Indian Patents. 270859:GRANULE AND ORALLY DISINTEGRATING TABLET COMPRISING OXYCODONE

Title of Invention	GRANULE AND ORALLY DISINTEGRATING TABLET COMPRISING OXYCODONE
Abstract	The present invention relates to granules comprising oxycodone, as well as to orally disintegrating tablets including same and optionally acetaminophen.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, rule 13) "GRANULE AND ORALLY DISINTEGRATING TABLET COMPRISING OXYCODONE" ETHYPHARM, of 194 Bureaux de la Colline, Batiment D, 92213 Saint Cloud Ccdcx. France. The following specification particularly describes the invention and the manner in which it is to be performed. WO 20(18/1)15220 PCT/EP2007/057912 GRANULE AND ORALLY DISINTEGRATING TABLET COMPRISING OXYCODONE 5 FIELD OF THE INVENTION The present invention relates to taste-masked granules containing oxycodone, as well as orally disintegrating tablets comprising said granules and 10 optionally acetaminophen. BACKGROUND OF THE RELATED ART Various orally disintegrating tablets are currently 15 available on the market. These tablets include a disintegrant and usually a pharmaceuticaily active ingredient ("active ingredient"} -and disintegrate or dissolve without a chewing action in less than three minutes, usually in less than 60 seconds, upon contact 20 with saliva, forming a suspension of small particles which is easy to swallow. Once easily swallowed, the particles containing the active ingredient release the same most preferably into 25 the stomach or into the upper part of the gastrointestinal tract. This type of tablet is described, for example,, in documents EF 548 356, EP 636 364, EP 1 003 48-3, EP 1 058 30 538, WO 98/46215, WO 00/06126, WO 00/27357 and WO 00/51568. WO 2008/015220 PCT/EP2007/0579I2 Orally disintegrating tablets are a convenient route for swallowing active agents since they do not require, but not exclude, absorbing water at the same time. 5 Owing to its ease of use, the orally disintegrating tablet is entirely suitable for ambulatory treatment, more particularly for certain patients and especially the elderly or young children, who have difficulties in swallowing such that they find it unpleasant, or even 10 impossible, to ingest tablets or gel capsules, even with a simultaneous intake of liquid-It is estimated that 50% cf the population experiences such difficulties, with the possible 15 consequence of the prescribed medicinal product not being taken and thus a major impact on the efficacy of the treatment (H. Seager, 1998, J. Pharm. Pharmacol. 50, 37 5-382) . 20 In the case where the active ingredient has for instance a bitter or an unpleasant taste, the small particles may consist of coated granules containing the said active ingredient, thus preventing a bad taste from developing in the mouth. Such coating can also be 25 provided ■ to prevent the active ingredient from being prematurely released in the mouth or to ensure delayed release in the stomach. A typical coating for taste-masking is an aminoalkyl methacrylate copolymer sold" by Rohm Pharma Polymers (Degussa) as EUDRAGIT'3 E 100 or EPO, 30 namely dimethyl aminoethyl methacylate copolymer, comprising a functional group with tertiary amine. WO 2008/015220 PCT/EP2007/057912 This coating is insoluble at a pH above 5.5, thus remains intact in contact with saliva but is readily soluble in gastric juice, due- to the protonation of the amine functions, thus releasing the active ingredient in 5 an immediate manner in the stomach. However, the Applicant has discovered that this copolymer is not suitable for making conventional coated granules for direct tableting from oxycodone in the form 10 of a base or a pharmaceutical^ acceptable salt such as oxycodone hydrochloride which is prescribed to relieve pain. It has been observed by "he Applicant that the 15 oxycodone content of such granules tends to decrease with time due to the degradation of oxycodone into oxidation by-products such as oxycodone N-oxide and oxymorphone. Without intending to be bound by any theory, it is believed that the nitrogen atom of the tertiary amines of 20 the dimethylaminoethyl methacrylate units of Eudragit© E100 may form hydrogen bonding with the hydrogen atom of the ammonium function of oxycodone hydrochloride, which in turn could facilitate oxidation reactions. Peroxides or other contaminants, originating from other excipients 25 or active ingredients, are also susceptible to induce oxidative degradation of oxycodone. Now, it is preferable that the final tablets retain' as much oxycodone for as long as possible under storage 30 conditions. This is both so that the efficacy of the tablet remains high, and so that the degradents and impurities produced by the breakdown of the active ingredients remain low. Specifically, it is preferable that at least about 90t WO 2008/015220 PCT/EP2007/057912 of the oxycodone, and more preferably at least about 95% of the oxycodone remain after storage for 14 days, and more preferably after 21 days at 80°C dry heat. 5 Oxycodone is for instance marketed as conventional tablets alone as an hydrochloride salt under the trademark Roxicodone®, or in combination with acetaminophen, by ENDO PHARMACEUTICALS under the trademark Percocet®. 10 However, formulating orally disintegrating tablets including both oxycodone and acetaminophen proved to be difficult, since it has been discovered that acetaminophen can promote the degradation cf an opiate 15 such as oxycodone by direct interaction especially in moist conditions or in the presence of residual humidity. It has also been observed that acetaminophen release was also slowed down when acetaminophen crystals were 20 combined with oxycodone hydrochloride in taste masked granules prepared according to US 2006/0134422, further dispersed within an orally disintegrating tablet. Thus standard methods of isolating oxycodone from acetaminophen can delay the release of the two active 25 agents and undesirably delay the onset cf pain relief to the patient. For the purposes of the present invention the expression "orally disintegrating tablets" refers to a 30 tablet which disintegrates or dissolves in the mouth in less than 60 seconds, preferably in less than 40 seconds upon contact with saliva, forming therefore small, particles which are easy to swallow. WO 2008/015220 PCT/EP2007/0579J2 The disintegration time here corresponds to the time between the moment when the tablet is placed on the tongue and the moment when the suspension resulting from 5 the disintegration or dissolution of the tablet is swallowed. Thus, there remains a need for orally disintegrating tablets in which a peroxide-sensitive active agent such 10 as oxycodone can be included without experiencing any substantial degradation, either alone or in combination with acetaminophen. Moreover, there remains a need for a means for 15 orally delivering a stable form of oxycodone to the gastrointestinal tract while avoiding premature release thereof in the mouth. In addition, it would be desirable to provide for an 20 orally disintegrating tablet comprising both oxycodone and acetaminophen while offering not only stable oxycodone, but also a good dissolution rate of acetaminophen, i.e. a release of 8 5% wt of acetaminophen from a tablet including 325 mg thereof, in less than 10 25 minutes at any pH ranging from pH 1.2 to pH 6.8 and at least 90% release of acetaminophen at 15 min. It would also be desirable to provide for an orally disintegrating tablet comprising both oxycodone and acetaminophen while having a Cnax of acetaminophen between 4.5 and 6.8 ng/mL 30 for a tablet including 10 mg oxycodone and 325 mg acetaminophen and providing for a fast dissolution rate of acetaminophen at an acidic pK, such as in the stomach. WO 20U8/U15220 PCT/EP2007/U57912 The object of this invention is thus to propose new dosage forms of oxycodone enabling to solve the above needs. 5 SUMMARY OF THE INVENTION Surprisingly, it has been discovered that the degradation of oxycodone could be prevented when oxycodone was formulated as specific coated granules 10 optionally included in an orally disintegrating tablet. Moreover, it has been discovered that oxycodone could be combined in a single orally disintegrating tablet with acetaminophen without degrading, provided that acetaminophen and oxycodone are not present in z'r.e \5 same granules. A first object of this invention thus pertains to granules comprising a neutral core coated with oxycodone or one of its pharmaceutically acceptable salts and at 20 least a binding agent, said oxycodone coating being further coated with a subcoat comprising a compound soluble in gastric fluids ; wherein said subcoat is further coated with a taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyl(meth)acryiate 25 units. A second object of this invention relates to a process for the manufacture of the above granules, wherein a suspension of oxycodone in a hydrcalcoholic 30 medium is sprayed onto neutral cores. A third object of this invention pertains to orally disintegrating tablets comprising: (a) granules WO 20U8/015220 PCT/EP2007/057912 comprising a neutral core coated with oxycodone or one of its pharmaceutically acceptable salts and at least a binding agent, said oxycodone coating being further coated with a subcoat comprising a compound soluble in 5 gastric fluid ; wherein said subcoat is further coated with a taste-masking coating comprising a polymer cr copolymer with dialkylaminoalkyl (meth)acrylate units, and (b) at least one disintegrant and at least one soluble diluent agent, wherein said disintegrant comprises 10 crospovidone. According to a fourth object, this invention also relates to orally disintegrating tablets comprising: fa) granules comprising a neutral core coated with oxycodone 15 or one of its pharmaceutical ly acceptable salts and at least a binding agent, said oxycodone coating being further coated with a subcoat comprising a compound soluble in gastric fluid ; wherein said subcoat is further coated with a taste-masking coating comprising a 20 polymer or copolymer with dialkylaminoalkyl(meth)acrylate units, (b) acetaminophen which is not included within oxycodone granules and may optionally be coated, and (c) at least one disintegrant and at least one diluent agent, wherein said disintegrant comprises crospovidone. 25 A fifth object of this invention pertains to a process for manufacturing said tablets, as. well as the tablets thus obtained. 30 This process comprises the steps of : (a) spraying onto neutral cores a suspension in a solvent of oxycodone or one of its WO 2008/U15220 PCT/EP2007/057912 pharmaceuticaly acceptable salts and at least one binding agent, so as to obtain pellets, (b) applying a subcoat onto said pellets, by spraying thereon a compound soluble in gastric fluid mixed 5 with a solvent, thus obtaining coated pellets, (c) optionally drying said coated pellets, (d) applying onto said coated pellets a taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyl(meth)acrylate units and 10 optionally a pore-forming agent, so as to obtain granules, fe) optionally applying an antistatic coating onto said granules, f f) mixing acetaminophen, optionally applied onto 15 neutral cores and/or coated, with said granules, at least one disintegrant comprising crospovidcne and at least one soluble diluent agent, so as to obtain a powder mixture, and (g) tableting said powder mixture, 20 wherein the solvent used in at least one of steps (a) and (b) is a hydroalcoholic solvent. A sixth object of this invention is directed to an 25 orally disintegrating tablet comprising acetaminophen and oxycodone as the only active ingredients, said tablet having an oxycodone content, after dry storage at 80°C for 14 days, preferably for 21 days, of at least about 90%, preferably of at least about 95%, of the initial 30 oxycodone content before storage. A seventh object of this invention pertains to the use of the aforementioned granules or tablets for the WO 2008/015220 PCT/EP2007/057912 management of breakthrough pain or more generally for the relief of moderate to severe pain and also for the manufacture of an analgesic medicament for oral administration in such use. It also pertains to a method 5 for reducing pain comprising oral administration of granules or tablets as described above. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 10 Oxycodone can be used as such or as a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salts" is intended to mean the derivatives of oxycodone in which the base compound is converted to its salt with an organic or inorganic 15 acid, examples of which comprise acetic, ascorbic, benzenesulfonic, benzoic, boric, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, glutaric, glycerophosphoric, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic, maleic, malic, malonic, mandelic, 20 methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, salicylic, succinic, sulphuric, tartaric, terephthalic, p-toluenesulfonic acid, and the like. 25 Preferred oxycodone salts are oxycodone hydrochloride and oxycodone terephthalate. In the following, "oxycodone" will be used indifferently for oxycodone or pharmaceutically 30 acceptable salts thereof. The amount of oxycodone or its salt may range from about 1% t:o 50%, preferably from abour 5f. to 2b% by WO 2008/015220 PCT/EP2007/057912 weight relative to the weight of the neutral core. According to a preferred embodiment/ it is possible to prepare oxycodone loaded granules of different strengths in order to accommodate the different dosage strengths of 5 the final tablets. Actually, in a preferred embodiment low strength granules containing about 5% to about 6% by weight of oxycodone (relative to the total weight of the drug loaded granules) may be used to prepare 2.5 mg and 5 mg dosage units and high strength granules containing 10 about 10% to about 12% of oxycodone (relative to the total weight of the drug loaded granules) may be used to prepare 7.5 mg and 10 mg dosage units. In this way, the tablet strength may be varied without making the tablet unpalatably large. 15 The granules according to this invention comprise a first layer comprising oxycodone which is applied onto neutral cores. 20 The neutral core may comprise any chemically and pharmaceutically inert excipient, existing in particle form, either crystalline or amorphous, for example sugars or sugar derivatives such as lactose, sucrose, hydrolyzed starch (maltodextrins), celluloses such as 25 microcrystalline cellulose, or mixtures thereof such as sucrose and starch; or mixtures thereof with a cellulose base. The oxycodone coating may be applied by spraying a 30 suspension or solution of oxycodone onto neutral cores, preferably in a fluidized-air coating device. Preferably, oxycodone will be used as a suspension in a hydroalcoholic medium. It has indeed been observed that WO 2008/015220 PCT/EP20U7/057912 using a hydroalcoholic medium instead of an aqueous medium provided for greater stability of the oxycodone. The hydroalcoholic medium advantageously comprises water and ethanol, for instance in a ratio of ethanol to water 5 ranging from t about 60:40 to about 92:8 and more preferably of about 75:25 to about 85:15. The present inventors have discovered that this solvent reduced oxycodone degradation, as evidenced by 10 the following Examples. The oxycodone layer also comprises a binding agent or binder. Said binder is conventionally used in proportions that can range up to 95% by weight relative 15 to the dry weight of the coating, preferably up to 50% by weight relative to the dry weight of the oxycodone coating. Its function is to bind the active ingredient and 20 other optional pharmaceutical excipients to the neutral core without loss, of material, thus forming a homogeneous layer of pharmaceutically active ingredient, evenly distributed around the neutral core. 25 The binder can be chosen from the group consisting of cellulose-based polymers, such as hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose; acrylic polymers; polyvinyl alcohols; alginic acid or sodium alginate ; starch or 30 pregelatinized starch; sucrose and derivatives thereof; guar gum; polyethylene glycols, and mixtures and copolymers thereof, for instance a graft copolymer of WO 2008/015220 PCT/EP2007/057912 polyvinyl alcohol and polyethylene glycol, such as sold by BASF under trade name ROLL I COAT IR. Hydroxypropylmethylcellulose (also referred to as 5 "HPMC" hereunder) is the preferred binder according to this invention. It can preferably be chosen from those for which the apparent viscosity (aqueous solution at 2% m/m, at 20 °C, USP method) is between 2.4 and 18 mPa-s, and even more preferably between 2.4 and 5 mPa-s. 10 The binder, when dissolved in a hydroalccholic solvent, is advantageously present in a proportion that can range up to 90%, preferably of between 5% and 60% and more preferably of about 50% by weight relative to the 15 weight of oxycodone. Moreover, the first (oxycodone) layer may also comprise one or more pharmaceutically acceptable excipients, apart from the binding agent. 20 The pharmaceutically acceptable excipients optionally present may be chosen from surfactants, antistatic agents, lubricants, and mixtures thereof. 25 The surfactant, which is optionally present in the oxycodone coating, can be chosen from cationic, anionic, nonionic or amphoteric agents, alone or as a mixture. The surfactant can be chosen, for example, from 30 compounds such as sodium iauryl sulphate, the monooleate, the monoiaurate, the monopaimitate, the monostearate, the trioleate, the tristearate or any other ester of pclyoxysthyler.ated sorbitan, preferably Tween® 20, 40, WO 2U08/015220 PCT/EP2007/057912 60 or 80, glycerides of polyoxyethylenated fatty acids, these fatty acids being saturated or unsaturated and composed of at least 8 carbon atoms, poloxamers, such as poloxamer 188, ethylene oxide/propylene oxide block 5 copolymers, such as Pluronic® F68 or F87, lecithin, stearyl alcohol, cetearyl alcohol, cholesterol, polyoxyethylenated castor oil, fatty alcohol polyoxyethylenated ethers, such as the Brij® products, and polyoxyethylenated stearates. 10 The surfactant is advantageously present in a proportion that can range up to 20%, preferably of between 0.1 and 20% by weight relative to the total dry-weight of the coating. 15 The antistatic agent can be used in a proportion that can range up to 10% by weight, relative to the dry weight of the coating applied around the neutral core. The antistatic agent may be chosen from the group 20 consisting of: colloidal silica and preferably precipitated silica, micronized or non-micronized talc, and mixtures thereof. The lubricant may be selected from the group 25 comprising magnesium, zinc, and calcium stearate, stearic acid, talc, pyrogenic silica, hydrogenated vegetable oils, sodium stearylfumarate, micronized polyoxyethylene glycol (micronized Macrogol 6000), leucine, sodium benzoate, and mixtures thereof. 30 As mentioned above, in the granules according to this invention, the first layer comprising oxycodone is further coated by a separating layer (also referred to as WO 2008/U15220 PCT/EP2007/OS7912 "subcoat") between the coating layer comprising oxycodone and the taste-masking polymeric layer, wherein said subcoat comprises at least a compound soluble in gastric fluid, i.e. in highly acidic conditions {pH comprised 5 between 1 and 2), preferably a polymer which can be chosen among the binding polymers or copolymers mentioned above. An example of a copolymer that can be used in the subcoat ' is a graft copolymer of polyvinyl alcohol and polyethylene glycol, such as sold by BASF under the trade 10 name KOLLICOAT0 IR. A preferred polymer is hydroxypropylmethylcellulose. The polymer or copolymer, included within the subcoat, acts as a separating layer in order to avoid direct contact between the oxycodone layer and the taste-masking polymer, and dissolves 15 rapidly without altering oxycodone release. The subcoat layer may also comprise an antistatic agent such as those listed previously. The subcoat is advantageously present in a 20 proportion that can range up to 50%, preferably of between 5% and 30% by weight relative to the weight of oxycodone coated cores. The subcoat can be applied by conventional means, 25 such as in a fluidized-air coating device, by spraying a solution or a dispersion of binder in an aqueous or preferably in a hydroalcoholic medium onto the cores coated with oxycodone. The hydroalcoholic medium advantageously comprises water and ethanol, for instance 30 in a ratio of ethanol to water ranging from about 60:40 to about 92:8 and more preferably of about 85:15. WO 2008/015220 PCT/EP2007/057912 This subcoat is itself coated by a taste-masking coating layer comprising a polymer or copolymer comprising dialkylaminoalkyl(meth)acrylate units, such as dimethylaminoethyl methacrylate units. This polymer can 5 be, for instance, a copolymer of dimethylaminoethyl methacrylate, methylmethacrylate and n-butyl methacrylate, such as the copolymer sold by ROHM PHARMA under the trade names EUDRAGIT0 E100 and EPO. 10 The taste-masking coating preferably further includes a pore-forming agent which can be a hydrophilic polymer soluble in gastric fluids, such as hydroxypropylmethylcellulose or other polymers used as binders such as polyvinylpyrrolidone, polyvinylalcohoi, 15 poiyethyleneglyccls, or a soluble agent, preferably chosen from the group of sugars such as sucrose, lactose or dextrose, of polyols such as mannitol, sorbitol or lactitol, or of organic acids and their salts such as citric acid, tartaric acid, succinic acid, or else of 20 inorganic salts such as sodium chloride. A preferred pcre-forming agent is hydroxypropylmethylcellulose. The pore-forming agent, which is optionally present in the taste-masking coating, can be used in a proportion 25 that can range up to 50%, preferably of between 5% and 30% by weight relative to the total dry weight of the taste-masking coating ingredients. It has indeed been shown that the provision of this 30 pore-forming agent within the taste-masking coating improved the release rate of oxycodone from the granule at a pH equal or greater than pH 5.5 such as in the intestine, by increasing the permeability of the taste- WO 2008/015220 PCT/EP2007/057912 masking film coating and thus preventing the slowing down of oxycodone release when the granules directly pass into the intestine, which may undesirably occur when the patient ingesting the granule has a fast digestion and/or 5 is stressed. The amount of pore-forming agent in the taste-masking coating and the total amount of taste-masking coating relative to the total weight of the oxycodone 10 granule with its subcoat have to be chosen so as to provide taste-masking effectiveness during the short period of time in the saliva and to ensure, following the swallowing of the granules, fas~ dissolving in pH ranging from pH 1.2 to pH 6. S. The ratio of the taste-masking 15 coating to the total dry weight of ingredients comprising the oxycodone granule with its subcoat ranges from about 10:90 to about 50:50 and more preferably of about 20:80 (or 25%). 20 The taste-masking layer may also comprise an antistatic agent, such as those listed above. The granules according to this invention can-advantageously be used in the manufacture of orally 25 disintegrating tablets. To this end, the granules described above can be mixed with at least one disintegrant and at least one soluble diluent agent preferably having binding 30 properties and then directly compressed so as to form tablets. WO 2008/015220 PCT/EP2007/057912 The compression force is adjusted so as to obtain a friability, measured according to the method of the European Pharmacopoeia, of less than 2%w/w and preferably less than 1.5%w/w, and so as to allow a disintegration 5 time of the tablet in the mouth under the action of saliva of less than or equal to 60 seconds and preferably less than or equal to 40 seconds. Hardness is preferably comprised between 10 and 10 180 N, preferably between 15 and 100 N and more preferably between 50 and 80 N, measured according to the method of the European Pharmacopoeia (2.9.8). The present invention thus also pertains to orally 15 disintegrating tablets comprising: (a) granules comprising a neutral core coated with oxycodone or one of its pharmaceutically acceptable salts and at least a binding agent, said oxycodone coating being further coated with a subcoat comprising a compound soluble in 20 gastric fluid ; wherein said subcoat is further coated with a taste-masking coating comprising a polymer Gr copolymer with dialkylaminoalkyl(meth)acrylate units, and (b) at least one disintegrant and at least one soluble diluent preferably having binding properties, wherein 25 said disintegrant comprises crospovidone. The above tablets can include, for instance, from 1 to 20 mg oxycodone hydrochloride, preferably from 2.5 to 10 mg oxycodone hydrochloride, per tablet. 30 The disintegrating agent may further comprise crosslinked sodium carboxymethylceilulose, which is WO 2008/015220 PCT/EP2007/057912 referred to as croscarmellose. The preferred disintegrant is crospovidone alone. Usually, the disintegrant represents from 1 to 15%, 5 and preferably from 2 to 10% and the soluble diluent agent represents from 20 to 8 0%, and preferably from 25 to 40% of the total weight of the tablet. The soluble diluent agent may be a polyol having 10 less than 13 carbon atoms and being present either in the form of a directly compressible product with an average particle size from 100 to 500 um, or in the form of a pcwder with an average particle size of less than 100 urn, or mixtures thereof. 15 In a preferred embodiment, said polyol is selected from the group consisting of mannitol, xylitol, sorbitol, and maltitol. In the case where there is only one soluble diluent agent, it is used in the form of a directly 20 compressible product, whereas, in the case where there are at least two soluble diluent agents, one is present in a directly compressible form and the other in a powder fcrm, it then being possible for the polyol to be the same, the ratio of directly compressible polyol and of 25 powdered polyol being 99:1 to 20:80, preferably 80:20 to 20:80. Preferably, the soluble diluent agent with binding properties is a mixture of mannitol in the form of a 30 powder with an average particle size of less than 100 urn, preferably Mannitol 60 and directly compressible mannitol with an average particle size from 100 to 500 [im, such as Mannitol 300. WO 2008/015220 PCT/EP2007/057912 It has been observed that crospovidone had a stabilizing effect on the degradation of oxycodone when the orally disintegrating tablets are stored under dry 5 atmosphere. The tablets according to this embodiment of the invention are thus preferably packaged in sealed containers such as blisters. In addition, they can advantageously include an anti-oxidant agent so as to better protect oxycodone from degradation which could 10 occur under moist conditions as a result of crospovidone degradation. Examples of saleable anti-cxidancs include ascorbic acid and its salts and esters, such as sodium ascorbate 15 and ascorbyl paimitate ; tocopherol and its esters such as tocopherol acetate ; and mixtures thereof. Usually, the anti-oxidant is present from 0.2 to 1 wt% relative to the total weight: of the tablet. It can 20 also be expressed as a ratio to the crospovidone used. In this regard, it is preferred that the anti-oxidant represents from 1 to 5 % of the weight of the crospovidone used. 25 In- particular, it has been found that ascorbyl paimitate efficiently prevented degradation of crospovidone under moist conditions and thus protected oxycodone from oxidation. The amount of ascorbyl paimitate that can be included in the tablets according 30 to this invention can range from C.2 to 1 % w/w relative to the total weight of the tablet. It can also be expressed as a ratio to the crospovidone used. In this regard, it is preferred that ascorbyl paimitate WO 2008/015220 PCT/EP2007/057912 represents from 1 to 5 % of the weight of the crospovidone used. The orally disintegrating tablet can also include 5 various additives such as a lubricant, a swelling agent, a permeabilizing agent, a sweetener, a flavouring agent, a colorant and their mixtures. The lubricant may be selected from those listed 10 previously. The amount of lubricant may range from 0.2 to 2 % (weight of lubricant/total weight of the tablet), preferably frem 0.5 to 1.5%. The lubricant can be 15 dispersed within the powder bed compressed into a tablet or, according to an advantageous embodiment, the totality of the lubricant can be dispersed on the surface of the tablet. 20 The swelling agent may be selected from the group comprising native and modified starches. The permeabilizing agent may be selected from the group comprising precipitated silica, maltodextrins, 25 beta-cyclodextrin, and mixtures thereof. The permeabilizing agent allows the creation of a hydrophilic network which facilitates the penetration of saliva and hence contributes to better disintegration of the tablet. The proportion of permeabilizing agent relative to the 30 weight of the tablet is preferably from 0.53 to 5% by weight. WO 2008/015220 PCT/EP2007/057912 The sweetener may be selected from the group comprising in particular aspartame, acesulfam potassium, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures 5 thereof. The flavouring agents and colorants are those conventionally used in pharmacy for the preparation of tablets. 10 These excipients will usually amount to less than 10 weight percent relative to the total weight of the tablet, preferably from 0.1 to 5 %, even more.preferably from C.2 to 4.5%. 15 Moreover, it has been found that acetaminophen could be included within said tablets, provided that it is separated from the above-described granules coated with oxycodone. In this way, both active ingredients can be 20 included in the same tablet while avoiding incompatibility problems between them. This invention thus also relates to orally disintegrating tablets comprising: (a) granules 25 comprising a neutral core coated with oxycodone or one of its pharmaceutical^ acceptable salts and at least a binder, said oxycodone coating being further, coated with a subcoat comprising a compound soluble in gastric fluid ; wherein said subcoat is further coated with a 30 taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyi(meth)acrylate units, (b) acetaminophen which is not included within said granules, and (c) at least one disintegrant and at least one WO 2008/015220 PCT/EP2007/057912 diluent, wherein said disintegrant comprises ccospovidone. In a preferred embodiment, the oxycodone and 5 acetaminophen tablet further comprises an anti-oxidant. Suitable anti-oxidants are those described above, whereby ascorbyl palmitate is preferred. The amounts of anti¬oxidant and in particular ascorbyl palmitate are those described above. 10 Acetaminophen can be provided as crystals or as granules wherein acetaminophen can be coated with a taste-masking coating. The excipients included within this taste-masking coating can be the same as listed 15 above. In this case, the taste-masking coating of the oxycodone granules and the taste-masking coating of the acetaminophen granules can be the same or different. In a preferred embodiment, the crystals of 20 acetaminophen are granulated with a binder and the obtained granules are coated with taste-masking coating. In a most preferred embodiment, the crystals cf acetaminophen are directly coated with a taste-masking 25 coating. The tablet can include, for instance, from 1 to 20 mg oxycodone, preferably from 2.5 to 10 mg oxycodone, per tablet. 30 The above-mentioned tablets car. contain from 30 to 750 mg acetaminophen, per tablet. WO 2008/U1522(> PCT/EP2007/057912 The1 tablet may further include the same additives as those d£scribed in relation with the acetaminophen-free tablet ^escribed above S The table according to the invention disintegrate in the mouth upon contact with saliva in less than 60 seconds, preferably in less than 40 seconds, forming a suspensi°n which is easy to swallow. JO Thse tablets, as well as the granules described previously/ can be used in the relief of moderate to severe pain, such as in the management of breakthrough pain, in particular breakthrough cancer pain, by oral administration. Ereakthrough pain means a transitory 15 flare of pain of moderate to severe intensity occurring en a ba£kground of otherwise controlled pain. Granules may for instance be administered as such, packaaed i-n pouches, or in the form of capsules. 20 Th0 invention will be understood more clearly from the foli°wing Examples which are not intended to restrict in any vay the scope of this invention. 25 EXAMPLES Example JL: Preparation of granules entrapping oxycodone Neutral cores were introduced into a fluid bed processor and 30 a suspension of oxycodone hydrochloride, hydroxypropylmethyl cellulose (HPMC) as a binder in a solvent of water and ethanol was sprayed on the neutral ceres. The composition of oxycodone pellets is given in Table 1 for Low and Hi WO 2008/015220 PCT/EP2007/0579I2 strengths. The oxycodone amount entrapped in the Hi and Low strength pellets is of about 11.55% and 5.78% by weight respectively. A subcoat was then applied to the oxycodone pellets. The subcoat contained HPMC and silicon dioxide (as 5 an antistatic) in a water/ethanol solvent as shown in Table 2 (the composition is the same whatever the strength) . After drying, the granules were again introduced to the fluid bed processor and coated with a taste-masking coating of Eudragit® E100 acrylic polymer, HPMC and silicon dioxide in a 10 water/ethanol solvent as shown in Table 3 (the composition is the same whatever the strength) . In a last step, before discharging the taste-masked oxycodone granules, an antistatic solution composed of a suspension of silicon dioxide in ethane1 is sprayed into the fluid bed processor. 15 The composition is given in table 4. The oxycodone amount entrapped in the final granules is of about 3.8% and 7.7% by weight for the Low and Hi strength granules respectively. Table 1 20 Composition of oxycodone hydrochloride pellets MATERIALS 2.5/ 5 MG STRENGTHS (LS) 7,5/10 MG STRENGTHS (HS) % TOTAL WEIGHT (KG) % TOTAL WEIGHT (KG) Neutral cores 91.33 15.20 82.67 13.76 LAYERING SOLUTION Oxycodone 5.78 0.96 11.55 1.92 HPMC 2.89 0.48 5.78 0.96 Water n/a 2.93* n/a* 5.86* Ethancl n/a* 10.63* n/a* 21.26* Total (dry) 100.00 16.64 100.00 16.64 solvent removed during process WO 2008/015220 PCT/EP2007/OS7912 Table 2 Composition of oxycodone pellets coated with a subcoat MATERIALS 2.5 - 10 MG STRENGTHS % TOTAL WEIGHT (KG) Oxycodone pellets 83.5 16.64 SUBCOATING SOLUTION HPMC 15.0 3.00 Syloid F244P 1.5 0.30 Water n/a 4.05* Ethanol n/a* 22.95. Total (dry) 100.00 19.94 5 ""solvent removed during process Table 3 Excipients used in the taske-masking coating 10 MATERIALS 2.5 - 10 MG STRENGTHS % TOTAL WEIGHT (KG) Oxycodone granules 79.74 19.94 COATING SOLUTION Eudragit E100 14.74 3.69 HPMC 3.68 0.92 Syloid F244P 1.84 0.41 Water n/a 14.19* Ethanol n/a* 21.28* Total 100.00 24.96 solvent removed during process WO 2U08/U15220 PCT7EP2007/057912 Table 4 Excipients used in the antistatic suspension applied on the taste-masked oxycodone granules MATERIALS 2.5 - 10 MG STRENGTHS % TOTAL WEIGHT (KG) Taste-masked oxycodone granules 99.80 24.96 ANTISTATIC SOLUTION Syloid F244P 0.20 0.05 Ethanol n/a 0.83* Total 100.00 25.01 solvent removed during process Example 2: Preparation of orally disintegrating tablets Acetaminophen (APAP) crystals were introduced into a fluid bed processor and a suspension containing Eudragit3 ElOO acrylic polymer, Eudragitra NE30D acrylic polymer, and silicon dioxide in ethanol was sprayed on the APAP. The total amount of coating represents 6% in weight relative to the initial weight of APAP crystals. The coated APAP crystals were mixed with the oxyccdone-coated neutral cores from Example 1 and with excipients, as listed in the table below, and tableted in accordance with standard tableting procedures for making orally disintegrating tablets. A Sviac 6 stations press was used with the following parameters (table 5}. Table 6 presents the recommended specifications tor tablet, characteristics. WO 2008/015220 PCT/EP2007/057912 Table .5 Example of press setting for a Sviac PR-6 PARAMETERS VALUE Turret speed 25 rpm Feed frame speed 10 rpm Punch diameter 15 mm Table 6 Recommended specifications for tablet physical characteristics 10 PARAMETERS TARGET RANGE Tablet, weight 1050 mg USP Tablet hardness 65 N 50-80 N Tablet thickness 5.60 mm 5.50-5.75 mm Friability NMT 1.5% Release NMT 1.5% Stability NMT 2% Disintegration time in mouth NMT 30 s NMT 45 s Water content NMT 2.0% Release NMT 2.0% Stability NMT 3.0% The composition of the compressed tablets is shown in the following Table 7. WO 2008/015220 PCT/EP2007/057912 Table 7 Composition of orally disintegrating tablets containing taste-masked oxycodone granules and taste-masked APAP 5 granules Materials % Coated oxycodone pellets 9.51 Coated APAP crystals (6% coating) 32.85 Mannitol 60 14.22 Mannitol 300 14.22 Macrocrystalline cellulose PH102 Crospovidone CL Sucralose Prosweet 10.00 15.00 1.00 0.38 Peppermint flavor 0.75 Silicon Dioxide 244 FP 0.50 Sodium Stearyl Fumarate 1.50 Red #40 aluminium lake 0.07 Total 100.00 Example 3 (comparative) : Preparation of granules coanprising oxycodone and acetaminophen 10 APAP crystals and silicon dioxide were introduced into a fluidized air bed installation and a layering solution of oxycodone dissolved in a solution of HPMC in water was sprayed thereon. The coated crystals were then reintroduced 15 into a fluidized bed coater and overcoated using a coating suspension of Eudragit0 E100 acrylic polymer in 95% ethanol with silica. The resulting coated granules were then dried. The composition of APAP granules coated with oxycodone and further coated with the taste-masking coating (for a final 20 strength of 325 mg / 2.5 me) is given in Table 8. WO 2008/015220 PCT/EP2007/057912 Table 8 Composition of APAP/oxycodone taste-masked granules r Materials % j Acetaminophen 82.33 Silicon Dioxide 244 FP 0.25 OXYCODONE LAYERING SOLUTION HPHC 0.28 Oxycodone HCl 0.63 Purified water n/a COATING SOLUTION Eudragit E100 Silicon Dioxide 244 FP Ethanol 15.0 1.51 n/a* 5 ^solvent removed during process Example 4 (comparative) : Preparation of orally disintegrating tablets 10 The granules obtained in Example 3 were blended with aspartame, peppermint, colorant, mannitol, crospovidone, microcrystalline cellulose and silica. The blend was then compressed into an orally disintegrating tablet according to conventional tabletting processes. The composition of the 15 tablets is summarized in Table 9 below. WO 20U8/U15220 PCT/EP2007/057912 Table 9 Table Composition 2.5 rag Oxycodone HC1/325 mg AFAF 10 mg Oxycodone HC1/32S mg APAP Weight (mg/tablet) Weight (mg/tablet) Granules Acetaminophen 325.0 325.0 Oxycodone HCl 2.5 10.0 HPMC 1.1 4.3 Eudragit E100 59.2 60.9 Silicon dioxide E~hyi alcohol Purified wa:sr Tableting excipients 12.2 QO QD 12.2 QD QD Mannitol 399.8 387.5 105.0 105.0 21.0 13.1 Crospovidone CL 105.0 Macrocrystalline ce llulose 1 105.0 Aspartame powder 21.0 Magnesium stearate 13.1 Peppermint 5.3 5.3 Colorant 0.7 0.7 Total Tablet Weight (mg) 1050 1050 5 Example 5: Assessment of the dissolution rate of acetaminophen and oxycodone The tablets produced according to Example 2 (invention) and A (comparative) were tested for their dissolution properties at 10 a pH near the pH of the saliva. Dissolution using USP type 2 (paddle) dissolution apparatus at 100 rpm yielded the results shown in Tables 10 and 11 below, for acetaminophen and oxycodone respectively. WO 2008/015220 PCT/EP2007/057912 Table 10 Dissolution (%) of acetaminophen Time (mn) Example 2 pH 6.8 Example 4 pH 6.8 2.5 7.5 15 56 89 8.3 20.8 94 58.3 30 98 93.75 As may be seen from this Table, the dissolution of tablets made in accordance with this invention was much faster than with the comparative tablets. 10 15 Moreover, the Cruax of acetaminophen in the comparative tablets of Example 2 was 4. 4 ng/mL for the tablets containing 2.5 mg oxycodone and 4.0 ng/mL for the tablets comprising 10 mg oxycodone. At pH 1-2 {close to that of gastric juices!, it took 27 min to release 85% of APAP in the tablets containing 2.5 mg oxycodone and 12.9 min in the tablets containing 10 mg oxycodone. This slow dissolution rate of APAP is expected to result in too slow an absorption rate of this drug. Table 11 20 Dissolution (%) of oxycodone Time (mn) Example 2 pH 6.8 Example 4 pH 6.8 0 0 0 5 10 15 30 97 100 100 100 33 74 81 90 WO 2008/015220 PCT/EP2007/057912 This table shows that the addition of a pore-forming agent in the taste-masking coating of oxycodone granules results in a significant increase in the dissolution rate of oxycodone, 5 especially at a pH greater than 5.5 such as pH 6.8. The addition of the pore-forming agent provides oxycodone taste-masked granules with pH-independent drug release profiles. Example 6: Assessment of the stability of oxycodone -10 Comparison with oxycodone coated acetaminophen crystals Acetaminophen crystals were introduced into a fluid bed processor and a suspension of oxycodone, h ydrcxypropy line thy 1 cellulose (HPMC) as a binder and a solvent cf water and 15 ethanol was sprayed on the crystals. The granules were prepared by using a Mini-Glatt equipment with 100 g of support and a layering duration of 30 min at 25°C. The solvent contained 4 g water and 40.5 g ethanol. The composition and process parameters mentioned in Table 11 20 below were used. The above procedure is repeated using neutral cores instead of acetaminophen crystals. The composition and process parameters mentioned in Table 12 below were used. 25 Table 12 Compositions tested Excipients Composition A {% dry) Composition B (% dry) APA? crystals Neutral cores Oxycodone HPMC 603 98.91% 0 0.761 0.33% G 98.91* 0.761 C.33% WO 2008/015220 PCT/EP2007/057912 The granules thus obtained were stored in forced degradation conditions (80 °C, dry heat) and the amount of oxycodone remaining as a function of time, relative to the initial 5 content of oxycodone, was then assessed by HPLC. The results showed no significant change in the oxycodone content of Composition B after 7 days, whereas it dropped to below 95% for Composition A. Moreover, the oxycodone content 10 was also stable when granules of Composition B were prepared at 50°C using an aqueous solvent, whereas it was only around 86% for granules of Composition A prepared under the same conditions. 15 This experiment demonstrates that oxycodone is more stable when coated on neutral cores than on acetaminophen crystals. This degradation of oxycodone is thought to be due to acetaminophen, which has been shown to degrade itself when in solution. 20 Example 7: Assessment of the stability - Comparison with granules without subcoat Oxycodone coated granules were prepared as. described in 25 Example 6 composition B, except that these granules were further coated with a taste-masking coating of Eudragit® E100 acrylic polymer and silicon dioxide (Syloid .244} in ethanol. These granules will be designated hereafter as Granules' C. Their composition is given in Table 13 below. WO 2008/015220 PCT/EP2007/057912 Table 13 Composition of coated oxycodone granules without subcoat Excipients Granules C Weight (g) % Oxycodone loaded granules {3.8% w/w oxycodone) 120.00 79.74 Eudragit E100 22.18 14.74 HPMC 5.54 3.68 Syloid 244 2.77 1.84 Purified water 85.38 128.06 n/a* Ethanoi n/a* TOTAL (Dry Mat.) 150.49 100 5 solvent removed during process Similar granules were also prepared, which further contained a subcoat as described in Example 1 above, between the oxycodone coating and the taste-masking coating. These 10 granules will be designated hereafter as Granules D. Their composition is given in table 14 below. Table 14 15 Composition of oxycodone coated granules with protective subcoat WO 2008/015220 PCT/EP2007/057912 Excipients Granules D Weight (g) % Oxycodone loaded granules (3.8% w/w oxycodone) 900.00 66.6 Suspension for subcoat HPMC Syioid 244 Purified water 161.68 16.17 218.3 1237.1 12.0 1.2 n/a n/a* Ethanol Suspension for coating Eudragit £100 HPMC Syioid 244 Purified water Ethancl 199.24 49.74 24.37 766.89 14.7 3.7 i 3 n/a* 1150.28 n/a* TOTAL (Dry Mat.) 1351.7 100 solvent removed during process Granules C only contained around 80% oxycodone after 21 days 5 at 80°C, whereas Granules D still contained 95% oxycodone at that time. Moreover, tablets were prepared with Granules D as described in Example 2 (Table 15) and compared with similar tablets 10 prepared with Granules C not containing a subcoat (Table 16). Table 15 Composition of orally disintegrating tablets including 15 oxycodone granules with a subcoat WO 2008/015220 PCT/EP20U7/057912 Materials % Coated oxycodone pellets (Granules D) 7.20 Coated APAP crystals (6% coating) 26.53 Mannitol 60 18.53 Mannitol 300 18.54 Microcrystaliine cellulose PH102 10.00 Crospovidone CL 15.00 Sucralose 1.00 Prosweet 0.38 Peppermint flavor 0.75 Silicon Dioxide 244 FP 0.50 Sodium Stearyl Fumarate 1.50 Red # 40 aluminium lake 0.C7 Total 100.00 Table 16 Composition of orally disintegrating tablets containing 5 oxycodone granules without a subcoat Materials % Coated oxycodone pellets (Granules C) Coated APAP crystals (6% coating) Mannitol 60 6.28 26.53 18.99 18.99 Mannitol 300 Microcrystaliine cellulose PH102 10.00 Crospovidone CL 15.00 Sucralose 1.00 Prosweet Peppermint flavor Silicon Dioxide 244 FP Sodium Snearyl Fumarate Red 40 aluminium lake 0.38 0.75 0.50 1.5C 0.07 Total 100.00 WO 2U08/015220 PCT/EP2MI7/057yi2 After 21 days at 80°C dry heat in blister pockets, the tablets including a subcoat still contained about 952 oxycodone, whereas the comparative tablets without subcoat 5 only contained about 70% oxycodone. This experiment makes clear that acrylic polymers bearing amino side groups, such as Eudragit0 E1Q0 or EPO, tend to degrade oxycodone and that this degradation can be inhibited 10 by providing a subcoat between the oxycodone coating and the taste-masking Eudraqit'5 coating. These results were confirmed by analyzing the total impurity contends of both cypes of cablets, after 21 days. The 15 impurities referred to included mainly oxidation products of oxycodone, such as oxycodone N-oxide + oxymorphone, but not those coming from the synthesis of oxycodone. The tablets including a subcoat only contained 0.30% impurities at that time, whereas the comparative tablets without subcoat 20 contained 0.49% impurities, when stored in blisters for 3 months at 40°C / 75% RK. A similar trend was observed when the tablets were stored for 28 days in an open dish instead of being kept at 80°C dry 25 heat in blister pockets. Example 8: Assessment of the stability of oxycodone Comparison with tablets without crospovidone 30 Tablets were prepared as described in Example 2, according to the composition presented in Table 15 and compared with similar tablets which dio not contain crospovidone as oresented in Table 17 below. WO 2U08/015220 PCT/EP2007/057912 Table 17 Composition of tablets without crospovidone containing taste-masked oxycodone granules with subcoat Materials % Coated oxycodone pellets (Granules D) Coated APAP crystals (6% coating} 7.20 26.53 26.03 26.04 Mannitol 60 Mannitol 300 Microcrystalline cellulose PH102 10.00 1.00 0.38 0.75 0.50 1.50 , 0.07 Sucralose Prosweet Peppermint flavor Silicon Dioxide 244 FP Sodium Stearyl Fumarate Red # 40 aluminium lake Total 100.00 After 21 days at 8Q°C dry heat in blister pockets, the tablets, including crospcvidcne still contained around 95c oxycodone, whereas the comparative tablets only contained 10 around 50% oxycodone. This experiment makes clear that acrylic polymers bearing amino side chains, such as Eudragit E100 or EPO, tend to degrade oxycodone (which has been confirmed by binary 15 mixtures of Eudragit15 E100 with oxycodone! and that this degradation can be inhibited under dry conditions by adding crospovidone as a disintegrant in the tablets. These results were confirmed by analyzing the total impurity 20 contents cf both types of tablets, after 21 days. "The impurities referred to included mainly oxidation oroducts :: WO 2008/015220 PCT/EP2007/057912 oxycodone, such as oxycodone N-oxide + oxymorphone, but noz those coming from the synthesis cf oxycodone. The tablets including crospcvidcne only contained 0.25% impurities at that time, whereas the comparative tablets contained 7.06% 5 impurities, as measured by HPLC. Example 9: Assessment of the stability - Comparison with granules made in an aqueous medium 10 Tablets were prepared as described in Example 2 according to the formula presented in Table 15 and compared with similar tablets in which the oxycodone coating and subcoating steps had been applied onto the neutral cores in an acuecus solvent instead of a hycroalcoholic solvent. The composition cf "he 15 oxycodone taste-masked granules obtained in an aqueous solvent is given in Table 18 ; the tablet formula is provided in Table 19. Table 18 20 Composition of oxycodone taste-masked granules obtained by drug loading and subcoating water-based processes Excipients Weight (g) % Neutral cores 1000.0 64.58 Solution for drug loading Oxycodone HCl 39.9 2.58 HPMC 19.95 1.29 Purified water 455.77 n/a* Suspension for subcoat HPMC Syloid 244 Purified water 159-0 15.9 1574.1 10.27 1.03 n/a- Suspension for coating WO 2008/015220 PCT/EP2007/0579I2 Eudragit E100 228.3 14.74 HPMC 56.92 3.63 Syloid 244 28.52 1.84 Purified water 878.5 n/a* Ethane1 1317.7 n/a* TOTAL 1548.5 100 (Dry Mat.) ^solvent removed during process Table 19 Composition of orally disintegrating tablets containing 5 taste-masked oxycodone granules prepared by an aqueous process Materials % Coated oxycodone pellets (table 16ter) 7.61 Coated APAP crystals {6% coating) 26.53 Mannitol 60 18.31 Mannitol 300 18.31 Microcrystalline cellulose PH102 10.00 Crospovidone CL 15.00 Sucraiose 1.00 Prosweet 0.38 Peppermint 0.75 Silicon Dioxide 244 FP 0.50 Red # 40 0.07 Sodium Stearyl Fumarate 0.77 Lubritab 0.77 Total 100.00 After 21 days at 80 °C dry heat in blister pockets, the 10 tablets containing granules prepared with a hydroalcohclic nedi'Jm contained C. 25% total impurities as defined in WO 2008/015220 PCT/EP2007/0579I2 Examples 8 and 9, whereas the comparative tablets already included 1.11% total impurities after only 14 days. Similarly, after 3 months storage at 40°C / 75% relative 5 hvsuidity in blister pockets, the tablets containing -granules prepared with a hydroalcoholic medium contained 0.23% of the sum of oxycodone N-oxide and oxymorphone impurities, whereas similar tablets containing granules made in an aqueous process included 1.43%»of these impurities. 10 This experiment shows that using a hydroalcoholic drug layering process improves the stability of oxycodone in the finished tablets. [5 Example 10: Assessment of the stability - Comparison with tablets without ascorbyl palmitate Two types of tablets were compared, i.e. tablets Tl sirnila:. as those described in Example 2 and corresponding tablets T2 20 wherein 5.04 rag (0.48% w/w) ascorbyl palmitate was added thereto. Stability tesning was conducted, according to which 0.1""-impurities were detected in Tl after one month and 0.20% 25 after two months, and the oxycodone value had dropped to 96% in these tablets. On the contrary, 0% impurities were detected in T2 even after three months, and the oxycodone content was stable during this period. WO 2008/U15220 PCT/EP2007/057912 1. Granule comprising a neutral core ccated by oxycodone or one of its pharmaceutically acceptable salts and at 5 least a binding agent, said oxycodone coating being further coated by a subcoat comprising a compound soluble in gastric fluids, wherein said subcoat is further coated by a taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyl(meth)acrylate units. 10 2. Granule according to Claim 1, wherein it comprises oxycodone hydrochloride. 3. Granule according to Claim 1 cr 2, wherein the 15 compound soluble in gastric fluid and the binder are independently selected from the group consisting of : cellulose-based polymers, such as hydroxypropylmethylceilulose, hydrcxypropylcellulose and hydroxyethylcellulose acrylic polymers ; polyvinyl 20 alcohols ; alginic acid or sodium alginate; starch cr pregelatinized starch ; sucroses and derivatives thereof ; guar gum ; polyethylene glycols, and mixtures and copolymers thereof. 25 4. Granule according to Claim 3, wherein the compound soluble in gastric fluid is hydroxypropylmethylceilulose. 5. Granule according to any of Claims 1 to 4, wherein the polymer or copolymer with dialkylaminoalkyl(meth)acrylate 30 units is a copolymer of dimethylaminoethyl methacrylate, methyimethacrylate and n-butyl methacrylate. WO 2008/01522(1 PCT/EP2007/057912 6. Granule according to any of Claims 1 to 5, wherein the taste-masking coating also includes a pore-forming agent. ~?. Granule according to Claim 6, wherein the pore-forming 5 agent is hydroxypropylmethylcellulose. 8. Process for the manufacture of granules according tc any of Claims 1 to 7, wherein a suspension of oxycodone in a hydroalcoholic medium is sprayed onto neutral cores. }Q 9. Orally disintegrating tablet comprising : (a) granules comprising a neutral core coated by oxycodone or one of its pharmaceutically acceptable salts and at least a cinder, said oxycodone coating being further coated by ~ (5 subcoat comprising a compound soluble in gastric fluid ; wherein said subcoat is further coated by a taste-maskinc coating comprising a polymer cr copolymer with diaikylaminoalkyl(meth)aerylate units and optionally a pore-forming agent, and (b) at least one disintegrant and 20 at least one diluent, wherein said disintegrant comprises crcspovidone. 10. Orally disintegrating tablet according to Claim 9, wherein it also includes an anti-oxidant agent. 25 11. Orally disintegrating tablet according to Claim 10, wherein the anti-oxidant agent is ascorbyl palmitate. 12. Orally disintegrating tablets comprising : (a) 30 granules comprising a neutral cere coated by oxycodone cr one of its pharmaceutically acceptable salts and at least one binding agent, said oxycodone coating being further WO 2008/01522(1 PCT/EP20O7/057912 gastric fluid ; wherein said subcoat is further coated by a taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyl(meth)acrylate units and optionally a pore-forming agent, (b) acetaminophen which is net 5 included within said granules, and (c) at least one disintegrant and at least one soluble diluent agent, wherein said disintegrant comprises crcspovidone. 13. Orally disintegrating tablet according to Claim 12, 10 wherein the compound soluble in gastric fluids is selected from the group consisting of : cellulose-based polymers, such as hydroxypropylmethylcellulose, hydroxypropylcellulose and hydrcxyethy1cellulose acrylic polymers ; polyvinyl alcohols ; aiginic acid or sodium 15 alginate ; starch or pregelatinized starch ; sucroses and derivatives thereof ; guar gum ; polyethylene glycols, and mixtures and copolymers thereof. 14. Orally disintegrating tablet according to Claim 13, 20 wherein the compound soluble in gastric fluid is hydroxypropylmethylcellulose. 15. Orally disintegrating tablet according to any cf Claims 11 to 14, wherein it also includes an anti-oxidant 25 agent. 16. Orally disintegrating tablet according to Claim 15, wherein the anti-oxidant agent is ascorbyl paimitate. 30 17. Orally disintegrating tablet according to any of Claims 12 to 17, wherein the pore-fcrming agent is hydroxypropylmethylcellulose. WO 20(18/015220 PCT/EP2007/057912 18. Orally disintegrating tablet according to any of Claims 11 to 17, wherein it contains from 2.5 to 1G mg oxycodone and from 80 to 750 mg acetaminophen. 5 19. Use of granules according to of Claims 1 to 6 for the manufacture of an analgesic medicament for oral administration intended to reduce pain. 20. Method for reducing pain, comprising oral 10 administration of granules according to any of Claims 1 to 6. 21. Use of a tablet according to any of Claims 9 to IS for the manufacture of an analgesic medicament for oral 15 administration intended to reduce pain. 22. Method for reducing pain, comprising oral administration of a tablet according to any of Claims 9 to 18. 20 23. Process for manufacturing orally disintegrating tablets, comprising the steps of : (a) spraying onto neutral cores a suspension in a 25 solvent of oxycodone or one of its pharmaceutically acceptable salts, and at least one binding agent, so as to obtain pellets, (b) applying a subcoat onto said pellets, by spraying thereon a compound soluble in gastric fluid mixed 30 with a solvent, thus obtaining coated pellets, (c) optionally drying said coated pellets, (d) applying onto said coated pellets a taste-masking coating comprising a polymer or copolymer with WO 2008/015220 PCT/EP2007/057912 dialkylaminoalkyl(meth)acrylate units and optionally a pore-forming agent, so as to obtain granules, (e) optionally applying an antistatic coating onto 5 said granules, (f) mixing acetaminophen, optionally applied onto neutral cores and/or coated, with said granules, at least one disintegrant comprising crospovidone and at least one soluble diluent agent/-so as to 10 obtain a powder mixture, and (g) tableting said powder mixture, wherein the solvent used in at least one of steps (a) and (b) is a hydroalcoholic solvent. 15 24. Orally disintegrating tablet obtainable by the process according to Claim 23. 25. Orally disintegrating tablet comprising acetaminophen 20 and oiycodone as the only active ingredients, said tablet having an oxycodone content, after dry storage at 80°C fo.: 14 days, preferably for 21 days, of at least about '30?, preferably of at least about 95%, of the initial oxycodone content before storage. Dated this 29th day of January, 2009.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
"GRANULE AND ORALLY DISINTEGRATING TABLET COMPRISING OXYCODONE"

ETHYPHARM, of 194 Bureaux de la Colline, Batiment D, 92213 Saint Cloud Ccdcx.
France.
The following specification particularly describes the invention and the manner in which it is to be performed.

WO 20(18/1)15220

PCT/EP2007/057912

GRANULE AND ORALLY DISINTEGRATING TABLET COMPRISING
OXYCODONE
5 FIELD OF THE INVENTION
The present invention relates to taste-masked granules containing oxycodone, as well as orally disintegrating tablets comprising said granules and 10 optionally acetaminophen.
BACKGROUND OF THE RELATED ART
Various orally disintegrating tablets are currently 15 available on the market. These tablets include a disintegrant and usually a pharmaceuticaily active ingredient ("active ingredient"} -and disintegrate or dissolve without a chewing action in less than three minutes, usually in less than 60 seconds, upon contact 20 with saliva, forming a suspension of small particles which is easy to swallow.
Once easily swallowed, the particles containing the active ingredient release the same most preferably into 25 the stomach or into the upper part of the gastrointestinal tract.
This type of tablet is described, for example,, in
documents EF 548 356, EP 636 364, EP 1 003 48-3, EP 1 058
30 538, WO 98/46215, WO 00/06126, WO 00/27357 and WO
00/51568.

WO 2008/015220

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Orally disintegrating tablets are a convenient route for swallowing active agents since they do not require, but not exclude, absorbing water at the same time.
5 Owing to its ease of use, the orally disintegrating
tablet is entirely suitable for ambulatory treatment, more particularly for certain patients and especially the elderly or young children, who have difficulties in swallowing such that they find it unpleasant, or even
10 impossible, to ingest tablets or gel capsules, even with a simultaneous intake of liquid-It is estimated that 50% cf the population experiences such difficulties, with the possible
15 consequence of the prescribed medicinal product not being taken and thus a major impact on the efficacy of the treatment (H. Seager, 1998, J. Pharm. Pharmacol. 50, 37 5-382) .
20 In the case where the active ingredient has for
instance a bitter or an unpleasant taste, the small particles may consist of coated granules containing the said active ingredient, thus preventing a bad taste from developing in the mouth. Such coating can also be
25 provided ■ to prevent the active ingredient from being prematurely released in the mouth or to ensure delayed release in the stomach. A typical coating for taste-masking is an aminoalkyl methacrylate copolymer sold" by Rohm Pharma Polymers (Degussa) as EUDRAGIT'3 E 100 or EPO,
30 namely dimethyl aminoethyl methacylate copolymer, comprising a functional group with tertiary amine.

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This coating is insoluble at a pH above 5.5, thus
remains intact in contact with saliva but is readily
soluble in gastric juice, due- to the protonation of the
amine functions, thus releasing the active ingredient in
5 an immediate manner in the stomach.
However, the Applicant has discovered that this copolymer is not suitable for making conventional coated granules for direct tableting from oxycodone in the form 10 of a base or a pharmaceutical^ acceptable salt such as oxycodone hydrochloride which is prescribed to relieve pain.
It has been observed by "he Applicant that the
15 oxycodone content of such granules tends to decrease with
time due to the degradation of oxycodone into oxidation
by-products such as oxycodone N-oxide and oxymorphone.
Without intending to be bound by any theory, it is
believed that the nitrogen atom of the tertiary amines of
20 the dimethylaminoethyl methacrylate units of Eudragit©
E100 may form hydrogen bonding with the hydrogen atom of
the ammonium function of oxycodone hydrochloride, which
in turn could facilitate oxidation reactions. Peroxides
or other contaminants, originating from other excipients
25 or active ingredients, are also susceptible to induce
oxidative degradation of oxycodone.
Now, it is preferable that the final tablets retain' as much oxycodone for as long as possible under storage 30 conditions. This is both so that the efficacy of the tablet remains high, and so that the degradents and impurities produced by the breakdown of the active ingredients remain low. Specifically, it is preferable that at least about 90t

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of the oxycodone, and more preferably at least about 95% of the oxycodone remain after storage for 14 days, and more preferably after 21 days at 80°C dry heat.
5 Oxycodone is for instance marketed as conventional
tablets alone as an hydrochloride salt under the trademark Roxicodone®, or in combination with acetaminophen, by ENDO PHARMACEUTICALS under the trademark Percocet®.
10
However, formulating orally disintegrating tablets including both oxycodone and acetaminophen proved to be difficult, since it has been discovered that acetaminophen can promote the degradation cf an opiate
15 such as oxycodone by direct interaction especially in moist conditions or in the presence of residual humidity.
It has also been observed that acetaminophen release was also slowed down when acetaminophen crystals were
20 combined with oxycodone hydrochloride in taste masked granules prepared according to US 2006/0134422, further dispersed within an orally disintegrating tablet. Thus standard methods of isolating oxycodone from acetaminophen can delay the release of the two active
25 agents and undesirably delay the onset cf pain relief to the patient.
For the purposes of the present invention the expression "orally disintegrating tablets" refers to a 30 tablet which disintegrates or dissolves in the mouth in less than 60 seconds, preferably in less than 40 seconds upon contact with saliva, forming therefore small, particles which are easy to swallow.

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The disintegration time here corresponds to the time
between the moment when the tablet is placed on the
tongue and the moment when the suspension resulting from
5 the disintegration or dissolution of the tablet is
swallowed.
Thus, there remains a need for orally disintegrating
tablets in which a peroxide-sensitive active agent such
10 as oxycodone can be included without experiencing any
substantial degradation, either alone or in combination
with acetaminophen.
Moreover, there remains a need for a means for
15 orally delivering a stable form of oxycodone to the
gastrointestinal tract while avoiding premature release
thereof in the mouth.
In addition, it would be desirable to provide for an
20 orally disintegrating tablet comprising both oxycodone
and acetaminophen while offering not only stable
oxycodone, but also a good dissolution rate of
acetaminophen, i.e. a release of 8 5% wt of acetaminophen
from a tablet including 325 mg thereof, in less than 10
25 minutes at any pH ranging from pH 1.2 to pH 6.8 and at
least 90% release of acetaminophen at 15 min. It would
also be desirable to provide for an orally disintegrating
tablet comprising both oxycodone and acetaminophen while
having a Cnax of acetaminophen between 4.5 and 6.8 ng/mL
30 for a tablet including 10 mg oxycodone and 325 mg
acetaminophen and providing for a fast dissolution rate
of acetaminophen at an acidic pK, such as in the stomach.

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The object of this invention is thus to propose new dosage forms of oxycodone enabling to solve the above needs.
5 SUMMARY OF THE INVENTION
Surprisingly, it has been discovered that the degradation of oxycodone could be prevented when oxycodone was formulated as specific coated granules 10 optionally included in an orally disintegrating tablet.
Moreover, it has been discovered that oxycodone
could be combined in a single orally disintegrating
tablet with acetaminophen without degrading, provided
that acetaminophen and oxycodone are not present in z'r.e
\5 same granules.
A first object of this invention thus pertains to granules comprising a neutral core coated with oxycodone or one of its pharmaceutically acceptable salts and at
20 least a binding agent, said oxycodone coating being further coated with a subcoat comprising a compound soluble in gastric fluids ; wherein said subcoat is further coated with a taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyl(meth)acryiate
25 units.
A second object of this invention relates to a process for the manufacture of the above granules, wherein a suspension of oxycodone in a hydrcalcoholic 30 medium is sprayed onto neutral cores.
A third object of this invention pertains to orally disintegrating tablets comprising: (a) granules

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comprising a neutral core coated with oxycodone or one of its pharmaceutically acceptable salts and at least a binding agent, said oxycodone coating being further coated with a subcoat comprising a compound soluble in 5 gastric fluid ; wherein said subcoat is further coated with a taste-masking coating comprising a polymer cr copolymer with dialkylaminoalkyl (meth)acrylate units, and (b) at least one disintegrant and at least one soluble diluent agent, wherein said disintegrant comprises 10 crospovidone.
According to a fourth object, this invention also relates to orally disintegrating tablets comprising: fa) granules comprising a neutral core coated with oxycodone
15 or one of its pharmaceutical ly acceptable salts and at least a binding agent, said oxycodone coating being further coated with a subcoat comprising a compound soluble in gastric fluid ; wherein said subcoat is further coated with a taste-masking coating comprising a
20 polymer or copolymer with dialkylaminoalkyl(meth)acrylate units, (b) acetaminophen which is not included within oxycodone granules and may optionally be coated, and (c) at least one disintegrant and at least one diluent agent, wherein said disintegrant comprises crospovidone.
25
A fifth object of this invention pertains to a process for manufacturing said tablets, as. well as the tablets thus obtained.
30 This process comprises the steps of :
(a) spraying onto neutral cores a suspension in a solvent of oxycodone or one of its

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pharmaceuticaly acceptable salts and at least one binding agent, so as to obtain pellets,
(b) applying a subcoat onto said pellets, by spraying
thereon a compound soluble in gastric fluid mixed
5 with a solvent, thus obtaining coated pellets,
(c) optionally drying said coated pellets,
(d) applying onto said coated pellets a taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyl(meth)acrylate units and
10 optionally a pore-forming agent, so as to obtain
granules, fe) optionally applying an antistatic coating onto
said granules,
f f) mixing acetaminophen, optionally applied onto
15 neutral cores and/or coated, with said granules,
at least one disintegrant comprising crospovidcne and at least one soluble diluent agent, so as to obtain a powder mixture, and (g) tableting said powder mixture, 20
wherein the solvent used in at least one of steps (a) and (b) is a hydroalcoholic solvent.
A sixth object of this invention is directed to an 25 orally disintegrating tablet comprising acetaminophen and oxycodone as the only active ingredients, said tablet having an oxycodone content, after dry storage at 80°C for 14 days, preferably for 21 days, of at least about 90%, preferably of at least about 95%, of the initial 30 oxycodone content before storage.
A seventh object of this invention pertains to the use of the aforementioned granules or tablets for the

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management of breakthrough pain or more generally for the relief of moderate to severe pain and also for the manufacture of an analgesic medicament for oral administration in such use. It also pertains to a method 5 for reducing pain comprising oral administration of granules or tablets as described above.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
10 Oxycodone can be used as such or as a
pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salts" is intended to mean the derivatives of oxycodone in which the base compound is converted to its salt with an organic or inorganic
15 acid, examples of which comprise acetic, ascorbic, benzenesulfonic, benzoic, boric, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, glutaric, glycerophosphoric, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic, maleic, malic, malonic, mandelic,
20 methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, salicylic, succinic, sulphuric, tartaric, terephthalic, p-toluenesulfonic acid, and the like.
25 Preferred oxycodone salts are oxycodone
hydrochloride and oxycodone terephthalate.
In the following, "oxycodone" will be used indifferently for oxycodone or pharmaceutically 30 acceptable salts thereof.
The amount of oxycodone or its salt may range from about 1% t:o 50%, preferably from abour 5f. to 2b% by

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weight relative to the weight of the neutral core. According to a preferred embodiment/ it is possible to prepare oxycodone loaded granules of different strengths in order to accommodate the different dosage strengths of 5 the final tablets. Actually, in a preferred embodiment low strength granules containing about 5% to about 6% by weight of oxycodone (relative to the total weight of the drug loaded granules) may be used to prepare 2.5 mg and 5 mg dosage units and high strength granules containing
10 about 10% to about 12% of oxycodone (relative to the total weight of the drug loaded granules) may be used to prepare 7.5 mg and 10 mg dosage units. In this way, the tablet strength may be varied without making the tablet unpalatably large.
15
The granules according to this invention comprise a first layer comprising oxycodone which is applied onto neutral cores.
20 The neutral core may comprise any chemically and
pharmaceutically inert excipient, existing in particle form, either crystalline or amorphous, for example sugars or sugar derivatives such as lactose, sucrose, hydrolyzed starch (maltodextrins), celluloses such as
25 microcrystalline cellulose, or mixtures thereof such as sucrose and starch; or mixtures thereof with a cellulose base.
The oxycodone coating may be applied by spraying a
30 suspension or solution of oxycodone onto neutral cores,
preferably in a fluidized-air coating device. Preferably,
oxycodone will be used as a suspension in a
hydroalcoholic medium. It has indeed been observed that

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using a hydroalcoholic medium instead of an aqueous medium provided for greater stability of the oxycodone. The hydroalcoholic medium advantageously comprises water and ethanol, for instance in a ratio of ethanol to water 5 ranging from t about 60:40 to about 92:8 and more preferably of about 75:25 to about 85:15.
The present inventors have discovered that this solvent reduced oxycodone degradation, as evidenced by 10 the following Examples.
The oxycodone layer also comprises a binding agent or binder. Said binder is conventionally used in proportions that can range up to 95% by weight relative 15 to the dry weight of the coating, preferably up to 50% by weight relative to the dry weight of the oxycodone coating.
Its function is to bind the active ingredient and
20 other optional pharmaceutical excipients to the neutral
core without loss, of material, thus forming a homogeneous
layer of pharmaceutically active ingredient, evenly
distributed around the neutral core.
25 The binder can be chosen from the group consisting
of cellulose-based polymers, such as hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose; acrylic polymers; polyvinyl alcohols; alginic acid or sodium alginate ; starch or
30 pregelatinized starch; sucrose and derivatives thereof; guar gum; polyethylene glycols, and mixtures and copolymers thereof, for instance a graft copolymer of

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polyvinyl alcohol and polyethylene glycol, such as sold by BASF under trade name ROLL I COAT IR.
Hydroxypropylmethylcellulose (also referred to as 5 "HPMC" hereunder) is the preferred binder according to this invention. It can preferably be chosen from those for which the apparent viscosity (aqueous solution at 2% m/m, at 20 °C, USP method) is between 2.4 and 18 mPa-s, and even more preferably between 2.4 and 5 mPa-s. 10
The binder, when dissolved in a hydroalccholic
solvent, is advantageously present in a proportion that
can range up to 90%, preferably of between 5% and 60% and
more preferably of about 50% by weight relative to the
15 weight of oxycodone.
Moreover, the first (oxycodone) layer may also comprise one or more pharmaceutically acceptable excipients, apart from the binding agent. 20
The pharmaceutically acceptable excipients optionally present may be chosen from surfactants, antistatic agents, lubricants, and mixtures thereof.
25 The surfactant, which is optionally present in the
oxycodone coating, can be chosen from cationic, anionic, nonionic or amphoteric agents, alone or as a mixture.
The surfactant can be chosen, for example, from
30 compounds such as sodium iauryl sulphate, the monooleate,
the monoiaurate, the monopaimitate, the monostearate, the
trioleate, the tristearate or any other ester of
pclyoxysthyler.ated sorbitan, preferably Tween® 20, 40,

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60 or 80, glycerides of polyoxyethylenated fatty acids, these fatty acids being saturated or unsaturated and composed of at least 8 carbon atoms, poloxamers, such as poloxamer 188, ethylene oxide/propylene oxide block 5 copolymers, such as Pluronic® F68 or F87, lecithin, stearyl alcohol, cetearyl alcohol, cholesterol, polyoxyethylenated castor oil, fatty alcohol
polyoxyethylenated ethers, such as the Brij® products, and polyoxyethylenated stearates. 10
The surfactant is advantageously present in a proportion that can range up to 20%, preferably of between 0.1 and 20% by weight relative to the total dry-weight of the coating.
15
The antistatic agent can be used in a proportion that can range up to 10% by weight, relative to the dry weight of the coating applied around the neutral core. The antistatic agent may be chosen from the group
20 consisting of: colloidal silica and preferably precipitated silica, micronized or non-micronized talc, and mixtures thereof.
The lubricant may be selected from the group 25 comprising magnesium, zinc, and calcium stearate, stearic acid, talc, pyrogenic silica, hydrogenated vegetable oils, sodium stearylfumarate, micronized polyoxyethylene glycol (micronized Macrogol 6000), leucine, sodium benzoate, and mixtures thereof. 30
As mentioned above, in the granules according to this invention, the first layer comprising oxycodone is further coated by a separating layer (also referred to as

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"subcoat") between the coating layer comprising oxycodone and the taste-masking polymeric layer, wherein said subcoat comprises at least a compound soluble in gastric fluid, i.e. in highly acidic conditions {pH comprised
5 between 1 and 2), preferably a polymer which can be chosen among the binding polymers or copolymers mentioned above. An example of a copolymer that can be used in the subcoat ' is a graft copolymer of polyvinyl alcohol and polyethylene glycol, such as sold by BASF under the trade
10 name KOLLICOAT0 IR. A preferred polymer is hydroxypropylmethylcellulose. The polymer or copolymer, included within the subcoat, acts as a separating layer in order to avoid direct contact between the oxycodone layer and the taste-masking polymer, and dissolves
15 rapidly without altering oxycodone release. The subcoat layer may also comprise an antistatic agent such as those listed previously.
The subcoat is advantageously present in a
20 proportion that can range up to 50%, preferably of
between 5% and 30% by weight relative to the weight of
oxycodone coated cores.
The subcoat can be applied by conventional means, 25 such as in a fluidized-air coating device, by spraying a solution or a dispersion of binder in an aqueous or preferably in a hydroalcoholic medium onto the cores coated with oxycodone. The hydroalcoholic medium advantageously comprises water and ethanol, for instance 30 in a ratio of ethanol to water ranging from about 60:40 to about 92:8 and more preferably of about 85:15.

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This subcoat is itself coated by a taste-masking coating layer comprising a polymer or copolymer comprising dialkylaminoalkyl(meth)acrylate units, such as dimethylaminoethyl methacrylate units. This polymer can 5 be, for instance, a copolymer of dimethylaminoethyl methacrylate, methylmethacrylate and n-butyl methacrylate, such as the copolymer sold by ROHM PHARMA under the trade names EUDRAGIT0 E100 and EPO.
10 The taste-masking coating preferably further
includes a pore-forming agent which can be a hydrophilic polymer soluble in gastric fluids, such as hydroxypropylmethylcellulose or other polymers used as binders such as polyvinylpyrrolidone, polyvinylalcohoi,
15 poiyethyleneglyccls, or a soluble agent, preferably chosen from the group of sugars such as sucrose, lactose or dextrose, of polyols such as mannitol, sorbitol or lactitol, or of organic acids and their salts such as citric acid, tartaric acid, succinic acid, or else of
20 inorganic salts such as sodium chloride. A preferred pcre-forming agent is hydroxypropylmethylcellulose.
The pore-forming agent, which is optionally present
in the taste-masking coating, can be used in a proportion
25 that can range up to 50%, preferably of between 5% and
30% by weight relative to the total dry weight of the
taste-masking coating ingredients.
It has indeed been shown that the provision of this
30 pore-forming agent within the taste-masking coating
improved the release rate of oxycodone from the granule
at a pH equal or greater than pH 5.5 such as in the
intestine, by increasing the permeability of the taste-

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masking film coating and thus preventing the slowing down of oxycodone release when the granules directly pass into the intestine, which may undesirably occur when the patient ingesting the granule has a fast digestion and/or 5 is stressed.
The amount of pore-forming agent in the taste-masking coating and the total amount of taste-masking coating relative to the total weight of the oxycodone
10 granule with its subcoat have to be chosen so as to provide taste-masking effectiveness during the short period of time in the saliva and to ensure, following the swallowing of the granules, fas~ dissolving in pH ranging from pH 1.2 to pH 6. S. The ratio of the taste-masking
15 coating to the total dry weight of ingredients comprising the oxycodone granule with its subcoat ranges from about 10:90 to about 50:50 and more preferably of about 20:80 (or 25%).
20 The taste-masking layer may also comprise an
antistatic agent, such as those listed above.
The granules according to this invention can-advantageously be used in the manufacture of orally 25 disintegrating tablets.
To this end, the granules described above can be
mixed with at least one disintegrant and at least one
soluble diluent agent preferably having binding
30 properties and then directly compressed so as to form
tablets.

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The compression force is adjusted so as to obtain a friability, measured according to the method of the European Pharmacopoeia, of less than 2%w/w and preferably less than 1.5%w/w, and so as to allow a disintegration 5 time of the tablet in the mouth under the action of saliva of less than or equal to 60 seconds and preferably less than or equal to 40 seconds.
Hardness is preferably comprised between 10 and 10 180 N, preferably between 15 and 100 N and more preferably between 50 and 80 N, measured according to the method of the European Pharmacopoeia (2.9.8).
The present invention thus also pertains to orally
15 disintegrating tablets comprising: (a) granules
comprising a neutral core coated with oxycodone or one of
its pharmaceutically acceptable salts and at least a
binding agent, said oxycodone coating being further
coated with a subcoat comprising a compound soluble in
20 gastric fluid ; wherein said subcoat is further coated
with a taste-masking coating comprising a polymer Gr
copolymer with dialkylaminoalkyl(meth)acrylate units, and
(b) at least one disintegrant and at least one soluble
diluent preferably having binding properties, wherein
25 said disintegrant comprises crospovidone.
The above tablets can include, for instance, from 1 to 20 mg oxycodone hydrochloride, preferably from 2.5 to 10 mg oxycodone hydrochloride, per tablet. 30
The disintegrating agent may further comprise crosslinked sodium carboxymethylceilulose, which is

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referred to as croscarmellose. The preferred disintegrant is crospovidone alone.
Usually, the disintegrant represents from 1 to 15%,
5 and preferably from 2 to 10% and the soluble diluent
agent represents from 20 to 8 0%, and preferably from 25
to 40% of the total weight of the tablet.
The soluble diluent agent may be a polyol having 10 less than 13 carbon atoms and being present either in the form of a directly compressible product with an average particle size from 100 to 500 um, or in the form of a pcwder with an average particle size of less than 100 urn, or mixtures thereof.
15
In a preferred embodiment, said polyol is selected from the group consisting of mannitol, xylitol, sorbitol, and maltitol. In the case where there is only one soluble diluent agent, it is used in the form of a directly
20 compressible product, whereas, in the case where there are at least two soluble diluent agents, one is present in a directly compressible form and the other in a powder fcrm, it then being possible for the polyol to be the same, the ratio of directly compressible polyol and of
25 powdered polyol being 99:1 to 20:80, preferably 80:20 to 20:80.
Preferably, the soluble diluent agent with binding properties is a mixture of mannitol in the form of a 30 powder with an average particle size of less than 100 urn, preferably Mannitol 60 and directly compressible mannitol with an average particle size from 100 to 500 [im, such as Mannitol 300.

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It has been observed that crospovidone had a stabilizing effect on the degradation of oxycodone when the orally disintegrating tablets are stored under dry 5 atmosphere. The tablets according to this embodiment of the invention are thus preferably packaged in sealed containers such as blisters. In addition, they can advantageously include an anti-oxidant agent so as to better protect oxycodone from degradation which could 10 occur under moist conditions as a result of crospovidone degradation.
Examples of saleable anti-cxidancs include ascorbic acid and its salts and esters, such as sodium ascorbate 15 and ascorbyl paimitate ; tocopherol and its esters such as tocopherol acetate ; and mixtures thereof.
Usually, the anti-oxidant is present from 0.2 to 1 wt% relative to the total weight: of the tablet. It can 20 also be expressed as a ratio to the crospovidone used. In this regard, it is preferred that the anti-oxidant represents from 1 to 5 % of the weight of the crospovidone used.
25 In- particular, it has been found that ascorbyl
paimitate efficiently prevented degradation of crospovidone under moist conditions and thus protected oxycodone from oxidation. The amount of ascorbyl paimitate that can be included in the tablets according
30 to this invention can range from C.2 to 1 % w/w relative to the total weight of the tablet. It can also be expressed as a ratio to the crospovidone used. In this regard, it is preferred that ascorbyl paimitate

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represents from 1 to 5 % of the weight of the crospovidone used.
The orally disintegrating tablet can also include
5 various additives such as a lubricant, a swelling agent,
a permeabilizing agent, a sweetener, a flavouring agent, a colorant and their mixtures.
The lubricant may be selected from those listed 10 previously.
The amount of lubricant may range from 0.2 to 2 %
(weight of lubricant/total weight of the tablet), preferably frem 0.5 to 1.5%. The lubricant can be 15 dispersed within the powder bed compressed into a tablet or, according to an advantageous embodiment, the totality of the lubricant can be dispersed on the surface of the tablet.
20 The swelling agent may be selected from the group
comprising native and modified starches.
The permeabilizing agent may be selected from the group comprising precipitated silica, maltodextrins,
25 beta-cyclodextrin, and mixtures thereof. The permeabilizing agent allows the creation of a hydrophilic network which facilitates the penetration of saliva and hence contributes to better disintegration of the tablet. The proportion of permeabilizing agent relative to the
30 weight of the tablet is preferably from 0.53 to 5% by
weight.

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The sweetener may be selected from the group
comprising in particular aspartame, acesulfam potassium,
sodium saccharinate, neohesperidine dihydrochalcone,
sucralose, monoammonium glycyrrhizinate, and mixtures
5 thereof.
The flavouring agents and colorants are those conventionally used in pharmacy for the preparation of tablets.
10
These excipients will usually amount to less than 10 weight percent relative to the total weight of the tablet, preferably from 0.1 to 5 %, even more.preferably from C.2 to 4.5%.
15
Moreover, it has been found that acetaminophen could be included within said tablets, provided that it is separated from the above-described granules coated with oxycodone. In this way, both active ingredients can be
20 included in the same tablet while avoiding incompatibility problems between them.
This invention thus also relates to orally disintegrating tablets comprising: (a) granules
25 comprising a neutral core coated with oxycodone or one of its pharmaceutical^ acceptable salts and at least a binder, said oxycodone coating being further, coated with a subcoat comprising a compound soluble in gastric fluid ; wherein said subcoat is further coated with a
30 taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyi(meth)acrylate units, (b) acetaminophen which is not included within said granules, and (c) at least one disintegrant and at least one

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diluent, wherein said disintegrant comprises ccospovidone.
In a preferred embodiment, the oxycodone and 5 acetaminophen tablet further comprises an anti-oxidant. Suitable anti-oxidants are those described above, whereby ascorbyl palmitate is preferred. The amounts of anti¬oxidant and in particular ascorbyl palmitate are those described above. 10
Acetaminophen can be provided as crystals or as granules wherein acetaminophen can be coated with a taste-masking coating. The excipients included within this taste-masking coating can be the same as listed 15 above. In this case, the taste-masking coating of the oxycodone granules and the taste-masking coating of the acetaminophen granules can be the same or different.
In a preferred embodiment, the crystals of 20 acetaminophen are granulated with a binder and the obtained granules are coated with taste-masking coating.
In a most preferred embodiment, the crystals cf acetaminophen are directly coated with a taste-masking 25 coating.
The tablet can include, for instance, from 1 to 20 mg oxycodone, preferably from 2.5 to 10 mg oxycodone, per tablet. 30
The above-mentioned tablets car. contain from 30 to 750 mg acetaminophen, per tablet.

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The1 tablet may further include the same additives as those d£scribed in relation with the acetaminophen-free tablet ^escribed above
S The table according to the invention disintegrate in the mouth upon contact with saliva in less than 60 seconds, preferably in less than 40 seconds, forming a suspensi°n which is easy to swallow.
JO Thse tablets, as well as the granules described
previously/ can be used in the relief of moderate to severe pain, such as in the management of breakthrough pain, in particular breakthrough cancer pain, by oral administration. Ereakthrough pain means a transitory 15 flare of pain of moderate to severe intensity occurring en a ba£kground of otherwise controlled pain.
Granules may for instance be administered as such, packaaed i-n pouches, or in the form of capsules.
20
Th0 invention will be understood more clearly from the foli°wing Examples which are not intended to restrict in any v*ay the scope of this invention.
25 EXAMPLES
Example JL: Preparation of granules entrapping oxycodone
Neutral cores were introduced into a fluid bed processor and 30 a suspension of oxycodone hydrochloride, hydroxypropylmethyl cellulose (HPMC) as a binder in a solvent of water and ethanol was sprayed on the neutral ceres. The composition of oxycodone pellets is given in Table 1 for Low and Hi

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strengths. The oxycodone amount entrapped in the Hi and Low strength pellets is of about 11.55% and 5.78% by weight respectively. A subcoat was then applied to the oxycodone pellets. The subcoat contained HPMC and silicon dioxide (as 5 an antistatic) in a water/ethanol solvent as shown in Table 2 (the composition is the same whatever the strength) . After drying, the granules were again introduced to the fluid bed processor and coated with a taste-masking coating of Eudragit® E100 acrylic polymer, HPMC and silicon dioxide in a
10 water/ethanol solvent as shown in Table 3 (the composition is the same whatever the strength) . In a last step, before discharging the taste-masked oxycodone granules, an antistatic solution composed of a suspension of silicon dioxide in ethane1 is sprayed into the fluid bed processor.
15 The composition is given in table 4. The oxycodone amount
entrapped in the final granules is of about 3.8% and 7.7% by weight for the Low and Hi strength granules respectively.
Table 1
20 Composition of oxycodone hydrochloride pellets

MATERIALS 2.5/ 5 MG STRENGTHS (LS) 7,5/10 MG STRENGTHS (HS)

% TOTAL WEIGHT
(KG) % TOTAL WEIGHT
(KG)
Neutral cores 91.33 15.20 82.67 13.76
LAYERING SOLUTION
Oxycodone 5.78 0.96 11.55 1.92
HPMC 2.89 0.48 5.78 0.96
Water n/a* 2.93* n/a* 5.86*
Ethancl n/a* 10.63* n/a* 21.26*
Total (dry) 100.00 16.64 100.00 16.64
*solvent removed during process

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Table 2 Composition of oxycodone pellets coated with a subcoat

MATERIALS 2.5 - 10 MG STRENGTHS

% TOTAL WEIGHT (KG)
Oxycodone pellets 83.5 16.64
SUBCOATING SOLUTION
HPMC 15.0 3.00
Syloid F244P 1.5 0.30
Water n/a* 4.05*
Ethanol n/a* 22.95*.
Total (dry) 100.00 19.94
5 ""solvent removed during process
Table 3 Excipients used in the taske-masking coating

10

MATERIALS 2.5 - 10 MG STRENGTHS

% TOTAL WEIGHT (KG)
Oxycodone
granules 79.74 19.94
COATING SOLUTION
Eudragit E100 14.74 3.69
HPMC 3.68 0.92
Syloid F244P 1.84 0.41
Water n/a* 14.19*
Ethanol n/a* 21.28*
Total 100.00 24.96
*solvent removed during process

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Table 4
Excipients used in the antistatic suspension applied on the
taste-masked oxycodone granules

MATERIALS 2.5 - 10 MG STRENGTHS

% TOTAL WEIGHT (KG)
Taste-masked
oxycodone
granules 99.80 24.96
ANTISTATIC SOLUTION
Syloid F244P 0.20 0.05
Ethanol n/a* 0.83*
Total 100.00 25.01
*solvent removed during process
Example 2: Preparation of orally disintegrating tablets
Acetaminophen (APAP) crystals were introduced into a fluid bed processor and a suspension containing Eudragit3 ElOO acrylic polymer, Eudragitra NE30D acrylic polymer, and silicon dioxide in ethanol was sprayed on the APAP. The total amount of coating represents 6% in weight relative to the initial weight of APAP crystals.
The coated APAP crystals were mixed with the oxyccdone-coated neutral cores from Example 1 and with excipients, as listed in the table below, and tableted in accordance with standard tableting procedures for making orally disintegrating tablets.
A Sviac 6 stations press was used with the following parameters (table 5}. Table 6 presents the recommended specifications tor tablet, characteristics.

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Table .5 Example of press setting for a Sviac PR-6

PARAMETERS VALUE
Turret speed 25 rpm
Feed frame speed 10 rpm
Punch diameter 15 mm
Table 6 Recommended specifications for tablet physical characteristics 10

PARAMETERS TARGET RANGE
Tablet, weight 1050 mg USP
Tablet hardness 65 N 50-80 N
Tablet thickness 5.60 mm 5.50-5.75 mm
Friability NMT 1.5% Release NMT 1.5% Stability NMT 2%
Disintegration time in mouth NMT 30 s NMT 45 s
Water content NMT 2.0% Release NMT 2.0% Stability NMT 3.0%
The composition of the compressed tablets is shown in the following Table 7.

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Table 7
Composition of orally disintegrating tablets containing
taste-masked oxycodone granules and taste-masked APAP
5 granules

Materials %
Coated oxycodone pellets 9.51
Coated APAP crystals (6% coating) 32.85
Mannitol 60 14.22
Mannitol 300 14.22
Macrocrystalline cellulose PH102
Crospovidone CL
Sucralose
Prosweet 10.00
15.00
1.00
0.38
Peppermint flavor 0.75
Silicon Dioxide 244 FP 0.50
Sodium Stearyl Fumarate 1.50
Red #40 aluminium lake 0.07
Total 100.00
Example 3 (comparative) : Preparation of granules coanprising oxycodone and acetaminophen 10
APAP crystals and silicon dioxide were introduced into a fluidized air bed installation and a layering solution of oxycodone dissolved in a solution of HPMC in water was sprayed thereon. The coated crystals were then reintroduced
15 into a fluidized bed coater and overcoated using a coating suspension of Eudragit0 E100 acrylic polymer in 95% ethanol with silica. The resulting coated granules were then dried. The composition of APAP granules coated with oxycodone and further coated with the taste-masking coating (for a final
20 strength of 325 mg / 2.5 me) is given in Table 8.

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Table 8 Composition of APAP/oxycodone taste-masked granules

r
Materials % j
Acetaminophen 82.33
Silicon Dioxide 244 FP 0.25
OXYCODONE LAYERING SOLUTION
HPHC 0.28
Oxycodone HCl 0.63
Purified water n/a*
COATING SOLUTION
Eudragit E100
Silicon Dioxide 244 FP
Ethanol 15.0 1.51 n/a*
5 ^solvent removed during process
Example 4 (comparative) : Preparation of orally disintegrating tablets
10 The granules obtained in Example 3 were blended with aspartame, peppermint, colorant, mannitol, crospovidone, microcrystalline cellulose and silica. The blend was then compressed into an orally disintegrating tablet according to conventional tabletting processes. The composition of the
15 tablets is summarized in Table 9 below.

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Table 9

Table Composition 2.5 rag Oxycodone HC1/325 mg AFAF 10 mg Oxycodone HC1/32S mg APAP

Weight (mg/tablet) Weight (mg/tablet)
Granules
Acetaminophen 325.0 325.0
Oxycodone HCl 2.5 10.0
HPMC 1.1 4.3
Eudragit E100 59.2 60.9
Silicon dioxide E~hyi alcohol Purified wa:sr Tableting excipients 12.2
QO QD 12.2
QD
QD
Mannitol 399.8 387.5 105.0 105.0
21.0 13.1
Crospovidone CL 105.0

Macrocrystalline
ce llulose 1 105.0

Aspartame powder 21.0

Magnesium stearate 13.1

Peppermint 5.3 5.3
Colorant 0.7 0.7
Total Tablet Weight (mg) 1050 1050
5 Example 5: Assessment of the dissolution rate of acetaminophen and oxycodone
The tablets produced according to Example 2 (invention) and A
(comparative) were tested for their dissolution properties at
10 a pH near the pH of the saliva. Dissolution using USP type 2
(paddle) dissolution apparatus at 100 rpm yielded the results
shown in Tables 10 and 11 below, for acetaminophen and
oxycodone respectively.

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Table 10 Dissolution (%) of acetaminophen

Time (mn) Example 2 pH 6.8 Example 4 pH 6.8
2.5 7.5 15 56
89 8.3

20.8

94 58.3
30 98 93.75

As may be seen from this Table, the dissolution of tablets made in accordance with this invention was much faster than with the comparative tablets.
10
15
Moreover, the Cruax of acetaminophen in the comparative tablets of Example 2 was 4. 4 ng/mL for the tablets containing 2.5 mg oxycodone and 4.0 ng/mL for the tablets comprising 10 mg oxycodone. At pH 1-2 {close to that of gastric juices!, it took 27 min to release 85% of APAP in the tablets containing 2.5 mg oxycodone and 12.9 min in the tablets containing 10 mg oxycodone. This slow dissolution rate of APAP is expected to result in too slow an absorption rate of this drug.
Table 11
20 Dissolution (%) of oxycodone

Time (mn) Example 2 pH 6.8 Example 4 pH 6.8
0 0 0
5 10 15 30 97 100 100 100 33
74 81 90

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This table shows that the addition of a pore-forming agent in the taste-masking coating of oxycodone granules results in a significant increase in the dissolution rate of oxycodone, 5 especially at a pH greater than 5.5 such as pH 6.8. The addition of the pore-forming agent provides oxycodone taste-masked granules with pH-independent drug release profiles.
Example 6: Assessment of the stability of oxycodone -10 Comparison with oxycodone coated acetaminophen crystals
Acetaminophen crystals were introduced into a fluid bed processor and a suspension of oxycodone, h ydrcxypropy line thy 1 cellulose (HPMC) as a binder and a solvent cf water and
15 ethanol was sprayed on the crystals. The granules were prepared by using a Mini-Glatt equipment with 100 g of support and a layering duration of 30 min at 25°C. The solvent contained 4 g water and 40.5 g ethanol. The composition and process parameters mentioned in Table 11
20 below were used.
The above procedure is repeated using neutral cores instead of acetaminophen crystals. The composition and process parameters mentioned in Table 12 below were used. 25
Table 12 Compositions tested

Excipients Composition A {% dry) Composition B (% dry)
APA? crystals Neutral cores Oxycodone HPMC 603 98.91% 0
0.761 0.33% G
98.91* 0.761 C.33%

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The granules thus obtained were stored in forced degradation conditions (80 °C, dry heat) and the amount of oxycodone remaining as a function of time, relative to the initial 5 content of oxycodone, was then assessed by HPLC.
The results showed no significant change in the oxycodone content of Composition B after 7 days, whereas it dropped to below 95% for Composition A. Moreover, the oxycodone content 10 was also stable when granules of Composition B were prepared at 50°C using an aqueous solvent, whereas it was only around 86% for granules of Composition A prepared under the same conditions.
15 This experiment demonstrates that oxycodone is more stable when coated on neutral cores than on acetaminophen crystals. This degradation of oxycodone is thought to be due to acetaminophen, which has been shown to degrade itself when in solution.
20
Example 7: Assessment of the stability - Comparison with granules without subcoat
Oxycodone coated granules were prepared as. described in 25 Example 6 composition B, except that these granules were further coated with a taste-masking coating of Eudragit® E100 acrylic polymer and silicon dioxide (Syloid .244} in ethanol. These granules will be designated hereafter as Granules' C. Their composition is given in Table 13 below.

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Table 13 Composition of coated oxycodone granules without subcoat

Excipients Granules C

Weight (g) %
Oxycodone loaded granules {3.8% w/w oxycodone) 120.00 79.74
Eudragit E100 22.18 14.74
HPMC 5.54 3.68
Syloid 244 2.77 1.84
Purified water 85.38 128.06 n/a*
Ethanoi
n/a*
TOTAL (Dry Mat.) 150.49 100
5 *solvent removed during process
Similar granules were also prepared, which further contained a subcoat as described in Example 1 above, between the oxycodone coating and the taste-masking coating. These 10 granules will be designated hereafter as Granules D. Their composition is given in table 14 below.
Table 14 15 Composition of oxycodone coated granules with protective
subcoat

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Excipients Granules D

Weight (g) %
Oxycodone loaded granules (3.8% w/w oxycodone) 900.00 66.6
Suspension for subcoat
HPMC
Syioid 244 Purified water 161.68 16.17 218.3 1237.1 12.0 1.2 n/a* n/a*
Ethanol

Suspension for coating
Eudragit £100 HPMC
Syioid 244 Purified water Ethancl 199.24 49.74 24.37
766.89 14.7 3.7
i 3
n/a*

1150.28 n/a*
TOTAL (Dry Mat.) 1351.7 100
*solvent removed during process
Granules C only contained around 80% oxycodone after 21 days 5 at 80°C, whereas Granules D still contained 95% oxycodone at that time.
Moreover, tablets were prepared with Granules D as described in Example 2 (Table 15) and compared with similar tablets 10 prepared with Granules C not containing a subcoat (Table 16).
Table 15
Composition of orally disintegrating tablets including
15 oxycodone granules with a subcoat

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Materials %
Coated oxycodone pellets (Granules D) 7.20
Coated APAP crystals (6% coating) 26.53
Mannitol 60 18.53
Mannitol 300 18.54
Microcrystaliine cellulose PH102 10.00
Crospovidone CL 15.00
Sucralose 1.00
Prosweet 0.38
Peppermint flavor 0.75
Silicon Dioxide 244 FP 0.50
Sodium Stearyl Fumarate 1.50
Red # 40 aluminium lake 0.C7
Total 100.00
Table 16
Composition of orally disintegrating tablets containing
5 oxycodone granules without a subcoat

Materials %
Coated oxycodone pellets (Granules C) Coated APAP crystals (6% coating) Mannitol 60 6.28 26.53 18.99 18.99
Mannitol 300

Microcrystaliine cellulose PH102 10.00
Crospovidone CL 15.00
Sucralose 1.00
Prosweet
Peppermint flavor Silicon Dioxide 244 FP Sodium Snearyl Fumarate Red * 40 aluminium lake 0.38 0.75 0.50 1.5C 0.07
Total 100.00

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After 21 days at 80°C dry heat in blister pockets, the tablets including a subcoat still contained about 952 oxycodone, whereas the comparative tablets without subcoat 5 only contained about 70% oxycodone.
This experiment makes clear that acrylic polymers bearing amino side groups, such as Eudragit0 E1Q0 or EPO, tend to degrade oxycodone and that this degradation can be inhibited 10 by providing a subcoat between the oxycodone coating and the taste-masking Eudraqit'5 coating.
These results were confirmed by analyzing the total impurity contends of both cypes of cablets, after 21 days. The
15 impurities referred to included mainly oxidation products of oxycodone, such as oxycodone N-oxide + oxymorphone, but not those coming from the synthesis of oxycodone. The tablets including a subcoat only contained 0.30% impurities at that time, whereas the comparative tablets without subcoat
20 contained 0.49% impurities, when stored in blisters for 3 months at 40°C / 75% RK.
A similar trend was observed when the tablets were stored for 28 days in an open dish instead of being kept at 80°C dry 25 heat in blister pockets.
Example 8: Assessment of the stability of oxycodone Comparison with tablets without crospovidone
30 Tablets were prepared as described in Example 2, according to the composition presented in Table 15 and compared with similar tablets which dio not contain crospovidone as oresented in Table 17 below.

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Table 17 Composition of tablets without crospovidone containing taste-masked oxycodone granules with subcoat

Materials %
Coated oxycodone pellets (Granules D) Coated APAP crystals (6% coating} 7.20 26.53 26.03 26.04
Mannitol 60

Mannitol 300

Microcrystalline cellulose PH102 10.00 1.00 0.38 0.75 0.50 1.50 , 0.07
Sucralose Prosweet
Peppermint flavor Silicon Dioxide 244 FP Sodium Stearyl Fumarate Red # 40 aluminium lake

Total 100.00
After 21 days at 8Q°C dry heat in blister pockets, the tablets, including crospcvidcne still contained around 95c oxycodone, whereas the comparative tablets only contained 10 around 50% oxycodone.
This experiment makes clear that acrylic polymers bearing amino side chains, such as Eudragit E100 or EPO, tend to degrade oxycodone (which has been confirmed by binary 15 mixtures of Eudragit15 E100 with oxycodone! and that this degradation can be inhibited under dry conditions by adding crospovidone as a disintegrant in the tablets.
These results were confirmed by analyzing the total impurity
20 contents cf both types of tablets, after 21 days. "The
impurities referred to included mainly oxidation oroducts ::

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oxycodone, such as oxycodone N-oxide + oxymorphone, but noz those coming from the synthesis cf oxycodone. The tablets including crospcvidcne only contained 0.25% impurities at that time, whereas the comparative tablets contained 7.06% 5 impurities, as measured by HPLC.
Example 9: Assessment of the stability - Comparison with granules made in an aqueous medium
10 Tablets were prepared as described in Example 2 according to the formula presented in Table 15 and compared with similar tablets in which the oxycodone coating and subcoating steps had been applied onto the neutral cores in an acuecus solvent instead of a hycroalcoholic solvent. The composition cf "he
15 oxycodone taste-masked granules obtained in an aqueous solvent is given in Table 18 ; the tablet formula is provided in Table 19.
Table 18 20 Composition of oxycodone taste-masked granules obtained by drug loading and subcoating water-based processes

Excipients Weight (g) %
Neutral cores 1000.0 64.58
Solution for drug loading
Oxycodone HCl 39.9 2.58
HPMC 19.95 1.29
Purified water 455.77 n/a*
Suspension for subcoat
HPMC
Syloid 244 Purified water 159-0
15.9
1574.1 10.27 1.03 n/a-
Suspension for coating

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Eudragit E100 228.3 14.74
HPMC 56.92 3.63
Syloid 244 28.52 1.84
Purified water 878.5 n/a*
Ethane1 1317.7 n/a*
TOTAL 1548.5 100
(Dry Mat.)
^solvent removed during process
Table 19 Composition of orally disintegrating tablets containing 5 taste-masked oxycodone granules prepared by an aqueous
process

Materials %
Coated oxycodone pellets (table 16ter) 7.61
Coated APAP crystals {6% coating) 26.53
Mannitol 60 18.31
Mannitol 300 18.31
Microcrystalline cellulose PH102 10.00
Crospovidone CL 15.00
Sucraiose 1.00
Prosweet 0.38
Peppermint 0.75
Silicon Dioxide 244 FP 0.50
Red # 40 0.07
Sodium Stearyl Fumarate 0.77
Lubritab 0.77
Total 100.00
After 21 days at 80 °C dry heat in blister pockets, the
10 tablets containing granules prepared with a hydroalcohclic
nedi'Jm contained C. 25% total impurities as defined in

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Examples 8 and 9, whereas the comparative tablets already included 1.11% total impurities after only 14 days.
Similarly, after 3 months storage at 40°C / 75% relative 5 hvsuidity in blister pockets, the tablets containing -granules prepared with a hydroalcoholic medium contained 0.23% of the sum of oxycodone N-oxide and oxymorphone impurities, whereas similar tablets containing granules made in an aqueous process included 1.43%»of these impurities. 10
This experiment shows that using a hydroalcoholic drug layering process improves the stability of oxycodone in the finished tablets.
[5 Example 10: Assessment of the stability - Comparison with tablets without ascorbyl palmitate
Two types of tablets were compared, i.e. tablets Tl sirnila:. as those described in Example 2 and corresponding tablets T2 20 wherein 5.04 rag (0.48% w/w) ascorbyl palmitate was added thereto.
Stability tesning was conducted, according to which 0.1""-impurities were detected in Tl after one month and 0.20% 25 after two months, and the oxycodone value had dropped to 96% in these tablets. On the contrary, 0% impurities were detected in T2 even after three months, and the oxycodone content was stable during this period.

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1. Granule comprising a neutral core ccated by oxycodone
or one of its pharmaceutically acceptable salts and at
5 least a binding agent, said oxycodone coating being further coated by a subcoat comprising a compound soluble in gastric fluids, wherein said subcoat is further coated by a taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyl(meth)acrylate units. 10
2. Granule according to Claim 1, wherein it comprises
oxycodone hydrochloride.
3. Granule according to Claim 1 cr 2, wherein the
15 compound soluble in gastric fluid and the binder are
independently selected from the group consisting of :
cellulose-based polymers, such as
hydroxypropylmethylceilulose, hydrcxypropylcellulose and hydroxyethylcellulose acrylic polymers ; polyvinyl 20 alcohols ; alginic acid or sodium alginate; starch cr pregelatinized starch ; sucroses and derivatives thereof ; guar gum ; polyethylene glycols, and mixtures and copolymers thereof.
25 4. Granule according to Claim 3, wherein the compound soluble in gastric fluid is hydroxypropylmethylceilulose.
5. Granule according to any of Claims 1 to 4, wherein the polymer or copolymer with dialkylaminoalkyl(meth)acrylate 30 units is a copolymer of dimethylaminoethyl methacrylate, methyimethacrylate and n-butyl methacrylate.

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6. Granule according to any of Claims 1 to 5, wherein the taste-masking coating also includes a pore-forming agent.
~?. Granule according to Claim 6, wherein the pore-forming 5 agent is hydroxypropylmethylcellulose.
8. Process for the manufacture of granules according tc
any of Claims 1 to 7, wherein a suspension of oxycodone
in a hydroalcoholic medium is sprayed onto neutral cores.
}Q
9. Orally disintegrating tablet comprising : (a) granules
comprising a neutral core coated by oxycodone or one of
its pharmaceutically acceptable salts and at least a
cinder, said oxycodone coating being further coated by ~
(5 subcoat comprising a compound soluble in gastric fluid ; wherein said subcoat is further coated by a taste-maskinc coating comprising a polymer cr copolymer with diaikylaminoalkyl(meth)aerylate units and optionally a pore-forming agent, and (b) at least one disintegrant and
20 at least one diluent, wherein said disintegrant comprises
crcspovidone.
10. Orally disintegrating tablet according to Claim 9,
wherein it also includes an anti-oxidant agent.
25
11. Orally disintegrating tablet according to Claim 10,
wherein the anti-oxidant agent is ascorbyl palmitate.
12. Orally disintegrating tablets comprising : (a)
30 granules comprising a neutral cere coated by oxycodone cr
one of its pharmaceutically acceptable salts and at least one binding agent, said oxycodone coating being further

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gastric fluid ; wherein said subcoat is further coated by a taste-masking coating comprising a polymer or copolymer with dialkylaminoalkyl(meth)acrylate units and optionally a pore-forming agent, (b) acetaminophen which is net 5 included within said granules, and (c) at least one disintegrant and at least one soluble diluent agent, wherein said disintegrant comprises crcspovidone.
13. Orally disintegrating tablet according to Claim 12,
10 wherein the compound soluble in gastric fluids is
selected from the group consisting of : cellulose-based polymers, such as hydroxypropylmethylcellulose, hydroxypropylcellulose and hydrcxyethy1cellulose acrylic polymers ; polyvinyl alcohols ; aiginic acid or sodium 15 alginate ; starch or pregelatinized starch ; sucroses and derivatives thereof ; guar gum ; polyethylene glycols, and mixtures and copolymers thereof.
14. Orally disintegrating tablet according to Claim 13,
20 wherein the compound soluble in gastric fluid is
hydroxypropylmethylcellulose.
15. Orally disintegrating tablet according to any cf
Claims 11 to 14, wherein it also includes an anti-oxidant
25 agent.
16. Orally disintegrating tablet according to Claim 15,
wherein the anti-oxidant agent is ascorbyl paimitate.
30 17. Orally disintegrating tablet according to any of Claims 12 to 17, wherein the pore-fcrming agent is hydroxypropylmethylcellulose.

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18. Orally disintegrating tablet according to any of Claims 11 to 17, wherein it contains from 2.5 to 1G mg oxycodone and from 80 to 750 mg acetaminophen.
5 19. Use of granules according to of Claims 1 to 6 for the manufacture of an analgesic medicament for oral administration intended to reduce pain.
20. Method for reducing pain, comprising oral
10 administration of granules according to any of Claims 1
to 6.
21. Use of a tablet according to any of Claims 9 to IS
for the manufacture of an analgesic medicament for oral
15 administration intended to reduce pain.
22. Method for reducing pain, comprising oral
administration of a tablet according to any of Claims 9
to 18.
20
23. Process for manufacturing orally disintegrating
tablets, comprising the steps of :
(a) spraying onto neutral cores a suspension in a
25 solvent of oxycodone or one of its
pharmaceutically acceptable salts, and at least one binding agent, so as to obtain pellets,
(b) applying a subcoat onto said pellets, by spraying
thereon a compound soluble in gastric fluid mixed
30 with a solvent, thus obtaining coated pellets,
(c) optionally drying said coated pellets,
(d) applying onto said coated pellets a taste-masking coating comprising a polymer or copolymer with

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dialkylaminoalkyl(meth)acrylate units and optionally a pore-forming agent, so as to obtain granules,
(e) optionally applying an antistatic coating onto
5 said granules,
(f) mixing acetaminophen, optionally applied onto
neutral cores and/or coated, with said granules,
at least one disintegrant comprising crospovidone
and at least one soluble diluent agent/-so as to
10 obtain a powder mixture, and
(g) tableting said powder mixture,
wherein the solvent used in at least one of steps (a) and (b) is a hydroalcoholic solvent. 15
24. Orally disintegrating tablet obtainable by the
process according to Claim 23.
25. Orally disintegrating tablet comprising acetaminophen
20 and oiycodone as the only active ingredients, said tablet
having an oxycodone content, after dry storage at 80°C fo.: 14 days, preferably for 21 days, of at least about '30?, preferably of at least about 95%, of the initial oxycodone content before storage.
Dated this 29th day of January, 2009.

Documents:

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Patent Number

270859

Indian Patent Application Number

209/MUMNP/2009

PG Journal Number

05/2016

Publication Date

29-Jan-2016

Grant Date

25-Jan-2016

Date of Filing

29-Jan-2009

Name of Patentee

ETHYPHARM

Applicant Address

194 BUREAUX DE LA COLLINE, BATIMENT D. 92213 SAINT CLOUD CEDEX.

Inventors:

#	Inventor's Name	Inventor's Address
1	HOARAU, DIDIER	5716 RUE SAINT URBAIN, H2T 2X3, MONTREAL.

PCT International Classification Number

A61K9/00

PCT International Application Number

PCT/EP2007/057912

PCT International Filing date

2007-07-31

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/821,449	2006-08-04	U.S.A.