CN1942174B - particle - Google Patents

Abstract

In the preparation of pharmaceutical formulations containing active ingredients, neutral poly (ethyl acrylate, methyl methacrylate) copolymers are used as carriers. The formulations are preferably prepared by melt extrusion and may have rubber-like characteristics and may exhibit damage resistance.

Description

particle

The present invention relates to microparticles, and in particular to melt extruded multiparticulates, which provide controlled release of active ingredients.

Background of the invention

Uniformly sized multiparticulates with improved drug release properties can be readily prepared by melt extrusion techniques. Melt extrusion is a solvent-free, single-step process for the preparation of multiparticulates and is particularly effective for drug release modification. By selecting appropriate thermoplastic polymers and additives, melt extrusion technology can be used to increase the solubility and thus bioavailability of very poorly water soluble drugs, as well as to delay the moderate to high Drug release of water soluble drugs.

The key to melt-extrusion technology is the application of a thermoplastic material, which acts as a binder for the inclusion of the drug in the solution or dispersion formed inside the matrix. Thermoplastic polymers having a low glass transition temperature (Tg) are preferably used in the melt extrusion process. Lower processing temperatures are also preferred in view of the stability of heat-sensitive drugs and other necessary excipients. The polymer glass transition temperature can also be further reduced to facilitate processing at lower temperatures with optional added plasticizers.

WO 9614058 exemplarily provides a sustained release pharmaceutical formulation comprising a melt extruded mixture of a therapeutically active agent, one or more substances and one or more hydrophobic fusible carriers, said one or more substances selected from the group consisting of alkyl cellulose, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof; said carrier Further retardation is provided and is selected from the group consisting of natural or synthetic paraffins, fatty acids, fatty alcohols, and mixtures thereof, the meltable carrier having a melting point of 30-200°C. Dividing the melt-extruded therapeutically active agent into unit doses comprising an effective amount of the therapeutically active agent to impart the desired therapeutic effect and which provide sustained release of the therapeutically active agent for about 8 to about 24 hour time period.

Furthermore, WO 9614058 describes a process for the preparation of sustained release pharmaceutical extrudates suitable for oral administration. The methods include:

The therapeutically active agent is mixed together with: (1) a substance selected from the group consisting of: alkyl cellulose, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, Hydrogenated vegetable oils, and mixtures thereof, and (2) meltable carriers selected from the group consisting of natural or synthetic paraffins, fatty acids, fatty alcohols, and mixtures thereof; melting point, and is contained in a sufficient amount to be sufficient to further delay the release of the therapeutically active agent,

heating the mixture to a temperature sufficient to soften the mixture sufficiently to compress the mixture;

extruding the heated mixture into strips with a diameter of 0.1-3 mm;

cooling the strip; and

aspherical multiparticulates that separate the strips into the extrudate, having a length of 0.1-5 mm; and

The non-spherical multiparticulates are divided into unit doses containing an effective amount of the therapeutically active agent that provides sustained release of the therapeutically active agent over a period of about 8 to about 24 hours.

In a specific preferred embodiment of WO 9614058, the hydrophobic substance is a pharmaceutically acceptable acrylic acid polymer, which includes, but is not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, Ethoxyethyl methacrylate, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymer, poly(methyl methacrylate ), poly(methacrylic acid)(anhydride), polymethacrylates, polyacrylamides, poly(methacrylic anhydride), and glycidyl methacrylate copolymers. Thus, in many embodiments, the hydrophobic substance is Eudragit RS PO (poly(ethyl acrylate, methyl methacrylate, trimethylamine chloromethacrylic acid)), optionally in Eudragit L100 (poly(methacrylic acid , in the presence of methyl methacrylate)).

Summary of the invention

The present invention provides a preparation using neutral poly(ethyl acrylate, methyl methacrylate) copolymer as a pharmaceutical carrier. Such copolymers can impart a controlled release profile to the formulation. Furthermore, applying the present invention, we are able to provide rubbery formulations by applying melt extrusion.

Neutral poly(ethyl acrylate, methyl methacrylate) copolymers are commercially available in the form of aqueous dispersions. Two such products, Eudragit NE 30 D and Eudragit NE 40 D, comprised 30% and 40% of the polymer, respectively. In particular, Eudragit NE 30 D forms water-insoluble films and is suitable for granulation in matrix tablets and sustained-release coatings without the addition of any plasticizers. Information on the preparation of tablets and coatings using Eudragit NE can be obtained from the following website: http://www.roehm.de/en/pharmapolymers.html.

For example, the website has a technical paper describing how to prepare ibuprofen sustained release matrix tablets by wet granulation using Eudragit NE 30D as binder and diffusion controller. Granules are prepared by mixing ibuprofen with Eudragit dispersion, milling using a sieve, and drying. The granules are milled, mixed with a disintegrant and other ingredients, and compressed into tablets. The amount of Eudragit NE is relatively low.

In WO 03004009 Eudragit NE is in the list of hydrophobic ingredients suggested for application with hydrophilic erodible ingredients and difficult to compress pharmaceutical agents. Since Eudragit NE is a wet dispersion and the object of WO 03004009 is to form compressible formulations by means other than wet granulation, the present invention appears to be another Eudragit.

In Pharmaceutical Technology 2004 (April): 62-85, Sood et al describe the preparation of diltiazem hydrochloride using extrusion spheroidization A controlled release pharmaceutical form of . A series of candidate substances were evaluated as granule matrix formers in a process that included wet granulation, wet granule extrusion, and spheroidization to form wet granules that were then dried. Eudragit NE 30 D was tested in formulations D19 and D20, which gave no improvement in controlled drug release.

In the present invention, we can use neutral poly(ethyl acrylate, methyl methacrylate) copolymer as a carrier in the formulation. Typically, formulations of the invention employ neutral poly(ethyl acrylate, methyl methacrylate) copolymers to provide a matrix in which to disperse the active ingredient. Thus, for example, the present invention provides multiparticulates each having such a matrix.

The formulations of the invention may be presented in unit dosage form, such as multiparticulate-filled capsules, using a neutral poly(ethyl acrylate, methyl methacrylate) copolymer as a carrier. The multiparticulates may be extrudates formed by extrusion of a dry mixture, particularly a mixture of wet-dried granules, comprising a neutral poly(ethyl acrylate, methyl methacrylate) copolymer.

In particular through the application of extrusion, the present invention provides controlled release multiparticulates which take the form of cylinders, or generally spheres, ellipsoids or disks.

For this purpose, the invention also provides dry mixtures as unfinished compositions comprising neutral poly(ethyl acrylate, methyl methacrylate) copolymers and active components. Such compositions are substantially anhydrous and suitable for extrusion as part of the method of providing the formulations of the invention. Typically, the unfinished composition is a dry granule, and may be an extruded granule.

In particular, we offer dry granules of neutral poly(ethyl acrylate, methyl methacrylate) copolymers and active ingredients, in which neutral poly(ethyl acrylate, methyl methacrylate ) The level of copolymer is relatively high. Typically, neutral poly(ethyl acrylate, methyl methacrylate) copolymers are employed in amounts of 20-60% by weight in dry granules.

According to the present invention, we also provide a process for the preparation of a controlled release pharmaceutical extrudate, wherein the mixture for extrusion comprises a neutral poly(ethyl acrylate, methyl methacrylate) copolymer.

Another aspect of the present invention pertains to methods of administration of the active ingredient, wherein said active ingredient is administered as a controlled release formulation using a neutral poly(ethyl acrylate, methyl methacrylate) copolymer as a pharmaceutically acceptable carrier .

A related aspect of the present invention is the use of neutral poly(ethyl acrylate, methyl methacrylate) copolymers in the preparation of pharmaceutical formulations to provide tamper resistance in situations where the active ingredient is compromised is important. The present invention provides a method of imparting tamper resistance to a pharmaceutical formulation comprising combining a neutral poly(ethyl acrylate, methyl methacrylate) copolymer with an active ingredient in the formulation.

Preferred Implementation Discussion

We have found that by employing neutral poly(ethyl acrylate, methyl methacrylate) copolymers in the preparation of controlled release pharmaceutical extrudates, we can obtain melt extruded multiparticulates exhibiting rubber-like characteristics. Such rubber-like extrusions may exhibit enhanced resistance to damage. In particular, it appears that said rubber-like character is imparted by the melt-extrusion step.

In one aspect, the present invention provides a controlled release pharmaceutical formulation obtained or obtainable by melt extrusion and comprising a neutral poly(ethyl acrylate, methyl methacrylate) copolymer and an active ingredient.

In a related aspect, the present invention provides formulations comprising rubber-like multiparticulates.

The rubber-like characteristics provide multiparticulates that are typically elastic and compressible without breaking, and preferably resilient.

As an illustration of the rubber-like characteristics, in a preferred form, the multiparticulates can be compressed by hand between two rigid surfaces, for example, between a coin and a tabletop or between two spoons. without breaking. The multiparticulates are generally distorted, but not fractured or shattered, and desirably regain more or less their original shape.

The rubber-like characteristics can help impart resistance to damage. Damage resistance is particularly important for opioid-containing analgesics and other active ingredients that are commonly abused. The vandal resistance of preferred multiparticulates of the invention can be demonstrated by shaking a dosed amount of multiparticulates in water and/or ethanol, eg 40% ethanol.

For example, in a glass flask, a dosed amount of multiparticulates can be mixed with 10 ml of liquid (water and/or ethanol) and then used with a Stuart Scientific Shaker, Model SF1, optionally after standing for 5 minutes at a rate of 500-600 microparticulates per minute. Shake for 15 minutes at a time. The amount of extracted active agent can then be determined by HPLC and detected by UV, for example at a wavelength of 210 nm.

When tested in this manner, preferred multiparticulates according to the invention exhibit at least one of the following active agent release characteristics:

Shaking in water at room temperature for 15 minutes: less than 10% active agent released, preferably less than 7.5% active agent released, more preferably less than 5% active agent released, e.g., 1.5-4% active agent freed.

5 minutes in water at 50°C followed by shaking at the same temperature for 15 minutes: less than 20% of the active agent is released, preferably less than 15% of the active agent is released, more preferably less than 12% of the active agent is released, For example, 4-12% of the active agent is released.

Placement in water at 75°C for 5 minutes followed by shaking at the same temperature for 15 minutes: less than 25% of the active agent is released, preferably less than 20% of the active agent is released, more preferably less than 15% of the active agent is released, For example, 10-15% of the active agent is released.

5 minutes in water at 100° C. followed by shaking at the same temperature for 15 minutes: less than 30% of the active agent is released, preferably less than 25% of the active agent is released, more preferably less than 20% of the active agent is released, For example, 12-20% of the active agent is released.

Shaking in 40% ethanol at room temperature for 15 minutes: less than 35% of the active agent is released, preferably less than 30% of the active agent is released, more preferably less than 25% of the active agent is released, for example, 15-25% of The active agent is released.

Alternatively, the damage resistance of the preferred multiparticulates of the present invention can be demonstrated by subjecting a dosed amount of multiparticulates to grinding in a mortar and pestle, rotating the pestle 24 times, and subjecting the The product was placed in 900ml of water and placed at 37°C for 45 minutes. The amount of extracted active agent can then be determined by HPLC and detected by UV, for example at a wavelength of 210 nm.

When tested in this manner, preferred multiparticulates according to the invention exhibit an active agent release profile of less than 12.5% active agent released, preferably less than 10% active agent released, more preferably less than 7.5% of the active agent is released, eg, 2-7.5% of the active agent is released.

In another method, the tamper resistance of the preferred multiparticulates of the present invention can be demonstrated by comminuting a dosage amount of the multiparticulates between two spoons or in a pellet mill, such as that provided by Apex Healthcare Products. Pill Pulverizer sold, then extracted on a spoon in 2ml of water heated to boiling and filtered. The amount of extracted active agent can then be determined by HPLC and detected by UV, for example at a wavelength of 210 nm.

When tested in this manner, preferred multiparticulates according to the invention exhibit an active agent release profile of less than 27.5% active agent released, preferably less than 15% active agent released, more preferably less than 5% of the active agent is released, eg, 1-5% of the active agent is released.

To impart such tamper resistance, the present invention provides the use of neutral poly(ethyl acrylate, methyl methacrylate) copolymers in the preparation of pharmaceutical formulations to provide resistance to tampering. A neutral poly(ethyl acrylate, methyl methacrylate) copolymer is combined with the active ingredient in the formulation.

In one aspect, the invention provides a method of imparting tamper resistance in a pharmaceutical formulation comprising mixing an active ingredient with a neutral poly(ethyl acrylate, methyl methacrylate) copolymer, and forming a compound that binds the active ingredient. A pharmaceutical formulation of the neutral poly(ethyl acrylate, methyl methacrylate) copolymer.

The neutral poly(ethyl acrylate, methyl methacrylate) copolymer is suitable for use in the mix for extrusion in amounts up to 66% by weight, such as 20-66% of the extrusion mix, more typically Preferably, 20-50% of the mixture is extruded, such as 30-40% of the mixture is extruded. These percentages also apply to the amount of neutral poly(ethyl acrylate, methyl methacrylate) copolymer in the dry granules of the present invention.

The neutral poly(ethyl acrylate, methyl methacrylate) copolymers can be used with other components, including drugs or other active ingredients. The reading is referred to WO 9614058, which is hereby fully incorporated by specific reference. The neutral poly(ethyl acrylate, methyl methacrylate) copolymer may form all or more preferably part of the release controlling substance applied in the extrusion process detailed in said patent.

In this regard, our preferred compositions include at least one other polymer which modifies release. In particular, it appears that the use of ethylcellulose or similar polymers may assist in conferring resistance to damage, in particular to extraction with alcohol. For example, alkyl cellulose, such as ethyl cellulose, is preferably present at 5-60% w/w of the formulation, preferably 10-50% w/w of the formulation, most preferably 20% w/w of the formulation An amount of -45% w/w was applied. Other suitable polymers include water insoluble ammonium methacrylate copolymers. The insoluble ammonium methacrylate copolymer may be Eudragit RSPO and Eudragit RL PO, which are ammonium methacrylate copolymers. In particular, the at least one other polymer is typically a poorly water-permeable thermoplastic polymer, or a relatively highly water-permeable thermoplastic polymer, which can significantly improve release, but without compromising resilience or Flexible amount of application.

Plasticizers and/or lubricants are preferred when using extruders with relatively low torque capabilities, such as the Leistritz Micro 18 machine. Similar formulations can be processed without or with relatively low levels of plasticizers and/or lubricants using larger extruders, such as the Leistritz Micro 27.

The plasticizer is usually selected from water-insoluble solids such as cetyl alcohol, stearyl alcohol and cetostearyl alcohol; water-soluble solids such as sorbitol and sucrose and high molecular weight polyethylene glycols, water-insoluble liquids , such as dibutyl sebacate and tributyl citrate and water-soluble liquids such as triethyl citrate, propylene glycol and low molecular weight polyethylene glycol. Tributyl citrate is a preferred plasticizer. Stearyl alcohol is also a preferred plasticizer. Another plasticizer is a high molecular weight polyethylene glycol of MW 1000-20000, such as PEG 6000.

A lubricant may be included. The lubricant is usually solid at room temperature and is suitably selected from stearic acid, glyceryl dibehenate, magnesium stearate, calcium stearate, talc and silicone dioxide (fused silica). The presence of lubricants in melt extrudate formulations improves mixing, kneading and transport, and reduces coagulation and sticking forces. Smooth extrusion at low to moderate temperatures improves batch-to-batch reproducibility and reduces strain on product and equipment. Stearic acid, possibly in salt form, is a preferred lubricant. Another preferred lubricant is glyceryl dibehenate.

，奥沙西泮，malprazolam，三唑仑和etazolam，氟硝西泮和甲喹酮；和解离麻醉剂，诸如氯胺酮；以及盐，酸式加成盐，及其酯。A drug is usually present in the formulations of the invention as the active agent. For example, reading reference WO9614058. Oxycodone is a typical drug for use in the products and methods of the invention. For example, other opioids are hydromorphone, hydrocodone, fentanyl and its analogs, buprenorphine, diamorphine, meperidine, dextropropoxyphene and diphenoxylate. Other active agents that may be formulated in accordance with the present invention include stimulants such as dexamphetamine, amphetamine, methamphetamine, sibutamine, methylphenidate; barbiturates such as methobarbitol and pentobarbital ; antidepressants such as diazepam, bromazepam, clorazepate

, oxazepam, malprazolam, triazolam, and etazolam, flunitrazepam, and methaqualone; and dissociative anesthetics, such as ketamine; and salts, acid addition salts, and esters thereof.

Thus, preferred multiparticulates of the present invention may comprise a neutral poly(ethyl acrylate, methyl methacrylate) copolymer; the active ingredient, at least one other polymer which modifies release, which is typically an alkyl cellulose; optionally a plasticizer; and optionally a lubricant.

Suitable percentage amounts of preferred ingredients are given in the table below, based on the total weight of the particular ingredients.

typical range preferred range more preferred range most preferred range Water-insoluble neutral poly(ethyl acrylate, methyl methacrylate) copolymer 5-66 15-50 20-45 25-45 Active Agent ^* up to 60 5-55 5-50 10-45 Other modified release polymers 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

^* In placebo formulations used in trials or developmental work, the amount of active agent may be 0%.

For example, a typical formulation may also contain up to 60% w/w active agent or placebo, 15-50% w/w neutral poly(ethyl acrylate, methyl methacrylate) copolymer; 5-60 % w/w, suitably 15-50% w/w, such as 15-25% or 25-45% of alkyl cellulose, preferably ethyl cellulose; and 0-25%, preferably 7.5-20% of a One or more plasticizers, such as stearyl alcohol and tributyl citrate. For example, up to 50% oxycodone may be present as the active agent. These components may be proprietary ingredients, or if desired, the formulation may contain added ingredients such as 5-60% insoluble ammonium methacrylate copolymer. Illustratively, the formulation may contain 10-60%, preferably 35-50%, of a low-permeability insoluble ammonium methacrylate copolymer, such as Eudragit RS PO, and/or it may contain 5-40%, such as 5 - 30%, preferably eg 5-25% of a highly permeable ammonium methacrylate copolymer such as Eudragit RL PO.

Other additives may also be used to produce multiparticulates within a range of predetermined specifications. Bulking agents, such as lactose, microcrystalline cellulose and calcium phosphate, are widely used as pharmaceutical excipients and may be used in the present invention to modify the release rate and/or complete release. Other release modifiers can also be considered to modify the rate of release and/or to enhance complete release.

The multiparticulates are preferably prepared by melt extrusion of granules, and in particular by a process comprising wet granulation of the components, and drying of the granules, and melt extrusion of the granules.

The granulation step can be carried out using conventional methods, for example, using a high shear mixer, such as a Gral mixer, or a fluid bed granulator or a fluid bed granulator with a rotary insert.

When a high shear mixer is used, the method may comprise the steps of:

a) granulation, preferably wet granulation;

b) optionally compressing the granules;

c) drying said granules or extruded granules, preferably by means of a fluid bed dryer;

d) optionally screening and/or milling step c) dried granules and dried extruded granules; and

e) melt extruding the product of step c) or d).

When using a fluidized bed separator with or without a rotary insert, the method may comprise the following steps:

a) granulation;

b) optionally compressing the granules;

c) drying said granules or extruded granules, preferably by means of a fluid bed dryer;

d) optionally screening and/or milling the product of step c); and

e) Dry granules or sieved or milled product of melt extrusion step c) or d).

The product of step (c) or (d) loaded onto the melt extruder, which is said optionally milled or sieved dry granulate, is itself a novel product according to the invention.

The granulation step can be carried out using conventional methods, for example, using a high shear mixer such as Gral. Typically, the dry components are added first; these are mixed by manipulating a high shear mixer, then the dispersion of polymer is added by spraying or dropwise, and mixing is continued.

Alternatively, for example, a liquid plasticizer can be added to the dry components and mixed by operating a high shear mixer, then the dispersion of polymer can be added by spraying or dropwise, and mixing continued.

The granules can then be extruded in optional step (b), for example using an Alexanderwerk extruder. The extrudate is then dried, preferably using a fluid bed dryer. The extrudate can be produced directly to a size suitable for fluid bed drying using a suitable extruder, such as the aforementioned Alexanderwerk, where small blades chop the tablet, or can be broken down to a suitable size. Alternatively, granules produced by high shear mixing may be of a suitable size or disintegrated into a size suitable for drying followed by melt extrusion.

The dry matter typically contains less than 5% w/w water, eg 2-3% w/w water, or less, such as traces.

The melt extrusion can be performed in a similar manner to that described in WO9614058.

For the present invention we prefer to apply a twin screw extruder. Basically, preferably at a relatively low temperature (eg 10-20° C.), the dry granules or milled product flow into the first part of the extruder barrel through a feeder to ensure the flow of the material to the high temperature barrel. constant flow. The feeders provide a balanced flow of material to the extruder. Consistency is necessary because irregular and varying flow rates may produce multiparticulates with different physical properties, such as density and porosity.

For the tasks of transporting, mixing and compressing the mixture as well as providing mechanical energy, preferred extruders are designed with a double screw, which can have synchronously rotating or counter-rotating screws. The extruder should be equipped with the required heating and cooling means. A significant portion of the spirals that carry out this melt-extrusion method are made of different smaller elements. The mixing and kneading process can be varied considerably by varying the type, length and configuration of the helical elements. Short residence times and moderate to low shear contribute to safe processing and stable products even with heat sensitive drugs.

Helix rotation speed may play a role in the quality of the multiparticulates produced. High rotational speeds without proper influx rate compensation can produce highly porous multiparticulates with variable drug release rates. On the other hand, low helical rotation will induce unnecessarily long residence times. A vacuum attached to the extruder barrel is necessary to remove entrapped air and residual moisture within the plasticized mass and thus make dense multiparticulates that are ideally low porosity.

Extrusion heads are typically designed to produce multi-strand ribbons of fixed diameter, eg 1.0mm. The number, shape and diameter of the holes can be varied to suit predetermined specifications.

Besides said screw speed, other main influencing parameters are screw torque, individual barrel temperature, and extrusion head pressure and temperature.

According to a cutting method of the invention, the extruded strip is transported from a die-head on a conveyor.

The diameter of the ribbon is affected by the inflow rate of the starting material, the speed of the screw, the temperature of the barrel, the diameter of the punching pad hole and the speed of the conveying and pressing roller. Delivery The extruded strip is suitably delivered to a laser scale or other measuring device. During this shipping process, the strip gradually cools down, but remains substantially flexible. On the laser scale device, the flexible ribbon maintains integrity between the pelletiser inflow nip rollers and during entry into the pelletiser. The rapidly cooled strands, depending on the formulation, may lose their integrity and break up into heterogeneously shaped and irregular multiparticulates during passage through the nip rollers and granulator.

A laser scale can be used to provide a continuous measurement of the strip diameter, eg 1.0mm.

The measured strips flow into the granulator via pressure rollers. The granulator cuts the incoming ribbon, eg using a rotary knife cutter, to a predetermined length, eg 1.0 mm. The inflow rate of the ribbon and the speed of the granulator cutter determine the length of the multiparticulates.

In conclusion, the coordination/interaction between feeder, extruder, conveyor and granulator is an important parameter affecting the quantity, quality and reproducibility of the final multiparticulate product.

Multiparticulates produced by the cutting process in which the extruded strands are carried away from the die pad typically take the shape of a cylinder. Preferably said cylinder has a diameter of about 1 mm and a length of about 1 mm.

In another preferred cutting method, a cutting machine cuts the extruded mixture as it emerges from the orifices of the die under pressure and still in a molten state. The cutter is suitably a rotary cutter having one or more blades that wrap around the surface of the punching pad until passing through the holes. Two diametrically opposed blades are preferred. Ideally, the outer surface of the punch pad is coated with a non-stick substance, such as polytetrafluoroethylene (PTFE). As the cut extruded multiparticulates expand and cool, they tend to form rounded surfaces. By suitably adjusting the extrusion rate and the speed of the cutting knife, and generally cylindrical multiparticulates, it is possible, for example, to arrange to obtain spherical or substantially spherical, ellipsoidal or disc-shaped multiparticulates. In one embodiment, an air flow is directed against the surface area of the pad, which air cools the extrudate and accelerates solidification at a reduced temperature.

Spherical multiparticulates produced by this method offer many advantages:

Better batch-to-batch reproducibility.

Easier coating and lower coating weight required.

Better capsule filling and higher yields.

More stable in high position.

Stronger resistance to damage.

Reduces or eliminates some of the problems that arise during shipping and granulating the strips, such as strip fragmentation into tablets of different lengths and possible static charges.

The multiparticulates may be divided into unit doses such that each individual unit dose comprises a dose of medicament for administration to a mammalian, preferably a human patient. For the preferred drug, oxycodone or a salt thereof, preferably hydrochloride, a suitable dose of the active agent is 5-400 mg, especially a dose of 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 120 mg or 160 mg . In this regard, the unit dose contains an amount of the therapeutically active agent effective to produce pain relief and/or analgesia in the patient. The dose of oxycodone administered to a patient will vary due to a number of factors including the patient's weight, tolerance, pain sensitivity, metabolic status and the nature of the other therapeutic agents administered.

The multiparticulates thus obtained can be applied as fillers in capsules. Accordingly, the present invention provides capsules suitable for one or two daily doses. Controlled release formulations can be provided in other dosage forms.

In a preferred embodiment, the multiparticulates are filled into gelatin capsules, each containing a unit dose. The fill weight in the capsule is preferably in the range 80-500 mg, more preferably 120-500 mg. In a variation of the invention, the unit dose of multiparticulates may be incorporated into other solid pharmaceutical formulations, for example using compression or shaping or making tablets, or by making the extruded product into the form of a suppository.

The preferred capsules or other unit dosage forms of the invention are preferably designed for administration every about 12 or 24 hours.

A preferred drug for inclusion within the multiparticulates is oxycodone or a salt thereof, preferably its hydrochloride. A unit dosage form suitable for administration every 12 hours suitably has the following in vitro hydroxyl Codone disintegration rate, i.e. release of 12.5-42.5% by weight of oxycodone after 1 hour, 25-56% by weight of oxycodone after 2 hours, 45-75% by weight of oxycodone after 4 hours, and 55-85% by weight of oxycodone released after 6 hours.

A unit dosage form containing oxycodone or its salt, preferably its hydrochloride, suitable for administration every 12 hours, when at 37°C 900ml of pH 1.2 aqueous buffer (simulated gastric juice without enzyme) 100rpm, by having HPLC detection of 206nm wavelength UV, when using USP BasketMethod "711" Apparatus 1 test, can also suitably have the following in vitro disintegration rate, that is, in 1 hour 0-40%, preferably 25-35%; in 2 hours 20-70%, preferably 40-60%; 40-80%, preferably 55-75% at 3 hours; 60-95%, preferably 65-90% at 4 hours; and greater than 70% at 5 hours.

Also, we prefer that the highest plasma levels of oxycodone obtained in vivo occur between 2-4.5 hours after administration of the unit dosage form.

Further information on the essential characteristics of said oxycodone formulations is given in WO 9310765, which is hereby fully incorporated by specific reference.

Alternatively, the oxycodone capsules or other unit dosage forms of the present invention are designed to be administered at approximately 24 hour intervals. For this purpose, the unit dosage form suitably has the following in vitro disintegration rate of oxycodone when tested by the USP Basket Method at 100 rpm in 900 ml of aqueous buffer solution between pH 1.6-7.2 at 37°C, namely, 0% to about 40% at 1 hour, about 8% to about 70% at 4 hours, about 20% to about 80% at 8 hours, about 30% to about 95% at 12 hours, about 35% to about 18 hours About 95%, and greater than about 50% at 24 hours.

Also, we prefer that the highest plasma levels of oxycodone obtained in vivo are achieved between about 2 hours and about 17 hours after administration in a steady state dosage form.

A unit dosage form containing oxycodone or its salt, preferably its hydrochloride, suitable for administration every 24 hours, when at 37°C 900ml of pH 1.2 aqueous buffer (simulated gastric juice without enzyme) 100rpm, by having The HPLC detection of 206nm wavelength UV, when using USP BasketMethod "711" Apparatus 1 test, also can suitably have following in vitro disintegration rate, that is, in 1 hour 10-30%, preferably 17-23%; In 2 hours 20-35%, preferably 24-32%; 35-75%, preferably 48-66% at 8 hours; and greater than 50%, preferably 68-92% at 16 hours.

Further information on the essential characteristics of said oxycodone formulations is given in WO 02087512, which is hereby fully incorporated by specific reference.

In a variation, the invention provides unit doses containing an opioid effective to prevent destruction and an opioid antagonist. In this regard, reference is made to WO 0313433, which is hereby fully incorporated by specific reference. In particular, the unit dose may contain oxycodone and naltrexone.

To this end, the present invention provides melt extruded multiparticulates of an opioid, such as oxycodone, and melt extruded multiparticulates of an opioid antagonist, such as naltrexone. In preferred formulations, the antagonist multiparticulates do not release the antagonist when administered routinely, and, for example, have a non-releasing coating. The two opioids and the opioid antagonist are preferably visually and physically identical.

An important aspect of the invention is a capsule having a unit dose fill of less than 500 mg comprising up to about 350 mg of oxycodone multiparticulates, and up to about 200 mg of tamper resistant oxycodone antagonist multiparticulates. For example, there may be 120-300 mg of oxycodone multiparticulates, and 125-175 mg of oxycodone antagonist multiparticulates.

Figure overview

Reference is made to the accompanying drawings in the Experimental Section below, in which:

Figure 1 shows the disintegration of oxycodone from a tablet prepared in Example 5.

Figure 2 shows the disintegration of oxycodone from tablets prepared in Examples 10-13.

Figure 3 shows the disintegration of oxycodone from pulverized tablets prepared in Examples 11-13.

Figure 4 shows the disintegration of oxycodone tablets prepared from Examples 11-13 after grinding with a pestle and mortar.

Figure 5 shows the disintegration of oxycodone in solvent from tablets prepared in Examples 10-13.

Embodiment of the invention

Examples 1, 2 and 3

Three batches of (example) multiparticulates were prepared in a similar manner:

Step 1. To begin, place the following in a Gral 10 high shear mixer, preheat to 40°C, and dry mix at high speed for 2 minutes:

Oxycodone Hydrochloride

Eudragit RS PO

stearyl alcohol

stearic acid

Step 2. Sieve the Eudragit NE 40 D dispersion through a 350micron strainer to eliminate aggregates, and transfer to an appropriate sized container.

Step 3. Spray the screened Eudragit NE 40 D dispersion onto the dry mixed mass of Step 1 in the mixing bowl at low spray pressure while maintaining stirring/chopping.

Step 4. Continue to apply Eudragit NE 40 D until granule formation occurs.

Step 5. Periodically interrupt the application of Eudragit NE 40 D to scrape the rim of the mixing bowl.

Step 6. After all Eudragit NE 40 D has been applied, dry the granules under the same temperature conditions and reduced stirring/chopping speed.

Step 7. The granules were then fed at a controlled rate into a Leistritz Micro 18 extruder equipped with a conveyor and granulator. The extruder had a 1.5 mm die, and the following heating stations: stations 3-8, 90°C-100°C; stations 9 and 10, 100°C. The inflow rate was 2.0-2.6 kg/hr and the screw speed 100-141 rpm with a torque/melt pressure of 50-60%/40-50 bar.

The extruded strips are removed from the punch pad of the conveyor and cut into cylindrical multiparticulates.

substance Example (% w/w) Example 1 Example 2 Example 3 anhydrous lactose 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 100 100 100

^* for Eudragit NE 40 D (water removed by drying)

Example 4

For this example, an alternative cutting method is applied. Extrudates emerge from 12 holes in the punch pad of a Leistritz Micro 18 extruder. A rotary cutter with double blades was used to cut the extrudate when holes in the pierce mat appeared under pressure and still in the molten state. As they expand and cool, the cut extruded particles tend to form rounded surfaces.

The following formulation was used to produce a placebo product containing lactose as a pharmaceutically inactive ingredient.

substance Example 4 (% w/w) anhydrous lactose 10.0 Eudragit RS PO 37.0 stearyl alcohol 10.0 stearic acid 6.0 Eudragit NE 40 D 37.0 ^* Total 100

^* Value expressed as solids content

By appropriate adjustment of extrusion diameter, including temperature and extrusion rate, spherical or substantially spherical multiparticulates can be obtained.

Examples 5 and 6

Two batches of multiparticulates were planned using tributyrate citrate as plasticizer (approximately 43% w/w drug loading). The percentage content, w/w, is as follows:

substance Example (%w/w) 5 6

Oxycodone Hydrochloride 42.2 42.2 Ethylcellulose N10 14.7 19.6 Eudragit NE 40 D ^* 35.3(S), [88.3(D)] 29.4(S), [73.5(D)] tributyl citrate 5.9 6.9 Glyceryl Dibehenate 2.0 1.9 Total 100 100

S = solid weight

D = weight of dispersion

^* 40% dispersion (% w/w), water loss by evaporation

The method used to prepare the multiparticulates of Example 5 in tablet form was as follows:

Step 1. Slowly add tributyl citrate to the ethyl cellulose in a Gral 10 high shear mixer and mix.

Step 2. Add Oxycodone to the mixture of Step 1 in the Gral 10 high shear mixer and mix for 5 minutes.

Step 3. Sieve the Eudragit NE 40 D dispersion through a 350micron strainer to eliminate aggregates, and transfer to an appropriate sized container. Then, with the help of a peristaltic pump, slowly add the sifted Eudragit NE 40 D to the mixture from step 2 in the Gral 10 mixing bowl, preheated to 38°C, while maintaining stirring/chopping.

Step 4. Continue to apply Eudragit NE 40 D until granulation occurs - add all of Eudragit NE 40 D.

Step 5. Periodically interrupt the application of Eudragit NE 40 D to scrape the rim of the mixing bowl.

Step 6. After all of the Eudragit NE 40 D has been added, the wet granules are extruded through a conventional extruder and dried in a fluid bed dryer at approximately 42°C.

Step 7. Cool the dried granules to room temperature and collect.

Step 8. Then, under the same conditions as in Example 1, the granules were flowed into a Leistritz Micro 18 extruder equipped with a 1.0 mm die, conveyor and granulator at a controlled rate. The extruded strips are removed from the punch pad on the conveyor and cut into cylindrical multiparticulates.

The method used to prepare the formulation of Example 6 was the same as Example 5, except in the following respects:

• No plasticizer was added in step 1. Instead, step 1 was eliminated and step 2 consisted of mixing oxycodone hydrochloride and ethylcellulose in a Gral 10 high shear mixer.

• The granules were screened (1.5 mm mesh) and the oversized granules were milled (1.0 mm mesh) and recombined with other granules.

• At the end of step 7, a lubricant (glyceryl dibehenate) was added to the dry granules immediately before flowing into the extruder.

• The extruder has a die with a 1.5 mm hole.

An alternative cutting method may be considered. The extrudate emerges from the orifice of the die pad of the Leistritz extruder. A rotary cutter with double blades is used to cut the extruded mixture as it emerges from the holes of the die under pressure and still molten. The blade wraps around the face of the punch pad to pass through the hole. As they expand and cool, cut extruded particles tend to form rounded surfaces.

Although a Leistritz Micro 18 extruder was used in the above examples, larger extruders, such as the Leistritz Micro 27, may be preferred to handle materials requiring higher processing torques.

Apply USP Basket Method "711" Apparatus 1, in 37 ℃ 900mlpH1.2 aqueous buffer (simulated gastric juice without enzyme) at 100rpm, by HPLC detection with 206nm wavelength UTV, the extruded tablets obtained in Example 5 were processed Disintegration was tested and the following results are given, which are plotted in Figure 1, along with the preferred curve for the once-a-day product.

time (hour) Example 5% Oxycodone released 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 twenty one 87 twenty two 88 twenty three 88 twenty four 88

Examples 7, 8 and 9

The same method and method as in the preceding examples were applied except for a temperature range of 100-120° C., a screw speed of up to 240 rpm, and a die size of 1.5 mm (Examples 7 and 8) and 1.0 mm (Example 9) diameter. Extrusion conditions, the formulations described below were processed to produce multiparticulates.

substance Example (% w/w) Example 7 Example 8 Example 9 Oxycodone Hydrochloride 43 43 43 Ethylcellulose N10 19 19 18 Eudragit NE 40D ^* 29 29 27 tributyl citrate 6 6 6 stearyl alcohol 3 Glyceryl Dibehenate 3 6 Total 100 100 100

^* The value indicated is solid content only. The weight of liquid dispersion is (value/40)×100

Examples 10-13

Using a method similar to that of the previous examples, multiparticulates were produced using the formulations described below.

substance Example (%w/w) Example 10 Example 11 Example 12 Example 13 Oxycodone Hydrochloride 10.0 10.0 10.0 10.0 Ethylcellulose 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 100 100 100 100

S = solid weight

D = weight of dispersion

^* 40% dispersion (% w/w), water loss by evaporation

The multiparticulates of Examples 10-13 above were subjected to a disintegration test using the USP Basket Method described in Example 5 above. The results are shown in Figure 2. These results demonstrate that, in this assay, the release profiles of the multiparticulates of Examples 12 and 13 are similar to that of a formulation (Example 5 of our pre-approved Application Publication No. WO 2005/000310), when in vivo When tested, the formulation was substantially bioequivalent to the oxycodone hydrochloride controlled release tablet.

The multiparticulates of Examples 10-13 had lower release profiles, which may suggest that they would be suitable for dosage forms administered at 24 hour intervals.

The multiparticulates of Examples 10-13 were tested to determine their potential for damage resistance as follows:

1) Crush 400mg of the multiparticulates of Examples 10-13 between two spoons or in a pill mill (such as the Pill Pulverizer sold by Apex Healthcare Products) and extract on the spoon in 2ml of water heated to boiling and filter. The amount of extracted oxycodone was then determined by HPLC and detected by UV at a wavelength of 210 nm and is shown in the graph of FIG. 3 .

2) In a mortar and pestle, 400 mg of the multiparticulates of Examples 10-13 were subjected to milling, the pestle was rotated 24 times, and the product was placed in 900 ml of water at 37°C for 45 minutes. The amount of dissolved oxycodone was then determined by the method described in 1), and the results are shown in bar graph form in FIG. 4 .

3) In each extraction of a)-e), 400 mg of the multiparticulates of one of the examples 10-13 were treated separately as follows: the multiparticulates were placed in the required solvent in a glass flask, and the flask was placed in a water bath Heat on high (if desired). The flasks were then subjected to shaking for the required time using a Stuart Scientific Flask Shaker Model SF1 apparatus at 500-600 shakes per minute. After extraction, the amount of dissolved oxycodone was then determined by the method used in 1).

a) Shake in 10ml of water for 15 minutes at room temperature;

b) Heating in 10ml of water at 50°C for 5 minutes, followed by shaking for 15 minutes;

c) heating at 75°C in 10ml of water for 5 minutes, followed by shaking for 15 minutes;

d) Heating in 10ml of water at 100°C for 5 minutes, followed by shaking for 15 minutes;

e) Shake in 40% ethanol for 15 minutes at room temperature.

The detection results are shown in the histogram of Fig. 5 .

Claims (51)

1. A controlled-release pharmaceutical formulation comprising melt-extruded multiparticulates, wherein the multiparticulates comprise a rubber-like matrix comprising neutral poly(ethyl acrylate, methyl methacrylate) copolymers and active agent. 2. A formulation according to claim 1, wherein said active agent is an opioid, a stimulant, a barbiturate, an antidepressant or a dissociating anesthetic. 3. A formulation according to claim 2, wherein said active agent is oxycodone or a pharmaceutically acceptable salt thereof. 4. The formulation according to claim 1, which resists destruction by reducing the release of the active agent when extracted in water, ethanol or aqueous ethanol liquid. 5. The formulation according to claim 1, when tested by a method of detection comprising: mixing a dosed amount of multiparticulates with 10 ml of liquid in a glass flask and using a Stuart Scientific Shaker Model SF1 at a rate of 500-600 times of shaking for 15 minutes, the formulation exhibits at least one of the following characteristics (a)-(e): (a) shaking in water for 15 minutes at room temperature: less than 7.5% of the active agent is released; (b) in water at 50°C for 5 minutes, followed by shaking at the same temperature for 15 minutes: less than 15% of the active agent is released; (c) standing at 75°C for 5 minutes, followed by shaking at the same temperature for 15 minutes: less than 20% of the active agent is released; (d) standing at 100°C for 5 minutes, followed by shaking at the same temperature for 15 minutes: less than 25% of the active agent is released; (e) Shaking in 40% ethanol for 15 minutes at room temperature: preferably less than 25% of the active agent is released. 6. The formulation according to claim 1, wherein said anti-disruption reduces release of active agent when said formulation and extract are milled. 7. A formulation according to claim 6 which releases less than 10% of the active agent when tested by a test method comprising subjecting a dosage amount of the formulation to grinding in a mortar and pestle , the pestle was rotated 24 times and placed in 900 ml of water for 45 minutes at 37°C. 8. A formulation according to claim 6 which releases less than 15% of the active agent when tested by a test method which comprises comminuting the dose in a pellet mill sold by Apex Healthcare Products and then Extract on a spoon in 2ml of water heated to boiling and filter. 9. The formulation according to claim 1, wherein said matrix comprises at least one other release-modifying polymer, wherein said polymer is an alkylcellulose or a water-insoluble ammonium methacrylate copolymer. 10. A formulation according to claim 9, wherein said other polymer is ethylcellulose. 11. The formulation according to claim 10, wherein the amount of ethyl cellulose is 10-50% by weight of the formulation. 12. The formulation according to any one of claims 9-11, comprising the following amounts of components, based on the total weight of the specified components:

13. A formulation according to claim 12 comprising the following amounts of components, based on the total weight of the specified components:

14. The formulation according to claim 12, comprising the following amounts of components, based on the total weight of the specified components:

15. The formulation according to claim 1, comprising up to 60% w/w active agent, 15-50% w/w neutral poly(ethyl acrylate, methyl methacrylate) copolymer; 5-60 % w/w ethylcellulose; and 7.5-20% plasticizer. 16. The formulation according to claim 15, further comprising 5-60% of an insoluble ammonium methacrylate copolymer. 17. The formulation according to claim 16, comprising 35-50% of a low-permeability insoluble ammonium methacrylate copolymer, and/or 5-30% of a highly-permeable ammonium methacrylate copolymer. 18. The formulation according to claim 1, which contains a bulking agent. 19. The formulation according to claim 1, which contains an opioid and an opioid antagonist. 20. A formulation according to claim 19 comprising 120-300 mg of oxycodone multiparticulates and 125-175 mg of oxycodone antagonist multiparticulates. 21. A formulation according to claim 19 or 20 comprising oxycodone and naltrexone. 22. A formulation according to claim 19 or 20 comprising melt extruded multiparticulates of the opioid and melt extruded multiparticulates of the opioid antagonist. 23. The formulation according to claim 1, which is in unit dosage form. 24. A formulation according to claim 23 containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 120 mg or 160 mg of oxycodone. 25. A formulation according to claim 23 or 24, which is suitable for once-daily administration. 26. A formulation according to claim 25 which has the following in vitro oxycodone disintegration rate when tested by the USP Basket Method at 100 rpm at 37° C. in 900 ml of an aqueous buffer solution between pH 1.6-7.2, i.e., at 1 0%-40% at 4 hours, 8%-70% at 4 hours, 20%-80% at 8 hours, 30%-95% at 12 hours, 35%-95% at 18 hours, and greater than 50% at 24 hours . 27. The formulation according to claim 26, wherein the highest plasma level of oxycodone obtained in vivo occurs 2-17 hours after administration of said unit dosage form. 28. The formulation according to claim 25, when tested by USP Basket Method "711" Apparatus 1 at 100 rpm in 900ml pH 1.2 aqueous buffer at 37°C, detected by HPLC with 206nm wavelength UV, said formulation has the following in vitro Oxycodone disintegration rate, i.e., 10-30% at 1 hour; 20-35% at 2 hours; 35-75% at 8 hours; and greater than 50% at 16 hours, wherein the pH 1.2 aqueous buffer Simulated gastric juice without enzymes. 29. A formulation according to claim 23 or 24 which is suitable for twice daily administration. 30. According to the formulation of claim 29, when tested in 900ml aqueous buffer solution (pH 1.6-7.2) at 37°C with USP Paddle Method (seeing U.S.Pharmacopoeia XXII 1990) at 100rpm, said formulation has the following in vitro hydrochloride the rate of ketone disintegration, i.e. 12.5-42.5% by weight of oxycodone released after 1 hour, 25-56% by weight of oxycodone after 2 hours, 45-75% by weight of oxycodone after 4 hours, and 55-85% by weight of oxycodone was released after 6 hours. 31. The formulation according to claim 29, when tested by USP Basket Method "711" Apparatus 1 at 37°C in 900ml pH 1.2 aqueous buffer at 100rpm, detected by HPLC with 206nm wavelength UV, said formulation has the following in vitro Oxycodone disintegration rate, i.e., 0-40% at 1 hour; 20-70% at 2 hours; 40-80% at 3 hours; 60-95% at 4 hours; and greater than 70% at 5 hours, where The pH 1.2 aqueous buffer is simulated gastric juice without enzymes. 32. The formulation according to claim 31, wherein the highest plasma level of oxycodone obtained in vivo occurs between 2-4.5 hours after administration of the unit dosage form. 33. Melt extruded multiparticulates, each comprising a matrix of 20% to 66% by weight of a neutral poly(ethyl acrylate, methyl methacrylate) copolymer and a pharmaceutically active compound. 34. Multiparticulates according to claim 33, wherein said pharmaceutically active compound is an opioid analgesic. 35. Multiparticulates according to claim 34, wherein said opioid is oxycodone or a salt thereof. 36. Multiparticulates according to claim 33, 34 or 35, which take the shape of a cylinder, or a generally spherical, ellipsoidal or discoidal shape. 37. A process for the preparation of a controlled release formulation comprising a matrix comprising a neutral poly(ethyl acrylate, methyl methacrylate) copolymer and an active agent, the process comprising melt extrusion comprising Blend of neutral poly(ethyl acrylate, methyl methacrylate) copolymer and active agent. 38. The method according to claim 37, wherein said neutral poly(ethyl acrylate, methyl methacrylate) copolymer is provided in the form of an aqueous dispersion comprising 40% of said multipolymer, which is mixed with said The active agents are mixed, and dried so that the mixture is used for melt extrusion. 39. A method according to claim 37 or 38, wherein said mixture includes a plasticizer. 40. The method according to claim 39, wherein said plasticizer is tributyl citrate, stearyl alcohol or high molecular weight polyethylene glycol. 41. A method according to any one of claims 37, 38 or 40, wherein said mixture includes a lubricant. 42. The method according to claim 41, wherein said lubricant is stearic acid, a stearate, or glyceryl dibehenate. 43. A method according to any one of claims 37, 38, 40 or 42, comprising wet granulation of the components for the mixture to be extruded to obtain wet granules, drying the granules, and melt extruding The dried granules are compressed. 44. The method according to claim 43, wherein said wet granules are compressed prior to drying. 45. The method according to claim 44, wherein said dried granules contain less than 3% w/w water. 46. A method according to any one of claims 37, 38, 40, 42, 44 or 45, wherein the melt extrusion of the dry granules is carried out in a twin screw extruder. 47. A method according to any one of claims 37, 38, 40, 42, 44 or 45, wherein said extruded strand is conveyed to a granulator and cut into multiparticulates. 48. A method according to any one of claims 37, 38, 40, 42, 44 or 45, wherein each multiparticulate has a diameter of 1 mm and a length of 1 mm. 49. A method according to any one of claims 37, 38, 40, 42, 44 or 45, wherein said cutter cuts said extruded mixture as it emerges from the extruder. 50. Use of a neutral poly(ethyl acrylate, methyl methacrylate) copolymer for the preparation of a pharmaceutical formulation as defined in any one of claims 1-32, which provides tamper resistance. 51. A method of imparting vandal resistance to a pharmaceutical formulation comprising a rubber-like matrix comprising a neutral poly(ethyl acrylate, methyl methacrylate) copolymer and an active agent comprising a mixing active Components and neutral poly(ethyl acrylate, methyl methacrylate) copolymers, melt-extruded multiparticulates, combining active ingredients in a matrix with neutral poly(ethyl acrylate, methyl methacrylate) copolymers, and forming said multiparticulates in a formulation.

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