DE19857716A1 - New solid formulation of Metrifonat - Google Patents
New solid formulation of MetrifonatInfo
- Publication number
- DE19857716A1 DE19857716A1 DE19857716A DE19857716A DE19857716A1 DE 19857716 A1 DE19857716 A1 DE 19857716A1 DE 19857716 A DE19857716 A DE 19857716A DE 19857716 A DE19857716 A DE 19857716A DE 19857716 A1 DE19857716 A1 DE 19857716A1
- Authority
- DE
- Germany
- Prior art keywords
- pharmaceutical formulation
- solid pharmaceutical
- formulation according
- metrifonat
- tablet
- 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.)
- Withdrawn
Links
- 239000007787 solid Substances 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 title claims description 18
- 238000009472 formulation Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229960001952 metrifonate Drugs 0.000 claims abstract description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 17
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 17
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 6
- 235000010980 cellulose Nutrition 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 5
- 239000001913 cellulose Substances 0.000 claims description 5
- 239000000337 buffer salt Substances 0.000 claims description 3
- 210000003169 central nervous system Anatomy 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000013583 drug formulation Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 239000003826 tablet Substances 0.000 description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 7
- 239000001768 carboxy methyl cellulose Substances 0.000 description 7
- OEBRKCOSUFCWJD-UHFFFAOYSA-N dichlorvos Chemical compound COP(=O)(OC)OC=C(Cl)Cl OEBRKCOSUFCWJD-UHFFFAOYSA-N 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 7
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- 239000000843 powder Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 208000000044 Amnesia Diseases 0.000 description 2
- 208000031091 Amnestic disease Diseases 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 206010041235 Snoring Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000006986 amnesia Effects 0.000 description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 201000002859 sleep apnea Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- -1 2,2-dichlorovinyl Chemical group 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 102000003914 Cholinesterases Human genes 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000257159 Musca domestica Species 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- PRKQVKDSMLBJBJ-UHFFFAOYSA-N ammonium carbonate Chemical class N.N.OC(O)=O PRKQVKDSMLBJBJ-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000011162 ammonium carbonates Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 229940048961 cholinesterase Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002635 electroconvulsive therapy Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 244000243234 giant cane Species 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000011177 media preparation Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- 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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die vorliegende Erfindung betrifft neue feste Zubereitungen von Metrifonat, die eine hohe Stabilität und gleichzeitig verbesserte Tablettier- bzw. Tabletteneigenschaften besitzen, sowie Verfahren zu deren Herstellung und Verwendung.The present invention relates to new solid preparations of metrifonate which have a high stability and at the same time improved tablet or tablet properties and processes for their manufacture and use.
Metrifonat (auch als Dipterex bekannt) eignet sich u. a. zur Behandlung von Erkran kungen des zentralen Nervensystems wie z. B. Alzheimersche Krankheit, Schizo phrenie, Depression, Dyskinesia tarditiva, Amnesie nach Elektrokonvulsionstherapie, Schnarchen oder Schlafapnoe. Darüber hinaus wird die Substanz seit längerem bei der Behandlung der Bilharziose eingesetzt.Metrifonat (also known as Dipterex) is suitable, among other things. for the treatment of disease effects of the central nervous system such as B. Alzheimer's Disease, Schizo phrenia, depression, dyskinesia tarditiva, amnesia after electroconvulsive therapy, Snoring or sleep apnea. In addition, the substance has been around for a long time used in the treatment of schistosomiasis.
So beschreibt die US-4,950,658 eine in vivo-Studie, in welcher Metrifonat als Precursor-Substanz zur Behandlung der Alzheimerschen Krankheit eingesetzt wird. Eine Aussage über die Zusammensetzung der durch Injektion und oral verabreichten Formulierungen ist dieser Schrift nicht zu entnehmen.For example, US Pat. No. 4,950,658 describes an in vivo study in which Metrifonat is used as Precursor substance used to treat Alzheimer's disease. A statement about the composition of those administered by injection and orally No formulations can be found in this document.
Auch die WO 96/38155 nennt Metrifonat als Precursor bei der Therapie von Erkrankungen des zentralen Nervensystems.WO 96/38155 also mentions metriphonate as a precursor in the therapy of Central nervous system disorders.
Die Anwendung von Metrifonat und einer Vielzahl weiterer Cholinesterasehemmer bei Schlafstörungen ist in der WO 97/22339 beschrieben.The use of Metrifonate and a variety of other cholinesterase inhibitors in sleep disorders is described in WO 97/22339.
Die US-3,111,457 offenbart die orale Verabreichung von Metrifonat an durch innere Parasiten befallene Tiere, insbesondere Pferde. Es wurde gefunden, daß ein Zusatz von etwa bis zu 30 Gew.-% Aluminiumhydroxid zum oral verabreichen Wirkstoff eine retardierende Wirkung hervorruft und der Wirkstoff dadurch geringere Toxizität entfaltet.US-3,111,457 discloses the oral administration of metrifonate to through internal Parasitic animals, especially horses. It was found that an additive from about up to 30% by weight aluminum hydroxide to the orally administered active ingredient causes a retarding effect and the active ingredient is therefore less toxic unfolds.
Es ist bekannt, daß sich Metrifonat abhängig von Feuchtigkeit, pH-Wert und/oder Temperatur zu DDVP [Dimethyl-(2,2-dichlorvinyl)phosphat] umlagert. It is known that Metrifonat depends on moisture, pH and / or Temperature rearranged to DDVP [dimethyl (2,2-dichlorovinyl) phosphate].
In der Z. Naturforschg. B 12 (1957) S. 196 ff. wurde im Rahmen der Untersuchung insektizid wirkender Phosphorsäureester der Zerfall von Metrifonat zu DDVP in Abhängigkeit vom pH-Wert beschrieben. Es wurde gefunden, daß ein derartiger Zerfall nur im pH-Wertbereich von pH 1 bis 5 vermieden werden kann.In the Z. Naturforschg. B 12 (1957) p. 196 ff. Was part of the investigation insecticidal phosphoric acid ester the disintegration of metrifonate to DDVP in Described as a function of the pH value. It has been found that such Decomposition can only be avoided in the pH range from pH 1 to 5.
1959 beschrieben hierzu Metcalfund Fukuto im J. Economic Entomology 52(1) (1959) S. 44 ff. den Zusammenhang der Umsetzung von Metrifonat zu DDVP und der in vitro-Hemmung der Cholinesterase am Modell der Stubenfliege.In 1959, Metcalfund Fukuto described this in J. Economic Entomology 52 (1) (1959) p. 44 ff. The connection between the implementation of Metrifonat to DDVP and the in vitro inhibition of cholinesterase in the housefly model.
Die Deutsche Offenlegungsschrift 25 43 975 beschreibt feste Metrifonat-Zuberei tungen mit einem Celluloseanteil von 22 bis 25 Gew.-%. Diese festen Zubereitungen sind nur dann stabil gegen Umlagerung oder andersartige Zersetzung, wenn den pH- Wert erhöhende Puffersubstanzen wie Calciumhydrogenphosphat oder Dinatriumhy drogenphosphat zugegeben werden, so daß eine aus dieser Zubereitung generierte wäßrige Dispersion einen pH-Wert von 6,5-7,5 hat. Der Wassergehalt dieser festen Zubereitung darf jedoch aus Stabilitätsgründen 2,5 Gew.-% nicht überschreiten.The German Offenlegungsschrift 25 43 975 describes solid Metrifonat-Zuberei with a cellulose content of 22 to 25% by weight. These solid preparations are only stable against rearrangement or other types of decomposition if the pH Value-increasing buffer substances such as calcium hydrogen phosphate or disodium hy drug phosphate are added, so that one generated from this preparation aqueous dispersion has a pH of 6.5-7.5. The water content of this solid However, for reasons of stability, the preparation must not exceed 2.5% by weight.
Eine mikrokristalline Cellulose enthaltende, gegen rheumatische Erkrankungen wir kende Zusammensetzung des strukturell nicht mit Metrifonat verwandten Acetyl cholinesterasehemmers Galantamin, ist in der WO 97/29750 offenbart.A microcrystalline cellulose containing, against rheumatic diseases we kend composition of acetyl, which is structurally unrelated to metriphonate cholinesterase inhibitor galantamine is disclosed in WO 97/29750.
Bekanntermaßen enthält mikrokristalline Cellulose bis zu 6 Gew.-% Wasser und besitzt einen pH-Wert von minimal pH 5 (Angaben und Methode nach "Europäisches Arzneibuch", Amtliche deutsche Ausgabe; 3. Ausgabe, Deutscher Apotheker Verlag, Stuttgart, 1997; S. 665-666).It is known that microcrystalline cellulose contains up to 6% by weight of water and has a pH value of at least pH 5 (information and method according to "European Pharmacopoeia ", official German edition; 3rd edition, Deutscher Apotheker Verlag, Stuttgart, 1997; Pp. 665-666).
Überraschenderweise wurde nun gefunden, daß die Stabilität von Metrifonat in festen Arzneimittelzubereitungen gleichbleibt, auch wenn der Anteil an mikrokristalliner Cellulose auf über 50 Gew.-% bezogen auf das Gesamtgewicht der Zubereitung erhöht wird. Damit steigt der Wassergehalt in der festen Arzneizubereitung auf Werte von größer als 2,5 Gew.-% und der pH-Wert kann unter die im Stand der Technik beschriebene Grenze von pH 6,5 fallen.Surprisingly, it has now been found that the stability of Metrifonat in solid Medicinal preparations remains the same, even if the proportion of microcrystalline Cellulose to over 50% by weight based on the total weight of the preparation is increased. This increases the water content in the solid medicinal preparation to values of greater than 2.5% by weight and the pH can be below that in the prior art described limit of pH 6.5 fall.
Durch die Erhöhung des Anteils an mikrokristalliner Cellulose werden aber die Stoff- und Formuliereigenschaften deutlich verbessert.By increasing the proportion of microcrystalline cellulose, however, the material and formulation properties significantly improved.
Erfindungsgemäße Stoffeigenschaften von Metrifonat enthaltenden, festen Arznei mittelzubereitungen sind beispielsweise Tabletteneigenschaften wie Bruchfestigkeit, Härte und mechanische Festigkeit von Tabletten, wie z. B. Abrieb.Substance properties according to the invention of solid medicament containing metriphonate Medium preparations are, for example, tablet properties such as breaking strength, Hardness and mechanical strength of tablets, e.g. B. Abrasion.
Erfindungsgemäße Formuliereigenschaften sind beispielsweise die Fließfähigkeit von Pulvern, aus denen z. B. Tabletten gepreßt werden können.Formulation properties according to the invention are, for example, flowability of powders from which z. B. tablets can be pressed.
Unter Stabilität des Wirkstoffs wird die Stabilität von Metrifonat in der festen Arzneimittelzubereitung insbesondere gegen Umlagerung zu DDVP verstanden.Under stability of the active ingredient is the stability of Metrifonat in the solid Medicinal preparation understood in particular against rearrangement to DDVP.
Eine erfindungsgemäße Arzneimittelzubereitung soll beispielsweise dann als stabil angesehen werden, wenn unter Standardlagerungsbedingungen (z. B. 25°C, 60% relative Luftfeuchte, 3 Jahre, verpackt in Glasflaschen) der Metrifonatgehalt dieser Arzneimittelzubereitung nicht unter 92,5 Gew.-% des Ausgangsgehaltes sinkt und der DDVP-Gehalt nicht höher als auf 0,3 Gew.-% bezogen auf den deklarierten Metrifonatgehalt in der Arzneimittelzubereitung steigt.A pharmaceutical preparation according to the invention should then be stable, for example be considered if under standard storage conditions (e.g. 25 ° C, 60% relative humidity, 3 years, packed in glass bottles) the metriphonate content of this Drug preparation does not fall below 92.5% by weight of the initial content and the DDVP content is not higher than 0.3% by weight based on the declared Metrifonate content in drug preparation increases.
Feste Arzneimittelformulierungen im Sinne der Erfindung sind Tabletten, Kapseln, Dragees, Pulver und Granulate, bevorzugt Tabletten.Solid pharmaceutical formulations within the meaning of the invention are tablets, capsules, Dragees, powders and granules, preferably tablets.
Diese festen Arzneimittelformulierungen können in bekannter Weise hergestellt werden, unter Verwendung weiterer inerter, nicht-toxischer, pharmazeutisch geeig neter Zuschlagstoffe, wie z. B. Cellulosederivate (z. B. Methylcellulose), Stärke, Polyvinylpyrrolidon, synthetische Gesteinsmehle (z. B. hochdisperse Kieselsäure, Sililsate); Zucker (z. B. Rohr-, Milch- und Traubenzucker), Zuckeralkohole (z. B. Mannitol, Sorbitol, Xylitol), Sprengmittel (z. B. Natriumcarboxymethylcellulose, quervernetztes Polyvinylpyrrolidon), Schmiermittel (z. B. Magnesiumstearat, Tal kum, Stearinsäure), Aromen, Farbstoffe und Geschmackskorrigenzien.These solid pharmaceutical formulations can be prepared in a known manner are, using other inert, non-toxic, pharmaceutically suitable neter aggregates, such as. B. cellulose derivatives (e.g. methyl cellulose), starch, Polyvinylpyrrolidone, synthetic rock powder (e.g. highly dispersed silica, Sililsate); Sugar (e.g. cane, milk and grape sugar), sugar alcohols (e.g. Mannitol, sorbitol, xylitol), disintegrants (e.g. sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone), lubricants (e.g. magnesium stearate, Tal kum, stearic acid), flavors, colors and taste corrections.
Bevorzugt sind erfindungsgemäße Arzneimittelformulierungen, deren Anteil an mikrokristalliner Cellulose zwischen 60 und 90 Gew.-% beträgt.Preferred pharmaceutical formulations according to the invention are those whose proportion of microcrystalline cellulose is between 60 and 90 wt .-%.
Der Gewichtsanteil von Metrifonat am Gesamtgewicht der Arzneimittelformulierung beträgt weniger als 50 Gew.-%, bevorzugt 7-38,5 Gew.-%.The proportion by weight of metriphonate in the total weight of the drug formulation is less than 50% by weight, preferably 7-38.5% by weight.
Der Gewichtsanteil der Zuschlagstoffe am Gesamtgewicht der Arzneimittelformu lierung beträgt 0 bis 5%, bevorzugt 1,5 bis 3%.The weight percentage of the additives in the total weight of the drug form lation is 0 to 5%, preferably 1.5 to 3%.
Besonders bevorzugt sind solche festen Arzneimittelformulierungen, die keine Puffersalze enthalten.Those solid medicament formulations which do not contain any are particularly preferred Contains buffer salts.
Puffersalze im Sinne der Erfindung sind beispielsweise Calciumhydrogenphosphat, Natriumdihydrogenphosphat, Dinatriumhydrogenphosphat, Kaliumdihydrogen phosphat oder Dikaliumhydrogenphosphat, Alkali- und Erdalkalicitrate und -acetate, Alkali-, Erdalkali- und Ammoniumcarbonate, oder Natrium- und Ammoniumchlorid.Buffer salts within the meaning of the invention are, for example, calcium hydrogen phosphate, Sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate or dipotassium hydrogen phosphate, alkali and alkaline earth citrates and acetates, Alkali, alkaline earth and ammonium carbonates, or sodium and ammonium chloride.
Die festen Arzneimittelformulierungen eignen sich zur Herstellung von Medika menten, die zur Behandlung von Erkrankungen des zentralen Nervensystems einge setzt werden können, wie z. B. der Alzheimerschen Krankheit, Schizophrenie, Depression, Dyskinesia tarditiva, Amnesie nach Elektrokonvulsionstherapie, Schnarchen oder Schlafapnoe.The solid pharmaceutical formulations are suitable for the production of medicaments ments used to treat diseases of the central nervous system can be set, such as B. Alzheimer's disease, schizophrenia, Depression, dyskinesia tarditiva, amnesia after electroconvulsion therapy, Snoring or sleep apnea.
Bevorzugt werden diese Medikamente zur Behandlung der Alzheimerschen Krank heit eingesetzt.These drugs are preferred for the treatment of Alzheimer's disease used.
Die erfindungsgemäßen festen Zubereitungen besitzen eine ausgezeichnete chemische Langzeitstabilität. The solid preparations according to the invention have excellent properties long-term chemical stability.
Nach 2 Jahren Lagerung einer festen Zubereitung der Zusammensetzung gemäß
Beispiel 1 unter standardisierten Klimabedingungen (siehe z. B. "The United States
Pharmacopeia, The National Formulary"; United States Pharmacopeial Convention,
Rockville, 1995; S. 1940-1941) ist der Wirkstoffgehalt praktisch unverändert. Das
Abbauprodukt DDVP bleibt über den gesamten Verlauf bei sehr niedrigen Werten
und erhöht sich nicht. Zur Verdeutlichung der Stabilität von Beispiel 1 dient folgende
Tabelle:
After 2 years of storage of a solid preparation of the composition according to Example 1 under standardized climatic conditions (see, for example, "The United States Pharmacopeia, The National Formulary"; United States Pharmacopeial Convention, Rockville, 1995; pp. 1940-1941) the active ingredient content is practically unchanged. The degradation product DDVP remains at very low values over the entire course and does not increase. The following table is used to illustrate the stability of Example 1:
Bei einer festen Zubereitung von Metrifonat gemäß Beispiel 4 sind nach 3 Jahren Lagerung bei 25°C, 60% rF noch 97,3% des Wirkstoffs unverändert wiederzufinden; der DDVP-Anteil beträgt 0,02%.In the case of a solid preparation of Metrifonat according to Example 4, after 3 years Storage at 25 ° C, 60% RH, 97.3% of the active ingredient can still be found unchanged; the DDVP share is 0.02%.
Besonders hervorzuheben sind jedoch auch die hervorragenden pharmazeutisch technologischen Eigenschaften der erfindungsgemäßen festen Formulierungen von Metrifonat. Particularly noteworthy, however, are the excellent pharmaceuticals technological properties of the solid formulations of the invention Metrifonat.
Verglichen mit den Metrifonat-Tablettenzubereitungen, die in der Deutschen Offen legungsschrift 25 43 975 beschrieben werden, ergeben sich beispielsweise 2- bis 3- mal größere Tablettenfestigkeiten (Angabe als "tensile strength") und Friabilitäten, die 1/10 und noch weniger betragen. Es zeigt sich sogar, daß die Anforderungen der USP XXIII zur Friabilität (≦ 1%; "The United States Pharmacopeia, The National Formulary"; United States Pharmacopeial Convention, Rockville, 1995; S. 1981) nur von den erfindungsgemäßen neuen Metrifonat-Formulierungen gehalten werden können.Compared with the Metrifonat tablet preparations used in the German Offen Legungsschrift 25 43 975 are described, there are for example 2- to 3- sometimes higher tablet strengths (indicated as "tensile strength") and friability, which are 1/10 and even less. It even shows that the requirements of the USP XXIII on friability (≦ 1%; "The United States Pharmacopeia, The National Formulary "; United States Pharmacopeial Convention, Rockville, 1995; S. 1981) only are held by the new metriphonate formulations according to the invention can.
Bevorzugt sind solche Tabletten, die eine Tablettenfestigkeit (tensile strength) von mehr als 4,0 N/mm2 aufweisen.Those tablets which have a tablet strength (tensile strength) of more than 4.0 N / mm 2 are preferred.
Tablettenfestigkeit (tensile strength) im Sinne der Erfindung wird beschrieben in J. Pharmaceut. Sci. 1970, 59, 688-91.Tablet strength (tensile strength) for the purposes of the invention is described in J. Pharmaceut. Sci. 1970, 59, 688-91.
Ebenso sind solche erfindungsgemäßen Tablettenformulierungen bevorzugt, deren Frialbilität weniger als 1%, vorzugsweise weniger als 0,5% beträgt.Such tablet formulations according to the invention are also preferred, their Frialbility is less than 1%, preferably less than 0.5%.
Frialbilität im Sinne der Erfindung kann nach der Methode bestimmt werden, die in "The United States Pharmacopeia, The National Formulary"; United States Pharma copeial Convention, Rockville, 1995; S. 1981 (USP XXIII) beschrieben wird.Frialbility within the meaning of the invention can be determined by the method described in "The United States Pharmacopeia, The National Formulary"; United States Pharma Cooperative Convention, Rockville, 1995; S. 1981 (USP XXIII).
Die folgende Tabelle zeigt Beispiele, in denen Tabletten mit einem Wirkstoffgehalt
von 50 mg und 100 mg verglichen werden. (Tablettierung mittels einer Standard-
Exzentertablettenpresse unter jeweils optimierten Bedingungen.)
The following table shows examples in which tablets with an active ingredient content of 50 mg and 100 mg are compared. (Tableting using a standard eccentric tablet press under optimized conditions in each case.)
Metrifonat wird gesiebt und in folgenden Mengen mit weiteren Hilfsstoffen gemischt:Metriphonate is sieved and added to the following quantities with other auxiliary materials mixed:
Die Mischung wird mittels Trockenkompaktierung (z. B. mit einem Walzenkompak tor) und anschließender Zerkleinerung (Sieb mit Maschenweite 1,0 mm) granuliert. Zu diesem Granulat werden weiterhin gegeben und gemischt:The mixture is compacted dry (e.g. with a roller compactor) tor) and subsequent comminution (sieve with a mesh size of 1.0 mm) granulated. To this granulate are further added and mixed:
Anschließend wird die Mischung zu Tabletten gepreßt, z. B. mit einem Gewicht von 333 mg (Tablettendurchmesser 9 mm).The mixture is then compressed into tablets, e.g. B. weighing 333 mg (tablet diameter 9 mm).
Die Gewichtsanteile von Metrifonat und Cellulose betragen demnach 30,0% bzw. 67,75%.The proportions by weight of metriphonate and cellulose are accordingly 30.0% and 67.75%.
Typische Werte für pH und Wassergehalt von Tabletten gemäß obengenannter
Zusammensetzung (Masse 167 mg, entsprechend 50 mg Metrifonat pro Tablette)
sind (gemessen unmittelbar nach Herstellung; gemessen wurde der pH-Wert einer
Dispersion der Formulierung in einem 10-fachen Gewichtsüberschuß von destillier
tem, kohlensäurefreiem Wasser bei 25°C):
Typical values for pH and water content of tablets according to the above-mentioned composition (mass 167 mg, corresponding to 50 mg metrifonate per tablet) are (measured immediately after production; the pH value of a dispersion of the formulation was measured in a 10-fold excess by weight of distilled tem, non-carbonated water at 25 ° C):
Wie Beispiel 1, jedoch werden alle Komponenten zusammengemischt und direkt zu Tabletten verarbeitet.As in Example 1, but all components are mixed together and added directly Tablets processed.
Wie Beispiel 2, jedoch werden alle Komponenten - mit Ausnahme von Magnesium stearat - gemischt, per Trockenkompaktierung und anschließender Zerkleinerung granuliert. Nach Zumischung von Magnesiumstearat wird tablettiert.As in Example 2, but all components - with the exception of magnesium stearate - mixed, by dry compaction and subsequent crushing granulated. After adding magnesium stearate, tablets are made.
Die Zubereitung entsprechend folgender Zusammensetzung:
The preparation according to the following composition:
wird zu Tabletten verarbeitet, z. B. mit einem Gewicht 800 mg (Tablettendurchmesser 13 mm), wobei die Herstellung gemäß Beschreibung der Beispiele 1, 2 oder 3 erfolgt.is processed into tablets, e.g. B. with a weight of 800 mg (tablet diameter 13 mm), the production according to the description of Examples 1, 2 or 3 he follows.
Bei Herstellung entsprechend der Reihenfolge in Beispiel 1 werden zum Trocken kompaktieren folgende Mengen verarbeitet:When made according to the sequence in Example 1, dry compact the following quantities processed:
Die weitere Zugabe der Bestandteile ist wie folgt:The further addition of the ingredients is as follows:
Die Gewichtsanteile von Metrifonat und Cellulose betragen demnach 12,5% bzw. 85,25%.The proportions by weight of metriphonate and cellulose are accordingly 12.5% and 85.25%.
Typische Werte von Tabletten gemäß o. g. Zusammensetzung (Masse 80 mg, entspre chend 10 mg Metrifonat pro Tablette) sind beispielsweise pH = 6,7; Wassergehalt = 4,4%. Typical values of tablets according to the above Composition (mass 80 mg, cor accordingly 10 mg metrifonate per tablet) are for example pH = 6.7; Water content = 4.4%.
Wie Beispiele 1-4, jedoch wird die Tablette in einem weiteren Prozeßschritt mit einer Lackschicht überzogen, die folgende Zusammensetzung hat:As in Examples 1-4, but the tablet is used in a further process step covered with a layer of varnish, which has the following composition:
Die Lackauftragsmenge beträgt 2-3 mg/cm2.The amount of paint applied is 2-3 mg / cm 2 .
Claims (11)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19857716A DE19857716A1 (en) | 1998-12-15 | 1998-12-15 | New solid formulation of Metrifonat |
| PCT/EP1999/009769 WO2000035459A1 (en) | 1998-12-15 | 1999-12-10 | New solid metriphonate formulations |
| AU30369/00A AU3036900A (en) | 1998-12-15 | 1999-12-10 | New solid metriphonate formulations |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19857716A DE19857716A1 (en) | 1998-12-15 | 1998-12-15 | New solid formulation of Metrifonat |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19857716A1 true DE19857716A1 (en) | 2000-06-21 |
Family
ID=7891078
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19857716A Withdrawn DE19857716A1 (en) | 1998-12-15 | 1998-12-15 | New solid formulation of Metrifonat |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3036900A (en) |
| DE (1) | DE19857716A1 (en) |
| WO (1) | WO2000035459A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003051364A1 (en) * | 2001-12-17 | 2003-06-26 | EGIS Gyógyszergyár Rt. | Amlopidine bezylate tablets with improved stability |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0813729B2 (en) * | 1987-03-06 | 1996-02-14 | 有恒薬品工業株式会社 | Poison bait for pest control |
| US4950658A (en) * | 1988-12-06 | 1990-08-21 | Board Of Trustees Of Southern Illinois Univ. | Method of medical treatment of Alzheimer's disease |
| US5336675A (en) * | 1991-05-14 | 1994-08-09 | Ernir Snorrason | Method of treating mania in humans |
| DE4217396A1 (en) * | 1992-05-26 | 1993-12-02 | Bayer Ag | Metrifonate-containing drug |
-
1998
- 1998-12-15 DE DE19857716A patent/DE19857716A1/en not_active Withdrawn
-
1999
- 1999-12-10 AU AU30369/00A patent/AU3036900A/en not_active Withdrawn
- 1999-12-10 WO PCT/EP1999/009769 patent/WO2000035459A1/en not_active Ceased
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003051364A1 (en) * | 2001-12-17 | 2003-06-26 | EGIS Gyógyszergyár Rt. | Amlopidine bezylate tablets with improved stability |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3036900A (en) | 2000-07-03 |
| WO2000035459A1 (en) | 2000-06-22 |
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