MXPA00008849A

MXPA00008849A - Composition

Info

Publication number: MXPA00008849A
Application number: MXPA/A/2000/008849A
Authority: MX
Inventors: Robert Glinecke; Susan Marie Milosovich; William Muldoon; Laurence Rousseau; Joseph Sauer
Original assignee: Smithkline Beecham Corporation; Smithkline Beecham Plc
Priority date: 1998-03-11
Filing date: 2000-09-08
Publication date: 2001-07-09

Abstract

Controlled release dosage forms useful in the treatment and/or prophylaxis of dementia, including Alzheimer's disease, in mammals, and for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease.

Description

COMPOSITION DESCRIPTIVE MEMORY The present invention relates to new formulations, and their use in the treatment and / or prophylaxis of certain disorders. The [R- (Z)] - a- (methoxyimino) -a- (1-azabicyclo [2.2.2] oct-3-yl) acetonitrile monochlorohydrate (compound X) and methods for its preparation are described in EP-A -0392803, WO95 / 31456 and WO93 / 17018. The compound improves the function of acetylcholine through 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. WO96 / 12486 describes the use of compound X in the manufacture of a medicament for improving the processing of amyloid precursor protein along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease. The rapid release oral and swallowable tablet formulations of Compound X result in rapid absorption of the compound in the circulation and require dosing twice a day for optimum efficiency. It has now been surprisingly discovered that it is possible to formulate Compound X which has a very high solubility in water, and is active in extremely low doses, such that the release is controlled to take place over a period of hours. Such a formulation would require dosing only once a day: this is likely to improve compliance in a patient population characterized by poor memory; It also reduces side effects in case of accidental overdose. Accordingly, in a first aspect the present invention provides a controlled release oral dosage form containing 0.04% w / w in blp of compound X and 98.5-99.5% w / w of mono, di and total triglycerides and mono and polyethylene glycol disinters consisting of Gelucire 50/13 (EP) and Gelucire 50/02 (Fr Ph) in a ratio of > 0.02 Gelucire 50/13 (EP) to Gelucire 50/02 (Fr Ph) in a hard gelatin capsule containing 0.10 mg / capsule of compound X, in blp, so that the release profile of the capsule in 1 mM HC1 It is 20-60% after 8 hours. Preferably, the release profile after 8 hours is 20-40% or 30-60%. Gelucire 50/13 (EP) is a mixture of mono, di and triglycerides and mono- and di-esters of polyethylene glycol specified in the European Pharmacopoeia "Stearoyl Macroglycerides" (supplement 1998) as: Specific mixtures of monoesters, diesters and triesters of glycerol and monoesters and Diesters of macrogols with an average relative molecular mass between 300 and 4000 comprising: Free glycerol content: < 3% Lauric acid (C12): < 5% Myristic acid (C14): < 5% Different nominal quantities of stearic acid (C18) and palmitic acid (C16). The sum of stearic acid and palmitic acid is not less than 90%. Gelucire 50/02 (Fr Ph) is a mixture of mono, di and triglycerides and mono and diesters of polyethylene glycol specified in the French pharmacopoeia "Glyceride Polyglycolyses Satures" (1990) as: specific mixtures of mono, di and triglycerides and mono and diesters of polyethylene glycol obtained either by partial alcoholysis of hydrogenated vegetable oils using polyethylene glycol of relative molecular weight on a scale of 200-2000, or by esterification of saturated fatty acids using polyethylene glycol of relative molecular weight on a scale of 200-2000 comprising: of free glycerol: < 3% caprylic acid (C8) < 15% Capric acid (C10): < 15% Lauric acid (C12): < 50% Myristic acid (C14): < 25% Palmitic acid (C16): < 55% Stearic acid (C18): < 97% The mono, di and triglycerides and the polyethylene glycol mono- and di-esters preferably form up to 99.41% of the dosage form. The ratio of Gelucire 50/13 (EP) to Gelucire 50/02 (Fr Ph) is preferably from < 0.055, more preferably < 0.053. In a preferred aspect the monkey mix, di and triglycerides and mono and diesters of polyethylene glycol consists of Gelucire 50/13 (Gattefosse) and Gelucire 50/02 (Gattefosse). More preferably, the composition comprises 97.41% Gelucire 50/13 (Gattefosse) and 2.00% Gelucire 50/02 (Gattefosse) or 94.41% Gelucire 50/13 (Gattefosse) and 5.00% Gelucire 50/02 (Gattefosse). The composition preferably further comprises propylene glycol, preferably at 0.45% w / w (1.13 mg / capsule). The composition preferably further comprises 3,4,5-trihydroxybenzoic acid propyl ester, preferably at 0.10% w / w (0.25 mg / capsule). In a preferred embodiment of the first aspect the composition is selected from: Component% p / p mg / capsule Compound X 0.04 blp 0.10 blp Gelucire 50/02 (EP) 94.41 236.00 Gelucire 50/13 (Fr P) 5.00 12.50 Propylene glycol 0.45 1.13 Propyl ester of acid 0.10 0.25 3,4,5-trihydroxybenzoic Component% p / p mg / capsule Compound X 0.04 blp 0.10 blp Gelucire 50/02 (EP) 97.41 243.52 Gelucire 50/13 (Fr Ph) 2.00 5.00 Propylene glycol 0.45 1.13 Propyl ester of acid 0.10 0.25 3,4,5-trihydroxybenzoic in a hard gelatin capsule. In a second aspect, the present invention provides a controlled release oral dosage form containing the compound X of the following composition: Ingredient mg / tablet% / tablet Compound X 0.005-0.1 blp Hydroxypropylmethylcellulose 37.5-45 25-30 Dibasic calcium phosphate dihydrate 45-52.5 30-35 Microcrystalline cellulose (size 19.5 13.0 nominal particle 50 microns) Microcrystalline cellulose (size 37.76 25.2 average particle nominal 100 microns) ) granulated, compressed into tablets and coated to a weight gain of 3% with a seal coating consisting of an aqueous dispersion solution of hydroxypropylmethylcellulose with plasticizer in purified water at 10% solids followed by a coating consisting of an aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer or a mixture of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer and aqueous dispersion of hydroxypropylmethylcellulose with polyethylene glycol plasticizer, so that 40-65% of the drug is released within 8 hours in water. The composition preferably further comprises sodium dihydrogen citrate, preferably at a level of 1.50 mg / tablet (1.0%) and / or magnesium stearate, preferably at a level of 1125 mg / tablet (0.75%). In preferred embodiments of the second aspect: Hydroxypropimethylcellulose is Methocel E4M CR; The microcrystalline cellulose (nominal particle size 50 microns) is Avicel PH101; The microcrystalline cellulose (nominal particle size 100 microns) is Avicel PH 102; The aqueous dispersion of hydroxypropylmethylcellulose has polyethylene glycol plasticizer and is preferably Opadry White or Opadry Clear (YS-1-9025A); and / or the aqueous dispersion of ethylcellulose has fractionated coconut oil plasticizer and is preferably Surelease Clear (E-7-19010). In a third aspect, the present invention provides a controlled release oral dosage form containing the compound X of the following composition: Ingredient mg / tablet% / tablet Compound X 0.005-0.1 blp Ethylcellulose 22.5-37.5 15-25 Dibasic calcium phosphate dihydrate 63.3-78.3 42.2-52.2 Microcrystalline cellulose 30.0-40.0 19.8-26.7 compressed into tablets and coated to a weight gain of 3% with a seal coating solution consisting of aqueous dispersion of hydroxymethylcellulose with plasticizer in purified water at a concentration of 10% solids followed by a coating consisting of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer or a mixture of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and aqueous dispersion of hydroxypropylmethylcellulose with plasticizer. In a preferred embodiment of the third aspect the composition additionally comprises sodium dihydrogen citrate, preferably at a level of 3.00 mg / tablet (2.0%) and / or colloidal silicon dioxide, preferably at a level of 0.75 mg / tablet (0.50%). ) and / or magnesium stearate preferably at a level of 1125 mg / tablet (0.75%) and / or the microcrystalline cellulose has an average particle size of 100 microns, preferably at a level of 32.5 mg / tablet (21.7%); and coated at a gain of 3% by weight with a seal coating solution consisting of aqueous dispersion of hydroxymethylcellulose with plasticizer in purified water at a concentration of 10% solids followed by a coating consisting of aqueous dispersion of ethylcellulose with acid oleic, ammonium hydroxide and plasticizer or a mixture of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer and aqueous dispersion of hydroxypropylmethylcellulose with polyethylene glycol plasticizer, so that 35-50% of the drug is released within 8 hours in water . In a second preferred embodiment of the third aspect the composition is wet granulated prior to compression using an aqueous dispersion of ethylcellulose containing oleic acid, ammonium hydroxide and plasticizer, preferably at a level of 7.5-15.0 mg / tablet (5.0-10.0% ). Where the composition is wet granulated, it additionally comprises sodium dihydrogen citrate, preferably at a level of 1.50 mg / tablet (1.0%), and / or magnesium stearate, preferably at a level of 1125 mg / tablet (0.75%). ), and / or the microcrystalline cellulose has an average particle size of 50 microns, preferably at a level of 37.5 mg / tablet (25%); and coated at a weight gain of 3% with a seal coating solution consisting of aqueous dispersion of hydroxymethylcellulose with plasticizer in purified water at a concentration of 10% solids followed by a coating consisting of aqueous dispersion of ethylcellulose with acid oleic, ammonium hydroxide and plasticizer or a mixture of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer and aqueous dispersion of hydroxypropylmethylcellulose with plasticizer so that 60-75% of the drug is released within 8 hours in water.

In preferred embodiments of the third aspect: Ethylcellulose is Ethocel Std 7; The microcrystalline cellulose (nominal particle size 50 microns) is Avicel PH101; Microcrystalline cellulose (nominal average particle size) 100 micras) is Avicel PH102; The aqueous dispersion of hydroxypropylmethylcellulose has polyethylene glycol plasticizer and is preferably Opadry Clear (YS-1-9025A); and / or The aqueous dispersion of ethylcellulose has fractionated coconut oil plasticizer and is preferably Surelease Clear (E-7-19010). By controlled release means that the release of the active substance from the dosage form is modified to occur at a slower rate than that of an immediate release product, such as a conventional ingestible tablet or capsule. The dosage form of the invention can be used in the treatment and / or prophylaxis of dementia, including Alzheimer's disease, in mammals, and / or to improve 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 are referred to hereinafter as "the disorders". The present invention provides a method for treating "disorders" by administering an effective amount of the controlled release oral dosage form of the invention to someone suffering in need thereof. The present invention further provides the use of a controlled release oral dosage form of the invention in the manufacture of a medicament for the treatment of "disorders". The present invention also provides a pharmaceutical composition for use in the treatment of "disorders" comprising a controlled release oral dosage form of the invention. The following example illustrates the present invention. The weight shown is the weight of free base (blp = pure liberated base). The mesh sizes are standard E.U.A.

EXAMPLE 1 Component% p / p mg / capsule Function Compound X 0.04 blp 0.10 blp Active Gelucire 50/02 * 94.41 236.00 Wax matrix Gelucire 50/13 * 5.00 12.50 Wax matrix Propylene glycol 0.45 1.13 Solvent Gallate from 0.10 0.25 Antioxidant propyl ** I EXAMPLE 2 Component% p / p mg / capsule Function Compound X 0.04 blp 0.10 blp Active Gelucire 50/02 * 97.41 243.52 Wax matrix Gelucire 50/13 * 2.00 5.00 Wax matrix Propylene glycol 0.45 1.13 Solvent Galato 0.10 propyl ** 0.25 Antioxidant * specific mixture of mono, di and triglycerides, and polyethylene glycol mono and diesters of the following compositions: Gelucire 50/13 (Gattefosse, certificate of analysis): Free glycerol content: < 3% caprylic acid: < 3% Capric acid: < 3% Lauric acid: < 5% Myristic acid: < 5% Palmitic acid: 40-50% Stearic acid: 48-58% Gelucire 50/02 (Gattefosse, certificate of analysis): Free glycerol content: < 3% caprylic acid: < 3% Capric acid: < 3% Lauric acid: 4-14% Myristic acid: 2-12% Palmitic acid: 32-42% Stearic acid: 37-47% "3,4,5-trihydroxybenzoic acid propyl ester.

Procedure for Examples 1 and 2 The waxes were melted together at about 60 ° C and mixed with propyl gallate. Compound X was dissolved in propylene glycol, and mixed in the waxes. The mixture was filled into capsules of size 3 hard gelatin capsule.

Release profiles Dissolution equipment that conforms to a No. 2 device USP. Medium: 1 mM HCl. Volume: 500 mL Temperature: 37 ° C. Blade speed: 50 rpm.

TABLE 1 Release Profile of Wax Filled Capsules of Example 1 Time (hours)% released 2 17 4 27 8 46 15 70 23 86 TABLE 2 Release profile of capsules filled with wax of example 2 Time (hours) Symbol of% released 2 10 4 18 8 29 15 44 23 56 EXAMPLE 3 Ingredient mg / tablet Function Compound X 0.005-0.1 pbl Active Methocel E4M CR 37.5 Hydrogel matrix 1.50 Citrate sodium dihydrogen stabilizer Phosphate dihydrate 52.5 Dibasic hydrophobic calcium dibasic diluent Avicel PH 101 19.5 Hydrophobic diluent Avicel PH102 37.76 Hydrophobic diluent 1,100 stearate Magnesium lubricant Purified water q.s.

Tablets were prepared by the following procedure: 1.- Premix of the drug with a small amount of the excipients. 2.- Wet granulation using high shear granulation. 3.- Dry granulation using fluid bed or furnace process. 4.- Sifting through a crushing screen. 5.- Mixture of the remaining excipients with the drug granulation. 6.- Lubrication with magnesium stearate. 7.- Compression in tablets. 8.- Tablets coated with polymer.

Seal coating solution A solution of Opadry Clear (YS-1-9025A) in purified water at 10% solids concentrations was manufactured by dissolving 100 grams of Opadry Clear in 900 grams of purified water.

Polymer Coating A polymer coating dispersion containing ethylcellulose (Surelease Clear (E-7-19010)) and Opadry Clear (YS-1-9025A) of the following composition was manufactured and used for polymer coating of the coated spheres of seal to a weight gain of 4-5%.

Component% p / p Function Sureiease Clear (E-7- 4.5 (25% as Coating of 19010) solids) polymer with plasticizer for release control Opadry Clear (YS-1- 0.5 Coating of 9025A) polymer for release control Purified water c.s Total 100 700 grams of tablet cores were coated using a Vector LDCS container at a weight gain of 3% with the Opadry Clear seal coating solution (YS-1-9025A). The seal-coated tablets were then coated with polymer at a weight gain of 4-5% using the Surelease / Opadry coating dispersion.

TABLE 3 Tablet release period of Example 3 of compound X in water Time (hour)% Dissolved H 'ecubrimien I 4% Coating at 5% 1 0.14 0.17 2 0.61 0.35 4 19.9 6.6 8 62 52 12 87 92 EXAMPLE 4 Ingredient mg / tablet Function Compound X 0.005-0.1 blp Active Ethocel Std 7 30.0 Hydrogel matrix Sodium dihydrogen citrate 1.50 Stabilizer Calcium phosphate dihydrate 70.76 Dibasic hydrophobic diluent Avicel PH101 37.5 Hydrophobic diluent Surelease Clear (E-7-19010) 9.0 Hydrogel matrix Magnesium stearate 1.125 Lubricant Tablets were prepared by the following procedure: 1. Pre-mix the drug with a small amount of the excipients. 2. Blend granulated with Surelease dispersion using high shear granulation and granulation resulting in wet sieve. 3. Dry granulation using fluid bed. 4. Sifting through a sieving mill. 5. Mix the remaining excipients with the drug granulation. 6. Lubricate with magnesium stearate. 7. Compress in tablets. 8. Coating of tablets with polymer. Seal coating solution: A solution of Opadry Clear (YS-1-9025A) in purified water at concentrations of 10% solids was manufactured by dissolving 100 grams of Opadry Clear in 900 grams of purified water. Polymer coating: A polymer coating dispersion containing ethylcellulose Surelease (E-7-19010) and Opadry Clear (YS-1-9025A) of the following composition was manufactured and used for polymer coating of the tablets coated on a stamp. 4-5% gain in weight.

Component% p / p Surelease Clear 4.25 function (25% as polymer coating for (E-7-19010) solids) release control with Opadry Clear 0.75 plasticizer Polymer coating for (YS-1-9025A) release control Purified water cs Total 100 700 grams of tablet cores were coated using a Vector LDCS container at a 3% weight gain with the Opadry Clear seal coating solution. The seal coated tablets were then coated with polymer at a weight gain of 4-5% using the Surelease / Opadry coating dispersion.

TABLE 4 Release profile for the tablet of Example 4 of compound X in water Time (hours)% Dissolved 4%. . . . 5% coating coating 1 2.1 0.57 2 7.4 3.1 4 35 26 8 73 71 12 90 88 EXAMPLE 5 Ingredient mg / tablet Function Compound X 0.005-0.1 blp Active Ethocel Std 7 37.5 Hydrogel matrix Sodium dihydrogen chloride 3.00 Stabilizer Calcium phosphate dihydrate 75.0 Dibasic hydrophobic diluent Avicel PH102 32.5 Hydrophobic diluent Colloidal silicon dioxide 0.75 Sliding magnesium stearate 1.125 Lubricant Tablets were prepared by the following procedure: 1. Pre-mix the drug with a small amount of the excipients. 2. Mix the remaining excipients with the premixed drug. 3. Lubricate with magnesium stearate. 4. Compress in tablets. 5. Coating tablets with polymer. Seal coating solution: A solution of Opadry Clear (YS-1-9025A) in purified water at concentrations of 10% solids was manufactured by dissolving 100 grams of Opadry Clear in 900 grams of purified water. Polymer coating: A polymer coating dispersion containing ethylcellulose (Surelease (E-7-19010)) and Opadry Clear (YS-1-9025A) of the following composition was manufactured and used for polymer coating of the coated tablets. seal to gain in weight of 4%.

Component% p / p Surelease Clear 3.4 Function (25% as polymer coating of (E-7-19010) solids) release control with Opadry Clear 0.6 plastifier Polymer coating for (YS-1-9025A) release control Purified water cs Total 100 700 grams of tablet cores were coated using a Vector LDCS container at a 3% weight gain with the Opadry Clear seal coating solution. The seal-coated tablets were then coated with polymer at a weight gain of 4% using the Surelease / Opadry coating dispersion.

TABLE 5 Release profile for tablet of example 5 of compound X in water Time (hours)% Dissolved 2 6.2 4 14 8 38 12 66 16 90 Trade name Generic description Provider Ethocel Std. 7 ethylcellulose (viscosity of 5% w / v Dow solution of 6.4 mPa average particle size 210 microns) Methocel E4M CR hydroxypropylmethylcellulose (nominal Dow viscosity, 2% in water, 4000)% methoxyl = 28-30, 95 % < 100 mesh Avicel PH 101 cellulose mocrocrystalline (size of FMC Corp average particle nominal 50 microns) Avicel PH102 cellulose microcrystalline (size of FMC Corp average particle nominal 100 microns) Opadry Clear dispersion aqueous Colorcon (YS-1-9025A) hydroxymethylcellulose with plasticizer polyethylene glycol Surelease Clear aqueous dispersion of ethyl cellulose Colorcon (E-7-19010) oleic acid ammonium hydroxide plasticizer of fractionated coconut oil

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A controlled release oral dosage form that contains [R- (Z)] - - (methoxyimino) -a- (1-azabicyclo [2.2.2] oct-3-yl) acetonitrile monohydrochloride (compound X) of the following composition. Ingredient mg / tablet% / tablet Compound X 0.005-0.1 blp Ethylcellulose 22.5-37.5 15-25 Dihydrate phosphate 63.3-78.3 42.2-52.2 calcium dibasic Cellulose 30.0-40.0 19.8-26.7 microcrystalline compressed into tablets and coated to a weight gain of 3% with a seal coating solution consisting of aqueous dispersion of hydroxymethylcellulose with plasticizer in purified water at 10% solids concentration followed by a coating consisting of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer or a mixture of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and aqueous dispersion of hydroxypropylmethylcellulose with plasticizer.
2. A dosage form according to claim 1 further comprising sodium dihydrogen citrate and / or colloidal silicon dioxide and / or magnesium stearate and / or microcrystalline cellulose has an average particle size of 100 microns; and coated at a weight gain of 3% with a seal coating solution consisting of aqueous dispersion of hydroxymethylcellulose with plasticizer in purified water at a solids concentration of 10% followed by a coating consisting of aqueous dispersion of ethylcellulose with oleic acid , ammonium hydroxide and plasticizer or a mixture of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer and aqueous dispersion of hydroxypropylmethylcellulose with polyethylene glycol plasticizer, so that 35-50% of the drug is released within 8 hours in water .
3. A dosage form according to claim 2 comprising sodium dihydrogen citrate at a level of 3.00 mg / tablet (2.0%) and / or colloidal silicon dioxide at a level of 0.75 mg / tablet (0.50%) ) and / or magnesium stearate at a level of 1125 mg / tablet (0.75%) and / or microcrystalline cellulose at a level of 32.5 mg / tablet (21.7%).
4. A dosage form according to claim 1, further characterized in that the composition is wet granulated before compression using an aqueous dispersion of ethyl cellulose containing oleic acid, ammonium hydroxide and plasticizer. 5. A dosage form according to claim 4, further characterized in that the dispersion of ethylcellulose is at a level of 7.5-15.0 mg / tablet (5.0-10.0%). 6. A dosage form according to claim 4 or 5, which additionally comprises sodium dihydrogen citrate and / or magnesium stearate and / or microcrystalline cellulose has an average particle size of 50 microns; and coated at a gain of 3% by weight with a seal coating solution consisting of aqueous dispersion of hydroxymethylcellulose with plasticizer in purified water at a concentration of 10% solids followed by a coating consisting of aqueous dispersion of ethylcellulose with oleic acid , ammonium hydroxide and plasticizer or a mixture of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer and aqueous dispersion of hydroxypropylmethylcellulose with plasticizer so that 60-75% of the drug is released within 8 hours in water. 7. A dosage form according to claim 6, comprising sodium dihydrogen citrate at a level of 1.50 mg / tablet (1.0%) and / or magnesium stearate at a level of 1125 mg / tablet (0.75%) ) and / or microcrystalline cellulose at a level of 37.5 mg / tablet (25%). 8. A dosage form according to any of claims 1 to 7, further characterized in that the aqueous dispersion of hydroxypropylmethylcellulose has polyethylene glycol plasticizer and / or the aqueous dispersion of ethylcellulose has fractionated coconut oil plasticizer. 9. - A controlled release oral dosage form according to claim 1 of the following composition: Ingredient mg / tablet Compound X 0.005-0.1 blp Ethocel Std 7 30.0 Sodium dihydrogen citrate 1.50 Dibasic calcium phosphate dihydrate 70.76 Avicel PH 101 37.5 Surelease Clear (E-7-19010) 9.0 Magnesium stearate 1.125 seal coating solution: a solution of Opadry Clear (YS-1-9025A) in purified water at concentrations of 10% solids manufactured by dissolving 100 grams of Opadry Clear in 900 grams of purified water (at a 3% weight gain ); Polymer coating: (weight gain of 4-5%) Component% p / p Surelease Clear (E-7-19010) 4.25 (25% as solids) Opadry Clear (YS-1-9025A) 0.75 Purified water C.S. Total 100. 10. - A controlled release oral dosage form according to claim 1 of the following composition: Ingredient mg / tablet Function Compound X 0.005-0.1 active blp Ethocel Std 7 37.5 hydrogel matrix Dihydrogen citrate 3.00 sodium stabilizer Phosphate dihydrate 75.0 hydrophobic diluent calcium dibasic Avicel PH 102 32.5 hydrophobic diluent Colloidal silicon dioxide 0.75 sliding Magnesium stearate 1.125 lubricant Seal coating solution: A solution of Opadry Clear (YS-1-9025A) in purified water at concentrations of 10% solids was manufactured by dissolving 100 grams of Opadry Clear in 900 grams of purified water (at a weight gain of 3 %); Polymer coating: (weight gain of 4%): Component% p / p Surelease Clear (E-7-19010) 3.4 (25% as solids) Opadry clear (YS-1-9025A) 0.6 Purified water CS: Total 100. 1 1.- A controlled release oral dosage form containing [R- (Z) -a- (methoxyimino) -α- (1) monohydrochloride. -azabicyclo [2.2.2] -oct-3-yl) acetonitrile (compound X) of the following composition: Ingredient mg / tablet% / tablet Compound X 0.005-0.1 blp Hydroxypropylmethylcellulose 37.5 - 45 25 - 30 Dibasic calcium phosphate dihydrate 45 - 52.5 30 - 35 Microcrystalline cellulose 19.5 13.0 (nominal particle size of 50 microns) Microcrystalline cellulose 37.76 25.2 (nominal particle size 100 microns) granulated, compressed into tablets and coated to a weight gain of 3% with a seal coating consisting of an aqueous dispersion solution of hydroxypropylmethylcellulose with plasticizer in purified water at 10% solids followed by a coating consisting of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer or a mixture of aqueous dispersion of ethylcellulose with oleic acid, ammonium hydroxide and plasticizer and aqueous dispersion of hydroxypropylmethylcellulose with polyethylene glycol plasticizer, so that 40-65% of the drug is released within 8 hours in water. 12. A dosage form according to claim 1 which additionally comprises: sodium dihydrogen citrate and / or magnesium stearate. 13. A dosage form according to claim 12 comprising sodium dihydrogen citrate at a level of 1.50 mg / tablet (1.0%) and / or magnesium stearate at a level of 1.125 mg / tablet (0.75%) . 14. A dosage form according to any of claims 11 to 13 further characterized in that the aqueous dispersion of hydroxypropylmethylcellulose has polyethylene glycol plasticizer and / or the aqueous dispersion of ethylcellulose has fractionated coconut oil plasticizer. 15. A controlled release oral dosage form according to claim 11 of the following composition: Ingredient mg / tablet Compound X 0.005-0.1 blp Methocel E4M CR 37.5 Sodium dihydrogen citrate 1.50 Dibasic calcium phosphate dihydrate 52.5 Avicel PH 101 19.5 Avicel PH 102 37.76 Magnesium stearate 1.125 Purified water C.S. Seal coating solution: A solution of Opadry Clear (YS-1-9025 A) in purified water at concentrations of 10% solids, was manufactured by dissolving 100 grams of Opadry Clear in 900 grams of purified water. Polymer coating (4-5% gain in weight: Component% p / p Surelease Clear (E-7-19010) 4.5 (25% as solids) Opadry Clear (YS-1-9025A) 0.
5 Purified water C.S. Total 100 16.- A controlled release oral dosage form containing 0.04% w / w in blp of [R- (Z)] - a- (methoxyimino) - - (1-azabicyclo [2.2.2] oct monohydrochloride] -3-yl) acetonitrile (compound X) and 98.5-99.5% w / w total of mono, di and triglycerides and mono and diesters of polyethylene glycol consisting of Gelucire 50/13 (EP) and Gelucire 50/02 (Fr Ph) in a relationship of > 0.02 Gelucire 50/13 (EP) to Gelucire 50/02 (Fr Ph), in a hard gelatin capsule containing 0.10 mg / capsule of compound X in blp, so that the release profile of the capsule in 1 mM HCl It is 20-60% after 8 hours. 17. A dosage form according to claim 16 further characterized in that the release profile after 8 hours is 20-40% or 30-60%. 18. A dosage form according to claim 16 or 17 comprising 97.41% Gelucire 50/13 and 2.00% Gelucire 50/02 or 94.41% Gelucire 50/13 and 5.00% Gelucire 50/02. 19. A dosage form according to any of claims 16 to 18 further comprising propylene glycol. 20. - A dosage form according to claim 19 further characterized in that it comprises propylene glycol at 0.45% w / w. 21. A dosage form according to any of claims 16 to 20 further comprising propyl 3,4,5-trihydroxybenzoic acid ester. 22. An oral dosage form according to claim 21 comprising propyl ester of 3,4,5-trihydroxybenzoic acid at 0.10% w / w. 23. A dosage form according to any of claims 16 to 22 comprising 0.04% in plp w / w of compound X. 24.- A dosage form according to claim 16 selected from: Component% p / p mg / capsule Compound X 0.04 blp 0.10 blp Gelucire 50/02 (EP) 94.41 236.00 Gelucire 50/13 (Fr pH) 5.00 12.50 propylene glycol 0.45 1.13 propyl ester of 3,4,5-trihydroxybenzoic acid 0.10 0.25 Component% p / p mg / capsule Compound X 0.04 blp 0.10 blp Gelucire 50/02 (EP) 97.41 243.52 Gelucire 50/13 (Fr pH) 2.00 5.00 propylene glycol 0.45 1.13 propyl ester of 3,4,5-trihydroxybenzoic acid 0.10 0.25 in a hard gelatin capsule. 25. A process for preparing a dosage form as defined in any of claims 1 to 24, the method of which comprises mixing the ingredients. 26. The use of a dosage form of any of claims 1 to 24 in the manufacture of a medicament for the treatment and / or prophylaxis of dementia, including Alzheimer's disease in mammals, and / or to improve protein processing of amyloid precursor along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease.