 120-300mg, and the oxycodone antagonist multiparticulates of 125-175mg.
Summary of drawings
At following experimental section with reference to the accompanying drawings, wherein:
Fig. 1 shows the disintegrate of the tablet that oxycodone prepares from embodiment 5.
Fig. 2 shows the disintegrate of the tablet that oxycodone prepares from embodiment 10-13.
Fig. 3 shows the disintegrate of the pulverizing tablet that oxycodone prepares from embodiment 11-13.
Fig. 4 shows the disintegrate of the tablet that oxycodone prepares from embodiment 11-13 in the back of milling with pestle and mortar.
Fig. 5 is presented at the disintegrate of the tablet that oxycodone prepares in the solvent from embodiment 10-13.
Inventive embodiments
Prepare 3 batches of (embodiment) multiparticulates according to similar methods:
Step 1. beginning is put into Gral 10 high shear mixer with following substances, is preheating to 40 ℃, and with high speed dry mixed 2 minutes:
Oxycodone hydrochloride
Eudragit RS PO
Stearyl alcohol
Stearic acid
Step 7. flows into Leistritz Micro 18 extruders of having equipped vehicle and pelletizer with granule then with controllable speed.Described extruder has 1.5mm die and following warm table: platform 3-8,90 ℃-100 ℃; Platform 9 and 10,100 ℃.Rate of influx is 2.0-2.6kg/hr, and helix speed 100-141rpm, has the moment of torsion/melting pressure of 50-60%/40-50 crust.
Described extruding band is transported from the die head of vehicle, and be cut into cylindrical multiparticulates.
| Material | Embodiment (%w/w) | ||
| Embodiment 1 | | | |
| Lactis Anhydrous | 10.0 | 10.0 | |
| Oxycodone hydrochloride | 10.0 | ||
| Eudragit RS PO | 40.0 | 32.0 | 32.0 |
| Stearyl alcohol | 10.0 | 10.0 | 10.0 |
| Stearic acid | 6.0 | 6.0 | 6.0 |
| Eudragit NE * | 34.0 | 42.0 | 42.0 |
| | 100 | 100 | 100 |
*Be Eudragit NE 40D (removing water) by drying
For this embodiment, use alternative cutting method.Extrudate occurs in 12 holes of the die head of Leistritz Micro 18 extruders.When extrudate pressure and still under the molten state when the hole of die head occurs, use rotary knife cutter and cut described extrudate with twolip.Because they expand and cooling, described cutting extruding microgranule trends towards forming circular surface.
Use following preparation production and contain the placebo product of lactose as medicinal inactive component.
| Material | Embodiment 4 (%w/w) |
| Lactis Anhydrous | 10.0 |
| Eudragit RS PO | 37.0 |
| Stearyl alcohol | 10.0 |
| Stearic acid | 6.0 |
| Eudragit NE 40D | 37.0 * |
| | 100 |
*Be expressed as the value of solids content
By suitable adjusting extruding diameter, it comprises temperature and extruding rate, can obtain spheric or spheric basically multiparticulates.
Use citric acid three butyrates and plan two batches of multiparticulates as plasticizer (approximately 43%w/w drug load).Degree, w/w, as follows:
| Material | Embodiment (%w/w) | |
| 5 | 6 | |
| Oxycodone hydrochloride | 42.2 | 42.2 |
| Ethyl cellulose N10 | 14.7 | 19.6 |
| Eudragit NE 40D * | 35.3(S)， [88.3(D)] | 29.4(S)， [73.5(D)] |
| Tributyl citrate | 5.9 | 6.9 |
| Two Glyceryl Behenates | 2.0 | 1.9 |
| | 100 | 100 |
The S=solid weight
D=dispersion liquid weight
*40% dispersion liquid (%w/w) passes through evaporation water loss
The method of multiparticulates of embodiment 5 that is used to prepare tablet form is as follows:
Step 1. is slowly added to tributyl citrate in the ethyl cellulose in Gral 10 high shear mixer and is mixed.
After all Eudragit NE 40D of step 6. were added into, wet granule was pushed by conventional extruder, and in about 42 ℃ of dryings in moving-bed dryer.
Step 7. is with exsiccant granule cool to room temperature, and collection.
The method of preparation that is used to prepare embodiment 6 is identical with embodiment 5, except aspect following:
In step 1, do not add plasticizer.On the contrary, got rid of step 1, and step 2 is made up of mixing oxycodone hydrochloride and ethyl cellulose in Gral 10 high shear mixer.
Described granule is screened (1.5mm mesh), and too big granule is milled (1.0mm mesh), and reconfigure with other granule.
Before step 7 latter stage flowing into extruder, immediately lubricant (two Glyceryl Behenates) is added in the exsiccant granule.
Described extruder has the die that has the 1.5mm hole.
Can consider a kind of alternative cutting method.Extrudate occurs from the hole of the die head of Leistritz extruder.When mixture for extrusion under the pressure and still melt when the hole of die occurs, use rotary knife cutter and cut described mixture for extrusion with twolip.Described blade around the surface of die head to passing the hole.Because they expand and cooling, the extruding microgranule of cutting trends towards forming circular surface.
Although use Leistritz Micro 18 extruders in the above-described embodiments, bigger extruder, for example Leistritz Micro 27, can preferred process need the material of higher processing moment of torsion.
Use USP Basket Method＜＜711〉〉 Apparatus 1,100rpm in the aqueous buffer solution (simulated gastric fluid that does not have enzyme) of 37 ℃ of 900ml pH 1.2, detect by HPLC with 206nm wavelength UV, the extruding tablet that obtains among the embodiment 5 is carried out disintegrate to be detected, and provide following result, it is drawn in accompanying drawing 1, with for the preferred curve of product once a day.
| Time (hour) | The oxycodone that |
| 0 | 0 |
| 1 | 30 |
| 2 | 41 |
| 3 | 48 |
| 4 | 53 |
| 5 | 58 |
| 6 | 62 |
| 7 | 66 |
| 8 | 69 |
| 9 | 71 |
| 10 | 74 |
| 11 | 76 |
| 12 | 78 |
| 13 | 78 |
| 14 | 81 |
| 15 | 82 |
| 16 | 82 |
| 17 | 84 |
| 18 | 85 |
| 19 | 85 |
| 20 | 86 |
| 21 | 87 |
| 22 | 88 |
| 23 | 88 |
| 24 | 88 |
Except temperature range 100-120 ℃, reach the helix speed of 240rpm, and outside the die size of 1.5mm (embodiment 7 and 8) and 1.0mm (embodiment 9) diameter, use method and the extruding condition identical with previous embodiment, process following preparation to produce multiparticulates.
| Material | Embodiment (%w/w) | ||
| Embodiment 7 | | Embodiment 9 | |
| Oxycodone hydrochloride | 43 | 43 | 43 |
| Ethyl cellulose N10 | 19 | 19 | 18 |
| Eudragit NE 40D * | 29 | 29 | 27 |
| | 6 | 6 | 6 |
| | 3 | ||
| | 3 | 6 | |
| | 100 | 100 | 100 |
*The value of expression only is a solids content.Liquid dispersion liquid weight is (value/40) * 100
Embodiment 10-13
Use and the previous embodiment similar methods, use following preparation to produce multiparticulates.
| Material | Embodiment (%w/w) | |||
| | Embodiment 11 | | Embodiment 13 | |
| Oxycodone hydrochloride | 10.0 | 10.0 | 10.0 | 10.0 |
| Ethyl cellulose N10 | 41.8 | 0 | 32.0 | 0 |
| | 0 | 41.8 | 0 | 22.0 |
| | 0 | 0 | 10.0 | 20.0 |
| Stearyl alcohol | 14.0 | 14.0 | 14.0 | 14.0 |
| Eudragit NE 40D * | 34.2(S)， [85.5(D)] | 34.2(S)， [85.5(D)] | 34.0(S)， [85.0(D)] | 34.0(S)， [85.0(D)] |
| | 100 | 100 | 100 | 100 |
The S=solid weight
D=dispersion liquid weight
*40% dispersion liquid (%w/w) passes through evaporation water loss
Be applied in the USP Basket Method that describes in the foregoing description 5, make the multiparticulates of the foregoing description 10-13 stand the disintegrate detection.The result shows in Fig. 2.These results prove, in this detection, the release profiles of the release profiles of embodiment 12 and 13 multiparticulates and a kind of preparation (we still unratified application publication number WO 2005/000310 embodiment 5) is similar, when detecting in vivo, described preparation biology basically is equal to OxyContin.
The multiparticulates of embodiment 10-13 has lower release profiles, this may the surface they will be applicable to dosage form 24 hours interval administration.
Detect the multiparticulates of embodiment 10-13, with the potential of definite its anti-destructive, as follows:
1) multiparticulates with 400mg embodiment 10-13 is pulverizing between two spoons or in pill crusher (the Pill Pulverizer that sells such as Apex Healthcare Products), is being heated to extraction and filtration in the ebullient water at 2ml on the spoon then.Determine the amount of the oxycodone of extraction then by HPLC, and detect, and in the chart of Fig. 3, show by the UV of 210nm wavelength.
2) in mortar and pestle, make the multiparticulates of 400mg embodiment 10-13 stand to mill, pestle rotates 24 times, and product is put into 900ml water, places 45 minutes at 37 ℃.Then by 1) described in method determine the amount of dissolved oxycodone, and described result shows at the block diagram shape of Fig. 4.
3) in each extraction a)-e), handle the multiparticulates of one of 400mg embodiment 10-13 as follows respectively: multiparticulates is put into the solvent that glass flask needs, then described flask is heated in water-bath (Jia Re words if desired).Make described flask stand need to continue shaking of time then, it uses Stuart Scientific Flask ShakerModel SF1 equipment, 500-600 swing of per minute.After the extraction, then by 1) in used method determine the amount of dissolved oxycodone.
A) at room temperature, in 10ml water, shook 15 minutes;
B) at 50 ℃, heating is 5 minutes in 10ml water, then carries out shaking in 15 minutes;
C) at 75 ℃, heating is 5 minutes in 10ml water, then carries out shaking in 15 minutes;
D) at 100 ℃, heating is 5 minutes in 10ml water, then carries out shaking in 15 minutes;
E) at room temperature, in 40% ethanol, shook 15 minutes.
Described testing result shows in the block diagram of accompanying drawing 5.
Claims (130)
1. the pharmaceutical formulation that discharges of a may command, it comprises the substrate of the rubber like that contains neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and active component.
2. according to the preparation of claim 1, wherein said active component is an opioid, analeptic, barbiturate/ester, antidepressant or dissociated anesthetis.
3. according to the preparation of claim 2, wherein said active agents is an oxycodone.
4. according to each preparation of aforementioned claim, when at water, when extracting in the alcoholic acid liquid of ethanol or aqueous, it destroys by release opposing that reduces active agents.
5. according to each preparation of aforementioned claim, it comprises multiparticulates.
6. according to each preparation of aforementioned claim, when detecting with a kind of detection method, described detection method comprises: in glass flask, multiparticulates and 10ml liquid mixing with the dosage amount, and use Stuart Scientific Shaker Model SF1, shook 15 minutes with 500-600 swing of per minute, described preparation shows at least a in the following characteristics (a)-(e):
(a) at room temperature in water, shook 15 minutes: be less than 7.5% active agents release;
(b) placed 5 minutes in water at 50 ℃, then shook 15 minutes: be less than 15% active agents release in identical temperature;
(c) placed 5 minutes in water at 75 ℃, then shook 15 minutes: be less than 20% active agents release in identical temperature;
(d) placed 5 minutes in water at 100 ℃, then shook 15 minutes: be less than 25% active agents release in identical temperature;
(e) in 40% ethanol, shook 15 minutes in room temperature: preferably be less than 25% active agents release.
7. according to each preparation of aforementioned claim, when milling described preparation and extract, wherein said anti-destructive reduces the release of active agents.
8. according to the preparation of claim 7, when detecting with a kind of detection method, its release is less than 10% active agents, described detection method comprises: in mortar and pestle, make the preparation of dosage amount stand to mill, pestle rotation 24 times, and put into 900ml water, continue 45 minutes at 37 ℃.
9. according to the preparation of claim 7, when detecting with a kind of detection method, its release is less than 15% active agents, described detection method comprises: dosage amounts is pulverized in the pill pulverizer that Apex Healthcare Products sells, be heated to extraction and filtration in the ebullient 2ml water on the spoon then.
10. according to each preparation of aforementioned claim, wherein said substrate comprises that at least a other improves the polymer that discharges.
11. according to the preparation of claim 10, wherein said other polymer is alkylcellulose or water-insoluble ammonio methacrylate copolymer.
12. according to the preparation of claim 11, wherein said other polymer is an ethyl cellulose.
13. according to the preparation of claim 12, the amount of wherein said ethyl cellulose is the 10-50 weight % of preparation.
14. according to each preparation of claim 10-13, based on the gross weight of concrete component, it contains the component of following amount:
Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble 15-50
Active agents 5-55
Other improves the polymer that discharges 5-75
Plasticizer 0-25
Lubricant 0-25.
15. according to the preparation of claim 14, based on the gross weight of concrete component, it contains the component of following amount:
Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble 20-45
Active agents 5-50
Other improves the polymer that discharges 5-60
Plasticizer 3-25
Lubricant 0-20.
16. according to the preparation of claim 14, based on the gross weight of concrete component, it contains the component of following amount:
Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble 25-45
Active agents 10-45
Other improves the polymer that discharges 5-45
Plasticizer 3-20
Lubricant 0-15.
17. according to each preparation of aforementioned claim, it comprises the nearly active agents of 60%w/w, the neutrality of 15-50%w/w is gathered (ethyl acrylate, methyl methacrylate) copolymer; The ethyl cellulose of 5-60%w/w; And the plasticizer of 7.5-20%.
18. according to the preparation of claim 17, it also contains the insoluble ammonio methacrylate copolymer of 5-60%.
19. according to the preparation of claim 18, it contains the insoluble ammonio methacrylate copolymer of the hypotonicity of 35-50%, and/or the ammonio methacrylate copolymer of the high osmosis of 5-30%.
20. according to each preparation of aforementioned claim, it contains extender.
21. according to each preparation of aforementioned claim, it contains opioid and opioid antagonists.
22. according to the preparation of claim 21, it comprises the oxycodone multiparticulates of 120-300mg and the oxycodone antagonist multiparticulates of 125-175mg.
23. according to the preparation of claim 21 or 22, it contains oxycodone and naltrexone.
24. according to the preparation of claim 21,22 or 23, it comprises the melt extruded multiparticulates of opioid melt extruded multiparticulates and opioid antagonists.
25. according to each the unit dose of pharmaceutical formulation of aforementioned claim, it is fit to be administered to the people.
26. according to the unit dose of claim 25, it contains 5mg, 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, the oxycodone of 120mg or 160mg.
27. according to the unit dose of claim 25 or 26, be administered once its suitable every day.
28. unit dosage form according to claim 27, when testing in the aqueous buffer solution of 100rpm between 37 ℃ of 900ml pH 1.6-7.2 by USP Basket Method, described unit dosage form has following external oxycodone disintegration rate, that is, about 40% at 1 hour 0%-, at 4 hours about 8%-about 70%, at 8 hours about 20%-about 80%, about 95% at 12 hours about 30%-, about 95% at 18 hours about 35%-, and at 24 hours greater than about 50%.
29. according to the unit dose of claim 28, the wherein maximum plasma level of the oxycodone that obtains in body generation in 2-17 hour after using described unit dosage form.
30. unit dosage form according to claim 27, when with USP Basket Method＜＜711〉〉 Apparatus 1 with the aqueous buffer solution (simulated gastric fluid that do not have enzyme) of 100rpm at 37 ℃ of 900ml pH 1.2 in during test, detect by HPLC with 206nm wavelength UV, described unit dosage form has following external oxycodone disintegration rate, that is, at 1 hour 10-30%; At 2 hours 20-35%; At 8 hours 35-75%; And at 16 hours greater than 50%.
31. according to the unit dose of claim 25 or 26, it is suitable for being administered twice every day.
32. unit dosage form according to claim 31, when testing in 37 ℃ of 900ml aqueous buffer solutions (pH1.6-7.2) with 100rpm with USP Paddle Method (referring to U.S.Pharmacopoeia XXII 1990), described unit dosage form has following external oxycodone disintegration rate, promptly, discharge the oxycodone of 12.5-42.5 weight % after 1 hour, discharge the oxycodone of 25-56 weight % after 2 hours, discharge the oxycodone of 45-75 weight % after 4 hours, and the oxycodone that discharges 55-85 weight % after 6 hours.
33. unit dosage form according to claim 31, when with USP Basket Method＜＜711〉〉 Apparatus 1 with the aqueous buffer solution (simulated gastric fluid that do not have enzyme) of 100rpm at 37 ℃ of 900ml pH 1.2 in during test, detect by HPLC with 206nm wavelength UV, described unit dosage form has following external oxycodone disintegration rate, that is, at 1 hour 0-40%; At 2 hours 20-70%; At 3 hours 40-80%; At 4 hours 60-95%; And at 5 hours greater than 70%.
34. according to the unit dose of claim 33, wherein the maximum plasma level of the oxycodone that obtains in the body is taking place between 2-4.5 hour after the administration of unit doses form.
35. the pharmaceutical formulation that may command discharges, it can obtain by melt extruded, and comprises neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and active component.
36. according to the preparation of claim 35, it shows the feature of rubber like.
37. according to the preparation of claim 35 and 36, during by water or alcohol or aqueous ethanol extraction, it has enhanced anti-destructive.
38. according to the preparation of claim 35,36 or 37, wherein said active agents is an opioid, analeptic, barbiturate/ester, antidepressant or dissociated anesthetis.
39. according to the preparation of claim 38, wherein said active agents is an oxycodone.
40. according to each preparation of claim 35-39, it comprises multiparticulates.
41. according to each preparation of claim 35-40, wherein said substrate comprises other polymer that at least a improvement discharges.
42. according to the preparation of claim 41, wherein said other polymer is alkylcellulose or water-insoluble ammonio methacrylate copolymer.
43. according to the preparation of claim 42, wherein said other polymer is an ethyl cellulose.
44. according to the preparation of claim 43, the amount of wherein said ethyl cellulose is the 10-50 weight % of described preparation.
45. according to each preparation of claim 41-44, based on the gross weight of concrete component, it contains the component of following amount:
Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble 15-50
Active agents 5-55
Other improves the polymer that discharges 5-75
Plasticizer 0-25
Lubricant 0-25.
46. according to the preparation of claim 45, based on the gross weight of concrete component, it contains the component of following amount:
Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble 20-45
Active agents 5-50
Other improves the polymer that discharges 5-60
Plasticizer 3-25
Lubricant 0-20.
47. according to the preparation of claim 46, based on the gross weight of concrete component, it contains the component of following amount:
Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble 25-45
Active agents 10-45
Other improves the polymer that discharges 5-45
Plasticizer 3-20
Lubricant 0-15.
48. according to each preparation of claim 35-47, it comprises the nearly active agents of 60%w/w, the neutrality of 15-50%w/w is gathered (ethyl acrylate, methyl methacrylate) copolymer; The ethyl cellulose of 5-60%w/w; And the plasticizer of 7.5-20%.
49. according to the preparation of claim 48, it also contains the insoluble ammonio methacrylate copolymer of 5-60%.
50. according to the preparation of claim 49, it contains the insoluble ammonio methacrylate copolymer of the hypotonicity of 35-50%, and/or the ammonio methacrylate copolymer of 5-30% high osmosis.
51. according to each preparation of claim 35-50, it contains extender.
52. according to each preparation of claim 35-50, it contains opioid and opioid antagonists.
53. according to the preparation of claim 52, it comprises the oxycodone multiparticulates of 120-300mg and the oxycodone antagonist multiparticulates of 125-175mg.
54. according to the preparation of claim 52 or 53, it contains oxycodone and naltrexone.
55. according to the preparation of claim 52,53 or 54, it comprises the melt extruded multiparticulates of opioid melt extruded multiparticulates and opioid antagonists.
56. according to each the unit dose of pharmaceutical formulation of claim 35-55, it is fit to be administered to the people.
57. according to the unit dose of claim 56, it contains 5mg, 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, the oxycodone of 120mg or 160mg.
58. according to the unit dose of claim 56 or 57, be administered once its suitable every day.
59. unit dosage form according to claim 58, when testing in the aqueous buffer solution of 100rpm between 37 ℃ of 900ml pH 1.6-7.2 with USP Basket Method, described unit dosage form has following external oxycodone disintegration rate, that is, about 40% at 1 hour 0%-, at 4 hours about 8%-about 70%, at 8 hours about 20%-about 80%, about 95% at 12 hours about 30%-, about 95% at 18 hours about 35%-, and at 24 hours greater than about 50%.
60. according to the unit dose of claim 58, the wherein maximum plasma level of the oxycodone that obtains in body generation in 2-17 hour after the administration of unit doses form.
61. unit dosage form according to claim 58, when with USP Basket Method＜＜711〉〉 Apparatus 1 with the aqueous buffer solution (simulated gastric fluid that do not have enzyme) of 100rpm at 37 ℃ of 900ml pH 1.2 in during test, detect by HPLC with 206nm wavelength UV, described unit dosage form has following external oxycodone disintegration rate, that is, at 1 hour 10-30%; At 2 hours 20-35%; At 8 hours 35-75%; And at 16 hours greater than 50%.
62. according to the unit dose of claim 56 or 57, it is suitable for being administered twice every day.
63. unit dosage form according to claim 62, when testing in 37 ℃ of 900ml aqueous buffer solutions (pH1.6-7.2) with 100rpm with USP Paddle Method (referring to U.S.Pharmacopoeia XXII 1990), described unit dosage form has following external oxycodone disintegration rate, promptly, discharge the oxycodone of 12.5-42.5 weight % after 1 hour, discharge the oxycodone of 25-56 weight % after 2 hours, discharge the oxycodone of 45-75 weight % after 4 hours, and the oxycodone that discharges 55-85 weight % after 6 hours.
64. unit dosage form according to claim 62, when with USP Basket Method＜＜711〉〉 Apparatus 1 with the aqueous buffer solution (simulated gastric fluid that do not have enzyme) of 100rpm at 37 ℃ of 900ml pH 1.2 in during test, detect by HPLC with 206nm wavelength UV, described unit dosage form has following external oxycodone disintegration rate, that is, at 1 hour 0-40%; At 2 hours 20-70%; At 3 hours 40-80%; At 4 hours 60-95%; And at 5 hours greater than 70%.
65. according to the unit dose of claim 64, wherein the maximum plasma level of the oxycodone that obtains in the body is taking place between 2-4.5 hour after the administration of unit doses form.
66. the pharmaceutical formulation that may command discharges, it obtains by melt extruded, and comprises neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and active component.
67. a dry granule, it comprises neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and opioid analgesic.
68. a dry granule, it comprises poly-(ethyl acrylate, methyl methacrylate) copolymer and medicinal activity compound of neutrality of 20 weight %-66 weight %.
69. according to the dry granule of claim 68, wherein said medicinal activity compound is an opioid.
70. according to the dry granule of claim 69, wherein said opioid is oxycodone or its salt.
71. a dry granule, it comprises in conjunction with poly-(ethyl acrylate, the methyl methacrylate) copolymer matrix of the neutrality of opioid analgesic.
72. according to the dry granule of claim 71, it is the extruding granule.
73. according to the dry granule of claim 71 or 72, it comprises nearly poly-(ethyl acrylate, methyl methacrylate) copolymer of neutrality of 66%.
74. according to the dry granule of claim 71,72 or 73, it comprises poly-(ethyl acrylate, methyl methacrylate) copolymer of neutrality of 20-50%.
75. according to the dry granule of claim 74, it comprise 30-40% poly-(ethyl acrylate, the methyl methacrylate) copolymer of neutrality.
76. multiparticulates, every kind comprises neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and opioid analgesic.
77. according to the multiparticulates of claim 76, it forms by melt extruded.
78. according to the multiparticulates of claim 78, it adopts cylindrical shape, perhaps is generally spherical, ellipsoid or disc shaped.
79. multiparticulates, every kind of poly-(ethyl acrylate, methyl methacrylate) copolymer of neutrality that comprises 20 weight %-66 weight %, and medicinal activity compound.
80. according to the multiparticulates of claim 79, wherein said medicinal activity compound is the opioid analgesic.
81. according to the multiparticulates of claim 80, wherein said opioid is oxycodone or its salt.
82. according to the multiparticulates of claim 80 and 81, it comprises that by melt extruded the drying composite of neutral poly-(ethyl acrylate, methyl methacrylate) copolymer makes.
83. according to the multiparticulates of claim 82, it adopts cylindrical shape, perhaps is generally spherical, ellipsoid or disc shaped.
84. the pharmaceutical formulation that may command discharges, it comprises the substrate that contains neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and opioid analgesic.
85. the pharmaceutical formulation that may command discharges, it comprises poly-(ethyl acrylate, methyl methacrylate) copolymer and the medicinal activity compound of the neutrality that contains 20 weight %-66 weight %.
86. according to the preparation of claim 85, it shows the feature of rubber like.
87. according to the preparation of claim 85 and 86, during by water or alcohol or aqueous ethanol extraction, it has enhanced anti-destructive.
88. according to each preparation of claim 84-87, wherein said opioid analgesic is an oxycodone.
89. according to each preparation of claim 84-88, it comprises multiparticulates.
90. according to each preparation of claim 84-89, wherein said substrate comprises other polymer that at least a improvement discharges.
91. according to the preparation of claim 90, wherein said other polymer is alkylcellulose or water-insoluble ammonio methacrylate copolymer.
92. according to the preparation of claim 91, wherein said other polymer is an ethyl cellulose.
93. according to the preparation of claim 92, the amount of wherein said ethyl cellulose is the 10-50 weight % of described preparation.
94. according to the preparation of claim 93, based on the gross weight of concrete component, it contains the component of following amount:
Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble 15-50
Active agents 5-55
Other improves the polymer that discharges 5-75
Plasticizer 0-25
Lubricant 0-25.
95. according to the preparation of claim 94, based on the gross weight of concrete component, it contains the component of following amount:
Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble 20-45
Active agents 5-50
Other improves the polymer that discharges 5-60
Plasticizer 3-25
Lubricant 0-20.
96. according to the preparation of claim 93, based on the gross weight of concrete component, it contains the component of following amount:
Neutral poly-(ethyl acrylate, the methyl methacrylate) copolymer of water-insoluble 25-45
Active agents 10-45
Other improves the polymer that discharges 5-45
Plasticizer 3-20
Lubricant 0-15.
97. according to each preparation of claim 85-96, it comprises the nearly active agents of 60%w/w, the neutrality of 15-50%w/w is gathered (ethyl acrylate, methyl methacrylate) copolymer; The 5-60%w/w ethyl cellulose; And the plasticizer of 7.5-20%.
98. according to the preparation of claim 97, it also contains the insoluble ammonio methacrylate copolymer of 5-60%.
99. according to the preparation of claim 98, it contains the insoluble ammonio methacrylate copolymer of the hypotonicity of 35-50%, and/or the ammonio methacrylate copolymer of 5-30% high osmosis.
100. according to each preparation of claim 85-99, it contains extender.
101. according to each preparation of claim 85-100, it contains opioid and opioid antagonists.
102. according to the preparation of claim 101, it comprises the oxycodone multiparticulates of 120-300mg and the oxycodone antagonist multiparticulates of 125-175mg.
103. according to the preparation of claim 101 or 102, it contains oxycodone and naltrexone.
104. according to the preparation of claim 101,102 or 103, it comprises the melt extruded multiparticulates of opioid melt extruded multiparticulates and opioid antagonists.
105. according to each the unit dose of pharmaceutical formulation of claim 87-104, it is fit to be administered to the people.
106. according to the unit dose of claim 105, it contains 5mg, 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, the oxycodone of 120mg or 160mg.
107. according to the unit dose of claim 105 or 106, be administered once its suitable every day.
108. unit dosage form according to claim 107, when testing in the aqueous buffer solution of 100rpm between 37 ℃ of 900ml pH 1.6-7.2 with USP Basket Method, described unit dosage form has following external oxycodone disintegration rate, that is, about 40% at 1 hour 0%-, at 4 hours about 8%-about 70%, at 8 hours about 20%-about 80%, about 95% at 12 hours about 30%-, about 95% at 18 hours about 35%-, and at 24 hours greater than about 50%.
109. according to the unit dose of claim 107, the wherein maximum plasma level of the oxycodone that obtains in body generation in 2-17 hour after the administration of unit doses form.
110. unit dosage form according to claim 107, when with USP Basket Method＜＜711〉〉 Apparatus 1 with the aqueous buffer solution (simulated gastric fluid that do not have enzyme) of 100rpm at 37 ℃ of 900ml pH 1.2 in during test, detect by HPLC with 206nm wavelength UV, described unit dosage form has following external oxycodone disintegration rate, that is, at 1 hour 10-30%; At 2 hours 20-35%; At 8 hours 35-75%; And at 16 hours greater than 50%.
111. according to the unit dose of claim 105 or 106, it is suitable for being administered twice every day.
112. unit dosage form according to claim 111, when testing in 37 ℃ of 900ml aqueous buffer solutions (pH1.6-7.2) with 100rpm by USP Paddle Method (referring to U.S.Pharmacopoeia XXII 1990), described unit dosage form has following external oxycodone disintegration rate, promptly, discharge the oxycodone of 12.5-42.5 weight % after 1 hour, discharge the oxycodone of 25-56 weight % after 2 hours, discharge the oxycodone of 45-75 weight % after 4 hours, and the oxycodone that discharges 55-85 weight % after 6 hours.
113. unit dosage form according to claim 111, when with USP Basket Method＜＜711〉〉 Apparatus 1 with the aqueous buffer solution (simulated gastric fluid that do not have enzyme) of 100rpm at 37 ℃ of 900ml pH 1.2 in during test, detect by HPLC with 206nm wavelength UV, described unit dosage form has following external oxycodone disintegration rate, that is, at 1 hour 0-40%; At 2 hours 20-70%; At 3 hours 40-80%; At 4 hours 60-95%; And at 5 hours greater than 70%.
114. according to the unit dose of claim 113, wherein the maximum plasma level of the oxycodone that obtains in the body is taking place between 2-4.5 hour after the administration of unit doses form.
115. a method that is used to prepare the preparation that may command discharges, it comprises that melt extruded contains the mixture of neutral poly-(ethyl acrylate, methyl methacrylate) copolymer and active agents.
116. method according to claim 115, wherein said neutrality is gathered (ethyl acrylate, methyl methacrylate) copolymer provides with the form of the aqueous liquid dispersion that comprises 40% described polymer, and it mixes with described active agents, and dry so that described mixture is used for melt extruded.
117. according to the method for claim 115 or 116, wherein said mixture comprises plasticizer.
118. according to the method for claim 117, wherein said plasticizer is a tributyl citrate, stearyl alcohol or high-molecular weight Polyethylene Glycol.
119. according to each method of claim 115-118, wherein said mixture comprises lubricant.
120. according to the method for claim 119, wherein said lubricant is a stearic acid, stearate, perhaps two Glyceryl Behenates.
121. according to each method of claim 115-120, it comprises the wet granulation that is used for being extruded with the component of the mixture that obtains wet granule, dry described granule, and the described exsiccant granule of melt extruded.
122. according to the method for claim 121, wherein said wet granule is extruding before dry.
123. according to the method for claim 122, wherein said exsiccant granule contains the water that is less than 3%w/w.
124. according to each method of claim 115-123, the melt extruded of wherein said dry granule is carried out in double-screw extrusion machine.
125. according to each method of claim 115-127, wherein said extruding band is transported to pelletizer, and cuts into multiparticulates.
126. according to each method of claim 115-125, wherein every kind of multiparticulates has the diameter of about 1mm and the about length of 1mm.
127. according to each method of claim 115-124, wherein when described extruding mixture self compaction machine occurred, described cutting machine cut described extruding mixture.
128. the application of neutral poly-(ethyl acrylate, methyl methacrylate) copolymer in the preparation pharmaceutical formulation, it provides anti-destructive.
129. method of giving the pharmaceutical formulation anti-destructive, it comprises mixed active component and neutral poly-(ethyl acrylate, methyl methacrylate) copolymer, and be formed in the substrate with neutral poly-(ethyl acrylate, methyl methacrylate) copolymer pharmaceutical formulation in conjunction with described active component.
130. the method for an administration of active ingredients, wherein said active component is used as the preparation that discharges according to each may command of claim 1-104.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0403100A GB0403100D0 (en) | 2004-02-12 | 2004-02-12 | Particulates |
| GB0403100.1 | 2004-02-12 | ||
| GBGB0501638.1A GB0501638D0 (en) | 2005-01-28 | 2005-01-28 | Particulates |
| GB0501638.1 | 2005-01-28 | ||
| PCT/GB2005/050014 WO2005079760A1 (en) | 2004-02-12 | 2005-02-11 | Particulates |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1942174A true CN1942174A (en) | 2007-04-04 |
| CN1942174B CN1942174B (en) | 2012-04-04 |
Family
ID=32011774
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800110496A Expired - Fee Related CN1942174B (en) | 2004-02-12 | 2005-02-11 | Particulates |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1942174B (en) |
| AR (1) | AR111679A2 (en) |
| GB (1) | GB0403100D0 (en) |
| ZA (1) | ZA200606647B (en) |
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| CN103282026A (en) * | 2010-12-09 | 2013-09-04 | 欧洲凯尔特公司 | Dosage form |
| CN103889456A (en) * | 2011-10-18 | 2014-06-25 | 普渡制药公司 | Acrylic polymer formulations |
| CN104394851A (en) * | 2012-04-18 | 2015-03-04 | 格吕伦塔尔有限公司 | Tamper resistant and dose-dumping resistant pharmaceutical dosage form |
| US9629807B2 (en) | 2003-08-06 | 2017-04-25 | Grünenthal GmbH | Abuse-proofed dosage form |
| US9636303B2 (en) | 2010-09-02 | 2017-05-02 | Gruenenthal Gmbh | Tamper resistant dosage form comprising an anionic polymer |
| US9655853B2 (en) | 2012-02-28 | 2017-05-23 | Grünenthal GmbH | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
| US9675610B2 (en) | 2002-06-17 | 2017-06-13 | Grünenthal GmbH | Abuse-proofed dosage form |
| US9737490B2 (en) | 2013-05-29 | 2017-08-22 | Grünenthal GmbH | Tamper resistant dosage form with bimodal release profile |
| US9750701B2 (en) | 2008-01-25 | 2017-09-05 | Grünenthal GmbH | Pharmaceutical dosage form |
| US9855263B2 (en) | 2015-04-24 | 2018-01-02 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
| US9872835B2 (en) | 2014-05-26 | 2018-01-23 | Grünenthal GmbH | Multiparticles safeguarded against ethanolic dose-dumping |
| US9913814B2 (en) | 2014-05-12 | 2018-03-13 | Grünenthal GmbH | Tamper resistant immediate release capsule formulation comprising tapentadol |
| US9925146B2 (en) | 2009-07-22 | 2018-03-27 | Grünenthal GmbH | Oxidation-stabilized tamper-resistant dosage form |
| US10058548B2 (en) | 2003-08-06 | 2018-08-28 | Grünenthal GmbH | Abuse-proofed dosage form |
| US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
| US10080721B2 (en) | 2009-07-22 | 2018-09-25 | Gruenenthal Gmbh | Hot-melt extruded pharmaceutical dosage form |
| US10130591B2 (en) | 2003-08-06 | 2018-11-20 | Grünenthal GmbH | Abuse-proofed dosage form |
| US10154966B2 (en) | 2013-05-29 | 2018-12-18 | Grünenthal GmbH | Tamper-resistant dosage form containing one or more particles |
| US10201502B2 (en) | 2011-07-29 | 2019-02-12 | Gruenenthal Gmbh | Tamper-resistant tablet providing immediate drug release |
| US10300141B2 (en) | 2010-09-02 | 2019-05-28 | Grünenthal GmbH | Tamper resistant dosage form comprising inorganic salt |
| US10449547B2 (en) | 2013-11-26 | 2019-10-22 | Grünenthal GmbH | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
| US10624862B2 (en) | 2013-07-12 | 2020-04-21 | Grünenthal GmbH | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer |
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| US10729658B2 (en) | 2005-02-04 | 2020-08-04 | Grünenthal GmbH | Process for the production of an abuse-proofed dosage form |
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| US11224576B2 (en) | 2003-12-24 | 2022-01-18 | Grünenthal GmbH | Process for the production of an abuse-proofed dosage form |
| US11844865B2 (en) | 2004-07-01 | 2023-12-19 | Grünenthal GmbH | Abuse-proofed oral dosage form |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5965161A (en) * | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| US20030021841A1 (en) * | 2001-07-02 | 2003-01-30 | Matharu Amol Singh | Pharmaceutical composition |
-
2004
- 2004-02-12 GB GB0403100A patent/GB0403100D0/en not_active Ceased
-
2005
- 2005-02-11 CN CN2005800110496A patent/CN1942174B/en not_active Expired - Fee Related
-
2006
- 2006-08-10 ZA ZA200606647A patent/ZA200606647B/en unknown
-
2018
- 2018-05-04 AR ARP180101179A patent/AR111679A2/en unknown
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| US9655853B2 (en) | 2012-02-28 | 2017-05-23 | Grünenthal GmbH | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
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| US10624862B2 (en) | 2013-07-12 | 2020-04-21 | Grünenthal GmbH | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer |
| US10449547B2 (en) | 2013-11-26 | 2019-10-22 | Grünenthal GmbH | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
| US9913814B2 (en) | 2014-05-12 | 2018-03-13 | Grünenthal GmbH | Tamper resistant immediate release capsule formulation comprising tapentadol |
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Also Published As
| Publication number | Publication date |
|---|---|
| GB0403100D0 (en) | 2004-03-17 |
| ZA200606647B (en) | 2008-02-27 |
| CN1942174B (en) | 2012-04-04 |
| AR111679A2 (en) | 2019-08-07 |
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