SK15912000A3 - Paroxetine ascorbate - Google Patents
Paroxetine ascorbate Download PDFInfo
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- SK15912000A3 SK15912000A3 SK1591-2000A SK15912000A SK15912000A3 SK 15912000 A3 SK15912000 A3 SK 15912000A3 SK 15912000 A SK15912000 A SK 15912000A SK 15912000 A3 SK15912000 A3 SK 15912000A3
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- paroxetine
- ascorbate
- paroxetine ascorbate
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 title claims abstract description 54
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 title claims abstract description 28
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 235000010323 ascorbic acid Nutrition 0.000 title claims abstract description 27
- 239000011668 ascorbic acid Substances 0.000 title claims abstract description 27
- 229960002296 paroxetine Drugs 0.000 title claims abstract description 27
- 229940072107 ascorbate Drugs 0.000 title claims abstract description 21
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 239000012458 free base Substances 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
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- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229960005070 ascorbic acid Drugs 0.000 claims description 6
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- 238000002425 crystallisation Methods 0.000 claims description 3
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- 208000000094 Chronic Pain Diseases 0.000 claims description 2
- 206010012289 Dementia Diseases 0.000 claims description 2
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- 201000007930 alcohol dependence Diseases 0.000 claims description 2
- 208000022531 anorexia Diseases 0.000 claims description 2
- 206010061428 decreased appetite Diseases 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
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- 206010040047 Sepsis Diseases 0.000 claims 1
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- 208000015114 central nervous system disease Diseases 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
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- 229940079832 sodium starch glycolate Drugs 0.000 description 3
- 239000008109 sodium starch glycolate Substances 0.000 description 3
- 229920003109 sodium starch glycolate Polymers 0.000 description 3
- PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
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- 239000012266 salt solution Substances 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
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- 239000003086 colorant Substances 0.000 description 1
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- 230000006835 compression Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
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- 208000024732 dysthymic disease Diseases 0.000 description 1
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- 238000001914 filtration Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000001483 mobilizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium glycolate Chemical compound [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229940071117 starch glycolate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Psychology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Oblasť technikyTechnical field
Tento vynález sa týka askorbátu paroxetínu, spôsobu jeho výroby a jeho použitia na liečenie chorobných stavov.The present invention relates to paroxetine ascorbate, a process for its manufacture and its use in the treatment of disease states.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Farmaceutické produkty s antidepresívnymi vlastnosťami a vlastnosťami proti Parkinsonovej chorobe sú opísané v US-A-3912743 a US-A-4007196. Zvlášť dôležitou zlúčeninou spomedzi opísaných zlúčenín je paroxetín, (~)trans izomér 4(4,-fluórfenyl)-3-(3,,4'-metyléndioxyfenoxymetyl)piperidín. Táto zlúčenina sa používa v terapii vo forme hydrochloridovej soli na liečbu a profylaxiu okrem iného depresie, obsedantno kompulzívnych porúch (OCD) a panických stavov.Pharmaceutical products having anti-depressant and anti-Parkinson's properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, (~) trans isomer of 4 (4-fluorophenyl) -3- (3 ', 4'-methylenedioxyphenoxymethyl) -piperidine. This compound is used in the hydrochloride salt therapy for the treatment and prophylaxis of, inter alia, depression, obsessive compulsive disorder (OCD) and panic conditions.
Teraz sa prekvapujúco našla nová soľ paroxetínu, ktorú možno alternatívne použiť namiesto hydrochloridu, ktorý je v súčasnosti na trhu, alebo ako medziprodukt pri výrobe hydrochloridu.Surprisingly, a new salt of paroxetine has now been found, which may alternatively be used in place of the hydrochloride currently on the market or as an intermediate in the production of the hydrochloride.
Podstata vynálezuSUMMARY OF THE INVENTION
Podstatou vynálezu je askorbát paroxetínu.The present invention provides paroxetine ascorbate.
V jednom uskutočnení sa nová soľ podľa tohto vynálezu poskytuje v nekryštalickej podobe, ktorá môže byť vo forme tuhej látky alebo oleja. Olej sa výhodne absorbuje na tuhý nosič, najmä nosič, ktorý sa používa ako zložka farmaceutického prípravku.In one embodiment, the novel salt of the invention is provided in a non-crystalline form, which may be in the form of a solid or an oil. The oil is preferably absorbed onto a solid carrier, in particular a carrier which is used as a component of the pharmaceutical composition.
V ďalšom uskutočnení sa nová soľ podľa tohto vynálezu poskytuje v kryštalickej forme. Ak kryštalická forma existuje vo viacerých polymorfných formách, každá polymorfná forma znamená ďalšie uskutočnenie tohto vynálezu.In another embodiment, the novel salt of the invention is provided in crystalline form. When the crystalline form exists in multiple polymorphic forms, each polymorphic form represents a further embodiment of the invention.
Askorbát paroxetínu možno vyrobiť zmiešaním stechiometrických množstiev kyseliny askorbovej a voľnej bázy paroxetínu. Je výhodné, aby kyselina alebo báza boli v roztoku, výhodnejšie je, ak sú v roztoku obidve. Zvýšená teplota sa môžeParoxetine ascorbate can be prepared by mixing stoichiometric amounts of ascorbic acid and paroxetine free base. It is preferred that the acid or base be in solution, more preferably both are in solution. Elevated temperature may
-2použiť na privedenie kyseliny do roztoku, ale dobré výťažky soli sa získajú odparením niektorých alebo všetkých rozpúšťadiel alebo kontrolovaným ochladením, výhodne po etapách. Najčastejšie používané rozpúšťadlá sú vhodné na zmobilizovanie voľnej bázy paroxetínu, ako je napríklad toluén, alkoholy, napríklad metanol, etanol, propán-2-ol, estery ako je napríklad etylacetát, ketóny ako je napríklad acetón a butanón, halogenované uhľovodíky ako napríklad dichlórmetán a étery ako je napríklad tetrahydrofurán a dietyléter, ale rozpúšťadiel, v ktorých kyselina askorbová nie je veľmi rozpustná sa je výhodne vyhnúť. Vhodné rozpúšťadlá pre kyselinu askorbovú zahrnujú vodu a nižšie alkoholy.Use to bring the acid into solution, but good salt yields are obtained by evaporating some or all of the solvents or by controlled cooling, preferably in stages. The most commonly used solvents are suitable for mobilizing paroxetine free base such as toluene, alcohols such as methanol, ethanol, propan-2-ol, esters such as ethyl acetate, ketones such as acetone and butanone, halogenated hydrocarbons such as dichloromethane and ethers such as tetrahydrofuran and diethyl ether, but solvents in which ascorbic acid is not very soluble are preferably avoided. Suitable solvents for ascorbic acid include water and lower alcohols.
Soľ možno izolovať v tuhej forme bežnými spôsobmi z roztoku, získaného ako bolo uvedené vyššie. Napríklad, nekryštalická soľ sa môže vyrobiť precipitáciou, sušením rozprašovaním a sušením zmrazovaním roztokov alebo vákuovým sušením olejov, alebo stuhnutím tavenín získaných z reakcie voľnej bázy a kyseliny. Kryštalická soľ sa môže vyrobiť kryštalizáciou alebo rekryštalizáciou z vhodných rozpúšťadiel.The salt can be isolated in solid form by conventional means from the solution obtained as above. For example, a non-crystalline salt can be produced by precipitation, spray drying and freeze drying of solutions or vacuum drying of oils, or by solidification of melts obtained from the reaction of the free base and the acid. The crystalline salt can be produced by crystallization or recrystallization from suitable solvents.
Keď sa získa soľ ako solvát, spojením s rozpúšťadlom, v ktorom sa rozpustí, takýto solvát tvorí ďalšie uskutočnenie tohto vynálezu. Solváty sa môžu obnoviť na nesolvátované soli ohriatím, napríklad sušením v peci, alebo spracovaním s odstránením rozpúšťadla, ktoré netvorí solvát.When a salt is obtained as a solvate, by combining it with the solvent in which it is dissolved, such solvate forms a further embodiment of the invention. Solvates can be recovered to unsolvated salts by heating, for example by oven drying, or by treatment with removal of the solvent that does not form a solvate.
Pred izoláciou soli paroxetínu sa môže voda odstrániť azeotropnou destiláciou, aby sa zabránilo vzniku hydrátov alebo aby sa získal produkt v bezvodej forme. V takomto prípade vhodnými rozpúšťadlami pre roztok soli sú tie rozpúšťadlá, ktoré vytvárajú s vodou azeotropnú zmes, ako napríklad toluén a propán-2-ol. Takéto zmesi rozpúšťadiel sa môžu tiež použiť aj z dôvodu, aby sa pomohlo azeotropnému odstráneniu vody.Before the isolation of the paroxetine salt, the water may be removed by azeotropic distillation to avoid formation of hydrates or to obtain the product in anhydrous form. In such a case, suitable solvents for the salt solution are those which form an azeotropic mixture with water, such as toluene and propan-2-ol. Such solvent mixtures may also be used to assist in the azeotropic removal of water.
Bežnejšie možno kryštalizáciu uskutočniť z akéhokoľvek rozpúšťadla, ktoré umožňuje vznik požadovanej kryštalickej štruktúry, použitím naočkovania požadovanej štruktúry, ak sa to vyžaduje, alebo je to vhodné. V prípade existencie polymorfov, sú jednotlivé polymorfy výhodne kryštalizované priamo z roztoku soli, hoci možno tiež uskutočniť rekryštalizáciu roztoku jedného polymorfu použitím naočkovania iného polymorfu.Conveniently, crystallization can be carried out from any solvent that allows the desired crystalline structure to be formed, by seeding the desired structure if desired or appropriate. If polymorphs exist, the individual polymorphs are preferably crystallized directly from the salt solution, although recrystallization of a solution of one polymorph can also be accomplished by seeding another polymorph.
-3voľna baza paroxetínu sa môže vyrobiť podľa postupov všeobecne uvedených v US patente č. 4,007,196 a EP-B-0 223 403. Kyselina askorbová je komerčne prístupná.The paroxetine-free base may be prepared according to the procedures generally disclosed in U.S. Pat. 4,007,196 and EP-B-0 223 403. Ascorbic acid is commercially available.
Zlúčeniny podľa tohto vynálezu môžu byť použité na liečbu a prevenciu nasledovných porúch;The compounds of the invention can be used to treat and prevent the following disorders;
Alkoholizmusalcoholism
Depresiadepression
Panická poruchaPanic disorder
Obezitaobesity
Migrénamigraine
Anorexiaanorexia
Premenštruačný syndróm (PMS)Premenstrual Syndrome (PMS)
Trichotillomániatrichotillomania
Zneužitie liečivDrug abuse
StrachFear
Obsedantno-kompulzívne poruchyObsessive-compulsive disorders
Chronická bolesťChronic pain
Starecká demenciaStarecká dementia
Bulímiabulimia
Sociálna fóbiaSocial phobia
Depresia v dospievaníDepression in adolescence
Dystýmiadysthymia
Poruchy tu konkretizované sú ďalej označené pojmom „Poruchy“.The disorders specified herein are hereinafter referred to as "Disorders".
Tento vynález ďalej poskytuje spôsob liečby a/alebo prevencie jednej alebo viacerých Porúch podávaním efektívneho a/alebo profylaktického množstva soli podľa vynálezu pacientovi, ak je to potrebné.The invention further provides a method of treating and / or preventing one or more Disorders by administering an effective and / or prophylactic amount of a salt of the invention to a patient, if necessary.
Tento vynález ďalej poskytuje farmaceutický prostriedok na použitie pri liečbe a/alebo prevencii Porúch, ktorý obsahuje prísadu soli podľa vynálezu s farmaceutický prijateľným nosičom.The present invention further provides a pharmaceutical composition for use in the treatment and / or prevention of a Disorder comprising the addition of a salt of the invention with a pharmaceutically acceptable carrier.
Tento vynález taktiež poskytuje použitie soli podľa vynálezu na liečbu a/alebo prevenciu Porúch.The invention also provides the use of a salt of the invention for the treatment and / or prevention of Disorders.
Tento vynález taktiež poskytuje použitie soli podľa vynálezu na výrobu lieku pri liečbe a/alebo prevenciu Porúch.The invention also provides the use of a salt of the invention for the manufacture of a medicament for the treatment and / or prevention of Disorders.
Najvýhodnejšie je tento vynález aplikovaný na liečbu depresie, OCD a paniky.Most preferably, the invention is applied to the treatment of depression, OCD and panic.
Prípravky podľa vynálezu sú zvyčajne prispôsobené na orálne podávanie, ale pod tento vynález spadajú aj prípravky určené na rozpúšťanie pri parenterálnom podávaní.The formulations of the invention are generally adapted for oral administration, but the present invention also encompasses formulations intended for dissolution when administered parenterally.
-4Prípravok je zvyčajne prezentovaný v jednodávkovej forme, obsahujúci od 1 do 200 mg účinnej zložky prepočítanej na voľnú bázu, častejšie od 5 do 100 mg, napríklad 10 až 50 mg tak ako 10, 12,5, 15, 20, 25, 30 alebo 40 mg u ľudí. Jednotlivú dávku najvýhodnejšie predstavuje 20 mg účinnej zložky prepočítanej na voľnú bázu. Takáto zmes sa za normálnych okolností užíva 1 až 6-krát denne, napríklad 2, 3 alebo 4-krát za deň, takže celkové množstvo podávanej účinnej zložky je v rozmedzí od 5 do 400 mg účinnej zložky prepočítanej na voľnú bázu. Najvýhodnejšie sa jednotlivá dávka podáva 1 x denne.The formulation is usually presented in unit dosage form containing from 1 to 200 mg of active ingredient calculated on the free base, more typically from 5 to 100 mg, for example 10 to 50 mg, such as 10, 12.5, 15, 20, 25, 30 or 40 mg in humans. Most preferably, a single dose is 20 mg of active ingredient calculated as the free base. Such a composition is normally taken 1 to 6 times a day, for example 2, 3 or 4 times a day, so that the total amount of active ingredient administered is in the range of 5 to 400 mg of active ingredient calculated on the free base. Most preferably, a single dose is administered once daily.
Výhodnými dávkovými formami sú tablety alebo kapsuly.Preferred dosage forms are tablets or capsules.
Prípravky podľa tohto vynálezu môžu byť vyrobené bežnými spôsobmi zmiešavania, ako je miešanie, plnenie a kompresia.The formulations of the invention may be made by conventional mixing methods such as mixing, filling and compression.
Vhodné nosiče na použitie podľa tohto vynálezu zahŕňajú riedidlo, väzbové činidlo, dezintegračné činidlo, farbivo, ochucovacia činidlo a/aiebo konzervačnú látku. Tieto činidlá môžu byť použité bežným spôsobom, napríklad podobným tým, ktoré sa používajú u antidepresív, ktoré sú na trhu.Suitable carriers for use in the present invention include a diluent, a binder, a disintegrant, a colorant, a flavoring, and / or a preservative. These agents can be used in a conventional manner, for example similar to those used with antidepressants on the market.
Medzi špecifické príklady farmaceutických prípravkov patria tie, ktoré sú opísané v EP-B-0 223 403 a US 4,007,196, kde možno produkty podľa tohto vynálezu používať ako účinné látky.Specific examples of pharmaceutical formulations include those described in EP-B-0 223 403 and US 4,007,196, where the products of the invention can be used as active ingredients.
Nasledujúce príklady ilustrujú tento vynález.The following examples illustrate the invention.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Príprava askorbátu paroxetínuPreparation of paroxetine ascorbate
1,28 mol roztoku paroxetínovej bázy v toluéne (5 ml, 6,38 mmol) sa pridá k roztoku kyseliny askorbovej (1,12 g, 6,38 mmol) v metanole (15 ml). Rozpúšťadlo sa odstráni vo vákuu, zvyšný olej sa rozriedi s toluénom (15 ml) a rozpúšťadlo sa odstráni vo vákuu. Trituráciou s dietyléterom (približne 15 ml) a filtráciou pod dusíkom sa získa bledožltá látka, ktorá sa premyje s dietyléterom (2 x 10 ml) a po dobu 3 hodín suší vo vákuovej sušičke.A solution of 1.28 mol of paroxetine base in toluene (5 mL, 6.38 mmol) was added to a solution of ascorbic acid (1.12 g, 6.38 mmol) in methanol (15 mL). The solvent was removed in vacuo, the residual oil was diluted with toluene (15 mL) and the solvent was removed in vacuo. Trituration with diethyl ether (approximately 15 mL) and filtration under nitrogen gave a pale yellow solid which was washed with diethyl ether (2 x 10 mL) and dried in a vacuum drier for 3 hours.
Výťažok 2,99 g.Yield 2.99 g.
-5IR nujolová gáza:-5IR nujol gauze:
Pásy na 1716, 1603, 1510, 1465, 1377, 1224, 1186, 1136, 1037, 930, 831, 722, 540Belts for 1716, 1603, 1510, 1465, 1377, 1224, 1186, 1136, 1037, 930, 831, 722, 540
Príklad 2 Výroba tablietExample 2 Production of tablets
Komerčné zdroje zložiek Fosforečnan vápenatý Mikrokryštalická celulóza Sodná soľ glykolátu škrobu * obchodné názvyCommercial sources of ingredients Calcium phosphate Microcrystalline cellulose Starch glycolate sodium * Trade names
Emcompress alebo Ditab* Avicel PH 102*Emcompress or Ditab * Avicel PH 102 *
Explotab*Explotab *
Spôsobprocess
1. Preosiať DCP cez sito a navážiť do Planetového mixéra.1. Sieve the DCP through a sieve and weigh into a Planet Mixer.
2. Pridať 30 mesh askorbátu paroxetínu do nádoby.2. Add 30 mesh paroxetine ascorbate to the container.
3. Pridať 20 mesh Avicelu a Explotabu a miešať všetky prášky po dobu 10 minút.3. Add 20 mesh Avicel and Explotab and mix all powders for 10 minutes.
4. Pridať stearan horečnatý a miešať 5 minút.4. Add magnesium stearate and mix for 5 minutes.
Pri tabletovaní do päťuholníkových tabliet použiť nasledujúce razidlá:Use the following punches when tabletting into pentagonal tablets:
mg tableta 9,5 mm s kruhovým obvodom mg tableta 8,25 mm s kruhovým obvodommg tablet 9.5 mm with circular circumference mg tablet 8.25 mm with circular circumference
-6Príklad 3 Výroba tabliet-6Example 3 Production of tablets
Spôsobprocess
1. Paroxetín askorbát, sodná soľ glykoláty škrobu a dihydrát fosforečnanu vápenatého sa preosiať a miešať spolu vo vhodnom mixéri.1. Paroxetine ascorbate, sodium starch glycolate and calcium phosphate dihydrate are sieved and mixed together in a suitable mixer.
(Planetový, Cuble alebo vysokovýkonný s nožmi)(Planetary, Cuble or High Power with Knives)
2. Pridať stearan horečnatý a zmes komprimovať do tablety za použitia jednoduchého razidla alebo pomocou rotačného tabletovacieho stroja.2. Add magnesium stearate and compress the mixture into a tablet using a simple punch or rotary tablet machine.
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9808896.6A GB9808896D0 (en) | 1998-04-25 | 1998-04-25 | Novel compound |
| PCT/GB1999/001244 WO1999055698A1 (en) | 1998-04-25 | 1999-04-23 | Paroxetine ascorbate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK15912000A3 true SK15912000A3 (en) | 2001-04-09 |
Family
ID=10831008
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK1591-2000A SK15912000A3 (en) | 1998-04-25 | 1999-04-23 | Paroxetine ascorbate |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1089995A1 (en) |
| JP (1) | JP2002513019A (en) |
| KR (1) | KR20010042977A (en) |
| CN (1) | CN1297448A (en) |
| AP (1) | AP2000001963A0 (en) |
| AU (1) | AU3618499A (en) |
| BG (1) | BG104940A (en) |
| BR (1) | BR9909868A (en) |
| CA (1) | CA2330055A1 (en) |
| EA (1) | EA200001104A1 (en) |
| GB (1) | GB9808896D0 (en) |
| HU (1) | HUP0102116A3 (en) |
| ID (2) | ID26654A (en) |
| IL (1) | IL139081A0 (en) |
| NO (1) | NO20005352D0 (en) |
| PL (1) | PL343677A1 (en) |
| SK (1) | SK15912000A3 (en) |
| TR (1) | TR200003084T2 (en) |
| WO (1) | WO1999055698A1 (en) |
| ZA (1) | ZA200005912B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0003232D0 (en) * | 2000-02-11 | 2000-04-05 | Smithkline Beecham Plc | Novel composition |
| US7227033B2 (en) | 2002-01-09 | 2007-06-05 | Emisphere Technologies, Inc. | Polymorphs of sodium 4-[(4-chloro-2-hydroxybenzoyl) amino] butanoate |
| IL159280A0 (en) * | 2001-06-14 | 2004-06-01 | Teva Pharma | A process for preparing paroxetine hcl which limits formation of pink colored compounds |
| CN110607553B (en) * | 2018-10-30 | 2024-03-22 | 中国科学院化学研究所 | A method for preparing single crystals or amorphous substances of drugs or drug intermediates with adjustable particle size |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1422263A (en) * | 1973-01-30 | 1976-01-21 | Ferrosan As | 4-phenyl-piperidine compounds |
| ES2058061T3 (en) * | 1985-10-25 | 1994-11-01 | Beecham Group Plc | DERIVED FROM PIPERIDINE, ITS PREPARATION AND ITS USE AS A MEDICINAL PRODUCT. |
| US5276042A (en) * | 1993-04-16 | 1994-01-04 | Crenshaw Roger T | Treatment of premature ejaculation |
| ES2117557B1 (en) * | 1996-02-29 | 1999-07-01 | Ferrer Int | NEW PROCEDURE FOR OBTAINING (-) - TRANS -N-P-FLUOROBENZOILMETIL-4- (P-FLUOROFENIL) -3- ((3,4- (METHYLENDIOXI) PHENOXI) METHYL) -PIPERIDINE. |
-
1998
- 1998-04-25 GB GBGB9808896.6A patent/GB9808896D0/en not_active Ceased
-
1999
- 1999-04-23 EA EA200001104A patent/EA200001104A1/en unknown
- 1999-04-23 IL IL13908199A patent/IL139081A0/en unknown
- 1999-04-23 CN CN99805160A patent/CN1297448A/en active Pending
- 1999-04-23 PL PL99343677A patent/PL343677A1/en not_active Application Discontinuation
- 1999-04-23 ID IDW20002169A patent/ID26654A/en unknown
- 1999-04-23 JP JP2000545858A patent/JP2002513019A/en active Pending
- 1999-04-23 CA CA002330055A patent/CA2330055A1/en not_active Abandoned
- 1999-04-23 SK SK1591-2000A patent/SK15912000A3/en unknown
- 1999-04-23 BR BR9909868-7A patent/BR9909868A/en not_active Application Discontinuation
- 1999-04-23 ID IDW20002168A patent/ID26083A/en unknown
- 1999-04-23 AU AU36184/99A patent/AU3618499A/en not_active Abandoned
- 1999-04-23 AP APAP/P/2000/001963A patent/AP2000001963A0/en unknown
- 1999-04-23 TR TR2000/03084T patent/TR200003084T2/en unknown
- 1999-04-23 KR KR1020007011809A patent/KR20010042977A/en not_active Withdrawn
- 1999-04-23 WO PCT/GB1999/001244 patent/WO1999055698A1/en not_active Ceased
- 1999-04-23 EP EP99918151A patent/EP1089995A1/en not_active Withdrawn
- 1999-04-23 HU HU0102116A patent/HUP0102116A3/en unknown
-
2000
- 2000-10-23 ZA ZA200005912A patent/ZA200005912B/en unknown
- 2000-10-24 NO NO20005352A patent/NO20005352D0/en not_active Application Discontinuation
- 2000-11-13 BG BG104940A patent/BG104940A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BG104940A (en) | 2001-09-28 |
| BR9909868A (en) | 2000-12-19 |
| IL139081A0 (en) | 2001-11-25 |
| CA2330055A1 (en) | 1999-11-04 |
| HUP0102116A3 (en) | 2002-12-28 |
| ZA200005912B (en) | 2001-12-19 |
| NO20005352L (en) | 2000-10-24 |
| EP1089995A1 (en) | 2001-04-11 |
| EA200001104A1 (en) | 2001-04-23 |
| AU3618499A (en) | 1999-11-16 |
| CN1297448A (en) | 2001-05-30 |
| NO20005352D0 (en) | 2000-10-24 |
| AP2000001963A0 (en) | 2000-12-31 |
| TR200003084T2 (en) | 2001-02-21 |
| ID26083A (en) | 2000-11-23 |
| GB9808896D0 (en) | 1998-06-24 |
| WO1999055698A1 (en) | 1999-11-04 |
| HUP0102116A2 (en) | 2002-05-29 |
| ID26654A (en) | 2001-01-25 |
| PL343677A1 (en) | 2001-08-27 |
| KR20010042977A (en) | 2001-05-25 |
| JP2002513019A (en) | 2002-05-08 |
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