DK166754B1 - Stabilt, injicerbart praeparat indeholdende 1,4-dihydroxy-5,8-bis-oe2-(2-hydroxyethylamino)-ethylaminoaa-anthraquinon, dihydrochlorid - Google Patents
Stabilt, injicerbart praeparat indeholdende 1,4-dihydroxy-5,8-bis-oe2-(2-hydroxyethylamino)-ethylaminoaa-anthraquinon, dihydrochlorid Download PDFInfo
- Publication number
- DK166754B1 DK166754B1 DK116687A DK116687A DK166754B1 DK 166754 B1 DK166754 B1 DK 166754B1 DK 116687 A DK116687 A DK 116687A DK 116687 A DK116687 A DK 116687A DK 166754 B1 DK166754 B1 DK 166754B1
- Authority
- DK
- Denmark
- Prior art keywords
- dihydroxy
- dihydrochloride
- bis
- hydroxyethylamino
- ethylaminoaa
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 5
- -1 2-HYDROXYETHYLAMINO Chemical class 0.000 title claims description 4
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000004471 Glycine Substances 0.000 claims description 6
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 5
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 5
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 5
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 5
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 5
- 239000004296 sodium metabisulphite Substances 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 239000000644 isotonic solution Substances 0.000 claims 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-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
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 229910001447 ferric ion Inorganic materials 0.000 description 1
- 229910001448 ferrous ion Inorganic materials 0.000 description 1
- 238000006864 oxidative decomposition reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Description
o
Forbindelsen 1,4-dihydroxy-5,8-bis-[2-(2-hydroxy- ethylamino)-ethylamino]-anthraquinon, dihydrochlorid med formlen: i DK 166754 B1
5 OH 0 NHCH2CH2NHCH2CH2OH
aAa I I ·2HC1
VYY
10 0H o NHCH2CH2NHCH2CH20H
er beskrevet i US-patentskrift nr. 4.197.249 og sælges under registreret varemærke "Novantrone" ©i Canada og 15 Europa og er i øjeblikket til behandling hos United States Food and Drug Administration for godkendelse som anti-cancer-middel.
Det er kendt, at denne forbindelse undergår oxidativ sønderdeling i vandig opløsning. Denne sønderdeling sker 20 langt hurtigere ved tilstedeværelsen af metalioner såsom cupro-, cupri-, ferro- eller ferriioner, selv når de forefindes i små mængder (f.eks. mindre end 10 ppm).
Da denne forbindelse udviser optimal pharmakologisk aktivitet i mennesker, når den indgives parenteralt (intra-25 muskulært, intravenøst) i modsætning til oral indgivelse, er det yderst vigtigt, at opløsninger af denne forbindelse forbliver stabile i længere perioder under normale opbevaringsforhold.
Det har vist sig, at hensyntagen til en kombination 30 af kritiske faktorer i et vandigt præparat af 1,4-dihydroxy--5,8-bis- [2- (2-hydroxyethylamino) -ethylamino ]-anthraquinon, dihydrochlorid giver et præparat, der er yderst stabilt under normale opbevaringsforhold.
Disse faktorer omfatter 1) medanvendelse af en egnet 35 antioxidant, 2) specifikt pH-område, og 3) medanvendelse af en egnet metalionchelator.
Med hensyn til antioxidanter har det vist sig, at den mest effektive er natriummetabisulfit.
2 DK 166754 B1
Det mest effektive pH-område er 2,0-3,5, idet 3,0 er det optimale.
Den mest effektive metalionchelator er en kombination 5 af dinatrium-EDTA og glycin.
Da det ønskede injicerbare præparat af 1,4-dihydroxy--5,8-bis-[2-(2-hydroxyethylamino)-ethylamino]-antraquinon, dihydrochlorid indeholder 1 til 5 mg af denne forbindelse per ml af præparatet, vil denne nye stabile formel have 10 en pH-værdi på 2,0 til 3,5, hvor 3,0 er det optimale, en natrimnbisulfitkoncentration på 0,01 til 0,10 vægt-%, hvor 0,5 vægt-% er det optimale, dinatrium-EDTA ved en koncentration på 0,01 til 0,11 vægt-%, hvor 0,10 vægt-% er det optimale, og en glycinkoncentration på 0,05 til 0,2 vægt-% 15 med 0,1 vægt-% som det optimale.
For at bevise den forøgede stabilitet af dette nye præparat fremstilles formler med følgende sammensætning, og der gennemføres stabilitetsstudier. Alle procentangivelser er efter vægt.
20
Formel I
1.4- Dihydroxy-5,8-bis-[2-(2-hydroxyethylamino)- -ethylamino]-antraquinon, dihydrochlorid ..... 2 mg/ml
Vand til injicering, U.S.P............... ad 100% 25 Frirum....................................... luft '
Formel II
1.4- Dihydroxy-5,8-bis-[2-(2-hydroxyethylamino)- ethylamino]-antraquinon, dihydrochlorid ...... 2 mg/ml 30 Cupriioner ...'................................ 7 ppm
Vand til injicering, U.S.P............... ad 100%
Frirum....................................... luft pH-værdi..................................... 5,50 35 DK 166754 B1
O
3
Formel III
1.4- Dihydroxy-5,8-bis-[2-(2-hydroxyethylamino)- -ethylamino]-antraquinon, dihydrochlorid ....... 2 mg/ml
Natrium, metabisulfit............................ 0,01% 5 Natriumacetat .................................. 0,005%
Iseddike ....................................... 0,046%
Natriumchlorid................................. 0,80%
Vand til injicering, U.S.P................. ad 100% pH-værdi ....................................... 3,5 10 Frirum ......................................... nitrogen
Formel IV
1.4- Dihydroxy-5,8-bis-[2-(2-hydroxyethylamino)- -ethylamino]-antraquinon, dihydrochlorid ....... 2 mg/ml 15 Natriummetabisulfit ............................ 0,05%
Dinatrium-EDTA ................................. 0,10%
Glycin ......................................... 0,10%
Natriumchlorid (isotonisk stof) ................ 0,786%
Vand til injicering, U.S.P................. ad 100% 20 pH-værdi ....................................... 3,0%
Frirum ......................................... som indikeret* * En portion ifyldes under nitrogen, to portioner under luft.
Resultaterne af disse stabilitetsstudier fremgår af 25 nedenstående: 30 35 DK 166754 B1
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DK 166754 B1
Ovenstående resultater viser fordelene ved dette hidtil ukendte præparat ifølge opfindelsen i forhold til det kendte præparat og en vandig opløsning af dette lægemiddel.
5 Ligesom de fleste anti-cancerlægemidler er doseringen af "Novantrone" ^ baseret på patientens kropsoverflade og sygdomstilstand. Det er yderst fordelagtigt udfra et omkostnings- og marketingsynspunkt, at "Novantrone"® -produktet fås i så små størrelser som 2 ml hætteglas. På 10 grund af det relativ højere forhold mellem frirum og volumen i små hætteglas i forhold til større hætteglas, bliver stabiliteten af dette produkt imidlertid kritisk i små 2 ml hætteglas. Det er vigtigt at lægge mærke til, at det hidtil ukendte præparat har vist sig at være overlegent i for-15 hold til tidligere præparater i hætteglas med både lille og relativt stort volumen.
For at illustrere stabiliteten i præparatet ifølge opfindelsen er der fremstillet en sammensætning som følger:
20 Formel V
1,4-Dihydroxy-5,8-bis-[2-(2-hydroxyethyl amino)--ethylamino]-antraquinon, dihydrochlorid ...... 2 mg/ml
Dinatrium-EDTA ................................ 0,10%
Natriummetabisulfit ........................... 0,04% 25 Glycin........................................ 0,10%
Natriumchlorid (isotonisk stof) ............... 0,60%
Vand til injicering, U.S.P................ ad 100% pH-værdi....................................... 3,0
Til denne formel (V) og til en sammensætning af formel 30 (I) er der blevet tilsat cupriioner i en koncentration på 6 ppm, og stabiliteten blev derefter undersøgt ved 56°C i 4 uger. Resultaterne efter dette tidsrum viste, at formel (I) tabte 98% af sin kraft på 2 dage, medens formel (V) beholdt 98,6% af kraften efter 4 uger.
35
Claims (2)
1. Farmaceutisk præparat, kendetegnet ved, at det omfatter 1-5 mg pr. ml præparat 1,4-dihydroxy- 5,8-bis- [2- (2-hydroxyethylamino) -ethylamino] -anthraguinon, 5 dihydrochlorid i en isotonisk opløsning ved en pH-værdi på 2,0-3,5, indeholdende natriummetabisulfit i en koncentration på 0,01-0,10 vægt-%, dinatrium-EDTA i en koncentration på 0,01-0,11 vægt-% og glycin i en koncentration på 0,05-0,20 vægt-%, 10
2. Præparat ifølge krav 1, kendetegnet ved, at koncentrationen af l,4-dihydroxy-5,8-bis-[2-(2-hydr-oxyethylamino)-ethylamino]-anthraquinon, dihydrochlorid er 2 mg/ml, og koncentrationerne af natriummetabisulfit, di-15 natrium-EDTA og glycin er henholdsvis 0,05 vægt-%, 0,10 vægt-% og 0,10 vægt-%. Λ
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US83724386A | 1986-03-07 | 1986-03-07 | |
| US83724386 | 1986-03-07 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK116687D0 DK116687D0 (da) | 1987-03-06 |
| DK116687A DK116687A (da) | 1987-09-08 |
| DK166754B1 true DK166754B1 (da) | 1993-07-12 |
Family
ID=25273922
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK116687A DK166754B1 (da) | 1986-03-07 | 1987-03-06 | Stabilt, injicerbart praeparat indeholdende 1,4-dihydroxy-5,8-bis-oe2-(2-hydroxyethylamino)-ethylaminoaa-anthraquinon, dihydrochlorid |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0236822B1 (da) |
| JP (1) | JPH0717500B2 (da) |
| KR (1) | KR900002030B1 (da) |
| AT (1) | ATE59290T1 (da) |
| AU (1) | AU593330B2 (da) |
| CA (1) | CA1283607C (da) |
| DE (1) | DE3766984D1 (da) |
| DK (1) | DK166754B1 (da) |
| ES (1) | ES2033247T3 (da) |
| FI (1) | FI84977C (da) |
| GR (1) | GR3001503T3 (da) |
| HK (1) | HK63991A (da) |
| HU (1) | HU199286B (da) |
| IE (1) | IE60025B1 (da) |
| IL (1) | IL81681A (da) |
| NO (1) | NO173635C (da) |
| NZ (1) | NZ219454A (da) |
| PH (1) | PH22808A (da) |
| PT (1) | PT84398B (da) |
| SG (1) | SG45292G (da) |
| ZA (1) | ZA871652B (da) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0705601B1 (de) * | 1994-10-04 | 2000-01-19 | LOMAPHARM Rudolf Lohmann GmbH KG Pharmazeutische Fabrik | Lösungen von Anthrachinonen zur parenteralen Applikation |
| DE19818802A1 (de) * | 1998-04-27 | 1999-10-28 | Dresden Arzneimittel | Stabile Mitoxantron-Lösungen |
| TW200526268A (en) * | 2003-12-17 | 2005-08-16 | Takeda Pharmaceutical | Injectable composition |
| EP2649993B1 (en) * | 2010-12-09 | 2017-04-05 | Maruishi Pharmaceutical Co., Ltd. | Stabilizer of acetaminophen |
| CN114601791B (zh) * | 2020-12-08 | 2023-09-19 | 成都倍特药业股份有限公司 | 一种盐酸米托蒽醌液体制剂及其制备方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3230143A (en) * | 1965-05-14 | 1966-01-18 | Merck & Co Inc | Antihypertensive injection methods using acid addition salts of alkyl esters of alpha-methyl-3, 4-dihy-droxyphenylalanine |
| US4223022A (en) * | 1978-01-16 | 1980-09-16 | Schering Corporation | Stabilized aminoglycoside antibiotic formulations |
| US4328213A (en) * | 1979-11-28 | 1982-05-04 | Schering Corporation | Stable injectable labetalol formulation |
| DE3574932D1 (de) * | 1984-02-27 | 1990-02-01 | American Cyanamid Co | Verwendung von 1,4 bisubstituierten anthrachinonen zur herstellung von immunsuppressiva. |
-
1987
- 1987-02-20 DE DE8787102448T patent/DE3766984D1/de not_active Expired - Lifetime
- 1987-02-20 EP EP87102448A patent/EP0236822B1/en not_active Expired - Lifetime
- 1987-02-20 ES ES198787102448T patent/ES2033247T3/es not_active Expired - Lifetime
- 1987-02-20 AT AT87102448T patent/ATE59290T1/de not_active IP Right Cessation
- 1987-02-26 IL IL81681A patent/IL81681A/xx not_active IP Right Cessation
- 1987-03-02 NZ NZ219454A patent/NZ219454A/en unknown
- 1987-03-04 PT PT84398A patent/PT84398B/pt unknown
- 1987-03-04 PH PH34969A patent/PH22808A/en unknown
- 1987-03-05 CA CA000531200A patent/CA1283607C/en not_active Expired - Lifetime
- 1987-03-06 AU AU69773/87A patent/AU593330B2/en not_active Expired
- 1987-03-06 KR KR1019870002031A patent/KR900002030B1/ko not_active Expired
- 1987-03-06 FI FI870994A patent/FI84977C/fi not_active IP Right Cessation
- 1987-03-06 HU HU87969A patent/HU199286B/hu not_active IP Right Cessation
- 1987-03-06 NO NO870950A patent/NO173635C/no unknown
- 1987-03-06 DK DK116687A patent/DK166754B1/da not_active IP Right Cessation
- 1987-03-06 JP JP62050398A patent/JPH0717500B2/ja not_active Expired - Lifetime
- 1987-03-06 ZA ZA871652A patent/ZA871652B/xx unknown
- 1987-03-06 IE IE56987A patent/IE60025B1/en not_active IP Right Cessation
-
1991
- 1991-02-26 GR GR90400362T patent/GR3001503T3/el not_active IP Right Cessation
- 1991-08-15 HK HK639/91A patent/HK63991A/en not_active IP Right Cessation
-
1992
- 1992-04-24 SG SG45292A patent/SG45292G/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |