EP1443902A2 - Verfahren zur herstellung von stabilen lösungen phenolischer substanzen und resultierende lösungen - Google Patents

Verfahren zur herstellung von stabilen lösungen phenolischer substanzen und resultierende lösungen

Info

Publication number
EP1443902A2
EP1443902A2 EP02803055A EP02803055A EP1443902A2 EP 1443902 A2 EP1443902 A2 EP 1443902A2 EP 02803055 A EP02803055 A EP 02803055A EP 02803055 A EP02803055 A EP 02803055A EP 1443902 A2 EP1443902 A2 EP 1443902A2
Authority
EP
European Patent Office
Prior art keywords
solutions
solution
new process
argon
process according
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Withdrawn
Application number
EP02803055A
Other languages
English (en)
French (fr)
Inventor
Bernard Dinnequin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratoire Aguettant SAS
Original Assignee
Laboratoire Aguettant SAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Laboratoire Aguettant SAS filed Critical Laboratoire Aguettant SAS
Publication of EP1443902A2 publication Critical patent/EP1443902A2/de
Withdrawn legal-status Critical Current

Links

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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates to the field of therapeutic chemistry and more particularly to the field of pharmacotechnology.
  • It relates more specifically to a process for producing stabilized solutions containing as active principle at least one phenolic substance characterized in that one proceeds to the deoxygenation of the solutions of phenolic substance by a lighter inert gas and in that the dead volumes of the tanks and the production pipes are deoxygenated before and after filling the products with a dense inert gas to obtain stabilized solutions of phenolic substance.
  • the method is characterized by the fact that all the operations are carried out with permanently deoxygenated water by bubbling with an inert gas, by the fact that the temperature of the water and of the solution is preferably maintained between 8 ° C and 10 ° C in order to avoid re-oxygenation and in that the pH of the solution during manufacture is adjusted above 3.0 and below 5.0.
  • antioxidant agent and in particular the addition of sulfites, complexing agent and / or anti-radical stabilizing agent as is usual in the preparations of the prior art, is not no longer needed.
  • Analysis of the solutions shows the absence of degradation product.
  • this process makes it possible to carry out sterilization by sterilizing double filtration at ordinary temperature or below room temperature, without having to use a sterilization or tyndallization process using heat.
  • the method according to the invention therefore has the advantage of not requiring the use of antioxidant, complexing agent, preservative or buffer solution and of allowing sterilization at low temperature. In this way the risks of oxidation of the molecules are considerably reduced.
  • easily oxidizable phenolic substances is meant in particular the catechoiamine derivatives, that is to say aromatic compounds optionally substituted on the ring by one or more hydroxyls and carrying an ⁇ -hydroxylated or ketone aliphatic chain and a terminal amino group, substituted or unsubstituted.
  • catechoiamines include adrenaline, noradrenaline, isosuproxin, isoprenaline, dobutamine, dopamine, dimetofrine, dipivefrin, ephedrine, ibopamine, metaraminol, octopamine, phenyl propanolamine, phenyl propyl methylamine, pholedrine, propyl hexedrine, pseudoephedrine, adrenalone, amidephrine, metaproterenoi, paracetamol or propacetamol.
  • a phenomenon of racemization the racemization of solutions of adrenaline or noradrenaline for example is a known phenomenon linked mainly to pH and temperature. It results in the formation of a dextrorotatory isomer with little pharmacological activity.
  • the racemization reaction can be significant at pH below 3.0. It is accelerated by raising the temperature. It is slowed down by keeping the solution at low temperature.
  • the dosages indicate that if the water for injectable solution contains about 0.1 ppm of dissolved oxygen, the oxygen content in the solution before filtration and the residual oxygen content in the primary packaging are often well below the value of 2 ppm.
  • the process for manufacturing stable solutions of phenolic substances comprises the following steps:
  • Nitrogen or any other inert gas is used for degassing PPi water, the solution during manufacture and during sterilizing double filtration, when the solution is transferred to the transfer tank and for degas the solution when filling the ampoules.
  • nitrogen is meant pure gas or any inert gas mixture where nitrogen is present.
  • Argon or any other dense inert gas is used for the deoxygenation of the manufacturing tanks and for their coating (manufacturing and transfer tanks), as well as for the deoxygenation of the empty ampoules or vials and the inerting of the residual volume of the ampoules full or full vials.
  • Argon is understood to mean any gas or gaseous mixture containing argon alone or in mixture with another noble gas more dense than air.
  • the inerting of the solutions in the bottles or ampoules is essential and avoids the oxidation of the catecholamine salt leading to the appearance of the degradation products which are investigated during the control of the finished product.
  • measurements of residual oxygen dissolved in the solution were carried out and specifications were fixed.
  • argon or other inert gases requires tests to be carried out in order to set the optimal conditions of use, in particular with regard to the inerting of the containers, which constitutes the most important critical point. .
  • noradrenaline solution without preservative 8 mg / 4 ml and 16 mg / 8 ml
  • dopamine hydrochloride solution without preservative at 50 mg and 200 mg in 5 ml.
  • Dobutamine hydrochloride solution at 2.5% (m / v) -250 mg-without preservative in 20 ml etc ...
  • the basic parameters (line speed and argon pressure) were set at the start based on the results obtained.
  • the dissolved oxygen contents are much higher (from 0.75 to 1.87 ppm).
  • the values are in compliance.
  • the rates are lower than normal depending on the duration of the outage. This proves the effectiveness of coating with an inert gas such as argon.
  • the argon pressure on the filler must be set according to the speed of the distributor at 7200 products / hour.
  • the collection tank must be immediately placed under argon after filtration, and maintained under argon pressure throughout the filling.
  • the preservative-free catechoiamine solution keeps perfectly for 12 months at 278 ° C.
  • the solution remains clear and colorless.
  • the pH does not vary.
  • the pH does not vary.
  • the concentration of active ingredient decreases and becomes out of the norm after 9 months of storage.
  • the invention also relates to injectable solutions based on catechoiamines provided that they are prepared according to the process of the invention. They find use in human or animal therapy, in particular as hypertensive and / or analgesic agents.
  • the water for injections is cooled and the dissolved oxygen content is stabilized at a maximum of 0.02 ppm by bubbling nitrogen or another inert gas.
  • the manufacturing tank is deoxidized by coating with argon or another dense inert gas.
  • the solution undergoes a sterilizing double filtration under an atmosphere of argon or another dense inert gas.
  • the solution is filled under double inerting: pre-inerting with nitrogen or any other inert gas and post-inerting with nitrogen or any other dense inert gas, so as to ensure a level of dissolved oxygen in the solution and a rate of residual oxygen in the free volume of the packaging, perfectly defined.
  • the controls were carried out on 5 samples in batches distributed throughout the manufacturing
  • the dissolved oxygen level is perfectly controlled throughout the manufacturing stages; for this, regular measurements are made at different stages.
  • the controls were carried out on 5 samples per batch distributed throughout the 5 manufacturing.
  • the dissolved oxygen level is perfectly controlled throughout the manufacturing stages; for this, regular measurements are made at the different stages.
  • the controls were carried out on 5 samples in batches distributed throughout the 0 manufacturing.
  • Example 2 By operating as in Example 1, starting with 0.25 g of adrenaline hydrochloride, 1,000 ampoules are obtained, each containing 0.25 mg of adrenaline per unit dose.
  • Example 2 By operating as in Example 1, starting with 2.00 g of isoprenaline hydrochloride, 10,000 ampoules are obtained, each containing 0.2 mg of isoprenaline hydrochloride per unit dose.
  • Example 7 Starting from 2.00 g of dopamine hydrochloride by operating as in Example 1, 10,000 ampoules are obtained, each containing 0.2 mg of dopamine hydrochloride per unit dose.
  • Example 7 Starting from 2.00 g of dopamine hydrochloride by operating as in Example 1, 10,000 ampoules are obtained, each containing 0.2 mg of dopamine hydrochloride per unit dose.
  • Example 2 By operating according to the procedure described in Example 1, starting from 2500 g of dobutamine hydrochloride, 10,000 ampoules are obtained, each containing 250 mg of dobutamine per unit dose.
  • Example 2 By operating according to the procedure described in Example 1, starting from 100 g of dipivefrin hydrochloride, 10,000 ampoules are obtained, each containing 0.01 g of dipivefrin per unit dose.
  • Example 2 By operating according to the procedure of Example 1, starting from 5000 g of terbutaline sulfate, 10,000 ampoules are obtained, each containing 0.5 g of terbutaline (sulfate) per unit dose.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP02803055A 2001-11-15 2002-11-15 Verfahren zur herstellung von stabilen lösungen phenolischer substanzen und resultierende lösungen Withdrawn EP1443902A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0114796 2001-11-15
FR0114796A FR2832063B1 (fr) 2001-11-15 2001-11-15 Procede de production de solutions stables de substances phenoliques et les solutions en resultant
PCT/FR2002/003922 WO2003041687A2 (fr) 2001-11-15 2002-11-15 Procede de production de solutions stables de substances phenoliques et les solutions en resultant

Publications (1)

Publication Number Publication Date
EP1443902A2 true EP1443902A2 (de) 2004-08-11

Family

ID=8869440

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02803055A Withdrawn EP1443902A2 (de) 2001-11-15 2002-11-15 Verfahren zur herstellung von stabilen lösungen phenolischer substanzen und resultierende lösungen

Country Status (4)

Country Link
US (1) US7199269B2 (de)
EP (1) EP1443902A2 (de)
FR (1) FR2832063B1 (de)
WO (1) WO2003041687A2 (de)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
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FR2880807B1 (fr) * 2005-01-19 2007-04-13 Aguettant Sa Lab Composition pharmaceutique injectable
WO2011071400A1 (en) 2009-12-10 2011-06-16 Tecnimede - Sociedade Técnico-Medicinal, S.A. Method and composition for preparing stable liquid formulations of paracetamol
US20110207824A1 (en) * 2010-02-25 2011-08-25 Moly Pharma Formulation of an injectable paracetamol solution, method for preparing and packaging such a solution and device for packaging such a solution
PL3287123T3 (pl) 2011-03-04 2020-11-02 Grünenthal GmbH Wodny preparat farmaceutyczny tapentadolu do podawania doustnego
CN103371969A (zh) * 2012-04-17 2013-10-30 上海禾丰制药有限公司 重酒石酸间羟胺注射液及其制剂工艺
UY35988A (es) * 2014-02-27 2015-09-30 Sint Sa Proceso para la producción de una solución inyectable de noradrenalina de baja concentración
US10105326B2 (en) * 2014-05-13 2018-10-23 Centre Hospitalier Regional Et Universitaire De Lille (Chru) Pharmaceutical solution comprising dopamine for use in treating parkinson's disease
PL2990031T3 (pl) 2014-08-28 2020-05-18 Sun Pharmaceutical Industries Ltd Pozajelitowa postać norepinefryny
CN104523582A (zh) * 2014-12-16 2015-04-22 成都新恒创药业有限公司 一种稳定的硫酸特步他林注射液及制备工艺
HRP20190231T1 (hr) 2015-03-27 2019-04-05 Grünenthal GmbH Stabilna formulacija za parenteralnu primjenu tapentadola
EP3120837A1 (de) 2015-07-22 2017-01-25 Stada Arzneimittel Ag Verfahren zur herstellung einer bortezomibester-lösung
CA3037810A1 (en) 2016-09-23 2018-03-29 Grunenthal Gmbh Stable formulation for parenteral administration of tapentadol
WO2018140894A1 (en) 2017-01-30 2018-08-02 Nevakar, Inc Norepinephrine compositions and methods therefor
US20250177328A1 (en) 2017-01-30 2025-06-05 Nevakar Injectables Inc. Norepinephrine compositions and methods therefor
WO2019150381A1 (en) * 2018-02-01 2019-08-08 Joshi Mahendra R A stable pharmaceutical composition and process for production of isoproterenol hydrochloride injection
FR3095122B1 (fr) * 2019-04-18 2021-04-09 Crossject Solution pharmaceutique d’adrénaline pour dispositif d’injection
EP4114336A1 (de) 2020-03-06 2023-01-11 Baxter International Inc. Verpacktes, abgedichtetes behältersystem zur stabilen lagerung einer sauerstoffempfindlichen pharmazeutischen formulierung
WO2022083993A1 (en) 2020-10-21 2022-04-28 Sintetica S.A. Stable, injectable noradrenaline solutions free of antioxidants
PL4231996T3 (pl) * 2020-10-21 2025-02-10 Sintetica S.A. Gotowe do użycia, worki do wlewów z noradrenaliną, o niskiej liczbie cząstek niewidocznych gołym okiem
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
CN112826793A (zh) * 2021-01-25 2021-05-25 石家庄四药有限公司 一种硫酸特布他林注射液及其制备方法
IL319375A (en) 2022-09-14 2025-05-01 Inbrain Pharma Pharmaceutical solution containing dopamine for injection
CN116983259A (zh) * 2023-09-27 2023-11-03 成都瑞尔医药科技有限公司 一种依托泊苷注射液的制备方法
CN119745847A (zh) * 2025-01-10 2025-04-04 上海上药第一生化药业有限公司 一种盐酸多巴酚丁胺药组合物及其制备方法和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2809619B1 (fr) * 2000-06-06 2004-09-24 Pharmatop Nouvelles formulations aqueuses de principes actifs sensibles a l'oxydation et leur procede d'obtention

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03041687A3 *

Also Published As

Publication number Publication date
WO2003041687A3 (fr) 2004-03-04
US20050070613A1 (en) 2005-03-31
US7199269B2 (en) 2007-04-03
FR2832063B1 (fr) 2004-08-27
WO2003041687A2 (fr) 2003-05-22
FR2832063A1 (fr) 2003-05-16

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