MXPA99002404A - Controlled release dosage form of [r-(z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo[2.2. 2]oct-3-yl)acetonitrile monohydrochloride - Google Patents

Abstract

A controlled release formulation of an acetonitrile compound and its use in the treatment and/or prophylaxis of certain disorders.

Description

METHOD OF CONTROLLED RELEASE OF MONOCLORHYDRATE OF [R- (Z)] -ALFA- (METOXYIMINO) -ALFA- (1-AZABICICLO [2.2.2] OCT-3- IDACETONITRILO) DESCRIPTIVE MEMORY The present invention relates to a new formulation and its use in the treatment and / or prophylaxis of certain disorders. The monohydrochloride of [R- (Z)] -alpha- (ethoxyimino) -alpha- (1-azabicyclo [2.2.2] oct-3-yl) acetonitrile (compound X) and methods for their preparation are described in EP documents. -A-0392803, W095 / 31456 and WO95 / 17018. The compound increases acetylcholine function by an action on muscarinic receptors within the central nervous system and is therefore of potential use in the treatment and / or prophylaxis of dementia in mammals. W096 / 12486 describes the use of compound X in the manufacture of a medicament for increasing the processing of the amyloid precursor protein along an amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease. Swallowing tablet formulations and rapid release oral solutions of Compound X result in rapid absorption of the compound in the circulation and require a dose of 2 per day for optimal efficacy.

Surprisingly, it has now been found that it is possible to formulate compound X, which has a very high solubility in water and is active at extremely low doses, in such a way that its release is controlled to take place over a period of hours . Such a formulation would require only one dose per day: compliance is likely to improve in a patient population characterized by memory deficiency; It can also reduce side effects in case of an accidental overdose. In accordance with the foregoing, the present invention provides a controlled release oral dosage form, containing compound X, its major free base or any other pharmaceutically acceptable salt thereof. By controlled release is meant any formulation technique where the release of the active substance from the dosage form is modified to be carried out at a rate lower than that of an immediate release product, such as a conventional tablet or capsule for swallowing. The controlled release includes a delayed release, where the release of the active substance from the dosage form is modified to occur later than a conventional immediate release product. The subsequent release of the active substance from a delayed release formulation can be controlled to occur at a lower rate.

Examples of controlled release formulations that are suitable for incorporation into compound X are described in: Sustained Relase Medications, Chemical Technology Review No. 177. Ed. J.C. Johnson. Noyes Data Corporation 1980. Controlled Drug Delivery, Fundamentáis and Applications, 2a. Edition. Eds. J.R. Robinson, V.H.L. Read. Marcel Dekker Inc. New York 1987. Said controlled release formulations are preferably formulated in such a way that the release of compound X is effected through the gastrointestinal tract and occurs predominantly during the first 8 to 12 hours after ingestion. Preferred formulations include wax matrices, swellable and / or gellable polymer or hydrogel matrices, polymer coated tablets or controlled release waxes, pills, granules or beads that include matrices or coated with controlled release polymers or waxes and formulated subsequently as capsules, compressed tablets or suspensions. Suitable waxes for matrix formation or controlled release coating include non-ionic beeswax derivatives such as Gelucire 62/05, 50/02 or 50/13 (Gattefosse), glyceryl behenate, other mono-, di- or tri-esters of acid Glycerol fatty acid such as Precirol AT05 (Gattefosse), microcrystalline wax, hydrogenated castor oil or hydrogenated vegetable oil, long chain aliphatic alcohols such as stearyl alcohol and carnauba wax. Suitable materials for the formation of hydrogel matrices or swellable and / or gellable polymer matrices can be selected from alkylcelluloses, hydroxyalkyl celluloses, polyvinyl alcohol, polymethacrylates, polymethylmethacrylates, methacrylate / divinylbenzene copolymers, carboxymethylamide, polyoxyalkylene glycols, polyvinylpyrrolidone and carboxymethylcellulose. In particular, the swellable polymeric material may be selected from interlaced sodium carboxymethylcellulose, crosslinked hydroxypropyl cellulose, high molecular weight polyhydroxypropylmethylcellulose, carboxymethylamide, potassium methacrylate / divinylbenzene copolymer, polymethylmethacrylate, crosslinked polyvinylpyrrolidone, and high molecular weight polyvinyl alcohol. The particular gellable polymeric material can be selected from methylcellulose, carboxymethylcellulose, low molecular weight hydroxypropylmethylcellulose, low molecular weight polyvinyl alcohols, polyoxyethylene glycols and non-crosslinked polyvinylpyrrolidone. The gellable and swellable polymeric material in particular may be selected from medium viscosity hydroxypropylmethylcellulose and medium viscosity polyvinyl alcohols. Controlled release polymers include hydrogel polymers such as those listed above, hydrophobic polymers and enteric or pH dependent polymers. Suitable materials for the formation of hydrophobic controlled release polymer coatings include alkylcelluloses, which may be used in the form of latex suspensions such as Surelease (Colorcon) or Aquacoat (FMC), and methacrylic acid derivatives, which may be used in the form of suspensions. of latexes such as Eudragit RS, RL and NE (Rohm). Suitable materials for the coating formation of pH-dependent or enteric polymers include methacrylic acid derivatives, which may be used in the form of latex suspensions such as Eudragit L and S (Rohm). Seal coatings, film layers used to separate several functional layers of the formulation or to provide a final coat to the exterior of the formulation, contain materials suitable for film formers such as alkylcelluloses, which can be used in the form of latex suspensions such as Surelease (Colorcon) or Aquacoat (FMC), and hydroxyalkylcelluloses such as hiroxypropylmethylcelluloses (for example Opadry (Colorcon)). The formulation may also include plasticizers such as triethyl citrate, dibutyl sebacate or medium chain triglycerides in the controlled release polymer layer.

The materials that make up the pills include adequate grades of microcrystalline cellulose such as Avicel PH101 (FMC). The granules can be formed from any commonly used pharmaceutical filler or diluent such as lactose, lactose monohydrate, mannitol, microcrystalline cellulose, dicalcium phosphate or starch. The globules can be formed by layering or sprinkling on coated seeds. Other suitable ingredients in controlled release dosage forms include polyethylene glycol and propylene glycol and these, as well as pharmaceutical fillers, can be used to modify the rate of release by inclusion in matrices, pills, granules or pellets. The formulation may also include hydrophobic excipients that retard release from the formulation such as ethylcellulose, talcum, colloidal silicon dioxide or glyceride monostearate and / or one or more binders such as hydroxypropylmethylcellulose, microcrystalline cellulose or polyvinylpyrrolidone. Moisturizing agents such as sodium lauryl sulfate, lubricants such as magnesium stearate and anti-adhesion agents such as colloidal silica may also be included. A particularly preferred formulation includes globules with drug-coated layers coated with a controlled release polymer, either alone or in combination with beads with drug layers not coated with a controlled release polymer (immediate release globules). In the coating process with drugs in coated beads, sugar-coated beads of appropriate size can be coated in layers with a solution or dispersion containing the active substance, inert excipients and / or retarders such as ethylcellulose, talcum, colloidal silicon dioxide or monostearate of glyceride and / or one or more binders such as hydroxypropylmethylcellulose or polyvinylpyrrolidone. The layered active substance can be achieved at a predetermined speed and temperature using either a coating vessel or a fluid bed dryer. The layered beads can be sealable in a sealable form with a suitable film-forming polymer such as hydroxypropylmethylcellulose (for example Opadry) or (Eudragit® L30D-55 (a methacrylic acid copolymer) and subsequently coated with one or more suitable controlled release polymers preferably selected from alkylcelluloses, hydroxyalkylcelluloses, sodium carboxymethylcellulose and methacrylic acid derivatives, such as ethylcellulose, Eudragit® RS, EudragitR RL or Metocel E4M, to produce beads that release compound X for a period of eight to twelve hours and / or X release compound in one or more rhythms.Stamped coated beads can be used for an immediate release dose The controlled release or a controlled release mixture and immediate release globules can be filled in an appropriately sized capsule or compressed with inert excipients into tablets of appropriate physical parameters such as shape, size, hardness and disintegration. s) further controls the release of any coating polymer (s) or with seal, preferably integrates from 10 to 30% by weight of the total dosage form. The plasticizer is usually present and can integrate at least 2% by weight. The binder (s) and retarder (s) typically make up 3-10% by weight. Another particularly preferred formulation includes an inflatable and / or gellable polymer matrix tablet. The polymer matrix is preferably a hydrogel polymer selected from alkylcelluloses such as methylcellulose, hydroxyalkylcellulose such as hydroxypropylcellulose and hydroxypropylmethylcellulose, polyvinyl alcohol, polymethacrylates, interlaced polyvinylpyrrolidone and sodium carboxymethylcellulose. The polymers typically integrate 10 to 50% by weight of the tablet. The matrix tablet can be sealed with a hydrophobic controlled release polymer coating such as ethylcellulose (Surelease (Colorcon)) to retard hydration of the hydrogel matrix in the tablet. The hydrophobic coating polymer typically integrates from 4 to 10% by weight of the tablet.

Said matrix tablet formulations can be prepared, either by direct compression or by wet granulation processes. The coating can be achieved by using a coating vessel. Other preferred formulations are described in U.S. Pat. No. 5,422,123. Thus, a particular aspect of the invention provides a system for controlled release of an active substance, which is compound X, its main free base or any other pharmaceutically acceptable salt thereof, includes (a) a deposit core which includes an effective amount of the active substance and having a defined geometric shape and (b) a support platform applied to said deposit core, wherein said deposit core contains at least the active substance and at least one member selected from the group that consists of (1) a polymeric material that is made upon contact with water or aqueous liquids and a gellable polymeric material wherein the ratio of said polymeric material swellable to said gellable polymeric material is in the range of 1.9 to 9: 1, and (2) a unique polymer material having both inflatable and gellable properties, and characterized in that the support platform is a elastic support, applied to said reservoir core to partially cover the surface of the reservoir core and follow the changes due to the hydration of the reservoir core and be slowly soluble and / or slowly gellable in aqueous fluids. The swellable polymeric material in (1) may be selected from interlaced sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, high molecular weight polyhydroxypropylmethylcellulose, carboxymethyl starch, potassium methacrylate / divinylbenzene copolymer, crosslinked polyvinylpyrrolidone, and polyvinyl alcohol. The gellable polymeric material in (1) can be selected from methylcellulose and non-interlaced polyvinylpyrrolidone. The support platform may include polymers such as polyhydroxypropylmethylcellulose, polyvinyl alcohol, polyacrylate, polymethacrylate, polyhydroxypropylcellulose and polyisodio carboxymethylcellulose; plasticizers such as polyoxyethylene glycols, castor oil, hydrogenated castor oil, ethyl phthalate butyl phthalate, natural glycerides, synthetic glycerides and semisynthetic glycerides; binders such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, gum arabic and alginic acid; hydrophilic agents such as mannitol, lactose, starch and colloidal silica; and / or hydrophobic agents such as hydrogenated castor oil, magnesium stearate, a fatty substance, wax, natural glycerides and synthetic glycerides. The polymer (s) typically integrates 30 to 90% by weight support platform, for example about 35 to 40%. The plasticizer can integrate at least 2% by weight of the support platform, for example approximately 15 to 20%. The binder (s), hydrophilic agent (s) and hydrophobic agent (s) typically integrate up to about 50% by weight of the support platform, for example about 40 to 50%. Said formulation can be prepared as generally described in document E.U.A. 5,422,123. The document E.U.A. -A-4 839 177 describes a major alternative of controlled release formulations, suitable for use in the present invention. In this way, a further aspect of the invention provides a system for the controlled rate release of compound X, which consists of: a) a deposit core that includes effective amounts of compound X and that has a defined geometric shape, b) a support platform applied to said deposit core wherein said deposit core contains, mixed with the active substance, at least one member selected from the group consisting of a (a) 5-80% by weight of the total weight of the deposit core of a polymeric material, which has a high degree of swelling upon contact with water or aqueous liquids and 90-10% by weight of the total weight of the deposit core of a gellable polymeric material, and (b) a unique polymeric material having both inflatable and gellable properties, and other adjuvants capable of providing the mixture with characteristics suitable for compression and for water intake, and characterized in that said support platform consists of a polymeric material. insoluble in aqueous liquids and partially coating said deposit core. The swellable polymeric material in (a) may be selected from interlaced sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, high molecular weight polyhydroxypropylmethylcellulose, carboxymethylamide, potassium methacrylate / divinylbenzene copolymer, polymethylmethacrylate, crosslinked polyvinylpyrrolidone, and high molecular weight polyvinyl alcohol. The polymeric material gellable in (a) can be selected from methylcellulose, low molecular weight hydroxypropylmethylcellulose, low molecular weight polyvinyl alcohols, polyoxyethylene glycols and non-interlaced polyvinylpyrrolidone, the swellable polymeric material and gellable in (b) can be selected from hydroxypropylmethylcellulose of medium viscosity and medium viscosity polyvinyl alcohols. The support platform may include insoluble polymeric material selected from acrylates, cellulose, ethylcellulose, cellulose acetate propionate, polyethylene, methacrylates, acrylic acid copolymers and high molecular weight polyvinyl alcohols. Said formulation can be prepared as generally described in US 4,839,177. WO 94/06416 describes a further alternative of controlled release formulations suitable for use in the present invention.

In this way, a further aspect of the invention provides a system for the controlled rate release of compound X, which consists of a compressed pharmaceutical tablet capable of releasing compound X at different speeds, consisting of 3 layers, where: a first layer contains X compounds with controlled or immediate release formulation, composed of polymeric substances of rapid swelling and / or soluble and / or wastable through contact with aqueous fluids and adjuvants; a second layer containing compound X, either the same or different from the first layer, with slow release formulation, composed of swellable and / or gellable polymeric substances and / or wastable by contact with aqueous fluids, and adjuvants; a low permeability barrier layer covering said second layer or alternatively, placed between the first and second layers, consisting of polymeric substances, adjuvants, plasticizing agents, and if necessary, compound X. The polymeric substances of the first layer they may be selected from interlaced polyvinylpyrrolidone, hydroxypropylcellulose and low and medium molecular weight hydroxypropylmethylcellulose, interlaced sodium carboxymethylcellulose, caboxymethyl starch, potassium methacrylate / divinylbenzene copolymer, polyvinyl alcohols, starches, starch derivatives, microcrystalline cellulose and cellulose derivatives, derivatives of β-cyclodextrin and dextrin. The polymeric substances of the second layer can be selected from the group consisting of hydroxypropylmethyl cellulose having a molecular weight of 1,000 to 4,000,000, hydroxypropylcellulose having a molecular weight of 2,000 to 2,000,000, carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, alginic acid and derivatives thereof, carboxymethylcellulose and derivatives thereof, poly (methylvinyl / maleic anhydride) ethers, ethylcellulose, methylcellulose and cellulose derivatives. The adjuvants of the first and second layers can be selected from the group consisting of starch, pregelatinized starch, calcium phosphate, mannitol, lactose, sucrose, glucose, sorbitol, microcrystalline cellulose, gelatin, polyvinylpyrrolidone, methylcellulose, starch solution, ethylcellulose, gum arabica, gum tragacanth, magnesium stearate, stearic acid, colloidal silica, glyceryl monostearate, hydrogenated castor oil, waxes, and mono, bi and trisubstituted glycerides. The polymeric substances of the barrier layer can be selected from the group consisting of hydroxypropylcellulose having a molecular weight of 1,000 to 4,000,000, hydroxypropylcellulose having a molecular weight of 2,000 to 2,000,000, carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, carboxymethylcellulose, ethylcellulose and methylcellulose. Adjuvants of the barrier layer can be selected from the group consisting of glyceryl monostearate, semisynthetic glyceride, glyceryl palmitoesterate, glyceryl behenate, polyvinylpyrrolidone, gelatin, ethylcellulose, methylcellulose, sodium carboxymethylcellulose, magnesium stearate, stearic acid, stearate sodium, talcum, sodium benzoate, boric acid and colloidal silica. The plasticizing agents of the barrier layer can be selected from the group consisting of hydrogenated castor oil, fatty acids, triglycerides and substituted glycerides, polyoxyethylene glycols and derivatives thereof, having a molecular weight of 400 to 60,000. Said formulation can be prepared as generally described in WO 94/06416. The dosage form preferably contains compound X itself. Compound X has active doses of about 5-125 micrograms (μg) (calculated as free base). It has been found through the administration to human patients that its efficacy as a cognition enhancer can be obtained in daily doses lower than 0.01 mg / kg, more particularly 0.003 mg / kg and lower, for example 0.0001-0.003 mg / kg as 0.00035 -0.003 mg / kg, 0.0007-0.003 mg / kg, 0. 0001-0,0007 mg / kg or 0.00035-0.002 mg / kg. Suitable unit doses to achieve said daily doses are 5, 12.5, 25.50 or 75 μg, administered daily twice or 50 μg or 10 μg, once daily. These unit doses are calculated on the basis of individuals of 50-70 kg and as free base. Suitably, the in vitro release profile of the dosage form, e.g. the amount of Compound X released in overtime will be selected, so it will provide an area under the in vitro plasma profile curve that is similar to that obtained following conventional oral administration of a fast release tablet, compound X of 5 to 75 μg (calculated as a free base) twice a day. Preferably, 25-70% is released for 4 hours and 70-100% is released for 8 hours. The dosage form of the invention can be used in the treatment and / or prophylaxis of dementia, including the Alzheimer's in mammals and to increase the processing of amyloid precursor protein along a non-amyloidogenic pathway in patients suffering from, or at risk of developing Alzheimer's disease. These disorders will be called "disorders" from now on. The present invention provides a method for treating "disorders" by administering an effective amount of a controlled release oral dosage form containing compound X, its major free base or any other pharmaceutically acceptable salt thereof for a patient who I need it. The present invention further provides the use of a controlled release oral dosage form containing compound X, its major free base or any other pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating "disorders." The present invention also provides a pharmaceutical composition for use in the treatment of "disorders", which includes a controlled release oral dosage form containing compound X, its principal free base or any other pharmaceutically acceptable salt thereof. The following examples illustrate the present invention.

EXAMPLES In the following examples, the weight shown is the weight of the free base; Compound X is the hydrochloride salt, (pfb = pure free base). The sizes of the mesh are standard of the United States.

EXAMPLE 1 WAX MATRIX Compound X 0.005-0.1 mg pfb Gelucire 65/05 (Gattefosse) 190 mg Propylene glycol 10 mg EXAMPLE 2 PILLARS COATED WITH FILM Component mg / capsule (500 mg) Function Compound X 0.005-0.1 mg pfb Active Lactose 300 Hydrophilic diluent Acivel PH 101 (FMC) 200 Inert pill matrix Film coating p / p of Surelease pill cores (Coloreon) 2-10% Controlled release polymer coating Silicone antifoam Anti-foaming agent EXAMPLE 3 PILLARS COATED WITH FILM Component mg / capsule (500 mg) Function Compound X 0.005-0.1 mg pfb Active Lactose 400 Hydrophilic diluent Acivel PH 101 100 Inert Pill Matrix Film Coating p / p Aquacoat Pill Cores (FMC) 2-10% controlled release polymer coating Silicone antifoam Anti-foaming agent Di-butilsebacat 20-30% (weight of polymer plasticizer) In Examples 2 and 3, the pills are produced by extrusion / spheronization, using water as the granulation liquid and an appropriate size fraction is obtained by sieving. The pills are then coated in a fluid bed coater (bottom spray) with 2-10% (w / w) of an aqueous Surelease dispersion (15% solids in dispersion). The desired release profiles are obtained by mixing uncoated pills (= immediate-release pills) and pills coated with adequate coating levels (= sustained-release pills), which are then filled into hard gelatin capsules.

EXAMPLE 4 MATRIX PILLS Component xng / capsule (500 mg) Function Compound X 0.005-0.1 mg pfb Active Glyceryl Behenate 200 Hydrophobic Matrix Acivel PH 101 300 Inert pill matrix Sodium lauryl sulfate 0.1 Wetting agent The pills are produced by extrusion / spheronization using water and sodium lauryl sulfate as the granulation liquid, and an appropriate size fraction is obtained by sieving. The pills can additionally be coated in a fluid bed coater (bottom spray) with aqueous polymer dispersions to further reduce release rates and obtain the desired release profiles.

EXAMPLE 5 HIDROGEL MATRIX Excipient% p / p g / tablet mg / tablet Compound X 0.003-0.07pfb 0.005pfb 0. lpfb Hydroxypropyl- 25 37.5 37.5 cellulose Purified water - - - Starch 100 109.5 108.5 Stearate 2 3.0 3.0 magnesium Total 100 150 150 The tablets can be prepared by the following procedure: 1.- Mix the starch and HPC in a high-slip mixer. 2. - Dissolve the drug in a small amount of water and sprinkle in the mixer while mixing. 3.- Wash the spray mechanism with a small volume of water in the mixer while mixing. 4. - Mix the granulate with enough water to achieve a medium to heavy granule. 5.- Partially dry the granule. 6.- Sifting through a suitable mill. 7.- Complete the drying of the ground granule. 8.- Lubricate with Mg stearate. 9.- Compress tablets with a target weight of 150 mg.

EXAMPLE 6 WAX MATRIX Excipient% P / P mg / tablet mg / tablet Compound X 0.003 to 0. 07pfb 0. .005pfb O.lpfb Anhydrous lactose 100 150 150 Gelucire 62/05 18 27.0 27.0 Stearate 2 3.0 3.0 magnesium Total 100 150 150 The tablets can be prepared in the following procedure: 1.- Pre-mix the drug with a small amount of lactose. 2. - Insert the premixed drug with the remaining lactose and the required% of Gelucire 62/05 in a pre-heated pelletizer. 3.- Pelletize until the required pill size has been achieved. 4.- Remove the pills and allow them to cool. 5.- Sift the pills until it is necessary. 6.- Lubricate the pills. 7.- Compress or encapsulate the pills.

EXAMPLE 7 BILATERATE TABLET OF CONTROLLED RELEASE Active layer Component mg / tablet Function Compound X 0.005-0.1 mg pfb Active Hydroxypropylmethyl68.5 Matrix cellulose anterior of hydrogel Mannitol 20 Soluble filler Ethylcellulose 7.5 Binder (applied in ethanolic solution) Magnesium stearate 2 Lubricant Colloidal silica 2 Non-stick EXAMPLE 7 (CONTINUED) Support platform Component mg / tablet Hydroxypropylmethyl function39.75 Hydrogel anterior cellulose matrix Castor oil 6.5 Filler, insoluble hydrogenated Ethylcellulose (applied 2.5 Binder in ethanolic solution) Pigment oxide 0.5 Pigment yellow iron Magnesium stearate 0.5 Lubricant Colloidal silica 0.25 Non-stick The tablets can be prepared as described in US5433123.

EXAMPLE 8 WAX MATRIX Component% p / p Function Compound X 0.02pfb Active Gelucire 50/02 91.5 Wax matrix Gelucire 50/13 5 Wax matrix Propylene glycol 1.98 Solvent Colloidal silica 1.5 Excipient EXAMPLE 8 (CONTINUED) hydrophobic Citrate diacid 0-1.5 Sodium stabilizer PROCESS Gelucire waxes melted together at around 60 ° C. Compound X was dissolved in propylene glycol and mixed in the waxes. Subsequently, the colloidal silica was also mixed, and the mixture was filled into layers of size 3 hard gelatin capsule.

TABLE 1 RELEASE PROFILE OF CAPSULES FILLED WITH COMPOUND WAX X IN WATER (0% CITRATE Time (hour;% Released 1 13 3 29 5 53 8 73 EXAMPLE 9 ETILCELLULOSE COATED BLOODS 200 mg of beads coated with sugar of mesh size 16-20, 20-25 or 25-30 can be used. A medicated layer solution of the following composition was used: Component% P / P Function Compound X 0.003-0.05pfb Active OpadryR Clear 3 Binder Citrate diacid 1.5 Sodium stabilizer Purified water c.b. Total 100 Seal coating solution: a solution of Opadry JR? Clear (YS-1-9025A) in purified water at 10% solids concentrations was made by dissolving 10 g of Opadry® Clear in 900 g of purified water. Polymer coating: A polymer coating dispersion containing ethylcellulose (Surelease "-) of the following composition was made and used for the polymer coating the coated beads with a weight gain of 10% to 25%, in particular 10, 12, 15, 17, 22 and 25%.

Component% p / p Surelease 60 function (25% Coating as solids) polymer controlled with plasticizer Purified water c.b. Total 100 Globules with drug layers were produced by layered drug solution in 25-30 mesh coated beads using a Niro STREA-1 fluid bed drier for 100 micrograms of drug layer as a free base in 200 mg of coated globules. The layered beads of the drug were sealed with Opadry® Clear seal coating solution for a 3% weight gain to produce the immediate release beads. A portion of immediate release pellets were coated with polymer for a weight gain of 10% to 25% with Surelease® coating dispersion. The polymer-coated final beads were produced by sealingly coating the polymer-coated beads for a 2% weight gain with a seal-coated coating solution.

Opadry? Clear.

TABLE 2 SCALE PROFILE OF LIBERATION OF GLOBULES COATED WITH ETILCELLULOSE, 10-25% IN WEIGHT OF COMPOUND X IN WATER Time (hour;% Released 1 0.8-36 2 5-57 4 13-75 8 18-91 EXAMPLE 10 GLOBULES COATED WITH ETILCELLULOSE 200 mg of beads coated with sugar of mesh size 16-20, 20-25 or 25-30 can be used. A medicated layer solution of the following composition was used: Component% P / P Function Compound X 0.003-0.05pfb Active p Opadry Clear 3 Binder Citrate diacid 1.5 Sodium stabilizer Purified water c.b. Total 100 Seal Coating: A seal coating dispersion containing Eudragit® L30D-55 of the following composition was made and used to seal the beads in drug coatings at a 4% weight gain.

Component% p / p Function EudragitR L30D-55 45 (30% as solid coating) with polymeric seal Triethyl citrate 2.02 Talc plasticizer 3.10 Anti-scaling Purified water c.b. Total 100 Polymer coating: A polymer coating dispersion containing ethylcellulose p (Surelease1 ^) of the following composition was made and used for polymer coating the coated beads with a 10% to 25% weight gain.

Component% P / P Surelease® 60 function (25% as solids coating) controlled release polymer with plasticizer Purified water c.b. Total 100 Layered globules of the drug were produced by layered drug solution in 25-30 mesh coated beads using a Nitro STREA-1 fluid bed drier for 100 micrograms of drug layer as a free base in 200 mg of blood cells. coated. The drug layered beads were coated with Eudragit® L30D-55 seal dispersion coating for a 4% gain in weight to produce the immediate release beads. A portion of immediate release pellets was coated with polymer for a weight gain of 10% to 25% with p Surelease coating dispersion. The polymer-coated final beads were produced by sealing the polymer-coated beads with a 2% weight gain with the Opadry seal coating solution.

Clear.

TABLE 3 RELEVANT PROFILE OF COATED BLOCKS WITH SEALED / ETILCELLULOSE COATING OF THE X COMPOUND IN WATER Time (hour;% Released, 10% Surelease 0.5 1.5 1 5 2 20 TABLE 3 (CONTINUED) 4 39 6 49 8 56 EXAMPLE 11 GLOBULES COATED WITH ETILCELLULOSE 200 mg of beads coated with sugar of mesh size 16-20, 20-25 or 25-30 can be used. A medicated layer solution of the following composition was used: Component% p / p Compound Function X 0.003--0. .05pfb Active OpadryR Clear 3 Binder Sodium diacid citrate 1.5 Stabilizer Purified water c.b. Total 100 Seal coating solution: A solution of Opadry, R * Clear (YS-1-9025A) in purified water at 10% solids concentrations was made by dissolving 100 grams of Opadry® Clear in 900 grams of purified water. Polymer coating: A coating dispersion of the ethylcellulose-containing polymer p (Aquacoat *) of the following composition was made and used for the polymer coating the coated coils with seal for a 10% weight gain.

Component% p / p Function p Aquacoat 50 (30% as solids Controlled release polymer coating Triethyl citrate 2.02 Plasticizer Purified water c.b. Total 100 Layered globules of the drug were produced by layered drug solution in 25-30 mesh coated beads using a Niro STREA-1 fluid drier for 100 micrograms of drug layer as a free base in 200 mg of coated beads . The layered beads of the drug were coated with Opadry * Clear p-seal solution for a 3% gain in weight to produce the immediate release beads. One portion of immediate release pellets were coated polymers for a weight gain of 10% with a p coating dispersion of Aquacoat *. The polymer-coated final beads were produced by sealing the polymer-coated beads with a 2% weight gain with an Opadry® Clear seal coating solution.

EXAMPLE 12 EUDRAGIT COATED GLOVES 200 mg of beads coated with sugar of mesh size 16-20, 20-25 or 25-30 can be used. A medicated layer solution of the following composition was used: Component% P / P Compound Function X 0.003-0. .05pfb Active Opadry- * Clear 3 Binder Sodium diacid citrate 1.5 Stabilizer Purified water c.b. Total 100 Seal coating solution: A solution of Opadry JR * Clear (YS-1-9025A) in purified water at 10% solids concentrations was made by dissolving 100 p grams of Opadry * Clear in 900 grams of purified water. Polymer coating: A coating dispersion of the polymer containing Eudragit® RS or RS / RL of the following composition was made and used for the polymer coating the coated coils with seal for a 10% weight gain.

Component% p / p Function Eudragit * RS 30D 45 (30% as solids Controlled release polymer coating Triethyl Citrate 2.02 Plasticizer Talc 3.10 Anti-peeling Purified water c.b. Total 100 Component% p / p Function EudragitR RS 30D 45 (30% as solids Controlled release polymer coating Eudragit * RS 30D 9 (30% as solids Controlled release polymer coating Triethyl citrate 2.02 Plasticizer Talcum 3.10 Anti-skidding Purified water c.b. Total 100 separate globules in drug layers were produced by layered drug solution in 25-30 mesh coated beads using a Niro STREA-1 fluid bed drier for 100 micrograms of drug layer as a free base in 200 mg of coated globules. The beads in drug layers were coated with a seal with an Opadry Clear seal coating solution for a 3% weight gain to produce the immediate release pellets. A portion of the immediate release beads was coated with polymer for a weight gain of 10% with a coating dispersion of Eudragit® RS or RS / RL. The polymer-coated final beads were produced by the seal coating that coated the polymer coated beads for a 2% weight gain with the Opadry * Clear seal coating solution.

TABLE 4 PROFILE OF RELEASED BLOOD COVERED BY EUDRAGIT ^ RS / RL OF COMPOUND X IN WATER Time% Released 0.5 0.2 1 0.3 2 0.4 4 1.9 6 13 8 20 EXAMPLE 13 GLOBULES COATED WITH METOCEL 200 mg of beads coated with sugar of mesh size 16-20, 20-25 or 25-30 can be used. A medicated layer solution of the following composition was used: Component% p / p Function Compound X 0.003-0.05pfb Active Methocel E4M 15 Controlled release polymer coating Sodium diacid citrate 1.5 Stabilizer Purified water c.b. Total 100 Seal coating solution: A solution of Opadry * Clear (YS-1-7006) in purified water at 10% solids concentrations was made by dissolving 100 grams of Opadry * Clear in 900 grams of purified water.

EXAMPLE 14 GLOBULES COATED WITH ETILCELLULOSE WITH A RETARDER 200 mg of beads coated with sugar of mesh size 16-20, 20-25 or 25-30 can be used. A medicated layer solution of the following composition was used: Component% p / p Compound Function X 0.003-0.0i5? Fb Binder OpadryR Clear 1.5 Retarder SureleaseR 1.5 Stabilizer Sodium diacid citrate 1.5 Purified water C.b. Total 100 Seal coating solution: A solution of Opardy JR * Clear (YS-1-9025A) in purified water at 10% solids concentrations was made by dissolving 100 grams of Opardy® Clear in 900 grams of purified water. Polymer Coating: A coating dispersion of the ethylcellulose-containing polymer (Surelease *) of the following composition was made and used for the polymer coating the coated coils with seal for a 10% weight gain.

Component% P / P Surelease® 60 function (25% as solids Controlled-release polymer coating with plasticizer Purified water c.b Total 100 Layered globules of the drug were produced by layered drug solution in 25-30 mesh coated beads using a Niro STREA-1 fluid bed drier for 100 micrograms of drug layer as a free base in 200 mg of coated globules. The layered beads of the drug were sealed with Opadry Clear seal coated p solution for a 3% gain in weight to produce the immediate release beads. A portion of the immediate release beads was coated with polymer for a 10% weight gain or a Surelease coating dispersion. The polymer-coated final beads can be produced by sealing the polymer-coated beads with a 2% weight gain with the Opadry® Clear seal coating solution.

TABLE 5 PROFILE OF RELEASE OF GLOBULES COATED WITH ETILCELLULOSA WITH RETARDER. OF COMPOUND X IN WATER Time (hr)% Li Lberadc) Without retarder With retarder 0. 5 12 8 1 37 22 2 57 35 4 73 48 6 85 53 8 58 EXAMPLE 15 GLOBULES COVERED WITH ENTREME LAYER 200 mg of beads coated with sugar of mesh size 16-20, 20-25 or 25-30 can be used. A medicated layer solution of the following composition was used: Component% w / w Function Compound X 0.003-0.05 pfb Active OpadryR Clear 3 Binder Citrate diacid 1.5 Sodium stabilizer Purified water c.b. Total 100 Coating solution with seal: a solution of Opadry JR * Clear (YS-1-9025A) in purified water at 10% solids concentrations was made by dissolving 100 grams of Opadry® Clear in 900 grams of purified water. Polymer coating: A polymer coating dispersion containing Eudragit * L30D-55 of the following composition was made and used for the polymer coating the sealed beads for a 20% weight gain.

Component% p / p Function Eudragit L30D-55 45.00 (30% as solid Polymer) enteric pH-dependent) Triethyl citrate 2.02 Talc plasticizer 3.10 Anti-scaling Purified water c.b. Total 100 Layered globules of the drug were produced by layered drug solution in 25-30 mesh coated beads using a Nitro STREA-1 fluid bed drier for 100 micrograms of drug layer as a free base in 200 milligrams of beads coated. The layered beads of the drug were sealed with an Opadry * Clear seal coating solution for a 3% weight gain to produce the immediate release beads. A portion of the immediate release pellets were coated with enteric coating for a 20% weight gain with an enteric coating dispersion of Eudragit. The final enteric coated beads were produced by stampering the enteric coated coated beads for a 2% weight gain with the Opadry Clear seal coating solution.

EXAMPLE 16 MATRIX TABLET Ingredient mg / tablet Function Compound X 0.005-0.1 pfb Active Hydroxypropylmethylcellulose 75.0 Matrix E4M CR hydrogel Diacid Citrate 3.00 Stabilizer Sodium Lactose, Fast Fio 70.38 Hydrophilic Diluent Magnesium stearate 1.50 OpadryR White lubricant 2.25 Seal coated polymer Seal coating solution: a solution of Opadry JR * Clear (YS-1-9025A in purified water at 10% solids concentrations was used when dissolving 100 grams of Opadry® Clear in 900 grams of purified water) Polymer coating: a dispersion of the polymer coating containing ethylcellulose ( Surelease) of the following composition was made and used for the polymer coating the beads coated with seal for a 10% weight gain.

Component% p / p Function p Surelease * 60 (25% as Solid Coating) of controlled release polymer Purified water c.b. Total 100 700 grams of core tablets were coated using a Vector LDCS container for a 3% weight gain with the OpadryR Clear seal coating solution. Seal-coated tablets were subsequently coated with polymer for a 4% weight gain using the Surelease® coating dispersion.

TABLE 6 RELEASE PROFILE FOR A COMPOSITE MATRIX TABLET X IN WATER Time (hr)% Dissolved 1 8 2 30 4 58 8 96 EXAMPLE 17 BILATERATE CONTROLLED RELEASE TABLET Active Layer Component mg / tablet Function Compound X 0.005-0.1 mg pfb Active Metocel K4M 15.00 Hydrogel polymer Lactose Monohydrate 62.0 Hydrophilic filler Polyvinypyrrolidone 3.0 Binder Magnesium stearate 1.0 Hydrophobic lubricant Siloid 244 1.0 Hydrophilic release agent EXAMPLE 7 (CONTINUED) Support Platform Component mg / tablet Function Compritol 888 15.0 Lactose Monohydrate Laminating Agent 29.0 Hydrophilic filler Polyvinylpyrrolidone 4.0 Binder Magnesium stearate 1.5 Hydrophobic lubricant Metocel E5 29.4 Hydrogel polymer Oxide of iron 0.1 Coloring

Claims (19)

NOVELTY OF THE INVENTION CLAIMS

1. - A controlled-release oral dosage form containing [R- (Z)] -alpha- (methoxyimino) -alpha- (1-azabicilko [2, 2, 2] oct-3-yl) acetonitrile monohydrochloride (compound X) ), its principal free base or any other pharmaceutically acceptable salt thereof.

2. A dosage form according to claim 1, further characterized in that it provides an in vitro release profile selected to provide an area under an in vitro plasma profile curve that is similar to that obtained following conventional oral administration of a compound X (calculated as a free base) of 5 to 75 μg of a fast-release tablet twice a day.

3. A dosage form, according to claim 1 or 2, further characterized in that it provides an in vitro release profile of 25-70% for 4 hours and 70-100% for 8 hours.

4. A dosage form according to any of claims 1 to 3, selected from wax matrices, swellable and / or gellable matrices, tablets coated with polymers or controlled release waxes and pills, granules or globules including matrices or coated with polymers or controlled release waxes and subsequently formulas such as capsules, compressed tablets or suspensions.

5. A dosage form according to any of the preceding claims which includes an inflatable and / or gellable matrix selected from alkylcelluloses, hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates, polymethylmethacrylates, methacrylate / divinylbenzene copolymers, carboxylmethylamide, polyoxyalkylene glycols, polyvinylpyrrolidone and carboxymethylcellulose .

6. A dosage form according to claim 5, further characterized in that the matrix is selected from alkylcelluloses, hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates, interlaced polyvinylpyrrolidone and sodium carboxymethylcellulose.

7. A dosage form according to claim 5 or 6 which includes a hydrogel matrix tablet coated with a hydrophobic controlled release polymer coating selected from alkylcelluloses and methacrylic acid derivatives.

8. A dosage form according to claim 7, further characterized in that the polymer matrix includes 10-50% and the hydrophobic controlled release polymer includes 4-10% by weight of the tablet.

9. A dosage form according to claims 7 or 8 that includes a tablet of the following composition (mg / tablet): Compound X; 0.005-0.1 pfb; hydroxypropylmethylcellulose, 75.0; sodium diacitrate citrate, 0-3.00; Lactose, Fast Fio, 70.38-73.38; magnesium stearate, 1.50; Opadry White, 2.25; seal coated with a solution of Opadry® Clear (YS-1-7006) in 10% solids concentrations and polymer coated with a 60% w / w dispersion (25% p solids) containing ethylcellulose (Surelease *) .

10. A dosage form according to any of claims 1 to 4, further characterized in that it includes drug layered globules coated with controlled release polymer, either alone or in combination with binders in drug layers not coated with a drug. controlled release polymer (immediate release globules) and optionally, inert excipients and / or retarders and / or one or more binders.

11. A dosage form according to claim 10, further characterized in that the layered globules are covered with seal with a polymer that forms a film.

12. - A dosage form according to claim 10 or 11, further characterized in that the coating of the controlled release polymer is selected from alkylcelluloses, hydroxyalkylcelluloses, sodium carboxymethylcellulose and methacrylic acid derivatives.

13. A dosage form according to any of claims 10 to 12, further characterized in that the polymer (s) comprise from 10 to 30% by weight of the total dosage form.

14. - A dosage form according to claim 10 in capsule form including coated sugar globules of a mesh size of 16-20, 20-25 or 25-30, coated for a drug load of 100 micrograms (calculated as free base) per 200 mg globules with a medicated aqueous layer solution of the following composition (% w / w): compound X; 0.003-0.06 pfb; Opadry, 3; sodium dihydride citrate, 0-1.5; seal coated with a solution of Opadry * Clear (YS-1-7006) in purified water at 10% solids concentrations for a 3% weight gain and a portion of pellets coated with more polymer for a weight gain of 10-25% with a dispersion at 60% w / w (25% as solids) containing ethylcellulose (Surelease®) and subsequently coated with seal for a gain in weight of 2% with the aforementioned seal coating.

15. The use of a controlled release oral dosage form according to claim 1, in the manufacture of a medically for treatment and / or prophylaxis of dementia, including Alzheimer's disease in mammals.

16. The use of a controlled release oral dosage form according to claim 1, in the manufacture of a medicament for increasing the processing of amyloid precursor protein along a non-amylodogenic pathway in patients suffering from, or having risk of developing, Alzheimer's disease.

17. A form or use of doses according to any of the preceding claims, further characterized in that the release in the gastrointestinal tract is carried out predominantly during the first eight to twelve hours after ingestion.

18. A form or use of doses according to any of the preceding claims, which contain [R- (Z) -alpha- (methoxyimino) -alpha- (1-azabicyclo [2.2.2] oct-3- monohydrochloride] il) acetonitrile.

19. A form or use of doses according to any of claims 1 to 18 containing compound X of 5 μg, 12.5 μg, 25 μg, 50 μg, 75 μg or 100 μg (calculated as free base).