CA2259212A1 - Ephedrine in granular form with a high active substance content - Google Patents
Ephedrine in granular form with a high active substance content Download PDFInfo
- Publication number
- CA2259212A1 CA2259212A1 CA 2259212 CA2259212A CA2259212A1 CA 2259212 A1 CA2259212 A1 CA 2259212A1 CA 2259212 CA2259212 CA 2259212 CA 2259212 A CA2259212 A CA 2259212A CA 2259212 A1 CA2259212 A1 CA 2259212A1
- Authority
- CA
- Canada
- Prior art keywords
- ephedrine
- active substance
- pseudoephedrine
- hydrochloride
- granules
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 title claims abstract description 76
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229960002179 ephedrine Drugs 0.000 title claims abstract description 36
- 239000013543 active substance Substances 0.000 title claims abstract description 17
- 239000008187 granular material Substances 0.000 claims description 12
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 claims description 11
- 229960003908 pseudoephedrine Drugs 0.000 claims description 7
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical group CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 7
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 229960004842 ephedrine sulfate Drugs 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- CAVQBDOACNULDN-NRCOEFLKSA-N (1s,2s)-2-(methylamino)-1-phenylpropan-1-ol;sulfuric acid Chemical compound OS(O)(=O)=O.CN[C@@H](C)[C@@H](O)C1=CC=CC=C1.CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 CAVQBDOACNULDN-NRCOEFLKSA-N 0.000 claims description 4
- BALXUFOVQVENIU-GHXDPTCOSA-N hydron;(1s,2r)-2-(methylamino)-1-phenylpropan-1-ol;chloride Chemical compound Cl.CN[C@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-GHXDPTCOSA-N 0.000 claims description 4
- BALXUFOVQVENIU-GNAZCLTHSA-N Ephedrine hydrochloride Chemical compound Cl.CN[C@@H](C)[C@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-GNAZCLTHSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- KWGRBVOPPLSCSI-SCZZXKLOSA-N (1r,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-SCZZXKLOSA-N 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims 1
- 239000007941 film coated tablet Substances 0.000 claims 1
- 239000007940 sugar coated tablet Substances 0.000 claims 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000654 additive Substances 0.000 description 7
- 239000011248 coating agent Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 235000019589 hardness Nutrition 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 150000001253 acrylic acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000005395 methacrylic acid group Chemical class 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- -1 sugars Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K9/1635—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
- A61K9/14—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
- 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
- A61K9/1658—Proteins, e.g. albumin, gelatin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention concerns ephedrine in granular form with an active substance content of between 85 and 99.5 %.
Description
l)4~0/()1162 CA 022~9212 1999-01-0~
" EPHEDRINE IN GRANULA~ M WITE~ A HIGH ACTIVE SUBSTANCE CCNTEI'~T"
Ephedrine is a known active substance for drugs. On oral dosage 5 it is, as a rule, used as base, hydrochloride, sulfate or phosphate and administered in 3 to 4 individual doses each comprising about up to 60 mg of active substance. Higher doses of ephedrine are present in slow-release forms.
lO The tableting properties of ephedrine and its salts are not good because compression thereof does not produce items of sufficient hardness. It is not possible to alter this unfavorable property of ephedrine by varying the particle sizes. In order to obtain ephedrine tablets of sufficient hardness to withstand further 15 manipulation in mechanical packaging or coating with a film coating layer it is necessary to incorporate relatively large amounts of other pharmaceutical ancillary substances into the relevant tablet formulas. This means that oral ~mi ni stration forms of ephedrine can contain not more than about 30-50 % of 20 active substance (not more than 30 % in the case of direct tableting), ie. a tablet cont~i n ing 60 mg of active substance weighs about 200 mg. The large content of ancillary substances makes the tablets costly and more di~ficult to swallow than corresponding smaller tablets.
The invention relates to ephedrine granules with an active substance content of from 85 to 99.5 %.
The ephedrine is present in the granules in the form of the base 30 or of a salt with a physiologically tolerated acid. Examples of suitable and preferred physiologically tolerated acids are phosphoric acid and, in particular, hydrochloric acid and sulfuric acid.
35 Suitable as ephedrine are anhydrous (+)-ephedrine, nonanhydrous (+)-ephedrine, (+)-ephedrine hydrochloride, (+)-ephedrine sulfate, anhydrous DL-ephedrine, nonanhydrous DL-ephedrine, DL-ephedrine hydrochloride, anhydrous (-)-ephedrine, nonanhydrous (-)-ephedrine, (-)-ephedrine hydrochloride, (-)-ephedrine sulfate 40 or (-)-ephedrine phosphate, and (+)-pseudoephedrine, (+)-pseudoephedrine hydrochloride, (+)-pseudoephedrine sulfate or (+)-pseudoephedrine phosphate or (-)-pseudoephedrine.
Particularly suitable as ephedrine are (-)-ephedrine and 45 (+)-pseudoephedrine and their salts with pharmacologically suitable acids.
.
0480/01162 CA 022~9212 1999-01-0 '~ 2 The ephedrine granules according to the invention can be produced by coating the ephedrine with a pharmaceutical ancillary substance for coating pharmaceutical active substances.
5 Suitable for this purpose are the known ancillary substances such as polysaccharides, for example cellulose derivatives, starch or starch derivatives, preferably corn starch or derivatives thereof; low molecular weight saccharides such as sugars, for example glucose or sucrose; polypeptide degradation products such 10 as gelatin; and synthetic products such as polyvinylpyrrolidones, copolymers of vinylpyrrolidone and vinyl acetate or polyacrylates, or copolymers of acrylic acids and methacrylic acids.
15 Particularly suitable ancillary substances are: hydroxymethyl-propylcellulose, especially products with a viscosity of 2 -8 cps in aqueous solution, polyvinylpyrrolidone (in particular Kollidon~ K 25, Kollidon~ K 30 and Kollidon~ K 9o)~ copolymers of vinylpyrrolidone and vinyl acetate (preferably Kollidon~ VA 64), 20 carboxymethylcellulose, carboxymethylstarch and gelatin.
The ephedrine content in the granules can be adjusted in [sic]
virtually as desired. It is, as a rule, from 85 to 99.5 %, preferably 90 to 99 %.
The ephedrine can be coated with the ancillary substance in a conventional way, for example in a fluidized bed, in conventional wet mixes or other mixes.
30 The substances employed for coating the ephedrine or the ephedrine salts must be applied to the ephedrine in the form of a suspension, solution or melt.
The treatment according to the invention of the ephedrine makes 35 it possible to compress the ephedrine directly to finished tablets in a direct tableting process together with a small amount of other pharmaceutical ancillary substances without the need to interpolate an elaborate granulation step. The novel process furthermore makes it possible for the first time to 40 produce ephdrine-containing [sicl tablets with an active substance content exceeding 80 %.
The following examples illustrate the invention.
45 A. Production of coated ephedrines:
, - - 0480/01162 CA 022~92l2 l999-Ol-0 Example 1 1 kg of (+)-pseudoephedrine hydrochloride was introduced into a fluidized bed granulator with Wurster insert and coated with 50 g 5 of hydroxypropylcellulose which had been melted at 180 C in the fluidized bed at an inlet air temperature of 80 C. After cooling, the powder was forced through a screen with a mesh width of 1 mm.
Example 2 1 kg of (+)-pseudoephedrine sulfate was intimately mixed in a wet mixer with a solution of 20 mg of polyvinylpyrrolidone (type K
30) in 300 ml of water. After removal of the water, the residue was forced through a screen with a mesh width of 0.9 mm.
Example 3 1 kg of (+)-pseudoephedrine hydrochloride was vigorously mixed in a wet mixer with a suspension of 80 g of corn starch in 400 ml of 20 water at 70 C. After drying, the residue was forced through a screen with a mesh width of 0.9 mm.
Example 4 25 A mixture of 1 kg of (+)-pseudoephedrine sulfate and 60 g of hydroxypropylmethylcellulose in a mixer was treated with water in portions and vigorously mixed until the composition resembled damp soil. The moist composition was dried and forced through a screen with a mesh width of 0.8 mm.
Example 5 2 kg of (-)-ephedrine sulfate crystals (particle size 95 % 0.5 mm, 98 % 1.2 mm) were introduced into a coating pan and sprayed 35 with a solution of 80 g of hydroxypropylmethylcellulose (3 cps) in 1 kg of ethanol. The coated crystals were dried in a rotating pan with circulating air at 80 C. They were subsequently freed of coarse material using a screen with a mesh width of 2.0 mm.
40 B. Use examples Example a 63.15 g of pseudoephedrine hydrochloride coated with 45 hydroxypropylmethylcellulose (viscosity in a 1 % strength aqueous solution: 3cp) ((+)-pseudoephedrine hydrochloride content: 95 %) were mixed with 26.25 g of lactose, 5.0 g of ~ollidon~
- 0480/01162 CA 022~92l2 l999-Ol-0~
, (polyvinylpyrrolidone K 30), 5.0 g of Kollidon~ CL (crosslinked, insoluble polyvinylpyrrolidone) and 0.6 g of magnesium stearate, and compressed in an eccentric press to tablets with a weight of 100 mg and a diameter of 6 mm. The pressure was 7.4 kN and the 5 resulting tablet hardness was 58.6 N. Active substance release in vitro was 91.7 % after 20 min.
Example b lO 63.2 g of (+)-pseudoephedrine hydrochloride coated with Kollidon~ K 30 (pseudoephedrine hydrochloride content: 95 %) were mixed with 10.4 g of microcrystalline cellulose, 6.0 g of Kollidon~ CL and 0.4 g of magnesium stearate, and compressed in an eccentric press to tablets with a diameter of 6 mm and a 15 weight of 80 mg (active substance content 75 %). The pressure was 4.5 kN. The resulting tablets showed an active substance release of 95.1 % after 20 min.
Example c 510 g of (-)-ephedrine hydrochloride coated with gelatin (pseudoephedrine [sic] hydrochloride content: 94 %) were mixed with lO g of very finely ground lactose, 5 g of magnesium stearate and 5 g of Aerosil~ 200, and compressed to tablets with 25 a weight of 265 mg and a diameter of 9 mm. The tablet hardness achieved with a pressure of 8.4 kN was 54 N. The cores obtained in this way were subsequently processed to slow-release tablets by coating with ethylcellulose.
30 Comparative example The superiority of the granules coated according to the invention is evident when only a mixture of Kollidon~ K 30 and uncoated pseudoephedrine hydrochloride is employed in Example B,b in place 35 of pseudoephedrine hydrochloride coated with Kollidon~ K 30:
60 g of (+)-pseudoephedrine hydrochloride were mixed with microcrystalline cellulose (119 g of Avicel~ PH 200), 9 g of Kollidon~ K 30, 11 mg of crosslinked PVP (Kollidon~ CL) and 1 g 40 of magnesium stearate, and compressed to tablets weighing 200 mg (active substance content 30 %). The tablet hardnesses obtained under a pressure of 3-4 kN were 70-72 N.
If the active substance content is increased to more than 35 % it 45 is no longer possible to obtain tablets of sufficient hardness (> 25 N) despite extremely high pressure, although the formula of 0480/01162 CA 02259212 1sss-01-05 .~ 5 this comparative example substantially corresponds to the formula of Example B b.
" EPHEDRINE IN GRANULA~ M WITE~ A HIGH ACTIVE SUBSTANCE CCNTEI'~T"
Ephedrine is a known active substance for drugs. On oral dosage 5 it is, as a rule, used as base, hydrochloride, sulfate or phosphate and administered in 3 to 4 individual doses each comprising about up to 60 mg of active substance. Higher doses of ephedrine are present in slow-release forms.
lO The tableting properties of ephedrine and its salts are not good because compression thereof does not produce items of sufficient hardness. It is not possible to alter this unfavorable property of ephedrine by varying the particle sizes. In order to obtain ephedrine tablets of sufficient hardness to withstand further 15 manipulation in mechanical packaging or coating with a film coating layer it is necessary to incorporate relatively large amounts of other pharmaceutical ancillary substances into the relevant tablet formulas. This means that oral ~mi ni stration forms of ephedrine can contain not more than about 30-50 % of 20 active substance (not more than 30 % in the case of direct tableting), ie. a tablet cont~i n ing 60 mg of active substance weighs about 200 mg. The large content of ancillary substances makes the tablets costly and more di~ficult to swallow than corresponding smaller tablets.
The invention relates to ephedrine granules with an active substance content of from 85 to 99.5 %.
The ephedrine is present in the granules in the form of the base 30 or of a salt with a physiologically tolerated acid. Examples of suitable and preferred physiologically tolerated acids are phosphoric acid and, in particular, hydrochloric acid and sulfuric acid.
35 Suitable as ephedrine are anhydrous (+)-ephedrine, nonanhydrous (+)-ephedrine, (+)-ephedrine hydrochloride, (+)-ephedrine sulfate, anhydrous DL-ephedrine, nonanhydrous DL-ephedrine, DL-ephedrine hydrochloride, anhydrous (-)-ephedrine, nonanhydrous (-)-ephedrine, (-)-ephedrine hydrochloride, (-)-ephedrine sulfate 40 or (-)-ephedrine phosphate, and (+)-pseudoephedrine, (+)-pseudoephedrine hydrochloride, (+)-pseudoephedrine sulfate or (+)-pseudoephedrine phosphate or (-)-pseudoephedrine.
Particularly suitable as ephedrine are (-)-ephedrine and 45 (+)-pseudoephedrine and their salts with pharmacologically suitable acids.
.
0480/01162 CA 022~9212 1999-01-0 '~ 2 The ephedrine granules according to the invention can be produced by coating the ephedrine with a pharmaceutical ancillary substance for coating pharmaceutical active substances.
5 Suitable for this purpose are the known ancillary substances such as polysaccharides, for example cellulose derivatives, starch or starch derivatives, preferably corn starch or derivatives thereof; low molecular weight saccharides such as sugars, for example glucose or sucrose; polypeptide degradation products such 10 as gelatin; and synthetic products such as polyvinylpyrrolidones, copolymers of vinylpyrrolidone and vinyl acetate or polyacrylates, or copolymers of acrylic acids and methacrylic acids.
15 Particularly suitable ancillary substances are: hydroxymethyl-propylcellulose, especially products with a viscosity of 2 -8 cps in aqueous solution, polyvinylpyrrolidone (in particular Kollidon~ K 25, Kollidon~ K 30 and Kollidon~ K 9o)~ copolymers of vinylpyrrolidone and vinyl acetate (preferably Kollidon~ VA 64), 20 carboxymethylcellulose, carboxymethylstarch and gelatin.
The ephedrine content in the granules can be adjusted in [sic]
virtually as desired. It is, as a rule, from 85 to 99.5 %, preferably 90 to 99 %.
The ephedrine can be coated with the ancillary substance in a conventional way, for example in a fluidized bed, in conventional wet mixes or other mixes.
30 The substances employed for coating the ephedrine or the ephedrine salts must be applied to the ephedrine in the form of a suspension, solution or melt.
The treatment according to the invention of the ephedrine makes 35 it possible to compress the ephedrine directly to finished tablets in a direct tableting process together with a small amount of other pharmaceutical ancillary substances without the need to interpolate an elaborate granulation step. The novel process furthermore makes it possible for the first time to 40 produce ephdrine-containing [sicl tablets with an active substance content exceeding 80 %.
The following examples illustrate the invention.
45 A. Production of coated ephedrines:
, - - 0480/01162 CA 022~92l2 l999-Ol-0 Example 1 1 kg of (+)-pseudoephedrine hydrochloride was introduced into a fluidized bed granulator with Wurster insert and coated with 50 g 5 of hydroxypropylcellulose which had been melted at 180 C in the fluidized bed at an inlet air temperature of 80 C. After cooling, the powder was forced through a screen with a mesh width of 1 mm.
Example 2 1 kg of (+)-pseudoephedrine sulfate was intimately mixed in a wet mixer with a solution of 20 mg of polyvinylpyrrolidone (type K
30) in 300 ml of water. After removal of the water, the residue was forced through a screen with a mesh width of 0.9 mm.
Example 3 1 kg of (+)-pseudoephedrine hydrochloride was vigorously mixed in a wet mixer with a suspension of 80 g of corn starch in 400 ml of 20 water at 70 C. After drying, the residue was forced through a screen with a mesh width of 0.9 mm.
Example 4 25 A mixture of 1 kg of (+)-pseudoephedrine sulfate and 60 g of hydroxypropylmethylcellulose in a mixer was treated with water in portions and vigorously mixed until the composition resembled damp soil. The moist composition was dried and forced through a screen with a mesh width of 0.8 mm.
Example 5 2 kg of (-)-ephedrine sulfate crystals (particle size 95 % 0.5 mm, 98 % 1.2 mm) were introduced into a coating pan and sprayed 35 with a solution of 80 g of hydroxypropylmethylcellulose (3 cps) in 1 kg of ethanol. The coated crystals were dried in a rotating pan with circulating air at 80 C. They were subsequently freed of coarse material using a screen with a mesh width of 2.0 mm.
40 B. Use examples Example a 63.15 g of pseudoephedrine hydrochloride coated with 45 hydroxypropylmethylcellulose (viscosity in a 1 % strength aqueous solution: 3cp) ((+)-pseudoephedrine hydrochloride content: 95 %) were mixed with 26.25 g of lactose, 5.0 g of ~ollidon~
- 0480/01162 CA 022~92l2 l999-Ol-0~
, (polyvinylpyrrolidone K 30), 5.0 g of Kollidon~ CL (crosslinked, insoluble polyvinylpyrrolidone) and 0.6 g of magnesium stearate, and compressed in an eccentric press to tablets with a weight of 100 mg and a diameter of 6 mm. The pressure was 7.4 kN and the 5 resulting tablet hardness was 58.6 N. Active substance release in vitro was 91.7 % after 20 min.
Example b lO 63.2 g of (+)-pseudoephedrine hydrochloride coated with Kollidon~ K 30 (pseudoephedrine hydrochloride content: 95 %) were mixed with 10.4 g of microcrystalline cellulose, 6.0 g of Kollidon~ CL and 0.4 g of magnesium stearate, and compressed in an eccentric press to tablets with a diameter of 6 mm and a 15 weight of 80 mg (active substance content 75 %). The pressure was 4.5 kN. The resulting tablets showed an active substance release of 95.1 % after 20 min.
Example c 510 g of (-)-ephedrine hydrochloride coated with gelatin (pseudoephedrine [sic] hydrochloride content: 94 %) were mixed with lO g of very finely ground lactose, 5 g of magnesium stearate and 5 g of Aerosil~ 200, and compressed to tablets with 25 a weight of 265 mg and a diameter of 9 mm. The tablet hardness achieved with a pressure of 8.4 kN was 54 N. The cores obtained in this way were subsequently processed to slow-release tablets by coating with ethylcellulose.
30 Comparative example The superiority of the granules coated according to the invention is evident when only a mixture of Kollidon~ K 30 and uncoated pseudoephedrine hydrochloride is employed in Example B,b in place 35 of pseudoephedrine hydrochloride coated with Kollidon~ K 30:
60 g of (+)-pseudoephedrine hydrochloride were mixed with microcrystalline cellulose (119 g of Avicel~ PH 200), 9 g of Kollidon~ K 30, 11 mg of crosslinked PVP (Kollidon~ CL) and 1 g 40 of magnesium stearate, and compressed to tablets weighing 200 mg (active substance content 30 %). The tablet hardnesses obtained under a pressure of 3-4 kN were 70-72 N.
If the active substance content is increased to more than 35 % it 45 is no longer possible to obtain tablets of sufficient hardness (> 25 N) despite extremely high pressure, although the formula of 0480/01162 CA 02259212 1sss-01-05 .~ 5 this comparative example substantially corresponds to the formula of Example B b.
Claims (7)
1. Ephedrine granules with an active substance content of from 85 to 99.5 %.
2. Ephedrine granules with an active substance content of from 94 to 99.5 %.
3. Ephedrine granules as claimed in claim 1, wherein the ephedrine is anhydrous (+)-ephedrine, nonanhydrous (+)-ephedrine, (+)-ephedrine hydrochloride, (+)-ephedrine sulfate, anhydrous DL-ephedrine, nonanhydrous DL-ephedrine, DL-ephedrine hydrochloride, anhydrous (-)-ephedrine, nonanhydrous (-)-ephedrine, (-)-ephedrine hydrochloride, (-)-ephedrine sulfate or (-)-ephedrine phosphate.
4. Ephedrine granules as claimed in claim 1, wherein the ephedrine is (-)-ephedrine or its hydrochloride or sulfate.
5. Ephedrine granules as claimed in claim 1, wherein the ephedrine is (+)-pseudoephedrine, (+)-pseudoephedrine hydrochloride, (+)-pseudoephedrine sulfate or (+)-pseudoephedrine phosphate or (-)-pseudoephedrine.
6. Ephedrine granules as claimed in claim 1, wherein the ephedrine is (+)-pseudoephedrine or its hydrochloride or sulfate.
7. The use of ephedrine granules as claimed in any of claims 1-6 for producing uncoated, film- or sugar-coated tablets.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19629032.5 | 1996-07-18 | ||
| DE1996129032 DE19629032A1 (en) | 1996-07-18 | 1996-07-18 | Ephedrine granules with a high active ingredient content |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2259212A1 true CA2259212A1 (en) | 1998-01-29 |
Family
ID=7800199
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2259212 Abandoned CA2259212A1 (en) | 1996-07-18 | 1997-07-08 | Ephedrine in granular form with a high active substance content |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0912168A2 (en) |
| AU (1) | AU4009797A (en) |
| BR (1) | BR9710469A (en) |
| CA (1) | CA2259212A1 (en) |
| DE (1) | DE19629032A1 (en) |
| WO (1) | WO1998003158A2 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2063141C (en) * | 1989-08-04 | 1997-03-04 | Edward J. Roche | Rotogranulations and taste masking coatings for preparation of chewable pharmaceutical tablets |
| DE4231493A1 (en) * | 1992-09-21 | 1994-03-24 | Nordmark Arzneimittel Gmbh | Process for the production of pellets from an ephedrine derivative |
| US5683720A (en) * | 1994-10-28 | 1997-11-04 | Fuisz Technologies Ltd. | Liquiflash particles and method of making same |
-
1996
- 1996-07-18 DE DE1996129032 patent/DE19629032A1/en not_active Withdrawn
-
1997
- 1997-07-08 WO PCT/EP1997/003598 patent/WO1998003158A2/en not_active Application Discontinuation
- 1997-07-08 BR BR9710469A patent/BR9710469A/en not_active IP Right Cessation
- 1997-07-08 EP EP97937468A patent/EP0912168A2/en not_active Withdrawn
- 1997-07-08 AU AU40097/97A patent/AU4009797A/en not_active Abandoned
- 1997-07-08 CA CA 2259212 patent/CA2259212A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| BR9710469A (en) | 1999-08-17 |
| WO1998003158A2 (en) | 1998-01-29 |
| AU4009797A (en) | 1998-02-10 |
| EP0912168A2 (en) | 1999-05-06 |
| DE19629032A1 (en) | 1998-01-22 |
| WO1998003158A3 (en) | 1998-03-05 |
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| EEER | Examination request | ||
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