Classifications

• • 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
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • 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
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • 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
• • 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
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • 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
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
• • 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
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/24—Antidepressants
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2813—Inorganic compounds
• • 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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• the invention relates to a solid pharmaceutical preparation containing one or more solid carriers and / or excipients and an active ingredient from the group of monoamine neurotransmitter re-uptake inhibitors with a 2,3-disubstituted tropane skeleton, their preparation and use for the manufacture of a medicament for Treatment or prevention of central nervous disorders or disorders.
• Monoamine Neurotransmitters Re-uptake inhibitors which have a 2,3-disubstituted tropane skeleton are compounds with pharmacologically valuable properties. They may, for example, have a high therapeutic benefit in the treatment of central nervous disorders such as dementia associated with Alzheimer's disease or Parkinson's disease.
• Such compounds are known e.g. from International Patent Applications WO 93/09814 and WO 97/30997, in which various dosage forms for such compounds are also proposed.
• the present invention was therefore based on the object of a solid pharmaceutical dosage form for monoamine neurotransmitter re-uptake inhibitors, which is a 2,3- Disubstituted tropane skeleton, with high stability, faster in vitro dissolution and good bioavailability and high content uniformity to provide.
• the invention thus relates to a solid pharmaceutical preparation containing one or more solid carriers and / or excipients and an active ingredient from the group of monoamine neurotransmitter re-uptake inhibitors with a 2,3-disubstituted tropane skeleton which (a) by spraying a Solution of the active ingredient is available on at least one carrier; and (b) optionally one or more wet binders, preferably in the spray solution.
• Another object of the invention is a process for the preparation of such pharmaceutical formulations, wherein
• the invention relates to the use of a pharmaceutical preparation according to any one of claims 1 to for the manufacture of a medicament for the treatment or prevention of central nervous disorders or disorders selected from the group consisting of depression, any form of dementia, Parkinson's disease or obesity.
• FIG. 1 shows the dissolution behavior of a pharmaceutical preparation according to the invention in the form of a film tablet with and without wet binding agent containing 1 mg of a compound of the formula LA at a pH of 1.2.
• FIG. 2 shows the dissolution behavior of a pharmaceutical preparation according to the invention in the form of a film tablet with and without wet binding agent containing 1 mg of a compound of the formula IA at a pH of 6.8.
• the monoamine neurotransmitter re-uptake inhibitors having a 2,3-disubstituted tropane skeleton are those of the formula (I) as disclosed, for example, in International Patent Applications WO 93/09814 and WO 97/30997:
• R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl;
• R 3 is CH 2 -XR ', wherein X is O, S, or NR ", wherein R" is hydrogen or alkyl; and R 'is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or -CO-alkyl; Heteroaryl which may be monosubstituted or polysubstituted by alkyl, cycloalkyl or cycloalkylalkyl; Phenyl, which may be substituted one or more times by a substituent selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; phenylphenyl; Pyridyl, which may be substituted one or more times by a substituent selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkyn
• R 3 is 1, 2,4-oxadiazol-3-yl, which may be substituted in the 5-position by alkyl, cycloalkyl, or cycloalkylalkyl; Phenyl, which may be substituted one or more times by a substituent selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; phenylphenyl; or Benzyl which may be substituted one or more times by a substituent selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and heteroaryl; or R 3 is 1, 2,4-oxadiazol-5-yl, which may be substituted in the 3-position by alkyl, cycloalkyl, or cycloalkylalkyl; Phenyl, which may be substituted one or more times by
• Formula I is R 3 .CH 2 -XR wherein
• X is O, S, or NR "; wherein R" is hydrogen or alkyl;
• R ' is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or -CO-alkyl.
• R ' is hydrogen; Alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or aryl; which may be substituted by a substituent selected from the group consisting of -COOH; -COO-alkyl; -COO-cycloalkyl and phenyl, which may be substituted one or more times by a substituent selected from the group consisting of halogen, CF 3 , CN, alkoxy, alkyl, alkenyl, alkynyl, amino, and nitro.
• R 4 is phenyl which is mono- or disubstituted by a substituent selected from the group consisting of halogen, CF, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, and Heteroaryl can be substituted.
• R 4 is phenyl which is monosubstituted or disubstituted by chlorine.
• 2,3-disubstituted tropane derivatives having a monoamine neurotransmitter re-uptake inhibitory activity which have a (1R, 2R, 3S) configuration.
• -CH NOR '; wherein R 'is hydrogen or alkyl; or 1, 2,4-oxadiazol-5-yl, which may be substituted in the 3-position by alkyl.
• R is preferably hydrogen, methyl, ethyl or propyl.
• R 1 represents a hydrogen atom or a C 1-6 alkyl group, in particular hydrogen, methyl or ethyl;
• R 2 is a halogen atom or a is a CF 3 or cyano group, especially fluorine, chlorine or bromine;
• R 3 is a hydrogen atom or a C 1-6 alkyl group or C 3-6 cycloalkyl C 1-3 alkyl group, especially methyl, ethyl or propyl; and m is 0 or an integer from 1 to 3, especially 1 or 2; or a tautomer, a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof.
• C ⁇ _ 6 alkyl as used above and below includes methyl and ethyl groups, as well as geradketttige and branched propyl, butyl, pentyl and hexyl groups. Particularly preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.
• C 3-6 cycloalkyl as used above and below includes cyclic propyl, butyl, pentyl and hexyl groups such as cyclopropyl and cyclohexyl.
• halogen as used above and below includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are particularly preferred.
• physiologically functional derivative as used above and below includes derivatives obtained from the compounds of formula (I) under physiological conditions, such as N-oxides.
• pharmaceutically acceptable acid addition salts includes acid addition salts formed with hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid, the salts of hydrochloric acid , Bromic acid, sulfuric acid, phosphoric acid, acetic acid and citric acid are particularly preferred. Most preferred is the salt of citric acid.
• the compounds of the formula (I) are selected from the group consisting of:
• the pharmaceutical preparation of the invention contains up to 5.00 wt.%, Preferably 0.01 to 3.00 wt .-%, in particular 0.10 to 1.50 wt .-%, usually preferably 0.10 to 0.80 wt .-% of an active ingredient from the group of monoamine neurotransmitter re-uptake inhibitors having a 2,3-disubstituted tropane skeleton, wherein the percentages refer to the particular salt used this active ingredient.
• a pharmaceutical preparation form obtainable by spraying a solution of the active ingredient, wherein the solvent contains water, an alcohol and optionally a wet binder.
• the ratio of the solvents alcohol and water may be 100: 0 to 0: 100 (wt%), preferably 20:80 to 80:20 (wt%), more preferably 40:60 to 60:40 (wt%) ,
• Preferred wet binders are Polyvmylpynolidion (povidone), copolymers of vinylpyrrolidone with other vinyl derivatives (copovidones), cellulose derivatives such as methylhydroxypropylcellulose, methylcellulose or hydroxypropylcellulose, in particular hydroxypropylcellulose (HPC).
• povidone Polyvmylpynolidion
• copovidones copolymers of vinylpyrrolidone with other vinyl derivatives
• cellulose derivatives such as methylhydroxypropylcellulose, methylcellulose or hydroxypropylcellulose, in particular hydroxypropylcellulose (HPC).
• the active ingredient precipitates on the carrier material during spraying in a predominantly crystalline form.
• carbohydrates such as lactose or mannose, in particular finely divided lactose and lactose monohydrate, but also or sugar alcohols such as mannitol, sorbitol or xylitol, in particular mannitol as carrier materials, are of particular importance.
• sugar alcohols such as mannitol, sorbitol or xylitol, in particular mannitol as carrier materials.
• These carriers have proven to be particularly advantageous in the formulation according to the invention.
• a preferred aspect of the present invention therefore relates to a preparation containing at least one compound of formula I which, in addition to the active substance, contains lactose, in particular finely divided lactose and lactose monohydrate as carrier.
• the ratio of lactose to the active ingredient is within a range of about 150: 1 to about 50: 1.
• the weight fraction of lactose based on the total mass of the tablet according to the invention is in a range of about 50-80% by weight, preferably between about 55-75% by weight.
• composition forms wherein the carrier materials are selected from the group consisting of carbohydrates and dry binders.
• dry binder stands for those auxiliaries which are suitable for binding other components together.
• the binders preferred according to the invention are selected from the group consisting of: powdered cellulose, microcrystalline cellulose, sorbitol, starch, polyvinylpyrrolidone (povidone), copolymers of Vinylpyrrolidone with other vinyl derivatives (copovidones), cellulose derivatives, in particular methylhydroxypropylcellulose, eg Methocel E 5 P, and mixtures of these compounds
• powdered cellulose especially microcrystalline cellulose and / or copovidone are included Most preferred is microcrystalline cellulose.
• anhydrous lactose and lactose monohydrate tablets with high mechanical stability and at the same time rapid drug release and thus good bioavailability are obtained.
• the weight ratio of lactose to binder is preferably about 5: 1 to about 1: 2, preferably about 3: 1 to about 1: 1, particularly preferably about 2.5: 1 to 1.5: 1.
• these disintegrating agents may optionally also be referred to as disintegrating agents.
• these are preferably selected from the group consisting of sodium starch glycolate, cross-linked polyvinylpyrrolidones (crospovidone), croscarmellose sodium salt (cellulose carboxymethylether sodium salt, crosslinked), carboxymethylcellulose, dried corn starch and mixtures thereof.
• crospovidone cross-linked polyvinylpyrrolidones
• croscarmellose sodium salt cellulose carboxymethylether sodium salt, crosslinked
• carboxymethylcellulose dried corn starch and mixtures thereof.
• particular preference is given to using sodium starch glycolate, crospovidone and, preferably, croscarmellose sodium salt.
• their weight fraction based on the total mass of the tablet according to the invention is preferably in a range of about 0.5-10% by weight, more preferably about 1.0-5.0% by weight.
• Suitable lubricants for the purposes of the present invention include, for example, silica, talc, stearic acid, sodium stearyl fumarate, magnesium stearate and glycerol tribehenate. Vegetable magnesium stearate is preferably used according to the invention. If the flow or flow regulators or lubricants mentioned above are used, their weight fraction based on the total mass of the administration form according to the invention is preferably in a range of about 0.1-10% by weight, preferably about 0.5-5% by weight. more preferably between 0.6 and 1.0% by weight.
• the preparation form according to the invention is a tablet, in particular a film-coated tablet.
• the film coating consists essentially of one or more film formers, one or more elasticity enhancing agents, the so-called plasticizers, one or more release agents, one or more pigments, and optionally one or more dyes.
• the film coating consists essentially of From 35 to 65% by weight of at least one film former, in particular HPMC; From 3.5 to 10% by weight of at least one elasticity-enhancing agent, in particular PEG; - 5 to 20 wt .-% of at least one coating, in particular a silicate; 10 to 40 wt .-% of at least one pigment, in particular titanium dioxide - 0 to 10% by weight of at least one dye, in particular of iron oxides. based on the total mass of the film coating.
• the film coating consists essentially of From 35 to 65% by weight of at least one film former, in particular HPMC; From 3.5 to 10% by weight of at least one elasticity-enhancing agent, in particular PEG; - 5 to 20 wt .-% of at least one coating, in particular a silicate; 10 to 40 wt .-% of at least one pigment, in particular titanium dioxide - 0 to 10% by weight of at least one dye, in particular of iron oxides. based on the total mass of the film coating.
• a pharmaceutical preparation characterized in that it consists essentially of the following components: (i) an active substance from the group of the monoamine neurotransmitter re-uptake inhibitors which have a 2,3-disubstituted tropane skeleton, preferably a compound of formula (I), in particular the compound of formula (IA); (ii) one or more carrier materials selected from the group consisting of carbohydrates and dry binders, preferably lactose and cellulose; (iii) one or more adjuvants selected from the group consisting of cellulose derivatives and salts of fatty acids, preferably HMC, CMC Na, cross-linked, and magnesium stearate; (iv) a film coating consisting essentially of one or more film formers, one or more elasticity enhancing agents, one or more release agents, one or more pigments, and optionally one or more colorants.
• an active substance from the group of the monoamine neurotransmitter re-uptake inhibitors which have a 2,3-disubstituted
• a pharmaceutical preparation in the form of a film tablet consisting essentially of the following components: (i) 0.01 to 5.00 wt .-% of an active ingredient from the group of monoamine neurotransmitter re-uptake inhibitors, which is a 2, 3-disubstituted Tropan skeleton, in particular 0.02 to 3.00 wt .-% of an active ingredient of the formula I; (Ii) 80.00 to 95.00 wt .-% of one or more carrier materials selected from the group consisting of carbohydrates and dry binders, in particular carrier materials consisting of: a. 27.5 to 32.5% by weight of anhydrous lactose; b. 27.5 to 32.5% by weight of lactose monohydrate; c.
• microcrystalline cellulose 25.0 to 30.0% by weight of microcrystalline cellulose; (Iii) l, 00 to 10.00 wt .-% of one or more adjuvants selected from the group consisting of cellulose derivatives and salts of fatty acids, in particular 2.00 to 8.00 wt .-% of one or more auxiliaries selected from the group consisting of HPC, CMC Na, cross-linked, and magnesium stearate; ; (iv) 0 to 10.00% by weight of a film coat consisting essentially of one or more film formers, one or more plasticizers, 1.00 to 5.00% by weight of a film coat comprising HPMC, MHPC, PEG, one or more silicates, titanium dioxide and one or more iron oxides or more pigments and optionally one or more dyes, especially 00 to 5.00 of a film coating comprising HPMC, MHPC, PEG, one or more silicates, titanium dioxide and one or more iron oxides.
• the active ingredient is dissolved in a solvent, optionally in the presence of a wet binder, sprayed onto the carriers, in particular finely divided, anhydrous lactose, lactose monohydrate and microcrystalline cellulose as binder, mixed, sieved and then dried.
• the product obtained is optionally cross-linked with further carrier, in particular microcrystalline cellulose and / or lactose, with disintegrants, in particular CMC Na, and finally with the flow agent, in particular magnesium stearate.
• the resulting mixture is then compressed on a suitable tablet press to give the tablets according to the invention.
• the pressing forces needed to produce tablets of suitable breaking strengths and thus the desired disintegration times depend on the shapes and sizes of the punching tools used.
• pressing force is in a range of 2 - 30 kN, especially 5 - 26 kN.
• Higher press forces can lead to tablets with slower drug release.
• Lower press forces can lead to mechanically unstable tablets.
• the tablet cores can have different formats, preferred are round, large-domed or biconvex and oval or oblong forms.
• a solution of the film-forming agent and the plasticizer is prepared in water, the insoluble release agents and pigments dispersed therein and the resulting suspension applied to the tablets.
• Film tablets are produced consisting of:
• Nozzle head 1.1 mm
• Spray pressure approx. 2 bar
• Swivel angle 100 ° (for drying and cooling)
• the mixer should run on interval switching, i. Mix for 1 minute, then 2 minutes rest.
• Dry sieve Use a suitable sieving machine to grind the dried granules.
• Process data Screening machine: Comil 197 S Screen size: RS 2007 Spacer ring: DR 125 4. Final Mix In a suitable tumbler mixer, mix dry sieve 3. 14587.500 g with (07) carboxymethylcell-NA, cross-linked (Ac-Di-Sol) INT 300,000 g. Then add (06) magnesium stearate plant INT 112.500 g pre-screened over 0.5 mm and mix homogeneously.
• Example 2 Analogously to Example 1, corresponding non-coated tablets are prepared, wherein a solution of the active ingredient of the formula (IA) in the form of the citrate dissolved in water and ethanol but without the addition of hydroxypropyl cellulose is applied to the carrier material.
• a solution of the active ingredient of the formula (IA) in the form of the citrate dissolved in water and ethanol but without the addition of hydroxypropyl cellulose is applied to the carrier material.
• Granulating fluid Purify water in a suitable mixing vessel (15) and add 664.092 g (14) ethanol 96% PAR INT 993.422 g (room temperature). Add successively (04) hydroxypropylcellulose (Klucel EF Pharm) INT 180,000 g and (01) formula (IA) citrate 39,600 g and dissolve. Solids content: 219.600 g 1877.114 g
• Lactose monohydrate (tablettose) Introduce INT 5800,000 g, mix homogeneously and mix with granulating liquid 1. Dampen 1877.114 g of solids: 219.600 g, granulate and then dry. 12105,000 g
• Nozzle head 1.1 mm
• Spray pressure approx. 2 bar
• Swivel angle 100 ° (for drying and cooling)
• the mixer should run continuously, 5 rpm.
• Process data Screening machine: Comil 197 S Screen size: RS 2007 Spacer ring: DR 125
• Tablet press Greases P1200 Tool: 6 mm WR 9, big arched with facet + BI logo Press speed 150,000 tbl / h Press force: approx. 7-9 kN
• tablet cores 5. 2639.970 g Coating suspension 8. 622.119 g Cover to a weight of 92.5 mg. Solids content 73.333 g 2713.303 g
• the tablets according to Examples 1 and 2 are each dissolved in 900 ml of a simulated gastric fluid of pH 1.2 or a simulated intestinal flora of pH 6.8 (0.05 M phosphate buffer) at a stirring speed of 50 rpm or 75 rpm.
• the content of the dissolved compound of the formula (IA) is determined by HPLC.

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• 2004
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  • 2004-11-17 TW TW093135259A patent/TW200529844A/zh unknown
• 2006
  • 2006-04-27 IL IL175246A patent/IL175246A0/en unknown
  • 2006-05-16 CO CO06046683A patent/CO5690555A2/es not_active Application Discontinuation
  • 2006-06-15 NO NO20062810A patent/NO20062810L/no not_active Application Discontinuation
• 2007
  • 2007-01-22 HK HK07100770.9A patent/HK1094676A1/xx not_active IP Right Cessation
• 2010
  • 2010-03-24 US US12/730,831 patent/US20100178342A1/en not_active Abandoned
• 2011
  • 2011-01-04 JP JP2011000224A patent/JP2011068690A/ja active Pending

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