SI20305A - Kristali natrijeve soli pravastatina - Google Patents
Kristali natrijeve soli pravastatina Download PDFInfo
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- SI20305A SI20305A SI9900191A SI9900191A SI20305A SI 20305 A SI20305 A SI 20305A SI 9900191 A SI9900191 A SI 9900191A SI 9900191 A SI9900191 A SI 9900191A SI 20305 A SI20305 A SI 20305A
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- sodium salt
- pravastatin sodium
- pravastatin
- ethyl acetate
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- VWBQYTRBTXKKOG-IYNICTALSA-M pravastatin sodium Chemical compound [Na+].C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 VWBQYTRBTXKKOG-IYNICTALSA-M 0.000 title claims abstract description 36
- 239000013078 crystal Substances 0.000 title claims description 28
- 238000000034 method Methods 0.000 claims abstract description 20
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960002965 pravastatin Drugs 0.000 claims abstract description 10
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 159000000000 sodium salts Chemical class 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 6
- 230000008018 melting Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002441 X-ray diffraction Methods 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000000855 fermentation Methods 0.000 abstract description 4
- 230000004151 fermentation Effects 0.000 abstract description 4
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 abstract description 3
- 229960002855 simvastatin Drugs 0.000 abstract description 3
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 abstract description 3
- 241000187643 Amycolatopsis Species 0.000 abstract description 2
- 241000228212 Aspergillus Species 0.000 abstract description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 abstract description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 abstract description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 abstract description 2
- 241000228347 Monascus <ascomycete fungus> Species 0.000 abstract description 2
- 241000235395 Mucor Species 0.000 abstract description 2
- 241000187654 Nocardia Species 0.000 abstract description 2
- 241000228143 Penicillium Species 0.000 abstract description 2
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 abstract description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000326 anti-hypercholesterolaemic effect Effects 0.000 abstract description 2
- 229960005370 atorvastatin Drugs 0.000 abstract description 2
- 239000003937 drug carrier Substances 0.000 abstract description 2
- 238000002955 isolation Methods 0.000 abstract description 2
- 229960004844 lovastatin Drugs 0.000 abstract description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 abstract description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 abstract description 2
- 229950009116 mevastatin Drugs 0.000 abstract description 2
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 abstract description 2
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 abstract description 2
- 244000005700 microbiome Species 0.000 abstract description 2
- 238000012986 modification Methods 0.000 abstract 2
- 230000004048 modification Effects 0.000 abstract 2
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 abstract 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 239000013543 active substance Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000035876 healing Effects 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 5
- 230000010354 integration Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 2
- 229960003765 fluvastatin Drugs 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- -1 . pravastatin sodium salts Chemical class 0.000 description 1
- OTYCUXCZGNDFQD-UHFFFAOYSA-N 7-naphthalen-1-ylheptanoic acid Chemical compound C1=CC=C2C(CCCCCCC(=O)O)=CC=CC2=C1 OTYCUXCZGNDFQD-UHFFFAOYSA-N 0.000 description 1
- 241000289659 Erinaceidae Species 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 229960001495 pravastatin sodium Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
- C07C69/33—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with hydroxy compounds having more than three hydroxy groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Obesity (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin njihovi derivati in analogi so poznani kot inhibitorji HMG-CoA reduktaze in se uporabljajo kot antihiperholesterolemiki.Večino jih proizvajajo s fermentacijo z mikroorganizmi različnih vrst, ki pripadajo rodovom Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor ali Penicillium, nekateri pa so rezultat obdelave fermentacijskih produktov z metodami kemijske sinteze oziroma so produkti totalne kemijske sinteze. Predloženi izum se nanaša na novo kristalinično obliko natrijeve soli pravastatina poznane pod kemijskim imenom 1-naftalenheptanojska kislina, 1,2,6,7,8,8a-heksahidro-beta,gama,6-trihidroksi-2-metil-8-(2- metil-1-oksobutoksi)-, mono natrijeva sol, ki je uporabna kot farmacevtska učinkovina, na metodo za njeno proizvodnjo in njeno izolacijo, na farmacevtsko formulacijo, ki vsebuje kristalinično obliko natrijeve soli pravastatina in farmacevtsko sprejemljiv nosilec ter na farmacevtsko metodo zdravljenja. Nova kristalinična oblika natrijeve soli pravastatina je uporabna za zdravljenje hiperholesterolemije in hiperlipidemije.ŕ
Description
Področje tehnike
Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin in cervastatin, njihovi derivati in analogi so poznani kot inhibitorji HMG-CoA reduktaze in se uporabljajo kot antihiperholesterolemiki. Večino jih proizvajajo s fermentacijo z mikroorganizmi različnih vrst, ki pripadajo rodovom Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor ali Penicillium, nekateri pa so rezultat obdelave fermentacijskih produktov z metodami kemijske sinteze (simvastatin) oziroma so produkti totalne kemijske sinteze (fluvastatin, atorvastatin in cervastatin).
Predloženi izum se nanaša na novo kristalinično obliko natrijeve soli pravastatina poznane pod kemijskim imenom 1-naftalenheptanojska kislina, l,2,6,7,8,8a-heksahidro-p,0,6-trihidroksi-2-metil-8-(2-metil-l-oksobutoksi)-, mono natrijeva sol, ki je uporabna kot farmacevtska učinkovina, predloženi izum se nanaša tudi na metodo za njeno proizvodnjo in njeno izolacijo, na farmacevtsko formulacijo, ki vsebuje kristalinično obliko natrijeve soli pravastatina in farmacevtsko sprejemljiv nosilec ter na farmacevtsko metodo zdravljenja. Nova kristalinična oblika natrijeve soli pravastatina je uporabna za zdravljenje hiperholesterolemije in hiperlipidemije.
Postopek priprave natrijeve soli pravastatina v kristalni obliki, ki je predmet predloženega izuma, omogoča poleg priprave natrijeve soli pravastatina v trdni (kristalni) obliki tudi metodo s katero odstranimo nekatere nečistoče. V primeru liofilizacijo se odstrani samo topilo, nečistoče pa ostanejo skupaj z natrijevo soljo pravastatina. Polege omenjenega pa liofilizacija v industrijskem merilu ni najbolj ekonomična. Tudi pri obarjanju se nečistoče zaradi neselektivnosti procesa oborijo skupaj z željeno substanco. Kristalizacija je v primerjavi z obema prej navedenima postopkoma priprave farmacevtskih učinkovin v trdni obliki edini selektivni proces, kjer se molekule željene substance selektivno vgrajujejo kristalno rešetko. Možnost vključevanja nečistoč v kristal je majhna, saj se v prostor med molekulami v kristalu lahko vključujejo le majhne molekule (sorodne nečistoče, ki so ponavadi v rangu velikosti željene substance, se v ta prostor zelo težko vključujejo), vključevanje drugih molekul v kristalno rešetko pa je termodinamsko nefavorizirano.
Prednost substanc v kristalnih strukturah pred tistimi v amorfnih je tudi v tem, da so njihovi tako fizikalni kot tudi kemijski parametri bolje definirani in da so bolj stabilne. Zadnje je še posebej pomembno za substance, ki so že po naravi nestabilne in občutljive na različne vplive okolja, kot so na primer svetloba, pH, zrak in temperatura.
Do danes je bilo poznano, da natrijeva sol pravastatina lahko obstaja le v amorfni obliki. Tako na primer Merck Index iz leta 1996 opisuje natrijevo sol pravastatina kot amorfno snov. Tudi postopki pridobivanja natrijeve soli pravastatina opisani v številnih patentih kot na primer US 4.537.859, US 4.448.979, US 4.410.629, US 4.346.227 omogočajo le pripravo amorfne oblike. V opisanih postopkih frakcije dobljene po ločbi na kromatografskih kolonah, ki vsebujejo natrijevo sol pravastatina, liofilizirajo in tako dobijo natrijevo sol v trdni - amorfni - obliki. V patentni prijavi WO 98/45410 je sicer opisano, da potem, ko natrijevo sol pravastatina očistijo z reverznofazno kromatografijo, lahko dobijo kristale z obarjanjem v mešanici etanola in etilacetata, vendar pa z naše strani opravljeni eksperimenti kažejo, da tovrstna kombinacija topil omogoča pripravo amorfne oblike, nikakor pa ne tudi kristalne oblike pravastatina.
Pri našem raziskovalnem delu, smo presenetljivo ugotovili, da je mogoče s primernim izborom topil in pravlnim zaporedjem njihove uporabe pripraviti natrijevo sol pravastatina tudi v kristalni obliki. Postopek priprave kristalov zaobsega raztapljanje amorfne natrijeve soli pravastatina v metanolu, dodajanje etilacetata v metanolno raztopino, pri čemer raztopino stalno mešamo in ohlajanje dobljene mešanice metanol/etilacetat. Iz ohlajene mešanice izpadejo igličasti kristali natrijeve soli pravastatina, ki jih odfiltriramo, speremo z etilacetatom in posušimo. Kristalizacija poteka najbolje, če je začetna koncentracija natrijeve soli pravastatina v metanolu med 0.03 do 0.3 g/ml, prednostno okoli 0.1 g/ml, volumen dodanega etilacetata pa ne presega petnajstkratnega volumna začetne raztopine natrijeve soli pravastatina v metanolu. Optimalna temperatura kristalizacije je pod 15°C prednostno okoli 8°C. Kristali izpadejo po treh do 20-ih urah. Dobljeni kristali so v obliki iglic, ki se včasih skupljajo v obliki ježkov, tališče tako pripravljenih kristalov pa je med 170 in 174°C.
Tako pripravljenim kristalom je bil posnet difraktogram, njihva oblika pa je razvidna iz slik narejenih pod elektronskim mikroskopom. Osnovne celice kristalom zaradi njene velikosti in visokega ozadja pri kotih nad 20 °20 ni bilo moč določiti. Primerjava posnetega difraktograma s standardi iz bank podatkov PDF in CSD (PDF-Powder Diffraction File, ki jo izdaja International Centre for Diffraction Data s sedežem na 12 Campus Boulevard, Newtown Square, PA 19073-3273 ZDA; CSD-Cambridge Structural Database System, ki ga izdaja Cambridge Crystallographic Data Centre na 12 Union Road, Cambridge CB2 1EZ, Velika Britanija), je pokazala, da gre v primeru kristalov natrijeve soli pravastatina pripravljenih po postopku, ki je predmet tega izuma, resnično za novo in edino do sedaj poznano kristalino obliko natrijeve soli pravastatina.
Predmet predloženega izuma so tudi farmacevtske formulacije, ki vsebujejo natrijevo sol pravastatina v obliki kristalov. Farmacevtska formulacija je lahko v obliki primerni za oralno oziroma paranteralno uporabo in se uporablja za zdravljenje hiperholesterolemije in hiperlipidemije. farmacevtska formulacija, ki je predmet tega izuma je lahko tako v obliki tablet, kapsul, granul in supozitorijev, kot tudi v obliki suspenzij.
Slika 1: Difraktogram amorfne natrijeve soli pravastatina posnetega na rentgenskem praškovnem difraktometru Philips PW1710 v območju od do 42 °2θ s korakom 0.025 °20 in integracijskim časom 1 s na korak.
Slika 2: Difraktogram kristalov natrijeve soli pravastatina posnetega na rentgenskem praškovnem difraktometru Philips PW1710 v območju od 2 do 48 °20 s korakom 0.035 °20 in integracijskim časom 1 s na korak.
Slika 3: Slika amorfne natrijeve soli pravastatina posneta na mikroskopu
OLYMPUS BX 50F s kamero CCD Sony DXC-950-P pri 400-kratni povečavi.
Slika 4: Slika kristalov natrijeve soli pravastatina na mikroskopu OLVMPUS
BX 50F s kamero CCD Sony DXC-950-P pri 400-kratni povečavi.
Predloženi izum prikazujejo, vendar v ničemer ne omejujejo naslednji primeri.
PRIMERI
Primer 1
Natrijevo sol pravastatina (lg) smo raztopili v metanolu (10 ml) in med mešanjem dodajali etilacetat (80 ml). Dobljeno bistro rumeno raztopino smo ohladili na 8°C in pustili stati preko noči. Izpadle dolge tanke igličaste kristale v obliki ježkov smo odfiltrirali, jih sprali z etilacetatom (20 ml) in posušili. Dobili smo 0.87 g bledorumenih kristalov s temperaturo tališča med 172 in 174°C.
Primer 2
Natrijevo sol pravastatina (2 g) smo raztopili v metanolu (20 ml) in med mešanjem dodajali etilacetat (120 ml). Dobljeno bistro rahlo rumeno raztopino smo ohladili na 8°C in pustili stati štiri ure. Izpadle dolge tanke igličaste kristale v obliki ježkov smo odfiltrirali, jih sprali z etilacetatom (20 ml) in posušili. Dobili smo 1.53 g brezbarvnih kristalov s temperaturo tališča med 172 in 174°C.
Primer 3
Natrijevo sol pravastatina (2 g) smo raztopili v metanolu (20 ml) in med mešanjem dodajali etilacetat (150 ml). Dobljeno bistro rahlo rumeno raztopino smo ohladili na 8°C in pustili stati štiri ure. Izpadle dolge tanke igličaste kristale v obliki ježkov smo odfiitrirali, jih sprali z etilacetatom (20 ml) in posušili. Dobili smo 1.66 g brezbarvnih kristalov s temperaturo tališča med 172 in 174°C.
Primer 4
Natrijevo sol pravastatina (2 g) smo raztopili v metanolu (20 ml) in med mešanjem dodajali etilacetat (170 ml). Dobljeno bistro rahlo rumeno raztopino smo ohladili na 8°C in pustili stati štiri ure. Izpadle dolge tanke igličaste kristale v obliki ježkov smo odfiitrirali, jih sprali z etilacetatom (20 ml) in posušili. Dobili smo 1.75 g brezbarvnih kristalov s temperaturo tališča med 172 in 174°C.
Claims (14)
- Patentni zahtevki:1. Postopek za pripravo natrijeve soli pravastatina v kristalni obliki, ki vključuje:a) raztapljanje natrijeve soli pravastatina v metanolu;b) dodajanje etilacetata v metanolno raztopino natrijeve soli pravastatina ob stalnem mešanju;c) ohlajanje mešanice metanol/etilacetat;d) kristalizacija.
- 2. Postopek po zahtevku 1 označen s tem, da je koncentracija natrijeve soli pravastatina v metanolu med 0.03 in 0.3 g/ml, prednostno okoli 0.1 g/ml.
- 3. Postopek po zahtevku 1 označen s tem, da predstavlja volumen dodanega etilacetata do petnajstkratni, prednostno do desetkratni volumen začetne metanolne raztopine natrijeve soli pravastatina.
- 4. Postopek po zahtevku 1 označen s tem, da ohladimo mešanico metanol/etilacetat na temperaturo pod 15°C, prednostno na okoli 8°C.
- 5. Postopek po zahtevku 1 označen s tem, da je čas kristalizacije med 3 in 20 ur prednostno okoli 4 ure.
- 6. Postopek po zahtevku 1 označen s tem, da izpadle kristale odfiltriramo, speremo z etilacetatom in posušimo.
- 7. Natrijeva sol pravastatina v kristalni obliki.
- 8. Natrijeva sol pravastatina v kristalni obliki po zahtevku 7, ki ima tališče med 170 in 174°C.
- 9. Natrijeva sol pravastatina v kristalni obliki, ki daje pri rentgenski difrakciji signal zadostno podoben tistemu prikazanemu na difraktogramu na Sliki 2.
- 10. Natrijeva sol pravastatina v kristalni obliki, označena s tem, da je pod mikroskopom pri 400-kratni povečavi jasno razvidno, da so kristali v obliki iglic.
- 11. Farmacevtska formulacija, ki vsebuje natrijevo sol pravastatina v kristalni obliki.
- 12. Farmacevtska formulacija po zahtevku 11, označena s tem, da so kristali natrijeve soli pravastatina v obliki iglic, ki so jasno razvidne pod mikroskopom pri 400-kratni povečavi.
- 13. Farmacevtska formulacija po zahtevku 11, označena s tem, da dajejo kristali natrijeve soli pravastatina pri rentgenski difrakciji signal zadostno podoben tistemu prikazanemu na difraktogramu na Sliki 2.
- 14. Uporaba kristalinične natrijeve soli pravastatina za pripravo farmacevtskih proizvodov za zdravljenje hiperholesterolemije in hiperlipidemije.
Priority Applications (31)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9900191A SI20305A (sl) | 1999-08-06 | 1999-08-06 | Kristali natrijeve soli pravastatina |
| DE60017568T DE60017568T2 (de) | 1999-08-06 | 2000-08-04 | Kristalle des natriumsalzes von pravastatin |
| RU2002102862/04A RU2247711C2 (ru) | 1999-08-06 | 2000-08-04 | Кристаллическая форма натриевой соли правастатина |
| US10/049,093 US7078558B1 (en) | 1999-08-06 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| KR1020077015051A KR20070086847A (ko) | 1999-08-06 | 2000-08-04 | 결정형의 프라바스타틴 소듐염 |
| PCT/IB2000/001103 WO2001010813A1 (en) | 1999-08-06 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| PT00946239T PT1200385E (pt) | 1999-08-06 | 2000-08-04 | Cristais do sal de sodio de pravastatina |
| EP00946239A EP1200385B2 (en) | 1999-08-06 | 2000-08-04 | Process for the preparation of crystals of the sodium salt of pravastatin |
| AT00946239T ATE287389T1 (de) | 1999-08-06 | 2000-08-04 | Kristalle des natriumsalzes von pravastatin |
| HR20020106A HRP20020106A2 (en) | 1999-08-06 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| JP2001515281A JP2003506424A (ja) | 1999-08-06 | 2000-08-04 | プラバスタチンナトリウムの結晶 |
| CA002379335A CA2379335A1 (en) | 1999-08-06 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| CZ2002414A CZ2002414A3 (cs) | 1999-08-06 | 2000-08-04 | Krystaly sodné soli pravastatinu |
| YU5402A YU5402A (sh) | 1999-08-06 | 2000-08-04 | Kristali natrijumove soli pravastatina |
| SK174-2002A SK1742002A3 (en) | 1999-08-06 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| SI200030653T SI1200385T2 (sl) | 1999-08-06 | 2000-08-04 | Kristali natrijeve soli pravastatina |
| IL14805000A IL148050A0 (en) | 1999-08-06 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| ES00946239T ES2235911T5 (es) | 1999-08-06 | 2000-08-04 | Procedimiento para la preparación de cristales de la sal sódica de pravastatina. |
| PL00365850A PL365850A1 (en) | 1999-08-06 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| HU0202536A HUP0202536A3 (en) | 1999-08-06 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| NZ516685A NZ516685A (en) | 1999-08-06 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| DK00946239T DK1200385T3 (da) | 1999-08-06 | 2000-08-04 | Krystaller af natriumsalt af pravastatin |
| CNB008113653A CN1205172C (zh) | 1999-08-06 | 2000-08-04 | 普伐他汀钠盐晶体 |
| KR1020027001231A KR100766928B1 (ko) | 1999-08-06 | 2000-08-04 | 결정형의 프라바스타틴 소듐염 |
| AU60109/00A AU782143B2 (en) | 1998-09-18 | 2000-08-04 | Crystals of the sodium salt of pravastatin |
| ZA200200437A ZA200200437B (en) | 1999-08-06 | 2002-01-17 | Crystals of the sodium salt of pravastatin. |
| BG106389A BG65368B1 (bg) | 1999-08-06 | 2002-02-05 | Кристали на натриевата сол на правастатин |
| IL148050A IL148050A (en) | 1999-08-06 | 2002-02-06 | Crystals of pravastatin sodium salt |
| US10/408,012 US6740775B1 (en) | 1999-08-06 | 2003-04-04 | Crystalline sodium salt of pravastatin |
| US11/400,872 US20060183929A1 (en) | 1999-08-06 | 2006-04-10 | Crystals of the sodium salt of pravastatin |
| IL187261A IL187261A0 (en) | 1999-08-06 | 2007-11-08 | Crystals of the sodium salt of pravastatin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI9900191A SI20305A (sl) | 1999-08-06 | 1999-08-06 | Kristali natrijeve soli pravastatina |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SI20305A true SI20305A (sl) | 2001-02-28 |
Family
ID=20432515
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI9900191A SI20305A (sl) | 1998-09-18 | 1999-08-06 | Kristali natrijeve soli pravastatina |
| SI200030653T SI1200385T2 (sl) | 1999-08-06 | 2000-08-04 | Kristali natrijeve soli pravastatina |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI200030653T SI1200385T2 (sl) | 1999-08-06 | 2000-08-04 | Kristali natrijeve soli pravastatina |
Country Status (24)
| Country | Link |
|---|---|
| US (3) | US7078558B1 (sl) |
| EP (1) | EP1200385B2 (sl) |
| JP (1) | JP2003506424A (sl) |
| KR (2) | KR100766928B1 (sl) |
| CN (1) | CN1205172C (sl) |
| AT (1) | ATE287389T1 (sl) |
| BG (1) | BG65368B1 (sl) |
| CA (1) | CA2379335A1 (sl) |
| CZ (1) | CZ2002414A3 (sl) |
| DE (1) | DE60017568T2 (sl) |
| DK (1) | DK1200385T3 (sl) |
| ES (1) | ES2235911T5 (sl) |
| HR (1) | HRP20020106A2 (sl) |
| HU (1) | HUP0202536A3 (sl) |
| IL (3) | IL148050A0 (sl) |
| NZ (1) | NZ516685A (sl) |
| PL (1) | PL365850A1 (sl) |
| PT (1) | PT1200385E (sl) |
| RU (1) | RU2247711C2 (sl) |
| SI (2) | SI20305A (sl) |
| SK (1) | SK1742002A3 (sl) |
| WO (1) | WO2001010813A1 (sl) |
| YU (1) | YU5402A (sl) |
| ZA (1) | ZA200200437B (sl) |
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| SI20305A (sl) * | 1999-08-06 | 2001-02-28 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Kristali natrijeve soli pravastatina |
| SI20070A (sl) * | 1998-09-18 | 2000-04-30 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Nove soli inhibitorjev HMG-CoA reduktaze |
| SK8312002A3 (en) | 1999-12-14 | 2003-05-02 | Biogal Gyogyszergyar | Novel forms of pravastatin sodium |
| JP2002121172A (ja) * | 2000-10-16 | 2002-04-23 | Sankyo Co Ltd | プラバスタチン又はその薬理上許容される塩の精製方法 |
| JP3236282B1 (ja) * | 2000-10-16 | 2001-12-10 | 三共株式会社 | プラバスタチンを精製する方法 |
| WO2002057229A1 (en) | 2001-01-19 | 2002-07-25 | Biocon India Limited | FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN) |
| US6716615B2 (en) | 2002-02-27 | 2004-04-06 | Yung Shin Pharmaceutical Ind. Co., Ltd. | Strains of saccharaothrix, process for producing pravastatin using the strains and isolation process of (HMG)-CoA reductase |
| CA2479005C (en) | 2002-03-18 | 2012-05-22 | Biocon Limited | Amorphous atorvastatin calcium or pravastatin sodium hmg-coa reductase inhibitors of desired particle size |
| JP4622855B2 (ja) * | 2003-06-10 | 2011-02-02 | 大正製薬株式会社 | 放射球状晶析物およびその製造方法並びにこれを利用するドライパウダー製剤 |
| CN1293874C (zh) * | 2003-08-18 | 2007-01-10 | 李朝晖 | 以洛伐他汀盐为主要活性成分的中药红曲及其制剂 |
| DE202004020671U1 (de) | 2003-11-24 | 2005-12-08 | Teva Gyogyszergyar Reszvenytarsasag | Pravastatin |
| EP1737449A1 (en) * | 2004-03-01 | 2007-01-03 | LEK Pharmaceuticals D.D. | Pharmaceutical composition |
| BRPI0514189A (pt) | 2004-08-06 | 2008-06-03 | Transform Pharmaceuticals Inc | composições farmacêuticas de estatina e métodos de tratamento relacionados |
| US20090042979A1 (en) * | 2004-08-06 | 2009-02-12 | Transform Pharmaceuticals Inc. | Novel Statin Pharmaceutical Compositions and Related Methods of Treatment |
| NZ552390A (en) * | 2004-08-06 | 2010-01-29 | Transform Pharmaceuticals Inc | Novel fenofibrate formulations and related methods of treatment |
| JP2007533663A (ja) * | 2005-02-09 | 2007-11-22 | テバ ジョジセルジャール ザ−トケルエン ムケド レ−スベニュタ−ルシャシャ−グ | プラバスタチンナトリウムの製造方法 |
| JP4895510B2 (ja) * | 2005-02-23 | 2012-03-14 | 株式会社トクヤマ | バリオールアミンの製造方法 |
| JP4813841B2 (ja) * | 2005-07-25 | 2011-11-09 | キユーピー株式会社 | プラバスタチンナトリウムの製造方法 |
| EP2288378A4 (en) * | 2008-04-16 | 2011-12-14 | Univ Utah Res Found | PHARMACOLOGICAL TARGETING OF VEGETABLE ILLNESS |
| CN101348476B (zh) * | 2008-09-05 | 2011-05-11 | 丽珠集团新北江制药股份有限公司 | 一种制备4,5,6,7-四氢普伐他汀及其钠盐的方法和固体结晶形式 |
| CN101648867B (zh) * | 2009-09-04 | 2012-07-11 | 天津大学 | 一种普伐他汀钠晶型及其制备方法和应用 |
| EP2343054A1 (en) | 2010-01-04 | 2011-07-13 | LEK Pharmaceuticals d.d. | Pellets and microparticles of pravastatin sodium and a process of making them |
| CN102533893A (zh) * | 2010-12-09 | 2012-07-04 | 浙江海正药业股份有限公司 | 一种制备莫那可林j的方法 |
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| CA2040865C (en) | 1990-05-15 | 2002-07-23 | James L. Bergey | Method for preventing, stabilizing or causing regression of atherosclerosis employing a combination of a cholesterol lowering drug and an ace inhibitor |
| NZ250609A (en) * | 1992-12-28 | 1995-07-26 | Sankyo Co | Hexahydronaphthalene esters and ring closed lactones; preparation and medicaments |
| KR100210482B1 (ko) * | 1997-04-10 | 1999-07-15 | 김종인 | 스트렙토마이세스엑스포리아투스(streptomycesexfoliatus)yj-118과이를이용한프라바스타틴나트륨의제조방법 |
| US6098031A (en) | 1998-03-05 | 2000-08-01 | Gsi Lumonics, Inc. | Versatile method and system for high speed, 3D imaging of microscopic targets |
| SI20305A (sl) * | 1999-08-06 | 2001-02-28 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Kristali natrijeve soli pravastatina |
| SI20070A (sl) * | 1998-09-18 | 2000-04-30 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Nove soli inhibitorjev HMG-CoA reduktaze |
| SI20072A (sl) * | 1998-09-18 | 2000-04-30 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Postopek za pridobivanje inhibitorjev HMG-CoA reduktaze |
| CN1590363A (zh) * | 1999-02-03 | 2005-03-09 | 药物研究所有限公司 | 结晶形式的普伐他汀的钠盐及其制备方法 |
| US6682913B1 (en) * | 1999-02-03 | 2004-01-27 | Institute For Drug Research Ltd. | Microbial process for preparing pravastatin |
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- 2000-08-04 WO PCT/IB2000/001103 patent/WO2001010813A1/en not_active Ceased
- 2000-08-04 KR KR1020027001231A patent/KR100766928B1/ko not_active Expired - Fee Related
- 2000-08-04 DE DE60017568T patent/DE60017568T2/de not_active Expired - Lifetime
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