MXPA06009167A

MXPA06009167A - Particulates

Info

Publication number: MXPA06009167A
Application number: MXPA/A/2006/009167A
Authority: MX
Inventors: Walden Malcolm; Mohammad Hassan; Tamber Harjit; Whitelock Steve; Gerard Hayes Geoffrey; Kathleen Danagher Helen; Allan Prater Derek
Original assignee: Kathleen Danagher Helen; Euroceltique Sa; Gerard Hayes Geoffrey; Mohammad Hassan; Allan Prater Derek; Tamber Harjit; Walden Malcolm; Whitelock Steve
Priority date: 2004-02-12
Filing date: 2006-08-11
Publication date: 2007-04-20

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

PARTICULATE MATERIAL Field of the Invention The present invention relates to particulate material, and in particular melted extruded multiparticulates which provide controlled release of the active ingredient. Background of the Invention Multiparticulates of uniform dimensions with modified release properties of the drug can be easily manufactured by melt extrusion technology. Melt extrusion is a solvent-free single step process for the manufacture of multiparticulate and is particularly useful for the modification of drug release by the selection of suitable thermoplastic polymers and additives, melted extrusion technology can be used, both to increase the solubility as subsequently the bioavailability of the drugs that are poorly soluble in water, as well as to delay the release of the drug to moderate the highly water soluble drugs for the controlled release products. The structure of the melted extrusion technology is the application of thermoplastic materials which act as linkers for the embedded drugs in the form of solution or dispersion within the matrix. Thermoplastic polymers with low glass transition temperatures (Tg) are preferred for melt extrusion processing. Lower processing temperatures are also preferred with respect to the stability of the heat-sensitive drugs and other necessary excipients. The glass transition temperatures of the polymer can also be further reduced to facilitate processing at lower temperatures with the optional addition of plasticizers. Illustratively, WO 9614058 provides a sustained release pharmaceutical formulation, comprising a melted extruded mixture of a therapeutically active agent, one or more materials selected from the group consisting of alkylcellulose, polymers and copolymers of acrylic and methacrylic acid, shellac, ceina, hydrogenated castor oil, hydrogenated vegetable oil and mixtures thereof; one or more hydrophobic vehicles that can melt, which provide an additional retarding effect and are selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols and mixtures thereof, the meltable vehicle has a point of fusion of 30 to 200 ° C. The melted extruded mixture divided into a unit dose containing an effective amount of said therapeutically active agent to produce a desired therapeutic effect and providing sustained release of the therapeutically active agent for a period of from about 8 to about 24 hours. In addition, WO 9614058 describes a method of preparing a sustained release pharmaceutical extrudate suitable for oral administration. The method comprises: mixing a therapeutically active agent together with (1) a material selected from the group consisting of alkylcellulose, polymers and copolymers of acrylic acid and methacrylic acid, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil and mixtures of and (2) a meltable vehicle selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols and mixtures thereof, the retardant material having a melting point between 30 and 200 ° C and being included in an amount sufficient to further delay the release of the therapeutically active agent. Heating the mixture to a temperature sufficient to soften the mixture sufficiently to extrude it; the extrusion of the heated mixture as a strip having a diameter of 0.1 to 3 mm; relative cooling; and the division of the strip to form non-steroidal extrudate multiparticulates having a length of 0.1 to 5 mm; and dividing the non-steroidal multiparticulate into unit doses containing an effective amount of the therapeutically active agent, the unit dose providing a sustained release of the therapeutically active agent for a period of time from about 8 to about 24 hours. In certain preferred embodiments of WO 9614058, the hydrophobic material is a pharmaceutically acceptable acrylic acid polymer, including but not limited to, copolymers of acrylic acid and methacrylic acid, methyl methacrylate, copolymers of methyl methacrylate, ethoxyethyl methacrylates, cyanoethyl methacrylate, copolymer aminoalkyl methacrylate, poly (acrylic acid), poly (methacrylic) acid, alkylamine copolymer of methacrylic acid, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers. Therefore, in many of the examples, the hydrophobic material is Eudragit RS PO (poly (ethyl acrylate, methyl methacrylate, trimethylammonium methacrylate) chloride, optionally in the presence of Eudragit L100 (poly (methacrylic acid methyl methacrylate)). Brief Description of the Invention The present invention provides formulations employing a neutral copolymer of poIi (ethyl acrylate, methyl methacrylate) as a pharmaceutically acceptable carrier. Said copolymer can impart controlled release properties to the formulation. In addition, with the present invention, we can provide a rubberized formulation through the use of melted extrusion. The neutral copolymer of poly (ethyl acrylate, methyl methacrylate) is commercially available in the form of an aqueous dispersion. Two of these products are, Eudragit NE 30 D and Eudragit NE 40 D, and comprise respectively 30% and 40% of the polymer. In particular, Eudragit NE 30 D forms water insoluble films and is suitable for granulation processes in the manufacture of matrix tablets and sustained release coatings without the addition of any plasticizer. Information on the use of Eudragit NE for preparing tablets and coatings can be found on the website: http://www.roehm.de/en/pharmapolymers.html. For example, the website has a technical article describing how to make sustained-release ibuprofen matrix tablets, using wet granulation using the Eudragit NE 30 D as a linker and diffusion control agent. The granules can be made by mixing the ibuprofen with the Eudragit dispersion, grinding them through a sieve and drying them. The granules are ground, mixed with disintegrants and other ingredients and then compressed into tablets. The amount of Eudragit NE is relatively low. In WO 03004009, the Eudragit NE is among a list of hydrophobic components suggested for use with hydrophilic digestible components and a pharmaceutical agent that is difficult to compress. It seems that the intention was to refer to another Eudragit, since Eudragit NE is a wet dispersion and the objective of WO 03004009 is to form a formulation that can be compressed by a process different from wet granulation. Sood et al, describe the use of extrusion spheronization to develop controlled release dosage forms for diltiazem hydrochloride in the publication Pharmaceutical Technology 2004 (April)): pages 62 to 85. A number of candidate materials were evaluated as agents of granule matrix formation in a process comprising wet granulation, extrusion of wet granules and spheronization to form wet granules, which are then dried. The Eudragit NE 30 D was tested in formulations D19 and D20, and had no improvement in the control of drug release. In the present invention, a neutral poly (ethyl acrylate) copolymer can be employed, methyl methacrylate) as the vehicle in the formulation. Generally, the formulation of the present invention uses neutral copolymer of poly (ethyl acrylate, methyl methacrylate) to produce a matrix within which an active ingredient is dispersed. Therefore, for example, the present invention provides microparticles each with said matrix. The formulations of the present invention can take the form of a unit dose, such as a capsule with a multiparticulate filler with neutral copolymer of poly (ethyl acrylate, methyl methacrylate) as carrier. The multiparticulates can be extrudates formed by extruding a dry blend, notably a mixture of dry granules which include a neutral copolymer of poly (ethyl acrylate, methyl methacrylate). Especially by the use of extrusion, the present invention provides controlled release multiparticulates which take the form of a cylinder and are generally spherical, elliptical or disk-shaped. To this end, the present invention further provides a dry blend with an unfinished composition comprising the neutral copolymer of poly (ethylene acrylate, methyl methacrylate) and an active ingredient. Said composition is substantially free of water and is suitable for extrusion as part of a process for producing a formulation of the present invention. Generally, the unfinished composition is a dry granulate and can be an extruded granulate. In particular, we provide a dry granulation of neutral copolymer of poly (ethylene acrylate, methyl methacrylate) and an active ingredient, wherein the neutral copolymer level of poly (ethyl acrylate, methyl methacrylate) is relatively high in order to impart the desired properties . Generally, amounts of 20% to 66% by weight of the neutral copolymer of poly (ethyl acrylate, methyl methacrylate) are employed in the dried granulate. In accordance with the present invention there is also provided a process for the preparation of a controlled release pharmaceutical extrudate, wherein the blend for extrusion includes a neutral copolymer of poly (ethyl acrylate, methyl methacrylate). Another aspect of the present invention resides in a method of administering an active ingredient, wherein the active ingredient is administered as a controlled release formulation employing a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) as the pharmaceutically acceptable carrier.

An aspect related to the present invention is the use of the neutral copolymer of poly (ethylacrylate, methyl methacrylate) in the preparation of a pharmaceutical formulation to produce the extrusion resistance, which is of importance where the active ingredient is open for manipulation. The present invention provides a method for imparting extrusion resistance to a pharmaceutical formulation which comprises incorporating a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) with the active ingredient in the formulation. Detailed Description of the Invention We find that by using a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) in the preparation of controlled release pharmaceutical extrudates, a melted extruded multiparticulate which has similar rubber characteristics can be obtained. Said hulled extrudates may exhibit improved resistance to handling. In particular, it appears that the rubberized characteristics are imparted by the melted extrusion step. In one aspect, the present invention provides a controlled release pharmaceutical formulation that can be obtained by melt extrusion and that includes a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) and an active ingredient. In a related aspect, the present invention provides a formulation which includes microparticles similar to rubber. The characteristics similar to rubber produce multiparticulates which are generally elastic and can be compressed without breaking, preferably elastic. In a preferred form, as a demonstration of rubber-like characteristics, multiparticulates can be compressed between two rigid surfaces, for example, a coin and the cover of a table or two spoons, without breaking. Multiparticulates can generally be distorted but not broken or separated and can ideally re-assume their original form more or less. The rubberized characteristics can help to impart resistance to handling. The resistance to handling is of special importance for products containing opioid analgesics and other active ingredients which are subjected to the manipulation. The resistance to handling of the preferred multiparticulates of the present invention can be demonstrated by stirring a dosage amount of microparticulates in water and / or ethanol, for example, 40% ethanol. For example, a multiparticulate dosage amount can be mixed in 10 ml of liquid (water and / or ethanol) in a glass flask and then subjected to stirring at 500 to 600 oscillations per minute, for 15 minutes using a Stuart stirrer Scientific Shaker Model SF1, optionally after resting for 5 minutes. The quantities of the active agent extracted then can be determined by HPLC and UV detection, for example, at a wavelength of 210 mm.

When tested in this manner, preferred multiparticulates according to the present invention showed at least one of the following release characteristics of the active ingredient. 15 minutes of agitation in water at room temperature: less than 10% release of the active agent, preferably less than 7.5% release of the active agent, more preferably less than 5% release of the active agent, eg, 1.5 % to 4% release of the active agent. 5 minutes of standing in water at a temperature of 50 ° C followed by 15 minutes of stirring at the same temperature: less than 20% release of the active agent, preferably less than 15%) of release of the active agent, more preferably less than 12% release of the active agent, for example, from 4% to 12% release of the active agent. 5 minutes of rest at a temperature of 75 ° C followed by agitation at the same temperature: less than 25% release of the active agent, preferably less than 20% release of the active agent, more preferably less than 15% release of the active agent, for example, 10% to 15% release of the active agent. 5 minutes rest at a temperature of 100 ° C followed by 15 minutes of stirring at the same temperature: less than 30% release of the active agent, preferably less than 25% release of the active agent, more preferably less than 20% release of the active agent, for example, from 12% to 20% of release of the active agent. 15 minutes of agitation in 40% ethanol at room temperature: less than 35% release of the active agent, preferably less than 30% release of the active agent, more preferably less than 25% release of the active agent, e.g. 15% to 25% release of the active agent. Alternatively, the resistance to handling of the preferred multiparticulates of the present invention can be demonstrated by subjecting a multiparticulate dosage amount to a grind in a mortar and pestle with 24 rotations of the pestle and the product placed in 900 ml of water at a time. temperature of 37 ° C for 45 minutes. The quantities of the active agent extracted can then be determined by HPLC and detection by UV rays, for example, at a wavelength of 210 nm. When tested using this method, the preferred multiparticulates according to the present invention showed the following release characteristics of the active ingredient: less than 12.5% release of the active agent, preferably less than 10% release of the active agent, more preferably less 7.5% release of the active agent, for example, from 2% to 7.5% release of the active agent. In a further method, the resistance to manipulation of the preferred multiparticulates of the present invention can be demonstrated by grinding a multiparticulate dosing amount between two spoons or a crusher, such as the Pili Sprayer as sold at Apex Healthcare Products. , and then extracting in 2 ml of water heated until boiling in a spoon being filtered. The amounts of active agent extracted can then be determined by HPLC and detection by UV rays, for example, at a wavelength of 210 nm. When tested using this method, the preferred multiparticulates according to the present invention showed the following release characteristics of the active ingredient: less than 27.5% release of the active agent, preferably less than 15% release of the active agent, more preferably less than 5% release of the active agent, for example, from 1% to 5% release of the active agent. In order to impart said resistance to manipulation, the present The invention provides the use of a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) in the preparation of a pharmaceutical formulation to provide resistance to manipulation. A neutral copolymer of poly (ethyl acrylate, methyl methacrylate) is incorporated with the active ingredient in the formulation. In one aspect, the present invention provides a method for imparting resistance to handling in a pharmaceutical formulation, which comprises mixing the active ingredient and the neutral copolymer of poly (ethyl acrylate, methyl methacrylate) and forming a pharmaceutical formulation incorporating the ingredient active with the neutral copolymer of poly (ethyl acrylate, methyl methacrylate). The neutral copolymer of poly (ethyl acrylate, methyl methacrylate) is suitably employed in a weight amount of up to 66% of the extrusion mixture, say 20% to 66% of the extrusion mixture, more generally the 20% to 50% of the extrusion mixture, such as 30% to 40% of the extrusion mixture. These percentages are also applicable to the amount of the neutral copolymer of poly (ethyl acrylate, methyl methacrylate), in a dry granulate of the present invention. The neutral copolymer of poly (ethyl acrylate, methyl methacrylate) can be used with other ingredients including a drug or other active ingredient. The reader can refer to WO 9614058, incorporated in the present description in its entirety as a specific reference. The neutral copolymer of poly (ethylene acrylate, methyl methacrylate) can all or most preferably form part of the release control material employed in the extrusion method of that patent specification. In this regard, our preferred compositions include at least one other polymer to modify the release. In particular, it seems that the use of ethyl cellulose or a similar polymer can help to impart resistance to handling, especially resistance to extraction by alcohol. An alkyl cellulose, such as ethyl cellulose, is preferably employed, for example, in an amount of 5% to 60% w / w of the formulation, preferably 10% to 50% w / w of the formulation, and more preferably 20%. % to 45% w / w of the formulation. Other suitable polymers include water-insoluble ammonium methacrylate copolymers. The insoluble ammonium methacrylate copolymers could be Eudragit RS PO and Eudragit RL PO, which are copolymers of ammonium methacrylate. In particular, said at least one of other polymers is generally a low water permeable thermoplastic polymer, or a relatively high water permeable thermoplastic polymer, which can significantly modify the release, but will be used in an amount which does not damage the elasticity or flexibility. When a plasticizer and / or a lubricant is preferred, for use in an extruder with a relatively low torsion capacity, such as the Leistritz Micro 18 machine. With a larger extruder, such as the Leistritz Micro 27 extruder, formulations can be processed. , with or without relatively low levels of plasticizer and / or lubricant. The plasticizer is generally 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 glycol, 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. The preferred plasticizer is tributyl citrate. Stearyl alcohol is also a preferred plasticizer. Another preferred plasticizer is a high molecular weight polyethylene glycol with a MW of 1000 to 20,000, such as PEG 6000. A lubricant may be included. The lubricant is generally solid at room temperature and is suitably selected from stearic acid, glycerol dibehenate, magnesium stearate, calcium stearate, talc and silicon dioxide (fused silica). The presence of the lubricant in the melted extrusion formulation improves mixing, kneading and transportation and reduces the forces of cohesion and adhesion. Soft extrusion at low to moderate temperatures improves the ability to reproduce from batch to batch and reduces deformation, both in the product and in the equipment. Stearic acid, possibly in the form of a salt, is a preferred lubricant. Another preferred lubricant is glycerol dibehenate. A drug is generally present as the active ingredient in the formulations of the present invention. The reader can consult WO 9614058, for examples. Oxycodone is a typical drug for use in the products and processes of the present invention. Other opioids are, for example, hydromorphone, hydrocodone, fentanyl and analogues thereof, buprenorphine, diamorphine, meperidine, propoxyphene and diphenoxylate. Other active agents that can be formulated according to the present invention include stimulants, such as dextroamphetamine, amphetamine, methamphetamine, sibutamine, methylphenidate; barbiturates, such as metobarbitol and pentobarbitol; antidepressants, such as diazepam, bromozepam, chlordiazepoxide, oxazepam, malprazolam, triazolam and etazolam, flunitrazapam and methaqualone; dissociative anesthetics, such as ketamine; and acid addition salts and esters thereof. Therefore, the preferred multiparticulates of the present invention may comprise a neutral copolymer of poly (ethyl acrylate, methyl methacrylate), an active ingredient; at least one of other polymers to modify the release which is generally an alkyl cellulose; optionally a plasticizer; and optionally a lubricant. Suitable percentage amounts for the preferred ingredients are given in the following table, based on the total weight of the specified ingredients: * The amount of the active ingredient can be 0% in placebo formulations for trials or development work. A typical formulation may contain as much as, for example, up to 60% w / w of the active ingredient or placebo, from 15% to 50% w / w of the neutral copolymer of poly (ethyl acrylate, methyl methacrylate), 5% by weight. 60% op / p, suitably from 15% to 50% w / w, for example from 15% to 25% or from 25% to 45% of an alkyl cellulose preferably ethyl cellulose and from 0% to 25% preferably 7.5% or 20% of one or more plasticizers, for example, stearyl alcohol and tributyl citrate. For example, up to 50% oxycodone may be present as the active ingredient. These ingredients may be the only components or if it is desired that the formulations may contain additional components, such as 5% to 60% > of an insoluble ammonium methacrylate copolymer. Illustratively, the formulation can comprise from 10% to 50%, preferably 35% to 50% of an insoluble ammonium methacrylate copolymer which is low permeability, such as Eudragit RS PO, and / or can contain the % to 40%? , for example 5% > at 30%), preferably for example from 5% to 25% > of an ammonium methacrylate copolymer, which is highly permeable, such as Eudragit RL PO. Other additives can also be used to produce the multiparticulates within a set of previously determined specifications. Volume agents, such as, for example, lactose, microcrystalline cellulose and calcium phosphate, are widely used as pharmaceutical excipients and can be used in the present invention to modify release rates and / or total release. Other release modifying agents may also be considered to regulate the release rate and / or improve the total release. The multiparticulates are preferably produced by the melted extrusion of a granule and in particular, by a process comprising the wet granulation of the ingredients and the drying of the granulates and the melted extrusion of the granulate. The granulation step can be carried out using conventional procedures, for example, using a high shear mixer, such as a Gral mixer or a fluidized bed granulator with a rotary insert. When a high cut mixer is used, the process may comprise the following steps; a) granulation; preferably wet granulation; b) optionally extruding the granulate; c) drying the granulate or the extruded granulate, preferably by means of a fluidized bed dryer; d) optionally casting and / or grinding the dried granulate or the dried extruded granulate of step c); and e) melted extrusion of the product of step c) or d). When using the fluidized bed granulator with or without rotary insert, the process may comprise the following steps: a) granulation; b) optionally extruding the granulate c) granulate drying or the extruded granulate, preferably by a fluidized bed dryer; d) optionally casting and / or grinding the product of step c); and e) melted extrusion of the dry or cast or ground granules of the product of step c) or step d). The product of step c) or d) which is to be loaded in the melted extruder, which is optionally ground or cast dry granulate, by itself is a novel product of the present invention. The granulation step can be carried out using conventional procedures, for example, in a high-cut mixer, such as a Gral mixer, generally, first the dry ingredients are added; these are mixed by the operation of the high cut mixer and then the dispersion of the polymer is added by spraying or in the form of drops and drying continues. For example, alternatively a liquid plasticizer can be added to the dry ingredients and mixed by the operation of the high cut mixer and the polymer dispersion then added by spraying or droplets and mixing continued. Then the granulate can be extruded in the optional step (b), for example, using an Alexanderwerk extruder. The extrudate is then dried using preferably a fluidized bed dryer. The extrudate can be produced directly from a suitable size for drying in the fluidized bed using a suitable extruder, such as the aforementioned Alexanderwerk extruder, wherein a small blade disrupts the granules, or they can be derailed to a suitable size. Alternatively, the granules produced by high shear mixing may be of a suitable size or debranched to a size suitable for drying followed by melted extrusion. The dry material will generally contain less than 5% > w / w of water, for example 2% to 3% w / w or water or less, such as trace amounts. The melt extrusion process can be carried out in a manner similar to that described in WO 9614058. For the present invention, we prefer to employ a twin screw extruder. Essentially, the dry granulate or the milled product is fed by a feeder in a first barrel segment of the extruder preferably at a relatively low temperature (eg, from 1 0 ° C to 20 ° C) to ensure a constant flow of the material to the barrels of high temperature. The feeder provides a uniform stream of material to the extruder. Consistency is desired, since irregular and variable feed rates can produce multiparticulates with different physical properties, such as density and porosity. The preferred extruder is designed with double screws, which can have co-rotating screws or counter rotation, for the tasks of transport, mixing and compression of the mixture, as well as providing mechanical energy. The extruder will be equipped with heating means and cooling means, as required. The screws that make up an important part of the melted extrusion process are constructed of different smaller elements. The mixing and kneading process can be significantly altered by changing the type, length and configuration of the screw elements. Short and moderate residence times at low shear forces contribute to safe processing and a stable product even with heat-sensitive drugs. The speeds of rotation of the screw can play a part in the quality of the multiparticulates produced. High rotation speeds without adequate compensation of the feed rate can produce high porosity multiparticulates with a variable drug release rate. On the other hand, a slow rotation of the screw would induce unnecessarily long dwell times. A vacuum source connected to the barrel of the extruder is desirable to remove trapped air and residual moisture from within the plasticized material and therefore, produce dense multiparticulates ideally of low porosity. The extrusion head is generally designed to produce multiple threads of a fixed diameter, for example 1.0 mm. The number, shape and diameter of the holes can be changed to adapt them to a previously determined specification. In addition to the speed of the screw, other main parameters of influence are the torsion of the screw, the individual temperature of the barrel and the pressure and temperature of the extrusion head. According to a cutting process of the present invention, the extruded yarns can be carried away from the die head on a conveyor. The diameter of the yarn is affected by the feed rate of the starting material, the speed of the screw, the temperature of the barrel, the diameter of the hole of the head of the die and the speed of transport and the speed of the rollers of contraction of the reef . The transportation is appropriate to take the extruded wires to a laser calibrator or other measuring device. During another transport process, the threads are cooled gradually, but essentially remain flexible. The flexible threads retain the integrity in the laser calibration apparatus, between the shrinking rollers of the granulator feed and during entry to the granulator. The rapidly cooled yarns, depending on the formulation, may lose their integrity and be destroyed during passage through the retraction rollers of the reef and granulator into unequally irregular multiparticulates of irregular size. The laser calibrator can be used to provide a continuous measurement of the wire diameter, for example 1.0 mm. The measured yarns are fed into the granulator by the retraction rollers of the reef. The granulator cuts the fed yarns, for example, using a rotary knife cutter to a predetermined length, for example of 1.0 mm. The index of feeding of the threads and the speed of the cutter of the granulator determines the length of the mulltiparticulates. Generally, the coordination / interaction between the feeder, the extruder, the conveyor and the granulator is an important parameter that affects the quantity, quality and reproducibility of final multiparticulate products. The multiparticulates produced by this cutting process wherein the extruded yarns are carried away from the die head, generally take the form of cylinders. Preferably the cylinders have a diameter of about 1 mm and a length of about 1 mm. In another preferred cutting process, a cutter cuts the extruded mixture as it melts under pressure and still melts from the holes in the die plate. The cutter is conveniently a rotary cutter with one or more blades which sweep over the surface of the head of the die to pass the holes. Two diametrically opposed blades are preferred. Ideally, the outer surface of the die head is coated with a non-sticky material, for example, polytetrafluoroethylene (PTFE). As the extruded multiparticulates expand and cool, they tend to form rounded surfaces. By suitable adjustment of the extrusion index and the speed of the blade and the cutter, as well as generally the cylindrical multiparticulates, it is possible, for example, to adapt them so that they are obtained spherical multiparticulates, or substantially spherical, elliptical or disc-shaped. In one embodiment, a flow of air directed into the region of the die head surface, the air being provided at a reduced temperature to cool the extrudate and for solidification at speed. The spherical multiparticulates produced by this method offer a number of advantages: A better ability to reproduce batch by batch. Easier coating and a lower coating weight required. Better filling of the capsule and higher performance. More stable at high temperature. More resistance to handling. They reduce or eliminate some problems that originate during the transportation and granulation of the threads, such as the fractures of the threads in granules of different lengths and the possible static charge. Multiparticulates can be divided into unit doses, so that each individual unit dose includes a dose of the drug for administration to a mammal, preferably a human patient. For the preferred drug, oxycodone or a salt thereof is preferably hydrochloride, a suitable dose of the active ingredient from 5 to 400 mg, especially 5 mg, 1.0 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg , 120 mg, or 160 mg, in unit dosages. In this aspect, a unit dose contains an effective amount of the therapeutically active agent to produce pain relief and / or analgesia to the patient. The dose of oxycodone administered to a patient will vary due to numerous factors, including the patient's weight, tolerance, severity of pain, metabolic condition and the nature of any other therapeutic agents that are being administered. The resulting multiparticulates can be used as a filler in a capsule. Therefore, the present invention provides a capsule suitable for a dosage once or twice per day. Another dosage form of the controlled release formulation can be provided. In a preferred embodiment, the multiparticulates are filled into gelatin capsules each containing a unit dose. The weight of the filling in the capsule is preferably in a range of 80 to 500 mg, more preferably 120 to 500 mg. In a variation of the present invention, the unit dose of the multiparticulates can be incorporated into other solid pharmaceutical dosage formulations, for example, using compression or tabletting, or forming the extrudate in the form of a suppository. Preferred capsules or other unit dose forms of the present invention are preferably designed for administration at approximately 12 hour or 24 hour intervals. A preferred drug for inclusion in the multiparticulates is oxycodone or the salt thereof, preferably the hydrochloride. A unit dosage form suitably for a dosage of every 12 hours, then will conveniently be an oxycodone solution in vitro, when measured by the USP Palette Method (see Pharmacopoeia XXI I 1 990) at 1000 rpm in 900 ml of aqueous regulator (pH between 1.6 and 7.2) at 37 ° C between 1 2.5% and 42.5% (by weight) of oxycodone released after one hour, between 25% and 56% or (by weight) of oxycodone released after 2 hours, between 45% and 75% (by weight) of oxycodone released after 4 hours and between 55% and 85% >; (by weight) of oxycodone released after 6 hours. The unit dose form containing oxycodone or a salt thereof, preferably the hydrochloride, suitable for dosing every 12 hours may also conveniently have the following dissolution index in vitro, when, it is measured using the USP basket method apparatus. «7 1 1 > > at a speed of 1 to 1000 rpm in 900 ml of the aqueous buffer at a pH of 1.2 (simulated gastric juice without enzymes) at a temperature of 37 ° C, with detection by HPLC with UV at a wavelength of 206 nm is dissolved from 0% to 40%, preferably from 25% to 35% in 1 hour, from 20% to 70%, preferably from 40% to 60% in 2 hours from 40%) to 80%, preferably from 55%. % to 75% > in 3 hours, from 60% to 95% or, preferably from 65% to 90% > at 4 hours, and more than 70% > at 5 o'clock. Furthermore, it is preferred that the peak plasma level of the oxycodone obtained in vivo occur between 2 and 4.5 hours after administration of the dosage form. Further information is provided on the desirable characteristics of said oxycodone formulations in WO 931 0765 which is incorporated in its entirety to the present description as a specific reference. As an alternative, oxycodone capsules or other unit dose forms of the present invention are designed for administration at approximately 24 hour intervals. For this purpose, the unit dose form conveniently has an oxycodone solution in vitro when measured in the USP basket method at a rate of 1 00 rpm in 900 ml of aqueous buffer at a pH between 1.6 and 7.2. at a temperature of 37 ° C from 0% to about 40% in 1 hour, from about 8% to about 70% in 4 hours, from about 20% to about 80% in 8 hours, of about 30% to about 95% in 12 hours, from about 35% to about 95% in 1 8 hours, and more preferably about 50% in 24 hours. In addition, it is preferred that the plasma peak levels of oxycodone obtained in vivo be reached from about 2 hours to about 17 hours after administration in a stable condition of the dosage form.

The unit dose form containing oxycodone or a salt thereof, preferably the hydrochloride, conveniently for a dosage of every 24 hours, may also suitably have the following dissolution rate in vitro, when it is measured using the basket method apparatus «7 1 1 > > at a rate of 1 to 100 rpm in 900 ml of aqueous buffer at a pH of 1.2 (simulated gastric juice without enzymes) at a temperature of 37 ° C with detection by HPLC with UV at a wavelength of 206 nm; from 10% to 30%, preferably from 17% to 23% in 1 hour, from 20% to 35% > preferably from 24% to 32% in two hours; from 35% to 75%, preferably from 48% to 66% at 8 hours, and more than 50%, preferably from 68% to 92% at 16 hours. More detailed information on the desirable characteristics for said oxycodone formulations is provided in WO 02087512 which is incorporated in its entirety to the present description as a specific reference. In one variation, the present invention provides unit doses which contain an opioid or an effective opioid antagonist to avoid manipulation. In this regard, reference is made to WO 0313433 which is incorporated in its entirety to the present description as a specific reference. In particular, the unit dose may contain oxycodone and naltrexone. For this purpose the present invention provides melted extruded multiparticulates of an opioid, such as oxycodone and melted extruded multiparticulates of an opioid antagonist, such as naltrexone. In a preferred formulation, the multiparticulate antagonists do not release the antagonist in conventional administration, and for example, have a non-release coating. Both populations of opioids and opioid antagonists are preferably physically and visually identical. An important aspect of the present invention is a capsule with a unit dose of less than 500 mg, comprising up to about 350 mg of oxycodone multiparticulates and up to about 200 mg of multiparticulate oxycodone antagonists that are tamper-resistant. For example, it may be from 120 to 300 mg of oxycodone multiparticulates and from 125 to 175 mg of the multiparticulate oxycodone antagonists that are tamper-resistant. BRIEF DESCRIPTION OF THE DRAWINGS Reference is made in the following experimental section to the accompanying drawings, in which: Figure 1 shows the dissolution of oxycodone from granules made in example 5. Figure 2 shows the dissolution of oxycodone from granules made in the examples from 1 0 to 1 3. Figure 3 shows the dissolution of the oxycodone from the ground granules of the examples from 1 1 to 1 3. Figure 4 shows the solution of the oxycodone from granules of the examples from 1 1 to 13 after grinding using a mortar and pestle. Figure 5 shows the solution in solvents of the oxycodone of the granules of the examples from 1 0 to 1 3. EXAMPLES OF THE PRESENT INVENTION Examples 1, 2 and 3 Three batches (example) of multiparticulates were manufactured following a similar procedure: Step 1, the following ingredients were initially placed in a high-gravity mixer, preheated to 40 ° C and mixed dry at high speed for 2 minutes: Oxicodone Hydrochloride Eudragit RS PO Stearic Acid Stearic Acid Step 2. The Eudragit dispersion NE 40 D was cast through a 350 micron mesh to remove the aggregates and transferred in an appropriately sized container. Step 3. The cast dispersion of Eudragit NE 40 D was sprayed at a low atomization pressure on the dry mixed material from step 1 and into a mixing bowl while maintaining the mixing / cutting. Step 4. Continued the application of Eudragit NE 40 D until the formation of granules occurred. Step 5. The application of Eudragit N E 40 D was periodically stopped to clean the sides of the mixing bowl. Step 6. After all the Eudragit NE 40 D had been applied, the granules were dried under the same temperature conditions and at reduced mixing / cutting speeds. Step 7: The granules were fed in a controlled index to a Leistritz Micro 18 extruder equipped with conveyor and granulator. The extruder had a die plate of 1.5 mm, and stations heated as follows; from stations 3 to 8, from a temperature of 90 ° C to 100 ° C; stations 9 and 10, at 100 ° C. The feed rate was 2.0 to 2.5 kg / hr and the screw speed was 100 to 141 rpm, with a torsion / melt pressure of 50% to 60% / 40,789 to 50,986 kg / cm2 (40 to 50 bars). The extruded wires were carried away from the die head on the conveyor and cut into cylindrical multiparticulates.

'As Eudragit NE 40 D (water removed by drying) Example 4 For this example, alternative cutting procedures were employed. The extrudates exit twelve holes from the die head of a Leistritz Micro 1 8 extruder. A rotary cutter with two blades is used to cut the extruded mixture, as it emerges under pressure and still melted from the holes in the die plate. The blades sweep, on the surface of the head of the die to pass the holes. As they expand and cool, the particles of the cut extrudate tend to form rounded surfaces. The following formulation was employed to produce a placebo product containing lactose as the pharmaceutically inactive ingredient.

* The value expressed as solids content. By properly adjusting the extrusion parameters including temperature and extrusion rates, substantially spherical or spherical multiparticulates can be obtained. Examples 5 v 6 Two batches of multiparticulates were planned using tributyl citrate as a plasticizer (circa 43% w / w drug loading). The percentages of the content, p / p, were as follows.

S = solid weight D = weight of the dispersion * Dispersion at 40% (% w / w), the water was lost by evaporation. A procedure for preparing the multiparticulates of Example 5 in the form of granules is as follows: Step 1. The tributyl citrate was slowly added to the ethyl cellulose in a high-shear 10 Gral mixer and mixed. Step 2. Oxycodone was added to a mixture from step 1 in the high-cut mixer Gral 10 and mixed for 5 minutes. Step 3. The dispersion of Eudragit NE 40 D was cast through a 350 micron mesh to remove the aggregates and transferred to an appropriately sized container. The cast dispersion of Eudragit NE 40 D was then added slowly by the aid of a peristaltic pump in the mixed materials from step 2 in the mixing bowl Gral 10 previously heated to 38 ° C, while mixing / cutting was maintained. Step 4. The application continued until the formation of granules occurred - the entire Eudragit N E 40 D was added. Step 5. The application of Eudragit N E 40 D was periodically stopped to allow cleaning of the sides of the mixing bowl. Step 6. After all the Eudragit N E 40 D had been added, the wet granules were extruded through a conventional extruder and dried in a fluidized bed dryer at a temperature of about 42 ° C. Step 7. The dried granules were cooled to room temperature and collected. Step 8. Then, the granules were fed at a controlled index to a Leistritz Micro extruder equipped with a 1.0 mm die plate, a conveyor and a granulator under the same conditions as in Example 1. The extruded yarns were carried away from the die head on a conveyor and cut into cylindrical multiparticulates. The procedure for preparing the formulation of the Example 6 was the same as in Example 5, except for the following aspects: • Plasticizer (tributyl citrate) was not added in step 1. Instead step 1 was excluded and step 2 consisted of the mixture of oxycodone hydrochloride and ethyl cellulose in the high shear mixer Gral 10. • The granules were cast (mesh 1.5 mm) and the granules of surplus size were milled (1.0 mm mesh) and recombined with the other granules. • A lubricant (glycerol dibehenate) was added to the dry granules immediately before being fed to the extruder at the end of step 7. • The extruder had a die plate with 1.5 mm holes. It can be considered an alternative cutting procedure. The extrudate emerges from the holes in the die head of a Leistritz extruder. A rotary cutter with two blades is used to cut the extruded mixture as it comes out under pressure and still melted from the holes in the die plate. The blades sweep the surface of the die head to pass the holes. As they expand and cool, the cut extrudate particles tend to form rounded surfaces. Although in the previous examples, a Leistritz Micro 18 extruder was used, a Leistritz Micro 27 extruder, preferred for handling materials that require a higher torsion for processing, can be used for example. The extruded granules obtained in Example 5 were tested for dissolution using the USP basket method «7 1 1 >; > , at a rate of 1 to 100 rpm in 900 ml of aqueous buffer at a pH of 1.2 (simulated gastric juices without enzymes) at a temperature of 37 ° C by detection by HPLC with UV at a wavelength of 206 nm and the following results were obtained which were plotted in Figure 1 together with a preferred profile for a once-a-day product.

Examples 7, 8 and 9 Using the same procedure under the extrusion conditions as for the previous examples apart from temperatures in a range of 100 to 120 ° C, the screw speed up to 240 rpm and dimensions of the die plate of 1 .5 mm in diameter (example 7 and 8) and 1.0 mm (example 9), the following formulations were processed to produce multiparticulates.

* The values shown are only the solids content. The weight of the liquid dispersion is (value / 40) x100 Examples 10 to 13 Using procedures similar to the previous examples, multiparticulates were produced with the following formulations.

S = solid weight D = weight of the dispersion * 40% dispersion (% w / w), the water was lost by evaporation. The above multiparticulates of examples 10 to 13 were subjected to the test by dissolution using the USP basket method described above in Example 5. The results are shown in Figure 2. These demonstrate that the release profiles of the multiparticulates of examples 12 and 13 are similar in this test to the release profile of a preparation (example 5 of our also pending application publication number WO 2005/000310), which, when tested in vivo is substantially bioequivalent to tablets of OxiContin. The multiparticulates of Examples 10 and 11 have slower dissolution profiles which may indicate that they would be suitable for use in dosage forms for dosing at 24 hour intervals. The microparticulates of examples 10 to 13 were tested for their potential for resistance to handling in the following manner: 1) 400 mg of multiparticulates of examples 10 and 13 were either crushed between two spoons or in a crusher of pills , such as a Pili spray that is available from Apex Healthcare Products and then extracted in 2 ml of water, heated until boiled in a spoon and filtered. The amounts of oxycodone extracted were then determined by HPLC and detection by UV rays at a wavelength of 210 nm and are shown in the graph of Figure 3. 2) 400 mg of the multiparticulate of examples 10 to 13 were subjected to grinding in a mortar and pestle with 24 rotations in the pestle and the product placed in 900 ml of water at a temperature of 37 ° C for 45 minutes. The dissolved amount of oxycodone was then determined by the method described in point 1) above and the results are plotted on the bar graph of Figure 4. 3) in each of the extractions from a to e), 400 mg of multiparticulates of one of examples 10 to 13 respectively were treated as follows: the microparticulates were placed in the indicated solvent in a glass flask which was then heated (if warming was indicated) in a water bath. Water. The flask was then stirred for the indicated time using a Stuart Scientific Model SF1 flask agitator, adjusted at a rate of 500 to 600 oscillations per minute. After extraction, the amount of dissolved oxycodone was determined by the method used in point 1. a) 15 minutes of stirring in 10 ml of water at room temperature; b) heating for 5 minutes in 10 ml of water at a temperature of 50 ° C followed by 15 minutes of stirring, c) heating for 5 minutes in 10 ml of water at a temperature of 75 ° C followed by 15 minutes of stirring; d) heating for 15 minutes in 10 ml of water at a temperature of 100 ° C followed by 15 minutes of stirring; e) 15 minutes of stirring in 10 ml of 40% ethanol at room temperature. The results are shown in the attached bar graph of Figure 5.

Claims

CLAIMS 1. A controlled release pharmaceutical formulation comprising a hulose matrix including a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) and an active ingredient.
2. A formulation as described in claim 1 characterized in that the active agent is an opioid, a stimulant, a barbiturate, an antidepressant or a dissociative anesthetic.
3. A formulation as described in claim 2, characterized in that the active agent is oxycodone.
4. A formulation as described in any of the preceding claims, which is resistant to handling by reducing the release of the active agent at the time of extraction in a liquid which is water, ethanol or aqueous ethanol.
5. A formulation as described in any of the preceding claims, which comprises multiparticulates.
6. A formulation as described in any of the preceding claims, which shows at least one of the following characteristics of (a) to (e) when tested by a test method comprising mixing in a dosage amount of multiparticulates with 10 ml of the liquid in a glass flask and stirring at a rate of 500 to 600 oscillations per minute for 15 minutes using a Stuart Scientific stirrer, Model SF1: (a) 1 5 minutes of stirring in water at room temperature : less than 7.5% > of release of the active agent; (b) 5 minutes of rest in water at a temperature of 50 ° C followed by 1 5 minutes of stirring at the same temperature: less than 15%) of release of the active agent; (c) 5 minutes of rest at a temperature of 75 ° C followed by 15 minutes of stirring at the same temperature: less than 20% release of the active agent; (d) 5 minutes of rest at a temperature of 1 00 ° C followed by 1 5 minutes of stirring at the same temperature: less than 25% release of the active agent; (e) 1 5 minutes of agitation in 40% ethanol at room temperature: preferably a release less than 25% > of the active agent.
7. A formulation as described in any of the preceding claims, characterized in that the resistance to handling realizes the release of the active agent at the time of grinding the formulation and extraction.
8. A formulation as described in claim 7, characterized in that it releases less than 10% of the active ingredient when tested by a test method comprising subjecting a dosage amount of the formulation to grinding in a mortar and pestle. pestle with 24 rotations of the pestle and place it in 900 ml of water at a temperature of 37 ° C for 45 minutes. 9. A formulation as described in claim 7, characterized in that it liberates at least 15% of the active agent when tested in a test method comprising grinding a dosage amount in a pill sprayer sold by Apex Healthcare Products, and then extracted in 2 ml of hot water until boiled in a spoon and filtered. A formulation as described in any of the preceding claims, characterized in that the matrix includes at least one other polymer to modify the release. eleven . A formulation as described in claim 10, characterized in that the other polymer is an alkyl cellulose or an ammonium methacrylate copolymer insoluble in water. 12. A formulation as described in claim 1, characterized in that the other polymer is ethyl cellulose. 13: A formulation as described in claim 12, characterized in that the amount of ethyl cellulose is from 10% to 50% by weight of the formulation. A formulation as described in any of claims 10 to 13, which contain the following amounts of ingredients, based on the total weight of the specified ingredients: 15. A formulation as described in claim 14, which contains the following amounts of ingredients, based on the total weight of the specified ingredients: 16. A formulation as described in claim 14, which contains the following amounts of ingredients, based on the total weight of the specified ingredients: 17. A formulation as described in any of the preceding claims, which comprises up to 50% w / w of the active ingredient, from 15 to 50% w / w of neutral copolymer of poly (ethyl acrylate, methyl methacrylate); of 5% > to 60% w / w of ethyl cellulose and after 7.5% to 20% of plasticizer. 1 8. A formulation as described in claim 17, which also contains from 5% to 60% > of an insoluble ammonium methacrylate copolymer.
9. A formulation as described in claim 18, which contains from 5% to 50% of an insoluble ammonium methacrylate copolymer which is low permeability and / or 5% > 30% of ammonium methacrylate copolymer which is highly permeable. 20. A formulation as described in any of the preceding claims, characterized in that it contains a bulking agent. twenty-one . A formulation as described in any of the preceding claims, which contains an opioid or an opioid antagonist. 22. The formulation as described in claim 21, characterized in that it comprises from 120 to 300 mg of multicyclic oxycodone and from 125 to 175 mg of multiparticulates of oxycodone antagonist. 23. A formulation as described in claim 21 or 22 characterized in that it contains oxycodone and naltrexone. 24. A formulation as described in claims 21, 22 or 23, characterized in that it comprises melted extruded multiparticulates of an opioid and melted extruded multiparticulates of an opioid antagonist. 25. A unit dose of a pharmaceutical formulation as described in any of the preceding claims suitable for administration to a human. 26. A unit dose as described in claim 25, which contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 120 mg or 160 mg, oxycodone. 27. A unit dose as described in claim 25 or 26 suitable for a once-a-day dosing. 28. A unit dose form as described in claim 27, which has an oxycodone dissolution index in vitro, when measured by the USP bucket method at 1000 rpm in 900 ml of aqueous buffer in a pH between 1.6 and 7.2 at a temperature of 37 ° C of about 0% > at about 40% in 1 hour, from about 8% to about 70% in four hours, from about 20% to about 80% in 8 hours, from about 30%) to about 95% in 12 hours. hours, from approximately 35% or approximately 95% in 1 8 hours, and more than approximately 50% at 24 hours. 29. A unit dose as described in claim 28 characterized in that the peak level in the oxycodone plasma obtained in vivo occurs in a period of 2 hours to 17 hours after administration of the dosage form. 30. A unit dosage form as described in claim 27, which has an oxycodone dissolution index in vitro when measured using the USP basket method apparatus "7 1 1 > > at a rate of 1 to 1000 rpm in 900 ml of aqueous buffer at a pH of 1.2 (simulated gastric juices in enzymes) in a unit dose form 37A with detection by HPLC with a UV at a wavelength of 206 nm, from 10% to 30% or in one hour, from 20% to 35% in 2 hours, from 35% to 75% in 8 hours, and more than 50% at 1 6 hours. 31 A unit dose as described in claim 25 or 26 suitable for a dosing twice a day. 32. A unit dose form as described in claim 31, which has an oxycodone dissolution index in vitro when measured by the USP palette method (see US Pharmcopoeia XXI I 1 990), or a speed from 1 00 rpm to 900 ml of aqueous buffer (pH between 1.6 and 7.2) at a temperature of 37 ° C between 12.5 and 42.5% (by weight) of oxycodone released after 1 hour, between 25% and 56 % (by weight) of oxycodone released after 12 hours, between 45% >; to 75% (by weight) of oxycodone released after 4 hours, and between 55% and 85% > (by weight) of oxycodone released after 36 hours. 33. A unit dosage form as described in claim 31, characterized in that it has an oxycodone dissolution index in vitro, when measured using the USP basket method "7 1 1 > > , at a speed of 1 to 1 00 rpm in 900 ml of aqueous buffer at a pH of 1.2 (simulated gastric juice without enzymes) at a temperature of 37 ° C with a detection by HPLC with UV at a wavelength of 206 nm, of about 0% > at 40% > in one hour, 20% > 70% in 2 hours, 40% to 80% in 3 hours, 60% to 95% in 4 hours and more than 70% in 5 hours. 34. A unit dose as described in claim 33, characterized in that the peak level in the oxycodone plasma obtained in vivo occurs between 2 and 4.5 hours after the administration of the dosage form. 35. A controlled release pharmaceutical formulation which can be obtained by melt extrusion and which includes a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) and an active ingredient. 36. A formulation as described in claim 35, which exhibits characteristics similar to rubber. 37. A formulation as described in claim 35 and 36, as an improved resistance to handling by extraction with water or alcohol or aqueous ethanol. 38. A formulation as described in claim 35, 36 or 37, characterized in that the active ingredient is an opioid, a stimulant or a barbituric or an antidepressant or a dissociative anesthetic. 39. A formulation as described in claim 38, characterized in that the active agent is oxycodone. 40. A formulation as described in any of claims 25 to 39, which comprises multiparticulate. 41. A formulation as described in any of claims 35 to 40, characterized in that the matrix includes at least one other polymer to modify the release. 42. A formulation as described in claim 41, characterized in that the other polymer is an alkyl cellulose or an insoluble copolymer of ammonium methacrylate. 43. A formulation as described in claim 42, characterized in that the other polymer is ethyl cellulose. 44. A formulation as described in claim 43, characterized in that the amount of ethyl cellulose is 10% at fifty%. in weight of the formulation. 45. A formulation as described in any of claims 41 to 44, which contain the following amounts of ingredients, based on the total weight of the specified ingredients: 46. A formulation as described in claim 45, which contains the following amounts of ingredients, based on the total weight of the specified ingredients: 47. A formulation as described in claim 46, which contains the following amounts of ingredients, based on the total weight of the specified ingredients: 48: A formulation as described in any of claims 35 to 47, which comprises 60% w / w of active agent, from 15% to 50% > p / p of neutral copolymer of poly (ethyl acrylate, methyl methacrylate); from 5% to 60% > p / p of ethyl cellulose from 7.5% to 20%. of plasticizer. 49: A formulation as described in claim 48, which contains in addition to 5% > 60% of an insoluble ammonium methacrylate copolymer. 50. A formulation as described in claim 49, which contains 35 to 50% of an insoluble ammonium methacrylate copolymer which is low permeability and / or 5% to 30% > of an ammonium methacrylate copolymer which is highly permeable. 51 A formulation as described in any of claims 35 to 50, which contains a bulking agent. 52. A formulation as described in any of claims 35 to 50, which contains an opioid or an opioid antagonist. 53. A formulation as described in claim 52, which comprises from 120 to 300 mg of multicyclic oxycodone and from 125 to 175 mg of multiparticulates of oxycodone antagonist. 54. A formulation as described in claim 52, or 53, which contains oxycodone and naltrexone. 55. A formulation as described in any of claims 52, 53 or 54, which comprises extruded multiparticulates melted from an opioid and melted extruded multiparticulates of an opioid antagonist. 56. A unit dose of a pharmaceutical formulation as described in any of claims 35 to 55, suitable for administration to a human. 57. A unit dose as described in claim 56, which contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 120 mg or 160 mg oxycodone. 58. A unit dose as described in claim 56 or 57 suitable for a once-a-day dosage. 59. A unit dosage form as described in claim 58, which has an oxycodone dissolution index in viwhen measured by a USP canister method at a speed of 1000 rpm in 900 ml of liquid regulator at a pH between 1.6 and 7.2 at a temperature of 37 ° C of from about 0% to about 40% in one hour of about 8% to about 70% in four hours, of about 20% or about 80% > in 8 hours, from approximately 30%) to approximately 95% in 1 2 hours, of approximately 35%. to approximately 95% in 1 8 hours, and more than 50% > in 24 hours. 60. A unit dose as described in claim 58, characterized in that the peak level in the oxycodone plasma obtained in vivo occurs in a period of 2 hours to 17 hours after the administration of the dosage form. 61 A unit dosage form as described in claim 58, which has an oxycodone dissolution index in viwhen measured using an apparatus of the USP «7 1 1» basket method. > at a speed of 1 to 1000 rpm in 900 ml of aqueous buffer at a pH of 1.2 (simulated gastric juice without enzymes) at a temperature of 37 ° C, with detection by HPLC with UV at a wavelength of 206 nm, from about 10% to about 30% in one hour, from 20% to 35% >; in two hours, from 35% to 75%. in 8 hours, and more than 50%. in 16 hours. 62. A unit dose as described in claim 56 or 57 suitable for a dosing twice a day. 63. A unit dose form as described in claim 62, which has an oxycodone dissolution index in vitro when measured by the USP palette method (see US Pharmacopoeia XXI I 1 990) at a rate 100 rpm 900 ml of aqueous buffer (pH between 1.6 and 7.2) at a temperature of 37 ° C, between 12.5% and 42.5% (by weight) of oxycodone released after 1 hour, between 25% > and 56% (by weight) of oxycodone released after 2 hours, between 45% and 75% (by weight) of oxycodone released after 4 hours and between 55% and 85% (by weight) of oxycodone released after 6 hours. 64. A unit dose form as described in claim 62, characterized in that it has a dissolution index, of oxycodone in vitro when measured using a USP "7 1 1" basket method apparatus at a rate of 1 at 1000 rpm and 900 ml of aqueous buffer at a pH of 1.2 (simulated gastric juice without enzymes) at a temperature of 37 ° C with detection by H PLC with UV at a wavelength of 206 nm of about 0% to 40% in one hour, from 20% to 70% > in 2 hours, 40% > at 80% > in 3 hours, 60% > at 95% > in 4 hours and more than 70% in 5 hours. 65. A unit dose as described in claim 24, characterized in that the peak level in the oxycodone plasma obtained in vivo occurs between 2 and 4.5 hours after administration of the dosage form. 66: A controlled release pharmaceutical formulation obtained by melt extrusion and including a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) and an active ingredient. 67. A dry granulate comprising a neutral copolymer of poIi (ethyl acrylate, methyl methacrylate) and an opioid analgesic. 68. A dry granulate comprising from 20% to 66% by weight of a neutral copolymer of poIi (ethyl acrylate, methyl methacrylate) and a pharmaceutically active compound. 69. A dry granulate as described in claim 68, characterized in that the pharmaceutically active compound is an opioid. 70. A dry granulate as described in claim 64, wherein the opioid is oxycodone or a salt thereof. 71: A dry granulate which comprises a matrix of a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) incorporating the opioid analgesic. 72. A dry granulate as described in claim 71, which is an extruded granulate. 73. A dry granulate as described in claim 71 or 72, which comprises up to 66%. of neutral copolymer of poly (ethyl acrylate, methyl methacrylate). 74. A dry granulate as described in claim 71, 72 or 73, which comprises from 20% to 50% neutral copolymer of poly (ethylacrylate, methyl methacrylate). 75. A dry granulate as described in claim 74, which comprises from 30% to 40% neutral copolymer of poly (ethyl acrylate, methyl methacrylate). 76. Multiparticulates which each comprise a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) and an opioid analgesic. 77. The multiparticulates as described in claim 76, formed by melted extrusion. 78. The multiparticulates as described in claim 78, which have the shape of a cylinder or are generally spherical, elliptical or disk shaped. 79. Multiparticulates each comprise 20% to 66%. by weight of a neutral copolymer of poly (ethylacrylate, methyl methacrylate) and a pharmaceutically active compound. 80. The multiparticulates as described in claim 79 characterized in that the pharmaceutically active component is an opioid analgesic. 81 The multiparticulates as described in claim 80 characterized in that the opioid is oxycodone, or a salt thereof. 82. The multiparticulates as described in claim 80 and 81, formed by the melt extrusion of a dry blend including a neutral copolymer of poly (ethyl acrylate, methyl methacrylate). 83. The multiparticulates as described in claim 82, which take the form of a cylinder or generally have a spherical, elliptical or disk shape. 84. A controlled release pharmaceutical formulation comprising a matrix including a neutral copolymer of poi (ethyl acrylate, methyl methacrylate) and an opioid analgesic. 85. A controlled release pharmaceutical formulation comprising a matrix including from 20% to 65% by weight of a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) and a pharmaceutically active compound. 86. A formulation as described in claim 85, which exhibits characteristics similar to rubber. 87. A formulation as described in claim 85 or 86 with improved resistance to handling by extraction with water or alcohol or aqueous ethanol. 88. A formulation as described in any of claims 84 to 87, characterized in that the opioid analgesic is oxycodone. 89. A formulation as described in any of claims 84 to 88, which comprises multiparticulates. 90. A formulation as described in any of claims 84 to 89, characterized in that the matrix includes at least one other polymer to modify the release. 91 A formulation as described in claim 90, characterized in that the other polymer is alkyl cellulose or a water-insoluble copolymer of ammonium methacrylate. 92. A formulation as described in claim 91 characterized in that the other polymer is ethyl cellulose. 93. A formulation as described in claim 92, characterized in that the amount of ethyl cellulose is 1 0% > 50% by weight of the formulation. 94. A formulation as described in claim 93, which contains the following amounts of ingredients, based on the total weight of the specified ingredients: 94. A formulation as described in claim 94, which contains the following amounts of ingredients, based on the total weight of the specified ingredients: 96. A formulation as described in claim 95, which contains the following amounts of ingredients, based on the total weight of the specified ingredients: 97. A formulation as described in any of claims 85 to 96, which comprises up to 60% op / p of active agent, 15% to 50% w / w of poly (ethyl acrylate) neutral copolymer , methyl methacrylate) from 5% to 60% w / w of ethyl cellulose and from 7.5% to 20% of plasticizer. 98. A formulation as described in claim 97, which further contains from 5% to 60% of an insoluble ammonium methacrylate copolymer. 99. A formulation as set forth in claim 98, which contains 35% to 50% of an insoluble ammonium methacrylate copolymer which is low permeability and / or 5% to 30% > of an ammonium methacrylate copolymer which is highly permeable. 1 00. A formulation as described in any of claims 85 to 99, which contains a bulking agent. 1 01. A formulation as described in any of claims 85 to 100, which contains an opioid and an opioid antagonist. 1 02. A formulation as described in claim 1, which comprises from 120 to 300 mg of oxycodone multiparticulate and 125 to 1 75 mg of multiparticulates of oxycodone antagonists. 1 03. A formulation as described in claim 1 or 1 02, which contains oxycodone and naltrexone. 1 04. A formulation as described in the claims of 1 01, 1 02 or 1 03, which comprises the melted extruded multiparticulate of an opioid and melted extruded multiparticulates of an opioid antagonist. 1 05. A unit dose of a pharmaceutical formulation as described in any of claims 87 to 1 04, suitable for administration to a human. 1 06. A unit dose as described in claim 1, which contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 120 mg, or 160 mg oxycodone . 1 07. A unit dose as described in claim 1 or 1 06 suitable for a once-a-day dosing. 1 08. A unit dose form as described in claim 1 07, which has an oxycodone dissolution index in vitro when measured by a USP Basket Method at a rate of 1 00 rpm in 900 ml of Aqueous regulator at a pH between 1.6 and 7.2 at a temperature of 37 ° C 0% >; to approximately 40%. in 1 hour, from about 8% to about 70% or in 4 hours, of about 20% > to approximately 80% or in 8 hours, of approximately 30%. to approximately 95%. in 12 hours, of approximately 35%. at about 95% or in 1 8 hours, and more than about 50% > in 24 hours. 1 09. A unit dose as described in claim 1, characterized in that the peak level in the oxycodone plasma obtained in vivo occurs in a period of 2 to 17 hours after the administration of the dosage form. 1
1 0. A unit dosage form as described in claim 1, characterized in that it has an oxycodone dissolution index in vitro when measured using a USP Bag Method Apparatus < < 71 1 > > at a speed of 1 to 1000 rpm in 900 ml of aqueous buffer at a pH of 1.2 (simulated gastric juices without enzymes) in the unit dose form from 37A to 37C with detection by HPLC with UV at a wavelength 206 nm; from 10% to 30% in 1 hour; from 20% to 35% in 2 hours; 35% or 75% in 8 hours; and more than 50% in 16 hours. 1
1 1 A unit dose as described in claim 1 or 06 suitable for a dosing twice a day. 1
12. A unit dosage form as described in claim 11, which has an oxycodone dissolution index in vitro when measured by a USP Palette Method (see U.S. Pharmacopocia XXI I 1990) at a rate of 1 00 rpm in 900 ml of aqueous buffer (pH between 1.6 and 7.2) at a temperature of 37 ° C of between 12.5% > and 42.5% > (by weight) of oxycodone released after 1 hour, between 25% and 56% > (by weight) of oxycodone released after 2 hours, between 45% 0 and 75% or (by weight) of oxycodone released after 4 hours and between 55% and 85% > (by weight) of oxycodone released after 6 hours. 1
1 3. A unit dosage form as described in claim 11, which has an in vitro oxycodone dissolution index when measured using a USP Bag Method Apparatus < < 71 1 > > at a speed of 1 to 1 00 rpm in 900 ml of aqueous buffer at a pH of 1.2 (simulated gastric juice without enzymes) at a temperature of 37 ° C with detection by a H PLC with UV at a wavelength of 206 nm, of about 0% > at 40% > in one hour, from 20% to 70% in 2 hours, from 40% to 80% in 3 hours, from 60% to 95% in 4 hours, and over 70% in 5 hours. 1
14. A unit dose as described in claim 11, wherein the peak level in the oxycodone plasma obtained in vivo occurs between 2 and 4.5 hours after the administration of the dosage form.
15. A process for preparing a controlled release formulation which comprises the melt extrusion of a mixture including a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) and an active ingredient.
16. A process as described in claim 15, characterized in that the neutral copolymer of poly (ethylacrylate, methyl methacrylate) is provided in the form of an aqueous dispersion comprising 40% of the polymer which is mixed with the active agent and dried to produce the melt extrusion mixture. 1 1 7.
A process as described in claim 1 1 5 or 1 1 6, characterized in that the mixture includes a plasticizer. 1.
A process as described in claim 1, characterized in that the plasticizer is tributyl citrate, stearyl alcohol or high molecular weight polyethylene glycol. 1 1 9.
A process as described in any of claims 1 1 to 1 1 8 characterized in that the mixture includes a lubricant. 120.
A process as described in claim 1, characterized in that the lubricant is stearic acid, salt of stearic acid or glycerol dibehenate. 121.
A process as described in any of claims 1 to 5 to 120, which comprises the wet granulation of the ingredients for the mixture to be extruded to provide a wet granulate, dry the granulate and extrusion melted from the dried granulate. 122.
A process as described in the claim 121, characterized in that the wet granulate is extruded before drying. 123.
A process as described in the claim 122, characterized in that the dry granulate contains less than 3% w / w of water. 124.
A process as described in any of claims 1 to 5 to 123, characterized in that the melted extrusion of the dried granulate is carried out in a double screw extruder. 125.
A process as described in any of claims 1 to 5 to 127, characterized in that the extruded yarns are transported to a granulator and cut into multiparticulates. 126.
A process as described in any of claims 1 to 15, characterized in that each multiparticulate has a diameter of about 1 mm and a length of about 1 mm. 127.
A process as described in any of claims 1 to 5 to 124, characterized in that the cutter cuts the extruded mixture as it leaves the extruder. 128.
The use of a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) in the preparation of a pharmaceutical formulation to provide resistance to handling. 129.
A method for reversing resistance to handling in a pharmaceutical formulation, which comprises mixing an active ingredient and a neutral copolymer of poly (ethyl acrylate, methyl methacrylate) and forming a pharmaceutical formulation incorporating the active ingredient in a matrix with the copolymer PoIi neutral (ethyl acrylate, methyl methacrylate).
30. A method of administering an active ingredient, characterized in that the active ingredient is administered as a controlled release formulation as described in any of claims 1 to 104.