CZ83299A3 - Dosage form of [r-(z)]-alpha-(methoxyimino)-alpha-(1-azabicyklo[2,2,2]okt-3-yl)acetonitrile monohydrochloride with controlled release - Google Patents

Abstract

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

Description

(54) Title of the invention application:

(R-(Z)I-alpha-(methoxyimino)-alpha-(1-azabicyclo[2,2,2]oct-3-ylacetonitrile 1 monohydrochloride controlled release dosage form (57) Annotation:

A controlled release acetonitrile compound formulation and its use are disclosed

M in the treatment and/or prophylaxis of dementia in mammals.

CZ 832-99 A3 • · » · 4 · 4

[R-(Z)]-α-(Methoxyimino)-α-(1-azabicyclo[2,2,2]oct-3-yl)acetonitrile monohydrochloride controlled-release dosage form

Field of technology

This invention relates to a novel medicinal composition and its use for the treatment and/or prophylaxis of certain disorders.

State of the art [R-(Z)]-α-(Methoxyimino)-α-(1-azabicyclo[2,2,2]oct-3-yl)acetonitrile monohydrochloride, compound of formula X, and methods of its preparation are described in EP -A-0 392 803, WO95/31456 and WO93/17018. This compound potentiates the effect of acetylcholine by acting on muscarinic receptors of the central nervous system and therefore has potential use for the treatment and/or prophylaxis of dementia in mammals.

WO96/12486 describes the use of a compound of formula X for the manufacture of a medicament which enhances the processing of an amyloid precursor protein in the non-amyloidogenic pathway in patients suffering from Alzheimer's disease or in patients at risk of developing this disease.

Rapid release formulations consisting of lozenges and oral solutions containing a compound of formula X lead to rapid absorption of the compound into the circulation in both cases. Therefore, twice daily dosing is required for optimal effectiveness.

• · · · ♦ · ···· · · · · • «· ··· · · · • · · · ·· ··· ·· · ·

The essence of the invention

Surprisingly, it has now been found that it is possible to formulate a compound of formula X which has a very high solubility in water, and which is effective at very low doses, in such a way that its release is controlled and takes place over a period of hours. Such a means would require only once-a-day dosing, which would likely improve the sense of harmony in a group of patients characterized by poor memory; this could also reduce side effects in the event of an unintended overdose.

The present invention provides a controlled release oral dosage form comprising a compound of formula X, its parent free base or any other pharmaceutically acceptable salt thereof.

Controlled release refers to any formulation technique in which the release of the active ingredient from the dosage form is modified so that it occurs more slowly than from an immediate release agent, such as a conventional tablet or suckable capsule.

Controlled release also includes delayed release, where the release of the active substance from the dosage form is modified so that it occurs later than from a conventional immediate release agent. The subsequent release of the active substance from the sustained release agent can also be controlled to occur at a slower rate.

Examples of controlled release agents that are suitable for incorporating a compound of formula X are described in:

• · • · ·· · · ·· · · • · · · · · · • · · · · · · · · • · · ·· ······ • · · · · · · ···· ··· ·· ··* ·· ··

Sustained Release Medications, Chemical Technology Review No. 177, ed. J.C. Johnson, Noyes Data Corporation (1980).

Controlled Drug Delivery, Fundamentals and Applications, 2nd ed., J.R. ed. Robinson and V.H.L. Lee, Marcel Dekker Inc. New York (1987).

Such controlled release agents are »

preferably processed in such a way that the release of the compound of formula X takes place throughout the gastrointestinal tract, and that it occurs especially during the first eight to twelve hours after ingestion.

Preferred compositions include waxy bases, swellable polymers or polymers capable of forming gel or hydrogel bases, tablets coated with release-controlling polymers or waxes, and pellets, granules or spheres which contain bases or which are coated with release-controlling polymers or waxes and subsequently formulated as capsules, compressed tablets or suspensions.

Waxes suitable for base formation or control coating release include non-ionic beeswax derivatives such as Gelucire 62/05, 50/02 or 50/13 (Gattefosse), glyceryl behenate, or other mono-, di- or triesters of fatty acids with glycerol, such as * Precirol ATO5 (Gatefosse), microcrystalline wax, hydrogenated castor oil or hydrogenated vegetable oil, long-chain aliphatic alcohols such as stearyl alcohol and carnauba wax.

Materials suitable for the preparation of hydrogel or swelling bases and/or bases of gel-forming polymers • · · · · · • · · • ·

may be selected from alkylcelluloses, hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates, polymethylmethacrylates, methacrylate-divinylbenzene copolymers, carboxymethylamide, polyoxyalkylene glycols, polyvinylpyrrolidone, and carboxymethylcellulose. The swelling polymer materials can be selected in particular from yellowed sodium carboxymethyl cellulose, yellowed hydroxypropyl cellulose, high molecular weight polyhydroxypropyl methyl cellulose, carboxymethyl amide, copolymers of the potassium salt of methacrylic acid and divinylbenzene, polymethyl methacrylate, crosslinked polyvinylpyrrolidone and high molecular weight polyvinyl alcohol. Polymeric materials capable of forming a gel can in particular be selected from methyl cellulose, carboxymethyl cellulose, low molecular weight hydroxypropyl methyl cellulose, low molecular weight polyvinyl alcohols, polyoxyethylene glycols and non-crosslinked polyvinylpyrrolidone. The swellable polymeric materials and polymeric materials capable of forming a gel may be selected mainly from medium viscosity hydroxypropylmethylcellulose and medium viscosity polyvinyl alcohols. .

Release controlling polymers include hydrogel polymers such as those listed above, hydrophobic polymers and enteric or pH dependent polymers.

Materials suitable for the preparation of hydrophobic release controlling polymer coatings include alkylcelluloses which can be used in the form of latex suspensions such as Surelease (Colorcon) or Aquacoat (FMC) and methacrylic acid derivatives which can be used in the form of latex suspensions such as Eudragit RS , RL and NE (Rohm) .

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Materials suitable for the formation of enteric and pH-dependent polymer coatings include derivatives of methacrylic acid, which can be used in the form of latex suspensions, such as Eudragit L and S (Rohm).

Impermeable coatings, thin layers used to separate different functional layers of the product, or used to create the outer layer of the product, contain materials suitable for creating a thin layer, such as alkyl celluloses, which can be used in the form of latex suspensions such as Surelease (Colorcon) or Aquacoat (FMC), or hydroxyalkylcelluloses, such as hydroxypropylmethylcellulose (eg Opadry (Colorcon)).

The formulation may also contain plasticizers such as triethyl citrate, dibutyl sebacate or medium chain triglycerides in the release controlling polymer layer.

Pellet forming materials contain suitable types of microcrystalline cellulose such as Avicel PH101 (FMC).

The granules may be formed from any commonly used pharmaceutical filler or diluent, such as lactose, lactose monohydrate, mannitol, microcrystalline cellulose, calcium monohydrogen phosphate or starch.

The spheres can be formed by coating or spraying the initial cores.

Other suitable ingredients for controlled-release dosage forms include polyethylene glycol and propylene glycol, and these, as well as pharmaceutical excipients, may be used to ··· ♦ · · · it · ·· · ·· ······ • · · · · · · ···· ··· ·· ··· ·· ·· to adjust the release rate, through their .

incorporation into drug bases, pellets, granules or balls.

These compositions may also contain hydrophobic excipients that delay release from the composition, such as ethyl cellulose, talc, colloidal silicon dioxide, or glyceryl monostearate, and/or one or more binders, such as hydroxypropylmethylcellulose, microcrystalline cellulose, or polyvinylpyrrolidone.

Humectants such as sodium lauryl sulfate, lubricants such as magnesium stearate, and glidants such as colloidal silica may also be added.

Particularly preferred compositions contain drug-coated beads coated with a release-controlling polymer, either alone or in combination with drug-coated beads that are not coated with a release-controlling polymer (immediate release beads). During the process of layering the drug into the initial bead cores, the appropriately sized initial sugar bead cores may be coated with a solution or dispersion containing the active ingredient, inert excipients, and/or release retarding additives such as ethyl cellulose, talc, colloidal silicon dioxide, or glyceryl monostearate, and /or one or more binders such as hydroxypropylmethylcellulose or polyvinylpyrrolidone. Layering of the active agent can be achieved at a preselected rate and at a preselected temperature using either a coating pan or a floating bed dryer. The beads produced can be coated with a closed coating of a suitable layer-forming polymer such as hydroxypropylmethylcellulose (eg Opadry) or Eudragit ^with L30D-55 (methacrylic acid copolymer) and then • · · · · · »· » 4 · » · · 4 · · 4 • · · 4 4·· ···· • · · · · · · ······ • · · · 4 4 «· 4·· ·· ··· ·· ·· coated with one or more release-controlling polymers, preferably selected from alkylcelluloses, hydroxyalkylcelluloses, sodium carboxymethylcellulose, and methacrylic acid derivatives, such as ethylcellulose, Eudragit® RS, Eudragit® RL, or Methocel E4M, to produce beads that release a compound of formula X over an eight hour to twelve hour time period and/or release the compound of formula X in one or more pulses. Balls with an impermeable coating can be used for immediate release dosing. Controlled-release beads, or a mixture of controlled and immediate-release beads, can then be filled into a capsule of appropriate size, or can be compressed together with inert excipients into tablets with appropriate physical parameters such as shape, size, hardness and disintegration. The release controlling polymer(s) plus any polymer(s) from the impermeable package preferably comprise 10 to 30% by weight of the total dosage form. The plasticizer is commonly represented and represents at least 2% by weight. Binder(s) and release retarder(s) normally make up 3 to 10% by weight.

Another, particularly preferred means are tablets with a swellable polymer and/or a polymer capable of forming a gel in the base. The polymer base is preferably a hydrogel polymer selected from alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxypropylcellulose and hydroxypropylmethylcellulose, polyvinyl alcohol, polymethacrylates, crosslinked polyvinylpyrrolidone and sodium carboxymethylcellulose. Polymers normally make up 10 to 50% by weight of tablets. The tablet base may be coated with a hydrophobic release control polymer such as ethyl cellulose (Surelease (Colorcon)) to ° ···« · · · · · · · • · ····· ···· • · · · · ·· «·♦··· • 4 4·· 4 4

9949 494 ·· ··· ·· ·· slowing down the hydration of the hydrogel base in the tablet. The hydrophobic polymer coating usually makes up 4 to 10% by weight of the tablet.

Formulations with this tablet base can be prepared either by direct compression or by a wet granulation process. Coating can be done using a coating pan.

Other preferred means are described in US Patent No. 5,422,123.

Therefore, another aspect of the invention provides a system for the controlled release of an active substance which is a compound of formula X, its free starting base or any other pharmaceutically acceptable salt thereof, which comprises (a) a storage core which contains an effective amount of the active substance, and which has a defined geometric form, and (b) comprises a support layer applied to said storage core, said storage core comprising at least an active agent and at least one agent selected from the group consisting of (1) a polymeric material that swells upon contact with water or an aqueous liquid, and a gel-forming polymeric material, wherein the ratio of said swelling polymeric material to gel-forming polymeric material is in the range of 1:9 to 9:1, and (2) a single polymeric material that has both swelling properties and gel-forming properties, and wherein the support layer is an elastic support layer applied to said storage core so that it partially overlaps the surface of the storage core and follows changes due to its hydration, and is slowly soluble and/or slowly gelling in aqueous liquids.

can be selected, cross-linked

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4

4 44

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4

4

4

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The swelling polymer material in (1) of cross-linked sodium carboxymethyl cellulose hydroxypropyl cellulose, high molecular weight polyhydroxypropyl methyl cellulose, carboxymethyl starch, copolymer of potassium methacrylic acid with divinylbenzene, cross-linked polyvinylpyrrolidone and polyvinyl alcohol. Polymeric materials capable of forming a gel in (1) may be selected from methylcellulose and non-crosslinked polyvinylpyrrolidone.

The support layer may contain polymers such as polyhydroxypropylmethylcellulose, polyvinyl alcohol, polyacrylate, polymethacrylate, polyhydroxypropylcellulose and poly(sodium carboxymethylcellulose); plasticizers such as polyoxyethylene glycols, castor oil, hydrogenated castor oil, ethyl phthalate, butyl phthalate, natural glycerides, synthetic glycerides and semi-synthetic glycerides; binders such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, gum arabic and alginic acid; hydrophilic substances such as mannitol, lactose, starch and colloidal silicon dioxide; and/or hydrophobic substances such as hydrogenated castor oil, magnesium stearate, fatty substance, wax, natural glycerides and synthetic glycerides. The polymer(s) typically comprise 30 to 90% by weight of the support layer, for example about 35 to 40%. The plasticizer will make up at least 2% by weight of the support layer, for example around 15 to 20%. Binder(s), hydrophilic preparation(s) and hydrophobic preparation(s) usually make up to 50% by weight of the support layer, for example around 40 to 50%.

» .* ♦··· ·· ·· • · · ··· · · · · « · · ···· · ·· · • · · · · · ··· ··· • · · · · · · ···· ··· ·· ··· ·· ··

Such compositions may be prepared as generally described in US Patent S. 5,422,123.

US-A-4,839,177 describes other alternative controlled release formulations suitable for use in the present invention.

Another aspect of the invention describes a system of controlled release rate of the compound of formula X, which consists of:

a) a storage core containing an effective amount of a compound of formula X, and which has a defined geometric form,

b) support layers applied to said storage core, wherein said storage core contains in mixture with an active substance at least one substance selected from the group consisting of (a) 5 to 80% by weight, based on the total weight of the storage core, of polymeric material , which exhibits a high degree of swelling upon contact with water or an aqueous liquid, and 90 to 10% by weight, based on the total weight of the core to be deposited, of a polymeric material capable of forming a gel, and (b) of a single polymeric material having both swelling properties and and the ability to form a gel and other auxiliary preparations capable of providing the mixture with properties suitable for compression and water absorption. Said support layer consists of a polymeric material insoluble in aqueous liquids and partially envelops the above-described storage core.

The swelling polymer material in a) can be selected from cross-linked sodium carboxymethyl cellulose, cross-linked hydroxypropyl cellulose, high molecular weight polyhydroxypropyl methyl cellulose, carboxymethyl amide, a copolymer of the potassium salt of methacrylic acid and divinylbenzene,

polymethyl methacrylate, crosslinked polyvinylpyrrolidone and high molecular weight polyvinyl alcohols. Polymeric materials capable of forming a gel in (a) may be selected from methyl cellulose, carboxymethyl cellulose, low molecular weight hydroxypropyl methyl cellulose, low molecular weight polyvinyl alcohols, polyoxyethylene glycols and non-crosslinked polyvinylpyrrolidone. The swellable and gelling polymeric materials in (b) may be selected from medium viscosity hydroxypropyl methylcellulose and medium viscosity polyvinyl alcohols. The support layer may contain insoluble polymeric materials selected from acrylates, cellulose, ethyl cellulose, cellulose acetate propionate, polyethylene, methacrylate, acrylic acid copolymers, and high molecular weight polyvinyl alcohols.

Such a composition may be prepared as generally described in US Patent No. 4,839,177.

WO 94/06416 further describes still other alternative controlled release formulations which are suitable for use in the present invention.

Therefore, yet another aspect of the invention describes a rate-controlled release system of a compound of formula X, which consists of a pharmaceutically compressed tablet capable of releasing a compound of formula X at different doses, and which consists of three layers, wherein:

- the first layer contains a compound of formula X in an immediate or controlled release agent, and this agent consists of polymeric substances that rapidly swell and/or dissolve and/or disintegrate when in contact with aqueous fluids, and an auxiliary substance;

» · » 9 • 99 • · · · • · · · · · · 99 9 9 9

- the second layer contains a compound of formula X, either identical or different to that found in the first layer, in a slow-release agent, where this layer is composed of polymeric substances that swell and/or are capable of forming upon contact with aqueous fluids gel and/or disintegrate, and from the excipient;

- a coating of a layer of the type of low permeability barrier coating the mentioned second layer, or, alternatively, a layer placed between the first and the second layer, which consists of polymeric substances, auxiliary substances, plasticizers, or, if necessary, also of the compound of the formula X.

The polymeric substances of the first layer can be selected from cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose of low or medium molecular weight, cross-linked sodium carboxymethyl cellulose, carboxymethyl starch, copolymer of potassium methacrylic acid and divinylbenzene, polyvinyl alcohols, starches, starch derivatives, microcrystalline cellulose and cellulose derivatives, -cyclodextrin and dextrin derivatives.

The polymeric substances of the second layer can be selected from the group consisting of hydroxypropylmethylcellulose with a molecular weight of from 1000 to 4,000,000, hydroxypropylcellulose with a molecular weight of from 2,000 to 2,000,000, carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, alginic acid and its derivatives, carboxymethyl cellulose and its derivatives, poly(methyl vinyl ethers/maleic anhydrides), ethyl cellulose, methyl cellulose and cellulose derivatives.

The excipients of the first and second layers may be selected from the group in which starch is included in advance

·· ···· ·· ·· • · · · · · · • · ··* · · · · • · · · · · · · · · • · · · · ·· ··· · · · · Gelled starch, calcium phosphate, mannitol, lactose, sucrose, glucose, sorbitol, microcrystalline cellulose, gelatin, polyvinylpyrrolidone, methylcellulose, starch solution, ethyl cellulose, gum arabic, gum tragacanth, magnesium stearate, stearic acid, colloidal silicon dioxide, glyceryl monostearate, hydrogenated castor oil oil, waxes, and mono-, bi-, and tri-substituted glycerides.

The polymeric substances of the barrier type layer can be selected from the group consisting of hydroxypropylmethylcellulose with a molecular weight of 1,000 to 4,000,000, hydroxypropylcellulose with a molecular weight of 2,000 to 2,000,000, carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, carboxymethyl cellulose, ethyl cellulose and methyl cellulose.

Barrier type excipients may be selected from the group consisting of glyceryl monostearate, semi-synthetic glycerides, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidine, gelatin, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, magnesium stearate, stearic acid, sodium stearate, talc, sodium benzoate, boric acid, and colloidal silicon oxide.

Plasticizers of the barrier type layer can be selected from the group consisting of hydrogenated castor oil, fatty acids, substituted triglycerides and glycerides, polyoxyethylene glycols and their derivatives with a molecular weight of from 400 to 60,000.

These compositions may be prepared as generally described in WO 94/06416.

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The dosage form preferably contains the compound of formula X as such.

A compound of formula X is active at doses of about 5 to 125 micrograms (g) (calculated as free base). From administration to human patients, it has been found that the effect of enhancing cognitive function is achieved by administering the compound in daily doses of less than 0.01 mg/kg, more precisely 0.003 mg/kg and less, for example 0.0001 to 0.003 mg/kg, as 0.00035 to 0.003 mg/kg, 0.0007 to 0.003 mg/kg, 0.0001 to 0.0007 mg/kg, or 0.00035 to 0.002 mg/kg.

Suitable unit doses to achieve such daily doses are 5, 12.5, 25, 50 or 75 μg, administered twice daily, or 50 μg or 100 μg once daily. Such dosage units as free bases are calculated for individuals weighing 50 to 70 kg.

Suitably, such an in vitro release profile from the dosage form, i.e. the amount of compound of formula X released over time, will be chosen such that it produces an area under the curve of the in vivo plasma profile which is similar to that obtained after conventional oral administration of a tablet with rapid release, with 5 to 75 μg of compound of formula X calculated as free base, twice daily. Preferably, 25 to 75% is released in 4 hours and 70 to 100% is released in 8 hours.

The dosage form of the invention can be used for the treatment and/or prophylaxis of dementia in mammals, including Alzheimer's disease, and for enhancing the degradation of amyloid precursor protein in the nonamyloidogenic pathway, in patients suffering from

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Alzheimer's disease, or in patients at risk of developing this disease. These faults are further referred to as “faults.

This invention describes a method of treating and preventing "disorders by administering to a subject in need thereof an effective amount of an oral controlled release dosage form comprising a compound of formula X, its free starting base, or any other pharmaceutically acceptable salt thereof."

The present invention further describes the use of a controlled release oral dosage form comprising a compound of formula X, its free starting base, or any other pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of “disorders.

The present invention also describes a pharmaceutical composition for use in the treatment of "disorders which comprises an oral controlled release dosage form comprising a compound of formula X, the free starting base thereof, or any other pharmaceutically acceptable salt thereof."

This invention is illustrated by the following examples.

Examples of embodiments of the invention

The weight given in the following examples means the weight of the free base; compound of formula X is the hydrochloride salt. (Pure free base, pfb = pure free base). The size of the particle is given in mm, "US mesh sizes" are given in brackets as the number of meshes per inch according to the US standard.

»· ·· • · · » · · · · • · · · ·

0.005 to 0.1 mg pure free base

190 mg mg

Example 1 (wax base) compound of formula X

Gelucire 62/05 (Gattefosse) propylene glycol

Example 2 (pellets coated with a thin layer)

Ingredient_mg per capsule (50 0 mg) Function

compound of formula X 0.005 up to 0.1 mg active clean free base component lactose 300 hydrophilic thinner Avicel PH 101 (FMC) 200 inert basic mass of pellets

Thin coating % wt/wt of pellet cores

Surelease 2 to 10% (Colorcon) Silicone Releaser

The function of the polymer coating is to control the release of the defoamer

Example 3 (pellets coated with a thin layer)

Ingredient compound of formula X lactose mg per capsule (500 mg)

0.005 to 0.1 mg pure free base

400

Function active ingredient hydrophilic • · • ·

Avicel PH 101

100 inert pellet base

Thin coating Aquacoat (FMC) % mass/mass of pellet cores up to 10%

Functions polymer coating controlling silicone defoamer dibutyl sebacate release defoamer up to 30% plasticizer (from polymer weight)

In Examples 2 and 3, pellets are prepared by extrusion/spheronization, using water as the granulating liquid, and the appropriate fraction size is achieved by sieving. The pellets are then coated in a floating layer coating device (spraying from the bottom) with 2 to 10% by weight Surelease aqueous dispersion (15% solids in the dispersion).

The desired release profiles are achieved by mixing uncoated pellets (= immediate release pellets) and coated pellets with an appropriate range of coating (= sustained release pellets), and then filling them into hard gelatin capsules.

Example 4 (base pellets)

Ingredient_mg per capsule (500 mg)_Function compound of formula X

0.005 to 0.1 pure free base active ingredient

glyceryl- 200 behenate

Avicel PH 101 300 sodium lauryl sulfate 0.1 hydrophobic base material inert base material pellets wetting agent

Pellets are produced by extrusion/spheronization, using water and sodium lauryl sulfate as granulation fluid, the appropriate fraction size is achieved by sieving. The pellets may be additionally coated in a floating bed (bottom spray) coating device with aqueous polymer dispersions to further reduce release rates and achieve desired release profiles.

Example 5 (hydrogel base material)

Excipient_% w/w mg per tablet mg per tablet

compound 0.003 to 0.07 0.005 0.1 X formulas clean free base hydroxypropyl- 25 37.5 37.5 cellulose purified - - - water starch up to 100 109.5 108.5 stearate 2 3.0 3.0 magnesium In total 100 150 150

Tablets can be prepared as follows:

• · ·· · · ·· ·· • · · · · · · • ···· · ·· · _F » · «· ······ • · · · · • · ··· ·· · ·

1. Mix the starch and HPC in a high shear mixer.

2. The drug is dissolved in a small volume of water and sprayed into the mixture during mixing.

3. Spray mechanism is washed with a small volume of water in the mixture during mixing.

4. The mixture is granulated with sufficient water to obtain medium to heavy granules.

5. The granules are partially dried.

6. The granules are crushed with a suitable crusher.

7. The drying of the crushed granules is completed.

8. It is lubricated with magnesium stearate.

9. It is compressed into tablets with a final weight of 150 mg.

Example 6 (wax base material)

Excipient % w/w mg per tablet mg per tablet compound 0.003 to 0.07 0.005 0.1 X formulas clean free base anhydrous up to 100 up to 150 up to 150 lactose Gelucire 18 27.0 27.0 62/05 stearate 2 3.0 3.0 magnesium In total 100 150 150

Tablets can be prepared as follows:

1. The drug is premixed with a small amount of lactose.

2. The premixed drug mixture is layered with the remaining lactose and the desired % of Gelucire 62/05 in a preheated pelletizer.

3. It is pelletized until the desired pellet size is reached.

The pellets are removed and then cooled. If necessary, the pellets are sieved. The pellets are lubricated.

Pellets are compressed or encapsulated

Example 7 bilayer controlled-release tablet)

Active layer components mg per tablet Function compound 0.005 up to 0.1 mg active X formulas clean free base component hydroxypropylmethyl- cellulose 68.5 hydrogel basic mass mannitol 20 soluble filter ethyl cellulose (in ethanol solution) 7.5 take the idol magnesium stearate 2 lubricating means colloidal oxide magnesium 2 means slippery Support layer components mg per tablet Function hydroxypropylmethylcellulose 39.75 creation hydrogel base matter hydrogenated castor oil oil 6.5 insoluble filler ethyl cellulose (in ethanol solution) 2.5 take the idol

yellow iron oxide pigment 0.5 pigment magnesium stearate 0.5 lubricating preparation colloidal silicon dioxide 0.25 preparation slippery

Tablets may be prepared as described in US Patent No. 5,433,123.

Example 8 (wax base material)

Component % w/w Function compound of formula X 0.02 pure free base active component Gelucire 50/02 91.5 wax base Gelucire 50/13 5 wax base propylene glycol 1, 98 solvent colloidal oxide 1.5 hydrophobic siliceous excipient dihydrogen citrate 0 to 1.5 stabilizing sodium means

Production process:

Gelucir waxes were melted together at a temperature of around 60 degrees Celsius. Compound X was dissolved in propylene glycol and mixed into the waxes.

Subsequently, colloidal silicon dioxide was mixed in and the mixture filled into containers consisting of hard gelatin capsules of size No. 3.

Table 1. Release profile of compound of formula X from wax-filled capsules in water (0% citrate) • ·

Time (h) released %

Example 9 (Ethyl cellulose coated beads)

200 mg of starting sugar ball cores with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh), 0.715 to 0.833 mm (20 to 25 US mesh), or 0.833 to 0.991 mm (16 to 20 US mesh) may be used. A layer of a solution with a drug with the following composition was used:

Component % mass ./weight Function compound of formula X 0.003 up to 0.05 active component Opadry® Clear clean base 3 loosely take the idol sodium dihydrogen citrate 1.5 stabilizing purified water In total q.s. 100 means

Solution for impermeable bedding: A solution of Opadry® Clear (YS-1-9025A) in purified water, with a concentration of 10% solid particles, was prepared by dissolving 100 g of Opadry® Clear in 900 g of purified water.

Polymer coating: A polymer coating dispersion containing ethyl cellulose (Surelease®) of the following composition was produced and used to coat impermeable coated balls with polymer, with an increase of 10 to 25% « 9 • · · · · · * • · · ♦ · •· ·· ··· ·· *·· by weight, especially 10, 12, 15, 17, 22 and 25% by weight.

Component_% w/w_Function

Surelease® 60 release (25% solids) control polymer coating with plasticizer purified q.s.

water

100 in total

Drug-coated beads were made by layering the drug solution onto starting beads with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh) using a NiroSTREA-1 bed drying device such that the free base drug of 100 pg was layered onto 200 mg of starting beads. In order to produce immediate release beads, drug coated beads were hermetically coated with Opadry® Clear coating solution, up to a subsequent increment of 3% by weight. A portion of the immediate release beads were coated with a polymer, Surelease® coating dispersion, with a subsequent addition of 10 to 25% by weight. The resulting polymer-coated balls were produced by further impermeable coating with Opadry® Clear solution for impermeable coating, already polymer-coated balls, up to a total increase of 2% by weight.

Table 2. Range of release profile from ethyl cellulose-coated beads, containing 10 to 25% by weight of compound of formula X in water • · • · · ·· «·· ·· ···

Time (h) 1

4' released %

0.8-36

5-57

13-75

18-91

Example 10 (Ethyl Cellulose Coated Beads)

200 mg of starting sugar ball cores with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh), 0.715 to 0.833 mm (20 to 25 US mesh), or 0.833 to 0.991 mm (16 to 20 US mesh) may be used. A layer of a solution with a drug with the following composition was used:

Component % w/w Function compound of formula X 0.003 to 0.05 active pure free base component Opadry® Clear 3 take the idol dihydrogen citrate 1.5 stabilize sodium start means In total 100

Impermeable Coating: An impermeable coating dispersion containing Eudragit® L30D-55, having the following composition, was prepared and used for impermeable coating of medicated layered beads, with an increase of 4% by weight.

Component_% w/w_Function

Eudragit® L30D-55 45 polymeric (30% solids) impermeable

triethyl citrate 2.02 talc 3.10 purified water q.s.

Total 100 coating plasticizer anti-tack agent

Polymer coating: A dispersion of a polymer coating, of the following composition, containing ethyl cellulose (Surelease®), was prepared and used to coat hermetically sealed spheres with polymer, with an addition of 10 to 25% by weight.

Component_% w/w_Function

Surelease® 60 release (25% solids) control polymer coating with plasticizer purified water q.s.

100 in total

Drug-coated beads were made by layering a drug solution onto starting bead cores with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh). In this, a Niro STREA-1 floating bed dryer was used, layering 100 pq of drug as free base on 200 mq of starting cores. The drug-coated beads were further imperviously coated with an impervious coating dispersion, Eudraqit® L30D-55 to an increment of 4% by weight. So the instant release balls were made. A portion of the immediate release balls ► ···· • · was coated with a polymer, the Surelease® coating dispersion, in an increment of 10 to 25% by weight. The resulting polymer-coated balls were prepared by impermeable coating the already polymer-coated balls with an impermeable coating solution , Opadry® Clear, up to an increase of 2% by weight.

Table 3. Release Profile of Compound X from Ethyl Cellulose Coated and Impermeable Eudragit® L30D Coated Beads in Water

Time (h)_released %, 10% Surelease®

0.5

1.5

Example 11 (Ethyl Cellulose Coated Beads)

200 mg of starting sugar ball cores with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh), 0.715 to 0.833 mm (20 to 25 US mesh), or 0.833 to 0.991 mm (16 to 20 US mesh) may be used. A layer of a solution with a drug with the following composition was used:

Component % w/w Function compound 0.003 to 0.05 active X formulas pure free base component Opadry® Clear 3 take the idol dihydrogen citrate 1.5 stable sodium start

• 00 0 » 000 0 0 0 0 000

00 0 ♦ 0 ·

0 0 ·

000,000

0

0 .00 agent purified water q.s

100 in total

Impermeable coating solution: A solution of Opadry® Clear (YS-1-9025A) in purified water, with a 10% solids concentration, was prepared by dissolving 100 g of Opadry® Clear in 900 g of purified water.

Polymer coating: A polymer coating dispersion containing ethyl cellulose (Aquacoat®) of the following composition was prepared and used to coat impermeable coated beads with polymer, with an increase of 10% by weight.

Component

Aquacoat® triethylcitrate purified water Total % wt. /wt.Features 50 release (30% as solids) control polymer coating

2.02 plasticizer

q.s.

100

The drug-coated spheres were prepared by stacking. of the drug solution onto starting core beads with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh), using a Niro STREA-1 floating bed dryer, layering 100 μς of free base drug onto 200 mg of starting cores. In order to prepare immediate release beads, the drug-coated beads were further imperviously coated with Opadry® Clear impervious coating solution, up to an increment of 3% by weight. Part of balls ···· • · ·>· this this· • · • · • » • this ·· *·· this this ··· ·· ·· • ·· · • ·· « ·<· ♦·· • « it· it· with immediate release was coated with polymer dispersion for coating Aquacoat®, up to an increase of 10% by weight. The resulting form of polymer-coated balls was prepared by impermeable coating already polymer-coated balls with Opadry® Clear impermeable coating solution, up to an increase of 2% by weight.

Example 12 (Eudragit coated beads)

200 mg of starting sugar ball cores with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh), 0.715 to 0.833 mm (20 to 25 US mesh), or 0.833 to 0.991 mm (16 to 20 US mesh) may be used. A layer of a solution with a drug with the following composition was used:

Component % w/w Function compound of formula X 0.003 to 0.05 active pure free base component Opadry® Clear 3 take the idol dihydrogen citrate 1.5 stabilize sodium start preparation purified water q.s. In total 100

Impermeable Sheeting Solution: A solution of Opadry® Clear (YS-1-9025A) in purified water, with a 10% solids concentration, was prepared by dissolving 100 g of Opadry® Clear in 900 g of purified water.

Polymer coating: A polymer coating dispersion containing Eudragit® RS or RS/RL, with the following composition, • · I «· was prepared and used to coat beads already impermeable with polymer, with an increase of 10% by weight.

Component % w/w Function Eudragit® RS 30D 45 polymeric (30% as fixed coating substance) controlling triethyl citrate 2.02 release plastic surgeon talc 3.10 means purified water q.s. against bonding In total 100 or Component % w/w Function Eudragit® RS 30D 36 polymeric (30% as fixed coating substance) controlling Eudragit® RL 30D 9 release polymeric (30% as fixed coating substance) controlling triethyl citrate 2.02 release plastic surgeon talc 3.10 means purified water q.s. against bonding In total 100

« 4

44

4 4 4

4 4 4 • 444 444 • 4

Λ 4 4 4

4 44 444 ·, 4 4 4 444 • 4 4 4 4 4

4 4 4 » •444 444 44 444

Drug-coated beads were prepared by layering a drug solution onto starting bead cores with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh) using a Niro STREA-1 floating bed dryer such that 100 pg of drug was present as free base layered on top of 200mg of starting cores. In order to produce immediate release beads, the drug coated beads were further imperviously coated with an impervious coating solution, Opadry® Clear, to an increment of 3% by weight. A portion of the immediate release beads was coated with the polymer, Eudragit® RS or RS/RL coating dispersion, in increments of 10% by weight. The resulting polymer-coated balls can be prepared by impermeable coating already polymer-coated balls with Opadry® Clear impermeable coating solution, up to an increase of 2% by weight.

Table 4. : Water release profile of compound X from Eudragit® RS/RL coated beads

Time (h)_ Released %

0.5

0.2

0.3

0.4

1.9

Example 13 (methocel-coated beads)

200 mg of starting sugar ball cores with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh), 0.715 to 0.833 mm (20 to 25 US mesh), or 0.833 to 0.991 mm (16 to 20 US mesh) may be used. A layer of a solution with a drug with the following composition was used:

«

Component % w/w Function compound of formula X 0.003 to 0.05 active pure free base component Methocel E4M 15 polymeric coating controlling release dihydrogen citrate 1.5 stabilize sodium start preparation purified water q.s. In total 100

Impermeable coating solution: A solution of Opadry® Clear (YS-1-7006) in purified water, with a solids concentration of 10%, was prepared by dissolving 100 g of Opadry® Clear in 900 g of purified water.

Example 14 (balls coated with ethyl cellulose and with a release retarder)

200 mg of starting sugar ball cores with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh), 0.715 to 0.833 mm (20 to 25 US mesh), or 0.833 to 0.991 mm (16 to 20 US mesh) may be used. A layer of a solution with a drug with the following composition was used:

Component % w/w Function compound of formula X 0.003 to 0.05 active pure free base component Opadry® Clear 1.5 take the idol Surelease® 1.5 preparation

sodium dihydrogen citrate 1.5 purified water q.s

A total of 100 • t

0 • 0 0 0 0 0

0 slow-release stabilizer

00 0 0 • · 0 • 0· 0 • 0

Impermeable coating solution: A solution of Opadry® Clear (YS-1-9025A) in purified water with a 10% solids concentration was prepared by dissolving 100 g of Opadry® Clear in 900 g of purified water.

Polymer coating: A polymer coating dispersion containing ethyl cellulose (Surelease®) having the following composition was prepared and used to polymer coat impermeable coated beads up to 10% by weight.

The λ i ® component

Surelease % w/w

(25% as fixed

Function polymer substance) release control coating, with plasticizer purified water Total

q.s.

100

Drug-coated beads were made by layering a drug solution onto starting beads with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh) using a Niro STREA-1 dryer in a floating layer such that • 4 ·

• · 4 · • · * 4 4 4 • · «4 4 4 layered 100 μς drug as free base on 200 mg starting beads. The drug-coated beads were imperviously coated with Opadry® Clear impervious coating solution to an increment of 3% by weight to produce immediate release beads. A portion of the immediate release beads was further coated with a polymer, Surelease® coating dispersion, to an increment of 10% by weight. The resulting polymer-coated beads were made by impermeable coating the polymer-coated beads with Opadry® Clear impermeable coating solution to an increment of 2% by weight.

Table 5. Release profile of compound X from ethyl cellulose-coated beads with a release retarder in water

Time (h)_Released %

No retardant With retardant 0.5 12 8 1 37 22 2 57 35 4 73 48 6 85 53 8 58

Example 15 (enteric coated beads)

200 mg of starting sugar ball cores with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh), 0.715 to 0.833 mm (20 to 25 US mesh), or 0.833 to 0.991 mm (16 to 20 US mesh) may be used. A layer of a solution with a drug with the following composition was used:

34 ·· · ♦· ···· .·*. • · · * · · · · · · · . . . . · · · ·«· ··· • · · · · · · «··· ··· ·· ··· ·· ** Component % w/w Function compound of formula X 0.003 to 0.05 active pure free base component Opadry® Clear 3 take the idol sodium dihydrogen citrate 1.5 stabilize will begin preparation purified water q.s. In total 100

Impermeable Sheeting Solution: A solution of Opadry® Clear (YS-1-9025A) in purified water, with a 10% solids concentration, was prepared by dissolving 100 g of Opadry® Clear in 900 g of purified water.

Polymer coating: A dispersion for polymer coating containing Eudragit® L30D-55, which has the following composition, was prepared and used for polymer coating of spheres already impermeable coated, up to an increase of 20% by weight.

Component

Eudragit L30D-55 talc triethyl citrate % w/w Functions

45.00 enteric (30% as solid) polymer (pH dependent)

2.02 plasticizer

3.10 anti-caking agent purified water Total

q.s.

100

Drug-coated beads were prepared by layering a drug solution onto starting beads with a particle size of 0.542 to 0.715 mm (25 to 30 US mesh) using a Niro STREA-1 floating bed dryer such that 100 µg of drug was coated as free base per 200 mg starting balls. In order to prepare immediate release beads, the drug coated beads were imperviously coated with Opadry® Clear impervious coating solution, up to a 3% weight gain. A portion of the immediate release beads was enteric coated with an enteric coating dispersion, Eudragit®, to an increment of 20% by weight. The resulting enteric-coated beads were produced by impermeable coating the already enteric-coated beads with Opadry® Clear solution for impermeable coating, up to an increase of 2% by weight.

Example 16 (basic tablet)

Component mg per tablet Function compound of formula X 0.005 up to 0.1 active clean free base component hydroxypropylmethylcellulose E4M CR 75.0 hydrogel basic mass dihydrogen citrate sodium 3.00 stabilize will begin preparation lactose, Fast Flo 70.38 hydrophilic thinner magnesium stearate 1.50 lubricating means Opadry® White 2.25 polymer

impermeable coating

Impermeable coating solution: A solution of Opadry® Clear (YS-1-9025A) in purified water with a 10% solids concentration was prepared by dissolving 100 g of Opadry® Clear in 900 g of purified water.

Polymer coating: A polymer coating dispersion containing ethyl cellulose (Surelease®) having the following composition was prepared and used to coat the polymer impermeable beads with an increase of 10% by weight.

Component_% wt. /weight_Function

Surelease® 60 polymer (25% solids) release control coating, with plasticizer purified q.s.

water

100 in total

700 g of tablet cores were coated, using a Vector LDCS pan, with Opadry® Clear impermeable coating solution, with a gain of 3% by weight. The impermeable coated tablets were subsequently polymer coated using Surelease® coating dispersion, with an increase of 4% by weight.

• · • · · · · ·

Table 6. Release profile of the compound of formula X in water, from the base of the tablet.

Time (h) Dissolved % 1 8 2 30 4 58 8 96

Example 17 (tablet p layers) controlled by relaxing two Active layer folder mg per tablet Function compound of formula X 0.005 up to 0.1 mg active clean free base component Methocel K4M 15.00 hydrogel polymer lactose monohydrate 62.0 hydrophilic filler polyvinylpyrrolidone 3.0 take the idol magnesium stearate 1.0 hydrophobic lubricating preparation Syloid 244 1.0 hydrophilic means increasing slipperiness Support layer components mg per tablet Function Compritol 888 15.0 plastic surgeon lactose monohydrate 29.0 hydrophilic filler

38 44 · ·♦ ···· B * ·« · 9 · · • · · · ··· · 4 4 · · · * ♦ 4 4 · · · 44 · »44 · · 444 polyvinylpyrrolidone 4.0 take the idol magnesium stearate 1.5 hydrophobic lubricating means Methocel E5 29, 4 hydrogel polymer iron oxide 0.1 dye

· ;

•

0 0·

PATENT CLAIMS

Claims (28)

·· 000 0 0 0 0 Controlled release oral dosage form comprising [R- (Z)] - α- (methoxyimino) -α- (1-azabicyclo [2.2.2] oct-3-yl) acetonitrile monohydrochloride , the compound of formula X, its free base or any other pharmaceutically acceptable salt thereof. A dosage form according to claim 1, characterized in that it provides an in vitro release profile selected to form an area under the in vivo release profile curve similar to that obtained after conventional oral administration of a rapid release tablet having a compound content. of formula X from 5 to 75 μς, calculated as the free base, twice a day. The dosage form according to claim 1 or 2, characterized in that it provides an in vitro release profile of 25 to 70% in 4 hours and 70 to 100% in 8 hours. Dosage form according to any one of claims 1 to 3, characterized in that it is selected from wax bases, swellable substances or gel-forming substances, release-coated tablets with waxing polymers or waxes, and pellets, granules or spheres containing the base substances. %, or are coated with release controlling polymers or waxes and subsequently formulated as capsules, compressed tablets or suspensions. A dosage form according to any preceding claim, comprising a swellable base or a gel-capable base selected from 999 · · · Hydroxypropylmethylcellulose E4M CR sodium dihydrogen citrate • 9 9 • 9 9 9 9 9 9 9 9 9 9 9 9 9 * From alkylcelluloses, hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates, polymethylmethacrylates, methacrylate-divinylbenzene copolymers, carboxymethylamide, polyoxyalkylene glycols, polyvinylpyrrolidone and carboxymethylcellulose. The dosage form of claim 5, wherein the matrix is selected from alkylcelluloses, hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates, cross-linked polyvinylpyrrolidone and sodium carboxymethylcellulose. Dosage form according to claim 5 or 6, characterized in that it comprises a hydrogel-based tablet coated with a hydrophobic polymer coating for controlling the release selected from alkyl celluloses and methacrylic acid derivatives. Dosage form according to claim 7, characterized in that the polymeric base comprises 10 to 50% of a hydrophobic release controlling polymer which is 4 to 10% by weight of the tablet. A dosage form according to claim 7 or 8, comprising a tablet having the following composition, in mg per tablet: Compound of Formula X 0.005 to 0.1 pure free base 75.0 0 to 3.00 lactose Fast Flo 70.38 stearat magnesium 1.50 Opadry® White 2,25, which is imperviously coated with Opadry® Clear (YS-1-7006) in purified water with a 10% solids concentration, polymer coated, 60% by weight dispersion (25% as solid) containing ethylcellulose (Surelease®), in increments of 10% by weight, formed into tablet cores, coated with Opadry® Clear for airtight coating, and coated with a polymer using a 60% by weight dispersion (25% as a solid) containing ethylcellulose (Surelease®), in increments of 4% by weight. Dosage form according to any one of claims 1 to 4, characterized in that it comprises drug-coated polymer coated beads, either alone or in combination with drug-coated beads that have not been coated with the release-controlling polymer (immediate-release beads). and optionally with inert excipients and / or release retarding agents and / or one or more binders. Dosage form according to claim 10, characterized in that the coated beads are sealed with a thin film-forming polymer. Dosage form according to claim 10 or 11, characterized in that the release-controlling polymer coating is selected from alkylcelluloses, hydroxyalkylcelluloses, sodium carboxymethylcelluloses and methacrylic acid derivatives. • · Dosage forms according to any one of claims 10 to 12, characterized in that the polymer (s) comprise 10 to 30% by weight of the total dosage form. A dosage form according to claim 10 in the form of a capsule, characterized in that it comprises starting sugar-bead cores having a particle size of 0.542-0.715 mm, 0.715-0.833 mm and 0.833-0.991 mm, which are coated with a drug in an amount of 100 μς per 200 mg. starting nuclei, calculated as the free base, with an aqueous drug solution having the following composition, in% by weight: Compound of Formula X 0.003-0.06 of pure free base Opadry® Clear 3 sodium dihydrogen citrate 0 to 1.5 sealed with a solution of Opadry® Clear (YS-1-7006) in purified water, 10% solids concentration, in increments of 3% by weight, and part of these beads are further coated with polymer to an increment of 10 to 25% by weight, using a 60% dispersion (25% solids) containing ethylcellulose (Surelease®) and then imperviously coated with the above airtight coating to a 2% increment. A method of treating and / or prophylaxis of dementia in a mammal, including Alzheimer's disease, comprising administering an effective amount of an oral controlled-release dosage form according to claim 1 to a subject in need thereof. 16. A method of enhancing amyloid precursor protein breakdown in a nonamyloidogenic pathway, in patients suffering from Alzheimer's disease, or in patients at risk of developing Alzheimer's disease, comprising administering an effective amount of an oral controlled release dosage form according to claim 1 to a patient in need thereof. E. Use of an oral controlled-release dosage form according to claim 1 for the manufacture of a medicament for the treatment and / or prophylaxis of dementia in mammals, including Alzheimer's disease. The use of the oral controlled release dosage form of claim 1, for the manufacture of a medicament for enhancing amyloid precursor protein degradation in a nonamyloidogenic pathway, in patients suffering from or at risk of developing Alzheimer's disease. A pharmaceutical composition for the treatment and / or prophylaxis of dementia in mammals, including Alzheimer's disease, comprising the oral controlled release dosage form of claim 1. A pharmaceutical composition for enhancing degradation, amyloid precursor protein, in a nonamyloidogenic way, in patients suffering from or at risk of developing Alzheimer's disease, comprising the oral controlled release dosage form of claim 1. 21. The dosage form, method, use or composition of any one of the preceding claims, characterized in that the release in the gastrointestinal tract occurs. especially during the first eight to twelve hours after ingestion. A dosage form, method, use or composition according to any preceding claim comprising [R- (Z)] - and (methoxyimino) -α- (1-azabicyclo [2.2.2] oct) (3-yl) acetonitrile monohydrochloride. 23. A dosage form, method, use or composition according to any one of claims 1 to 22, comprising 5 µm of a compound of formula X, calculated as the free base. The dosage form, method, use or composition of any one of claims 1 to 22, comprising 12.5 µg of a compound of formula X, calculated as the free base. A dosage form, method, use or composition according to any one of claims 1 to 22, comprising 25 µm of a compound of formula X, calculated as the free base. A dosage form, method, use or composition according to any one of claims 1 to 22 comprising 50 µg of a compound of formula X, calculated as the free base. A dosage form, method, use or composition according to any one of claims 1 to 22 comprising 75 µg of a compound of formula X, calculated as the free base. 4 · · · · · · 4 · · · 4 ·· · · · · · 28. The dosage form, method, use or composition of any one of claims 1 to 22 comprising 100 µg of a compound of formula X, calculated as the free base.