Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

• composition comprising an opioid agonist and an opioid antagonist prepared by melt granulation using lipid esters
• the present invention pertains to new pharmaceutical formulations containing an opioid agonist and an opioid antagonist, such as oxycodone and naloxone or any pharmaceutically acceptable salts and/or hydrates or solvates thereof.
• an opioid agonist and an opioid antagonist such as oxycodone and naloxone or any pharmaceutically acceptable salts and/or hydrates or solvates thereof.
• the present invention provides pharmaceutical formulations containing these active ingredients, which are sustained release formulations exhibiting excellent release properties and have abuse deterrent properties.
• the present invention further provides methods for making the same.
• WO 03/084520 A2 and WO 03/084504 A2 teach pharmaceutical formulations, which are said to release the two active compounds from a non-swellable diffusion matrix in a sustained, invariant and independent manner.
• matrices comprise polymers based on ethylcellulose and at least one fatty alcohol, preferably stearyl alcohol, as the components that essentially influence the release characteristics of the matrix.
• Fatty alcohols do not regularly occur in human body. They can originate from natural or synthetic sources, but are not of human origin.
• EP2277521 discloses an oral dosage form comprising an opioid agonist and an opioid antagonist which is dispersed in a matrix comprising one or more hydrophobic material. Said matrix renders the antagonist substantially non-releasable when the dosage form is administered orally intact while in EP2283842 the opioid antagonist is in a substantially non- releasable form by coating the particles with a coating that substantially prevents release of the antagonist.
• WO2002092060 discloses a controlled release tablet comprising an opioid agonist in a controlled release matrix and an opioid antagonist having an orakparenteral potency ratio > 1 contained in a controlled release matrix; wherein ammonium methacrylate polymer is present in the controlled release matrix.
• WO2003013476 and WO2003013479 disclose a controlled release oral dosage form comprising oxycodone hydrochloride and a gelling agent comprising polyethylene oxide.
• composition comprising an opioid agonist and antagonist coated with inner-acid soluble layer and an outer base-soluble layer is disclosed.
• WO2004026283 discloses a composition comprising a sequestering unit and an opioid agonist wherein opioid antagonist is over-coated with opioid agonist.
• WO2005079760 and WO2006079550 disclose the use of sparingly water permeable thermoplastic polymer or hydrophilic polymer in an opioid controlled release matrix to impart resistance to alcohol extraction of the opioid.
• WO2007085637 discloses the controlled release dosage form of oxycodone hydrochloride and naloxone hydrochloride comprising a homogenous controlled release matrix comprising a hydrophobic material and at least one fatty alcohol or fatty acid selected from C12 to C36 aliphatic alcohols or acids.
• WO2012020097 discloses the use of hydroxypropyl cellulose for the manufacturing of a prolonged release pharmaceutical composition comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof.
• the present invention provides further pharmaceutical formulations containing oxycodone and naloxone, which exhibit such favorable release profiles.
• inventive formulations are characterized in appended claims 1 and 14. Preferred embodiments thereof are described in subsequent dependent claims 2 to 9. Methods for making such formulations are also described in appended claims 10 to 13,
• Figures 1 and 2 show the release characteristics of several exemplified compositions of the present invention.
• the pharmaceutical formulation of the present invention comprises an opioid agonist and an opioid antagonist, such as oxycodone and naloxone or any pharmaceutically acceptable salts and/or hydrates or solvates thereof, one or more binder, one or more diluent, one or more lubricant, one or more flow enhancing agent and optionally other pharmaceutical acceptable excipients selected from the group but not limited to glidants, pH modifiers, antioxidants and surfactants.
• the pharmaceutical formulation of the present invention may comprise in addition to the opioid agonist and antagonist at least one other active substance.
• the pharmaceutical formulation of the present invention can be in the form of a tablet or capsule wherein they can be uncoated or coated.
• the coating is applied onto the solid pharmaceutical formulation it is composed of at least one polymer for coating and at least one further pharmaceutically acceptable excipient, which can be selected but not limited from plasticizers, anti-tacking agents, pigments and coloring agents, pore formers.
• the thickness of the coating can be in the range from 5 to 80 ⁇ , preferably 10-50 pm and most preferably 10- 40 pm.
• the coating can optionally decrease permeability for gases such as oxygen and/or for moisture. Such decreased permeability can be achieved by the use of functional polymers which in combination with selected further excipients in the coating give the desired properties of the coating.
• the melting point of substances is to be determined according to Ph.Eur. 2.2.14.
• the softening point is defined as the temperature at which the sample softens on heating but does not form a melt of low viscosity.
• Softening point can be determined according to Ph.Eur. 2.2.17 (preferably METHOD B).
• the measuring principle of softening point differs from that of the drop point in respect to the sample cup: it has an opening of 6,35 mm. Sample is loaded in a standard softening point sample cup and it should flow 20mm out of the 6,35mm sample cup opening. (Instrument Mettler Toledo FP900, FP83HT cell)
• the mean particle size of particulate substances is to be determined by laser diffraction method, using Malvern Mastersizer 2000 equipped with Hydro 2000S dispersion unit, vegetable oil (sunflower oil) is used as dispersant.
• the term “pharmaceutically acceptable salts” refers to all salts formed with organic and/or inorganic counter ions in any possible physical state including crystalline and amorphous forms of anhydrous, hydrated or solvated forms of the respective pharmaceutically active ingredient, which are safe for administration to human patients.
• all amount indications are provided on a weight basis or weight/weight basis, as appropriate. If the active pharmaceutical ingredient is used in the form of a pharmaceutically acceptable salt, the weight of the entire salt is to be considered, including the weight component of the counter ion. If the active pharmaceutical ingredient is used in the form of a solvate or hydrate, the additional weight associated with solvent or water components in the substance is to be disregarded. That is, a theoretical weight of the anhydrous pure substance (or its pharmaceutically acceptable salt and/or hydrate or solvate, if appropriate) is to be calculated and considered in connection with the present invention.
• the term taurine agonist and the term may relate to active pharmaceutical ingredients which are in a form of salts with organic and inorganic acids belonging to a group of water soluble or water freely soluble compounds as defined by European Pharmacopeia (Ph.
• Eur 3 rd Ed. i.e that 1 g of opioid agonist and/or opioid antagonist in the form of approriate salt is soluble in 10 to 30 ml of water (water soluble according European Pharmacopeia) and/or that 1 g of opioid agonist and/or opioid antagonist in the form of approriate salt is soluble in 1 to 10 ml of water (freely soluble according to European Pharmacopeia).
• hydrophilic is defined as a pharmaceutically acceptable excipient which is soluble in water at 25°C in concentration of at least 0.1 weight/vol%, preferably of at least 0.5 weight/vol% and most preferably of at least 1.0 weight/vol%, wherein volume indications refer to the volume of the formed solution. It is typically capable of forming highly viscous and sticky solutions at higher concentrations.
• hydrophobic (molten) binder is defined as a pharmaceutically acceptable excipient which is insoluble or slightly soluble in water at 25°C. This means, in accordance with USP30 NF25, that the excipient has a solubility in water at 25°C of 10 mg/mL or less. It is typically designated with melting and/or softening point in the range of 35 to 160°C, preferably 40 to 130°C, more preferably between 42 and 85°C and even more preferably between 45 and 80°C. It is specially preferred that the hydrophobic binder is selected from the up of esters with the following general formula:
• excipients used for manufacturing the pharmaceutical formulation according to present invention can be used in an "as is form" or can be mechanically pretreated in order to optimize particle size and particle size distribution by milling and/or sieving.
• the present invention provides pharmaceutical formulations containing an opioid agonist and an opioid antagonist, such as oxycodone and naloxone, which are derived from WO 03/084520 and WO 03/08440.
• opioid antagonist such as oxycodone and naloxone
• WO 03/084520 and WO 03/08440 are derived from WO 03/084520 and WO 03/08440.
• these prior art patent applications teach the use of ethylcellulose and a fatty alcohol such as stearyl alcohol as essential components of a non-swellable diffusion matrix, which gives rise to the desired release characteristics.
• the present inventors have surprisingly found that ethylcellulose and or fatty alcohol may be replaced by the alternative components without compromising the release characteristics.
• the present invention has been completed based on these findings.
• Oxycodone or a pharmaceutically acceptable salt and/or solvate or hydrate thereof is a narcotic analgesic which is used to help relieve moderate to severe pain of different origin, as for example injuries, arthritis, cancer, to treat pain after a surgical operation. It belongs to a class of drags known as narcotic (opiate) analgesics. Oxycodone or pharmaceutically acceptable salts thereof is a type of a strong opioid. It works on nervous system and brain to reduce the way a human feels pain.
• Oxycodone hydrochloride used in the pharmaceutical formulation according to the present invention may be' prepared according to any manufacturing process known from the state art such as for example WO 99/02529, WO 2004/108090, US7071336, WO 2005/097801, WO2006019364, US7153966, WO 2006/094672, WO 2006/138020, WO 2007/062184, WO 2007/103105, WO 2007/137785, WO 2007/1241 14, WO 2007/ 137785, WO 2008/070656, WO 2008/070658, WO 2008/130553, WO 2009/004491, EP 2062896B1, WO 2010/144641, WO 2011/021029, WO 2011/032214, WO 2011/034747, WO 2011/117172, WO 2011/154827, WO 2012/003468, WO 2012/14963, WO 2013/085937, WO 2013/119886, US 8846923, WO 2014/0133
• oxycodone hydrochloride used in the pharmaceutical formulation according to the present invention may have an average particle size (D [4,3] -volume distribution) less than 100 um, preferably less than 75 ⁇ and more preferably between 5 - 70 pm and/or dg 0 less than 250 ⁇ , preferably less than 200 ⁇ and more preferably between 10 and 150 um.
• D [4,3] -volume distribution average particle size (D [4,3] -volume distribution) less than 100 um, preferably less than 75 ⁇ and more preferably between 5 - 70 pm and/or dg 0 less than 250 ⁇ , preferably less than 200 ⁇ and more preferably between 10 and 150 um.
• Naloxone or pharmaceutically acceptable salt and/or solvate or hydrate thereof is an opioid antagonist that is added to the pharmaceutical formulation of the present invention to counteract opioid induced side effects, as for example constipation by blocking the action of oxycodone at opioid receptors locally in the gut, nausea, vomiting, pruritis, urinary retention, respiratory depression, physical dependence, tolerance, hyperexcitability, and hyperalgeia.
• opioid antagonists block or reverse all of the effect of opioid agonists.
• the pharmaceutical formulation according to the present invention may comprise other active ingredients suitable to be incorporated into the same formulation.
• Residue (R ' ) is a residue that may be derived from an alcohol, which can be selected from monohydroxylic alcohols, which can be selected but not limited from dodecanoic, tetradecanoic, hexadecanoic; octadecanoic or eiconoic alcohols; dihydroxylic alcohols such as ethyleneglycol or oligohydroxylic alcohols having 3 to 30, preferably 3 to 20 and most preferably 3 to 10 hydroxylic groups in their molecule such as glycerol, saccharose, sorbitan. In case dihydroxylic or oligohydrohylic alcoholic residues are used as R' total or partial esters can be used.
• Residue R' may thus include one or more hydroxyl groups and/or one or more acyl ester groups R-COO in addition to the core moiety of the alcohol. If more than one acyl ester group is present, the acyl ester groups may be the same or different from each other.
• Exemplified compounds are glycerol monostearate, glycerol distearate, glycerol palmitostearate, partial fatty acid esters of saccharose, sorbitan mono, di or tri acyl esters such as sorbitan monostearate, sorbitan dilaurate, sorbitan trilaurate or the like.
• Pharmaceutically acceptable esters used in the present invention are further characterized by having a melting or softening point below 160°C, preferably below 130°C and most preferably below 95°C.
• the pharmaceutical formulation of the present invention may comprise more than one molten binders, i.e a mixture of two or more molten binders can be used.
• the pharmaceutical formulation of the present invention is in another special aspect characterized by the use of at least one molten binder and by the absence of hydrophilic binder in said formulation,
• the weight ratio between molten binder and matrix former is advantageously selected to regulate the release kinetics and profile of active ingredient(s) from solid dosage form and the desired processability. If the content of molten binder is kept within appropriate limits, it is possible to avoid that the formulation is compromised by the stickiness during the agglomeration process and/or compression of the tablets or clogging of the sieve openings during sieving may occur. On the other hand, when the concentration of the molten binder is too low, incomplete formation of granules due to insufficient binding capacity could result on one hand and on the other hand too fast release in vivo and in vitro of incorporated active ingredients could result.
• the weight ratio between molten binder and matrix former is from 0.8 : 0.2 to 0.2 : 0.8, preferably from 0.7 : 0.3 to 0.3 : 0.7 and more preferably from 0.6 : 0.4 to 0.4 : 0.6.
• the weight ratio between glyceryl distearate and ethylcellulose is from 0.8 : 0.2 to 0.2 : 0.8, preferably from 0.7 : 0.3 to 0.3 : 0.7 and more preferably from 0.6 : 0.4 to 0.4 : 0.6.
• ethylcellulose used in the pharmaceutical formulation according to the present invention may have an average particle size (D [4,3]-volume distribution) less than 700 ⁇ , preferably less than 600 um and more preferably between 200 and 500 um and/or d o less than 1300 ⁇ , preferably less than 900 um and more preferably between 300 and 800 ⁇ .
• D [4,3]-volume distribution average particle size (D [4,3]-volume distribution) less than 700 ⁇ , preferably less than 600 um and more preferably between 200 and 500 um and/or d o less than 1300 ⁇ , preferably less than 900 um and more preferably between 300 and 800 ⁇ .
• weight ratio between molten binder and matrix former is from 0.6 : 0.4 to 0.4 : 0.6.
• oxycodone hydrochloride which has an average particle size less than 50 ⁇ and/or d90 between 10 and 150 um and/or a D [4,3]-volume distribution between 5 - 70 ⁇ and/or wherein naloxone hydrochloride dihydrate has an average particle size less than 40 ⁇ and/or d90 between 15 and 150 ⁇ and/or a D [4,3]-volume distribution between 5-50 ⁇ .
• amount indications in the above tables are to be understood as indications of absolute weight, the unit being milligrams.
• the amount of opioid agonist and opioid antagonist used in the pharmaceutical formulation for the pediatric use or for patients with severe renal and/or hepatic disfunction can be downsized below the minimal amount as for example given in the above table.
• dosages of 2.5mg, 5mg, lOmg, 15mg, 20mg, 30mg and 40mg of oxycodone hydrochloride and 1.25mg, 2.5mg, 5mg, 7.5mg, lOmg, 15mg and 20mg of naloxone hydrochloride dihydrate are available by up- or down-scaling based on the above parts-by-weight indications.
• the amount of naloxone hydrochloride dihydrate present in the pharmaceutical formulation of the present invention does not reduce the level of analgesic effect of oxycodone hydrochloride upon oral administration.
• the dosage is advantageously adjusted to the intensity of pain and the sensitivity of the individual patient.
• the pharmaceutical formulation of the present invention may be administered once, twice, three times or even more times per day, preferably once, twice or three times, more preferably twice per day.
• Solid dosage forms of the present invention preferably tablets containing oxycodone and naloxone in the form of free base or preferably pharmaceutically acceptable salts and/or hydrates or solvates thereof with organic and/or inorganic pharmaceutically acceptable acids, where salts with inorganic acids such as hydrochloric acid are preferred, can be prepared by state of the art processes that allow melting of the molten binder component, wherein processes which include granulation of at least one active ingredient are preferred. Granulation of one or both active ingredients can be performed by wet, dry or melt granulation methods, where direct mixtures or granulating methods in the absence of solvents such as dry granulation, roller compaction, melt granulation, thermoplastic granulation and melt extrusion are preferred.
• compositions of the present invention can be manufactured by means of the following processes.
• the processes of the present invention comprise the following steps:
• Step c) Filling the granules, optionally after mixing them with other excipients, into capsules or compressing the granules in tablet form.
• Step c) can include also mixing of granulate obtained under step b) with extragranular excipients to obtain a compression mixture, which is further compressed into tablets of desired weight, shape and dimensions.
• Extragranular excipients can be selected from but are not limited to lubricants, glidants, flow enhancing agents, diluents.
• the tablet weight may be 50-1 ,000 mg, preferably 75-500 mg, more preferably 100-300 mg and is adjusted by the quantity of the diluent.
• Step (a) may comprise the sub-steps of
• the above-mentioned sub-steps (ii) and (iii) are optional and may be applied as desired, depending on the particle size of the starting materials.
• the relative order of the above-mentioned mixing, grinding and/or sieving steps is not particularly limited.
• the type of mixing employed in the present invention is also not particularly limited.
• any conventionally employed method for mixing particulate compositions in the field of pharmaceutical sciences and manufacturing may be employed.
• the particles may be mixed by simple shaking in a PE bag or by using state of the art pharmaceutical mixers such as container mixers of different shape (uniconical, biconical, V-blender), turbula mixers, share mixers such as high and low share mixers, fluid bed mixers.
• the present invention is however not limited to this embodiment.
• step (b) may be carried out in an extruder, a roller compactor, in a slugging device, or in a high or low shear mixer, which allows granulation of the mixture at the selected elevated temperature.
• fluid bed granulation using a modified fluid bed apparatus can performed by either spraying of molten binder onto the fluidized powder bed or by "in situ" melt granulation of a mixture of all intragranular ingredients including at least one binder having a low melting point according to the definition of present invention in the fluidized air heated to the temperature of the melting point of such binder.
• the heat of fluidized air melts or softens the binder and the resulting melted/softened material binds the powder particles into agglomerates.
• the temperature of fluidized air is decreased allowing the granulation mass to cool down to at least room temperature.
• the obtained granulate can be optionally sieved and/or, if needed, milled to the desired particle size. It is essential to choose a granulation temperature (or peak temperature in a temperature profile), which ensures that the molten binder component actually melts or softens during granulation.
• the granulation temperature such that it does not reach temperature ranges that could lead to thermal decomposition of the components of the formulation.
• processing conditions such that the internal temperature during granulation is in the temperature range of from Tm to Tm+10°C and preferably from Tm to Tm+5°C, wherein Tm represents the melting or softening point of the molten binder component.
• the granulated (compacted) mass may be screened to yield granules of the desired particle size.
• a preferred mean particle size of the granules is from 0.05 mm to 1 mm.
• the granules obtained in step (b) may be mixed with further components such as flow enhancing agent and lubricant.
• the resultant granules or composition may then either be filled into capsules or be further compressed to yield tablets. Any conventionally used tableting method may be suitable in this connection.
• Granulate or granules of step (b) can be manufactured by any state of the art agglomeration technique and equipment capable of performing agglomeration at elevated temperatures, i.e temperatures required for melting and/or softening of hydrophobic binder.
• Suitable granulation techniques can be selected from, but are not limited to, hot melt granulation or thermoplastic granulation in high shear mixers/granulators such as those produced by Collete Grail, Glatt or similar, hot melt granulation in fluid bed granulators and/or hot melt extrusion using single screw or preferably twin screw extruders.
• molten binder is added in one embodiment of the present invention to the powder mixture comprising both active ingredients and the agglomeration of powder mixture particles, i.e. granulation is achieved by the heat produced due to friction and torque and/or external heating of the product bowl in case of high shear mixers or by heated inlet air in case of fluid bed granulators.
• agglomeration i.e granulation in case of using high shear or fluid bed granulators is achieved by spraying molten binder into the powder mixture while mixing.
• molten binder is admixed with both active ingredients and the rest o the intragranular excipients and conveyed to single or twin screw extruder, where extrudates are formed by melting or softening of molten binder by the heat formed by friction and torque and optionally by additional external heating of the extruder barrel.
• step (b) When granules of step (b) are obtained by hot melt extrusion (HME) in a special embodiment of the present invention, binding of the powder mixture which comprises both active ingredients can be performed with amorphous polymers which are softened by external heating of the extrusion barrel or by heat produced "in process” by friction and torque.
• a suitable plasticizer In order to decrease the Tg of the amorphous polymer a suitable plasticizer can be used.
• the plasticizer is preferably selected from substances having a molecular weight of less than 25,000, preferably of less than 20,000 and most preferably of less than 10,000.
• plasticizers can be used to decrease the glass transition temperature of the polymer and increase plasticity of the material.
• the plasticizer can be selected from hydrophilic and /or hydrophobic ones, whereas the hydrophobic ones are preferred according to present invention.
• Plasticizers are preferably selected from, but are not limited to, triethyl citrate (TEC), tributyl citrate (TBC), acetyl triethyl citrate (ATEC), dibutyl sebacate (DBS) diethyl phthalate (DEP), dibutyl phthalate (DBP), diesters and triesters of alcohols that are preferably selected from, but are not limited to, triacetin (TA), vegetable oils, fractioned coconut oil, acetylated monoglycerides.
• TEC triethyl citrate
• TBC tributyl citrate
• ATEC acetyl triethyl citrate
• DBS dibutyl sebacate
• DEP diethyl phthalate
• DBP dibutyl phthalate
• diesters and triesters of alcohols that are preferably selected from, but are not limited to, triacetin (TA), vegetable oils, fractioned coconut oil, acetylated
• step (b) Melt granulation using high share granulators is the preferred manufacturing process by the present invention due to its robustness and availability of the equipment.
• the granulate obtained in step (b) is further processed into single unit solid dosage forms such as capsules and/or tablets in step (c).
• the obtained tablets may be further provided with a water soluble film coating.
• Film coating is used in one aspect of the present invention for smoothing the surface of the tablet and to enable coloring them to permit easier swallowing of the tablets and better differentiation among different strengths.
• film coating is used to decrease the ability of the tablet cores to absorb moisture, i.e. to decrease the moisture permeability.
• polymers forming low moisture films are used such as polyvinyl alcohol, polymethacrylic acid derivatives e.g. as commercially available under trade names Eudragit ® E and/or Eudragit ® L, block copolymers of polyvinyl alcohol and polyethylene glycol e.g. as commercially available under trade names Kollicoat ® IR and Kollicoat ® Protect.
• opioids which are very effective in controlling pain, are frequently abused to induce euphoric states in a number of ways.
• the pharmaceutical formulations containing an opioid and being originally prepared to relief pain can be crushed, the opioid is extracted from the obtained powder and administered in very different ways, as for example parenteral, oral, nasal, smoking, swallowing, sublingual or buccal administration.
• a potential abuse and safety problem also presents alcohol-induced dose dumping of opioid drug.
• Another embodiment of the present invention is reduced risk of abusing the pharmaceutical formulation of the present invention via alternative, i.e. non-oral, use of whole, tampered and/or crushed and or dissolved present solid composition, such as parenteral, inhalation and/or transdermal use.
• the present invention is inter alia directed to sustained release formulations providing sustained release of an opioid agonist and an opioid antagonist.
• the release rate of the opioid agonist and the antagonist from the pharmaceutical formulation of the present invention is controlled to maintain an analgesically effective amount of the agonist in the blood throughout the dosing period and to maintain the concentration of the opioid antagonist throughout the dosing period sufficient for decreasing the side effects associated with the opioid agonist but not sufficient to negate the analgesic efficacy of the agonist.
• the pharmaceutical formulation of the present invention releases the opioid agonist and the antagonist at substantially proportionate rates.
• substantially proportionate is used in the context of the present specification to indicate that variation of ⁇ 20% is permissible at any point in time.
• the release rates of the opioid agonist and antagonist are approximately proportionate over time, more preferably over a dosing period.
• the pharmaceutical formulation of the present invention releases oxycodone hydrochloride between 1 -60%, preferably between 5-55%, more preferably between 10-50% and even more preferably between 20-45% after 0.5 hour and/or naloxone hydrochloride between 1 -60%, preferably between 5-55%, more preferably between 10-50% and even more preferably between 20-45% after 0.5 hour.
• the pharmaceutical formulation of the present invention releases oxycodone hydrochloride between 30-90%, preferably between 40-80%, more preferably between % and even more preferably between 50-75% after 2 hours and/or naloxone hydrochloride between 30-90%, preferably between 40-80%, more preferably between % and even more preferably between 50-75% after 2 hours.
• the pharmaceutical formulation of the present invention releases oxycodone hydrochloride between 60-100%, preferably between 65-100%, more preferably between 68-98% and even more preferably between 65-95% after 4 hours and/or naloxone hydrochloride between 60-100%, preferably between 65-100%, more preferably between 68-98% and even more preferably between 65-95% after 4 hours.
• the pharmaceutical formulation of the present invention releases not less than 75%, preferably not less than 78% and more preferably not less than 80% of oxycodone hydrochloride after 12 hours and/or the pharmaceutical formulation of the present invention releases not less than 75%, preferably not less than 78% and more preferably not less than 80% of naloxone hydrochloride after 12 hours.
• Indications of release characteristics in % characterize the released dose of the active agent (on a weight basis) in relation to the total amount of this active agent contained in the dosage form (on a weight basis).
• Dispersion medium Sunflower oil
• Sample preparation A small amount of the sample, which was taken from a representative packaging unit, is placed in a test tube. Add a few drops of sunflower oil and shake it (vortex) until homogenous dense suspension is formed. Then dilute with a few milliliters of sunflower oil and shake again.
• Dispersive air pressure lbar (or higher if the powder is cohesive)
• Particle size of oxycodone hydrochloride used in examples 8, 13 and 17 was (D [4,3]-volume distribution) 49 ⁇ and doo 102 ⁇ , and particle size of naloxone hydrochloride dihydrate was (D [4,3] -volume distribution) 31 ⁇ and ds>o o ⁇ m.
• Particle size of oxycodone hydrochloride used in examples 10, 14 and 15 was (D [4,3 J- volume distribution) 14 ⁇ and doo 33 ⁇ and particle size of naloxone hydrochloride dihydrate was (D [4,3]-volume distribution) 13 ⁇ and doo 29 ⁇ ⁇ .
• Tablet manufacture took place using the following procedure: Oxycodone hydrochloride, Ethylcellulose, Glyceryl distearate and Lactose monohydrate were homogenized in PE bag. The resulting mixture was granulated in a heated double-wall high shear mixer Collette 10. The set temperature of the heated wall was 80°C and the granulation end point was within a range of Tm ⁇ 5°C wherein Tm represents the melting or softening point of the molten binder. Granulate was sieved through Erweka mesh 18 (1.0) mm. The sieved granulate was mixed with talcum and magnesium stearate. All produced tablet cores had a mass of 137.9 mg. The cores were subsequently film coated with a polyvinyl alcohol (PVA) based film coating.
• PVA polyvinyl alcohol

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• 2015
  • 2015-07-31 EP EP15745469.5A patent/EP3174534A1/en not_active Withdrawn
  • 2015-07-31 WO PCT/EP2015/067670 patent/WO2016016431A1/en active Application Filing

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