CA2265661A1 - Controlled release dosage form of r-(z)-alpha-methoxyimino-alpha-(1-azabicyclo2.2.2oct-c-yl)acetonitrile monohydrochloride - Google Patents
Controlled release dosage form of r-(z)-alpha-methoxyimino-alpha-(1-azabicyclo2.2.2oct-c-yl)acetonitrile monohydrochloride Download PDFInfo
- Publication number
- CA2265661A1 CA2265661A1 CA002265661A CA2265661A CA2265661A1 CA 2265661 A1 CA2265661 A1 CA 2265661A1 CA 002265661 A CA002265661 A CA 002265661A CA 2265661 A CA2265661 A CA 2265661A CA 2265661 A1 CA2265661 A1 CA 2265661A1
- Authority
- CA
- Canada
- Prior art keywords
- dosage form
- coated
- beads
- form according
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
A controlled release formulation of an acetonitrile compound and its use in the treatment and/or prophylaxis of certain disorders.
Description
101520253035W0 98/ 10762CA 02265661 l999-03- llPCT/GB97/02418CONTROLLED RELEASE DOSAGE FORM OF [R-(Z)]-ALPHA-(METHOXYIMINO)-ALPHA-(l-AZABICYCLO[2.2.2]OCT-3-YL)ACETONITRILE MONOHYDROCHLORIDEThe present invention relates to a novel formulation, and to its use in the treatmentand/or prophylaxis of certain disorders.[R-(Z)]-0:-(methoxyimino)-on-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrilemonohydrochloride (compound X) and methods for its preparation are disclosed inEP-A-03 92803, W095/31456 and WO93/ 17018. The compound enhances acetylcholinefunction via an action at muscarinic receptors within the central nervous system, and istherefore of potential use in the treatment and/or prophylaxis of dementia in mammals.WO96/ 12486 discloses the use of compound X in the manufacture of amedicament for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer'sdisease.Fast-release swallow tablet and oral solution formulations of compound X bothresult in rapid absorption of the compound into the circulation, and require twice a daydosing for optimal efficacy.It has now been surprisingly found that it is possible to formulate compound X,which has very high water solubility and is active at extremely low doses, in such a waythat release is controlled to take place over a period of hours. Such a formulation wouldrequire dosing only once a day: this is likely to improve compliance in a patientpopulation characterised by poor memory; it may also reduce side-effects in case ofaccidental overdosing.Accordingly, the present invention provides a controlled release oral dosage formcontaining compound X, its parent free base or any other pharmaceutically acceptable saltthereof.By controlled release is meant any formulation technique wherein release of theactive substance from the dosage form is modiï¬ed to occur at a slower rate than that froman immediate release product, such as a conventional swallow tablet or capsule.Controlled release includes delayed release wherein release of the active substancefrom the dosage form is modiï¬ed to occur at a later time than that from a conventionalimmediate release product. The subsequent release of active substance from a delayedrelease formulation may also be controlled to occur at a slower rate.Examples of controlled release formulations which are suitable for incorporatingcompound 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 Edition. Eds. J .R.Robinson, V.H.L. Lee. Marcel Dekker Inc. New York 1987.- 1 -101520253035WO 98110762CA 02265661 l999-03- llPCT/GB97/02418Such controlled release formulations are preferably formulated in a manner suchthat release of compound X is effected throughout the gastroâintestinal tract, and takesplace predominantly over the ï¬rst eight to twelve hours following ingestion.Preferred formulations include wax matrices, swellable and/or gellable polymer orhydrogel matrices, tablets coated with release controlling polymers or waxes, and pellets,granules or beads comprising matrices or coated with release controlling polymers orwaxes and then formulated as capsules, compressed tablets or suspensions.Suitable waxes for matrix formation or release controlling coating include non-ionic beeswax derivatives such as Gelucire 62/05, 50/02 or 50/13 (Gattefosse), glycerylbehenate, other fatty acid mono-, di- or tri-esters of glycerol such as Precirol ATO5(Gattefosse), microcrystalline wax, hydrogenated castor oil or hydrogenated vegetable oil,long-chain aliphatic alcohols such as stearyl alcohol and camuba wax.Suitable materials for the formation of hydrogel matrices or swellable and/orgellable polymer matrices may be selected from alkyl celluloses, hydroxyalkylcelluloses,polyvinyl alcohol, polymethacrylates, polymethylmethacrylates,methacrylate/divinylbenzene copolymers, carboxymethylamide, polyoxyalkylene glycols,polyvinyl pyrrolidone and carboxymethyl cellulose. The swellable polymeric material inparticular may be selected from crosslinked sodium carboxymethylcellulose, crosslinkedhydroxypropylcellulose, high molecular weight polyhydroxypropylmethylcellulose,carboxymethylamide, potassium methacrylate/divinylbenzene copolymer,polymethylmethacrylate, crosslinked polyvinylpyrrolidone and high molecular weightpolyvinyl alcohol. The gellable polymeric material in particular may be selected frommethylcellulose, carboxymethylcellulose, low-molecular weighthydroxypropylmethylcellulose, low-molecular weight polyvinylalcohols,polyoxyethyleneglycols and non-cross-linked polyvinylpyrrolidone. The swellable andgellable polymeric material in particular may be selected from mediumâviscosityhydroxypropylmethylcellulose and medium-viscosity polyvinylalcohols.Release controlling polymers include hydrogel polymers such as those listedabove, hydrophobic polymers and enteric, or pH dependent, polymers.Suitable materials for the formation of hydrophobic release controlling polymercoatings include alkyl celluloses, which may be used in the form of latex suspensionssuch as Surelease (Colorcon) or Aquacoat (FMC), and methacrylic acid derivatives,which may be used in the form of latex suspensions such as Eudragit RS, RL and NE(Rohm).Suitable materials for the formation of enteric or pH dependent polymer coatingsinclude methacrylic acid derivatives, which may be used in the form of latex suspensionssuch as Eudragit L and S (Rohm).CA 02265661 l999-03- 11W0 98I10762 PCT/GB97/02418Seal coats, ï¬lm layers used to separate the various functional layers of theformulation or to provide a ï¬nal layer to the outside of the formulation, contain suitablematerials for ï¬lm forming such as alkylcelluloses, which may be used in the form of latexsuspensions such as Surelease (Colorcon) or Aquacoat (FMC), and hydroxyalkycelluloses5 such as hydroxypropylmethylcellulose (for example Opadry (Colorcon)).The formulation may also include plasticisers such as triethyl citrate, dibutylsebacate or medium chain triglycerides in the release controlling polymer layer.Pellet-forrning materials include suitable grades of microcrystalline cellulose suchas Avicel PH101 (FMC).l0 Granules may be formed from any of the commonly used pharmaceutical ï¬llers ordiluents such as lactose, lactose monohydrate, mannitol, microcrystalline cellulose,dicalcium phosphate or starch.Beads may be formed by layering or spraying on non-pareil seeds.Other suitable ingredients in controlled-release dosage forms include polyethylene15 glycol and propylene glycol and these, as well as the pharmaceutical ï¬llers, may be usedto modify the release rate by inclusion in matrices, pellets, granules or beads.The formulation may also include hydrophobic excipients that retard the releasefrom the formulation such as ethylcellulose, talc, colloidal silicon dioxide or glycerylmonostearate and/or one or more binders such as hydroxypropylmethylcellulose,20 microcrystalline cellulose or polyvinylpyrrolidone.Wetting agents such as sodium lauryl sulphate, lubricants such as magnesiumstearate and glidants such as colloidal silica may also be included.A particularly preferred formulation comprises drug-layered beads coated with arelease controlling polymer either alone or in combination with drug-layered beads not25 coated with a release controlling polymer (immediate release beads). In the drug layeringprocess onto non-pareil beads, appropriate size non-pareil sugar beads may be layeredwith a solution or dispersion containing the active substance, inert excipients, and/orretardants such as ethylcellulose, talc, colloidal silicon dioxide or glyceryl monostearateand/or one or more binders such as hydroxypropylmethylcellulose or30 polyvinylpyrrolidone. The layering of the active substance may be accomplished at apredetermined rate and temperature using either a coating pan or a ï¬uid bed drier. Thelayered beads may be seal coated with a suitable ï¬lm forming polymer such ashydroxypropylmethylcellulose (e.g. Opadry) or Eudragit® L30D-55 (a methacrylic acidcopolymer) and then may be coated with one or more suitable release controlling35 polymers preferably selected from from alkyl celluloses, hydroxyalkylcelluloses, sodiumcarboxymethyl cellulose and methacrylic acid derivatives, such as ethylcellulose,Eudragit® RS, Eudragit® RL or Methocel E4M, to produce beads that release compound-3- 101520253035W0 98/10762CA 02265661 l999-03- llPCT/GB97/02418X over an eight to twelve hour period and/or release compound X in one or more pulses.Seal coated beads may be used for an immediate release dose. The controlled release or amixture of controlled release and immediate release beads may then be ï¬lled into anappropriate size capsule or compressed with inert excipients into tablets of appropriatephysical parameters such as shape, size, hardness and disintegration. The polymer(s),release controlling plus any seal coat polymer(s), preferably make up 10 to 30% byweight of the total dosage form. Plasticizer is normally present and may make up at least2% by weight. Binder(s) and retardant(s) typically make up to 3-10% by weight.Another particularly preferred formulation comprises a swellable and/or gellablepolymer matrix tablet. The polymer matrix is preferably a hydrogel polymer selectedfrom alkyl celluloses such as methylcellulose, hydroxyalkylcelluloses such ashydroxypropylcellulose and hydroxypropylmethylcellulose, polyvinyl alcohol,polymethacrylates, cross-linked polyvinylpyrrolidone and sodium carboxymethylcellulose. The polymers typically make up 10 to 50% by weight of the tablet. The matrixtablet can be sealed with a hydrophobic release controlling polymer coating such asethylcellulose (Surelease (Colorcon)) to retard the hydration of the hydrogel matrix in thetablet. The hydrophobic coating polymer typically make up 4 to 10% by weight of thetablet.Such matrix tablet formulations can be prepared by either direct compression orwet granulation processes. Coating may be accomplished using a coating pan.Other preferred formulations are described in US Patent No. 5,422,123.Thus, a particular aspect of the invention provides a system for the controlledrelease of an active substance which is compound X, its parent free base or any otherpharmaceutically acceptable salt thereof, comprising (a) a deposit-core comprising aneffective amount of the active substance and having deï¬ned geometric form, and (b) asupport-platform applied to said deposit-core, wherein said deposit-core contains at leastthe active substance, and at least one member selected from the group consisting of (1) apolymeric material which swells on contact with water or aqueous liquids and a gellablepolymeric material wherein the ratio of the said swellable polymeric material to saidgellable polymeric material is in the range 1:9 to 9: 1, and (2) a single polymeric materialhaving both swelling and gelling properties, and wherein the support-platforrn is anelastic support, applied to said deposit-core so that it partially covers the surface of thedeposit-core and follows changes due to hydration of the deposit-core and is slowlysoluble and/or slowly gellable in aqueous ï¬uids.The swellable polymeric material in (1) may be selected from crosslinked sodiumcarboxymethylcellulose, crosslinked hydroxypropylcellulose, high molecular weightpolyhydroxypropylâmethylcellulose, carboxy-methyl starch, potassium-4-101520253035W0 98I10762CA 02265661 l999-03- llPCT/GB97/02418methacrylate/divinylbenzene copolymer, crosslinked polyvinylpyrrolidone and polyvinylalcohol. The gellable polymeric material in (1) may be selected from methylcellulose andnon-cross-linked polyvinylpyrrolidone.The support-platforrn may comprise; polymers such aspolyhydroxypropylmethylcellulose, polyvinyl alcohol, polyacrylate, polymethacrylate,polyhydroxpropyl cellulose and polysodium carboxymethylcellulose; plasticizers such aspolyoxyethylene glycols, castor oil, hydrogenated cator oil, ethyl phthalate, butylphthalate, natural glycerides, synthetic glycerides and semisynthetic glycerides; binderssuch as polyvinylpyrrolidone, methylcellulose, ethyl cellulose gum arabic and alginicacid; hydrophilic agents such as mannitol, lactose, starch and colloidal silica; and/orhydrophobic agents such as hydrogenated castor oil, magnesium stearate, a fattysubstance, wax, natural glycerides and synthetic glycerides. The polymer(s) typicallymake up 30 to 90% by weight of the support-platforrn, for example about 35 to 40%.Plasticizer may make up at least 2% by weight of the support-platform, for example about15 to 20%. Binder(s), hydrophilic agent(s) and hydrophobic agent(s) typically total up toabout 50% by weight of the support-platform, for example about 40 to 50%.Such formulation may be prepared as generally described in US 5,422,123.USâA-4 839 177 discloses a further alternative controlled release formulationssuitable for use in the present invention.Thus a further aspect of the invention provides a system for the controlled-raterelease of compound X,â consisting of:a) a deposit-core comprising effective amounts of compound X and having deï¬nedgeometric form,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 consistingof a (a) 5-80% by weight of the total weight of deposit-core of a polymeric materialhaving a high degree of swelling on contact with water or aqueous liquids and 90-10% byweight of the total weight of the deposit core of a gellable polymeric material, and (b) asingle polymeric material having both swelling and gelling properties, and otheradjuvants able to provide the mixture with suitable characteristics for compression and forintake of water, and wherein said support-platform consists of a polymeric materialinsoluble in aqueous liquids and partially coating said deposit core.The swellable polymeric material in (a) may be selected from crosslinked sodiumcarboxymethylcellulose, crosslinked hydroxypropylcellulose, high molecular weightpolyhydroxypropyl-methylcellulose, carboxy-methylamide, potassiummethacrylate/divinylbenzene copolymer, polymethylmethacrylate, crosslinkedpolyvinylpyrrolidone and high molecular weight polyvinyl alcohol. The gellablepolymeric material in (a) may be selected from methylcellulose, carboxymethylcellulose,_ 5 _101520253035W0 98/ 10762CA 02265661 l999-03- llPCTIGB97/02418low-molecular weight hydroxypropylmethylcellulose, low-molecular weightpolyvinylalcohols, polyoxyethyleneglycols and non-cross-linked polyvinylpyrrolidone.The swellable and gellable polymeric material in (b) may be selected from medium-viscosity hydroxypropylmethylcellulose and medium-viscosity polyvinylalcohols. Thesupport platform may comprise insoluble polymeric material selected from acrylates,cellulose, ethylcellulose, cellulose acetate-propionate, polyethylene, methacrylates,acrylic acid copolymers and high-molecular weight polyvinylalcohols.Such formulation may be prepared as generally described in US 4,839,177.W0 94/06416 discloses a yet further alternative controlled release formulationssuitable for use in the present invention.Thus a yet further aspect of the invention provides a system for the controlled-raterelease of compound X, consisting of a pharmaceutical compressed tablet capable ofreleasing compound X at different rates, consisting of three layers, wherein- a first layer contains compound X with immediate or controlled release formulation,composed of rapidly swelling and/or soluble and/or erodible polymeric substances bycontact with aqueous ï¬uids, and adj uvants;- a second layer contains compound X, either equal to or different from those of the firstlayer, with slow release formulation, composed of swelling and/or gellable and/orerodible polymeric substances by contact with aqueous ï¬uids, and adjuvants;- a lowâpermeability barrier-type layer coating said second layer or, alternatively, placedbetween the ï¬rst and second layer, consisting of polymeric substances, adjuvants,plasticizing agents and, if necessary, compound X.The polymeric substances of the first layer may be selected from cross-linkedpolyvinylpyrrolidone, low- and medium-molecular-weight hydroxypropyl cellulose andhydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose,carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinylalcohols, starches, starch derivatives, microcrystalline cellulose and cellulose derivatives,B-cyclodextrin and dextrin derivatives.The polymeric substances of the second layer may be selected from the groupconsisting of hydroxypropyl methylcellulose having molecular weight from 1,000 to4,000,000, hydroxypropyl cellulose having molecular weight from 2,000 to 2,000,000,carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, marmans, xanthans,alginic acid and derivatives thereof, carboxymethylcellulose and derivatives thereof,poly(methyl vinyl ethers/maleic anhydride), ethylcellulose, methylcellulose, and cellulosederivatives.The adjuvants of the ï¬rst and second layers may be selected from the groupconsisting of starch, pregelled starch, calcium phosphate. mannitol, lactose, saccharose,_ glucose, sorbitol, microcrystalline cellulose, gelatin, polyvinylpyrrolidone,-5-101520253035W0 98/ 10762CA 02265661 l999-03- llPCT/GB97/02418methylcellulose, starch solution, ethylcellulose, arabic gum, tragacanth gum, magnesiumstearate, stearic acid, colloidal silica, glyceryl monostearate, hydrogenated castor oil,waxes, and monoâ, bi-, and trisubstituted glycerides.The polymeric substances of the barrier type layer may be selected from the groupconsisting of hydroxypropyl methylcellulose having molecular weight from 1,000 to4,000,000, hydroxypropyl cellulose having molecular weight from 2,000 to 2,000,000,carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans,carboxymethylcellulose, ethylcellulose, and methylcellulose.The adjuvants of the barrierâtype layer may be selected from the group consistingof glyceryl monostearate, semisynthetic glycerides, glyceryl palmitostearate, glycerylbehenate, polyvinylpyrrolidone, gelatine, ethylcellulose, methylcellulose, sodiumcarboxymethylcellulose, magnesium stearate, stearic acid, sodium stearate, talc, sodiumbenzoate, boric acid, and colloidal silica.The plasticizing agents of the barrierâtype layer may be selected from the groupconsisting of hydrogenated castor oil, fatty acids, substituted triglycerides and glycerides,polyoxyethylene glycols and derivatives thereof having molecular weight from 400 to60,000.Such formulation may be prepared as generally described in WO 94/06416.The dosage form preferably contains compound X itself.Compound X has active doses around 5-125 micrograrnme (ug) (calculated as freebase). It has been found through administration to human patients that efficacy as acognition enhancer may be obtained at daily doses below 0.0lmg/kg more particularly0.003mg/kg and below, for example 0.0001-0.003mg/kg, such as 0.00035-0.003mg/kg,0.0007â0.003mg/kg, 0.0001-0.0007mg/kg or 0.00035-0.002mg/kg.Suitable unit doses to achieve such daily doses are 5, 12.5, 25, 50 or 75p.g,administered twice daily or 50ug or 100pg, once daily. Such unit doses are calculated onthe basis of 50-70kg individuals and as free base.Suitably, the in vitro release proï¬le of the dosage form i.e. the amount ofcompound X released over time will be selected so that it will provide an area under thein viva plasma proï¬le curve that is similar to that obtained following conventional oraladministration of a fast release tablet, 5 to 75 pg (calculated as free base) compound Xtwice a day. Preferably 25-70% is released over 4hours and 70-100% is released over 8hours.The dosage form of the invention may be used in the treatment and/or prophylaxisof dementia, including Alzheimer's disease, in mammals, and for enhancing amyloidprecursor protein processing along a non-amyloidogenic pathway in patients suffering10152025W0 98/ 10762CA 02265661 l999-03- llPCT/GB97l02418from, or at risk of developing, Alzheimer's disease. These disorders are herein afterreferred to as "the Disorders".The present invention provides a method of treating "the Disorders" byadministering an effective amount of a controlled release oral dosage form containingcompound X, its parent free base or any other pharmaceutically acceptable salt thereof, toa sufferer in need thereof.The present invention further provides the use of a controlled release oral dosageform containing compound X, its parent free base or any other pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for treating "the Disorders".The present invention also provides a pharmaceutical composition for use in thetreatment of "the disorders" which comprises a controlled release oral dosage formcontaining compound X, its parent free base or any other pharmaceutically acceptable saltthereof.The following examples illustrate the present invention.ExamplesIn the following examples, the weight shown is the weight of free base; compound X isthe hydrochloride salt. (ptb = pure free base). Mesh sizes are US standard.Example 1 (Wax matrix)Compound X 0.005-0.1 mg pfbGelucire 62/05 (Gattefosse) 190 mgPropylene glycol 10 mgExample 2 (Film coated pellets)Component mg/capsule (500 mg) FunctionCompound X 0.005-0.1 mg pfb ActiveLactose 300 Hydrophilic diluentAvicel PH 101 (FMC) 200 Inert pellet matrixFilm coat: w/w of pellet coresSurelease (Colorcon) 2 - 10% Release controlling polymer coatSilicone antifoarn Antifoaming agent1015CA 02265661 l999-03- 11W0 98/10762 PCT/GB97/02418Example 3 (Film coated pellets)Component mg/capsule (500 mg) FunctionCompound X 0.005-0.1 mg pfb ActiveLactose 400 Hydrophilic diluentAvicel PH 101 100 Inert pellet matrixFilm coat: w/w of pellet coresAquacoat (FMC) 2 â 10% Release controlling polymer coatSilicone antifoam Antifoaming agentDi-butylsebacate 20 â 30% (of polymerweight)PlasticizerIn Examples 2 and 3, pellets are produced by extrusion/spheronization, usingwater as a granulation liquid and an appropriate size fraction is obtained by screening.Pellets are then coated in a ï¬uid bed coater (bottom spray) with 2â10% (w/w) of anaqueous Surelease dispersion (15% solids in dispersion).Desired release proï¬les are obtained by mixing uncoated (= immediate releasepellets) and coated pellets of suitable coating levels (= sustained release pellets), that arethen ï¬lled into hard gelatine capsules.Example 4 (matrix pellets)Component mg/capsule (500 mg) FunctionCompound X 0.005â0.l mg ptb ActiveGlyceryl behenate 200 Hydrophobic matrixAvicel PH 101 300 Inert pellet matrixSodium lauryl sulphate 0.1 Wetting agentPellets are produced by extrusion/spheronization using water and sodiumlaurylsulphate as a granulation liquid, and an appropriate size fraction is obtained byscreening. Pellets may additionally be coated in a ï¬uid bed coater (bottom spray) withaqueous polymer dispersions to further reduce release rates and obtain the desired releaseproï¬les.101520CA 02265661 l999-03- 11WO 98/10762Example 5 (Hydrogel matrix)Excipient â/o w/w mg /tabletCompound X 0.003 -0.07pfb 0.005pï¬)Hydroxypropylcellulose 25 37.5Puriï¬ed water - -Starch to 100 109.5Magnesium stearate 2 3.0Total 100 150Tablets may be prepared by the following procedure:1. Blend the starch and HPC in a high shear mixerPCT/GB97/02418mg/tablet0.1pfb37.5108.53.01502. Dissolve the drug into a small quantity of water and spray into blend while mixing3. Wash spray mechanism with small volume of water into blend while mixing4. Granulate mix with sufï¬cient water to achieve a medium to heavy granule5. Partially dry granule6. Screen through a suitable mill7. Complete drying of milled granule8. Lubricate with Mg stearate9. Compress into tablets with a target weight of 150mgExample 6 (Wax matrix)Excipient % w/w mg /tablet mg/tabletCompound X 0.003 to 0.07pfb 0.005pfb 0.1pfbLactose Anhydrous to 100 to 150 to 150Gelucire 62/05 18 27.0 27.0Magnesium stearate 2 3.0 3.0Total 100 150 150Tablets may be prepared by the following procedure:1. Preblend the drug with a small quantity of lactose2. Sandwich the drug preblend with the remaining lactose and the required % of Gelucire62/05 in a preheated pelletiser.Pelletise until the required pellet size has been achievedRemove the pellets and allow them to cool. Screen pellets as necessary. Lubricate pellets.\'°âVâ:â*âP°Compress or encapsulate pellets-10-101520253035CA 02265661 l999-03- 11W0 98/10762 PCT/GB97/02418Example 7 (Controlled release bilayer tablet)Active LayerComponent mg/tablet FunctionCompound X 0.005-0.1mg ptb ActiveHydroxypropylmethylcellulose 68.5 Hydrogelmatrix formerMannitol 20 Soluble ï¬llerEthyl cellulose (applied in ethanolic solution) 7.5 BinderMagnesium stearate 2 LubricantColloidol silica 2 GlidantSupport platformComponent mg/tablet FunctionHydroxypropylmethylcellulose 39.75 Hydrogel matrixformerHydrogenated castor oil 6.5 Insoluble ï¬llerEthylcellulose (applied in ethanolic solution) 2.5 BinderYellow iron oxide pigment 0.5 PigmentMagnesium stearate 0.5 LubricantColloidal silica 0.25 GlidantTablets may be prepared as described in US5433l23.Example 8 (Wax matrix)Component % w/w FunctionCompound X 0.02pib ActiveGelucire 50/02 91.5 Wax matrixGelucire 50/13 5 Wax matrixPropylene glycol 1.98 SolventColloidal silica 1.5 Hydrophobic excipientSodium dihydrogen citrate O-1.5 StabilizerProcess:The Gelucire waxes were melted together at around 60 degrees C. Compound X wasdissolved in propylene glycol, and blended into the waxes. The colloidal silica was thenalso blended in, and the mixture filled into size 3 hard gelatin capsule shells.-11-1015202530WO 98/10762CA 02265661 l999-03- llPCT/GB97/02418Table 1.: Release Proï¬le of wax-ï¬lled capsules of Compound X in water (0% citrate)Time (hr) % Released1 133 295 5 38 73Example 9 (Ethylcellulose coated beads)200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 mesh size may be used. Amedicated layer solution of the following composition was used:Component % w/w FunctionCompound X 0.003-0.05pfb ActiveOpadry® Clear 3 BinderSodium dihydrogen citrate 1.5 StabilizerPuriï¬ed water q.s.Total 100Seal coating solution: A solution of Opadry® Clear (YS-l-9025A) in puriï¬ed water at10% solids concentrations was made by dissolving 100 grams of Opadry® Clear into 900grams of puriï¬ed water.Polymer Coating: A polymer coating dispersion containing ethylcellulose(Surelease®) of the following composition was made and used for polymer coating theseal coated beads at an 10% to 25% weight gain, in particular 10, 12, 15, 17, 22 and 25%.Component % w/w FunctionSurelease® 60 (25% as solids) Release controlling polymer coatwith plasticiserPuriï¬ed water q.s.Total 100Drug layered beads were produced by layering the drug solution onto 25-30 mesh non-pareil beads using a Niro STREA-1 ï¬uid bed dryer so as to layer 100 micrograms of thedrug as the free base onto 200 mg of the non-pareil beads. The drug layered beads wereseal coated with Opadry® Clear seal coating solution to a weight gain of 3% to produce- 12 -1015202530W0 98/ 10762CA 02265661 l999-03- llPCT/GB97/02418the immediate release beads. A portion of the immediate release beads were polymercoated to a weight gain of 10% to 25% with the Surelease® coating dispersion. The ï¬nalpolymer coated beads were produced by seal coating the polymer coated beads to aweight gain of 2% with the Opadry® Clear seal coating solution.Table 2. Release Proï¬le Range of Ethylcellulose coated beads, 10-25% by weight ofCompound X in WaterTime (hr) % Released0.8-365-5713-7518-91O0-bI\J*ââExample 10 (Ethylcellulose coated beads)200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 mesh size may be used. Amedicated layer solution of the following composition was used:Component % wlw FunctionCompound X 0.003-0.05pfb ActiveOpadry® Clear 3 BinderSodium dihydrogen citrate 1.5 StabilizerPuriï¬ed water q.s.Total 100Seal coating: A seal coating dispersion containing Eudragit® L30D-55 of thefollowing composition was made and used for seal coating the drug layered beads at an4% weight gain.Component % w/w FunctionEudragit® L30D-55 45 (30% as solids) Polymeric seal coatTriethyl citrate 2.02 PlasticizerTale 3. 1 0 Anti-tackPuriï¬ed water q.s.Total 100-13-10152025W0 98/ 10762CA 02265661 l999-03- llPCTIGB97/02418Polymer Coating: A polymer coating dispersion containing ethylcellulose(Surelease®) of the following composition was made and used for polymer coating theseal coated beads at an 10% to 25% weight gain.Component % w/w FunctionSurelease® 60 (25% as solids) Release controlling polymer coatwith plasticiserPuriï¬ed water q.s.Total 100Drug layered beads were produced by layering the drug solution onto 25-30 mesh non-pareil beads using a Niro STREA-1 ï¬uid bed dryer so as to layer 100 micrograms of thedrug as the free base onto 200 mg of the non-pareil beads. The drug layered beads wereseal coated with Eudragit® L30D-55 seal coating dispersion to a weight gain of 4% toproduce the immediate release beads. A portion of the immediate release beads werepolymer coated to a weight gain of 10% tp 25% with the Surelease® coating dispersion.The ï¬nal polymer coated beads were produced by seal coating the polymer coated beadsto a weight gain of 2% with the Opadry® Clear seal coating solution.Table 3: Release Profile of Eudragit® L30D Seal Coated/EthylcelluloseCoated Beads of Compound X in WaterTime (hr) % Released, 10% Surelease0.5 1.51 52 204 396 498 56Example 11 (Ethylcellulose coated beads)200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 mesh size may be used. Amedicated layer solution of the following composition was used:-14-1015202530CA 02265661 l999-03- 11W0 98/10762 PCT/GB97/02418Component % w/w FunctionCompound X 0.003-0.05pfb ActiveOpadry® Clear 3 BinderSodium dihydrogen citrate 1.5 StabilizerPuriï¬ed water q.s.Total 1 00Seal coating solution: A solution of Opadry® Clear (YS-lâ9025A) in puriï¬ed water at10% solids concentrations was made by dissolving 100 grams of Opadry® Clear into 900grams of puriï¬ed water.Polymer Coating: A polymer coating dispersion containing Ethylcellulose(Aquacoat®) of the following composition was made and used for polymer coating theseal coated heads at a 10% weight gain.Component % w/w FunctionAquacoat® 50 (30% as solids) Release controlling polymer coatTriethyl Citrate 2.02 PlasticizerPuriï¬ed water q.s.Total 100Drug layered beads were produced by layering the drug solution onto 25-30 mesh non-pareil beads using a Niro STREA-1 ï¬uid bed dryer so as to layer 100 micrograms of thedrug as the free base onto 200 mg of the non-pareil beads. The drug layered beads wereseal coated with Opadry® Clear seal coating solution to a weight gain of 3% to producethe immediate release beads. A portion of the immediate release beads were polymercoated to a weight gain of 10% with the Aquacoat® coating dispersion. The ï¬nalpolymer coated beads were produced by seal coating the polymer coated beads to aweight gain of 2% with the Opadry® Clear seal coating solution.Example 12 (Eudragit coated beads)200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 mesh size may be used. Amedicated layer solution of the following composition was used:-15-101520253035CA 02265661 l999-03- 11WO 98/10762 PCT/GB97I024l8Component % w/w FunctionCompound X 0.003-0.05ptb ActiveOpadry® Clear 3 BinderSodium dihydrogen citrate 1.5 StabilizerPuriï¬ed water q.s.Total 100Seal coating solution: A solution of Opadry® Clear (YS-1-9025A) in puriï¬ed water at10% solids concentrations was made by dissolving 100 grams of Opadry® Clear into 900grams of puriï¬ed water.Polymer Coating: A polymer coating dispersion containing Eudragit® RS or RS/RLof the following composition was made and used for polymer coating the seal coatedbeads at an 10% weight gain.Component % w/w FunctionEudragit® RS 30D 45 (30% as solids) Release controlling polymer coatTriethyl citrate 2.02 PlasticizerTale 3. 10 Anti-tackPuriï¬ed water q.s.Total 100orComponent % w/w FunctionEudragit® RS 30D 36 (30% as solids) Release controlling polymer coatEudragit® RL 30D 9 (30% as solids) Release controlling polymer coatTriethyl citrate 2.02 PlasticizerTale 3. l 0 Anti-tackPuriï¬ed water q.s.Total 100Drug layered beads were produced by layering the drug solution onto 25-30 mesh non-pareil beads using a Niro STREA-1 ï¬uid bed dryer so as to layer 100 micrograms of thedrug as the free base onto 200 mg of the non-pareil beads. The drug layered beads wereseal coated with Opadry® Clear seal coating solution to a weight gain of 3% to producethe immediate release beads. A portion of the immediate release beads were polymer-16-510152025W0 98/ 10762CA 02265661 l999-03- llPCT/GB97/02418coated to a weight gain of 10% with the Eudragit® RS or RS/RL coating dispersion. Theï¬nal polymer coated beads can be produced by seal coating the polymer coated beads to aweight gain of 2% with the Opadry® Clear seal coating solution.Table 4: Release Proï¬le of Eudragit® RS/RL coated beads of Compound X in waterTime (hr) % Released0.5 0.20.30.41.913200OO\-P-10>-âExample 13 (Methocel coated beads)200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 mesh size may be used. Amedicated layer solution of the following composition was used:Component % w/w FunctionCompound X 0.003-0.05pfb ActiveMethocel E4M 15 Release controlling polymer coatSodium dihydrogen citrate 1.5 StabilizerPuriï¬ed water q.s.Total 100Seal coating solution: A solution of Opadry® Clear (YS-1-7006) in puriï¬ed water at 10%solids concentrations was made by dissolving 100 grams of Opadry® Clear into 900grams of puriï¬ed water.Example 14 (Ethylcellulose coated beads with a retardant)200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 mesh size may be used. Amedicated layer solution of the following composition was used:-17-1015202530CA 02265661 l999-03- 11W0 98/10762 PCTIGB97/02418Component % w/w FunctionCompound X 0.003-0.05pfb ActiveOpadry® Clear 1.5 BinderSurelease® l .5 RetardantSodium dihydrogen citrate 1.5 StabilizerPuriï¬ed water q.s.Total 100Seal coating solution: A solution of Opadry® Clear (YS-l-9025A) in puriï¬ed water at10% solids concentrations was made by dissolving 100 grams of Opadry® Clear into 900grams of puriï¬ed water.Polymer Coating: A polymer coating dispersion containing Ethylcellulose(Surelease®) of the following composition was made and used for polymer coating theseal coated beads at 10% weight gain.Component % w/w FunctionSurelease® 60 (25% as solids) Release controlling polymer coatwith plasticiserPuriï¬ed water q.s.Total 100Drug layered beads were produced by layering the drug solution onto 25-30 mesh non-pareil beads using a Niro STREAâ1 ï¬uid bed dryer so as to layer 100 micrograms of thedrug as the free base ontc 200 mg of the non-pareil beads. The drug layered beads wereseal coated with Opadry® Clear seal coating solution to a weight gain of 3% to producethe immediate release beads. A portion of the immediate release beads were polymercoated to a weight gain of 10% with the Surelease® coating dispersion. The ï¬nalpolymer coated beads can be produced by seal coating the polymer coated beads to aweight gain of 2% with the Opadry® Clear seal coating solution.-13-10152025CA 02265661 l999-03- 11W0 98/ 10762 PCT/GB97/02418Table 5. Release Proï¬le of Ethylcellulose Coated Beads,with Retardant, of Compound X in WaterTime (hr) % ReleasedWithout Retardant With Retardant0.5 12 81 37 222 57 354 73 486 85 538 58Example 15 (Enteric coated beads)200 mg of nonâpareil sugar beads of 16-20, 20-25 or 25-30 mesh size may be used. Amedicated layer solution of the following composition was used:Component % w/w FunctionCompound X 0.003-0.05pib ActiveOpadry® Clear 3 BinderSodium dihydrogen citrate 1.5 StabilizerPuriï¬ed water q.s.Total 100Seal coating solution: A solution of Opadry® Clear (YS-1-9025A) in puriï¬ed water at10% solids concentrations was made by dissolving 100 grams of Opadry® Clear into 900grams of puriï¬ed water.Polymer Coating: A polymer coating dispersion containing Eudragit® L3 0Dâ55 ofthe following composition was made and used for polymer coating the seal coated beadsat an 20% weight gain.Component % wlw FunctionEudragit L30D-55 45.00 (30% as solids) Enteric (pH dependent) polymerTriethyl citrate 2.02 PlasticizerTalc 3.1 0 Anti-tackPuriï¬ed water q.s.Total 100-19-101520253035CA 02265661 l999-03- 11WO 98/10762 PCT/GB97/02418Drug layered beads were produced by layering the drug solution onto 25-30 mesh non-pareil beads using a Niro STREA-1 ï¬uid bed dryer so as to layer 100 micrograms of thedrug as the free base onto 200 mg of the non-pareil beads. The drug layered beads wereseal coated with Opadry® Clear seal coating solution to a weight gain of 3% to producethe immediate release beads. A portion of the immediate release beads were entericcoated to a weight gain of 20% with the Eudragit® enteric coating dispersion. The ï¬nalenteric coated beads were produced by seal coating the enteric coated beads to a weightgain of 2% with the Opadry Clear seal coating solution.Example 16 (matrix tablet)Ingredient mg/tablet FunctionCompound X 0.005-0. l pfb ActiveHydroxpropyl Methcellulose E4M CR 75.0 Hydrogel matrixSodium Dihydrogen Citrate 3.00 StabilizerLactose, Fast Flo 70.38 Hydrophilic diluentMagnesium Stearate 1.50 LubicantOpadry® White 2.25 Seal coat polymerSeal coating solution: A solution of Opadry® Clear (YS-l-9025A) in puriï¬ed water at10% solids concentrations was made by dissolving 100 grams of Opadry® Clear into 900grams of puriï¬ed water.Polymer Coating: A polymer coating dispersion containing Ethylcellulose(Surelease®) of the following composition was made and used for polymer coating theseal coated beads at 10% weight gain.Component % w/w FunctionSurelease® 60 (25% as solids) Release controlling polymer coatwith plasticiserPuriï¬ed water q.s.Total 100700 grams of core tablets were coated using a Vector LDCS pan to a 3% weight gain withthe Opadry® Clear seal coating solution. The seal coated tablets were then âpolymercoated to 4% weight gain using the Surelease®coating dispersion.-20-101520W0 98/10762CA 02265661 l999-03- llPCTIGB97/02418Table 6. Release Proï¬le for a Matrix Tablet of Compound X in waterTime (hr) % Dissolved1 82 304 588 96Example 17 (Controlled release bilayer tablet)Active LayerComponent mg/tablet FunctionCompound X 0.005-0.1mg pib ActiveMethocel K4M 15.00 Hydrogel polymerLactose monohydrate 62.0 Hydrophilic ï¬llerPolyvinylpyrrolidone 3.0 BinderMagnesium stearate 1.0 Hydrophobic lubricantSyloid 244 1.0 Hydrophilic glidantSupport platformComponent mg/tablet FunctionCompritol 888 1 5 .0 PlasticizerLactose monohydrate 29.0 Hydrophilic ï¬llerPolyvinylpyrrolidone 4.0 BinderMagnesium stearate 1.5 Hydrophobic lubricantMethocel E5 29.4 Hydrogel polymerIron oxide 0.] Colourant-2]-
Claims (28)
1. A controlled release oral dosage form containing [R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride (compound X), its parent free base or any other pharmaceutically acceptable salt thereof.
2. A dosage form according to claim 1 which provides an in vitro release profileselected to provide an area under the in vivo plasma profile curve that is similar to that obtained following conventional oral administration of a fast release tablet 5 to 75µg (calculated as free base) compound X twice a day.
3 A dosage form according to claim 1 or 2 which provides an in vitro release profile of 25-70% over 4 hours and 70-100% over 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 release controlling polymers or waxes, and pellets, granules or beads comprising matrices or coated with releasecontrolling polymers or waxes and then formulated as capsules, compressed tablets or suspensions.
5. A dosage form according to any preceding claim comprising a swellable and/or gellable matrix selected from alkyl celluloses, hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates, polymethylmethacrylates, methacrylate/divinylbenzene copolymers, carboxymethylamide, polyoxyalkylene glycols, polyvinyl pyrrolidone and carboxymethyl cellulose.
6. A dosage form according to claim 5 wherein the matrix is selected from alkyl celluloses, hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates, cross-linked polyvinylpyrrolidone and sodium carboxymethyl cellulose.
7. A dosage form according to claim 5 or 6 comprising a hydrogel matrix tablet coated with a hydrophobic release controlling polymer coating selected from alkyl celluloses and methacrylic acid derivatives.
8. A dosage form according to claim 7 wherein the polymer matrix comprises 10-50% and the hydrophobic release controlling polymer comprises 4-10% by weight of the tablet.
9. A dosage form according to claim 7 or 8 comprising a tablet of the following composition (mg/tablet):
Compound X 0.005-0.1pfb Hydroxpropyl Methcellulose F~M CR 75.0 Sodium Dihydrogen Citrate 0-3.00 Lactose, Fast Flo 70.38-73.38 Magnesium Stearate 1.50 Opadry R White 2.25 seal coated with a solution of Opadry R Clear (YS-1-7006) in purified water at 10% solids concentrations and polymer coated with a 60% w/w (25% as solids) dispersion containing Ethylcellulose (Surelease R) at 10% weight gain, formed into core tablets, coated with the Opadry R Clear seal coating solution and polymer coated to 4% weight gain using 60%
w/w (25% as solids) dispersion containing Ethylcellulose (Surelease R).-
Compound X 0.005-0.1pfb Hydroxpropyl Methcellulose F~M CR 75.0 Sodium Dihydrogen Citrate 0-3.00 Lactose, Fast Flo 70.38-73.38 Magnesium Stearate 1.50 Opadry R White 2.25 seal coated with a solution of Opadry R Clear (YS-1-7006) in purified water at 10% solids concentrations and polymer coated with a 60% w/w (25% as solids) dispersion containing Ethylcellulose (Surelease R) at 10% weight gain, formed into core tablets, coated with the Opadry R Clear seal coating solution and polymer coated to 4% weight gain using 60%
w/w (25% as solids) dispersion containing Ethylcellulose (Surelease R).-
10. A dosage form according to any of claims 1 to 4 which comprises drug-layeredbeads coated with a release controlling polymer either alone or in combination with drug-layered beads not coated with a release controlling polymer (immediate release beads) and optionally, inert excipients and/or retardants and/or one or more binders.
11. A dosage form according to claim 10 wherein the layered beads are seal coated with a film-forming polymer.
12. A dosage form according to claim 10 or 11 wherein the release controlling polymer coating is selected from from alkyl celluloses, hydroxyalkylcelluloses, sodium carboxymethyl cellulose and methacrylic acid derivatives.
13. A dosage form according to any of claims 10 to 12 wherein the polymer(s) make up 10 to 30% by weight of the total dosage form.
14. A dosage form according to claim 10 in capsule form comprising non-pareil sugar beads of 16-20, 20-25 or 25-30 mesh size, coated to a drug loading of 100microgrammes (calculated as free base) per 200mg beads, with a medicated aqueous layer solution of the following composition (%w/w):
Compound X 0.003-0.06pfb Opadry R Clear 3 Sodium dihydride citrate 0-1.5 seal coated with a solution of Opadry R Clear (YS-1-7006) in purified water at 10% solids concentrations to a weight gain of 3%, and a portion of the beads further polymer coated to a weight gain of 10-25% with a 60%w/w (25% as solids) dispersion containing ethylcellulose (Surelease R) and then seal coated to a weight gain of 2% with the above seal coat.
Compound X 0.003-0.06pfb Opadry R Clear 3 Sodium dihydride citrate 0-1.5 seal coated with a solution of Opadry R Clear (YS-1-7006) in purified water at 10% solids concentrations to a weight gain of 3%, and a portion of the beads further polymer coated to a weight gain of 10-25% with a 60%w/w (25% as solids) dispersion containing ethylcellulose (Surelease R) and then seal coated to a weight gain of 2% with the above seal coat.
15. A method of treatment and/or prophylaxis of dementia, including Alzheimer's disease, in mammals by administering an effective amount of a controlled release oral dosage form according to claim 1, to a sufferer in need thereof.
16. A method for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease by administering an effective amount of a controlled release oral dosage form according to claim 1, to a sufferer in need thereof.
17. The use of a controlled release oral dosage form according to claim 1, in the manufacture of a medicament for treatment and/or prophylaxis of dementia, including Alzheimer's disease, in mammals.
18. The use of a controlled release oral dosage form according to claim 1, in the manufacture of a medicament for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease.
19. A pharmaceutical composition for treatment and/or prophylaxis of dementia, including Alzheimer's disease, in mammals which comprises a controlled release oral dosage form according to claim 1.
20. A pharmaceutical composition for enhancing amyloid precursor protein processing along a non-amyloidogenic pathway in patients suffering from, or at risk of developing, Alzheimer's disease which comprises a controlled release oral dosage form according to claim 1.
21. A dosage form, method, use or composition according to any preceding claim in which release in the gastro-intestinal tract takes place predominantly over the first eight to twelve hours following ingestion.
22. A dosage form, method, use or composition according to any preceding claim containing [R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride.
23. A dosage form, method, use or composition according to any of claims 1 to 22containing 5µg compound X (calculated as free base).
24. A dosage form, method, use or composition according to any of claims 1 to 22containing 12.5µg compound X (calculated as free base).
25. A dosage form, method, use or composition according to any of claims 1 to 22containing 25µg compound X (calculated as free base).
26. A dosage form, method, use or composition according to any of claims 1 to 22containing 50µg compound X (calculated as free base).
27. A dosage form, method, use or composition according to any of claims 1 to 22containing 75µg compound X (calculated as free base).
28. A dosage form, method, use or composition according to any of claims 1 to 22containing 100µg compound X (calculated as free base).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9619074.9 | 1996-09-12 | ||
| GBGB9619074.9A GB9619074D0 (en) | 1996-09-12 | 1996-09-12 | Composition |
| PCT/GB1997/002418 WO1998010762A2 (en) | 1996-09-12 | 1997-09-08 | Controlled release dosage form of r-(z)-alpha-methoxyimino-alpha-(1-azabicyclo2.2oct-c-yl)acetonitrile monohydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2265661A1 true CA2265661A1 (en) | 1998-03-19 |
Family
ID=10799833
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002265661A Abandoned CA2265661A1 (en) | 1996-09-12 | 1997-09-08 | Controlled release dosage form of r-(z)-alpha-methoxyimino-alpha-(1-azabicyclo2.2.2oct-c-yl)acetonitrile monohydrochloride |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0929301A2 (en) |
| JP (1) | JP2001500150A (en) |
| KR (1) | KR20000036039A (en) |
| CN (2) | CN1235544A (en) |
| AR (1) | AR008176A1 (en) |
| AU (1) | AU724086B2 (en) |
| BR (1) | BR9711734A (en) |
| CA (1) | CA2265661A1 (en) |
| CO (1) | CO5031291A1 (en) |
| CZ (1) | CZ83299A3 (en) |
| GB (1) | GB9619074D0 (en) |
| HU (1) | HUP9904401A3 (en) |
| ID (1) | ID19589A (en) |
| IL (1) | IL128781A0 (en) |
| MA (1) | MA24359A1 (en) |
| NO (1) | NO991194L (en) |
| NZ (1) | NZ334268A (en) |
| PE (1) | PE2499A1 (en) |
| PL (1) | PL332074A1 (en) |
| TR (1) | TR199900505T2 (en) |
| WO (1) | WO1998010762A2 (en) |
| ZA (1) | ZA978133B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2775597B1 (en) * | 1998-03-04 | 2001-04-20 | Gattefosse Ets Sa | ORAL PELLET ADAPTED TO IMPROVE THE BIOAVAILABILITY OF THE ACTIVE SUBSTANCE, METHOD OF MANUFACTURE |
| TR200002626T2 (en) * | 1998-03-11 | 2001-03-21 | Smithkline Beecham Plc | compound |
| DE19918325A1 (en) * | 1999-04-22 | 2000-10-26 | Euro Celtique Sa | Extruded drug dosage form, e.g. granulate for tableting, comprising an active agent in a polysaccharide-containing matrix, giving a release profile which is controllable by extrusion conditions and/or the inclusion of additives |
| FR2796840B1 (en) * | 1999-07-26 | 2003-06-20 | Ethypharm Lab Prod Ethiques | LOW-DOSE TABLETS AND METHOD OF PREPARATION |
| US6733781B2 (en) * | 2000-12-06 | 2004-05-11 | Wyeth | Fast dissolving tablet |
| PE20040134A1 (en) | 2002-07-25 | 2004-03-06 | Pharmacia Corp | PRAMIPEXOL ONCE-A-DAY DOSAGE FORM |
| KR101139744B1 (en) * | 2003-04-25 | 2012-04-26 | 미쓰비시 타나베 파마 코퍼레이션 | Composition for oral administration containing alkylene dioxybenzene derivative |
| PL1628642T3 (en) * | 2003-05-14 | 2007-01-31 | Aptalis Pharma Ltd | Controlled drug release composition resistant to in vivo mechanic stress |
| US20050142191A1 (en) * | 2003-06-23 | 2005-06-30 | Neurochem (International) Limited | Pharmaceutical formulations of amyloid inhibiting compounds |
| JP2005272347A (en) * | 2004-03-24 | 2005-10-06 | Ohara Yakuhin Kogyo Kk | Method for producing solid preparation |
| CA2576386A1 (en) * | 2004-08-13 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof |
| JP4757872B2 (en) | 2004-08-13 | 2011-08-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Tablet formulation with extended release comprising pramipexole or a pharmaceutically acceptable salt thereof, process for its production and use thereof |
| EP1970056A1 (en) * | 2007-03-15 | 2008-09-17 | Polichem S.A. | Time-specific delayed/pulsatile release dosage forms |
| US9132096B1 (en) | 2014-09-12 | 2015-09-15 | Alkermes Pharma Ireland Limited | Abuse resistant pharmaceutical compositions |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2219636T3 (en) * | 1989-04-13 | 2004-12-01 | Beecham Group P.L.C. | NEW COMPOUNDS. |
| GB9409718D0 (en) * | 1994-05-14 | 1994-07-06 | Smithkline Beecham Plc | Novel compounds |
| GB9421472D0 (en) * | 1994-10-25 | 1994-12-07 | Smithkline Beecham Plc | Novel methods |
| AR004178A1 (en) * | 1995-07-29 | 1998-11-04 | Smithkline Beecham Plc | PROCEDURE FOR THE FORMULATION OF A PHARMACY, A PHARMACEUTICAL COMPOSITION OBTAINABLE THROUGH THIS PROCEDURE AND THE USE OF THE SAME. |
-
1996
- 1996-09-12 GB GBGB9619074.9A patent/GB9619074D0/en active Pending
-
1997
- 1997-09-08 WO PCT/GB1997/002418 patent/WO1998010762A2/en not_active Application Discontinuation
- 1997-09-08 HU HU9904401A patent/HUP9904401A3/en unknown
- 1997-09-08 NZ NZ334268A patent/NZ334268A/en unknown
- 1997-09-08 IL IL12878197A patent/IL128781A0/en unknown
- 1997-09-08 JP JP10513352A patent/JP2001500150A/en active Pending
- 1997-09-08 CN CN97199411A patent/CN1235544A/en active Pending
- 1997-09-08 BR BR9711734A patent/BR9711734A/en unknown
- 1997-09-08 AU AU41288/97A patent/AU724086B2/en not_active Ceased
- 1997-09-08 CA CA002265661A patent/CA2265661A1/en not_active Abandoned
- 1997-09-08 PL PL97332074A patent/PL332074A1/en unknown
- 1997-09-08 EP EP97939064A patent/EP0929301A2/en not_active Withdrawn
- 1997-09-08 TR TR1999/00505T patent/TR199900505T2/xx unknown
- 1997-09-08 CZ CZ99832A patent/CZ83299A3/en unknown
- 1997-09-08 KR KR1019997002030A patent/KR20000036039A/en not_active Application Discontinuation
- 1997-09-09 CO CO97052280A patent/CO5031291A1/en unknown
- 1997-09-10 AR ARP970104130A patent/AR008176A1/en not_active Application Discontinuation
- 1997-09-10 MA MA24792A patent/MA24359A1/en unknown
- 1997-09-10 ID IDP973137A patent/ID19589A/en unknown
- 1997-09-10 ZA ZA978133A patent/ZA978133B/en unknown
- 1997-09-10 PE PE1997000805A patent/PE2499A1/en not_active Application Discontinuation
-
1999
- 1999-03-11 NO NO991194A patent/NO991194L/en unknown
-
2003
- 2003-01-23 CN CN03102977A patent/CN1446535A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ID19589A (en) | 1998-07-23 |
| JP2001500150A (en) | 2001-01-09 |
| ZA978133B (en) | 1999-04-12 |
| AR008176A1 (en) | 1999-12-09 |
| TR199900505T2 (en) | 1999-06-21 |
| HUP9904401A2 (en) | 2000-06-28 |
| IL128781A0 (en) | 2000-01-31 |
| CO5031291A1 (en) | 2001-04-27 |
| EP0929301A2 (en) | 1999-07-21 |
| BR9711734A (en) | 1999-08-24 |
| WO1998010762A2 (en) | 1998-03-19 |
| KR20000036039A (en) | 2000-06-26 |
| MA24359A1 (en) | 1998-07-01 |
| HUP9904401A3 (en) | 2001-03-28 |
| PE2499A1 (en) | 1999-03-24 |
| GB9619074D0 (en) | 1996-10-23 |
| NZ334268A (en) | 2000-10-27 |
| CN1235544A (en) | 1999-11-17 |
| CZ83299A3 (en) | 1999-08-11 |
| PL332074A1 (en) | 1999-08-30 |
| WO1998010762A3 (en) | 1998-06-04 |
| AU4128897A (en) | 1998-04-02 |
| AU724086B2 (en) | 2000-09-14 |
| CN1446535A (en) | 2003-10-08 |
| NO991194D0 (en) | 1999-03-11 |
| NO991194L (en) | 1999-03-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6468560B2 (en) | Controlled release dosage form of [R-(Z)]-α-(methoxyimino)-α-(1-azabicyclo[2.2.2]oct-3yl) acetonitrile monohydrochloride | |
| US6436438B1 (en) | Tramadol multiple unit formulations | |
| US8747898B2 (en) | Controlled release oral dosage form | |
| CA1264296A (en) | Formulations providing three distinct releases | |
| US4794001A (en) | Formulations providing three distinct releases | |
| JP2637981B2 (en) | Absorption control drug composition | |
| US6077533A (en) | Powder-layered oral dosage forms | |
| US4904476A (en) | Formulations providing three distinct releases | |
| CA2348090C (en) | Oral pulsed dose drug delivery system | |
| US5807579A (en) | Pseudoephedrine combination pharmaceutical compositions | |
| JP3015105B2 (en) | Powder coated oral dosage form | |
| EP0605174B1 (en) | Delayed, Sustained-release pharmaceutical preparation | |
| US6589553B2 (en) | Controlled release oral dosage form | |
| US20080044467A1 (en) | Formulation and process for drug loaded cores | |
| CA2520321A1 (en) | Oral extended release compressed tablets of multiparticulates | |
| CZ303495B6 (en) | Multiparticulate modified release composition, use thereof and solid oral dosage form | |
| US20020156133A1 (en) | Oral administration forms for administering a fixed tramadol and diclofenac combination | |
| KR20090091084A (en) | Controlled-release pharmaceutical formulation | |
| CA2265661A1 (en) | Controlled release dosage form of r-(z)-alpha-methoxyimino-alpha-(1-azabicyclo2.2.2oct-c-yl)acetonitrile monohydrochloride | |
| US20030224045A1 (en) | Combination immediate release sustained release levodopa/carbidopa dosage forms | |
| US7060293B1 (en) | Powder-layered oral dosage forms | |
| JP2892858B2 (en) | Controlled release formulation and method for producing the same | |
| WO2009024858A1 (en) | Controlled release dosage form of galantamine | |
| KR100505899B1 (en) | Pharmaceutical capsule compositions containing loratadine and pseudoephedrine | |
| US8173164B2 (en) | Oral administration forms for administering a fixed tramadol and diclofenac combination |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |