CN1446535A - Chlorhydric [R(2)-alpha-methoxyimindogen-alpha-(1-dicycloaza [2.2.2] caryl-3-group) acetonitrile control-released dosage form - Google Patents

Chlorhydric [R(2)-alpha-methoxyimindogen-alpha-(1-dicycloaza [2.2.2] caryl-3-group) acetonitrile control-released dosage form Download PDF

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CN1446535A
CN1446535A CN03102977A CN03102977A CN1446535A CN 1446535 A CN1446535 A CN 1446535A CN 03102977 A CN03102977 A CN 03102977A CN 03102977 A CN03102977 A CN 03102977A CN 1446535 A CN1446535 A CN 1446535A
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dosage form
controlled release
compounds
polymer coating
package
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S·M·米洛索维奇
W·穆尔多恩
J·A·纳珀
L·罗瑟奥
J·肖尔
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SmithKline Beecham Ltd
SmithKline Beecham Corp
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    • 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
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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    • A61P25/00—Drugs for disorders of the nervous system
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Abstract

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

Description

Hydrochloric acid [R-(Z)]-α-methoxyimino-α-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile controlled release form
The application is to be that JIUYUE in 1997 8 days, application number are dividing an application of 97199411.0 patent application the applying date.
Technical field
The present invention relates to a kind of new preparation, and its application in treating and/or preventing some disease.
Background technology
EP-A-0392803, WO95/31456 and WO93/17018 disclose hydrochloric acid [R-(Z)]-α-methoxyimino-α-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile (compounds X) and its preparation method.This chemical compound strengthens the function of acetylcholine by the muscarinic receptor that acts on the central nervous system, thereby might be used for the treatment of and/or prevent mammiferous dementia.
WO96/12486 discloses compounds X and has been used for preparing and is suffering from Alzheimer or having ill tendency person to strengthen the medicine of amyloid precursor protein function along non-amyloid gene approach.Swallow sheet and oral administration solution preparation of promptly the releasing of compounds X all can make this chemical compound absorb rapidly to enter blood circulation, need twice administration every day to obtain the suitableeest effect.
Summary of the invention
Be surprisingly found out that now will having high water solublity and very low dose and be activated compounds X, to be mixed with the controlled release preparation that plays a role in a few hours be possible.Such preparation only need be administered once every day: might improve with the poor memory is the patient's of feature conformability; Also reduced just in case wrongly take side effect due to excessive.
Therefore, the invention provides the controlled release oral dosage form that inclusion compound X, its parent free alkali or their any other pharmacy are suitable for salt.
So-called controlled release is meant and immediate release formulations, compares as swallow sheet or capsule of routine, and wherein the speed that discharges from this dosage form of active substance becomes slower any preparation technique.
Controlled release comprises that time-delay discharges promptly to be compared with common immediate release dosage form, makes active substance wherein occur in the time late from the release of this dosage form.Also can control active substance is further discharged from the time-delay release dosage form with slower speed.
The example of the suitable controlled release preparation that contains compounds X is narrated in following document:
Sustained Release Medications, Chemical TechnologyReview No.177. writes .Noyes Data Corporation1980. by .J.C.Johnson
Controlled Drug Delivery, Fundamentals and Applications, second edition. by J.R.Robinson, V.H.L.Lee writes, Marcel Dekker Inc. New York 1987.
The preferred manner of formulation of this controlled release preparation makes compounds X discharge at whole gastrointestinal tract, and mainly occurs in after the administration preceding 8-12 hour and discharge.
But preferred preparation comprises wax-matrix, swellable and/or gelatin polymer or hydrogel matrix, uses the sheet that discharges controlling polymers or wax coating; with contain substrate or with the piller, granule or the pearl that discharge controlling polymers or wax coating, and and then make capsule, tabletting or suspension.
Be suitable for that substrate forms or the wax of controlled release coat comprise nonionic Cera Flava derivant such as Gelucire 62/05,50/02 or 50/13 (manufacturing of Gattefosse company), behenic acid glyceride, other fatty acid single, two or triglyceride such as Precirol AT05 (manufacturing of Gattefosse company), microcrystalline Cellulose wax, castor oil hydrogenated or hydrogenated vegetable oil, long-chain fatty alcohol such as stearyl alcohol and Brazil wax.
But the material that is suitable for forming hydrogel matrix or swellable and/or gelatin polymer substrate can be selected from alkylcellulose, hydroxy alkyl cellulose, polyvinyl alcohol, polymethacrylates, polymethyl methacrylate, methacrylate/divinyl benzene copolymer, carboxymethyl amide, polyether polyols, polyvinylpyrrolidone and carboxymethyl cellulose.The swellable polymeric material is selected from cross-linking sodium carboxymethyl cellulose, crosslinked hydroxypropyl cellulose, high-molecular weight poly-hydroxypropyl emthylcellulose, carboxymethyl amide, methacrylic acid potassium/divinyl benzene copolymer, polymethyl methacrylate, crospolyvinylpyrrolidone and high molecular weight polyvinyl alcohol especially.But the gel polymerisation material is selected from methylcellulose, carboxymethyl cellulose, low-molecular-weight hydroxypropyl emthylcellulose, low molecular weight polyethylene alcohol, polyoxyethylene glycol and noncrosslinking polyvinylpyrrolidone especially.But swellable and gelatin polymer material are selected from moderately viscous hydroxypropyl emthylcellulose and moderately viscous polyvinyl alcohol especially.
Release the control polymer and comprise aquogel polymer, hydrophobic polymer and enteric solubility or the pH dependent polymers that as above exemplifies.
The appropriate materials that forms hydrophobicity controlled release polymer coating comprises the alkylcellulose that can the latex suspension form uses such as Surelease (manufacturings of Colorcon company) or Aquacoat (FMC Corp.'s manufacturing) and methacrylic acid derivative such as Eudragit RS, RL and NE (manufacturing of Rohm company) that can the use of latex suspension form.
The appropriate materials that forms enteric solubility or pH dependent polymers coating comprises the methacrylic acid derivative that can the latex suspension form uses, as Eudragit L and S (manufacturing of Rohm company).
Package, be used for barrier formulation difference in functionality layer or provide preparation outermost rete, comprise the alkylcellulose that suitable filmogen can the latex suspension form uses, with hydroxy alkyl cellulose such as hydroxypropyl emthylcellulose (for example Opadry (manufacturing of colorcon company)), alkylcellulose Surelease (manufacturing of Colorcon company) or Aquacoat (FMC Corp.'s manufacturing).
The controlled release polymer layer of preparation also can comprise plasticizer such as triethyl citrate, dibutyl sebacate or median chain triglyceride oil.
Piller forms microcrystalline Cellulose such as the Avicel PH 101 (FMC Corp.'s manufacturing) that material comprises suitable grade.
Granule can be used filler or diluent such as lactose, lactose monohydrate, mannitol, microcrystalline Cellulose, dicalcium phosphate or starch always by any pharmaceutics and make.
Pearl can or spray by parcel on thick kind grain and form.
Other component that is fit to comprises Polyethylene Glycol and propylene glycol in the controlled release form, and forgives the medicinal filler that is used to change rate of release in substrate, piller, granule or pearl.
Preparation also can comprise hydrophobic vehicle such as ethyl cellulose, Talcum, colloidal silicon dioxide or glyceryl monostearate and/or one or more binding agents such as hydroxypropyl emthylcellulose, microcrystalline Cellulose or the polyvinylpyrrolidone that delays preparation release.
Also can comprise wetting agent such as sodium lauryl sulphate, lubricant such as magnesium stearate and fluidizer such as glue silicon.
Particularly preferred preparation comprises the combination of medicated layer beadlet with the medicated layer beadlet (promptly releasing pearl) of no controlled release polymer coating of the medicated layer beadlet of independent controlled release polymer coating or controlled release polymer coating.In medicine layered approach to thick beadlet, suitably the coarse grain of size sugar pearl can be with solution or dispersion layering, and described solution or dispersion contain active substance, inert excipient and/or delayer such as ethyl cellulose, Talcum, dioxide/silica gel or glyceryl monostearate and/or one or more binding agents such as hydroxypropyl emthylcellulose or polyvinylpyrrolidone.Can use coating pan or fluidized bed dryer to finish the active substance layering according to predetermined speed and temperature.This stratified pearl can be used suitable film forming polymer such as hydroxypropyl emthylcellulose (for example Opadry) or Eudragit  L30D-55 (a kind of methacrylic acid copolymer) package, carry out coating with one or more controlled release polymers that are fit to then, make compounds X during the little duration of 8-12 in and/or the beadlet that in one or more pulses, discharges, described controlled release polymer is selected from alkylcellulose especially, hydroxy alkyl cellulose, sodium carboxymethyl cellulose and methacrylic acid derivative such as ethyl cellulose, Eudragit  RS, Eudragit  RL or Methocel E4M.The package pearl can be used for promptly releasing agent.Then can be with controlled release beadlet or controlled release beadlet with pack into a kind of capsule of suitable size or be pressed into the tablet of suitable physical parameter such as shape, size, hardness and disintegrative of the mixture of promptly releasing pearl with the inertia excipient.Polymer, controlled release polymer add any package polymer, preferably account for the 10-30% of dosage form gross weight.The plasticizer normal presence also can account for 2% weight ratio at least.Binding agent and delayer typically account for the 3-10% weight ratio.
But another particularly preferred preparation comprises the polymeric matrix sheet of a kind of swellable and/or gel.Preferably a kind of aquogel polymer of this polymeric matrix, this aquogel polymer are selected from alkylcellulose such as methylcellulose, hydroxy alkyl cellulose such as hydroxypropyl cellulose and hydroxypropyl emthylcellulose, polyvinyl alcohol, polymethacrylates, crospolyvinylpyrrolidone and sodium carboxymethyl cellulose.This polymer typically accounts for the 10-50% of tablet weight.Substrate tablet can be sealed to block the hydrolysis of hydrogel matrix in the tablet with a kind of hydrophobic controlled release polymer such as ethyl cellulose (Surelease (manufacturing of Colorcon company)).Hydrophobic coating polymer typically accounts for the 4-10% of tablet weight.
This substrate tablet preparation can be by direct compression method or the preparation of wet separation grain method.Coating is finished by coating pan.
Other preferred preparation is in U.S. Patent No. 5,422, is described in 123.
Thus, a concrete aspect of the present invention provides and comprises that active substance is a compounds X, its parent free alkali or their any other pharmaceutically are suitable for the controlled release system of salt, it comprises the deposition core that (a) contains the effective dose active substance and have geometry in particular, (b) a kind of load bearing seat that is applied to described deposition core, wherein said deposition core comprises active substance at least, with at least a but to be selected from the composition (1) with next group to contact with water or property of water-bearing liquid be the polymeric material of swollen polymeric material and gel, wherein but this swellable polymeric material is 1 with the ratio of the polymeric material that is somebody's turn to do gel: 9-9: 1, (2) but the single polymeric material of a kind of not only swellable but also gelling performance, wherein load bearing seat is a resilient support, it is applied to described deposition core, it partly covers the surface of this deposition core as a result, with because the hydration of deposition core and changing thereupon, but and in liquid, aqueous solvable at leisure and/or gel at leisure.
(1) the optional self-crosslinking sodium carboxymethyl cellulose of swellable polymeric material, crosslinked hydroxypropyl cellulose, high-molecular-weight poly hydroxypropyl emthylcellulose, carboxymethyl starch, methacrylic acid potassium/divinyl benzene copolymer, crospolyvinylpyrrolidone and polyvinyl alcohol in.(1) but in gelatin polymer can be selected from methylcellulose and uncrosslinked polyvinylpyrrolidone.
Described load bearing seat can comprise that polymer is as poly-hydroxypropyl emthylcellulose, polyvinyl alcohol, polyacrylate, polymethacrylates, poly-hydroxypropyl cellulose and poly-sodium carboxymethyl cellulose; Plasticizer such as polyoxyethylene glycol, Oleum Ricini, castor oil hydrogenated, ethyl phthalate, butyl phthalate, natural glycerin ester, synthetic glyceride and semi-synthetic glyceride; Binding agent such as polyvinylpyrrolidone, methylcellulose, ethyl cellulose Radix Acaciae senegalis and alginic acid; Hydrophilizing agent such as mannitol, lactose, starch and silica gel; And/or water-repelling agent such as castor oil hydrogenated, magnesium stearate, lipid material, wax, natural glycerin ester and synthetic glyceride.Polymer typically accounts for the 30-90% of load bearing seat weight, for example accounts for about 35-40%.Plasticizer can account for 2% of load bearing seat weight at least, for example about 15-20%.Binding agent, hydrophilizing agent and water-repelling agent typically account for 50% of load bearing seat weight altogether, for example about 40-50%.
Said preparation can be according to United States Patent (USP) 5,422, the method preparation of general description in 123.
US-A-4 839 177 discloses and has been applicable to another selectable controlled release preparation of the present invention.
Like this, the further aspect of the present invention provides the control rapid release place system of compounds X, and its composition is:
A) contain the deposition core of effective quantification compound X and definite geometry,
B) be applied to the load bearing seat of described deposition core, wherein said deposition core comprise account for deposition core gross weight 5-80% with the blended at least a composition (a) that is selected from next group of active substance with water or liquid, aqueous the contact after highly swollen polymer, but with the gelatin polymer that accounts for deposition core gross weight 90-10%, but and the single polymers that (b) had not only had expansiveness but also had gelling property, with can be this mixture suitable compressibility and absorptive other adjuvant be provided, wherein said load bearing seat is made up of the polymer that insoluble in liquid, aqueous and part cover described deposition core.
(a) sodium carboxymethyl cellulose of the optional self-crosslinking of polymers capable of swelling, crosslinked hydroxy propyl cellulose, high-molecular-weight poly hydroxypropyl emthylcellulose, carboxymethyl amide, methacrylic acid potassium/divinyl benzene copolymer, polymethacrylates, crospolyvinylpyrrolidone and high molecular weight polyvinyl alcohol in.(a) but in gelatin polymer can be selected from methylcellulose, hydroxy methocel, low-molecular-weight hydroxypropyl emthylcellulose, low molecular weight polyethylene alcohol, polyoxyethylene glycol and non-crosslinked polyvinylpyrrolidone.(b) but in swellable and gelatin polymer can be selected from moderately viscous hydroxypropyl emthylcellulose and moderately viscous polyvinyl alcohol.Load bearing seat can comprise and is selected from acrylate, cellulose, ethyl cellulose, acetate-cellulose propionate, polyethylene, methacrylate, acrylic copolymer and high molecular weight polyvinyl alcohol.
Such preparation generally can be as at US 4,839, the narration preparation in 177.
WO94/06416 discloses and has been applicable to another selectable controlled release preparation of the present invention.
Therefore, another aspect of the present invention provides the control rapid release place system of compounds X, is made of the medicament tabletting that discharges compounds X with friction speed, and it consists of three layers, wherein
-ground floor inclusion compound X promptly releases or controlled release preparation, and by being rapid swelling and/or dissolving and/or the polymer that weathers with liquid, aqueous the contact, and adjuvant constitutes;
The slow releasing preparation of-second layer inclusion compound X, wherein compounds X and ground floor are identical or different, by constituting with liquid, aqueous back swelling and/or the gel and/or the polymer that weathers and adjuvant of contacting;
-low permeability barrier layer, it coats the described second layer, perhaps place first or the second layer between, by polymer, adjuvant, plasticizer, if necessary and compounds X constitute.
Hydroxypropyl cellulose and hydroxypropyl emthylcellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch, methacrylic acid potassium/divinyl benzene copolymer, polyvinyl alcohol, starch, starch derivatives, microcrystalline Cellulose and cellulose derivative, beta-schardinger dextrin-and the dextrin derivative of the optional self-crosslinking polyvinylpyrrolidone of ground floor polymer, low or middle molecular weight.
Second layer polymer is selected from molecular weight 1,000-4,000,000 hydroxypropyl emthylcellulose, molecular weight 2,000-2,000,000 hydroxypropyl cellulose, carboxy vinyl polymer, polyvinyl alcohol, glucosan, scleroglucan, mannan, xanthan gum, alginic acid and its derivant, carboxymethyl cellulose and derivant thereof, poly-(ethylene methacrylic ether/maleic anhydride), ethyl cellulose, methylcellulose and cellulose derivative.
Ground floor and second layer adjuvant can be selected from starch, the preceding starch of gel, calcium phosphate, mannitol, lactose, sucrose, glucose, Sorbitol, microcrystalline Cellulose, gelatin, polyvinylpyrrolidone, methylcellulose, starch solution, ethyl cellulose, arabic gum, Tragacanth, magnesium stearate, stearic acid, silica sol, glyceryl monostearate, castor oil hydrogenated, wax and list, two, tri-substituted glycerol esters.
Barrier polymer can be selected from molecular weight 1,000-4,000,000 hydroxypropyl emthylcellulose, molecular weight 2,000-2,000,000 hydroxypropyl cellulose, carboxy vinyl polymer, polyvinyl alcohol, glucosan, scleroglucan, mannan, xanthan gum, carboxymethyl cellulose, ethyl cellulose and methylcellulose.
The barrier layer adjuvant can be selected from glyceryl monostearate, semi-synthetic glyceride, Palmic acid tristerin, docosane acid glyceride, polyvinylpyrrolidone, gelatin, ethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, magnesium stearate, stearic acid, sodium stearate, Talcum, sodium benzoate, boric acid, and silica sol.
The barrier layer plasticizer is selected from triglyceride and glyceride, polyoxyethylene glycol and its molecular weight 400-60 of castor oil hydrogenated, fatty acid, replacement, 000 derivant.
Such preparation can be according to the general method preparation of describing of WO94/06416.
The preferred inclusion compound X of this dosage form itself.
The compounds X effective dose is (pressing free alkali calculates) about 5-12 μ g.Have been found that by with below the daily dose 0.01mg/kg body weight, more preferably 0.003mg/kg and following, to patient's administration, can obtain the effect of cognitive enhancer as 0.0001-0.003mg/kg, 0.00035-0.003mg/kg, 0.0007-0.003mg/kg, 0.0001-0.0007mg/kg or 0.00035-0.002mg/kg
Reach this of dosage, suitable unit dose is 5,12.5,25,50 or 75 μ g every day, and be administered twice every day, and perhaps 50 μ g or 100 μ g are once a day.This unit dose is pressed based on whose body weight 50-70kg and is pressed free alkali and calculate.
Select the release in vitro pattern of dosage form aptly, be the amount that discharges compounds X in a period of time, when making it in vivo test is provided under the curve of blood plasma 5-75 μ g of twice oral routine of area and every day (by free alkali calculating) to release the area under curve that obtains behind the sheet similar.Discharge 25-70% in preferred 4 hours and discharge 70-100% in 8 hours.
Dosage form of the present invention can be used for treating and/or preventing dementia, comprises the mammal Alzheimer, and is used for strengthening the function of amyloid precursor protein along suffering from Alzheimer or ill tendency person's no amyloid gene approach being arranged.After this disease described herein is referred to as " described disease ".
The invention provides the method for treatment " described disease ", this method is the controlled release oral dosage form that is suitable for salt by inclusion compound X, its parent free alkali or their any other pharmacy that imposes on the patient's effective dose that needs.
The present invention further provides the application that contains in controlled release preparation that compounds X, its parent free alkali or their any other pharmacy be suitable for salt treats and/or prevents " described disease " in preparation the medicine.
The present invention also provides the Pharmaceutical composition that is used for the treatment of and/or prevents " described disease ", and said composition comprises the controlled release preparation that contains the suitable salt of compounds X, its parent free alkali or their any other pharmacy.
The specific embodiment
The following examples describe the present invention in detail.
In embodiment the following example, shown in weight be free alkali weight; Compounds X is hydrochlorate (the pure free alkali of pfb=).The purpose size is by Unite States Standard.
1 ( 〕X 0.005-0.1mg pfbGelucire 62/05 ( Gattefosse ) 190mg 10mg2 ( ) mg/ ( 500mg ) X 0.005-0.1mg pfb 300 Avicel PH 101 ( FMC ) 200 ： w/wSurelease ( Colorcon ) 2-10％ 3 ( ) mg/ ( 500mg ) X 0.005-0.1mg pfb 400 Avicel PH 101 ( FMC ) 100 w/wAquacoat ( FMC ) 2-10％ 20-30％ ( )
Among the embodiment 2 and 3, make water make piller through extruding/spheroidizing as granulation liquid.Suitable size sieve part of sieving and obtaining.In fluidized-bed coating machine (bottom sprays), use 2-10% (w/w) Surelease aqueous dispersion (15% solid in the dispersion) coated pellets then.Will be not coated pellets (=time-delay the discharges piller) mixing of coated pellets (=promptly release piller) and suitable coating degree, the hard capsule of packing into then can obtain required release mode.
Embodiment 4 (substrate piller) component mg/ capsule (500 mg) function compounds X 0.005-0.1mg pfb active component docosane acid glyceride 200 hydrophobic matrix Acicel PH 101 300 inertia piller substrate sodium lauryl sulphates 0.1 wetting agent
Water and sodium lauryl sulphate be as granulation liquid, makes the sieve screening of the suitable size that obtains of piller through extruding/spheroidizing.In fluidized-bed coating machine (bottom sprays), can further use the aqueous polymer dispersion coated pellets again to reduce rate of release, the release mode that obtains expecting.
Embodiment 5 (hydrogel matrix) excipient %w/w mg/ sheet mg/ sheet compounds X 0.003-0.07pfb 0.005 pfb 0.1 pfb hydroxypropyl cellulose 25 37.5 37.5 pure water---starch adds to 100 109.5 108.5 dolomols 2 3.0 3.0
Amount to 100 150 150
Prepare tablet according to the following steps:
1. mixing starch and hydroxypropyl cellulose in high shearforce mixer
2. be sprayed onto in the mixture with the low amounts of water dissolved substance and while mixing
3. be sprayed in the mixture low amounts of water is floating while mixing
4. mix with competent water and making the severe granule by the time that granulates in obtaining
5. part dried particles
6. sieve with suitable mill
7. the finish-drying granule of milling
8. use the magnesium stearate moistening
9. compacting weighs the tablet of index 150mg in flakes
Embodiment 6 (wax-matrix) excipient %w/ mg/ sheet mg/ sheet compounds X 0.003-0.07 pfb 0.005 pfb 0.1 pfb Lactis Anhydrous adds to 100 and adds to 150 and add to 150Gelucire 62,/05 18 27.0 27.0 magnesium stearate 2 3.0 3.0
Amount to 100 150 150
Prepare tablet by following step:
1. with medicine and lactose premixing in a small amount
2. make in the ball machine pre-heated, with remaining lactose with need the Gelcire 62/05 of % that premixed medicine is made sandwich
3. pill is until the piller of needs size
4. take out piller and make it cooling
5. piller as required sieves
6. lubricated piller
7. with piller compression or encapsulated
The method that embodiment 7 (controlled release double-layer tablet) active layer component mg/ sheet function compounds X 0.005-0.1mg pfb active component hydroxypropyl methylcellulose 68.5 hydrogel matrix precursor D-sorbites 20 solubility filler ethyl celluloses (being used for ethanolic solution) 7.5 adhesive dolomols, 2 lubricant cataloids, 2 glidant load bearing seat component mg/ sheet function hydroxypropyl methylcelluloses, 39.75 hydrogel matrix precursor rilanit specials, 6.5 insoluble filler ethyl celluloses (being used for ethanolic solution) 2.5 adhesive ferric oxide yellow pigments, 0.5 pigment dolomol, 0.5 lubricant cataloid, 0.25 glidant is described according to United States Patent (USP) 5433123 prepares tablet.
The hydrophobic excipients dihydro of embodiment 8 (wax-matrix) component %w/w function compounds X 0.02 pfb active component Gelucire, 50,/02 91.5 wax-matrix Gelucire 50,/13 5 wax-matrix propane diols, 1.98 solvent colloid silica 1 .5 natrium citricum 0-1.5 stabilizing agent
Process:
Gelucire wax one coexists and dissolves about 60 ℃.Compounds X is dissolved in propylene glycol, and is incorporated in the wax.And then mix silica sol, mixture is packed in No. 3 hard gelatin capsule shells.
Table 1: the wax filled capsules of compounds X is release mode in water (0% citric acid)
Time (hour) release %
1 13
3 29
5 53
8 73
Embodiment 9 (ethyl cellulose coating pearl)
Use the coarse grain sugar pearl 200mg of 16-20,20-25 or 25-30 mesh size, the medicated layer solution that uses as form below.
Component %w/w function
Compounds X 0.003-0.05 pfb active component
Pure 3 binding agents of Opadry 
Dihydro sodium citrate 1.5 stabilizing agents
Pure water is an amount of
Amount to 100
Package solution: will make the pure water solution of the Opadry  pure (YS-1-9025A) of 10% solid concentration in the pure 900g of the being dissolved in pure water of 100gOpadry .
Polymer coating: the polymeric dispersions that contains ethyl cellulose (Surekease ) that preparation is formed below, be used for the polymer coating of package pearl, make its weightening finish 10%-25%, especially 10,12,15,17,22 and 25%.The controlled release polymer coating pure water of component %w/w function Surelease  60 (25% solid) band plasticizer is an amount of to amount to 100
Use Niro STREA-1 fluidized bed dryer that drug solution is formed the medicine layer on 25-30 purpose coarse grain pearl, make 100mg medicine free alkali stratification on 200mg coarse grain pearl, thereby make the medicated layer beadlet.With the pure package solution of Opadry  package medicated layer beadlet, make its weightening finish 3% promptly release pearl in order to produce.A part is promptly released pearl and is carried out polymer coating with Surelease  coating dispersion, makes its weightening finish 10-25%.Make its weightening finish 2% with the pure package solution of Opadry  package polymer coating pearl, thereby make final polymerization thing coating pearl.
Table 2. accounts for the release mode scope of compounds X weight 10-25% ethyl cellulose coating pearl in water
Time discharges %
1 0.8-3.6
2 5-57
4 13-75
8 18-91
Embodiment 10 (ethyl cellulose coating pearl)
Use the coarse grain sugar pearl 200mg of 16-20,20-25 or 25-20 order size.Use the medicine layer solution of following composition.
Component %w/w function
Compounds X 0.003-0.05 pfb active component
Pure 3 binding agents of Opadry 
Dihydro sodium citrate 1.5 stabilizing agents
Pure water is an amount of
Amount to 100
Package: preparation is formed below contains Eudragit  L30D-55 package dispersion, and the package that is used for the medicated layer beadlet makes its weightening finish 4%.Component %w/w function Eudragit  L30D-55 45 (30% solids content) polymer package triethyl citrate 2.02 plasticizer Talcums 3.10 antiplastering aid pure water are an amount of to amount to 100
Polymer coating: what be prepared as follows composition contains ethyl cellulose (Surelease ) polymer coating dispersion, is used for package polymer coating pearl and makes its weightening finish 10-25%.The controlled release polymer coating pure water of component %w/w function Surelease  60 (25% solid) plasticizer-containing is an amount of to amount to 100
Use Niro STREA-1 fluidized bed dryer that drug solution is formed the medicine layer on 25-30 purpose coarse grain pearl, make 100mg medicine free alkali stratification on 200mg coarse grain pearl, thereby make the medicated layer beadlet.With Eudragit  L30D-55 package dispersion package medicated layer beadlet, make its weightening finish 4% promptly release pearl in order to produce.A part promptly release pearl with Surelease  coating dispersion carry out polymer coating make its weightening finish 10-25%.With the pure package solution of Opadry  package polymer coating pearl, make its weightening finish 2%, thereby make final polymer coating pearl.
Table 3:Eudragit  L30D-55 package/ethyl cellulose coating compounds X release mode in water
Time (hour) release %, 10% Surelease
0.5 1.5
1 5
2 20
4 39
6 49
8 56
Embodiment 11 (ethyl cellulose coating pearl)
Use the coarse grain sugar pearl 200mg of 16-20,20-25 or 25-30 order size.Use the medicine layer solution of following composition.
Component %w/w function
Compounds X 0.003-0.05 pfb active component
Pure 3 binding agents of Opadry 
Dihydro sodium citrate 1.5 stabilizing agents
Pure water is an amount of
Amount to 100
Package solution: will make the pure water solution of 10% solid concentration Opadry  pure (YS-1-9025A) in the pure 900g of the being dissolved in pure water of 100gOpadry .
Polymer coating: what be prepared as follows composition contains Eudragit  RS or RS/RL polymer coating dispersion, and the polymer coating that is used for the package pearl makes its weightening finish 10%.
Component %w/w function
Aquacoat  50 (30% solid) controlled release polymer coating
Triethyl citrate 2.02 plasticizers
Pure water is an amount of
Amount to 100
Use Niro STREA-1 fluidized bed dryer etc. that drug solution is formed the medicine layer on 15-30 purpose coarse grain pearl, make 100mg medicine free alkali stratification on 200mg coarse grain pearl, thereby make the medicated layer beadlet.Make its weightening finish 3% promptly release beadlet with the pure package solution of Opadry  package medicated layer beadlet in order to produce.One promptly divides and promptly releases beadlet and carry out polymer coating with Aquacoat  coating dispersion, makes it increase weight 10～25%.Make its weightening finish 2% with the pure package solution of Opadry  package polymer coating pearl, thereby make final polymer coating pearl.
Embodiment 12 (Eudragit coating pearl)
In coarse grain sugar pearl with use 200mg 16～20,20～25 or 25～30 order sizes.Use the medicine layer solution of following composition:
Component %w/w function
Compounds X 0.003-0.05pfb active component
Pure 3 binding agents of Opadry 
Dihydro sodium citrate 1.5 stabilizing agents
Pure water is an amount of
Amount to 100
Package solution: will make the pure water solution of the Opadry  pure (YS-1-9025A) of 10% solid concentration in the blunt water of the pure 900g of being dissolved in of 100g Opadry .
Polymer coating:be prepared as follows the Eudragit  RS or the RS/RL polymer coating dispersion of composition, an amount of total 100 of the polymer coating that is used for the package pearl makes its weightening finish 10%. component %w/w function Eudragit  RS 30D 45 (30% solid) controlled release polymer dressing triethyl citrates 2.02 plasticizer talcums 3.10 antiplastering aid pure water or an amount of total 100 of component %w/w function Eudragit  RS 30D 36 (30% solid) controlled release polymer dressing Eudragit  RL 30D 9 (30% solid) controlled release polymer dressing triethyl citrate 2.02 plasticizer talcums 3.10 antiplastering aid purified water
Use Niro STREA-1 fluidized bed dryer that drug solution is formed the medicine layer on 25-30 purpose coarse grain pearl, make 100mg medicine free alkali stratification on 200mg coarse grain pearl, thereby make the medicated layer beadlet.Make its weightening finish 3% promptly release beadlet with the pure package solution of 0padry  package medicated layer beadlet in order to produce.A part promptly release beadlet with Eudragit  RS or RS/RL coating dispersion carry out polymer coating make its weightening finish 10%.Make its weightening finish 2% with the pure package solution of Opadry  package polymer coating pearl, thereby make final polymer coating pearl.
Table 4: Eudragit  RS/RL coating pearl release mode in water of compounds X
Time (hour) release %
0.5 0.2
1 0.3
2 0.4
4 1.9
6 13
8 20
Embodiment 13 (methylcellulose coating pearl)
Use the coarse grain sugar pearl 200mg of 16-20,20-25 or 25-30 order size.Use the medicine layer solution of following composition: component %w/w function compounds X 0.003-0.05 pfb active component methylcellulose E4M 15 controlled release polymer coating dihydro sodium citrates 1.5 stabilizing agent pure water are an amount of to amount to 100
Package solution: will make the pure water solution of the Opadry  pure (YS-1-7006) of 10% solid concentration in the pure 900g of the being dissolved in purified water of 100gOpadry .
Embodiment 14 (delaying ethyl cellulose coating beadlet)
Use the coarse grain sugar beadlet 200mg of 16-20,20-25 or 25-30 order size.Use the medicine layer solution of following composition.
Component %w/w function
Compounds X 0.003-0.05 pfb active component
Pure 1.5 binding agents of Opadry 
Surelease  1.5 delayers
Dihydro sodium citrate 1.5 stabilizing agents
Pure water is an amount of
Amount to 100
Package solution: will make the pure water solution of the Opadry  pure (YS-1-9025A) of 10% solid concentration in the pure 900g of the being dissolved in pure water of 100gOpadry .
Polymer coating: what be prepared as follows composition contains ethyl cellulose (Surelease ) polymer coating dispersion, and the polymer coating that is used for the package pearl makes its weightening finish 10%.The controlled release polymer coating pure water of component %w/w function Surelease  60 (25% solid) plasticizer-containing is an amount of to amount to 100
Use Niro STREA-1 fluidized bed dryer that drug solution is formed the medicine layer on 25-30 purpose coarse grain pearl, make 100mg medicine free alkali stratification on 200mg coarse grain pearl, thereby make the medicated layer beadlet.Make its weightening finish 3% promptly release pearl with the pure package solution of Opadry  package medicated layer beadlet in order to produce.A part promptly release pearl with Surelease  coating dispersion carry out polymer coating make its weightening finish 10%.Make its weightening finish 2% with the pure package solution of Opadry  package polymer coating pearl, thereby make final polymer coating pearl.
Table 5: compounds X contain delayer ethyl cellulose coating pearl release mode in water
Time (hour) release %
Do not contain delayer and contain delayer
0.5 12 8
1 37 22
2 57 35
4 73 48
6 85 53
8 58
Embodiment 15 (enteric coating pearl)
Use the coarse grain sugar pearl 200mg of 16-20,20-25 or 25-30 order size.Use the medicine layer solution of following composition.
Component %w/w function
Compounds X 0.003-0.05 pfb active component
Pure 3 binding agents of Opadry 
Dihydro sodium citrate 1.5 stabilizing agents
Pure water is an amount of
Amount to 100
Package solution: will make the pure water solution of the Opadry  pure (YS-1-9025A) of 10% solid concentration in the pure 900g of the being dissolved in purified water of 100gOpadry .
Polymer coating: what be prepared as follows composition contains Eudragit  L30D-55 polymer coating dispersion, and the polymer coating that is used for the package pearl makes its weightening finish 20%.The sliding 3.10 antiplastering aid pure water of component %w/w function Eudragit  L30D-55 45.00 (30% solid) enteric (pH dependence) polymer triethyl citrate 2.02 plasticizers are an amount of to amount to 100
Use Niro STREA-1 fluidized bed dryer that drug solution is formed the medicine layer on 25-30 purpose coarse grain pearl, make 100mg medicine free alkali stratification on 200mg coarse grain pearl, thereby make the medicated layer beadlet.Make its weightening finish 3% promptly release pearl with the pure package solution of Opadry  package medicated layer beadlet in order to produce.A part is promptly released pearl and is carried out enteric coated its weightening finish 20% that makes with Eudragit  enteric coating dispersion.Make its weightening finish 2% with the enteric coated pearl of the pure package solution of Opadry  package, thereby make final enteric coated pearl.
Embodiment 16 (matrix tablet) ingredient m g/ sheet function compounds X 0.05-0.1 pfb active component hydroxypropyl methylcellulose E4M CR 75.0 hydrogel matrix dihydro natrium citricums 3.00 stabilizing agent lactose, the fast white 2.25 package polymer of Flo 70.38 hydrophilic diluent dolomol 1.50 lubricant Opadry 
Package solution: will make the pure water solution of the Opadry  pure (YS-1-9025A) of 10% solid concentration in the pure 900g of the being dissolved in pure water of 100gOpadry .
Polymer coating: what be prepared as follows composition contains ethyl cellulose (Surelease ) polymer coating dispersion, and the polymer coating that is used for the package pearl makes its weightening finish 10%.The controlled release polymer coating pure water of component %w/w function Surelease  60 (25% solid) plasticizer-containing is an amount of to amount to 100
Use LDCS carrier pot (Vector LDCS pan) that the 700g label is made its weightening finish 3% with the pure package solution of Opadry  package.With Surelease  coating dispersion the package sheet is carried out polymer coating then, make its weightening finish 4%.
Table 6. compounds X substrate tablet release mode in water
Time (hour) dissolving %
1 8
2 3
4 58
8 96
Embodiment 17 (controlled release double-layer tablet)
Active layer
Component mg/ sheet function
Compounds X 0.005-0.1mg pfb active component
Methylcellulose K4M 15.00 aquogel polymers
Lactose monohydrate 62.0 hydrophilic filleies
Polyvinylpyrrolidone 3.0 binding agents
Magnesium stearate 1.0 hydrophobic lubricants
Syloid 244 1.0 hydrophilic fluidizer
Load bearing seat
Component mg/ sheet function
Compritol 888 15.0 plasticizers
Lactose monohydrate 29.0 hydrophilic filleies
Polyvinylpyrrolidone 4.0 binding agents
Magnesium stearate 1.5 hydrophobic lubricants
Methylcellulose E5 29.4 aquogel polymers
Ferrum oxide 0.1 coloring agent

Claims (28)

1. one kind contains the controlled release oral dosage form that [R-(Z)]-α-methoxyimino-α-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile one hydrochlorate (compounds X), its parent free alkali or their other any pharmacy are suitable for salt.
2. according to the dosage form of claim 1, it provides the release in vitro pattern of selecting, and the area under curve that obtains behind twice orally give 5-75 of area and every day μ g (calculating by free alkali) compounds X fast-release tablet under the curve of blood plasma when described pattern can provide in vivo test is similar.
3. according to the dosage form of claim 1 or 2, it provides the release in vitro pattern that discharges 25-70% in 4 hours and discharge 70-100% in 8 hours.
4. according to each dosage form in the claim 1 to 3; but it is selected from wax-matrix, swellable and/or gel-type vehicle, with the sheet of controlled release polymer or wax coating; with contain substrate or with piller, granule or the pearl of controlled release polymer or wax coating, and be mixed with capsule, the tablet that compresses or suspension then.
5. according to the dosage form of aforementioned each claim, but it comprises swellable and/or gel-type vehicle, and described substrate is selected from alkylcellulose, hydroxy alkyl cellulose, polyvinyl alcohol, polymethacrylates, polymethyl methacrylate, methacrylate/divinyl benzene copolymer, carboxymethyl amide, polyether polyols, polyvinylpyrrolidone and carboxymethyl cellulose.
6. according to the dosage form of claim 5, its mesostroma is selected from alkylcellulose, hydroxy alkyl cellulose, polyvinyl alcohol, polymethacrylates, crospolyvinylpyrrolidone and sodium carboxymethyl cellulose.
7. according to the dosage form of claim 5 or 6, comprise the hydrogel matrix coated tablet with hydrophobic controlled release polymer coating, described polymer coating is selected from alkylcellulose and methacrylic acid derivative.
8. according to the dosage form of claim 7, wherein polymeric matrix is that the 10-50% and the hydrophobic controlled release polymer of tablet weight are the 4-10% of tablet weight.
9. according to the dosage form of claim 7 or 8, the tablet that comprises following composition (mg/ sheet): compounds X 0.005-0.1pfb hydroxypropyl emthylcellulose E4M CR 75.0 dihydro sodium citrate 0-3.00 lactose, fast Flo 70.38-73.38 magnesium stearate 1.50Opadry  white 2.25
With Opadry  pure (YS-1-7006) the pure water solution package of 10% solid concentration with contain ethyl cellulose (Surelease ) dispersion with 60%w/w (25% solid) and carry out polymer coating and make its weightening finish 10%, form label, with Opadry  pure package solution package with contain ethyl cellulose (Surelease ) dispersion with 60%w/w (25% solid) and carry out polymer coating and make it increase weight 4%.
10. according to the dosage form of each claim among the claim 1-4; the medicated layer beadlet that it comprises the medicated layer beadlet of independent controlled release polymer coating or controlled release polymer coating is with the combination of the medicated layer beadlet (promptly releasing pearl) of no controlled release polymer coating and randomly comprise the inertia excipient and/or delayer and/or one or more binding agents.
11. according to the dosage form of claim 10, medicated layer beadlet film forming polymer package wherein.
12. according to the dosage form of claim 10 or 11, wherein the controlled release polymer coating is selected from alkylcellulose, hydroxy alkyl cellulose, sodium carboxymethyl cellulose and methacrylic acid derivative.
13. according to each dosage form among the claim 10-12, wherein polymer accounts for the 10-30% of dosage form gross weight.
14. dosage form according to claim 10, it is a capsule form, the coarse grain sugar pearl that comprises 16-20,20-25 or 25-30 order size carries out coating with the medicine layer aqueous solution of following composition (%w/w), makes per 200 μ g beadlet loads, 100 μ g (pressing free alkali calculating) medicine:
Compounds X 0.003-0.06pfb
Opadry  pure 3
Dihydro sodium citrate 0-1.5
Opadry  pure (YS-1-7006) pure water solution package with 10% solid concentration makes its weightening finish 3%, further use 60%w/w (25% solid) to contain vinyl cellulose (Surelease ) dispersion with a part of beadlet and carry out polymer coating and make its weightening finish 10-25%, and make it increase weight 2% with above-mentioned package solution package then.
15. one kind treats and/or prevents dementia, comprises the method for mammal Alzheimer, uses the controlled release oral dosage form of the claim 1 of effective dose by giving the patient who needs.
16. one kind along suffering from Alzheimer or having ill tendency person's non-amyloid gene approach to strengthen the method for amyloid precursor protein function, described method is by using the controlled release oral dosage form of the claim 1 of effective dose for the patient who needs.
17. the controlled release oral dosage form of claim 1 treats and/or prevents dementia in preparation, comprises the application in the medicine of mammal Alzheimer.
18. the controlled release oral dosage form of claim 1 along suffering from Alzheimer or ill tendency person's non-amyloid gene approach being arranged, strengthens the application in the medicine of amyloid precursor protein function in preparation.
19. one kind treats and/or prevents dementia, comprises the pharmaceutical composition of mammal Alzheimer, it comprises the controlled release oral dosage form of claim 1.
20. one kind along suffering from Alzheimer or ill tendency person's non-amyloid gene approach being arranged, and strengthens the pharmaceutical composition of amyloid precursor protein function, it comprises the controlled release oral dosage form of claim 1.
21. according to dosage form, method, application or the compositions of each aforementioned claim, it is in stomach-intestinal canal discharges after mainly occurring in administration preceding 8-12 hour.
22. according to dosage form, method, application or the compositions of each aforementioned claim, it comprises [R-(Z)]-α-methoxyimino-α-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile one hydrochlorate.
23. according to dosage form, method, application or the compositions of each claim of 1-22, it comprises 5 μ g compounds Xs (pressing free alkali calculates).
24. according to dosage form, method, application or the compositions of each claim of 1-22, it comprises 12.5 μ g compounds Xs (pressing free alkali calculates).
25. according to dosage form, method, application or the compositions of each claim of 1-22, it comprises 25 μ g compounds Xs (pressing free alkali calculates).
26. according to dosage form, method, application or the compositions of each claim of 1-22, it comprises 50 μ g compounds Xs (pressing free alkali calculates).
27. according to dosage form, method, application or the compositions of each claim of 1-22, it comprises 75 μ g compounds Xs (pressing free alkali calculates).
28. according to dosage form, method, application or the compositions of each claim of 1-22, it comprises 100 μ g compounds Xs (pressing free alkali calculates).
CN03102977A 1996-09-12 2003-01-23 Chlorhydric [R(2)-alpha-methoxyimindogen-alpha-(1-dicycloaza [2.2.2] caryl-3-group) acetonitrile control-released dosage form Pending CN1446535A (en)

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GBGB9619074.9A GB9619074D0 (en) 1996-09-12 1996-09-12 Composition
GB9619074.9 1996-09-12

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CN03102977A Pending CN1446535A (en) 1996-09-12 2003-01-23 Chlorhydric [R(2)-alpha-methoxyimindogen-alpha-(1-dicycloaza [2.2.2] caryl-3-group) acetonitrile control-released dosage form

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CN1292696A (en) 1998-03-11 2001-04-25 史密丝克莱恩比彻姆有限公司 Composition
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
US8679533B2 (en) 2002-07-25 2014-03-25 Pharmacia Corporation Pramipexole once-daily dosage form
US20060252820A1 (en) * 2003-04-25 2006-11-09 Tetsuya Suzuki Composition for oral administration containing alkylene dioxybenzene derivative
DE602004002405T3 (en) * 2003-05-14 2013-06-20 Aptalis Pharma Limited CONTROLLED MEDICATION RELEASE COMPOSITION WITH IN VIVO MECHANICAL RESISTANCE
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
WO2006015943A2 (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
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