Tamper-resistant products for opioid delivery

[0001] Pharmaceutical products are sometimes subject to abuse. For example, a specific dose of opioid agonist may be more potent when administered parenterally compared to the same dose administered orally. Certain preparations can be manipulated to obtain the opioid agonist contained therein for illegal use. Controlled release preparations with an opioid agonist are sometimes crushed by drug abusers to obtain the opioid contained therein for immediate release by oral or parenteral administration.

[0002] Opioid antagonists are combined with certain opioid agonists to prevent parenteral abuse of opioid agonists. In the art, the combination of pentazocine and naloxone immediate release is used in tablets available from St. Ser. North America, commercially available as Talwin®Nx from Sanofi-Winthrop. Talwin®Nx contains immediate-release pentazocine hydrochloride equivalent to 50 mg of the free base and naloxone hydrochloride equivalent to 0.5 mg of the free base. Combination therapy with tilidine (50 mg) and naloxone (4 mg) has been available in Germany for the treatment of pain since 1978 (Valoron®N, Goedecke). The combination preparation buprenorphine and naloxone was introduced in 1991 in New Zealand (Temgesic®Nx, Reckitt & Colman) for the treatment of pain.

[0003] Purdue Pharma LP currently makes available on the market an extended release oxycodone formulation in dosage forms containing 10, 20, 40 and 80 mg oxycodone hydrochloride under the trade name OxyContin.

[0004] In the patents of Ser. US Patent Nos. 5,266,331; US 5508042; US 5549912 and US 5656295 disclose sustained release oxycodone formulations.

[0005] In US Patent No. Ser. U.S. Patent No. 5,472,943, Crain et al. describe methods for increasing the analgesic potency of bimodal opioid agonists by administering an agonist with an opioid antagonist.

[0006] Patent descriptions of Ser. United States Nos. 6,277384; US 6475494; and US 6,335,957, Kaiko et al .; and US 6,228,863, Colucci et al., are directed to reducing the abuse potentially associated with opioid analgesic dosage forms.

[0007] PCT Publication No. WO 01/58451 entitled "Tamper Resistant Oral Opioid Agonist Formulations" is directed at reducing abuse potentially associated with dosage forms of opioid analgesics by incorporating a masked opioid antagonist into the opioid agonist dosage form.

[0008] There is still a need in the art for oral dosage forms containing an opioid agonist that have reduced potential for abuse.

Objects and summary of the invention [0009] The object of the present invention is to provide an oral dosage form comprising an opioid antagonist that substantially prevents the release of the opioid antagonist.

[0010] It is an object of certain embodiments of the invention to provide an oral dosage form containing an opioid antagonist formulation that is useful for reducing the potential for abuse of an opioid agonist.

[0011] It is an object of certain embodiments of the invention to provide an oral dosage form containing an opioid antagonist formulation that is useful for reducing the potential for abuse of an opioid agonist without affecting the analgesic effect of the opioid agonist or causing removal by precipitation.

[0012] It is an object of certain embodiments of the invention to provide an oral dosage form comprising an effective dose of an opioid agonist and a dose of the opioid antagonist that does not change or substantially does not change the analgesic efficacy of the opioid agonist when the dosage form is administered orally intact. However, if the dosage form is violated, the opioid antagonist is substantially released and may prevent abuse by interfering with the opioid agonist.

[0013] It is an object of certain embodiments of the invention to provide an oral dosage form containing an effective dose of an opioid agonist in a controlled release form that does not release the entire content of the agonist available for immediate release when the dosage form has been compromised.

[0014] It is an object of certain embodiments of the invention to provide an oral dosage form comprising opioid agonist particles and masked antagonist particles, wherein the agonist particles and antagonist particles are similar, e.g., in appearance, texture, aroma, taste, hardness, shape, size and / or a combination thereof, or being practically indistinguishable from one another in terms of one or more of these properties.

[0015] The purpose of certain embodiments of the invention is to provide a method for preventing abuse of an oral dosage form containing an opioid agonist by introducing into the dosage form an opioid antagonist that is masked, e.g., is not bioavailable when the dose is administered intact but is bioavailable. when the dosage form is compromised (e.g., in an attempt to abuse a dose of an opioid agonist).

[0016] It is an object of certain embodiments of the invention to provide a method of treating pain in human patients, comprising administering an oral dosage form of an opioid agonist with reduced potential for abuse by oral, parenteral, intranasal and / or sublingual route.

[0017] The above objectives, among others, are achieved by the present invention, which in part relates to a pharmaceutical oral dosage form comprising (a) a particle comprising an opioid antagonist dispersed in a melt extruded matrix, the matrix containing from 1% to 80% by weight of one or more pharmaceutically acceptable first hydrophobic materials, and (b) a layer of a second hydrophobic material coated on the particle.

[0018] In another embodiment, the present invention relates to a pharmaceutical oral dosage form comprising (a) a particle comprising an opioid antagonist dispersed in a melt extruded matrix, the matrix comprising one or more pharmaceutically acceptable first hydrophobic materials, and (b) a layer of a second hydrophobic material coated on the particle in an amount of 2% to 30% by weight based on the weight of the particle.

[0019] Additional embodiments of the present invention are described in the appended claims.

[0020] Alternatively, the second hydrophobic material is from 5% to 25%, from 10% to 20%, from 10% to 25%, from 15% to 25%, from 22% to 28%, or from 5% to 15 % by weight of the particles.

[0021] In some embodiments, the invention relates to a pharmaceutical oral dosage form comprising a) a plurality of particles comprising an opioid antagonist that is dispersed in a melt extruded matrix containing a first hydrophobic material and a layer comprising a second hydrophobic material applied to each of the particles the hydrophobic material constitutes from 2% to 30% by weight of the weight of the particles; b) a plurality of particles containing an opioid agonist that is dispersed in a third hydrophobic material; and c) a capsule containing a plurality of opioid agonist particles and a plurality of opioid antagonist particles. Alternatively, the second hydrophobic material constitutes from 5% to 25%, from 10% to 20%, from 10% to 25%, from 15% to 25%, from 22% to 28%, or from 5% to 15% by weight of the mass particles.

[0022] Also described herein is a dosage form comprising a plurality of particles comprising a first matrix and an opioid agonist; and a plurality of particles (e.g., extruded particles) comprising a second matrix and opioid antagonist, and a layer applied to each of the particles containing the opioid antagonist, wherein the second matrix and layer serve to mask the opioid antagonist during exposure to environmental fluids.

[0023] According to the present invention, the matrix of the opioid antagonist particles comprises a hydrophobic material and the layer on the opioid antagonist particles comprises a hydrophobic material.

[0024] In some embodiments, the layer is placed on particles containing an opioid agonist to produce opioid agonist particles that are similar in appearance or virtually indistinguishable from particles containing an opioid antagonist, thereby reducing the ability of the abuser to physically separate the antagonist containing particles from the agonist containing particles . The agonist layer may be a functional layer to obtain controlled release or to increase controlled release. Alternatively, the agonist layer may be a non-functional layer, e.g., a thin coating, which does not provide controlled release capability.

[0025] In certain embodiments, the invention relates to an oral dosage form comprising (i) a plurality of particles containing an opioid agonist in release form and (ii) a plurality of particles comprising a melt extruded matrix comprising a hydrophobic material in an amount of 1% to 80% by weight, an opioid antagonist that is dispersed in the matrix, and a layer containing hydrophobic material applied to the particles, so that the matrix and layer prevent or substantially prevent release of the antagonist when the dosage form is administered intact to the patient.

[0026] In some embodiments, the ratio of the amount of antagonist released from the dosage form after the violation to the amount of antagonist released from the intact dosage form, based on dissolution of the dosage form for 1 hour in

700 ml of simulated gastric fluid (SGF) using a USP Type device

II (stirrer) at 50 rpm at 37 ° C, is 20: 1 or more; 50: 1 or more; 100: 1 or more; 150: 1 or more, or 1000: 1 or more.

[0027] In some embodiments, the ratio of the amount of antagonist released from the dosage form after the violation to the amount of antagonist released from the intact dosage form, based on dissolution of the dosage form for 2 hours, 4 hours, 12 hours, 24 hours and / or 36 hours in 700 ml SGF, using a USP Type II device (stirrer) at 50 rpm at 37 ° C for the first hour, and then replacing with 900 ml of simulated intestinal fluid (SIF) is 20: 1 or more, 50: 1 or more; 100: 1 or more, 150: 1 or more, or 1000: 1 or more.

[0028] In some embodiments, the weight percent of antagonist released from the intact dosage form, based on dissolution of the dosage form for 1 hour in 700 mL SGF, using a USP Type II device (stirrer) at 50 rpm at 37 ° C , is below 1.0%; less than 0.5%; less than 0.2%; or less than 0.1% by weight.

[0029] In some embodiments, the weight percent of antagonist released from the intact dosage form, based on dissolution of the dosage form for 2 hours in 700 mL SGF, using a USP Type II device (stirrer) at 50 rpm at 37 ° C for the first hour and then converting to 900 ml SIF, it is below 2.0%; less than 1.0%; less than 0.5%; or less than 0.25%. [0030] In some embodiments, the weight percent of antagonist released from the intact dosage form, based on dissolution of the dosage form for 4 hours in 700 mL SGF, using a USP Type II device (stirrer) at 50 rpm at 37 ° C for the first hour and then converting to 900 ml SIF, it is less than 2.2%; less than 1.5%; less than 1.0%; or less than 0.75%.

[0031] In some embodiments, the weight percent of antagonist released from the intact dosage form, based on dissolving the dosage form for 12 hours in 700 mL SGF, using a USP Type II device (stirrer) at 50 rpm at 37 ° C for the first hour and then converting to 900 ml SIF, it is below 3.0%; less than 1.8%; less than 1.25%; or below 0.3%.

[0032] In some embodiments, the weight percent of antagonist released from the intact dosage form, based on dissolving the dosage form for 24 hours in 700 mL SGF, using a USP Type II device (stirrer) at 50 rpm at 37 ° C for the first hour and then converting to 900 ml SIF, it is below 4.8%; less than 2.5%; less than 1.8%; or below 0.4%. [0033] In some embodiments, the weight percent of antagonist released from the intact dosage form, based on dissolving the dosage form for 36 hours in 700 mL SGF, using a USP Type II device (stirrer) at 50 rpm at 37 ° C for the first hour and then converting to 900 ml SIF, it is below 7.0%; less than 6.5%; less than 3.0%; or below 1.5%. [0034] In some embodiments, the intact dosage form releases

1.0% or less antagonist after 1 hour, 2.0% or less antagonist after 2 hours, 2.2% or less antagonist after 4 hours, 3.0% or less antagonist after 12 hours, 4.8% or less antagonist after 24 hours, and 7.0% or less antagonist after 36 hours, based on dissolving the dosage form in 700 ml SGF, using a USP Type II device (stirrer) at 50 rpm at 37 ° C for the first hour and then replacing with 900 ml SIF.

[0035] In some embodiments, the intact dosage form releases 0.5% or less antagonist after 1 hour, 1.0% or less antagonist after 2 hours, 1.5% or less antagonist after 4 hours, 1.8% or less antagonist after 12 hours, 2.5% or less antagonist after 24 hours and 6.5% or less antagonist after 36 hours based on dissolving the dosage form in 700 ml SGF, using USP Type II device (stirrer) at 50 revolutions per minute, at 37 ° C for the first hour and then converting to 900 ml SIF.

[0036] In some embodiments, the intact dosage form releases 0.2% or less of the antagonist after 1 hour, 0.5% or less of the antagonist after 2 hours, 1.0% or less of the antagonist after 4 hours, 1.25% or less antagonist after 12 hours, 1.8% or less antagonist after 24 hours, and 3.0% or less antagonist after 36 hours based on dissolution of the dosage form in 700 ml SGF, using USP Type II device (stirrer) at 50 revolutions for a minute, at 37 degrees C for the first hour and then converting to 900 ml SIF. [0037] In some embodiments, the intact dosage form releases 0.1% or less of the antagonist after 1 hour, 0.25% or less of the antagonist after 2 hours, 0.75% or less of the antagonist after 4 hours, 0.3% or less antagonist after 12 hours, 0.4% or less antagonist after 24 hours, and 1.5% or less antagonist after 36 hours, based on dissolution of the dosage form in 700 ml SGF, using a USP Type II device (stirrer) at 50 revolutions per minute at 37 degrees C for the first hour and then converting to 900 ml SIF. [0038] In some embodiments, the weight percent of the agonist released from the dosage form after tampering, based on dissolving the dosage form for 1 hour in 700 mL SGF, using a USP Type II device (stirrer) at 50 rpm at 37 ° C C is below 50%, below 40%, or below

35%.

[0039] In some embodiments, the ratio of the mean Cmax of the antagonist after the administration of a patient population of a single dose of the intact dosage form to the mean antagonist Cmax of the administration of the patient population of a single dose of the intact dosage form is 20: 1 or more; 50: 1 or more; 75: 1 or more, 100: 1 or more; 125: 1 or more; 150: 1 or more; or 1000: 1 or more. These values ​​preferably relate to fasting.

[0040] In some embodiments, the ratio of the mean Cmax of the antagonist after the administration of a patient population of a single dose of the intact dosage form to the mean antagonist Cmax of the administration of the patient population of a single dose of the intact dosage form is from 20: 1 to about 1000: 1;

from 20: 1 to 150: 1; 20: 1 to 125: 1; from 20: 1 to 100: 1; from 20: 1 to 75: 1; or from 20: 1 to 50: 1. In other embodiments, the range is from about 50: 1 to 1000: 1; from 75: 1 to 1000: 1; from

100: 1 to 1000: 1; from 125: 1 to 1000: 1; or from 150: 1 to 1000: 1. These values ​​preferably relate to fasting.

[0041] In certain embodiments of the invention, the ratio of the mean AUC of the antagonist after the administration of a patient population of a single dose of the intact dosage form to the mean of the antagonist AUC after the administration of the patient population of a single dose of the intact dosage form is 5: 1 or more; 25: 1 or more; 75: 1 or more, 100: 1 or more, 150: 1 or more, 200: 1 or more, or 250: 1 or more. These values ​​preferably relate to fasting.

[0042] In some embodiments, the ratio of the mean AUC of the antagonist after the administration of a patient population of a single dose of the intact dosage form to the mean of the antagonist AUC after the administration of the patient population of a single dose of the intact dosage form is from 5: 1 to 250: 1; from 5: 1 to 200: 1; from 5: 1 to 150: 1; from 5: 1 to 100: 1; from 5: 1 to 75: 1; or from 5: 1 to 25: 1. In other embodiments, the range is from 25: 1 to 250: 1; from 75: 1 to 250: 1; from 100: 1 to 250: 1; from 150: 1 to 1000: 1; or from 200: 1 to 250: 1. These values ​​preferably relate to fasting.

[0043] In some embodiments, the invention further relates to a method of preventing the abuse of an opioid agonist using the dosage forms disclosed herein, according to which if the dosage form is compromised and is administered orally, intranasally, parenterally and / or sublingually, the effect of the opioid agonist is significantly or completely blocked by the release of the opioid antagonist.

[0044] Also described herein are methods of treating pain by administering to a patient in need of such treatment, e.g. orally, any of the forms of the invention disclosed herein containing an analgesic.

[0045] In embodiments in which many particles containing an opioid agonist and many particles containing an opioid antagonist are similar to each other or virtually indistinguishable from each other, the similarity or practical indistinguishability of the particles may be due to (i) the presence of functional or non-functional layers, (ii) similar methods of producing particles that do not need to be coated, (iii) different methods of producing particles, which result in similar or practically indistinguishable end products, (iv) different methods of producing particles resulting in different end products, which are then subjected to an additional processing step (e.g. coating), which leads to similarity or practical indistinguishability, (v) or any other method that gives the desired properties (e.g. appearance, texture, smell, taste, hardness, shape, dimension, etc.).

[0046] In some preferred embodiments, the average particle diameter is from 0.1 to 12 mm; from 0.1 to 2.5 mm; from 0.2 to 6 mm; from 0.5 to 3 mm; from 0.5 mm to 2 mm; or from 1 mm to 2 mm.

[0047] The amount of opioid antagonist released, if any, upon administration of the intact dosage form is such that the dosage form remains analgesic effective.

[0048] In some embodiments of the present invention, the ratio of opioid agonist to masked opioid antagonist is from 1: 1 to 50: 1 by weight; preferably from 1: 1 to 20: 1 by weight; or from 15: 1 to 30: 1 by weight. The weight ratio of opioid agonist to opioid antagonist refers to the weight of active ingredients. For example, the mass of the opioid antagonist does not include the mass of the layer and matrix, which together serve to mask the opioid antagonist. In some preferred embodiments, the weight ratio of agonist to masked antagonist is from about 1: 1 to about 10: 1 by weight.

[0049] The oral dosage forms of the present invention containing the opioid agonist in combination with the opioid antagonist form substantially unable to release it include, but are not limited to, tablets and capsules. The oral dosage forms of the present invention may include any desired pharmaceutical excipients known to those skilled in the art. Oral dosage forms may provide immediate release of the opioid agonist and / or controlled release of the opioid agonist.

[0050] The abuse resistant dosage forms of the present invention are useful in combination with controlled release dosage forms that contain a dose of opioid agonist that is intended to be released over a prolonged period of time. Drug abusers can take such controlled release products and crush, crush, extract, or otherwise damage the product to release the full content of the dosage form for immediate absorption. Because tampering with the dosage forms of the invention causes the opioid antagonist also to become available for absorption, the present invention provides a means to prevent such abuse.

[0051] Also described herein is a method of treating pain using the dosage form disclosed herein. The method may include providing an oral dosage form containing the opioid agonist in release form and a masked antagonist as disclosed herein, and orally administering the intact oral dosage form to a mammal (e.g., human) in need of such treatment.

[0052] Also described herein is a method for preparing the oral dosage forms disclosed herein. In some embodiments, the invention includes a method of making an oral dosage form comprising extrusion producing multiple particles containing an opioid antagonist dispersed in a matrix containing a hydrophobic material; and applying a layer comprising a hydrophobic material to the extruded particles, wherein the matrix and layer serve to mask the antagonist when the dosage form is administered intact. The method may further comprise combining the masked antagonist with a form capable of releasing (e.g., controlled release) the opioid agonist in a manner that maintains the integrity of the masked antagonist. In all embodiments of the invention, the hydrophobic material of the matrix may or may not be the same as the hydrophobic material of the layer.

[0053] Although preferred embodiments of the invention include the opioid antagonist in a form that completely prevents the release of the opioid antagonist, the invention also includes the antagonist in substantially non-releasing form. The terms "substantially non-releasing" and "substantially non-releasing" refer to an antagonist that can be released in small amounts until the released amount does not, or substantially does not affect analgesic efficacy, when the dosage form is administered orally to humans as intended.

[0054] For the masked antagonist particles, there are several possibilities according to the present invention. First, the matrix is ​​able to partially mask the antagonist without the layer and the layer enhances masking. Secondly, the layer is able to partially mask the antagonist without the matrix, and the matrix enhances masking. Third, the matrix is ​​not able to mask the antagonist without the layer, the layer is not able to mask the antagonist without the matrix, and the matrix and the layer together are capable of masking the antagonist (e.g., the matrix and layer are capable of providing controlled release of the antagonist individually, but the matrix and the layer together in the same dosage form masks the antagonist). In the first and second possibilities, the matrix and / or layer enhances masking by being able to provide controlled release of the antagonist individually.

[0055] In certain preferred embodiments of the invention, the form substantially unable to release the antagonist is resistant to the effects of anti-constipation agents (e.g., mineral oil) used to treat delayed colonic passage, and is resistant to conditions of gastritis.

[0056] In preferred embodiments of the present invention, the form substantially unable to release the opioid antagonist is susceptible to mechanical, thermal and / or chemical tampering, e.g. tampering by crushing, shearing, milling, chewing and / or dissolving in solvent in combination with heating (e.g. above approx

45 ° C) oral dosage form. In the event of a breach, the integrity of the form substantially unable to release the opioid antagonist is compromised and the opioid antagonist becomes available for immediate release, and thus at least partially and preferably significantly blocks the effect of the opioid agonist. Thus, when an oral dosage form containing an opioid agonist and an opioid antagonist is chewed, crushed, ground or dissolved and heated in a solvent, then administered orally, intranasally, parenterally and / or sublingually, the analgesic and / or euphoric effect of the opioid is reduced or eliminated .

[0057] Also described herein is a method of reducing the potential abuse of an opioid agonist in an oral dosage form. The method includes providing the opioid agonist in an oral dosage form as described herein.

[0058] The term "analgesic efficacy" for the purposes of the present invention is defined as satisfactory reduction or elimination of pain, along with a tolerable level of side effects, as determined by the human patient.

[0059] The term "substantially no blocking of the analgesic effect of the opioid agonist" for the purposes of the present invention means that the opioid antagonist does not block the action of the opioid agonist sufficiently to render the dosage form less therapeutically effective in pain relief.

[0060] The term "tampering" refers to any mechanical, thermal and / or chemical manipulation that causes changes in the physical properties of an intact dosage form to release at least part of the opioid agonist for more rapid or immediate release, or to obtain the opioid agonist available for improper administration (e.g. parenteral administration). Violation of the intact dosage form can be performed e.g. by crushing, shearing, milling, chewing, dissolving in a solvent, heating (e.g. above about 45 ° C), or any combination thereof leading to this purpose.

[0061] In some embodiments, the tampering of the dosage form can be crushing to powder using a mortar and pestle. In other embodiments, the tampering may be performed using a pill crusher with a screw cap or using two stainless steel tablespoons.

[0062] In some embodiments, using a mortar and pestle, crushing can be performed to simulate chewing. For example, three strokes of the pestle can simulate mild chewing, six strokes of the pestle can simulate moderate chewing, and twelve strokes of the pestle can simulate accurate chewing. In some embodiments, a mortar and pestle can be used to crush the dosage form to a powder, using, e.g., 24, 50, 500 or 600 strokes of the pestle.

[0063] In some embodiments, using a pill crusher with a screw cap, the dosage form is placed in the crusher and the screw cap is rotated to crush the dosage form. The cap is then loosened, the crusher knocks on a hard surface and the crushing is repeated two more times.

[0064] In some embodiments, using stainless steel tablespoons, the dosage form is placed on one spoon, the second spoon is placed on the first spoon, and the dosage form is crushed between the spoons using hand pressure.

[0065] The term "layer is essentially free of antagonist" means that the layer does not contain an opioid antagonist, except for possibly small amounts that may migrate from the extruded component.

[0066] The term "at least partially blocking opioid activity" for the purposes of the present invention means that the opioid antagonist at least significantly blocks the euphoric effect of the opioid agonist.

[0067] The term "controlled release" when used for an opioid agonist, for the purposes of the present invention is defined as releasing the drug from the formulation at a rate that will provide a longer duration of action than a single dose of the normal release (i.e. immediate release) formulation. For example, a typical oral immediate release formulation may release the drug, e.g. at 1 hour intervals compared to an oral controlled release formulation that may release the drug, e.g. within 4 to 24 hours.

[0068] For the purposes of the present invention, the term "opioid agonist" is used interchangeably with the term "opioid" or "opioid analgesic" and includes one agonist or combinations of more than one opioid agonist, and also includes the use of the mixed base free opioid agonist antagonists, partial agonists, their pharmaceutically acceptable salts, their stereoisomers, their ethers, their esters, and mixtures of any of the foregoing.

[0069] For the purposes of the present invention, the term "opioid antagonist" will include one antagonist and combinations of more than one antagonist, and also includes the use of the free base antagonist, its pharmaceutically acceptable salts, its stereoisomers, its ethers, its esters, and mixtures any of the above.

[0070] It is understood that the invention disclosed herein includes the use of all pharmaceutically acceptable salts of the disclosed opioid agonists and antagonists. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, aspargate, glutamate etc.

[0071] Certain opioid agonist and antagonist compounds used in the present invention may contain one or more asymmetric centers and may form enantiomers, diastereomers, or other stereoisomeric forms. The present invention is intended to cover the use of all such possible forms as well as their racemic and resolved forms and mixtures thereof. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, the invention is intended to include both E and Z geometric isomers. All tautomers are also within the scope of this invention.

[0072] The term "layer" means a material applied to a particle (which may include the material itself and one or more optional intermediate layers, such as, e.g., a sealing coating) that can be used, e.g., as a coating. The application of layers to substrates can be carried out by methods known in the art, e.g. by spray coating, dipping or enrobing.

[0073] The term "superimposed" means that the material applied to the particle covers at least a portion of the particle, with or without an intermediate layer or layers between the substance and the particle. In some embodiments, the material completely covers the particle.

[0074] The term "stereoisomers" as used herein generally refers to all isomers of individual molecules differing only in the orientation of their atoms in space. This also applies to enantiomers and isomers of compounds that have more than one chiral center in their structure and which are not mirror images of others (diastereomers).

[0075] The term "chiral center" refers to a carbon atom to which four different substituents are attached.

[0076] The term "enantiomer" or "enantiomeric" refers to a molecule that is non-superimposable on its mirror image and is therefore optically active, wherein the enantiomer twists the plane of polarized light in one direction, and the molecule being its mirror reflection twists the plane of light polarized in the opposite direction.

[0077] The term "racemic" refers to a mixture of equal parts of enantiomers that is optically inactive. [0078] The term "separation" refers to separating a mixture or enriching or depleting a mixture into one of two enantiomeric forms of the molecule.

[0079] The term "X% by weight of particle weight" or "X% by weight increase" relative to the hydrophobic material applied to the particles of the present invention, means that the hydrophobic material is measured in% by weight of the particle, rather than by weight of the total coated layers of the particle . For example, 100 mg of an uncoated particle, later coated with a layer for 10% weight gain, will contain 10 mg of hydrophobic material in the layer.

[0080] The term "diameter" means the cross-sectional diameter of the particles, which is mainly dependent on the diameter of the hole used in the extrusion process.

[0081] The term "length" means the length of the extruded particles, which is mainly dependent on the cutting distance of the extruded thread.

[0082] The term "pharmaceutical product" means a dosage form suitable for administration or a component of a dosage form.

Brief description of the drawings [0083]

Fig. 1 is a graphical representation of plasma concentration versus time for intact naltrexone HEM preparation (whole), crushed MEM preparation

Naltrexone HCl (ground) and Naltrexone immediate release (IR NTX) HCl dosage forms in tablet form for Example 1.

Fig. 2 is a graphical representation of the naltrexone concentration curve (pg / ml) over time for Example 5.

Fig. 3 is a graphical representation of the naltrexone concentration curve (pg / ml) over time for Example 13A.

Fig. 4 is a graphical representation of the naltrexone concentration curve (pg / ml) over time for Example 13B.

Detailed Description [0084] The present invention is based on the observation that masked opioid antagonist particles can be improved by coating extruded opioid antagonist particles with a coating that further reduces antagonist "leakage" from intact form when exposed to environmental fluids. By using the invention, when the masked antagonist is combined with an opioid agonist, preferably only a small amount of the antagonist (i.e., an amount that does not affect the anesthesia provided by the agonist) is released under prescribed conditions of use. Most preferably, under prescribed conditions of use, no or no measurable amount of antagonist is released.

[0085] In some embodiments, the present invention includes an oral dosage form comprising a plurality of particles containing an orally a therapeutically effective amount of an opioid agonist in combination with a plurality of extruded masked particles containing an opioid antagonist, in an amount that at least significantly blocks the action of the opioid agonist, in the case of when the dosage form is violated. Preferably, many pharmaceutically acceptable particles comprising an opioid antagonist and many pharmaceutically acceptable particles comprising an opioid agonist are visually similar, and most preferably they are visually indistinguishable.

[0086] In some embodiments, the ratio of the opioid agonist to the opioid antagonist is such that when the oral dosage form is violated in violation of the consistency of the particles containing the opioid antagonist, an amount of antagonist is released that would significantly reduce or eliminate the euphoric effect of the opioid agonist upon administration. for humans, orally, parenterally, intranasally and / or sublingually.

[0087] For example, in some preferred embodiments of the invention, the euphoric effect of the opioid agonist may be significantly reduced or eliminated by the opioid antagonist when the dosage form is parenterally and / or sublingually abused. In some embodiments, when the dosage form is chewed, crushed or dissolved and heated in a solvent, and administered orally, intranasally, parenterally and / or sublingually, the analgesic or euphoric effect of the opioid is significantly reduced or eliminated due to the release of the opioid antagonist. In some embodiments, the opioid drug effect is at least partially blocked by the opioid antagonist. In certain other embodiments, the opioid drug effect is significantly blocked by the opioid antagonist. In some other embodiments, the opioid drug effect is completely blocked by the opioid antagonist.

[0088] Since the intact oral dosage form of the present invention, when administered properly as intended, substantially does not release the opioid antagonist, the amount of antagonist may vary more widely than when the opioid antagonist is available for release in the gastrointestinal tract. after oral administration.

[0089] The opioid antagonist in masked form includes a plurality of extruded particles comprising an opioid antagonist that is dispersed in a matrix, with a layer applied to each of the particles, wherein the matrix and the layer render the antagonist substantially unable to release. In one embodiment, the layer comprises a pharmaceutically acceptable hydrophobic material. In another embodiment, the matrix comprises a pharmaceutically acceptable hydrophobic material. In another embodiment, both the matrix and the layer comprise a pharmaceutically acceptable hydrophobic material. The hydrophobic matrix material may be the same or different from the hydrophobic layer material. The hydrophobic material is preferably present in an amount such that the antagonist is not released or substantially not released from the coated matrix and thus is unavailable or essentially not available to be absorbed when the oral dosage form passes through the gastrointestinal tract. [0090] According to the present invention, the opioid antagonist is dispersed in the matrix by melt extrusion, the matrix comprising one or more pharmaceutically acceptable hydrophobic materials.

[0091] In certain embodiments of the invention, the particles containing the opioid agonist are multiple particles in an extruded controlled release matrix. In certain embodiments, it has been found that when a plurality of particles in an extruded controlled-release matrix are violated in an attempt to obtain an opioid agonist available for immediate release, only a portion of the agonist is secreted for immediate release. In some embodiments, the weight percent of the agonist released from the extruded dosage form after a violation based on dissolution of the dosage form for 1 hour in 700 mL SGF, using a USP Type II device (stirrer) at 50 rpm at 37 degrees C, is below 50%; less than 40%; or below 35%.

[0092] Since only a portion of the opioid antagonist can be secreted for immediate release from multiple matrix particles after the violation, the antagonist may be included in a greater amount to provide after release the amount necessary to achieve the intended purpose of the invention. Eg. if in the embodiment of the invention 50% of the antagonist is released after a violation, the dosage form can be formulated using 4 mg of the antagonist content in the event that 2 mg of the antagonist is required after the violation. Since the oral dosage forms of the present invention do not release or substantially release the antagonist upon administration of the intact dosage form, the high content of the antagonist will not lead to release from the intact dosage form of the amount of antagonist that would be detrimental to the analgesic analgesic effect.

[0093] Materials for use in the extruded matrices of the present invention include, for example and without limitation, hydrophilic and / or hydrophobic materials such as rubbers, cellulose ethers, acrylic resins, materials of protein origin; digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, fatty acid glyceryl esters, mineral and vegetable oils and waxes (natural and synthetic), and stearyl alcohol; and polyalkylene glycols. The matrices may contain from 1% to 80% (by weight) of at least one hydrophilic material or preferably at least one hydrophobic material.

[0094] The hydrophobic material is any hydrophobic material suitable for this purpose, but is preferably selected from the group consisting of alkyl celluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof. In certain preferred embodiments of the present invention, the hydrophobic material is a pharmaceutically acceptable acrylic polymer including, but not limited to, any copolymers of acrylic acid and methacrylic acid, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethoxyethyl methacrylate, cyanoethyl methacrylate copolymer, aminoalkyl methacrylate copolymer (acrylic acid), poly (methacrylic acid), copolymer of methacrylic acid and alkylamine, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic anhydride), and glycidyl methacrylate copolymers.

[0095] Acrylic polymers useful in the present invention include, but are not limited to, acrylic resins containing copolymers synthesized from acrylic and methacrylic acid esters (e.g., a copolymer of a lower acrylic acid alkyl ester and a lower methacrylic acid alkyl ester) containing about 0.02 up to 0.03 mole of tri (lower alkyl) ammonium groups per mole of acrylic and methacrylic monomers used. An example of a suitable acrylic resin is a polymer manufactured by Rohm Pharma GmbH and sold under the trade name Eudragit® RS. Eudragit® RS30D is preferred. Eudragit® RS is a water insoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) and trimethylammonium ethyl methacrylate chloride (TAM), in which the molar ratio of TAM to other components (EA and MM) is 1:40. Acrylic resins such as Eudragit® RS can be used as an aqueous suspension.

[0096] In other embodiments, the hydrophobic material is selected from materials such as one or more hydroxyalkyl cellulose, such as hydroxypropyl methyl cellulose.

[0097] In some embodiments, the hydrophobic materials useful in the invention have a melting point from 30 ° C to 200 ° C, or from 45 ° C to 90 ° C.

[0098] In some embodiments, the hydrophobic material contains natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or cetostearyl alcohol), fatty acids, including, but not limited to, fatty acid esters, fatty acid glycerides (mono-, di- and triglycerides), hydrogenated fats, hydrocarbons, neutral waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials containing hydrocarbon backbones. Suitable waxes include, e.g., beeswax, glycowax, castor wax and carnauba wax. For the purposes of this invention, a wax type substance is defined as any material that is normally solid at room temperature and has a melting point of 30 ° C to 100 ° C.

[0099] In some embodiments, the hydrophobic material comprises a cellulose polymer selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate and triacetate cellulose. An example of ethyl cellulose is ethyl cellulose containing from 44 to 55% of ethoxy groups. Ethyl cellulose can be used as an alcohol solution. In some other embodiments, the hydrophobic material includes polylactic acid, polyglycolic acid or a copolymer of polylactic acid and polyglycolic acid.

[0100] In some embodiments, the hydrophobic material comprises a cellulose polymer selected from the group consisting of cellulose ether, cellulose ester, cellulose ester ether and cellulose. In some embodiments, cellulosic polymers have a degree of substitution, DS, glucose unit from above zero and up to 3 inclusive. By degree of substitution is meant the average number of hydroxyl groups present in the glucose unit of the cellulosic polymer that are replaced by a substituent. Representative materials include a polymer selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose mono-, di- and trialkanylates, cellulose mono-, di- and triaroate, and mono-, di- and tri- and cellulose trialkenylates. Exemplary polymers include cellulose acetate with a DS of up to 1 and an acetyl group content of up to 21%; cellulose acetate with an acetyl content of 32 to 39.8%; cellulose acetate with a DS of 1 to 2 and an acetyl content of 21 to 35%; and cellulose acetate with a DS of 2 to 3 and an acetyl content of 35 to 44.8%.

[0101] Specific cellulose polymers include cellulose propionate with a DS of 1.8, a content of propyl groups from 39.2 to 45%, and a content of hydroxyl groups from 2.8 to 5.4%; cellulose acetate butyrate with a DS of 1.8, an acetyl content of 13-15% and a butyryl content 34-39%; cellulose acetate butyrate with an acetyl group content from 2 to 29%, a butyryl group content from 17 to 53% and a hydroxyl group content from 0.5 to 4.7%; cellulose triacylate DS of 2.9 to 3, such as cellulose triacetate, cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose tribosuccinate and cellulose trioctoate; cellulose diacylates with a DS of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctoate, cellulose dipentanoate, and mixed cellulose esters such as cellulose acetate butyrate, cellulose acetate butanoate and cellulose acetate propionate.

[0102] Additional cellulose polymers include acetaldehyde dimethyl cellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, and dimethylamine cellulose acetate cellulose.

[0103] In some embodiments, the pharmaceutically acceptable hydrophobic material includes a biodegradable polymer comprising lactic and glycolic acid copolymer ("PLGA"), polylactide, polyglycolide, polyanhydride, polyorthoester, polycaprolactone, polyphosphazene, polysaccharide, proteinaceous polymer, polymer, polydolymer, polydolymer polylactic acid and poly (ethylene oxide), poly (hydroxybutyrate), polyphosphoester or a mixture or blend of any of the foregoing.

[0104] In some embodiments, the biodegradable polymer comprises PLGA, with a molecular weight of 2000 to 500000 daltons. The ratio of lactic acid to glycolic acid is from 100: 0 to 25:75, with a ratio of lactic acid to glycolic acid of 65:35 is preferred.

[0105] PLGA can be prepared using the procedure described in US Pat. Ser. No. 4,293539 (Ludwig et al.), The disclosure of which is hereby incorporated by reference in its entirety. Briefly, Ludwig produces a copolymer by condensation of lactic acid and glycolic acid in the presence of an easily removable polymerization catalyst (e.g. a strongly acidic ion exchange resin such as Dowex HCR-W2-H). The amount of catalyst is not critical to the polymerization process but is typically from 0.01 to 20 parts by weight based on the total weight of combined lactic acid and glycolic acid. The polymerization reaction can be carried out without solvents at a temperature of 100 ° C to 250 ° C, for 48 to 96 hours, preferably under reduced pressure, to facilitate the removal of water and by-products. PLGA is then isolated by filtration of the molten reaction mixture in an organic solvent such as dichloromethane or acetone and then filtration to remove the catalyst.

[0106] In some preferred embodiments, the extruded matrix comprises a combination of two or more hydrophobic materials. If the matrix contains two or more hydrophobic materials, the at least one hydrophobic material is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of these substances. Examples include, but are not limited to, beeswax, carnauba wax, stearic acid and stearyl alcohol.

[0107] When the hydrophobic material is a hydrocarbon, the hydrocarbon preferably has a melting point between 25 ° C and 90 ° C. Long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The matrix may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.

[0108] In certain preferred embodiments, the extruded matrix contains up to 60% (by weight) of at least one polyalkylene glycol.

[0109] One suitable extruded matrix comprises at least one water-soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂, an aliphatic alcohol and, optionally, at least one polyalkylene glycol. The hydroxyalkyl cellulose is preferably hydroxy (C₁ to C.₆) alkyl cellulose, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose or hydroxyethyl cellulose.

The amount of hydroxyalkyl cellulose in an oral dosage form will be determined, inter alia, by the exact rate of release of the active ingredient required. The aliphatic alcohol may be, e.g., lauryl alcohol, myristyl alcohol or stearyl alcohol. However, in particularly preferred embodiments, the aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of aliphatic alcohol in the oral dosage form will be determined, inter alia, by the exact rate of release of the active ingredient required. This amount will also vary depending on whether poly (alkylene glycol) is present in the oral dosage form. In the absence of poly (alkylene glycol), the oral dosage form will preferably contain from

20% to 50% (by weight) of the aliphatic alcohol. When at least one poly (alkylene glycol) is present in the oral dosage form, the combined weight of the aliphatic alcohol and poly (alkylene glycol) preferably comprises from 20% to 50% (by weight) of the total dosage form.

[0110] In one embodiment, the ratio of hydroxyalkyl cellulose or acrylic resin to aliphatic alcohol / polyalkylene glycol determines, to a significant extent, the release rate of the active ingredient from the formulation. The preferred ratio of hydroxyalkyl cellulose to aliphatic alcohol / poly (alkylene glycol) is from

1: 2 to 1: 4, with a ratio of 1: 3 to 1: 4 being particularly preferred. [0111] The poly (alkylene glycol) may be, e.g., poly (propylene glycol) or poly (ethylene glycol). The average molecular weight of poly (alkylene glycol) is preferably from 1000 to 15000, and especially from 1500 to 12000.

[0112] Another suitable extruded matrix comprises alkyl cellulose (especially ethyl cellulose), alcohol C₁₂ to C.₃₆ aliphatic and, optionally, polyalkylene glycol. [0113] Another suitable extruded matrix comprises an acrylic polymer (especially Eudragit® RSPO), alcohol C₁₂ to C.₃₆ aliphatic and, optionally, polyalkylene glycol.

[0114] In certain preferred embodiments, the matrix comprises a combination of at least two pharmaceutically acceptable hydrophobic materials.

[0115] As disclosed above, a plurality of extruded particles comprising a pharmaceutically acceptable matrix containing an opioid antagonist are layered using one or more hydrophobic materials which, in addition to the matrix material, can provide masking of the opioid antagonist. The hydrophobic coating material can be selected from any of the substances listed above. In some preferred embodiments, the hydrophobic material is a cellulosic material or polymer, an acrylic polymer, or a combination thereof. The terms "first hydrophobic material", "second hydrophobic material" and "third hydrophobic material" according to the invention include one or more hydrophobic materials in at least a partial dispersion or layered order. The first, second and third hydrophobic material can be the same or different. In some embodiments, the first and second hydrophobic materials may be the same; the first and third hydrophobic materials may be the same; the second and third hydrophobic materials may be the same; or the first, second and third hydrophobic material can be the same.

[0116] In embodiments with more than one hydrophobic material in the layer, the hydrophobic materials may be dispersed or partially dispersed. Alternatively, the hydrophobic materials may be layered. For example, the layer in an amount of 25% by weight of the particles may comprise 15% by weight of the ethyl cellulose layer based on the weight of the particles and 10% by weight of the acrylic polymer layer based on the weight of the particles applied to the ethyl cellulose layer.

[0117] The coating composition may be applied by spraying the composition onto a plurality of extruded particles using any suitable spraying device known in the art. For example, a Wurster fluidized bed system can be used in which an air stream, introduced from below, liquefies the coated material and causes drying when spraying the coating. The thickness of the coating will depend on the properties of the particular coating composition used.

[0118] Hydrophobic materials suitable for layering the extruded particles of the present invention include cellulosic materials and polymers, including alkyl cellulose. One preferred alkyl cellulose polymer is ethyl cellulose, although other cellulose polymers and / or alkyl cellulose polymers can easily be used, alone or in combination, as all or part of the hydrophobic coating of the invention.

[0119] One commercially available ethyl cellulose aqueous dispersion is Aquacoat® (FMC Corp., Philadelphia, Pennsylvania, USA), which is prepared by dissolving ethyl cellulose in a water-immiscible organic solvent and then emulsifying in water in the presence of a surfactant and stabilizer. After homogenization to produce submicron droplets, the organic solvent is evaporated under reduced pressure to form a pseudolatex.

[0120] Another aqueous dispersion of ethyl cellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, USA). This product is made by incorporating a plasticizer into the dispersion during the manufacturing process. A homogeneous mixture of hot molten polymer, plasticizer (dibutyl sebacate) and stabilizer (oleic acid) is obtained, which is then diluted with an alkaline solution to form an aqueous dispersion that can be applied directly to many particles.

[0121] In other preferred embodiments of the present invention, the hydrophobic material of the layer is a pharmaceutically acceptable acrylic polymer including, but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymers, and combinations thereof.

[0122] In some preferred embodiments, the acrylic polymer comprises one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

[0123] In some preferred embodiments, it may be necessary to incorporate two or more ammonio methacrylate copolymers with different physical properties, such as different molar ratios of quaternary ammonium groups to neutral (meth) acrylic esters.

[0124] In some embodiments, the acrylic layer comprises a mixture of two acrylic resin varnishes commercially available from Rohm Pharma (Darmstadt, Germany) under the trade names Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to other neutral (meth) acrylic esters is 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D . The average molecular weight is about 150,000. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. In some embodiments, the Eudragit® RS of the present invention is selected from the group consisting of Eudragit® RSPM, Eudragit® RSPO, Eudragit® RS100, Eudragit® RS12.5, and mixtures thereof. The phrase "Eudragit® RSPM" means generally unground Eudragit® RS powders, the phrase "Eudragit® RSPO" means finely ground Eudragit® RS powders, and the phrase "Eudragit® RS 100" means Eudragit® RS granules, while the phrase "Eudragit® RS12. 5 "means Eudragit® RS products in the form of solutions in which Eudragit® RS is dissolved in an organic solvent. In some embodiments, Eudragit® RL for use in the present invention is selected from the group consisting of Eudragit® RLPM, Eudragit® RLPO, Eudragit® RL100, Eudragit® RL12.5, and mixtures thereof. The terms "PM," "PO," ".100," and "12.5" have the meanings given above for Eudragit® RS. A mixture of the Eudragit® RS series and the Eudragit® RL series in any ratio is also used as the ammonio methacrylate copolymer of the present invention.

[0125] Eudragit® RL / RS dispersions according to the present invention can be mixed together in any desired ratio to finally obtain a masked formulation having the desired dissolution profile. For example, desired preparations can be obtained, for example, with a coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL: 90% Eudragit® RS. Of course, one skilled in the art will recognize other acrylic polymers that can also be used, such as e.g. Eudragit® L.

[0126] The layer may be applied in the form of an organic or aqueous solution or dispersion. The layer can be applied, resulting in a weight gain of 2 to 25% by weight of many pharmaceutically acceptable particles containing an opioid antagonist to achieve the desired masking. Coatings obtained using aqueous dispersions are described in detail in e.g. Ser. United States Nos. 5273760 and 5286493. Other examples of coatings that can be used in the present invention are found in US Pat. Ser. United States Nos. 5,234,351; US 5356467 and US 5472712.

[0127] In certain embodiments in which a plurality of extruded particles containing an opioid antagonist are film-coated using an aqueous dispersion of a hydrophobic material, the aqueous dispersion of the hydrophobic material preferably contains an effective amount of a plasticizer.

[0128] In embodiments of the present invention in which the layer is prepared from an aqueous dispersion of a hydrophobic material, the introduction of an effective amount of a plasticizer into the aqueous dispersion will further improve the physical properties of the layer. For example, since ethyl cellulose has a relatively high glass transition temperature and does not form flexible films under typical coating conditions, it is preferable to include a plasticizer in the ethyl cellulose coating solution. In general, the amount of plasticizer contained in the solution depends on the concentration of the film-former, e.g., usually 1 to 50 percent by weight of the film-former.

[0129] Examples of suitable plasticizers for ethyl cellulose include water-insoluble plasticizers, such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and glycerol triacetate, although other water-insoluble plasticizers (such as acetylated monoglycerides, castor oil, etc.). Triethyl citrate is a particularly preferred plasticizer for aqueous dispersions of ethyl cellulose.

[0130] Examples of potentially suitable plasticizers for acrylic polymers of the present invention include, but are not limited to, citric acid esters such as NF XVI triethyl citrate, tributyl citrate, dibutyl phthalate, and propylene glycol. Other plasticizers that have been found to be suitable for increasing the flexibility of thin layers formed of acrylic layers, such as Eudragit® RL / RS lacquer solutions include polyethylene glycols, diethyl phthalate, castor oil, and glycerol triacetate. Triethyl citrate is a particularly preferred plasticizer for aqueous dispersions of acrylic polymers.

[0131] The plasticized hydrophobic material can be applied to many pharmaceutically acceptable particles containing an opioid antagonist by spraying using any suitable spraying equipment known in the art. The preferred method uses a Wurster fluidized bed system in which an air stream, introduced from below, liquefies the core material and causes drying when the coating is sprayed.

[0132] The coating solutions of the present invention may additionally contain, in addition to the hydrophobic material, a plasticizer, and a solvent system (e.g.

water), dye to give a nice look and make the product stand out. Suitable coloring agents include dye dispersions based on alcohol or propylene glycol, ground aluminum lakes and opacifiers such as titanium dioxide and iron oxide pigments. Coloring agents may be added to the dispersion of a hydrophobic material during film formation. Alternatively, any other suitable method of providing color to the formulations of the present invention may be used. Eg. a color coating such as Opadry® can be applied to the pharmaceutically acceptable coated particles.

[0133] In some embodiments, a small amount of talc may be used to reduce the tendency of the aqueous dispersion to stick during processing, and / or to use as a gloss agent.

[0134] Many pharmaceutically acceptable particles may contain an opioid agonist dispersed in a controlled release matrix that slowly releases the opioid agonist in a controlled manner over a period of time, e.g., during digestion and exposure to gastric fluid and then intestinal fluid. The particle matrix preferably provides controlled release of the agonist over a period of time from 8 to 24 hours, preferably from 12 to 24 hours. A controlled release matrix for use in particles containing an opioid agonist may include those materials as described above for hydrophilic and / or hydrophobic materials (such as gums, cellulose ethers, acrylic resins, protein derived materials; digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, fatty acid glyceryl esters, mineral and vegetable oils and waxes (natural and synthetic), and stearyl alcohol; and polyalkylene glycols).

[0135] In some embodiments, the particles comprising an opioid agonist may comprise an immediate release matrix with a controlled release layer applied on its surface. The controlled release layer may contain one or more of the hydrophobic materials described above.

[0136] In some embodiments, many of the pharmaceutically acceptable particles comprising an opioid agonist are optionally coated with one or more substances suitable for: (i) controlling the release of the opioid agonist; (ii) protecting the formulation, or (iii) forming a coating virtually indistinguishable from the coating covering the antagonist-containing particles; or a combination of (i), (ii) or (iii). Eg. in one embodiment, a coating enabling pH-dependent or pH-independent release is used, e.g., when exposed to gastrointestinal (GI) fluids. The pH-dependent coating serves to release the opioid in a desired portion of the gastrointestinal (GI) tract, e.g. in the stomach or small intestine, so as to provide an absorption profile that can provide the patient with at least about eight hours and preferably about twelve hours to about twenty-four hours of anesthesia. When a pH-independent layer is desired, the layer is designed to achieve opioid release regardless of pH changes in environmental fluids, e.g. in the gastrointestinal tract (GI). It is also possible to make compositions that release a portion of the dose in one desired portion of the gastrointestinal (GI) tract, e.g. in the stomach, and release the remainder of the dose in another portion of the gastrointestinal (GI) tract, e.g. in the small intestine.

[0137] In some embodiments, many pharmaceutically acceptable particles comprising an opioid agonist or opioid antagonist are cured. Preferably, the particles are cured to an end point at which many pharmaceutically acceptable particles provide stable dissolution (or lack of dissolution). The cure endpoint can be determined by comparing the dissolution profile (curve) of the dosage form immediately after curing to the dissolution profile (curve) of the dosage form after exposure to accelerated storage conditions, e.g., at least one month at 40 ° C and 75% relative humidity. Cured preparations are described in detail in e.g. Ser. US Patent Nos. 5,273,760; US 5286493; US 5,500,227; US 5,580,578; US 5639476; US 5681585 and US 6024982. Other examples of controlled release formulations and coatings that can be used according to the present invention include those described in US Patent Nos. Ser. United States Nos. 5,234,351; US 5356467 and US 5472712.

[0138] In some embodiments, many of the pharmaceutically acceptable particles comprising an opioid agonist and / or pharmaceutically acceptable particles comprising an opioid antagonist are coated with a thin layer of material that does not substantially affect the release of the opioid agonist and / or opioid antagonist from the pharmaceutically acceptable particles. In some embodiments, a thin coating, such as Opadry®, is applied to many pharmaceutically acceptable particles. A thin coating is used, if any, preferably to significantly reduce agglomeration of the particles or to make it difficult to distinguish between particles containing the agonist and particles containing the antagonist from each other. Preferably, the thin coating of the present invention should be able to form a strong, continuous film, i.e. smooth and nice-looking, capable of retaining pigments and other coating additives, non-toxic, inert, and touch-dried.

[0139] In addition to the above components, either or both types of particles containing an opioid agonist and particles containing an antagonist may also contain appropriate amounts of other materials, such as diluents, lubricants, binders, auxiliary granulating agents, spheroidalities, dyes, flavorings and glidants that are typical in the pharmaceutical field. The amounts of these additional materials will be sufficient to obtain the desired effect on the desired formulation.

[0140] Examples of lubricants include, but are not limited to, magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate and magnesium palmitate.

[0141] Suitable binders, such as low viscosity water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water-soluble hydroxy (lower) alkyl cellulose, such as hydroxypropyl cellulose, is preferred.

[0142] Dyes may include titanium dioxide and / or dyes suitable for food products, such as dyes known as FD & C dyes, and natural coloring agents, such as grape skin extract, red beet powder, beta carotene, annatto, carmine (red lacquer obtained from cochineal), turmeric, pepper, and combinations of any of the above.

[0143] Flavorings incorporated into the compositions can be selected from synthetic aromatic oils and flavoring agents and / or natural oils, plant leaf extracts, flowers, fruits, and combinations of any of the foregoing.

[0144] Specific examples of pharmaceutically acceptable carriers, diluents, granulating auxiliaries, glidants and other excipients that can be used to prepare oral dosage forms are described in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).

[0145] Many processes can be used to prepare the dosage forms of the present invention as long as the techniques used do not destroy the integrity of the masked antagonist (e.g., when combining antagonist particles with agonist particles). Damage to the integrity of the masked antagonist particles may lead to the release of some opioid antagonist upon administration of an intact dosage form which impairs the agonist's effectiveness.

[0146] The particles of the present invention are produced by melt extrusion techniques involving melting a normally solid hydrophobic material, e.g. wax, and introducing a powdered drug therein. In some embodiments, an additional hydrophobic substance, e.g. ethyl cellulose or a water-insoluble acrylic polymer, can be added to the hydrophobic melt. [0147] The additional hydrophobic material may include one or more wax type thermoplastic substances. In some embodiments, the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal (GI) fluids during the initial release phases. Useful wax-like substances may be those with a water solubility of less than 1: 5000 (by weight).

[0148] In some embodiments, the preparation of a suitable melt-extruded matrix of the present invention may include the steps of mixing an opioid agonist or opioid antagonist, together with at least one or more hydrophobic materials to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least sufficiently soften the mixture to extrude it. The resulting homogeneous mixture is then extruded, e.g. to form elongated threads. The extrudate is preferably cooled and cut into many particles (e.g., a large number of particles) by any method known in the art. The extruded article preferably has an average diameter of from about 0.1 to about 12 mm, from about 0.1 to about 2.5 mm, from about 0.2 to about 6 mm, from 0.5 to about 3 mm; from about 0.5 mm to about 2 mm, or from about 1 mm to about 2 mm.

[0149] Suitable hydrophobic materials useful in making the melt-extruded matrix include, but are not limited to, acrylic polymers, cellulosic polymers, and aliphatic alcohols, as described above.

[0150] An optional method for producing the extrusion-molded molten materials of the present invention includes steps in which a hydrophobic material, a therapeutically active substance, and optionally a binder are dosed directly to the extruder; mixing and heating the ingredients to obtain a homogeneous mixture; the homogeneous mixture is extruded to form elongated threads; the threads containing the homogeneous mixture are cooled; threads are cut into particles having a size from about 0.1 mm to about 12 mm. In this aspect of the invention, a relatively continuous manufacturing procedure is carried out.

[0151] The diameter of the extruder gap or outlet may be adjusted to change the thickness of the extruded threads. In addition, the extruder outlet need not be round; it can be elongated, rectangular, etc. Outgoing threads can be cut into particles using a hot cutting wire, a single-knife cutter, etc.

[0152] Melt-extruded dies can be, e.g., in the form of granules, spheres or pellets, depending on the outlet of the extruder. For the purposes of the present invention, the terms "melt extruded dies" and "melt extruded die system (s)," multiple melt extruded particles "and" melt extruded particles "refer to multiple units, preferably of similar sizes and / or shapes, containing one or more active substances and one or more excipients, preferably including hydrophobic material as described herein. In this regard, melt extruded dies will have sizes in the range of from about 0.1 to about 12 mm; from about 0.1 to about 2.5 mm; from about 0.2 to about 6 mm; from about 0.5 to about 3 mm; from about 0.5 mm to about 2 mm; or from about 1 mm to about 2 mm in diameter and / or length. In addition, it should be understood that the melt extruded dies can have any geometric shape in this size range. In certain embodiments, the extrudate can be cut into particles of the desired length and divided into unit doses of opioid antagonist or opioid agonist without requiring a spheronization step.

[0153] In other embodiments of the invention, the molten extruded material is prepared without introducing an opioid agonist and / or opioid antagonist, which are then added to the extrudate produced article. Such formulations will typically contain drugs mixed together with the extruded matrix material, and then the mixture can be converted into multiple particles by methods known in the art. Such preparations may be advantageous e.g. in the case where the opioid agonist or opioid antagonist contained in the formulation is sensitive to the temperatures required to soften one or more hydrophobic materials.

[0154] An extrusion / spheronization process is an additional method described herein for making many pharmaceutically acceptable particles. In this process, the opioid agonist or opioid antagonist is collected in a wet state with a binder, extruded through a perforated plate or die, and placed on a rotary disk. The extrudate is preferably broken into pieces that are rounded to spheres, balls, or rounded rods on a rotating plate. A preferred method and composition for this method involves the use of water to collect a wet composition containing, e.g., from about 20% to 75% cellulose derivative mixed with e.g. from about 80% to 25% of an opioid agonist or opioid antagonist.

[0155] An additional method described herein for the preparation of many pharmaceutically acceptable particles includes the use of an organic solvent to facilitate mixing of the opioid antagonist or agonist with the matrix material. This technique can be used when it is desired to use a matrix material with another inadequately high melting point, which, if the material is used in the molten state, may break down the drug or matrix material, or may cause an unacceptable viscosity of the melt that prevents mixing of the drug (e.g. opioid agonist or opioid antagonist) with matrix material. The drug and matrix material can be combined with a small amount of solvent to form a paste, which is then forced through a screen to form granules from which the solvent is later removed. Alternatively, the drug and matrix material can be combined with a sufficient amount of solvent to completely dissolve the matrix material, and the resulting solution (which may contain solid drug particles) is spray dried to form multiple pharmaceutically acceptable particles. This technique is advantageous when the matrix material is a high molecular weight synthetic polymer such as cellulose ether or cellulose ester. Solvents typically used in this process include acetone, ethanol, isopropanol, ethyl acetate, and mixtures thereof.

[0156] As mentioned above, many extruded particles containing an opioid antagonist have a layer that contains a hydrophobic material applied to each of the particles. Preferably, the layered coated particles containing an opioid antagonist significantly reduce or prevent release of the opioid antagonist, while the pharmaceutically acceptable particles containing the opioid agonist preferably provide controlled release of the opioid agonist for a period of time from 8 to 24 hours or more, most preferably for a period of time from 12 to 24 hours .

[0157] In preferred embodiments, the layer applied to the matrix containing the antagonist is impermeable or substantially impermeable to the antagonist and is insoluble or substantially insoluble in the gastrointestinal (GI) system. Preferably, when the intact dosage form of the present invention is administered orally to humans, the opioid antagonist is substantially not released and is therefore not available for absorption by the body. Thus, the opioid antagonist, although in dosage form, does not substantially block the analgesic efficacy of the opioid agonist. However, if the oral dosage form of the present invention is violated, the opioid antagonist contained therein is released to at least partially block the action of the opioid agonist. This aspect of the invention may reduce the possibility of potential abuse or withdrawal of the opioid agonist from the oral dosage form. For example, if a person attempts to abuse a drug contained in the oral dosage form of the present invention by e.g. chewing, crushing, milling or dissolving this form in a solvent using heating (e.g. to a temperature above 45 ° C to 50 ° C), both the layer and matrix will be damaged and stop masking the opioid antagonist. Upon administration of the affected dosage form, the opioid antagonist will be released and will preferably substantially block the euphoric effect of the opioid agonist.

[0158] Many of the pharmaceutically acceptable particles (i.e., layered extruded opioid antagonist particles and opioid agonist particles) of the present invention are then incorporated into an oral dosage form, optionally using conventional excipients known in the art.

[0159] In one preferred embodiment, oral dosage forms are prepared that comprise an effective amount of particles containing an opioid agonist and particles containing an opioid antagonist within the capsule. For example, many pharmaceutically acceptable particles may be placed in a gelatin capsule in an amount sufficient to provide an effective sustained release dose after digestion. The capsule may be sealed or unsealed to allow the particles to spill.

[0160] In another embodiment, an appropriate amount of the layered antagonist-containing particles is combined with the opioid-agonist-containing particles and compressed into an oral tablet, without significantly damaging the coherence of many pharmaceutically acceptable particles.

[0161] In another embodiment, an appropriate amount of the layered antagonist-containing particles is combined with the opioid formulation (e.g., sustained release granulate) and compressed into a tablet in which the antagonist-containing particles are immersed in an agonist-containing matrix, without compromising coherence many pharmaceutically acceptable particles.

[0162] Techniques and compositions for preparing tablets (compressed and shaped), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980).

[0163] In some embodiments, oral dosage forms may also contain an amount of immediate release opioid agonist to provide an immediate therapeutic effect. In some embodiments, an immediate-release opioid agonist may be incorporated, e.g., as separate pellets in a gelatin capsule, or may be introduced in a layer covering the surface of the agonist-containing particles after forming the dosage form.

[0164] The controlled release formulations of the present invention preferably slowly release the opioid agonist, e.g., during digestion and subsequent treatment of gastric fluids followed by intestinal fluids. The controlled release profile of the formulations of the invention can be changed, e.g. by changing the amount of retardant, i.e., hydrophobic material, by changing the amount of plasticizer relative to the hydrophobic material, by introducing additional ingredients or excipients, by changing the production method, etc.

[0165] In preferred embodiments, the opioid agonists useful in the present invention include, but are not limited to, alfentanil, allylprodin, alphaprodynin, anileridine, benzylmorphine, besiramid, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dexpromomamid, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafetyl butyrate, dipipanone, eptazocin, etheheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroethorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine, isometadone, ketobemidone, levorphanol, levofenacylmorphan, lofentanyl, meperidine, meptazine, metazocin, metformin, metadorfin, metformin nalorphine, nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaverium, pentazocine, fenadoxone, fenomorphan, fenazocine, phenoperidine, piminodine, pyrithramide, propeptazine, promedol, properidine, propoxyphene, sufentanil, tylidin, tramadol, their pharmaceutically acceptable salts, and mixtures of any of the foregoing. In some embodiments, the amount of opioid agonist in the dosage form can be about 75 ng to 750 mg.

[0166] In preferred embodiments, the opioid antagonist of the present invention is selected from naltrexone, naloxone, nalmefene, cyclazocin, levalorfan, their pharmaceutically acceptable salts, and mixtures of any of the foregoing. In certain preferred embodiments, the opioid antagonist is naltrexone or a pharmaceutically acceptable salt thereof (e.g., naltrexone HCl). In some embodiments, the amount of opioid antagonist present in a substantially non-releasing form may be from about 0.5 mg to about 50 mg, from about 1 mg to about 25 mg, from about 2 mg to about 20 mg, from about 5 mg to about 15 mg, from about 2 mg to about 10 mg, or from about 4 mg to about 10 mg, or from about 6 mg to about 8 mg.

[0167] Naloxone is an opioid antagonist that almost eliminates the action of an agonist. Subcutaneous doses of up to 12 mg naloxone cause indistinguishable subjective effects, while 24 mg naloxone causes only slight drowsiness. Small doses (0.40.8 mg) of naloxone administered to a man intramuscularly or intravenously prevent or immediately reverse the action of a morphine-type opioid agonist. As described, one mg of intravenous naloxone completely blocks 25 mg of heroin. The effect of naloxone is seen almost immediately after intravenous administration. The drug is absorbed after oral administration but, as described, is rapidly metabolised to an inactive form during the first passage through the liver, so it has been reported to have significantly less potency than when administered parenterally. An oral dose greater than 1 g has been reported to be almost completely metabolized in less than 24 hours. It has also been reported that 25% of sublingual naloxone is absorbed. Weinberg, et al., Sublingual Absorption of selected Opioid Analgesics, Clin Pharmacol Ther. (1988); 44: 335-340.

[0168] Other opioid antagonists, such as cyclazocin and naltrexone, which contain cyclopropylmethyl substituents on the nitrogen atom retain a significant portion of their oral effectiveness and their periods of action are much longer, reaching 24 hours after oral administration.

[0169] In a preferred embodiment of the invention, the opioid agonist includes oxycodone, hydrocodone, hydromorphone, morphine, oxymorphone, codeine or pharmaceutically acceptable salts thereof, while the opioid antagonist comprises naltrexone or pharmaceutically acceptable salts thereof and is present in an amount of from 2 mg to 15 mg, in an amount of 5 mg to 10 mg, or from 6 mg to 8 mg.

[0170] In embodiments in which the opioid agonist is hydrocodone or a pharmaceutically acceptable salt thereof, the sustained release oral dosage forms may contain analgesic doses from 8 mg to 50 mg of hydrocodone or its salt per unit dosage form. In oral sustained release dosage forms in which the hydromorphone or pharmaceutically acceptable salt thereof is a therapeutically active opioid, it is included in an amount of 2 mg to 64 mg of hydromorphone or salt thereof. In another embodiment, the opioid agonist is morphine or a pharmaceutically acceptable salt thereof, and the controlled release oral dosage form of the present invention comprises from 2.5 mg to 800 mg morphine or a salt thereof. In yet another embodiment, the opioid agonist is oxycodone or a pharmaceutically acceptable salt thereof, and the controlled release oral dosage form comprises from 2.5 mg to 800 mg oxycodone or a salt thereof. In certain preferred embodiments, the oral sustained release dosage form comprises 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 160 mg or 320 mg oxycodone hydrochloride. Oxycodone controlled-release preparations are known in the art. In some embodiments, the opioid agonist is tramadol or a pharmaceutically acceptable salt thereof, and controlled-release oral dosage forms may contain from 25 mg to 800 mg tramadol per unit dosage form. The dosage form may contain more than one opioid agonist to obtain an equivalent therapeutic effect compared to the therapeutic effect achieved by the product containing the single agonist. Alternatively, the dosage form may contain molar equivalent amounts of other salts of opioid agonists useful in the present invention. [0171] In some embodiments, the stabilizer is included in the dosage form to prevent degradation of the opioid antagonist. In some embodiments, the stabilizers used in the dosage form include, and are not limited to, organic acids, carboxylic acids, acid salts of amino acids (e.g. cysteine, L-cysteine, cysteine ​​hydrochloride, glycine hydrochloride or cystine dihydrochloride), sodium metabisulfite, ascorbic acid and its derivatives, malic acid, isoascorbic acid, citric acid, tartaric acid, palmitic acid, sodium carbonate, sodium bicarbonate, calcium carbonate, hydrogen phosphate calcium, sulfur dioxide, sodium sulfite, sodium bisulfate, tocopherol, as well as its water and fat soluble derivatives, such as e.g. tocofersolate or tocopherol acetate, sulfites, bisulfites and acid sulfites or alkali metals, alkaline earth metals and other metals, PHB esters, gallates, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT), and 2,6-di-t-butyl alpha-dimethylamino-p-cresol, t-butyl hydroquinone, di-t-amyl hydroquinone, di-t-butyl hydroquinone, butyl hydroxy toluene, butyl hydroxy anisole, pyrocatechol, pyrogalol, propyl gallate, and nordihydroglassic acid as well fruit acids, phosphoric acids, sorbic and benzoic acids, as well as their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, conidendrine, diethyl carbonate, methylenedioxylene , cephalins, β, β'dithiopionic acid, biphenyl and other phenyl derivatives, their pharmaceutically acceptable salts, and mixtures thereof.

[0172] The oral dosage form of the present invention may further contain, in addition to the opioid agonist and antagonist, one or more drugs that may or may not synergistically interact with them. Thus, in some embodiments, in addition to the opioid antagonist, the dosage form may comprise a combination of two opioid agonists. Eg. the dosage form may contain two opioid agonists exhibiting different properties, such as half-life, solubility, potency, and a combination of any of the above. In yet other embodiments, the dosage form comprises one or more opioid agonists and in addition a non-opioid drug in addition to the opioid antagonist. Such non-opioid drugs may advantageously provide additional anesthesia, and include drugs such as e.g. aspirin, acetaminophen; non-steroidal anti-inflammatory drugs ("NSAIDs"), e.g., ibuprofen, ketoprofen, etc .; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g.

morphinan, such as dextromethorphan or dextrorphan, or ketamine; cyclooxygenase-II inhibitors ("COX-II inhibitors"); and / or glycine receptor antagonists. The additional agent may be contained in the same particles as the first agonist, or in other particles.

[0173] In certain preferred embodiments of the present invention, the invention allows the use of lower doses of opioid analgesics by introducing an additional non-opioid agonist such as NSAID or inhibitor

COX-2. By using smaller amounts of one or both drugs, you can reduce the side effects associated with effective pain management in humans.

[0174] Suitable non-steroidal anti-inflammatory agents include agents such as ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pyroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, triprofen, triprofen, , 4- (4-cyclohexyl-3-chlorophenyl) -4-oxobutyric acid ( bucloxic acid), indometacin, sulindac, tolmetin, zomepirac, thiopinac, zidometacin, acemetacin, fentiazac, clidanak, oxspinak, mefenamic acid, meclofenamic acid, flufenamic acid, niflumamic acid, tolfenamicox, fllfuramamoxic, diflamamicox pharmaceutically acceptable salts, mixtures thereof, etc. Suitable doses of these drugs are well known to those skilled in the art.

[0175] N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art and include, e.g., morphinates such as dextromethorphan or dextrorphan, ketamine, d-methadone, or pharmaceutically acceptable salts thereof. For the purposes of this invention, the term "NMDA antagonists" also includes drugs that block the main intracellular pathway of NMDA receptor activation, e.g., a ganglioside such as GM₁ or GT_1b, phenothiazine such as trifluoperazine or naphthalenesulfonamide, such as N- (6-aminotexyl) -5-chloro-1-naphthalenesulfonamide. These drugs are intended to inhibit the development of tolerance and / or addiction to narcotic drugs, e.g. narcotic analgesics, such as morphine, codeine, etc., as described in US Pat. Ser. U.S. Patent Nos. 5321012 and 5556838 (both Mayer et al.), And for the treatment of chronic pain as described in US Pat. Ser. United States No. US 5502058 (Mayer et al.).

[0176] Treatment of chronic pain by using glycine receptor antagonists and identifying such drugs is described in US Pat. Ser. No. US 5514680 (Weber et al.).

[0177] COX-2 inhibitors have been described in the art and many chemical structures are known to elicit cyclooxygenase-2 inhibition. COX-2 inhibitors have been described, e.g. Ser. United States Nos. 5,616,601; US 5604260; US 5593994; US 5550142; US 5,536,752; US 5521213; US 5,475,995; US 5639780; US 5604253; US 5552422; US 5,510,368; US 5436265; US 5409944; and US 5,130,311. Some preferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP28238), meloxicam, 6-methoxy-2-naphthylacetic acid (6-MNA), MK-966 (also known as Vioxx), nabumeton (prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T614; their pharmaceutically acceptable salts, and combinations thereof. Dosage levels of the COX-2 inhibitor on the order of from 0.005 mg to about 140 mg per kilogram body weight per day are therapeutically effective in combination with an opioid analgesic. Alternatively, the patient may be administered about 0.25 mg to about 7 g of COX-2 inhibitor daily in combination with an opioid analgesic. Combinations of opioid agonists and COX-2 inhibitors are disclosed in International Patent Application WO 99/13799.

[0178] In yet other embodiments, the dosage form may comprise a non-opioid drug that provides the desired effect other than anesthesia, such as, e.g., antitussive, expectorant, anti-emetic, vasoconstrictor, antihistamine, local anesthetic, etc.

[0179] The present invention is also directed to the dosage forms disclosed herein employing other active substance / antagonist (i.e. non-opioid) combinations to prevent abuse of the active substance. For example, when benzodiazepine is used as the active ingredient in the dosage form of the present invention, a masked benzodiazepine antagonist may be formulated in the dosage form. When barbiturate is used as the active ingredient in the dosage form of the present invention, the masked barbiturate antagonist can be formulated in the dosage form. When amphetamine is used as the active ingredient in the dosage form of the present invention, a masked amphetamine antagonist can be formulated in the dosage form.

[0180] The term "benzodiazepines" refers to benzodiazepines and drugs that are benzodiazepine derivatives and are capable of inhibiting central nervous system activity. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepan, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quasepam, temazepam, and methyl, triazam

[0181] Benzodiazepine antagonists for use in the present invention include, but are not limited to, flumazenil.

[0182] Barbiturates refer to sedative-hypnotic drugs derived from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methehexytal, methylphenobarbital, metarbital, pentobarbital, phenobarbital, secobarbital and mixtures thereof. [0183] Barbiturate antagonists for use in the present invention include, but are not limited to, amphetamines as described.

[0184] Stimulants refer to drugs that stimulate the central nervous system. Stimulants include, but are not limited to, amphetamines such as amphetamine, dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and mixtures thereof.

[0185] Stimulant antagonists for use in the present invention include, but are not limited to benzodiazepines, as described herein.

[0186] The present invention is also directed to the dosage forms disclosed herein utilizing adverse agents other than antagonists to suppress abuse of the active substance. The term "adverse agent" refers to any agent that may produce an unpleasant effect when administered in an unmasked form. Examples of adverse agents other than antagonists include emetic, irritant and intense bitter flavors.

[0187] Emetic agents include, but are not limited to, ipecak and apomorphine.

[0188] Irritants include, but are not limited to, capsaicin, capsaicin analogs, and mixtures thereof. Capsaicin analogs include resiniferatoxin, tinyatoxin, heptanoyl isobutylamide, heptanoylguacilamide, other isobutylamides or guaiacylamides, dihydrocapsaicin, homovanillic acid octyl ester, nonanoylatedilylamide, and mixtures thereof.

[0189] Intense bitter flavoring agents include, but are not limited to, flavoring oils; flavor flavors; oleoresins; flavoring extracts from plants, leaves, flowers; fruit flavors; sucrose derivatives; chlorosacrose derivatives; quinine sulfate; denatonium benzoate; and their combinations. [0190] The invention will now be described in more detail with reference to the accompanying examples.

Example 1 (reference example)

Naltrexone HCl Capsules, 2 mg [0191] This is a comparative example of the naltrexone HCl opioid antagonist that was formulated to be melt-extruded multiple particles (referred to below as "MEM") to obtain a masked product. Based on selected polymers and excipients, MEM pellets release very little naltrexone when intact, but release significant amounts of naltrexone when they are broken (crushed). This example is included as a reference to show how coatings in the examples following Example 1 can increase the masking properties. The naltrexone HCl formulation of Example 1 is listed in the table below.

Table 1A Composition

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>Naltrexone HCl</td><td> 2,0</td><td> 0,10</td>

<td>Eudragit RSPO</td><td> 88,0</td><td> 4,40</td>

<td>Stearyl alcohol</td><td> 15,0</td><td> 0,75</td>

<td>Stearic acid</td><td> 15,0</td><td> 0,75</td>

<td>Butylated hydroxytoluene (BHT)</td><td> 1,0</td><td> 0,05</td>

<td>Hard gelatin capsules size # 2</td><td> 61,0</td><td> 3,05</td>

<td>globally</td><td> 182,0</td><td> 9,10</td>

[0192] The naltrexone HCl formulation of Example 1 was prepared using the following process:

Manufacturing Process [0193]

1. Grinding: Stearyl alcohol flakes are passed through an oscillating mill equipped with a 16 mesh screen to give a powder that is easily miscible.

2. Mixing: Naltrexone HCl, Eudragit RSPO, ground stearyl alcohol, stearic acid and BHT are mixed in a twin shell mixer.

3. Extrusion: The mixed material obtained in step 2 is fed into the twin screw extruder continuously and the extrudate is collected (Leistritz ZSE-27) at a rate in the range of 1.7 kg / hour to 2.6 kg / hour. The blend is extruded at a cylinder temperature of 75 ° C to 100 ° C in the form of a thread with a diameter of about 1 mm. Extruded threads accumulate on the conveyor.

4. Cooling: The threads on the conveyor can be cooled.

5. Pelletizing: The cooled threads are cut into pellets about 1 mm long using a pelletizing device.

6. Screening: The pellets are sieved through a vibrating funnel using 16 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product.

7. Encapsulation: The sieved pellets are filled into hard gelatin capsules at a target load of 121 mg.

In vitro dissolution:

[0194] The formulations prepared by the method of Example 1 gave the following results, which are detailed in Table 1B using the in vitro dissolution testing method below.

Method:

[0195]

1. The device - USP Type II (stirrer), 75 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 24, 36 hours

3. Centers: 700 ml SGF (simulated gastric fluid) for one hour, followed by replacement with 900 ml SIF (simulated intestinal fluid)

4. Analytical method: High performance liquid chromatography

Results:

[0196]

Table 1B

<td>Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 24</td><td> 36</td>

<td>Average% dissolution</td><td> 1,3</td><td> 2,6</td><td> 2,9</td><td> 3,6</td><td> 4,0</td><td> 5,2</td><td> 6,2</td>

Simulated infringement process and dissolution:

[0197] The formulations prepared by the method of Example 1 were subjected to a simulated tampering process and then subjected to the in-vitro dissolution testing method presented below. The dissolution results for 1 hour are given in Table 1C. In the tampering process, naltrexone pellets were ground using a mortar and pestle (600 strokes) to powder for the purposes of this dissolution test.

Dissolution method: Same as above

Results:

[0198] Table 1C

<td>Time (hours)</td><td> 1</td>

<td>Average% dissolution</td><td> 33,5</td>

Crushed part ratio: intact part [0199] The ratio of crushed part to intact part means the ratio of% dissolution of crushed pellets in 1 hour to% dissolution of intact pellets in 36 hours.

Results of the ratio of crushed part to intact part: 33.5% / 6.2% = 5.4: 1

In vivo pharmacokinetic / bioavailability study in humans [0200] Capsules (MEM) obtained using the above process and formulation were used in a clinical trial to determine pharmacokinetics / bioavailability compared to immediate release naltrexone tablets. Human patients were administered the following dosage forms: intact naltrexone MEM HCl (whole), crushed naltrexone MEM HCl (ground) or immediate-release naltrexone HCl tablets (IR NTX). The results are shown graphically in Figure 1. Dose-regulated (up to 1 mg NT NTX tablet) exposure range (AUCt) of the intact (whole) and crushed (ground) preparation compared to the immediate-release naltrexone (IR NTX) preparation and the Cmax controlled dose of IR NTX, crushed (ground) preparation ) and intact (whole) are given in Table 1D below.

Table 1D

<td>Preparation</td><td>Parameter</td><td>IRNTX</td><td>Crushed MEM (ground)</td><td>Intact (whole) MEM</td>

<td>AND</td><td>Average AUCt (Pg / ml^.hour)</td><td> 564,4</td><td> 373,4</td><td> 84,7</td>

<td></td><td>Mean Cmax (pg / ml)</td><td> 142,1</td><td> 43,1</td><td> 5,3</td>

[0201] Dose-regulated plasma concentrations show that there is minimal release of naltrexone from the MEM dosage form when taken intact. Naltrexone levels are increased when the crushed (ground) MEM preparation is taken. Based on the average Cmax, the ratio of crushed MEM capsules / intact MEM capsules is about 8. Similarly, for average AUCt, the ratio of crushed MEM capsules / intact MEM capsules is about

4.4. This indicates that the ratios of total and maximum exposure are significantly increased due to crushing.

Example 2 mg naltrexone HCl pellets coated with ethylcellulose [0202] In Example 2, a naltrexone MEM preparation was prepared in a similar manner to that described in Example 1 and then the MEM was coated with ethyl cellulose (Surelease) using different amounts (5%, 10%, 15%, and 20% weight gain). The uncoated naltrexone HCl formulation of Example 2 is listed in Table 2A below:

Table 2A Composition of the pellet

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>Naltrexone HCl</td><td> 2,0</td><td> 0,10</td>

<td>Eudragit RSPO</td><td> 88,0</td><td> 4,40</td>

<td>Stearyl alcohol</td><td> 15,0</td><td> 0,75</td>

<td>Stearic acid</td><td> 15,0</td><td> 0,75</td>

<td>Butylated hydroxytoluene (BHT)</td><td> 1,0</td><td> 0,05</td>

<td>globally</td><td> 121,0</td><td> 6,05</td>

[0203] The uncoated naltrexone HCl formulation of Example 2 was prepared using the following process:

Manufacturing Process [0204]

1. Grinding: Stearyl alcohol flakes are passed through an oscillating mill equipped with a 16 mesh screen to give a powder that is easily miscible.

2. Mixing: Naltrexone HCl, Eudragit RSPO, ground stearyl alcohol, stearic acid and BHT are mixed in a twin shell mixer.

3. Extrusion: The mixed material obtained in step 2 is fed continuously to the twin screw extruder (Leistritz ZSE-27) at a rate in the range of 2.9 kg / hour to 4.8 kg / hour. The blend is extruded at a cylinder temperature in the range of 95 ° C to 105 ° C in the form of a thread with a diameter of about 1 mm. Extruded threads accumulate on the conveyor.

4. Cooling: The threads on the conveyor can be cooled.

5. Pelletizing: The cooled threads are cut into pellets about 1 mm long using a pelletizing device.

6. Screening: The pellets are sieved through a vibrating funnel using 16 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product.

In Vitro Dissolution [0205] The uncoated formulations prepared by the method of Example 2 gave the following results, which are detailed in Table 2B using the in vitro dissolution testing method below.

Method:

[0206]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 18, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0207]

Table 2B

<td>Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 18</td><td> 24</td><td> 36</td>

<td>Average% dissolution</td><td> 2,1</td><td> 2,6</td><td> 2,9</td><td> 3,2</td><td> 3,8</td><td> 4,2</td><td> 4,7</td><td> 5,3</td>

Simulated infringement process and dissolution:

[0208] Formulations prepared by the method of Example 2 were subjected to a simulated tampering process and then subjected to the dissolution testing method below. The dissolution results for 45 minutes are given in Table 2C. In the tampering process, the uncoated naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0209]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0210]

Table 2C

<td>Time (minutes)</td><td> 45</td>

<td>Average% dissolution</td><td> 31</td>

Ratio of crushed to intact [0211] Ratios of crushed to intact means the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours.

Results of the ratio of crushed part to intact part: 31% / 5.3% = 5.8: 1 [0212] Naltrexone HCl pellets prepared by the method of Example 2 and listed in Table 2A were then covered with a hydrophobic coating. The pellets were coated with weight gains of 5%, 10%, 15% and 20% using a hydrophobic coating (Surelease); and 20% using a hydrophobic coating (Surelease) and a colored coating (Opadry). An example of a coating and color coating formulation giving a 20% weight gain is detailed in the table below.

2D table

20% weight gain with colored coating

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>Naltrexone HCl, 2 mg pellets</td><td> 121,0</td><td> 0,50</td>

<td>Surelease (solids)</td><td> 24,2</td><td> 0,10</td>

<td>Opadry Pink</td><td> 6,05</td><td> 0,025</td>

<td>globally</td><td> 151,25</td><td> 0,625</td>

[0213] The coated naltrexone HCl formulations of Example 2 were prepared using the following process:

Manufacturing Process [0214]

1. Functional coating dispersion: The Surelease suspension is diluted to 15% by weight solids by mixing with water.

2. Dispersion of the colored coating: Opadry is mixed with water to obtain a dispersion of 10% by weight.

3. Functional coating: The Surelease dispersion is sprayed onto the naltrexone pellets prepared above at 700 g, using a fluidized bed reactor (GPCG-1) and the following performance guidelines:

- Air flow rate: 7.0 to 9.0 m / s

- Inlet air temperature: 40 - 50 ° C

- Dispersion spray rate: 8-11 g / minute

Samples were taken after spraying the theoretical amount of dispersion leading to 5%, 10%, 15% and 20% weight gain.

4. Color coating: After functional coating, the Opadry dispersion is sprayed onto the coated pellets, using the following parameter guidelines:

- Air flow rate: 7.0 m / s

- Inlet air temperature: 50 ° C

- Dispersion spray rate: 8.5 g / minute

5. Screening: Pellets are sieved through a 14 US mesh screen and 20 US mesh screen. Material retained on a 20 US mesh screen is collected as the desired product.

6. Curing: Place the sieved pellets and samples in an oven at 45 ° C for 24 hours.

[0215] Coated pellets up to 5%, 10% and 15% weight gain were prepared by the method described above for coated pellets with 20% weight gain, using 6.05, 12.1 and 18.15 mg Surelease per unit, respectively.

In Vitro Dissolution [0216] The coated preparations of the method of Example 2 gave the following results, which are detailed in Table 2E using the in vitro dissolution test method below.

Method:

[0217]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 18, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0218]

Table 2E

<td colspan="2">Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 18</td><td> 24</td><td> 36</td>

<td rowspan="6">Average% dissolution</td><td>uncovered</td><td> 2,1</td><td> 2,6</td><td> 2,9</td><td> 3,2</td><td> 3,8</td><td> 4,2</td><td> 4,7</td><td> 5,3</td>

<td> 5%</td><td> 0,0</td><td> 0,6</td><td> 0,9</td><td> 1,4</td><td> 1,8</td><td> 2,2</td><td> 2,4</td><td> 3,2</td>

<td> 10%</td><td> 0,0</td><td> 0,7</td><td> 0,6</td><td> 1,0</td><td> 1,2</td><td> 1,6</td><td> 1,8</td><td> 2,3</td>

<td> 15%</td><td> 0,0</td><td> 0,0</td><td> 0,5</td><td> 0,8</td><td> 1,1</td><td> 1,4</td><td> 1,6</td><td> 2,1</td>

<td> 20%</td><td> 0,0</td><td> 0,0</td><td> 0,0</td><td> 0,7</td><td> 0,9</td><td> 1,3</td><td> 1,5</td><td> 2,0</td>

<td>20% by weight / Opadry</td><td> 0,0</td><td> 0,0</td><td> 0,7</td><td> 1,0</td><td> 1,2</td><td> 1,5</td><td> 1,6</td><td> 2,0</td>

As can be seen from the dissolution results, the dissolution of naltrexone pellets generally decreases as the amount of polymer coating increases.

Simulated infringement process and dissolution:

[0219] The formulations prepared by the method of Example 2 were subjected to a simulated tampering process and then subjected to the dissolution test method below. The dissolution results for 45 minutes are given in Table 2F. In the tampering process, the uncoated and coated naltrexone pellets were separately ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0220]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0221]

Table 2F

<td colspan="2">Time (minutes)</td><td> 45</td>

<td rowspan="6">Average% dissolution</td><td>uncovered</td><td> 31</td>

<td> 5%</td><td> 19</td>

<td> 10%</td><td> 21</td>

<td> 15%</td><td> 21</td>

<td> 20%</td><td> 21</td>

<td>20% by weight / Opadry</td><td> 20</td>

Crushed part ratio: intact part [0222] The ratio of crushed part to intact part means the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours. The results are given in Table 2G below.

Results of the ratio of crushed part to intact part:

[0223]

Table 2G

<td colspan="2">Crushed part ratio: intact part</td>

<td>uncovered</td><td> 5,8</td>

<td> 5%</td><td> 5,9</td>

<td> 10%</td><td> 9,1</td>

<td> 15%</td><td> 10,0</td>

<td> 20%</td><td> 10,5</td>

<td>20% by weight / Opadry</td><td> 10,0</td>

As can be seen from the dissolution results, as the amount of coating increases, the ratio of crushed to intact increases.

Results of example 2 compared to example 1 [0224] Thus, the coating of the MEM formulation in Example 2, which has the same composition as the uncoated MEM formulation of Example 1, results in a decrease in drug release over 36 hours from above 5% to about 2% . Consequently, the "leakage" of the antagonist from the uncoated MEM formulation of Example 1 is also significantly reduced by using a functional coating. The ratio of crushed to intact can increase from about 5: 1 to 10: 1.

Example 3 mg naltrexone HCl pellets coated with eylocellulose [0225] In Example 3, pellets containing 8 mg of naltrexone were prepared and then coated using ethyl cellulose (Surelease) in various amounts (5%, 10%, 15%, and 20%, 25% and 30% weight gain). The uncoated naltrexone HCl formulation of Example 3 is listed in the table below.

Table 3A Composition of the pellet

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>Naltrexone HCl</td><td> 8,0</td><td> 0,397</td>

<td>Eudragit RSPO</td><td> 84,0</td><td> 4,165</td>

<td>Stearyl alcohol</td><td> 14,0</td><td> 0,694</td>

<td>Stearic acid</td><td> 14,0</td><td> 0,694</td>

<td>Butylated hydroxytoluene (BHT)</td><td> 1,0</td><td> 0,05</td>

<td>globally</td><td> 121,0</td><td> 6,00</td>

[0226] The uncoated naltrexone HCl formulations of Example 3 were prepared using the following process:

Manufacturing Process [0227]

1. Grinding: Stearyl alcohol flakes are passed through an oscillating mill equipped with a 16 mesh screen to give a powder that is easily miscible.

2. Mixing: Naltrexone HCl, Eudragit RSPO, ground stearyl alcohol, stearic acid and BHT are mixed in a twin shell mixer.

3. Extrusion: The mixed material obtained in step 2 is fed continuously to the twin screw extruder (Leitritz ZSE-27) at a rate of 3.9 kg / hour. The blend is extruded at a cylinder temperature in the range of 95 ° C to 100 ° C in the form of a thread with a diameter of about 1 mm. The extruded threads are collected on a conveyor.

4. Cooling: The threads on the conveyor can be cooled.

5. Pelletizing: The cooled threads are cut into pellets about 1 mm long using a pelletizing device.

6. Screening: The pellets are sieved through a vibrating funnel using 16 TBC mesh and 26 TBC mesh sieves. Material retained on 26 TBC mesh sieves is collected as the desired product.

In Vitro Dissolution [0228] The uncoated formulation prepared by the method of Example 3 gave the following results, which are detailed in Table 3B using the following in vitro dissolution test method.

Method:

[0229]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 6, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0230]

Table 3B

<td>Time (hours)</td><td> 1</td><td> 6</td><td> 12</td><td> 24</td><td> 36</td>

<td>Average% dissolution</td><td> 4,2</td><td> 8,6</td><td> 11,4</td><td> 15,5</td><td> 18,7</td>

Simulated infringement process and dissolution:

[0231] Formulations prepared by the method of Example 3 were subjected to a simulated tampering process and then subjected to the dissolution test method below. The dissolution results for 45 minutes are given in Table 3C. In the tampering process, the uncoated naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0232]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0233]

Table 3C

<td>Time (minutes)</td><td> 45</td>

<td>Average% dissolution</td><td> 57</td>

The ratio of crushed part to intact part [0234] The ratio of crushed part to intact part means the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours.

Results of the ratio of crushed part to intact part: 57% / 18.7% = 3.0 [0235] Naltrexone HCl pellets prepared by the method of Example 3 and listed in Table 3A were then coated with a hydrophobic coating. The pellets were coated with weight gains of 5%, 10%, 15%, 20% and 25% using a hydrophobic coating (Surelease); and 30% using a hydrophobic coating (Surelease) and a colored coating (Opadry). An example of a formulation with a hydrophobic coating and a colored coating giving a 30% weight gain is detailed in the table below.

3D table

Composition of coated pellets by 30% weight gain

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>8 mg naltrexone HCl pellet</td><td> 121,0</td><td> 0,50</td>

<td>Surelease (solids)</td><td> 36,3</td><td> 0,15</td>

<td>Opadry Pink</td><td> 6,1</td><td> 0,025</td>

<td>globally</td><td> 163,4</td><td> 0,675</td>

[0236] The coated naltrexone HCl formulations of Example 3 were prepared using the following process:

Manufacturing Process [0237]

1. Functional coating dispersion: The Surelease suspension is diluted to 15% by weight solids by mixing with water.

2. Dispersion of the colored coating: Opadry is mixed with water to obtain a dispersion of 10% by weight.

3. Functional coating: The Surelease dispersion is sprayed onto the naltrexone pellets prepared above at 700 g, using a fluidized bed reactor (GPCG-1) and the following performance guidelines:

- Air flow rate: 8.6 to 9.6 m / s

- Inlet air temperature: 40 - 50 ° C

- Dispersion spray rate: 9 - 14.8 g / minute

Samples were taken after spraying the theoretical amount of dispersion leading to 5%, 10%, 15%, 20%, 25%, 30% weight gain, about 6.05, 12.1, 18.15,

24.2 and 30.25 mg Surelease per unit, respectively.

4. Color coating: After functional coating, the Opadry dispersion is sprayed onto the coated pellets, using the following parameter guidelines:

- Air flow rate: 8.6 - 9.0 m / s

- Inlet air temperature: 47 ° C

- Dispersion rate: 9.0 g / minute

5. Screening: Pellets are sieved through a 14 US mesh screen and 20 US mesh screen. Material retained on a 20 US mesh screen is collected as the desired product.

6. Curing: Place the sieved pellets and samples in an oven at 45 ° C for 24 hours.

In Vitro Dissolution [0238] Formulations coated using a hydrophobic coating (Surelease) and colored coating (Opadry) prepared according to Example 3 gave the following results, which are detailed in Table 3E using the in vitro dissolution testing method below.

Method:

[0239]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 6, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0240]

Table 3E

<td colspan="2">Time (hours)</td><td> 1</td><td> 6</td><td> 12</td><td> 24</td><td> 36</td>

<td rowspan="7">Average% dissolution</td><td>uncovered</td><td> 4,2</td><td> 8,6</td><td> 11,4</td><td> 15,5</td><td> 18,7</td>

<td> 5%</td><td> 0,3</td><td> 1,9</td><td> 3,1</td><td> 4,7</td><td> 5,9</td>

<td> 10%</td><td> 0,2</td><td> 0,7</td><td> 1,1</td><td> 1,9</td><td> 2,6</td>

<td> 15%</td><td> 0,2</td><td> 0,5</td><td> 0,8</td><td> 1,4</td><td> 1,9</td>

<td> 20%</td><td> 0,2</td><td> 0,4</td><td> 0,6</td><td> 1,1</td><td> 1,5</td>

<td> 25%</td><td> 0,1</td><td> 0,4</td><td> 0,6</td><td> 1,1</td><td> 1,5</td>

<td>30% w / Opadry</td><td> 0,1</td><td> 0,4</td><td> 0,7</td><td> 1,0</td><td> 1,4</td>

As can be seen from the dissolution results, the dissolution of naltrexone pellets generally decreases as the amount of polymer coating increases.

Simulated infringement process and dissolution:

[0241] The formulations prepared by the method of Example 3 were subjected to a simulated tampering process and then subjected to the dissolution testing method set out below. The dissolution results for 45 minutes are given in Table 3F. In the tampering process, the uncoated and coated naltrexone pellets were separately ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0242]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0243]

Table 3F

<td colspan="2">Time (minutes)</td><td> 45</td>

<td rowspan="7">Average% dissolution</td><td>uncovered</td><td> 57</td>

<td> 5%</td><td> 60</td>

<td> 10%</td><td> 56</td>

<td> 15%</td><td> 49</td>

<td> 20%</td><td> 48</td>

<td> 25%</td><td> 56</td>

<td>30% w / Opadry</td><td> 52</td>

The ratio of crushed part to intact part [0244] The ratio of crushed part to intact part means the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours. The results are given in Table 3G below.

Results of the ratio of crushed part to intact part:

Table 3G

<td colspan="2">Crushed part ratio: intact part</td>

<td>uncovered</td><td> 3,0</td>

<td> 5%</td><td> 10,2</td>

<td> 10%</td><td> 21,5</td>

<td> 15%</td><td> 25,8</td>

<td> 20%</td><td> 32,0</td>

<td> 25%</td><td> 37,3</td>

<td>30% w / Opadry</td><td> 37,1</td>

[0245] As can be seen from the dissolution results above, as the amount of coating increases, the amount of naltrexone released from intact pellets decreases significantly (from over 18% to less than 2% in 36 hours), whereas when crushed, about 50 is released % antagonist, and the ratio of crushed to intact parts increases significantly.

[0246] After coating, 8 mg intact pellets show a significant reduction in the release of naltrexone compared to uncoated intact pellets. However, the release from crushed 8 mg coated pellets is greater compared to crushed uncoated 2 mg pellets.

Example 4

Coated with methacrylic copolymer 8 mg naltrexone HCl pellets [0247] In Example 4, pellets containing 8 mg naltrexone were prepared by the method of Example 3, but coated with methacrylic copolymer (Eudragit RS 30D) in various amounts (5%, 10%, 15%, and 20% and 25% weight gain). The uncoated naltrexone HCl formulation of Example 4 is listed in Table 4A below:

Table 4A Composition of the pellet

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>Naltrexone HCl</td><td> 8,0</td><td> 0,397</td>

<td>Eudragit RSPO</td><td> 84,0</td><td> 4,165</td>

<td>Stearyl alcohol</td><td> 14,0</td><td> 0,694</td>

<td>Stearic acid</td><td> 14,0</td><td> 0,694</td>

<td>Butylated hydroxytoluene (BHT)</td><td> 1,0</td><td> 0,05</td>

<td>globally</td><td> 121,0</td><td> 6,00</td>

[0248] The uncoated naltrexone HCl formulation of Example 4 was prepared using the following process:

Manufacturing Process [0249]

1. Grinding: Stearyl alcohol flakes are passed through an oscillating mill equipped with a 16 mesh screen to give a powder that is easily miscible.

2. Mixing: Naltrexone HCl, Eudragit RSPO, ground stearyl alcohol, stearic acid and BHT are mixed in a twin shell mixer.

3. Extrusion: The mixed material obtained in step 2 is continuously fed into the twin screw extruder (Leistritz ZSE-27) at a rate of 3.9 kg / hour. The blend is extruded at a cylinder temperature in the range of 95 ° C to 100 ° C in the form of a thread with a diameter of about 1 mm. Extruded threads accumulate on the conveyor.

4. Cooling: The threads on the conveyor can be cooled.

5. Pelletizing: The cooled threads are cut into pellets about 1 mm long using a pelletizing device.

6. Screening: The pellets are sieved through a vibrating funnel using 16 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product.

In Vitro Dissolution [0250] The uncoated formulations prepared by the method of Example 4 gave the following results, which are detailed in Table 4B using the in vitro dissolution test method below.

Method:

[0251]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 6, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0252]

Table 4B

<td>Time (hours)</td><td> 1</td><td> 6</td><td> 12</td><td> 24</td><td> 36</td>

<td>Average% dissolution</td><td> 4,2</td><td> 8,6</td><td> 11,4</td><td> 15,5</td><td> 18,7</td>

Simulated infringement process and dissolution:

[0253] The formulations prepared by the method of Example 4 were subjected to a simulated tampering process and then subjected to the dissolution testing method set out below. The dissolution results for 45 minutes are given in Table 4C. In the tampering process, the uncoated naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0254]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0255]

Table 4C

<td>Time (minutes)</td><td> 45</td>

<td>Average% dissolution</td><td> 57</td>

The ratio of crushed part to intact part [0256] The ratio of crushed part to intact part means the ratio of dissolution of crushed pellets in 45 minutes to dissolution of intact pellets in 36 hours.

Results of the ratio of crushed to intact: 57% / 18.7% = 3.0 [0257] Naltrexone HCl pellets prepared by the method of Example 4 and listed in Table 4A were then coated with a hydrophobic coating. The pellets were coated with a weight gain of 5%, 10%, 15% and 20% using a hydrophobic coating (based on Eudragit); and 25% weight gain using a hydrophobic coating (based on Eudragit) and a colored coating (Opadry). An example of a 25% weight gain formulation after applying the hydrophobic coating and the colored coating is detailed in the table below.

Table 4D

Composition of coated pellets for a 25% weight gain

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>8 mg naltrexone HCl pellet</td><td> 121,0</td><td> 0,50</td>

<td>Eudragit RS 30D (solids)</td><td> 30,25</td><td> 0,125</td>

<td>Triethyl citrate</td><td> 6,05</td><td> 0,025</td>

<td>Cab-O-Sil</td><td> 1,5</td><td> 0,0062</td>

<td>Opadry Pink</td><td> 6,0</td><td> 0,025</td>

<td>globally</td><td> 164,8</td><td> 0,68</td>

[0258] The coated naltrexone HCl formulations of Example 4 were prepared using the following process:

Manufacturing process [0259]

1. Functional coating dispersion: Eudragit RS 30D is mixed with triethyl citrate to plasticize for 15 minutes. Cab-O-Sil is dispersed in a sufficient amount of water to obtain a total dispersion of 20% by weight of solids. A Cab-O-Sil dispersion is added to the Eudragit mixture.

2. Dispersion of the colored coating: Opadry is mixed with water to obtain a dispersion of 10% by weight.

3. Functional coating: The Eudragit dispersion is sprayed onto the naltrexone pellets produced above at a load of 700 g using a fluidized bed reactor (GPCG-1) and the following performance guidelines:

- Air flow rate: 8.5 to 9.5 m / s

- Inlet air temperature: 35 ° C

- Dispersion spray rate: 14 g / minute

Samples were taken after spraying the theoretical amount of dispersion leading to 5%, 10%, 15%, 20%, and 25% weight gain.

4. Color coating: After functional coating, the Opadry dispersion is sprayed onto the coated pellets, using the following parameter guidelines:

- Air flow rate: 8.5 m / s

- Inlet air temperature: 35 - 45 ° C

- Dispersion spray rate: 8.5 g / minute

5. Screening: Pellets are sieved through a 14 US mesh screen and 20 US mesh screen. Material retained on a 20 US mesh screen is collected as the desired product.

6. Curing: Place the sieved pellets and samples in an oven at 45 ° C for 24 hours.

[0260] Coated pellets for 5%, 10%, 15% and 20% weight gain were prepared by the method described above for coated pellets with 20% weight gain using 6.05, 12.1, 18.15 and 24.2 mg Eudragit RS30D (solids) per unit, respectively.

In vitro dissolution [0261] Preparations coated with a hydrophobic coating prepared by the method of Example 4 gave the following results, which are detailed in Table 4E using the in vitro dissolution testing method below.

Method:

[0262]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 6, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0263]

Table 4E

<td colspan="2">Time (hours)</td><td> 1</td><td> 6</td><td> 12</td><td> 24</td><td> 36</td>

<td rowspan="6">Average% dissolution</td><td>uncovered</td><td> 4,2</td><td> 8,6</td><td> 11,4</td><td> 15,5</td><td> 18,7</td>

<td> 5%</td><td> 0,3</td><td> 1,4</td><td> 2,5</td><td> 4,6</td><td> 6,6</td>

<td> 10%</td><td> 0,1</td><td> 0,5</td><td> 0,7</td><td> 1,0</td><td> 1,4</td>

<td> 15%</td><td> 0,1</td><td> 0,4</td><td> 0,6</td><td> 0,8</td><td> 1,0</td>

<td> 20%</td><td> 0,1</td><td> 0,3</td><td> 0,4</td><td> 0,5</td><td> 0,6</td>

<td>25% w / Opadry</td><td> 0,0</td><td> 0,1</td><td> 0,2</td><td> 0,2</td><td> 0,3</td>

[0264] As can be seen from the dissolution results, the dissolution of naltrexone pellets generally decreases as the amount of polymer coating increases.

Simulated infringement process and dissolution:

[0265] The formulations prepared by the method of Example 4 were subjected to a simulated tampering process and then subjected to the dissolution test method below. The dissolution results for 45 minutes are given in Table 4F. In the tampering process, the uncoated and coated naltrexone pellets were separately ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0266]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography Results:

[0267] Table 4F

<td colspan="2">Time (minute)</td><td> 45</td>

<td rowspan="6">Average% dissolution</td><td>uncovered</td><td> 57</td>

<td> 5%</td><td> 55</td>

<td> 10%</td><td> 55</td>

<td> 15%</td><td> 61</td>

<td> 20%</td><td> 49</td>

<td>25% w / Opadry</td><td> 47</td>

Crushed part ratio: intact part [0268] The ratio of crushed part to intact part means the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours. The results are given in Table 4G below.

Results:

[0269]

Table 4G

<td colspan="2">Crushed part ratio: intact part</td>

<td>uncovered</td><td> 3,0</td>

<td> 5%</td><td> 8,3</td>

<td> 10%</td><td> 39,3</td>

<td> 15%</td><td> 61,0</td>

<td> 20%</td><td> 81,7</td>

<td>25% w / Opadry</td><td> 156,7</td>

[0270] As can be seen from the dissolution results above, as the amount of coating increases, the amount of naltrexone released from intact pellets decreases significantly (from over 18% to about 1% or less in 36 hours), but when crushed, it is still about 50% of the antagonist released and the crumb: intact ratio increases.

[0271] This product shows that the application of the coating results in a significant reduction in the release of naltrexone from intact pellets, while maintaining the ability to release significant amounts of the antagonist from the crushed pellets.

Example 5 [0272] In Example 5, the formulation of Example 4 was re-prepared on an experimental scale under GMP conditions and used for in-vivo estimation.

[0273] Pellets containing 8 mg of naltrexone were prepared by the method of example 4 and coated using a hydrophobic coating to obtain a 15% weight gain (based on Eudragit RS 30D). These pellets were then filled into # 2 capsules. The uncoated naltrexone HCl formulation of Example 5 is listed in the table below.

Table 5A

<td>Ingredient</td><td>n / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>Naltrexone HCl</td><td> 8,0</td><td> 2,40</td>

<td>Eudragit RSPO</td><td> 84,0</td><td> 25,20</td>

<td>Stearyl alcohol</td><td> 14,0</td><td> 4,20</td>

<td>Stearic acid</td><td> 14,0</td><td> 4,20</td>

<td>Butylated hydroxytoluene (BHT)</td><td> 1,0</td><td> 0,30</td>

<td>globally</td><td> 121,0</td><td> 36,30</td>

[0274] Uncoated pellets according to example 5 were prepared using the following process:

Manufacturing Process [0275]

1. Grinding: Stearyl alcohol flakes are passed through an oscillating mill equipped with a 16 mesh screen to give a powder that is easily miscible.

2. Mixing: Naltrexone HCl, Eudragit RSPO, ground stearyl alcohol, stearic acid, and BHT are mixed in a twin shell mixer.

3. Extrusion: The mixed material obtained in step 2 is continuously fed into the twin screw extruder (Leistritz ZSE-27) at a rate ranging from 4.0 kg / hour to 4.8 kg / hour. The blend is extruded at a cylinder temperature in the range of 80 ° C and 100 ° C in the form of threads with a diameter in the range of 0.8 mm to 1.2 mm. Extruded threads accumulate on the conveyor.

4. Cooling: The threads on the conveyor can be cooled.

5. Pelleting: The cooled threads are cut into pellets in the range 0.8 mm to 1.4 mm using a pelletizing device.

6. Screening: The pellets are sieved through a vibrating funnel using 16 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product.

[0276] Naltrexone HCl pellets prepared by the method of Example 5 and listed in Table 5A were then coated with a hydrophobic coating. The pellets were coated to obtain a 15% weight gain using a hydrophobic coating (based on Eudragit RS 30D). The coated pellets are listed in the table below.

Table 5B

Composition of encapsulated coated pellets for a 15% weight gain

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>8 mg naltrexone HCl pellet</td><td> 121,0</td><td> 10,00</td>

<td>Eudragit RS30D (solids)</td><td> 18,2</td><td> 1,50</td>

<td>Triethyl citrate</td><td> 3,6</td><td> 0,30</td>

<td>Cab-O-Sil</td><td> 0,9</td><td> 0,07</td>

<td>Opadry Pink</td><td> 6,05</td><td> 0,50</td>

<td>globally</td><td> 149,7</td><td> 12,37</td>

Manufacturing Process [0277]

1. Functional coating dispersion: Eudragit RS 30D is mixed with triethyl citrate to plasticize for 15 minutes. Cab-O-Sil is dispersed in a sufficient amount of water to obtain a total dispersion of 20% by weight of solids. A Cab-O-Sil dispersion is added to the Eudragit mixture.

2. Dispersion of the colored coating: Opadry is mixed with water to obtain a dispersion of 10% by weight.

3. Functional coating: The Eudragit dispersion is sprayed onto the naltrexone pellets produced above at a load of 9 kg using a fluidized bed reactor (GPCG-15) and the following performance guidelines:

- Air flow: 700 to 780 CFM

- Inlet air temperature: 35 ° C

- Dispersion spray rate: 115 to 135 g / minute

4. Color coating: After functional coating, the Opadry dispersion is sprayed onto the coated pellets, using the following parameter guidelines:

- Air flow: 750 to 760 CFM

- Inlet air temperature: 35 - 45 ° C

- Dispersion spray rate: 75 to 95 g / minute

5. Sieving: The pellets are sieved through a vibrating separator using 14 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product.

6. Encapsulation: The sieved pellets are filled into hard gelatin capsules at a target load of 149.7 mg.

In vitro dissolution (intact pellets) [0278] Formulations coated with the hydrophobic coating in Example 5 in the form of bulky pellets and encapsulated pellets gave the following results, which are detailed in Table 5C after subjecting to the following in vitro dissolution test method.

Dissolution Method:

[0279]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0280]

Table 5C

<td colspan="2">Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 24</td><td> 36</td>

<td>Average%</td><td>Volume pellets</td><td> 0,0</td><td> 0,0</td><td> 0,1</td><td> 0,4</td><td> 0,4</td><td> 0,7</td><td> 0,8</td>

<td>dissolution</td><td>Encapsulated pellets</td><td> 0,2</td><td> 0,3</td><td> 0,4</td><td> 0,5</td><td> 0,6</td><td> 0,9</td><td> 1,0</td>

Simulated tampering process and dissolution (crushed pellets):

[0281] The formulations prepared by the method of Example 5 were subjected to a simulated tampering process and then subjected to the following dissolution test method. In the tampering process, the coated naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0282]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0283]

Table 5D

<td>Time (minutes)</td><td> 45</td>

<td>Average% dissolution</td><td> 46,4</td>

Crushed portion: intact ratio [0284] The ratio of crushed portion to intact portion is the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours. The results are listed below.

Results of the ratio of crushed part to intact part: 46.4 / 0.8 = 58.0

In vivo pharmacokinetic / bioavailability study in humans [0285] Capsules prepared using the above manufacturing process of the present example and formulation were used in a clinical trial to determine the pharmacokinetics / bioavailability of MEM preparations under various conditions and then compared with the pharmacokinetics / bioavailability of naltrexone tablets release. Human patients were given intact naltrexone HEM MCI formulation as a capsule (1 capsule or 5 capsules - on an empty stomach); crushed naltrexone MEM HCl (ground content of 1 capsule - on an empty stomach); immediate-release naltrexone HCl tablet - on an empty stomach; or 1 intact MEM capsule in a fed state. The study was open, single dose, 5-stage, crossover, on 15 healthy subjects with a 14-day washout period between treatments. Therapies are designed as follows:

A. 1x8 mg naltrexone MEM capsule, intact, on an empty stomach.

B. 1 x 8 mg naltrexone MEM capsule, with the contents of the capsule crushed, in an empty stomach.

C. 1x8 mg naltrexone MEM capsule, intact, after food.

D. 5 x 8 mg (40 mg) MIT naltrexone capsule, intact, in fasting state.

E. 2 x 0.5 mg (1 mg) immediate-release naltrexone tablets, in an empty stomach.

[0286] Plasma concentrations showed that a very small amount of naltrexone was released when the MEM formulation of naltrexone pellets was taken intact. The results of the naltrexone concentration (pg / ml) curve versus time are shown in Figure 2. Plasma levels of naltrexone increased significantly when naltrexone pellets were taken orally in a crushed / ground state. The mean Cmax ratio of crushed MEM (N = 14) / intact MEM (N = 15) capsule formulation was 112.34. Similarly, the mean AUCt ratio of crushed MEM (N = 14) / intact MEM (N = 15) capsule formulation was 31.55.

[0287] The comparison of the results obtained in vitro and in-vivo for the uncoated MEM preparation according to example 1 and the coated MEM preparation according to example 5 is shown in Table 5E and 5F below:

Table 5E

<td colspan="3">Preparation:</td><td>Example 1 2 mg, uncovered</td><td>Example 5 8 mg w / 15% Eudragit</td>

<td rowspan="3">In-Vitro</td><td colspan="2">Release from an intact capsule within 36 hours</td><td>0.124 mg</td><td>0.08 mg</td>

<td colspan="2">Crushed preparation</td><td>0.670 mg</td><td>3.71 mg</td>

<td colspan="2">Crushed ratio: intact</td><td> 5,4</td><td> 46,4</td>

<td rowspan="4">In-Vivo</td><td rowspan="2">AUC (Pg / ml * h)</td><td>Intact</td><td> 84,7</td><td> 132,38*</td>

<td>crushed</td><td> 373,4</td><td> 4177,3*</td>

<td rowspan="2">Cmax⁽pg^{/ Ml)}</td><td>Intact</td><td> 5,3</td><td> 4,44*</td>

<td>crushed</td><td> 43,1</td><td> 498,8*</td>

<td>* standard</td><td colspan="4">based on data for 5 * 8 mg</td>

Table 5F

<td></td><td>Capsule intact</td><td>Capsule crumbled</td><td>Capsule intact</td><td>Capsule intact</td><td>IR tablet</td>

<td></td><td>8 mg</td><td>8 mg</td><td>8 mg</td><td>5 X 8 mg</td><td>2 X 0.5 mg</td>

<td></td><td>On empty stomach</td><td>On empty stomach</td><td>After meal</td><td>On empty stomach</td><td>On empty stomach</td>

<td></td><td>N = 15</td><td> 14</td><td> 14</td><td> 15</td><td> 6</td>

<td>Cmax⁽pg^{/ Ml)}</td><td> 3,6</td><td> 498,8</td><td> 7,2</td><td> 22,2</td><td> 140,5</td>

<td>AUCt (Pg.h / mL)</td><td> 51,9</td><td> 4177,3</td><td> 123,8</td><td> 661,9</td><td> 424,5</td>

Example 6

Coated with methacrylic copolymer 2 mg naltrexone MEM HCl preparation [0288] The uncoated naltrexone HCl formulation according to example 6 is detailed in Table 6A below:

Table 6A Composition of the pellet

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>Naltrexone HCl</td><td> 2,0</td><td> 0,10</td>

<td>Eudragit RSPO</td><td> 88,0</td><td> 4,40</td>

<td>Stearyl alcohol</td><td> 15,0</td><td> 0,75</td>

<td>Stearic acid</td><td> 15,0</td><td> 0,75</td>

<td>Butylated hydroxytoluene (BHT)</td><td> 1,0</td><td> 0,05</td>

<td>globally</td><td> 121,0</td><td> 6,05</td>

[0289] The naltrexone HCl formulation of Example 6 was prepared using the following process:

Manufacturing Process [0290]

1. Grinding: Stearyl alcohol flakes are passed through an oscillating mill equipped with a 16 mesh screen to give a powder that is easily miscible.

2. Mixing: Naltrexone HCl, Eudragit RSPO, ground stearyl alcohol, stearic acid and BHT are mixed in a twin shell mixer.

3. Extrusion: The mixed material obtained in step 2 is fed continuously to the twin screw extruder (Leistritz ZSE-27) at a rate in the range of 2.9 kg / hour to 4.8 kg / hour. The blend is extruded at a cylinder temperature in the range of 95 ° C to 105 ° C in the form of a thread with a diameter of about 1 mm. Extruded threads accumulate on the conveyor.

4. Cooling: The threads on the conveyor can be cooled.

5. Pelletizing: The cooled threads are cut into pellets about 1 mm long using a pelletizing device.

6. Screening: The pellets are sieved through a vibrating funnel using 16 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product

In vitro dissolution (intact pellets):

[0291] The formulations prepared by the method of Example 6 gave the following dissolution results as detailed in Table 6B, using the in vitro dissolution testing method below.

Method:

[0292]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 18, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0293]

Table 6B

<td>Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 18</td><td> 24</td><td> 36</td>

<td>Average% dissolution</td><td> 2,1</td><td> 2,6</td><td> 2,9</td><td> 3,2</td><td> 3,8</td><td> 4,2</td><td> 4,7</td><td> 5,3</td>

The process of simulated violation and dissolution (crushed pellets):

[0294] The formulations prepared by the method of Example 6 were subjected to a simulated tampering process and then subjected to the in-vitro dissolution testing method presented below. The dissolution results for 1 hour are given in Table 6C. In the tampering process, naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0295]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0296]

Table 6C

<td>Time (minutes)</td><td> 45</td>

<td>Average% dissolution</td><td> 31</td>

Ratio of crushed part to intact [0297] Ratios of crushed part to intact part means the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours.

Ratio of crushed to intact: 31% / 5.3% = 5.8: 1 [0298] Naltrexone HCl pellets prepared by the method of Example 6 and listed in Table 6A were then coated with a hydrophobic coating. The pellets were coated to obtain a 15% weight gain using a hydrophobic coating (based on Eudragit RS 30D). The product with a 15% weight gain is detailed in the following table:

Table 6D: Composition of coated pellets for a 15% weight gain

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>2 mg naltrexone HCl pellet</td><td> 121,0</td><td> 0,500</td>

<td>Eudragit RS30D (solids)</td><td> 18,2</td><td> 0,075</td>

<td>Triethyl citrate</td><td> 3,6</td><td> 0,015</td>

<td>Cab-O-Sil</td><td> 0,9</td><td> 0,004</td>

<td>globally</td><td> 143,7</td><td> 0,594</td>

[0299] The coated naltrexone HCl formulations of Example 6 were prepared using the following process:

Manufacturing process [0300]

1. Functional coating dispersion: Eudragit RS 30D is mixed with triethyl citrate to plasticize for 15 minutes. Cab-O-Sil is dispersed in a sufficient amount of water to obtain a total dispersion of 20% by weight of solids. A Cab-O-Sil dispersion is added to the Eudragit mixture.

2. Functional coating: The Eudragit dispersion is sprayed onto the naltrexone pellets produced above at a load of 700 g using a fluidized bed reactor (GPCG-1) and the following performance guidelines:

- Air flow rate: 9.0 m / s

- Inlet air temperature: 35 ° C

- Dispersion spray rate: 8.8 g / minute

3. Screening: Pellets are sieved through a 14 US mesh screen and 20 US mesh screen. Material retained on a 20 US mesh screen is collected as the desired product.

In vitro dissolution (intact pellets):

[0301] Formulations coated using a hydrophobic coating prepared according to Example 6 gave the following results, which are detailed in Table 6E using the in vitro dissolution testing method below.

Method:

[0302]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0303]

Table 6E

<td>Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 24</td><td> 36</td>

<td>Average% dissolution</td><td> &lt;0,6*</td><td> &lt;0,6</td><td> &lt;0,6</td><td> &lt;0,6</td><td> &lt;0,6</td><td> &lt;0,6</td><td> &lt;0,6</td>

The detection limit is 0.6%

The process of simulated violation and dissolution (crushed pellets):

[0304] The coated formulations prepared according to the method of Example 6 were subjected to a simulated tampering process followed by the following dissolution test method. The dissolution results for 1 hour are detailed in Table 6F. In the tampering process, naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution method: Same as above

Results:

[0305]

Table 6F

<td>Time (hours)</td><td> 1</td>

<td>Average% dissolution</td><td> 7</td>

The ratio of crushed part to intact part [0306] The ratio of crushed part to intact part means the ratio of% dissolution of crushed pellets in 1 hour to% dissolution of intact pellets in 36 hours.

[0307] Crumb to intact ratio: 7% / 0.6% = 12 (note: since naltrexone was observed in amounts less than the detection limit of intact pellets, the crushed / intact ratio may be significantly greater than 12).

Example 7 mg Naltrexone MEM HCl preparation coated with methacrylic copolymer followed by Surelease [0308] In Example 7, two-step application of subsequent coatings to the MEM preparation was carried out, first using Eudragit RS30D for a weight gain of 15%, then using Surelease for an additional 10% weight gain (based on uncoated extruded pellets). Pellets containing 8 mg of naltrexone prepared by the method of Example 5 were coated with a methacrylic copolymer (Eudragit RS30D) to

15% weight gain followed by ethyl cellulose (Surelease) to 10% weight gain. This product shows a significant reduction in the release of naltrexone from intact pellets, while an increase in the release from crushed pellets. The uncoated naltrexone HCl formulation of Example 7 is listed in Table 7A below.

Table 7A Composition of the pellet

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>Naltrexone HCl</td><td> 8,0</td><td> 2,40</td>

<td>Eudragit RSPO</td><td> 84,0</td><td> 25,20</td>

<td>Stearyl alcohol</td><td> 14,0</td><td> 4,20</td>

<td>Stearic acid</td><td> 14,0</td><td> 4,20</td>

<td>Butylated hydroxytoluene (BHT)</td><td> 1,0</td><td> 0,30</td>

<td>globally</td><td> 121,0</td><td> 36,30</td>

[0309] The uncoated naltrexone HCl formulation of Example 7 was prepared using the following process:

Manufacturing process [0310]

1. Grinding: Stearyl alcohol flakes are passed through an oscillating mill equipped with a 16 mesh screen to give a powder that is easily miscible.

2. Mixing: Naltrexone HCl, Eudragit RSPO, ground stearyl alcohol, stearic acid and BHT are mixed in a twin shell mixer.

3. Extrusion: The mixed material obtained in step 2 is continuously fed into the twin screw extruder (Leistritz ZSE-27) at a rate ranging from 4.0 kg / hour to 4.8 kg / hour. The blend is extruded at a cylinder temperature in the range of 85 ° C to 90 ° C in the form of threads with a diameter in the range of 0.8 mm to 1.2 mm. Extruded threads accumulate on the conveyor.

4. Cooling: The threads on the conveyor can be cooled.

5. Pelleting: The cooled threads are cut into pellets in the range 0.8 mm to 1.4 mm using a pelletizing device.

6. Screening: The pellets are sieved through a vibrating funnel using 16 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product.

[0311] Naltrexone HCl pellets prepared by the method of Example 7 and listed in Table 7A were then coated using a hydrophobic coating. The pellets were coated to achieve a 15% weight gain using methacrylic copolymer followed by a 10% weight gain (based on uncoated pellets) using ethyl cellulose. The coated pellets are listed in the table below.

Table 7B

Composition of pellets coated with methacrylic copolymer up to 15% weight gain, followed by ethyl cellulose up to 10% weight gain

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>8 mg Naltrexone HCl pellet (Lot # 955-25)</td><td> 121,0</td><td> 0,500</td>

<td>Eudragit RS30D (solids)</td><td> 18,2</td><td> 0,075</td>

<td>Triethyl citrate</td><td> 3,6</td><td> 0,015</td>

<td>Cab-O-Sil</td><td> 0,9</td><td> 0,004</td>

<td>Surelease</td><td> 12,1</td><td> 0,050</td>

<td>Opadry Pink</td><td> 6,05</td><td> 0,025</td>

<td>globally</td><td> 161,85</td><td> 0,669</td>

[0312] A coated naltrexone HCl formulation was prepared using the following process:

Manufacturing process [0313]

1. Methacrylate Dispersion: Eudragit RS 30D is mixed with triethyl citrate to plasticize for 15 minutes. Cab-O-Sil is dispersed in a sufficient amount of water to obtain a total dispersion of 20% by weight of solids. A Cab-O-Sil dispersion is added to the Eudragit mixture.

2. Dispersing the ethylcellulose coating: Surelease is mixed with sufficient water to obtain a total 15% by weight of solids dispersion.

3. Dispersion of the colored coating: Opadry is mixed with water to obtain a dispersion of 10% by weight.

4. Methacrylic coating application: The Eudragit dispersion is sprayed onto the naltrexone pellets produced above at a load of 700 g using a fluidized bed reactor (GPCG-1) and the following performance guidelines:

- Air flow rate: 8.8 to 9.0 m / s

- Inlet air temperature: 35 ° C

- Dispersion spray rate: 9.6 g / minute

5. Application of ethyl cellulose coating: After coating with Eudragit, the Surelease dispersion is sprayed onto the coated pellets, using the following parameter guidelines:

- Air flow rate: 9.0 m / s

- Inlet air temperature: 40 ° C to 45 ° C

- Dispersion spray rate: 9.2 to 9.6 g / minute

6. Color coating: After functional coating, the Opadry dispersion is sprayed onto the coated pellets, using the following parameter guidelines:

- Air flow: 8.8 to 9.0 m / s

- Inlet air temperature: 50 ° C

- Dispersion spray rate: 9.3 g / minute

7. Screening: Pellets are sieved through a 14 US mesh screen and 20 US mesh screen. Material retained on a 20 US mesh screen is collected as the desired product.

In vitro dissolution (intact pellets):

[0314] Formulations coated using a hydrophobic coating (methacrylic copolymer coating and ethyl cellulose coating) prepared by the method of Example 7 gave the following results, which are detailed in Table 7C after being subjected to the following in vitro dissolution test method.

Method:

[0315]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0316]

Table 7C

<td>Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 24</td><td> 36</td>

<td>Average% dissolution</td><td> &lt;0,15*</td><td> &lt;0,15</td><td> &lt;0,15</td><td> &lt;0,15</td><td> &lt;,15</td><td> 0,2</td><td> 0,4</td>

<td colspan="8">* below detection limit (0.15%)</td>

Simulated tampering process and dissolution (crushed pellets):

[0317] Formulations prepared by the method of Example 7 were subjected to a simulated tampering process and then subjected to the dissolution testing method set out below. In the tampering process, the coated naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test. The dissolution results are given in Table 7D.

Dissolution Method:

[0318]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0319]

Table 7D

<td>Time (minutes)</td><td> 45</td>

<td>Average% dissolution</td><td> 37</td>

Ratio of crushed parts: intact parts:

[0320] The ratio of crushed part to intact part means the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours.

Ratio of crushed to intact: 92.5

Example 8 mg Naltrexone MEM HCl preparation coated with Surelease followed by methacrylic copolymer [0321] Pellets containing 8 mg of naltrexone were prepared by the method of Example 5 and coated with ethyl cellulose (Surelease) for a 10% weight gain followed by methacrylic copolymer (Eudragit RS 30D) ) up to 15% weight gain (based on uncoated pellets). This product shows a significant reduction in the release of naltrexone from intact pellets, while increased release from crushed pellets.

[0322] The uncoated naltrexone HCl formulation of Example 8 is listed in Table 8A below.

Table 8A Composition of the pellet

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>Naltrexone HCl</td><td> 8,0</td><td> 2,40</td>

<td>Eudragit RSPO</td><td> 84,0</td><td> 25,20</td>

<td>Stearyl alcohol</td><td> 14,0</td><td> 4,20</td>

<td>Stearic acid</td><td> 14,0</td><td> 4,20</td>

<td>Butylated hydroxytoluene (BHT)</td><td> 1,0</td><td> 0,30</td>

<td>globally</td><td> 121,0</td><td> 36,30</td>

[0323] The uncoated naltrexone HCl formulation of Example 8 was prepared using the following process:

Manufacturing process [0324]

1. Grinding: Stearyl alcohol flakes are passed through an oscillating mill equipped with a 16 mesh screen to give a powder that is easily miscible.

2. Mixing: Naltrexone HCl, Eudragit RSPO, ground stearyl alcohol, stearic acid and BHT are mixed in a twin shell mixer.

3. Extrusion: The mixed material obtained in step 2 is continuously fed into the twin screw extruder (Leistritz ZSE-27) at a rate ranging from 4.0 kg / hour to 4.8 kg / hour. The blend is extruded at a cylinder temperature in the range of 85 ° C to 90 ° C in the form of threads with a diameter in the range of 0.8 mm to 1.2 mm. Extruded threads accumulate on the conveyor.

4. Cooling: The threads on the conveyor can be cooled.

5. Pelleting: The cooled threads are cut into pellets in the range 0.8 mm to 1.4 mm using a pelletizing device.

6. Screening: The pellets are sieved through a vibrating funnel using 16 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product.

[0325] Naltrexone HCl pellets prepared by the method of Example 8 and listed in Table 8A were then coated with a hydrophobic coating. The pellets were coated to a 10% weight gain using ethylcellulose, and then to a 15% weight gain using methacrylic copolymer (based on uncoated pellets). The coated pellets are listed in the table below.

Table 8B

Composition of pellets coated with ethyl cellulose for a 10% weight gain, followed by using a methacrylic copolymer to 15% weight gain

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>8 mg naltrexone HCl pellet</td><td> 121,0</td><td> 0,500</td>

<td>Surelease</td><td> 12,1</td><td> 0,050</td>

<td>Eudragit RS30D (solids)</td><td> 18,2</td><td> 0,075</td>

<td>Triethyl citrate</td><td> 3,6</td><td> 0,015</td>

<td>Cab-O-Sil</td><td> 0,9</td><td> 0,004</td>

<td>Opadry Pink</td><td> 6,05</td><td> 0,025</td>

<td>globally</td><td> 161,85</td><td> 0,669</td>

[0326] The naltrexone HCl preparation of Example 8 was prepared using the following process:

Manufacturing process [0327]

1. Dispersing the ethylcellulose coating: Surelease is mixed with sufficient water to obtain a total 15% by weight of solids dispersion.

2. Methacrylate Dispersion: Eudragit RS 30D is mixed with triethyl citrate to plasticize for 15 minutes. Cab-O-Sil is dispersed in a sufficient amount of water to obtain a total dispersion of 20% by weight of solids. A Cab-O-Sil dispersion is added to the Eudragit mixture.

3. Dispersion of the colored coating: Opadry is mixed with water to obtain a dispersion of 10% by weight.

4. Application of ethyl cellulose coating: Spray the Surelease dispersion onto coated pellets at a load of 700 g using a fluidized bed reactor (GPCG-1) and the following parameter guidelines:

- Air flow rate: 9.0 to 9.2 m / s

- Inlet air temperature: 50 ° C

- Dispersion rate: 10 g / minute

5. Methacrylate Coating: After Surelease Coating is completed, the Eudragit dispersion is sprayed onto the naltrexone pellets prepared above using a fluidized bed reactor and the following performance guidelines:

- Air flow rate: 9.0 m / s

- Inlet air temperature: 35 ° C

- Dispersion rate: 10.7 g / minute

6. Color coating: After functional coating, the Opadry dispersion is sprayed onto the coated pellets, using the following parameter guidelines:

- Air flow rate: 750 to 760 CFM

- Inlet air temperature: 50 ° C

- Dispersion spray rate: 9.2 g / minute

7. Screening: Pellets are sieved through a 14 US mesh screen and 20 US mesh screen. Material retained on a 20 US mesh screen is collected as the desired product.

8. Curing: The sieved pellets are placed in an oven at 45 ° C, some are removed after 24 hours and the remaining material after 48 hours.

In vitro dissolution (intact pellets):

[0328] Formulations coated using a hydrophobic coating (ethylcellulose and methacrylic copolymer coatings), prepared by the method of Example 8, gave the following dissolution results as detailed in Table 8C, using the following dissolution test method.

Method:

[0329]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0330]

Table 8C

<td>Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 24</td><td> 36</td>

<td>Average% dissolution</td><td> 0,1</td><td> 0,1</td><td> 0,2</td><td> 0,3</td><td> 0,3</td><td> 0,5</td><td> 0,7</td>

Simulated tampering process and dissolution (crushed pellets):

[0331] The formulations prepared by the method of Example 8 were subjected to a simulated tampering process and then subjected to the dissolution testing method set out below. In the tampering process, the coated naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test. The dissolution results are given in Table 8D.

Dissolution Method:

[0332]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0333]

Table 8D

<td>Time (minutes)</td><td> 45</td>

<td>Average% dissolution</td><td> 30</td>

Crushed portion: intact ratio [0334] The ratio of crushed portion to intact portion is the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours. The results are listed below.

Ratio of crushed to intact: 42.9

Comparison of three pellets coated with up to 25% weight gain [0335] In examples 4, 7, and 8, the pellet MEM preparation of naltrexone was coated with a total coating weight up to 25% using different coating materials or the order of application. The ratio of crushed part to intact part is compared as follows:

Table 8F

<td></td><td>25% Eudragit RS</td><td>15% Eudragit RS then 10% Surelease</td><td>10% Surelease then 15% Eudragit RS</td>

<td>% dissolution of the part crushed</td><td> 47</td><td> 37</td><td> 43</td>

<td>% dissolution of the part intact</td><td> 0,3</td><td> 0,3</td><td> 0,7</td>

<td>The ratio of parts crushed / intact</td><td> 157</td><td> 93</td><td> 43</td>

[0336] Based on the in-vitro dissolution database of crushed and intact MEM pellets, it was found that the 25% coating with Eudragit RS is slightly better than the combination of coatings.

Example 9 [0337] 10 mg controlled release oxycodone hydrochloride tablets can be prepared in this prophetic example as follows. Organically produced oxycodone hydrochloride (10 mg / tablet) and spray dried lactose (71.25 mg / tablet) are transferred to a suitable mixer and mixed for about 6 minutes. Eudragit® RS PM in powder form (6 mg / tablet) is dispersed in ethanol. While mixing the powders, they are granulated with the dispersion and mixing continues to form a wet granulate. To reach the granulation end point, additional ethanol is added if necessary. The granules are transferred to fluidized bed driers and dried at 30 ° C, and then passed through a 12-mesh screen. The remaining Eudragit® RS PM (9 mg / tablet) is dispersed in a solvent consisting of 90 parts ethanol and 10 parts purified water, and sprayed onto the granules in a fluid bed granulator / dryer at 30 ° C. The obtained granulate is then passed through a 12-mesh screen. Then stearyl alcohol (25 mg / tablet) is melted at a temperature of about 60-70 ° C. The hot granules are again introduced into the mixer. Melted stearyl alcohol is added with stirring. The coated granules are removed from the mixer and allowed to cool. Then, they are passed through a 12-mesh screen. The granulate is then mixed with the naltrexone particles according to example 5 and pharmaceutically desirable tableting auxiliaries, e.g. talc and magnesium stearate, in a suitable mixer and pressed into tablets.

Example 10

Method of treating pain [0338] The oral dosage form of the present invention may be administered to a patient to alleviate pain. The oral dosage form may contain orally an effective amount of the opioid agonist and opioid antagonist in a substantially non-releasing form. Coating of antagonist-containing particles serves to advantageously reduce leakage of the antagonist from intact antagonist-containing particles.

[0339] When an oral dosage form is administered orally and introduced into the gastrointestinal tract (GI) of a patient in need of pain treatment, the opioid agonist is released from the dosage form during normal digestion, providing anesthesia to the patient. In contrast, the opioid antagonist, because it is introduced in a substantially non-releasing form, is essentially not released when it passes through the gastrointestinal (GI) tract. Preferably, the form substantially unable to release the antagonist is resistant to laxatives (mineral oil) used to treat delayed colonic passage and is resistant to conditions of gastritis. Patients who take the oral dosage form as indicated without violating it (e.g. by mechanical stirring, heating, or dissolution in a solvent), they will not absorb the opioid antagonist at any time interval when dosing the formulation in an appropriate amount that would reduce the analgesic efficacy of the opioid agonist. In other words, the amount of opioid antagonist released from the intact dosage form (during oral administration), absorbed from the gastrointestinal tract (GI) and accumulated in the patient's body will not increase to a level that significantly affects or changes the analgesic efficacy of the opioid agonist dose contained in dosage forms.

Example 11

Method for preventing abuse of an opioid agonist [0340] The oral dosage form of the present invention may be used to prevent potential abuse of an opioid agonist contained in this form. The oral dosage form contains an opioid agonist in combination with an opioid antagonist. The opioid antagonist exists in a form that is essentially unable to release during digestion. Thus, when the oral dosage form is orally introduced into the gastrointestinal (GI) tract, as intended, without disturbing it, the release of the antagonist in the gastrointestinal tract is substantially prevented. But if the oral dosage form is violated, e.g. by mechanical mixing (e.g. crushing, shearing, milling), heating (e.g. at temperatures above 45 ° C, preferably from 45 ° to 50 ° C), or dissolving the dosage form in a solvent (with or without heating), the opioid antagonist becomes available and inhibits opioid activity. Thus, when the dosage form is violated and subsequently administered orally, intranasally, parenterally or sublingually, the effect of the opioid agonist is at least partially blocked by the opioid antagonist.

Example 12 [0341] Controlled release hydromorphone HCl capsules with naltrexone HCl pellets can be prepared in this prophetic example as follows. The composition of the preparation is detailed in Table 12A below:

Table 12A

<td>Ingredient</td><td>Quantity / unit (mg)</td>

<td>Hydromorphone HCl</td><td> 12,0</td>

<td>Eudragit RSPO</td><td> 76,5</td>

<td>ethylcellulose</td><td> 4,5</td>

<td>Stearyl alcohol</td><td> 27,0</td>

<td>Opadry Pink</td><td> 6,0</td>

<td>Naltrexone HCl pellets (example 5)</td><td> 149,7</td>

<td>globally</td><td> 275,7</td>

<td>Hard gelatin capsules</td><td></td>

[0342] Capsules according to example 5 are prepared using the following process:

Manufacturing Process:

1. Grinding: Stearyl alcohol flakes are passed through an impact mill.

2. Mixing: Hydromorphone HCl, Eudragit, ethyl cellulose and ground stearyl alcohol are mixed in a twin-shell mixer.

3. Extrusion: The mixed material is continuously fed into the twin screw extruder and the threads obtained are collected on a conveyor.

4. Cooling: The threads on the conveyor can be cooled.

5. Pelleting: The cooled threads are cut into pellets using a pelleting device.

6. Sieving: Sieve pellets and collect the desired part on a sieve.

7. Thin film coating: An aqueous dispersion of Opadry Pink is sprayed onto the opioid fluid bed pellets.

8. Encapsulation: Coated extruded hydromorphone HCl pellets 126 mg and Naltrexone HCl pellets (Example 5) at 149.7 mg are filled into hard gelatin capsules.

[0343] Amendments to the present invention will be apparent to those skilled in the art and are intended to be within the scope of the claims appended hereto.

Example 13

Example 13a [0344] In Example 13a, naltrexone HCl pellets prepared by the method of Example 5 and listed in Table 5A were then coated with a hydrophobic coating. The pellets were coated to a 25% weight gain using a hydrophobic coating (based on Eudragit RS 30D). The coated pellets are listed in the table below.

Table 13A

Composition of encapsulated coated pellets with a 25% weight gain

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>8 mg naltrexone HCl pellet</td><td> 121,0</td><td> 7,00</td>

<td>Eudragit RS30D (solids)</td><td> 30,25</td><td> 1,75</td>

<td>Triethyl citrate</td><td> 6,05</td><td> 0,35</td>

<td>Cab-O-Sil</td><td> 1,51</td><td> 0,09</td>

<td>Opadry White Y-5-18024A</td><td> 6,05</td><td> 0,35</td>

<td>globally</td><td> 164,86</td><td> 9,54</td>

[0345] The following process was used to produce pellets according to example 13A:

Manufacturing Process:

1. Functional coating dispersion: Eudragit RS 30D is mixed with triethyl citrate to plasticize for 15 minutes. Cab-O-Sil is dispersed in a sufficient amount of water to obtain a total dispersion of 20% by weight of solids. A Cab-O-Sil dispersion is added to the Eudragit mixture.

2. Dispersion of the colored coating: Opadry is mixed with water to obtain a dispersion of 10% by weight.

3. Functional coating: The Eudragit dispersion is sprayed onto the naltrexone pellets produced above at a load of 9 kg using a fluidized bed reactor (GPCG-15) and the following performance guidelines:

- Air flow: 400 to 450 CFM

- Inlet air temperature: 40 ° C

- Dispersion spray rate: 75 to 90 g / minute

4. Color coating: After functional coating, the Opadry dispersion is sprayed onto the coated pellets, using the following parameter guidelines:

- Air flow: 400 to 450 CFM

- Inlet air temperature: 50 - 55 ° C

- Dispersion spray rate: 60 to 70 g / minute

5. Sieving: The pellets are sieved through a vibrating separator using 14 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product.

6. Encapsulation: The sieved pellets are filled into hard gelatin capsules at a target load of 164.86 mg.

In vitro dissolution (intact pellets) [0346] Formulations coated with the hydrophobic coating in Example 13a in the form of bulky pellets and encapsulated pellets gave the following results, which are listed in Table 13B after being subjected to the following in vitro dissolution test method.

Dissolution Method:

[0347]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Table 13B

<td colspan="2">Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 24</td><td> 36</td>

<td>Average%</td><td>volumetric pellets</td><td> 0,0</td><td> 0,0</td><td> 0,1</td><td> 0,2</td><td> 0,3</td><td> 0,3</td><td> 0,3</td>

<td>dissolution</td><td>encapsulated pellets</td><td> 0,0</td><td> 0,0</td><td> 0,1</td><td> 0,2</td><td> 0,4</td><td> 0,4</td><td> 0,5</td>

Simulated tampering process and dissolution (crushed pellets):

[0348] The formulations prepared by the method of Example 13a were subjected to a simulated tampering process and then subjected to the following dissolution test method. In the tampering process, the coated naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0349]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0350]

Table 13C

<td>Time (minutes)</td><td> 45</td>

<td>Average% dissolution</td><td> 27</td>

The ratio of crushed part to intact part [0351] The ratio of crushed part to intact part means the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours. The results are listed below.

Results of the ratio of crushed part to intact part: 27.0 / 0.5 = 54

Example 13b [0352] In Example 13b, naltrexone HCl pellets prepared by the method of Example 5 and listed in Table 5A were then coated with a hydrophobic coating. The pellets were coated to a 30% weight gain using a hydrophobic coating (based on Surelease E-7-10901).

The coated pellets are listed in the table below.

Table 13D

The composition of the encapsulated coated pellet with a 30% weight gain

<td>Ingredient</td><td>Quantity / unit (mg)</td><td>Quantity / Lot (kg)</td>

<td>8 mg naltrexone HCl pellet</td><td> 121,0</td><td> 7,00</td>

<td>Surelease (solids)</td><td> 36,3</td><td> 2,10</td>

<td>Opadry White Y-5-18024A</td><td> 6,05</td><td> 0,35</td>

<td>globally</td><td> 163,35</td><td> 9,45</td>

[0353] The following process was used to produce pellets according to example 13B:

Manufacturing process [0354]

1. Functional coating dispersion: Eudragit RS 30D is mixed with triethyl citrate to plasticize for 15 minutes. Cab-O-Sil is dispersed in a sufficient amount of water to obtain a total dispersion of 20% by weight of solids. A Cab-O-Sil dispersion is added to the Eudragit mixture.

2. Dispersion of the colored coating: Opadry is mixed with water to obtain a dispersion of 10% by weight.

3. Functional coating: The Eudragit dispersion is sprayed onto the naltrexone pellets produced above at a load of 9 kg using a fluidized bed reactor (GPCG-15) and the following performance guidelines:

- Air flow: 400 to 450 CFM

- Inlet air temperature: 40 ° C

- Dispersion spray rate: 75 to 90 g / minute

4. Color coating: After functional coating, the Opadry dispersion is sprayed onto the coated pellets, using the following parameter guidelines:

- Air flow: 400 to 450 CFM

- Inlet air temperature: 50 - 55 ° C

- Dispersion spray rate: 60 to 70 g / minute

5. Sieving: The pellets are sieved through a vibrating separator using 14 TBC mesh and 26 TBC mesh sieves. Material retained on a 26 TBC mesh screen is collected as the desired product.

6. Encapsulation: The sieved pellets are filled into hard gelatin capsules at a target load of 164.86 mg.

In vitro dissolution (intact pellets) [0355] Formulations coated with the hydrophobic coating in Example 13b in the form of bulky pellets and encapsulated pellets gave the following results, which are listed in Table 13E after being subjected to the following in vitro dissolution test method.

Dissolution Method:

[0356]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sampling time: 1, 2, 4, 8, 12, 24, 36 hours

3. Centers: 700 ml SGF for one hour, followed by exchange for 900 ml SIF

4. Analytical method: High performance liquid chromatography

Results:

[0357]

Table 13E

<td colspan="2">Time (hours)</td><td> 1</td><td> 2</td><td> 4</td><td> 8</td><td> 12</td><td> 24</td><td> 36</td>

<td>Average%</td><td>volumetric peleteki</td><td> 0,3</td><td> 0,3</td><td> 0,4</td><td> 0,7</td><td> 0,9</td><td> 1,4</td><td> 1,7</td>

<td>dissolution</td><td>encapsulated pellets</td><td> 0,4</td><td> 0,5</td><td> 0,6</td><td> 0,7</td><td> 0,9</td><td> 1,3</td><td> 1,6</td>

Simulated tampering process and dissolution (crushed pellets):

[0358] The formulations prepared by the method of Example 13b were subjected to a simulated tampering process and then subjected to the following dissolution test method. In the tampering process, the coated naltrexone pellets were ground using a mortar and pestle (24 strokes) to powder for the purposes of this dissolution test.

Dissolution Method:

[0359]

1. Machine: USP Type II (stirrer), 50 rpm at 37 ° C

2. Sample time: 45 minutes

3. Centers: 700 ml SGF

4. Analytical method: High performance liquid chromatography

Results:

[0360]

Table 13F

<td>Time (minutes)</td><td> 45</td>

<td>Average% dissolution</td><td> 26</td>

The ratio of crushed part to intact part [0361] The ratio of crushed part to intact part means the ratio of% dissolution of crushed pellets over 45 minutes to% dissolution of intact pellets over 36 hours. The results are listed below.

Results of the ratio of crushed part to intact part: 26.0 / 1.6 = 16.3

In vivo pharmacokinetic / bioavailability study in humans [0362] Capsules obtained using the above process of Examples 13a and b were used in two separate clinical studies to determine the pharmacokinetics / bioavailability of MEM preparations under different conditions and then compared with the immediate pharmacokinetics / bioavailability of naltrexone tablets release. Human patients were given intact naltrexone MEM HCl formulation as a capsule (1 capsule - on an empty stomach or 5 capsules - on an empty stomach); crushed naltrexone MEM HCl (ground content of 1 capsule - on an empty stomach); immediate-release naltrexone HCl tablet; or 1 intact MEM capsule in a fed state. These studies were open, single dose, 5-step, cross-sectional, in healthy subjects. Therapies are designed as follows:

A. 1x8 mg naltrexone MEM capsule formulation, intact, in fasting state.

B. 1 x 8 mg naltrexone MEM capsule, with the contents of the capsule crushed, in an empty stomach.

C. 1x8 mg naltrexone MEM capsule formulation, intact, fed.

D. 5 x 8 mg (40 mg) MIT naltrexone capsule, intact, in fasting state.

E. 1x1 mg immediate-release naltrexone tablets, in an empty stomach.

[0363] The resulting initial plasma concentrations show that there is slight release of naltrexone when intact naltrexone MEM pellets are taken. The results of the naltrexone concentration (pg / ml) time versus time curve are shown in Figures 3 and 4. Plasma levels of naltrexone were significantly increased when naltrexone pellets were taken orally crushed / ground. The average Cmax ratio of crushed MEM / intact MEM capsule formulation for 25% Eudragit coating and 30% Surelease coating was 187.91 and 71.98, respectively. Similarly, the mean AUCt ratio of crushed MEM / intact MEM capsule formulation for 25% Eudragit coating and 30% Surelease coating was 66.07 and 39.27, respectively.

[0364] The comparison of the in-vitro and in-vivo results obtained for the coated MEM preparations according to examples 13a and 13b is shown in Table 13G below:

Table 13G

<td colspan="3">Preparation:</td><td>Example 13a 8 mg w / 25% Eudragit</td><td>Example 13b 8 mg w / 30% Surelease</td>

<td rowspan="3">In-Vitro</td><td colspan="2">Release from an intact capsule in within 36 hours</td><td> 0,5%</td><td> 1,6%</td>

<td colspan="2">Crushed preparation</td><td> 27%</td><td> 26%</td>

<td colspan="2">Crushed ratio: intact</td><td> 54</td><td> 16,3</td>

<td rowspan="4">In-Vivo</td><td rowspan="2">AUC (Pg / ml * h)</td><td>Intact*</td><td> 55,78</td><td> 85,15</td>

<td>crushed</td><td> 3685,37</td><td> 3344,09</td>

<td rowspan="2">Cmax⁽pg^{/ Ml)}</td><td>Intact*</td><td> 1,73</td><td> 6,74</td>

<td>crushed</td><td> 325,1</td><td> 485,15</td>

* normalized based on data for 5 * 8 mg

Table 13H

<td></td><td>Capsule intact</td><td>Capsule crumbled</td><td>Capsule intact</td><td>Capsule intact</td><td>Pill IR</td>

<td></td><td>8 mg</td><td>8 mg</td><td>8 mg</td><td>5 X 8 mg</td><td>1 X 1 mg</td>

<td></td><td>On empty stomach</td><td>On empty stomach</td><td>After meal</td><td>On empty stomach</td><td>On empty stomach</td>

<td></td><td>N = 20</td><td> 20</td><td> 19</td><td> 19</td><td> 20</td>

<td>Cmax (pg / ml) Example 13a</td><td> 1,52</td><td> 325,10</td><td> 1,74</td><td> 8,63</td><td> 218,03</td>

<td>AUCt (pg.h / mL) Example 13a</td><td> 27,61</td><td> 3685,37</td><td> 21,41</td><td> 278,9</td><td> 578,92</td>

<td>Cmax (pg / ml) Example 13b</td><td> 7,28</td><td> 485,15</td><td> 8,48</td><td> 33,68</td><td> 292,23</td>

<td>AUCt (pg.h / ml) Example 13b</td><td> 22,11</td><td> 3344,09</td><td> 65,56</td><td> 425,76</td><td> 543,59</td>