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
  • A61K31/28—Compounds containing heavy metals
  • A61K31/282—Platinum 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
  • A61K9/14—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
• • 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
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
  • A61K9/2846—Poly(meth)acrylates
• • 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
• • 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
  • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
• • 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
  • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
• • 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
  • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
• • 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
  • A61K9/5005—Wall or coating material
  • A61K9/5015—Organic compounds, e.g. fats, sugars
• • 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
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of 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
  • A61K9/48—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
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
  • A61K9/5047—Cellulose ethers containing no ester groups, 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
  • A61K9/48—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
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5052—Proteins, e.g. albumin
  • A61K9/5057—Gelatin
• • 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

Definitions

• This invention relates to a solid pharmaceutical composition containing a tetravalent platinum complex as active substance.
• the constitution of this pharmaceutical composition ensures perfect stability of the active substance and its enteric and or controlled release.
• This invention also relates to a method of manufacturing this pharmaceutical composition.
• platinum complexes exhibit a broad antitumor effect which is utilized in treatment of a large number of tumor diseases. So far, the therapeutic practice used only complexes of bivalent platinum, especially cisplatinum, carboplatinum or oxaliplatinum. These bivalent platinum complexes are unstable in the gastrointestinal system and/or they are very poorly absorbed. This makes impossible the use of bivalent platinum complexes in an oral, for the patient more advantageous, dosage form. Later it has been found that some complexes of tetravalent platinum don' t suffer from this drawback and retain their antitumor activity even on peroral administration. These complexes of tetravalent platinum were disclosed as novel chemical compounds for peroral administration particularly in EP 0 328 274 and EP 0423 707.
• complexes of tetravalent platinum in general exhibit very poor solubility in water (in the region of about 0.03 g/100 g), low bulk density (in the region of about 0.2 g/ml), low tap density (in the region of about 0.4 g/ml), and an extremely high electrostatic charge.
• the said physical properties represent an important problem for the preparation of a solid pharmaceutical composition.
• complexes of tetravalent platinum are chemically unstable in contact with metals or with many currently used pharmaceutical excipients, which lowers the stability of the active substance in the pharmaceutical composition.
• the invention relates to the pharmaceutical composition containing as active substance a platinum complex of general formula I
• a and A' each independently is an NH 3 group or an amino or diamino group containing 1 to 18 carbon atoms
• B and B' each independently is a halogen atom, a hydroxy group or a -O-C(O)-R or -O-C(O)-R/ group
• R and R' each independently is hydrogen atom or an alkyl, alkenyl, aryl, aralkyl, alkylamino or alkoxy group containing 1 to 10 carbon atoms, or a functional derivative of these groups
• X and X' each independently is a halogen atom or a monocarboxylate group containing 1 to 20 carbon atoms, or X and X' together represent a dicarboxylate group containing 2 to 20 carbon atoms, in a mixture with at least one pharmaceutically acceptable excipient, characterized in that it is a granulate of particle size less than 0.5 mm, prepared by wet granulation of water- wetted mixture of
• the pharmaceutical composition advantageously is formed by a granulate prepared by wet granulation of water- wetted mixture of platinum complex of general formula I, at least one neutral saccharide in an amount equal to at least 5 % by weight and at least one natural and/or modified polycaccharide in an amount equal to at least 2 % by weight, both based on the total weight of the granulate.
• the pharmaceutical composition advantageously contains at least one pharmaceutically acceptable disintegrant and/or at least one pharmaceutically acceptable lubricant.
• the pharmaceutical composition according to the invention advantageously contains (OC-6-43)-bis(acetato)-( 1 -adamanlylamme)-ammine-dicl ⁇ loroplatinum(IN) complex.
• the mixture for the wet granulation advantageously contains lactose, manitol, sorbitol, fructose, glucose and/or sucrose.
• the mixture for the wet granulation advantageously contains maize, wheat and/or potato starch.
• the surface of the granulate or tablet is advantageously separated by an inert sealing layer formed by at least one neutral saccharide such as sucrose, and/or by at least one natural and/or modified polysaccharide such as natural or modified maize, wheat or potato starch or gelatin or gum arabic, the amount of the inert sealing layer being not higher than 15 % by weight, based on the total weight of the granulate or tablet.
• an inert sealing layer formed by at least one neutral saccharide such as sucrose, and/or by at least one natural and/or modified polysaccharide such as natural or modified maize, wheat or potato starch or gelatin or gum arabic, the amount of the inert sealing layer being not higher than 15 % by weight, based on the total weight of the granulate or tablet.
• the layer of at least one pharmaceutically acceptable substance enabling the controlled release of the active substance is advantageously formed by ethyl cellulose and/or methacrylic acid and/or its derivatives, advantageously by polymers and/or copolymers of methacrylic , plague drawbacks WO 2005/077357
• this layer being at most 40 % by weight, based on the weight of the granulate, capsule or tablet.
• the layer of at least one pharmaceutically acceptable substance enabling enteric dissolution of the active substance only in the intestine is advantageously formed by cellulose acetate and/or cellulose acetylphthalate and/or cellulose acetosuccinate and/or hydroxypropyl methyl cellulose phthalate and/or hydroxypropyl methyl cellulose succinate and/or polyvinyl alcohol phthalate and/or benzophenyl salicylate and/or a styrene-maleic acid copolymer and/or shellac and/or methacrylic acid and/or its derivatives, advantageously by polymers or copolymers of methacrylic acid, the amount of this layer being at most 15 % by weight, based on the weight of the granulate, capsule or tablet.
• the invention is also related to a method of manufacturing the pharmaceutical composition according to the present invention, characterized in that a water-wetted mixture of platinum complex of general formula I, at least one neutral saccharide and at least one natural and/or modified polysaccharide is subjected to wet granulation to obtain a granulate of particle size less than 0.5 mm, whereupon the obtained granulate is optionally filled into a capsule the outer surface of which is optionally coated with a layer of at least one pharmaceutically acceptable substance enabling enteric dissolution of the active substance only in the intestine and/or by a layer of at least one pharmaceutically acceptable substance enabling controlled release of the active substance, or is filled into a sachet, or the obtained granulate is mixed with at least one disintegrant and/or at least one lubricant and the mixture is optionally compressed into tablets, and the surface of the tablets and optionally the surface of the granulate or capsule is coated with a layer of at least one pharmaceutically acceptable substance enabling enteric dissolution of the active substance only
• the surface of granulate and tablet Prior to coating with a layer of at least one pharmaceutically acceptable substance enabling enteric dissolution of the active substance only in the intestine and/or with a layer of at least one pharmaceutically acceptable substance enabling controlled release of the active substance, the surface of granulate and tablet is advantageously coated with an inert sealing layer, formed by at least one neutral saccharide such as sucrose, and/or by at least one natural and/or modified polysaccharide such as natural or modified maize, wheat or potato starch or gelatin or gum arabic.
• an inert sealing layer formed by at least one neutral saccharide such as sucrose, and/or by at least one natural and/or modified polysaccharide such as natural or modified maize, wheat or potato starch or gelatin or gum arabic.
• the wet granulation is carried out to obtain a granulate of such particle distribution that 90 % of the particles are of size less than 2.0 mm and at most 20 % of particles are of size less than 0.09 mm.
• the wet granulation is advantageously carried out in an apparatus in which the surfaces in contact with the mixture to be granulated are inert towards this mixture.
• the filling into capsules and sachets and tabletting is advantageously carried out in an apparatus in which surfaces in contact with the mixture to be filled into capsules or sachets or with the mixture to be tabletted are inert towards this mixture.
• the coating of the granulate and tablets with an inert sealing layer, a layer of at least one pharmaceutically acceptable substance enabling enteric dissolution of the active substance only in the intestine, or a layer of at least one pharmaceutically acceptable substance enabling controlled release of the active substance is advantageously carried out in an apparatus in which the surfaces in contact with the granulate or tablets are pre-coated with a material constituting the inert sealing layer, a layer of at least one pharmaceutically acceptable substance enabling enteric dissolution of the active substance only in the intestine, or a layer of at least one pharmaceutically acceptable substance anabling controlled release of the active substance.
• a tetravalent platinum complex of general formula I may serve (OC-6-43)-bis(acetato)-(l -adamantylamine)-amniine-dicMoroplatinurn(lN) complex of formula II
• the platinum complex of general formula I is unstable in contact with many currently used excipients, e.g. fillers such as phosphates, sulfates or carbonates, standard lubricants, binders and film-forming substances such as acrylic acid esters and their copolymers, cellulose ethers, esters and copolymers or vinyl esters.
• excipients e.g. fillers such as phosphates, sulfates or carbonates, standard lubricants, binders and film-forming substances such as acrylic acid esters and their copolymers, cellulose ethers, esters and copolymers or vinyl esters.
• constitutional excipients compatible wit a platinum complex of general formula I are neutral saccharides as fillers, natural and/or modified polysaccharides as binders, and optionally magnesium stearate as lubricant and natural and/or modified polysaccharides as extragranular disintegrants.
• the resulting granulate, tablet or capsule is further coated with at least one layer of film-forming substance ensuring an enteric and/or controlled release of the active substance. Because of incompatibility between the active substance and most of the currently used film-forming substances, prior to the coating with the said film-forming substance the granulate and tablets are protected by coating with an inert sealing layer protecting the active substance from decomposition and hindering the migration of the film-forming substance into the core of the granulate or tablet.
• material of the inert sealing layer may be employed a neutral saccharide such as sucrose, and/or natural and/or modified polysaccharide such as natural or modified maize, wheat or potato starch or gelatin or gum arabic, optionally mixtures thereof in various ratios, in the form of aqueous or aqueous-alcoholic hydrogel.
• This sealing layer enables protection of the active substance from the enterosolvent coating and/or from coating enabling controlled release of the active substance.
• the weight of dry material of the applied inert sealing layer amounts to at most 15 % by weight, advantageously 4 to 12 % by weight, based on the total weight of the granulate or tablet. In the case of gelatin capsules such protection is not necessary, because the material of the capsule alone protects effectively the active component from the negative effect of the film-forming substance.
• the granulate coated with an inert sealing layer and the tablet coated with an inert sealing layer, or optionally a capsule is coated with an acid-resistant, i.e. enterosolvent, coating that enables release of the active substance only in the small intestine, i.e. only in medium with pH in the region from 4.5 to 8, depending on the enterosolvent coating composition.
• an acid-resistant, i.e. enterosolvent i.e. enterosolvent
• the film-forming substance may be e.g. cellulose acetate (CA), cellulose acetylphthalate (CPA), cellulose acetosuccinate (CAS), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose succinate (HPMCS), polyvinyl alcohol phthalate (PNAP), benzophenyl salicylate (BPS), styrene-maleic acid copolymer, shellac, or copolymers of methacrylic acid such as Eudragit L, Eudragit L-55 and Eudragit S, in the form of their plastif ⁇ ed aqueous dispersions Eudragit L 30 D or L-55 30 D and Eudragit S 30 D or in the form of organic or aqueous-alcoholic solutions Eudragit L 12.5 and Eudragit S 12.5, or mixtures thereof in various ratios, the amount of dry matter of the enterosolvent layer being at most 15 % by weight, advantageously 8 to 10 % by weight,
• the granulate, protected with the inert sealing layer, or tablets, protected with the inert sealing layer, or optionally capsules may be further coated with a layer enabling controlled release of the active substance.
• the release of the active substance from thus-modified pharmaceutical composition corresponds to two limits, A and B, denoting the amount of active substance released in the time given by the dissolution test under conditions of the paddle method according to USP: dissolving medium: 0.1 M HC1, dissolving medium volume: 9O0 ml, paddle rotation speed : 100 r.p. , dissolving medium temperature: 37 °C.
• limit A amounts to 5 to 25 % within 30 minutes, 15 to 65 % within 60 minutes, 40 to 85 % within 120 minutes and at least 85 % within 180 minutes
• limit B is 5 to 25 % within 60 minutes, 15 to 65 % within 180 minutes, 40 to 85 % within 360 minutes and at least 85 % wiliiin 720 minutes.
• the film-forming substance may be e.g. ethyl cellulose (EC) or its aqueous dispersions Surrelease or Aquacoat, or acrylate copolymers, e.g.
• Eudragit NE or Eudragit RL or Eudragit RS in the form of their plastified aqueous dispersions Eudragit NE 30 D, Eudragit RS 30 D, Eudragit RL 30 D, as well as in the form of their organic solutions Eudragit RS 12.5 and Eudragit RL 12.5, or mixtures thereof in various ratios, the amount of the dry matter of the layer enabling controlled release of the active substance being at most 40 % by weight, advantageously 8 to 30 % by weight, based on the total weight of the granulate, capsule or tablet.
• the granulate, coated with a layer for controlled release of the active substance, or tablets, coated with a layer for controlled release of the active substance may be directly filled into capsules that have been already adapted for the enterosolvent application or will be additionally coated with an enterosolvent layer.
• undesired chemical reactions have been surprisingly found when the granulate gets into contact with metallic surface of conventional pharmaceutical technological equipments for processing and manufacturing solid pharmaceutical compositions. This fact hinders the use of standard manufacturing techniques such as compacting in the preparation of the granulate or compressing into tablets without surface finish of the punches and dies.
• the wet granulate of the pharmaceutical composition according to this invention shoud be advantageously processed in an equipment whose surfaces coming into contact with the granulated mixture are inert towards it.
• Good inert materials proved to be glass, porcelain, teflon or enamel.
• the active substance comes into contact with metals when conventional coating equipments with metal surface such as drum coating apparatuses, top- spray fluid bed driers, Wurster coating systems or rotoprocessors are used.
• the surface of the equipment in contact with the processed pharmaceutic composition may be coated with a layer of an inert material which at the same time forms material of the inert sealing layer.
• the surface of the apparatus may be coated before the application of the inert sealing layer.
• the granulate representing the basis of the pharmaceutic composition according to the invention, is prepared by wet granulation method in which a mixture of the platinum complex of general formula I with at least one neutral saccharide and with at least one natural and/or modified polysaccharide is wetted with water and mixed in a suitable mixer at a suitable speed and for suitable time.
• the obtained granulate is then dried in vacuo or at atmospheric pressure. It has been found that the dissolution rate of the granulate is reciprocally proportional to the size of individual granules and therefore the granulate is advantageously disintegrated to have such particle distribution that 90 % of the particles are smaller than 2.0 mm and at most 20 % of the particles are smaller than 0.09 mm. This disintegration is carried out e.g. by milling in a ball mill or by manual or machine trituration in suitable apparatuses.
• the apparatus for filling the granulate into capsules, or the tabletting press for compressing the granulate into tablets must be inert towards the granulate at sites of contact with it.
• the pharmaceutical composition according to this invention is characterized by good stability at 40 °C and 75 % relative humidity, this being illustrated by the fact that during 6 months the relative increase of impurities is less than 2 % by weight and that after the said time the content of any individual unknown impurity does not exceed 0.1 % by weight, based on the weight of the starting platinum complex of formula II. Also, within the said time there was no increase in the amount of the (acetato)-(l-adamantylamine)-ammine-trichloroplatinum(IN) complex of formula [ PtCl 3 (ac) (am) ( ⁇ H 3 ) ], known as impurity accompanying the platinum complex of formula II. Examples
• the granulate is dried at 70 °C until humidity of 2-4 % is reached.
• the dry granulate is ground e.g. in a porcelain ball mill to obtain material containing 100 % of particles of size less than 0.5 mm.
• the granulate is dried at 70 °C until humidity of 2-4 % is reached.
• the dry granulate is ground e.g. in a porcelain ball mill to obtain material containing 90 % of particles of size less than 2.0 mm and at most 20 % of particles of size less than 0.09 mm.
• Inlet air temperature 50 - 70 °C
• Nozzle diameter 0.8 mm
• Coating layer weight 4 — 20 % by weight
• the spraying is executed until achieving the target weight gain of the granulate corresponding to the desired weight of the coating layer.
• the spraying is carried out using 64% (by weight) sucrose solution or 8% (by weight) starch hydrogel prepared by dissolution of modified maize starch at room temperature or by dissolution of natural maize starch at 70 °C.
• aqueous hydrogel of a mixture containing 4 % (by weight) of gum arabic and 5 % (by weight) of gelatin A or B may be used.
• the coating may be carried out also in a conventional drum coating apparatus.
• the spraying is executed until achieving the target weight gain of the drug form corresponding to the desired weight of the coating layer.
• the spraying is carried out using 64% (by weight) sucrose solution or 8% (by weight) starch hydrogel prepared by dissolution of modified maize starch at room temperature or by dissolution of natural maize starch at 70 °C.
• aqueous hydrogel of a mixture containing 4 % (by weight) of gum arabic and 5 % (by weight) of gelatin A or B may be used.
• the coating may be carried out also in a conventional drum coating apparatus.
• the spraying is executed until achieving the target weight gain of the granulate corresponding to the desired weight of the coating layer.
• the spraying is carried out using 20% (by weight) aqueous dispersion of Eudragit L or 10% (by weight) aqueous dispersion of HPMCP.
• the coating may be carried out also in a conventional drum coating apparatus.
• Inlet air temperature 50 - 70 °C
• Nozzle diameter 0.8 mm
• Coating layer weight 8 - 10 % by weight
• the spraying is executed until achieving the target weight gain of the drug form corresponding to the desired weight of the coating layer.
• the spraying is carried out using 20% (by weight) aqueous dispersion of Eudragit L or 10% (by weight) aqueous dispersion of HPMCP.
• the coating may be carried out also in a conventional drum coating apparatus.
• the spraying is executed until achieving the target weight gain of the granulate corresponding to the desired weight of the coating layer.
• the spraying is carried out using 15% (by weight) aqueous dispersion of ethyl cellulose (Surrelease).
• plastified 20% (by weight) laquer dispersion of Eudragit RS or RP, or mixture thereof in a suitable ratio may be used.
• the coating may be carried out also in a conventional drum coating apparatus.
• the spraying is carried out using 15% (by weight) aqueous dispersion of ethyl cellulose (Surrelease).
• plastified 20% (by weight) aqueous dispersion of Eudragit RS or RP, or mixture thereof in a suitable ratio may be used.
• the coating may be carried out also in a conventional drum coating apparatus.
• Granulates and tablets prepared according to Examples 21 and 22 may be filled into hard gelatin capsules adapted for release in the intestine.
• Granulates coated with a layer for controlled release, prepared according to Example 21, may be further coated with a layer for enteric release according to Example 19.
• Tablets coated with a layer for controlled release, prepared according to Example 22, may be further coated with a layer for enteric release according to Example 20.
• the amount of the active substance released is given in % by weight

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• 2004
  • 2004-02-12 CZ CZ2004235A patent/CZ295584B6/cs not_active IP Right Cessation
• 2005
  • 2005-02-10 WO PCT/CZ2005/000016 patent/WO2005077357A1/en active Application Filing

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