CN1942174B

CN1942174B - Particulates

Info

Publication number: CN1942174B
Application number: CN2005800110496A
Authority: CN
Inventors: G·G·海斯; H·K·达纳赫; H·莫哈迈德; D·A·普拉特; H·坦伯尔; M·沃尔登; S·怀特洛克
Original assignee: Euro Celtique SA
Current assignee: Euro Celtique SA
Priority date: 2004-02-12
Filing date: 2005-02-11
Publication date: 2012-04-04
Anticipated expiration: 2025-02-11
Also published as: AR111679A2; CN1942174A; ZA200606647B; GB0403100D0

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

Microgranule

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 through the preparation of melt extruded technology.Melt extruded is the single stage method with solvent of exempting from that is used to prepare multiparticulates, and improves effective especially for drug release.Through 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 said 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.Can also the polymer glass transition temperature further 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, and it comprises the therapeutic activity medicament, the melt extruded mixture of one or more materials and one or more hydrophobic fusile carriers; Said 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; Said 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, said meltable carrier has 30-200 ℃ fusing point.The therapeutic activity medicament of said melt extruded is divided into UD, and its said therapeutic activity medicament that comprises effective dose to be giving the therapeutical effect of needs, and it provides said 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.Said 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; Said delayer material has 30-200 ℃ fusing point, and in being included in sufficient amount, being enough to further delay the release of said therapeutic activity medicament,

Said mixture heated to enough temperature, to be enough to softening said mixture, is enough to push said mixture;

The band of mixture extruding becoming with said heating with 0.1-3mm diameter;

With said band cooling; With

Said band is divided into the non-spheroid multiparticulates of said extrudate, and it has the length of 0.1-5mm; With

Said non-spheroid multiparticulates is divided into the UD of the said therapeutic activity medicament that contains effective dose, and said UD provides the sustained release of said therapeutic activity medicament, continues about 24 hours time period of about 8-.

In the specific preferred embodiment of WO 9614058, said hydrophobic substance is medicinal acrylic acid polymer, and it includes but not limited to, acrylic acid and EUDRAGIT S100; Methyl methacrylate, methylmethacrylate copolymer, methacrylic acid ethoxy ethyl ester, cynaoethyl methacrylate; The aminoalkyl methacrylate copolymer gathers (acrylic acid), gathers (methacrylic acid), methacrylic acid alkylamine copolymer; Gather (methyl methacrylate), gather (methacrylic acid) (acid anhydride), polymethacrylates; Polyacrylamide gathers (methacrylic anhydride), and glycidyl methacrylate copolymer.Therefore, in many examples, said hydrophobic substance is that Eudragit RS PO (gathers (ethyl acrylate; Methyl methacrylate; Trimethylamine chloro methacrylic acid)), randomly under the EudragitL100 existence of (gathering (methacrylic acid, methyl methacrylate)).

Summary of the invention

The present invention provides application neutrality to gather the preparation of (ethyl acrylate, methyl methacrylate) copolymer as pharmaceutical carrier.Such copolymer can give said preparation controllable release characteristics.And, use the present invention, through using melt extruded, we can provide (rubbery) preparation of rubbery.

The neutrality of aqueous liquid dispersion form is gathered (ethyl acrylate, methyl methacrylate) copolymer and can be purchased.Two kinds of such products, Eudragit NE 30 D and Eudragit NE 40 D comprise 30% and 40% said polymer respectively.Especially, Eudragit NE 30 D form the water-insoluble thin film, and are suitable for not adding any plasticizer and prepare the granulated processed in substrate tablet and the coating that continues 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, said network address has one piece of technical papers, and how its description is through 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 through 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 through 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 are used the may command that squeeze turns into preparation diltiazem hydrochloride and are discharged 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.In preparation D19 and D20, detect Eudragit NE 30 D, it does not improve in control drug release.

In the present invention, we can use neutrality and gather (ethyl acrylate, methyl methacrylate) copolymer as the carrier in the preparation.Typically, preparation of the present invention is used neutrality and is gathered (ethyl acrylate, methyl methacrylate) copolymer and be provided at the wherein substrate of dispersed activity component.Therefore, for example, the present invention provides the multiparticulates that has such substrate respectively.

Preparation of the present invention can adopt the form of UD, and such as the capsule that is full of multiparticulates, it uses neutrality to gather (ethyl acrylate, methyl methacrylate) copolymer as carrier.Said multiparticulates can be through the extruding drying composite, the extrudate that the mixture of wet especially dry granule forms, and it comprises that neutrality gathers (ethyl acrylate, methyl methacrylate) copolymer.

Through using squeezing action, the present invention provides the multiparticulates of may command release especially, and 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 said uncompleted compositions comprises that neutrality gathers (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, said uncompleted compositions is dry granule, and can be the granule that squeezes out.

Especially, the dry granule that we provide neutrality to gather (ethyl acrylate, methyl methacrylate) copolymer and active component, in order to give the characteristic that needs, it is higher relatively that wherein neutrality is gathered the level of (ethyl acrylate, methyl methacrylate) copolymer.Typically, the neutrality of the amount of application 2 0-60 weight % is gathered (ethyl acrylate, methyl methacrylate) copolymer in dry granule.

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 that neutrality gathers (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 gathered the preparation that (ethyl acrylate, methyl methacrylate) copolymer discharges as the may command of pharmaceutical carrier and used as using neutrality.

Related fields of the present invention are in the preparation pharmaceutical formulation, to use neutrality to gather (ethyl acrylate, methyl methacrylate) copolymer so that destruction (tamper) resistance to be provided, and it is in the situation of infringement in said active component is important.The present invention provides the method for giving the pharmaceutical formulation anti-destructive, and it is included in and in the preparation neutrality is gathered (ethyl acrylate, methyl methacrylate) copolymer and combine with active component.

Preferred embodiment is discussed

We find, gather (ethyl acrylate, methyl methacrylate) copolymer through using neutrality in the medicinal extrudate that discharges in the preparation may command, and we can obtain to show the melt extruded multiparticulates of rubber like characteristic.Such rubber like extrudate can show enhanced to destructive resistance.Especially, seem that said rubber like characteristic given by the melt extruded step.

On the one hand, the pharmaceutical formulation that the present invention provides may command to discharge, it obtains or can obtain through melt extruded, and comprises neutrality and gather (ethyl acrylate, methyl methacrylate) copolymer and active component.

In related fields, the present invention provides the preparation of the multiparticulates that comprises rubber like.

The characteristic of said rubber like provides typically flexible and compressible and can not rupture, and multiparticulates preferably with resilience.

As the demonstration of said rubber like characteristic, in a kind of preferred form, said multiparticulates can use hands between two rigid planes, for example, between coin and the desktop or between two spoons, compresses and can not rupture.Said multiparticulates usually can torsional deformation, but can not rupture or broken, and can recover its original shape ideally more or less again.

Said rubber like characteristic 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 through in water and/or ethanol, 40% ethanol for example, and the multiparticulates that shakes dosage amounts proves.

For example, in glass flask, can the multiparticulates of dosage amounts 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 confirm the amount of the active agents of extraction through HPLC then, and, for example, detect at the 210nm wavelength through 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 in water, shook 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.

In 40% ethanol, shook 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 through following manner, promptly; Make the multiparticulates of dosage amounts in mortar and pestle, stand to mill; Pestle rotates 24 times, and said product is placed 900ml water, places 45 minutes at 37 ℃.Can confirm the amount of the active agents of extraction through HPLC then, and, for example, detect at the 210nm wavelength through 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 through following manner; Promptly; The multiparticulates of dosage amounts is perhaps being pulverized in the pill pulverizer between two spoons,, be heated to extraction and filtration in the ebullient water at 2ml on the spoon then such as the Pill Pulverizer that sells by Apex Healthcare Products.Can confirm the amount of the active agents of extraction through HPLC then, and, for example, detect at the 210nm wavelength through 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 present invention is provided at and uses neutrality in the preparation pharmaceutical formulation and gather (ethyl acrylate, methyl methacrylate) copolymer, to provide destructive resistance.Neutrality is gathered (ethyl acrylate, methyl methacrylate) copolymer and is combined in preparation with active component.

On the one hand; The present invention is provided at the method for giving anti-destructive in the pharmaceutical formulation; It comprises active component and neutrality is gathered (ethyl acrylate; Methyl methacrylate) copolymer mixes, and forms the pharmaceutical formulation that combines said active component and said neutrality to gather (ethyl acrylate, methyl methacrylate) copolymer.

Said 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 that neutrality is gathered (ethyl acrylate, methyl methacrylate) copolymer.

Said neutrality gather (ethyl acrylate, methyl methacrylate) copolymer 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 through concrete reference.Whole perhaps parts more preferably that said neutrality gathers that (ethyl acrylate, methyl methacrylate) copolymer can form the release control material used in the pressing method that said patent details.

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 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 said preparation, the 10-50%w/w of said preparation preferably, most preferably the amount of the 20-45%w/w of said preparation is used.Other suitable polymer comprises the water-insoluble ammonio methacrylate copolymer.Said 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 not slacken resilience force or elastic amount is used.

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.

Said 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 ATBC and water-soluble liquid, such as triethyl citrate, propylene glycol and low molecular poly.ATBC 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.Said lubricant is a solid in room temperature usually, and suitably is selected from stearic acid, two Compritol 888 ATOs, 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 possibly be preferred lubricant with the form of salt.Another kind of preferred lubricant is two Compritol 888 ATOs.

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; Such as diazepam, 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 that neutrality gathers (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
					Water-insoluble neutrality is gathered (ethyl acrylate, methyl methacrylate) copolymer	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 the perhaps 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 ATBC.For example, nearly 50% oxycodone can be used as the active agents existence.These components can be proprietary composition, and perhaps if desired, said preparation can contain the composition of interpolation, such as the insoluble ammonio methacrylate copolymer of 5-60%.Illustrative ground; Said preparation can contain 10-60%, and the insoluble ammonio methacrylate copolymer of the hypotonicity of preferred 35-50% is 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 be prepared in the 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 with adjustment rate of release and/or enhancing fully.

The preferably preparation of the melt extruded through granule of said multiparticulates, and wet granulation and the dry said granule through comprising said component in particular, and the method for the melt extruded of said granule.

Said 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, said method can comprise the steps:

A) granulation, preferably wet granulation;

B) randomly push said granule;

C) granule of said granule or extruding is dry, the mode through 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, said method can comprise the steps:

A) granulation;

B) randomly push said granule;

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 product that screens or mill.

Last appearance step (c) or the product (d) to the melt extruded machine, it be the said dry granule of randomly milling or screening, 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; Through handling the high shear force agitator these are mixed, perhaps dropwise add the dispersion liquid of polymer then through spraying, and continue to mix.

Alternatively, for example, can liquid plasticizer be added in the dried ingredients, and mix, perhaps dropwise add the dispersion liquid of polymer then through spraying, and continue to mix through handling the high shear force agitator.

Can in optional step (b), push said granule then, for example use the Alexanderwerk extruder.It is dry with said extrudate preferably to use moving-bed dryer then.Said extrudate can Direct Production become to be applicable to the exsiccant size of thermopnore, and it uses suitable extruder, and such as the Alexanderwerk that preamble is mentioned, wherein small blade shreds said tablet, perhaps can resolve into suitable size.Alternatively, mixing the granule of producing through high shear force can be that big or small perhaps the resolving into that suits is applicable to dry size of then carrying out melt extruded.

Said 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.

Said melt extruded can be to carry out with 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 said dry granule or the product of milling are through the first of feeder inflow extruder barrel (barrel), to guarantee the constant flow of material to the high temperature bucket.Said feeder provides isostatic flow of material to extruder.Because irregular turnover rate with variation possibly 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 said 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.Said 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 said implementation is processed by different littler elements.Through changing the type of said screw element, length and configuration can change said mixing and kneading method significantly.Short hold stay the time with in by the time low-shearing force help safety processing and stable even have a product of thermo-responsive medicine.

The spiral rotary speed possibly 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 processes 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 said 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, said extruding band is transported from the die head (die-head) on the vehicle.

The diameter of band receives 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 said extruding band is transported to laser scale or other measuring device.Transport in the processing procedure this, said band little by little cools down, but keeps pliability basically.On the laser scale device, between pelletizer (pelletiser) inflow force feed Kun and in entering pelletizer process, flexible being kept perfectly property of band.Quick refrigerative band depends on preparation, possibly lose its integrity, and in through force feed Kun and pelletizer process, is broken into the inhomogenous and irregular multiparticulates of shape.

The laser scale can be used to provide the successive measurement of ferret diameter, for example 1.0mm.

The band of said measurement flows into pelletizer through force feed Kun.The band that said 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 through this cutting method typically adopts cylindrical shape, and the extruding band is transported from die head in the wherein said method.Preferably said cylinder has the length of diameter with 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 said extruding mixture.Said cutting machine is suitably the rotary knife cutter with one or more blades, said insert ring around the surface of die head up to passing the hole.Preferred two direct relative blades.Ideally, the outer surface of said die head encapsulates with adhesive material not, for example polytetrafluoroethylene (PTFE).Because the extruding multiparticulates of said cutting expands and cooling, they trend towards forming circular surface.Through the speed of suitable adjusting extruding rate and cutter, and common cylindrical multiparticulates, for example, possibly 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, said extrudate of said air cooling and accelerated solidification.

The spherical multiparticulates of producing by this method provides many advantages:

Better a collection of repeatability.

Easier encapsulating with lower needs encapsulates weight.

Better capsule is filled and higher output.

More stable under a high position.

Stronger anti-destructive.

Reduce or eliminate transport with the said band process of granulation in some problems of producing, be fragmented into the tablet of different length and possible electrostatic charge such as band.

Said multiparticulates can be divided into UD, so that each individual unit dosage comprises uses to mammal, preferably the potion medicine of human patients.For preferred medicine, oxycodone or its salt, hydrochloride preferably, the suitable dosage of said active agents is 5-400mg, especially 5mg, 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, 120mg or 160mg dosage.In this respect, UD contains the therapeutic activity medicament of effective dose, the patient is produced pain relief and/or analgesia.Using will be owing to many factors vary to the dosage of patient's oxycodone, 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 present 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, said multiparticulates is filled in the gelatin capsule, its each contain UD.Filling weight in the capsule preferably in the 80-500mg scope, 120-500mg more preferably.In variation of the present invention, the UD 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 process tablet is perhaps through processing 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 whenever using at a distance from 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 (pH1.6-7.2) 100rpm; When testing through USP PaddleMethod (referring to U.S.Pharmacopoeia XXII 1990); Be applicable to that so every unit dosage form at a distance from administration in 12 hours suitably has following external oxycodone disintegration rate; That is, 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, preferably its hydrochloride is applicable to every unit dosage form at a distance from administration in 12 hours; As aqueous buffer solution (simulated gastric fluid that does not have enzyme) 100rpm, detect through HPLC, when using USP BasketMethod " 711 " Apparatus 1 test with 206nm wavelength UV at 37 ℃ of 900mlpH1.2; 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 characteristic of necessity of said oxycodone preparation provides in WO 9310765, and it is incorporated into this fully through concrete reference.

As alternative, oxycodone capsule of the present invention or other unit dosage form are designed to use in every separated about 24 hours.For this purpose, 100rpm in the aqueous buffer solution between 37 ℃ of 900mlpH1.6-7.2 is when testing through USP Basket Method; Said unit dosage form suitably has following external oxycodone disintegration rate, that is, and and 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, preferably its hydrochloride is applicable to every unit dosage form at a distance from administration in 24 hours; As aqueous buffer solution (simulated gastric fluid that does not have enzyme) 100rpm, detect through HPLC, when using USP BasketMethod " 711 " Apparatus 1 test with 206nm wavelength UV at 37 ℃ of 900mlpH1.2; 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 at 16 hours greater than 50% 68-92% preferably.

More information about the characteristic of necessity of said oxycodone preparation provides in WO 02087512, and it is incorporated into this fully through concrete reference.

In variation, the present invention provides and contains the UD that effectively prevents to destroy opioid and opioid antagonists.In this respect, with reference to WO 0313433, it is incorporated into this fully through concrete reference.Especially, said UD can contain oxycodone and naltrexone.

For this purpose, the present 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 said antagonist, and, for example, have encapsulating of not discharging.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 UD, 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.

Embodiment 1,2 and 3

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 2. through the screening of 350micron filter screen, with the elimination aggregation, and is transferred to Eudragit NE 40 D dispersion liquids in the container of suitable size.

Step 3. is sprayed to the Eudragit NE 40 D dispersion liquids that screen on the material of the dry mixed of step 1 in mixing bowl under low atomisation pressure, keeps stirring/chopping simultaneously (chopping).

Step 4. continues to use Eudragit NE 40 D, forms up to granule and takes place.

Step 5. is periodically interrupted the application of Eudragit NE 40 D, with the said edge that mixes bowl of swiping.

Step 6. after all Eudragit NE 40 D are employed, with said granule under the uniform temp condition and the stirring that reduces/chop and carry out drying under the speed.

Step 7. flows into Leistritz Micro 18 extruders of having equipped vehicle and pelletizer with granule then with controllable speed.Said 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.

Said extruding band is transported from the die head of vehicle, and be cut into cylindrical multiparticulates.

Material	Embodiment (%w/w)
					Embodiment 1	Embodiment 2	Embodiment 3
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
				Total amount	100	?100	100

^*Be Eudragit NE 40 D (removing water) through drying

Embodiment 4

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 said extrudate with twolip.Because they expand and cooling, said 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?40?D	37.0 ^*
Total amount	100

^*Be expressed as the value of solids content

Through suitable adjusting extruding diameter, it comprises temperature and extruding rate, can obtain spheric or spheric basically multiparticulates.

Embodiment 5 and 6

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?40?D ^*	35.3(S)， [88.3(D)]	29.4(S)， [73.5(D)]
			ATBC	5.9	6.9
Two Compritol 888 ATOs	2.0	1.9
			Total amount	100	100

The S=solid weight

D=dispersion liquid weight

^*40% dispersion liquid (%w/w) is through evaporation water loss

The method of multiparticulates of embodiment 5 that is used to prepare tablet form is following:

Step 1. is slowly added to ATBC in the ethyl cellulose in Gral 10 high shear mixer and is mixed.

Step 2. is added oxycodone in the mixture of the step 1 in Gral 10 high shear mixer to, and mixes 5 minutes.

Step 3. through the screening of 350micron filter screen, with the elimination aggregation, and is transferred to Eudragit NE 40 D dispersion liquids in the container of suitable size.Through the help of peristaltic pump, Eudragit NE 40 D that screen are slowly added in the compounding substances of the step 2 in Gral 10 mixing bowls then, be preheating to 38 ℃, keep simultaneously stirring/chopping.

Step 4. continues to use Eudragit NE 40 D, forms up to granule all Eudragit NE 40 D of an adding take place.

After all Eudragit NE 40 D of step 6. were added into, wet granule was pushed through conventional extruder, and in about 42 ℃ of dryings in moving-bed dryer.

Step 7. is with exsiccant granule cool to room temperature, and collection.

Step 8. under the condition identical with embodiment 1, flows into equipment 1.0mm die, Leistritz Micro 18 extruders of transveyer and pelletizer with said granule with controllable speed then.The extruding band is transported from the die head on the transveyer, and cuts into cylindrical multiparticulates.

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.

Said 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 Compritol 888 ATOs) is added in the exsiccant granule.

Said 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 is melting when the hole of die occurs under the pressure He still, use rotary knife cutter and cut said mixture for extrusion with twolip.Said 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 900mlpH1.2; HPLC through having 206nm wavelength UTV detects, and the extruding tablet that obtains among the embodiment 5 is carried out disintegrate detect, 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 embodiment 5 % discharge
		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

Embodiment 7,8 and 9

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 8	Embodiment 9
Oxycodone hydrochloride	43	?43	?43
				Ethyl cellulose N10	19	?19	?18
Eudragit?NE?40D ^*	29	?29	?27
				ATBC	6	?6	?6
Stearyl alcohol		?3
				Two Compritol 888 ATOs	3		?6
Total amount	100	?100	?100

^*The value of expression is merely 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 10	Embodiment 11	Embodiment 12	Embodiment 13
Oxycodone hydrochloride	10.0	10.0	10.0	10.0
					Ethyl cellulose N10	41.8	0	32.0	0
Eudragit?RS?PO	0	41.8	0	22.0
					Eudragit?RL?PO	0	0	10.0	20.0
Stearyl alcohol	14.0	14.0	14.0	14.0
					Eudragit?NE40D ^*	34.2(S)， [85.5(D)]	34.2(S)， [85.5(D)]	34.0(S)， [85.0(D)]	34.0(S)， [85.0(D)]
Total amount	100	100	100	100

The S=solid weight

D=dispersion liquid weight

^*40% dispersion liquid (%w/w) is 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, said preparation biology basically is equal to OxyContin.

The multiparticulates of embodiment 10-13 has lower release profiles, this maybe the surface they will be applicable to dosage form 24 hours interval administration.

Detect the multiparticulates of embodiment 10-13, to confirm the potential of 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.Confirm the amount of the oxycodone of extraction then through HPLC, and detect, and in the chart of Fig. 3, show through 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 through 1) described in method confirm the amount of dissolved oxycodone, and said result shows at the block diagram shape of Fig. 4.

3) in each extraction a)-e), the multiparticulates of one of 400mg embodiment 10-13 is handled respectively as follows: multiparticulates is put into the solvent that glass flask needs, then said flask is heated (words of heating if desired) in water-bath.Make said 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 through 1) in used method confirm 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.

Said testing result shows in the block diagram of accompanying drawing 5.

Summary of drawings

At following experimental section with reference to accompanying drawing, 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

Claims

1. the pharmaceutical formulation that discharges of a may command, it comprises the melt extruded multiparticulates, wherein said multiparticulates comprises and contains substrate and the activating agent that neutrality is gathered the rubber like of (ethyl acrylate, methyl methacrylate) copolymer.

2. according to the preparation of claim 1, wherein said activating agent is an opioid, analeptic, barbiturate/ester, antidepressant or dissociated anesthetis.

3. according to the preparation of claim 2, wherein said activating agent is oxycodone or its pharmaceutical salts.

4. according to the preparation of claim 1, when at water, when extracting in the alcoholic acid liquid of ethanol or aqueous, it destroys through release opposing that reduces activating agent.

5. according to the preparation of claim 1; When detecting with a kind of detection method; Said detection method comprises: in glass flask, with the multiparticulates and the 10ml liquid mixing of dose amount, and use Stuart Scientific Shaker Model SF1; Shook 15 minutes with 500-600 swing of per minute, said 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% activating agent release;

(b) placed 5 minutes in water at 50 ℃, then shook 15 minutes: be less than 15% activating agent release in identical temperature;

(c) placed 5 minutes at 75 ℃, then shook 15 minutes: be less than 20% activating agent release in identical temperature;

(d) placed 5 minutes at 100 ℃, then shook 15 minutes: be less than 25% activating agent release in identical temperature;

(e) in 40% ethanol, shook 15 minutes in room temperature: preferably be less than 25% activating agent release.

6. according to the preparation of claim 1, when milling said preparation and extract, wherein said anti-destructive reduces the release of activating agent.

7. according to the preparation of claim 6, when detecting with a kind of detection method, its release is less than 10% activating agent; Said detection method comprises: in mortar and pestle, make the preparation of dose amount stand to mill, pestle rotation 24 times; And put into 900ml water, continue 45 minutes at 37 ℃.

8. according to the preparation of claim 6; When detecting with a kind of detection method; Its release is less than 15% activating agent; Said 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.

9. according to the preparation of claim 1, wherein said substrate comprises that at least a other improves the polymer that discharges, and wherein said polymer is alkylcellulose or water-insoluble ammonio methacrylate copolymer.

10. according to the preparation of claim 9, wherein said other polymer is an ethyl cellulose.

11. according to the preparation of claim 10, the amount of wherein said ethyl cellulose is the 10-50 weight % of preparation.

12. according to each preparation of claim 9-11, based on the gross weight of concrete component, it contains the component of following amount:

13. according to the preparation of claim 12, based on the gross weight of concrete component, it contains the component of following amount:

14. according to the preparation of claim 12, based on the gross weight of concrete component, it contains the component of following amount:

15. according to the preparation of claim 1, it comprises the nearly activating agent 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%.

16. according to the preparation of claim 15, it also contains the insoluble ammonio methacrylate copolymer of 5-60%.

17. according to the preparation of claim 16, 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%.

18. according to the preparation of claim 1, it contains extender.

19. according to the preparation of claim 1, it contains opioid and opioid antagonists.

20. according to the preparation of claim 19, it comprises the oxycodone multiparticulates of 120-300mg and the oxycodone antagonist multiparticulates of 125-175mg.

21. according to the preparation of claim 19 or 20, it contains oxycodone and naltrexone.

22. according to the preparation of claim 19 or 20, it comprises the melt extruded multiparticulates of opioid melt extruded multiparticulates and opioid antagonists.

23. according to the preparation of claim 1, it is the form of UD.

24. according to the preparation of claim 23, it contains 5mg, 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, the oxycodone of 120mg or 160mg.

25. according to the preparation of claim 23 or 24, be administered once its suitable every day.

26. according to the preparation of claim 25, when testing in the aqueous buffer solution of 100rpm between 37 ℃ of 900ml pH 1.6-7.2 through USP Basket Method, it has following external oxycodone disintegration rate; That is, at 1 hour 0%-40%, at 4 hours 8%-70%; At 8 hours 20%-80%; At 12 hours 30%-95%, at 18 hours 35%-95%, and at 24 hours greater than 50%.

27. according to the preparation of claim 26, the maximum plasma level of the oxycodone that wherein obtains in the body is generation in 2-17 hour after using said unit dosage form.

28. preparation according to claim 25; When testing in the aqueous buffer solution of 37 ℃ of 900ml pH 1.2 with 100rpm with USP Basket Method " 711 " Apparatus1; HPLC through having 206nm wavelength UV detects; Said preparation has following external oxycodone disintegration rate, that is, and and at 1 hour 10-30%; At 2 hours 20-35%; At 8 hours 35-75%; And 16 hours greater than 50%, the aqueous buffer solution of wherein said pH 1.2 is not for having the simulated gastric fluid of enzyme.

29. according to the preparation of claim 23 or 24, it is suitable for being administered twice every day.

30. preparation according to claim 29; When in 37 ℃ of 900ml aqueous buffer solutions (pH1.6-7.2), testing with 100rpm with USP Paddle Method (referring to U.S.Pharmacopoeia XXII 1990), said preparation 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.

31. preparation according to claim 29; When testing in the aqueous buffer solution of 37 ℃ of 900ml pH 1.2 with 100rpm with USP Basket Method " 711 " Apparatus1; HPLC through having 206nm wavelength UV detects; Said preparation has following external oxycodone disintegration rate, that is, and and at 1 hour 0-40%; At 2 hours 20-70%; At 3 hours 40-80%; At 4 hours 60-95%; And 5 hours greater than 70%, the aqueous buffer solution of wherein said pH 1.2 is not for having the simulated gastric fluid of enzyme.

32. according to the preparation of claim 31, the maximum plasma level of the oxycodone that wherein obtains in the body is taking place between 2-4.5 hour after the administration of unit doses form.

33. the multiparticulates of melt extruded, every kind comprises that the neutrality of 20 weight %-66 weight % gathers the substrate and the medicinal activity compound of (ethyl acrylate, methyl methacrylate) copolymer.

34. according to the multiparticulates of claim 33, wherein said medicinal activity compound is the opioid analgesic.

35. according to the multiparticulates of claim 34, wherein said opioid is oxycodone or its salt.

36. according to the multiparticulates of claim 33,34 or 35, it adopts cylindrical shape, perhaps is generally spherical, ellipsoid or disc shaped.

37. method that is used to prepare the preparation that may command discharges; Said preparation comprises that containing neutrality gathers (ethyl acrylate; Methyl methacrylate) substrate of copolymer and activating agent; Said method comprises that melt extruded contains the mixture that neutrality is gathered (ethyl acrylate, methyl methacrylate) copolymer and activating agent.

38. method according to claim 37; Wherein said neutrality is gathered (ethyl acrylate; Methyl methacrylate) copolymer provides with the form of the aqueous liquid dispersion that comprises 40% said polymer, and it mixes with said activating agent, and dry so that said mixture is used for melt extruded.

39. according to the method for claim 37 or 38, wherein said mixture comprises plasticizer.

40. according to the method for claim 39, wherein said plasticizer is an ATBC, stearyl alcohol or high-molecular weight Polyethylene Glycol.

41. according to claim 37,38 or 40 each methods, wherein said mixture comprises lubricant.

42. according to the method for claim 41, wherein said lubricant is a stearic acid, stearate, perhaps two Compritol 888 ATOs.

43. according to claim 37,38,40 or 42 each methods, it comprises the wet granulation that is used for being extruded with the component of the mixture that obtains wet granule, dry said granule, and the said exsiccant granule of melt extruded.

44. according to the method for claim 43, wherein said wet granule is extruding before dry.

45. according to the method for claim 44, wherein said exsiccant granule contains the water that is less than 3% w/w.

46. according to claim 37,38,40,42,44 or 45 each methods, the melt extruded of wherein said dry granule is carried out in double-screw extrusion machine.

47. according to claim 37,38,40,42,44 or 45 each methods, wherein said extruding band is transported to pelletizer, and cuts into multiparticulates.

48. according to claim 37,38,40,42,44 or 45 each methods, wherein every kind of multiparticulates has the length of diameter and the 1mm of 1mm.

49. according to claim 37,38,40,42,44 or 45 each methods, wherein when said extruding mixture self compaction machine occurred, said cutting machine cut said extruding mixture.

50. neutrality is gathered the application of (ethyl acrylate, methyl methacrylate) copolymer in each defined pharmaceutical formulation of preparation claim 1-32, it provides anti-destructive.

51. comprising, a method of giving the pharmaceutical formulation anti-destructive, said pharmaceutical formulation contain substrate and the activating agent that neutrality is gathered the rubber like of (ethyl acrylate, methyl methacrylate) copolymer; It comprises that mixed active component and neutrality gathers (ethyl acrylate; Methyl methacrylate) copolymer, the melt extruded multiparticulates, active component and neutrality in the binding matrix are gathered (ethyl acrylate; Methyl methacrylate) copolymer and in preparation, form said many granules.