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WO2011111070A2 - Nouvelle association injectable - Google Patents

Nouvelle association injectable Download PDF

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Publication number
WO2011111070A2
WO2011111070A2 PCT/IN2011/000159 IN2011000159W WO2011111070A2 WO 2011111070 A2 WO2011111070 A2 WO 2011111070A2 IN 2011000159 W IN2011000159 W IN 2011000159W WO 2011111070 A2 WO2011111070 A2 WO 2011111070A2
Authority
WO
WIPO (PCT)
Prior art keywords
citicoline
edaravone
solution
injectable formulation
injectable
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.)
Ceased
Application number
PCT/IN2011/000159
Other languages
English (en)
Other versions
WO2011111070A3 (fr
Inventor
Dharmesh Mahendrabhai Shah
Guruprasad Ramchandra Wader
Trushit Pramodray Mehta
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.)
BDR PHARMACEUTICALS INTERNATIONAL PVT Ltd
Original Assignee
BDR PHARMACEUTICALS INTERNATIONAL PVT Ltd
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 BDR PHARMACEUTICALS INTERNATIONAL PVT Ltd filed Critical BDR PHARMACEUTICALS INTERNATIONAL PVT Ltd
Publication of WO2011111070A2 publication Critical patent/WO2011111070A2/fr
Publication of WO2011111070A3 publication Critical patent/WO2011111070A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/0012—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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 stable injectable formulations comprising of a combination of a Cytidine derivative (I) and a pyrazolone derivative (II) of the following formulae, useful in the treatment of CNS disorders and ischemic strokes.
  • the present invention also relates to process of preparation of the said formulation.
  • Formula (I) as mentioned above represents Cytidine derivatives which exhibit pharmacological action in the biosynthesis of phosphatidycholine (Ptd Cho) and shows beneficial effects in various CNS injuries and neurogenerative diseases.
  • the neuroprotective action has resulted in its vide use in cerebral stroke treatment as well as in Alzheimer's disease.
  • Rl represents amino group or substituted amino group.
  • the substituents are alkyl, branched alkyl, aryl or heteroaryl group.
  • Notable amongst the active Cytidine derivatives is a compound Citicoline (IA) wherein Rl is NH2.
  • Citicoline is widely used in treatment of stroke and Cognitive Dysfunction in the elderly patients.
  • Cicoline also known as CDP-Choline or Cytidine 5'-diphosphocholine
  • CDP-Choline is a form of the essential nutrient Choline. It exhibits clinical efficacy in elderly patients in treatment of cognitive deficits, inefficient memory and early stage Alzheimer's disease.
  • Citicoline is also been useful as a therapy in stroke patients. Produced endogenously, Citicoline serves as a Choline donor in the metabolic path ways for biosynthesis of acetylcholine and neuronal membrane phospholipids, chiefly phosphatidylcholine.
  • Exogenous citicoline, as the sodium salt is useful for its cholinergic and neuroprotective action.
  • Citicoline is available in tablet and injectable forms for therapeutic applications. The recommended daily dosage is lgm /day.
  • Formula (II) represents Pyrazolone group compounds which exhibit antioxidant properties, wherein Rl, R2 and R3 can be same or different including hydrogen or alkyl, branched alkyl, saturated or unsaturated alkyl, substituted alkyl such as hydroxyl, halo, nitro, amino, sulfonyl, straight chain or branched chain alkyl, substituted or un-substituted aryl, hetero alkyl or heteroaryl with one or more hetero items.
  • Rl, R2 and R3 can be same or different including hydrogen or alkyl, branched alkyl, saturated or unsaturated alkyl, substituted alkyl such as hydroxyl, halo, nitro, amino, sulfonyl, straight chain or branched chain alkyl, substituted or un-substituted aryl, hetero alkyl or heteroaryl with one or more hetero items.
  • Rl, R2 and R3 can be same or different including hydrogen or alkyl, branche
  • Edaravone is chemically 3-methyl-l-phenyl-2-pyrazol-in-5-one. Being a free radial scavenger, it provides a potential treatment for Cerebral Ischemia and in regeneration of cells and tissues in cardiopulmonary arrest. It is administered as an intravenous injection. The recommended daily dosage is restricted to 60 mg/day.
  • Edaravone exhibits excellent antioxidant properties, its usage is restricted due to toxicity related issues associated with it. It is felt essential to augment beneficial effects of Edaravone without increasing the toxic effects, so that a formulation with enhanced efficacy without having additional side effects can be offered to the patients.
  • the inventors of the current invention aimed to study the synergistic effects of Edaravone and Cytidine derivatives to achieve a greater efficacy, without increasing the daily recommended dosages of Edaravone. Further, the present invention also provides a stable injectable formulation comprising Edaravone and Cytidine derivatives which is stable under accelerated conditions. Disclosure of the Invention;
  • the present invention provides stable Injectable formulation comprising combination of Citicoline (IA) and Edaravone (Il-a) along with suitable injectable excipients useful in the treatment of CNS disorders and ischemic strokes.
  • the route of administration of the Injection of the present invention is Intravenous drips.
  • the present invention encompasses the pharmaceutical salt, hydrate, solvate or polymorphic forms of the above two actives.
  • Citicoline (IA) and Edaravone (Il-a) are present in the formulation in the range of ratio of 5: 1 to 50: 1 , more preferably 25: 1.5.
  • Citicoline concentration can be adjusted in the range of 10 mg/ml to 100 mg/ml, preferably, 10 mg/ml to 50 mg/ml, more preferably 25 mg/ml concentration and Edaravone concentration can be adjusted in the range of 0.5 mg/ml to 10 mg/ml preferably 1.5 mg/ml
  • Total volume of the injection per dose is 20 ml containing 500 mg Citicoline and 30 mg Edaravone.
  • the dosage is adjusted as per the therapeutically accepted quantity namely Citicoline 1 gm/day and Edaravone 60 mg/day.
  • the dosage is generally in two divided doses, that is two injections per day.
  • the present invention provides a stable Injectable formulation comprising combination of Citicoline (IA) and Edaravone (Il-a) with Cyclodextrin derivatives and suitable injectable excipients.
  • Cyclodextrin derivative used in the present invention can be either single component or a mixture of the commercially available derivatives selected from, Alpha Cyclodextrin, Beta-Cyclodextrin, modified derivatives of these Alfa or Beta Cyclodextrin in various proportions.
  • the Cyclodextrin derivatives used in present invention is from 0.1% Mole ratio to 20% Mole ratio with respect to the Edaravone employed.
  • the solution preparation can be made either by using any injectable approved organic solvent such as aliphatic alcohols, dimethyl sulfoxide, polyethylene glycols or in absence of any such organic solvents.
  • the Injectable solutions can be additionally added with stabilizers such as chelating agents like EDTA and its salts, Citric Acid and its salts or Nitrilo acetic acid derivatives and its salts. Additionally the solution can be further stabilized by using antioxidants like Sodium Bisulphite, Sodium Metabisulphie, Cystiene Hydrochloride, Thiol acetic acid or Phenolic group derivatives. Also, approved stabilizers such as Butylated Hydroxy Anisole and its derivatives, Parabens and its salts can be employed in appropriate proportions.
  • stabilizers such as chelating agents like EDTA and its salts, Citric Acid and its salts or Nitrilo acetic acid derivatives and its salts. Additionally the solution can be further stabilized by using antioxidants like Sodium Bisulphite, Sodium Metabisulphie, Cystiene Hydrochloride, Thiol acetic acid or Phenolic group derivatives.
  • approved stabilizers such as Butylated Hydroxy Ani
  • the inventors of the present invention have carried out intensive investigations to study the effects to augment therapeutic efficacy of Edaravone while combining with other products having similar therapeutic effects and .
  • antioxidant and neurogenerative action was greatly enhanced in animal models when Citicoline and Edaravone both were simultaneously administrated by injectable route.
  • the antioxidant and neuroprotective action was found to be enhanced in comparison with the administration of either Citicoline or Edaravone alone.
  • the pH of the solution is then checked and adjusted in the range of 3 to 6, most preferably 3.5 to 5.5. After adjusting the pH, the solution is further stirred for 20 to 30 minutes, and then filtered successively through 0.45 and 0.2 micron size Poly filter membranes. The bulk solution is then analyzed by HPLC and UV for Edaravone content and Citicoline Sodium content. The Solution is then aseptically filled in 20 ml Vials and sealed to obtain regular injection preparation.
  • the invention also provides methods of treating CNS disorders and ischemic strokes, which comprises administering 'an effective amount' of the 'formulation of the present invention' to the subject suffering from CNS disorders and ischemic strokes.
  • the subject mentioned herein is human.
  • the invention further discloses use of the 'composition of the present invention comprising combination of Citicoline and Edaravone' in preparing the medicament to treat CNS disorders and ischemic strokes.
  • Injectable formulation was prepared by using following method.
  • the final Volume of the solution is made-up to 1000 ml by adding appropriate amount of Water for Injection.
  • the solution is stirred to dissolve and adjust the pH to 3.5 by using orthophosphoric acid.
  • the solution is then successively filtered through 0.45 micron and 0.25 micron poly membranes and then aseptically filled in 30 ml capacity vials having 20 ml solution per vial.
  • the solution of the vial contains Edaravone 1.5 mg per ml and Citicoline 25 mg per ml.
  • a Glass assembly In a Glass assembly, abovementioned components are mixed, the final volume of the solution is made-up to 1000 ml by adding appropriate amount of water for injection. The solution is stirred to dissolve and adjust the pH to 3.5 by using orthophosphoric acid. The solution is then successively filtered through 0.45 micron and 0.25 micron poly membranes and then aseptically filled in 30 ml capacity vials having 20 ml solution per vial. The solution of the vial contains Edaravone 1.5 mg per ml and Citicoline 25 mg per ml.
  • Example 5 In a Glass assembly, abovemnetioned components are mixed, the final volume of the solution is made-up to 1000 ml by adding appropriate amount of water for injection. The solution is stirred to dissolve and adjust the pH to 3.5 by using orthophosphoric acid. The solution is then successively filtered through 0.45 micron and 0.25 micron poly membranes and the solution is then aseptically filled in 30 ml capacity vials having 20 ml solution per vial. The solution of the vial contains Edaravone 1.5 mg per ml and Citicoline 25 mg per ml. The Stability of the Injectable solutions is found to be acceptable during a period of one year of study. Example 5:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention a pour objet une formulation injectable stable comprenant une association de Citicoline et d'Edaravone avec un dérivé de Cyclodextrine, utile pour le traitement de troubles du système nerveux central et d'accidents vasculaires cérébraux ischémiques et concerne en outre un procédé de préparation de ladite formulation.
PCT/IN2011/000159 2010-03-09 2011-03-09 Nouvelle association injectable Ceased WO2011111070A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2592MU2009 2010-03-09
IN2592/MUM/2009 2010-03-09

Publications (2)

Publication Number Publication Date
WO2011111070A2 true WO2011111070A2 (fr) 2011-09-15
WO2011111070A3 WO2011111070A3 (fr) 2011-12-22

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2011/000159 Ceased WO2011111070A2 (fr) 2010-03-09 2011-03-09 Nouvelle association injectable

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WO (1) WO2011111070A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103006550A (zh) * 2012-12-11 2013-04-03 哈药集团三精制药股份有限公司 一种胞磷胆碱钠注射液及其制备方法
CN103351342A (zh) * 2013-07-03 2013-10-16 浙江中医药大学 一种依达拉奉药物共晶及其制备方法
CN104490771A (zh) * 2014-12-19 2015-04-08 成都天台山制药有限公司 胞磷胆碱钠注射液药物组合物和制法
CN105012230A (zh) * 2014-04-30 2015-11-04 长春海悦药业有限公司 一种依达拉奉的药物组合物
CN110090225A (zh) * 2019-04-19 2019-08-06 济南康和医药科技有限公司 一种依达拉奉氯化钠注射液及其制备方法
CN111840220A (zh) * 2020-08-19 2020-10-30 开封康诺药业有限公司 一种胞磷胆碱钠注射液及其制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060264357A1 (en) * 1997-04-22 2006-11-23 Zikria Bashir A Capillary membrane stabilization and reduction of tissue injury through use of biodegradable macromolecules with antioxidants and/or other chemicals
US6683066B2 (en) * 2001-09-24 2004-01-27 Yanming Wang Composition and treatment method for brain and spinal cord injuries
TW200633990A (en) * 2004-11-18 2006-10-01 Takeda Pharmaceuticals Co Amide compound
WO2006094236A1 (fr) * 2005-03-03 2006-09-08 Sirtris Pharmaceuticals, Inc. Dérivés de n-phénylbenzamide en tant qu'agents régulant la sirtuine
WO2007130419A2 (fr) * 2006-05-04 2007-11-15 Merck & Co., Inc. Inhibiteurs de l'histone desacétylase pour le traitement de la neurodégénération

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103006550A (zh) * 2012-12-11 2013-04-03 哈药集团三精制药股份有限公司 一种胞磷胆碱钠注射液及其制备方法
CN103351342A (zh) * 2013-07-03 2013-10-16 浙江中医药大学 一种依达拉奉药物共晶及其制备方法
CN103351342B (zh) * 2013-07-03 2015-08-05 浙江中医药大学 一种依达拉奉药物共晶及其制备方法
CN105012230A (zh) * 2014-04-30 2015-11-04 长春海悦药业有限公司 一种依达拉奉的药物组合物
CN105012230B (zh) * 2014-04-30 2018-01-16 长春海悦药业股份有限公司 一种依达拉奉的药物组合物
CN104490771A (zh) * 2014-12-19 2015-04-08 成都天台山制药有限公司 胞磷胆碱钠注射液药物组合物和制法
CN110090225A (zh) * 2019-04-19 2019-08-06 济南康和医药科技有限公司 一种依达拉奉氯化钠注射液及其制备方法
CN111840220A (zh) * 2020-08-19 2020-10-30 开封康诺药业有限公司 一种胞磷胆碱钠注射液及其制备方法
CN111840220B (zh) * 2020-08-19 2022-09-30 开封康诺药业有限公司 一种胞磷胆碱钠注射液及其制备方法

Also Published As

Publication number Publication date
WO2011111070A3 (fr) 2011-12-22

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