TAMPER RESISTANT DOSAGE FORMS

Abstract

Tamper resistant controlled release formulations.

Claims

1. Use of an amount of an opioid antagonist in an amount at least sufficient to substantially antagonize a therapeutic amount of opioid agonist, when both, the opioid agonist and the opioid antagonist, are administered intravenous at the same time, in the form of a controlled release dosage form comprising a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist, to prevent the formation of an extract of said controlled release matrix formulation comprising the opioid agonist by a one step extraction procedure comprising the steps of: a) crushing the formulation of one dosage form using a pill crusher or a tablet mortar, or using two spoons, wherein the crushing is performed at least 4 times using the spoons, b) extracting the crushed formulation of one dosage form on a spoon using 2 ml boiling tap water as extracting agent and a cigarette lighter as heating means for a time period that is necessary to boil the water, and c) filtering the solution using cotton, wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 20%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form.

2-20. (canceled)

Description

BRIEF DESCRIPTION OF THE FIGURES

[0028] FIGS. 1 to 11 depict the extraction test results of Examples 1 and 2.

DETAILED DESCRIPTION OF THE INVENTION

[0029] According to one embodiment the invention is directed to the use of an amount of an opioid antagonist in an amount at least sufficient to substantially antagonize a therapeutic amount of opioid agonist when both, the opioid agonist and the opioid antagonist, are administered intravenous at the same time, in the form of a controlled release dosage form comprising a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist, to prevent the formation of an extract of said controlled release matrix formulation comprising the opioid agonist by a one step extraction procedure comprising the steps of: [0030] a) crushing the formulation of one dosage form using a pill crusher or a tablet mortar, or using two spoons, wherein the crushing is performed at least 4 times using the spoons, [0031] b) extracting the crushed formulation of one dosage form on a spoon using 2 ml boiling tap water as extracting agent and a cigarette lighter as heating means for a time period that is necessary to boil the water, and [0032] c) filtering the solution using cotton,
wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 20%-points, preferably more than 15%-points, more preferably more than 12%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form.

[0033] In a further aspect the invention is directed to the use of an amount of an opioid antagonist in an amount at least sufficient to substantially antagonize a therapeutic amount of opioid agonist when both, the opioid agonist and the opioid antagonist, are administered intravenous at the same time, in the form of a controlled release dosage form comprising a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist, to prevent the formation of an extract of said controlled release matrix formulation comprising the opioid agonist by a one step extraction procedure comprising the steps of: [0034] a) crushing the formulation of one dosage form using a pill crusher or a tablet mortar, or using two spoons, wherein the crushing is performed at least 4 times using the spoons [0035] b) extracting said crushed formulation on a spoon using 2 ml boiling deionized water as extracting agent and a cigarette lighter as heating means for a time period that is necessary to boil the water, and [0036] c) filtering the solution using cotton,
wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 15%-points, preferably more than 10%-points, more preferably more than 7%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form.

[0037] In a further aspect the invention is directed to the use of an amount of an opioid antagonist in an amount at least sufficient to substantially antagonize a therapeutic amount of opioid agonist when both, the opioid agonist and the opioid antagonist, are administered intravenous at the same time, in the form of a controlled release dosage form comprising a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist, to prevent the formation of an extract of said controlled release matrix formulation comprising the opioid agonist by a one step extraction procedure comprising the steps of: [0038] a) crushing the formulation of 10 dosage form using a pill crusher [0039] b) extracting said crushed formulation in a glass vial using 100 ml of extraction solvent selected from the group of deionized water, hydrochloride acid (2N), acetic acid (2N), sodium hydroxide solution (0.1N, 0.5N, 1N or 2 N) and ethanol (40%), and shaking for at least 15 minutes at at least room temperature,
wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 10%-points, preferably more than 5%-points and more preferably more than 3% points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form. Preferably, the formation of said extract is prevented, even wherein shaking is performed for 120 minutes. Preferably the formation of said extract is also prevented when deionized water is used as extraction solvent and during extraction the deionized water is heated to 50° C., preferably 75° C. and most preferred 100° C. for 5 minutes.

[0040] In a different aspect the invention is directed to the use of an amount of an opioid antagonist in an amount at least sufficient to substantially antagonize a therapeutic amount of opioid agonist when both, the opioid agonist and the opioid antagonist, are administered intravenous at the same time, in the form of a controlled release dosage form comprising a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist, to prevent the formation of an extract of said controlled release matrix formulation comprising the opioid agonist by a one step extraction procedure comprising the steps of: [0041] a) heating deionized water to 70° C. [0042] b) adding intact formulation of one dosage form and stirring for 15 minutes [0043] c) separating the extract
wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 15%-points preferably more than 10%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form.

[0044] According to the present invention the opioid agonist is selected from alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts of any of the forgoing and mixtures of any of the foregoing, and the like, preferably from pharmaceutically acceptable salts of any of codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone

[0045] According to the invention the opioid antagonist is selected form the group of naloxone, naltrexone and nalorphine.

[0046] According to a preferred embodiment of the invention the opioid agonist is oxycodone hydrochloride and the opioid antagoninst is naloxone hydrochloride used in an amount ratio of 2:1.

[0047] According to the invention the dosage form comprises a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist.

[0048] Preferably the hydrophobic material is an alkyl cellulose, especially ethyl cellulose. Preferably the amount of the hydrophobic material, preferably the alkyl cellulose, more preferably ethyl cellulose, is less than 20% (by wt), preferably less than 15% (by wt), most preferred less than 10% (by wt) but more than 5% (by wt) of the controlled release matrix formulation. The alkyl cellulose can be used in the form of particles or aqueous alkyl cellulose dispersions.

[0049] In case of ethyl cellulose particles, the ethyl cellulose has preferably a viscosity in the range of 3 to 110 cP, when measured in a 5% solution at 25° C. in an Ubbelohde viscosimeter with a solvent of 80% toluene and 20% alcohol. Preferably, the viscosity is in the range of 18 to 110 cP and most preferred in the range of 41-49 cP. A suitable ethyl cellulose is provided by Dow Chemical Company under the trade name Ethocel™ Standard 45.

[0050] In case of aqueous ethyl cellulose dispersions, a dispersion of ethyl cellulose 20 cP with dibutyl/sebacate, ammoniumhydroxide, oleic acid and colloidal anhydrous silica is preferred, which is available under the trade name Surlease™ E-7-7050.

[0051] According to the present invention the hydrophobic polymer is used in combination with at least one second controlled release matrix material selected from C.sub.12 to C.sub.36 aliphatic alcohols and the corresponding aliphatic acids, preferably stearyl alcohol, cetyl alcohol and cetostearyl alcohol and the corresponding stearic and palmitic acids and mixtures thereof, wherein the amount of C.sub.12 to C.sub.36 aliphatic alcohol or aliphatic acid is preferably at least 5%, more preferred at least 10% (by wt), more preferred at least 15% (by wt) and most preferred 20% to 25% (by wt) of the controlled release matrix formulation.

[0052] The dosage form may comprise, besides the hydrophobic polymer, preferably the alkyl (ethyl) cellulose, and the aliphatic alcohol or aliphatic acid, fillers and additional substances/adjuvants, such as granulating aids, lubricants, dyes, flowing agents and plasticizers.

[0053] Lactose, glucose or saccharose, starches and their hydrolysates, microcrystalline cellulose, cellatose, sugar alcohols such as sorbitol or mannitol, polysoluble calcium salts like calciumhydrogenphosphate, dicalcium- or tricalciumphosphat may be used as fillers.

[0054] Povidone may be used as granulating aid.

[0055] Highly-dispersed silica (Aerosil®), talcum, corn starch, magnesium oxide and magnesium- or calcium stearate may preferably be used as flowing agents or lubricants.

[0056] Magnesium stearate and/or calcium stearate can be preferably be used as lubricants. Fats like hydrated castor oil can also preferably be used.

[0057] According to such certain embodiments, a formulation is especially preferred which comprises ethylcellulose, stearyl alcohol, magnesium stearate as lubricant, lactose as filler and providone as a granulating aid.

[0058] The production of the homogenous controlled release matrix formulation or preliminary stages thereof, which are in accordance with the invention, by extrusion technology is especially advantageous.

[0059] In one preferred embodiment, pharmaceutical formulations or preliminary stages thereof are produced by melt extrusion with co- or counter-rotating extruders comprising two screws. Another such preferred embodiment is the production by means of extrusion, with extruders comprising one or more screws. These extruders may also comprise kneading elements.

[0060] Extrusion is also a well-established production process in pharmaceutical technology and is well known to the person skilled in the art. The person skilled in the art is well aware that during the extrusion process, various parameters, such as the feeding rate, the screw speed, the heating temperature of the different extruder zones (if available), the water content, etc. may be varied in order to produce products of the desired characteristics.

[0061] The aforementioned parameters will depend on the specific type of extruder used. During extrusion the temperature of the heating zones, in which the components of the inventive formulation melt, may be between 40 to 120° C., preferably between 50 to 100° C., more preferably between 50 to 90° C., even more preferably between 50 to 70° C. and most preferably between 50 to 65° C., particularly if counter-rotating twin screw extruders (such as a Leistritz Micro 18 GGL) are used. The person skilled in the art is well aware that not every heating zone has to be heated. Particularly behind the feeder where the components are mixed, cooling at around 25° C. may be necessary. The screw speed may vary between 100 to 500 revolutions per minute (rpm), preferably between 100 to 250 rpm, more preferably between 100 to 200 rpm and most preferably around 150 rpm, particularly if counter-rotating twin screw extruders (such as a Leistritz Micro 18 GGL) are used. The geometry and the diameter of the nozzle may be selected as required. The diameter of the nozzle of commonly used extruders typically is between 1 to 10 mm, preferably between 2 to 8 mm and most preferably between 3 to 5 mm. The ratio of length versus diameter of the screw of extruders that may be used for production of inventive preparations is typically around 40:1.

[0062] Generally, the temperatures of the heating zones have to be selected such that no temperatures develop that may destroy the pharmaceutically active compounds. The feeding rate and screw speed will be selected such that the pharmaceutically active compounds are released from the preparations produced by extrusion in a sustained, independent and invariant manner. If e.g. the feeding rate is increased, the screw speed may have to be increased correspondingly to ensure the same retardation.

[0063] The person skilled in the art knows that all the aforementioned parameters depend on the specific production conditions (extruder type, screw geometry, number of components etc.) and may have to be adapted such that the preparations produced by extrusion provide for the required release.

[0064] Preferably the C.sub.12 to C.sub.36 aliphatic alcohol or aliphatic acid melts and the ethylcellulose can be dissolved in said C.sub.12 to C.sub.36 aliphatic alcohol or aliphatic acid during the melt extrusion process to enhance homogeneity.

[0065] According to a preferred embodiment of the invention ethyl cellulose is used in an amount less than 10% (by wt) but more than 5% (by wt) of the matrix formulation and the C.sub.12 to C.sub.36 aliphatic alcohol is steary alcohol used in an amount of between 20% and 25% (by wt) and the opioid agonist is oxycodone hydrochloride and the opioid antagoninst is naloxone hydrochloride which are present in the dosage form in an amount ratio of 2:1 and the controlled release matrix formulation is prepared by a melt extrusion process.

[0066] According to the invention the resulting controlled release matrix formulation can be used in the form of multi particulates or the formulations can be formed into a tablet. The multi particulates or the tablet can be film coated. The film coat can provide further controlled release. In preferred embodiments the film coat does not provide further controlled release.

[0067] The invention is further described by means of an oxycodone hydrochloride/naloxone hydrochloride with an amount ratio to 2:1, namely 10 mg/5 mg and 40 mg/20 mg. It should however be understood that the following description is illustrative only and should not be taken in any way as restriction of the invention.

[0068] Preparation of the Oxycodone/Naloxone dosage forms comprising 10 mg/5 mg and 20 mg/40 mg oxycodone hydrochloride and naloxone hydrochloride.

[0069] The invention can be illustrated by the following embodiments enumerated in the numbered paragraphs below: [0070] 1. Use of an amount of an opioid antagonist in an amount at least sufficient to substantially antagonize a therapeutic amount of opioid agonist, when both, the opioid agonist and the opioid antagonist, are administered intravenous at the same time, in the form of a controlled release dosage form comprising a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist, to prevent the formation of an extract of said controlled release matrix formulation comprising the opioid agonist by a one step extraction procedure comprising the steps of: [0071] a) crushing the formulation of one dosage form using a pill crusher or a tablet mortar, or using two spoons, wherein the crushing is performed at least 4 times using the spoons, b) extracting the crushed formulation of one dosage form on a spoon using 2 ml boiling tap water as extracting agent and a cigarette lighter as heating means for a time period that is necessary to boil the water, and c) filtering the solution using cotton, [0072] wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 20%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form. [0073] 2. Use according to embodiment 1 to prevent the formation of an extract, wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 15%-points, preferably more than 12%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form. [0074] 3. Use of an amount of an opioid antagonist in an amount at least sufficient to substantially antagonize a therapeutic amount of opioid agonist when both, the opioid agonist and the opioid antagonist, are administered intravenous at the same time, in the form of a controlled release dosage form comprising a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist, to prevent the formation of an extract of said controlled release matrix formulation comprising the opioid agonist by a one step extraction procedure comprising the steps of: [0075] a) crushing the formulation of one dosage form using a pill crusher or a tablet mortar, or using two spoons, wherein the crushing is performed at least 4 times using the spoons [0076] b) extracting said crushed formulation on a spoon using 2 ml boiling deionized water as extracting agent and a cigarette lighter as heating means for a time period that is necessary to boil the water, and [0077] c) filtering the solution using cotton, [0078] wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 15%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form. [0079] 4. Use according to embodiment 1 to prevent the formation of an extract, wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 10%-points, preferably more than 7%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form. [0080] 5. Use of an amount of an opioid antagonist in an amount at least sufficient to substantially antagonize a therapeutic amount of opioid agonist, when both, the opioid agonist and the opioid antagonist, are administered intravenous at the same time, in the form of a controlled release dosage form comprising a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist, to prevent the formation of an extract of said controlled release matrix formulation comprising the opioid agonist by a one step extraction procedure comprising the steps of: [0081] a) crushing the formulation of 10 dosage form using a pill crusher [0082] b) extracting said crushed formulation in a glass vial using 100 ml of extraction solvent selected from the group of deionized water, hydrochloride acid (2N), acetic acid (2N), sodium hydroxide solution (0.1N, 0.5N, IN or 2 N) and ethanol (40%), and shaking for at least 15 minutes at least room temperature, wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 10%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form. [0083] 6. Use according to embodiment 5 to prevent the formation of an extract, wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 5%-points or more than 3%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form. [0084] 7. Use according to embodiments 5 or 6 to prevent the formation of an extract, wherein shaking is performed for 120 minutes. [0085] 8. Use according to any one of embodiments 5 to 7 to prevent the formation of an extract, wherein deionized water is used as extraction solvent and during extraction the deionized water is heated to 50° C., preferably 75° C. and most preferred 100° C. for 5 minutes. [0086] 9. Use of an amount of an opioid antagonist in an amount at least sufficient to substantially antagonize a therapeutic amount of opioid agonist, when both, the opioid agonist and the opioid antagonist, are administered intravenous at the same time, in the form of a controlled release dosage form comprising a homogeneous controlled release matrix formulation comprising a hydrophobic material, including at least one hydrophobic polymer and at least one fatty alcohol or fatty acid, and said therapeutic amount of an opioid agonist and said sufficient amount of opioid antagonist, to prevent the formation of an extract of said controlled release matrix formulation comprising the opioid agonist by a one step extraction procedure comprising the steps of: [0087] a) heating deionized water to 70° C. [0088] b) adding intact formulation of one dosage form and stirring for 15 minutes [0089] c) separating the extract [0090] wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 15%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form. [0091] 10. Use according to embodiment 9 to prevent the formation of an extract, wherein the opioid antagonist is present in said extract in a weight percent amount, based on the total amount of opioid antagonist in the dosage form, that is more than 10%-points less than the weight percent amount of opioid agonist present in the extract, based on the total amount of opioid agonist in the dosage form. [0092] 11. Use according to any one of the preceding embodiments wherein the formulations is prepared by a melt extrusion step to form a homogenous matrix. [0093] 12. Use according to any one of the preceding embodiments, wherein the opioid is selected from alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts of any of the forgoing and mixtures of any of the foregoing, and the like, preferably from pharmaceutically acceptable salts of any of codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone. [0094] 13. Use according to any one of he preceding embodiments, wherein the opioid antagonist is selected form the group of naloxone, naltrexone and nalorphine. [0095] 14. Use according to any one of the preceding embodiments, wherein the opioid agonist is oxycodone hydrochloride and the opioid antagoninst is naloxone hydrochloride. [0096] 15. Use according to any one of the preceding embodiments, wherein the opioid agonist is oxycodone hydrochloride and the opioid antagoninst is naloxone hydrochloride which are present in the dosage form in an amount ratio of 2:1. [0097] 16. Use according to any one of the preceding embodiments, wherein the hydrophobic polymer is an alkyl cellulose, preferably ethylcellulose. [0098] 17. Use according to embodiment 16, wherein the amount of the alkyl cellulose, preferably ethyl cellulose, is less than 20% (by wt), preferably less than 15% (by wt), most preferred less than 10% (by wt) but more than 5% (by wt) of the matrix formulation. [0099] 18. Use according to any one of the preceding embodiments, wherein the fatty alcohol or fatty acid is selected from C.sub.12 to C.sub.36 aliphatic alcohols or acids, preferably stearyl alcohol, cetyl alcohol, cetostearyl alcohol, stearic acid, palmitic acid and mixtures thereof. [0100] 19. Use according to embodiment 18, wherein the amount of C.sub.12 to C.sub.36 aliphatic alcohol or acid is at least 5%, more preferred at least 10% (by wt), more preferred at least 15% (by wt) and most preferred 20% to 25% (by wt) of the matrix formulation. [0101] 20. Use according to any one of the preceding embodiments wherein the amount of ethyl cellulose is less than 10% (by wt) of the matrix formulation further comprising steary alcohol in an amount of between 20% and 25% (by wt) and oxycodone hydrochloride and naloxone hydrochloride in an amount ratio of 2:1.

EXAMPLE 1

[0102] Oxycodone/naloxone dosage form comprising 10 mg oxycodone hydrochloride and 5 mg naloxone hydrochloride

TABLE-US-00001 Component weight [mg/tablet] Oxycodone hydrochloride.sup.1) 10.50 corresponding to Oxycodone hydrochlorid anhydrous 10.00 naloxone hydrochloride dihydrate 5.45 corresponding to Naloxone hydrochlorid anhydrous 5.00 Povidone K30 5.00 Ethyl cellulose 45 cp 10.00 Stearyl alcohol 25.00 Lactose monohydrate 64.25 Talc 2.50 Magnesium-Stearate 1.25 film coating opadry II HP white - 3.72 85F18422° .sup.1)calculated based on expected moisture content °qualitative composition: see Table 1

EXAMPLE 2

[0103] Oxycodone/naloxone dosage form comprising 40 mg oxycodone hydrochloride and 20 mg naloxone hydrochloride

TABLE-US-00002 Component weight [mg/tablet] Oxycodone hydrochloride.sup.1) 42.00 corresponding to Oxycodone hydrochlorid anhydrous 40.00 naloxone hydrochloride dihydrate 21.80 corresponding to Naloxone hydrochlorid anhydrous 20.00 Povidone K30 14.50 Ethyl cellulose 45 cp 24.00 Stearyl alcohol 59.00 Lactose monohydrate 109.00 Talc 5.00 Magnesium-Stearate 2.5 film coating opadry II HP yellow 8.33 85F32109° 2) calculated based on expected moisture content °qualitative composition: see Table 1

TABLE-US-00003 TABLE 1 Qualitative composition of the film coat white pink yellow Reference to Opadry II HP 85F18422 85F24151 85F32109 Standard Polyvinylalcohol part. + + + Ph. Eur.* hydrolized Titanium dioxide + + + Ph. Eur.* (E 171) Macrogol 3350 + + + Ph. Eur.* Talcum + + + Ph. Eur.* Iron oxide red + NF*/ (E 172) EC Directive Iron oxide yellow + NF*/ (E 172) EC Directive *current Edition

[0104] The above described dosage forms were prepared by melt extrusion.

[0105] Oxycodone hydrochloride and naloxone hydrochloride are blended with povidone, ethylcellulose, stearyl alcohol and lactose, the blend is screened to remove agglomerates and further blended. The blend is melt extruded utilizing a heated twin screw extruder, to form strands which are milled to produce granules. The granules are blended with talc and magnesium stearate, compressed into capsule shaped tablets, which are then film coated.

Tamper Tests

Used Materials

[0106] 2 ml Syringes Injection needles [0107] DB Plastipak™ (0,90×40 mm) [0108] Batch 0502018 100 Sterican® [0109] Batch 98K2982510 [0110] B/Braun Melsungen/Germany [0111] Cotton [0112] Lohmann Rauscher [0113] Batch 1055314 [0114] Rengsdorf, Germany [0115] ACU-Med Pill Crusher EZ-SWALLOW™ Pill Crusher [0116] Health Enterprises, Inc. American Medical Industries [0117] North Attleboro, Mass. 02760, USA Dell Papids, USA [0118] Tablet Mortar [0119] Medi-Globe® Vertriebs GmbH [0120] Eppstein, Germany

Extraction Tests

[0121] 1) (Intravenous) The methods for evaluating the intravenous technique involved crushing a tablet of Example 1 or 2, followed by extraction into a small quantity of water. The resultant solution was then drawn into an insulin syringe. Crushing the tablets was accomplished by using different pill crushers and stainless steel tablespoons.

[0122] Using a heat extraction procedure the opioids are extracted from the crushed material. The procedure required 2 ml water, tap water or deionized water (D-water), a cigarette lighter for heating the solution on the spoon, cotton to filter the solution, and insulin syringes to transfer the filtrate to a flask for analysis. Each experiment was repeated three times.

[0123] The quantity of oxycodone and naloxone extracted from the material was evaluated using an assay HPLC method with UV detection at 230 nm wavelength. Percent recovery was calculated on the basis of the total amount of oxycodone and naloxone in the tablet that was determined at the beginning of the tests.

[0124] 2) (simple extraction) To simulate tampering the product by simple extraction, the dosage form was crushed (10 tablets or Example 1 or 2/experiment) with a pill crusher, combined with 100 ml of an extraction solvent (D-water, acidic, basic and 40% ethanol media), heated to a specified temperature, shaken for 15 minutes and 120 minutes and analysed for extractability. Each experiment was repeated 3 times.

[0125] The quantity of oxycodone and naloxone extracted from the material was evaluated using an assay HPLC method with UV detection at 230 nm wavelength. Percent recovery was calculated on the basis of the total amount of oxycodone and naloxone that was determined at the beginning of the tests.

[0126] 3) (additional test) To simulate the effect of swallowing the intact dosage form with a hot, non-alcoholic drink, deionized water (D-water) was heated to 70° C., the intact tablet of Example 1 or 2 was added and stirred for 15 min. After cooling to room temperature, the murky solution was transferred to a flask and measured for its pH. Each experiment was repeated 3 times.

[0127] The quantity of oxycodone and naloxone extracted from the material (murky solution) was evaluated using an assay HPLC method with UV detection at 230 nm wavelength. Percent recovery was calculated on the basis of the total amount of oxycodone and naloxone that was determined at the beginning of the tests.

[0128] The details of the test procedures are summarized in Table 2 below.

TABLE-US-00004 TABLE 2 Tampering Equipment Knowledge Dosage Form Extraction Extraction Extraction Technique Required Required Treatment Time Solvent(s) Temperature (° C.) 1) Intravenous Spoons, Simple Crushed Time required Water 100 Pill Crusher, to boil (boiling) Syringe, Lighter, Cotton 2) Simple Pill Crusher, Slightly More Crushed 15 minutes, Water, RT, 50, 75, 100 Extraction Glass Vial for Advanced 2 hours 40% ethanol, Shaking, HCl 2N, RT Water Bath, CH.sub.3COOH 2N, RT Thermometer NaOH 0.1N, RT 0.5N, 1N, 2N RT 3) Additional Glass Vial, Simple Intact 15 minutes Water  70 Test Water Bath, Thermometer

[0129] The test results are as follows.

Test Results “Intravenous” Using Example 1

[0130]

TABLE-US-00005 % recovery % recovery Crushing Method Water Oxycodone* Naloxone* Δ % points Pill Crusher Tap Water 67 56 11 ACU-MED Tablet-Mortar Tap Water 69 58 11 Pill Crusher Tap Water 68 58 10 EZ-SWALLOW Pill Crusher D-Water 78 72 6 ACU-MED Tablet-Mortar D-Water 72 67 5 Pill Crusher D-Water 69 64 5 EZ-SWALLOW Two Spoons Tap Water 75 63 12 (Crushed 4 times) Two Spoons Tap Water 72 60 12 (Crushed 8 times) Two Spoons D-Water 80 74 6 (Crushed 4 times) Two Spoons D-Water 82 75 7 (Crushed 8 times) *Average of 3 replicates

[0131] The results are also presented in FIGS. 1 and 2.

Test Results “Intravenous” Using Example 2

[0132]

TABLE-US-00006 % recovery % recovery Crushing Method Water Oxycodone* Naloxone* Δ % points Pill Crusher Tap Water 73 66 7 ACU-MED Tablet-Mortar Tap Water 67 61 6 % recovery % recovery Pill Crusher Tap Water 66 59 7 EZ-SWALLOW Pill Crusher D-Water 76 72 4 ACU-MED Tablet-Mortar D-Water 68 65 3 Pill Crusher D-Water 70 67 3 EZ-SWALLOW Two Spoons Tap Water 77 69 8 (Crushed 4 times) Two Spoons Tap Water 74 66 8 (Crushed 8 times) Two Spoons D-Water 76 69 7 (Crushed 4 times) Two Spoons D-Water 79 76 3 (Crushed 8 times) *Average of 3 replicates

[0133] The results are also presented in FIGS. 3 and 4.

Test Results “Simple Extraction” Using Example 1

[0134]

TABLE-US-00007 Temperature/ PH (Test - % recovery % recovery Δ % Solvent Time Stirring/Time solution) Oxycodone* Naloxone* points D-Water RT 15 min 6.9 68 69 1 D-Water RT 120 min 6.9 98 99 1 D-Water 50° C./5 min 15 min 7.0 84 84 0 D-Water 50° C./5 min 120 min 7.0 99 100 1 D-Water 75° C./5 min 15 min 7.2 98 97 1 D-Water 75° C./5 min 120 min 7.0 98 98 0 D-Water 100° C./5 min  15 min 7.2 98 95 3 D-Water 100° C./5 min  120 min 7.2 99 96 3 HCl 2N RT 15 min not 75 75 0 measurable HCl 2N RT 120 min not 98 100 2 measurable Ethanol 40% RT 15 min 6.6 58 58 0 Ethanol 40% RT 120 min 6.6 100 99 1 CH.sub.3COOH 2N RT 15 min 2.1 78 79 1 CH.sub.3COOH 2N RT 120 min 2.1 100 102 2 NaOH 2N RT 15 min 13.8 12 76 64 NaOH 2N RT 120 min 13.8 12 77 65 NaOH 1N RT 15 min 13.7 9 52 53 NaOH 1N RT 120 min 13.7 12 68 56 NaOH 0.5N RT 15 min 13.5 8 51 43 NaOH 0.5N RT 120 min 13.5 12 71 59 NaOH 0.1N RT 15 min 13.0 15 43 28 NaOH 0.1N RT 120 min 12.9 20 67 47 *Average of 3 replicates

[0135] The results are also presented in FIGS. 5 to 7.

Test Results “Simple Extraction” Using Example 2

[0136]

TABLE-US-00008 Temperature/ PH (Test- % recovery % recovery Δ % Solvent Time Stirring/Time solution) Oxycodone* Naloxone* points D-Water RT 15 min 6.7 82 83 1 D-Water RT 120 min 6.7 96 96 0 D-Water 50° C./5 min 15 min 6.7 90 90 0 D-Water 50° C./5 min 120 min 6.6 98 98 0 D-Water 75° C./5 min 15 min 6.9 97 95 2 D-Water 75° C./5 min 120 min 6.9 99 97 2 D-Water 100° C./5 min  15 min 7.0 98 95 3 D-Water 100° C./5 min  120 min 7.1 98 95 3 HCl 2N RT 15 min not 65 65 0 measurable HCl 2N RT 120 min not 98 99 1 measurable Ethanol 40% RT 15 min 6.6 79 80 1 Ethanol 40% RT 120 min 6.6 97 98 1 CH.sub.3COOH 2N RT 15 min 2.1 84 84 0 CH.sub.3COOH 2N RT 120 min 2.1 99 99 0 NaOH 2N RT 15 min 13.8 4 53 49 NaOH 2N RT 120 min 13.8 4 63 59 NaOH 1N RT 15 min 13.7 6 60 54 NaOH 1N RT 120 min 13.7 6 85 79 NaOH 0.5N RT 15 min 13.4 6 54 48 NaOH 0.5N RT 120 min 13.4 6 83 77 NaOH 0.1N RT 15 min 12.8 9 46 87 NaOH 0.1N RT 120 min 12.7 10 76 66 *Average of 3 replicates

[0137] The results are also presented in FIGS. 8 to 10.

Test Results “Additional Test”

[0138]

TABLE-US-00009 Intact Dosage PH % recovery % recovery Δ % Form (Test-Solution) Oxycodone* Naloxone* points Example 1 6.8 99 90 9 Example 2 6.9 96 94 4 *Average of 3 replicates

[0139] The results are also presented in FIG. 11.

[0140] The results of all experiments confirm that typical street abuse i.e. separation of the oxycodone from the naloxone from the oxycodone/naloxone tablets is not possible. The difference in the relative amount of oxycodone and naloxone extracted by the test based on the amount present in the extracted tablets (A % points) is small in cases where a larger relative amount of oxycodone is extracted.

[0141] It is not possible to separate the components oxycodone and naloxone from each other by simple extraction and/or different crushing methods.

[0142] The recovery rate of both substances is comparable in all experiments, except simple extraction in basic media. In these experiments, it can be observed, that the concentration of extracted oxycodone is significantly lower than naloxone. After filtration, the remaining mass isn't usable for any conventional abuse activities. It also contains the tablet matrix and oxycodone is soaked with strong caustic. A purification procedure would probably not be practicable on the street, because this would depend on the ability to carry out an advanced extraction.