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WO2016038626A1 - Compositions pharmaceutiques de vitamine kl - Google Patents

Compositions pharmaceutiques de vitamine kl Download PDF

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Publication number
WO2016038626A1
WO2016038626A1 PCT/IN2015/000356 IN2015000356W WO2016038626A1 WO 2016038626 A1 WO2016038626 A1 WO 2016038626A1 IN 2015000356 W IN2015000356 W IN 2015000356W WO 2016038626 A1 WO2016038626 A1 WO 2016038626A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
pharmaceutical composition
active ingredient
formulation
dose
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/IN2015/000356
Other languages
English (en)
Inventor
Mukund Keshav Gurjar
Sougata Pramanick
Samit Satish 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.)
Emcure Pharmaceuticals Ltd
Original Assignee
Emcure Pharmaceuticals 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 Emcure Pharmaceuticals Ltd filed Critical Emcure Pharmaceuticals Ltd
Publication of WO2016038626A1 publication Critical patent/WO2016038626A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • the present invention relates to pharmaceutical compositions comprising trans isomer of Vitamin Kl and processes for preparation thereof.
  • Vitamin K is the generic name for 2-methyl-l,4-naphthoquinone derivatives having activity on blood-coagulation and electron transport systems. Vitamin K was first identified in 1929 by Danish scientist Henrik Dam during his investigations regarding the role of cholesterol in metabolism of chicken. These substances were found to be essential for synthesizing prothrombin in the liver, which is a precursor of the enzyme thrombin causing blood coagulation reaction and were also known to prevent release of calcium from the bones.
  • Vitamin Kl also known as phylloquinone, phytonadione or phytomenadione is known to be the active ingredient which exhibits significant anticoagulant activity.
  • Vitamin Kl chemically identified as, 2-Methyl-3-[(2E,7R,l lR)-3,7,l l,15- tetramethyl-2-hexadecenyl]-l,4-naphthalenedione has two geometrical isomers (cis / trans or Z / E isomers) as well as two asymmetric centres at C7 and CI 1, each generating a pair of two enantiomers.
  • 2'trans- 7R, 11R stereoisomer having chemical structure as given below, is the only active isomer and hence, the desired diastereomer.
  • Vitamin Kl Injection (Phytonadione Injectable Emulsion, USP) is indicated for the following coagulation disorders which is due to formation of factors II, VII, IX and X when caused by vitamin K deficiency or interference with vitamin K activity. a) anticoagulant-induced prothrombin deficiency caused by coumarin or indanedione derivatives;
  • hypoprothrombinemia secondary to factors limiting absorption or synthesis of vitamin K, e.g., obstructive jaundice, biliary fistula, sprue, ulcerative, colitis, . celiac disease, intestinal resection, cystic fibrosis of the pancreas, and regional enteritis;
  • vitamin K e.g., obstructive jaundice, biliary fistula, sprue, ulcerative, colitis, . celiac disease, intestinal resection, cystic fibrosis of the pancreas, and regional enteritis
  • Vitamin K injection formulation in the adult patients is in the range of 2.5 to 25 mg or more (rarely up to 50 mg) to prevent the anticoagulant induced prothrombin deficiency as well as to treat hypoprothrombenemia.
  • the analytical method for injectable formulations of Vitamin Kl comprises liquid chromatographic (LC) analysis using the stationary phase octadecyl silanes (ODS or CI 8), chemically bonded to porous silica or ceramic particles, and a mixture of alcohol and water as mobile phase.
  • LC liquid chromatographic
  • ODS octadecyl silanes
  • CI 8 octadecyl silanes
  • mobile phase is a mixture of n-hexane and n-amyl alcohol.
  • the API assay method from USP is capable of distinguishing the geometrical (also called cis / trans or Z/E) isomers, whereas the USP method for injectable emulsion does not exhibit separation for cis-trans isomers.
  • the USP method for injectable emulsion does not exhibit separation for cis-trans isomers.
  • none of these methods is capable of distinguishing diastereomers of Vitamin Kl .
  • the LC method developed and used by present inventors is capable of separating geometrical isomers as well as the diastereomers of Vitamin Kl .
  • It is therefore an object of the present invention to provide a pharmaceutical composition comprising primarily of the desired, active diastereomer of vitamin Kl in its pure form.
  • Another object of the present invention is to provide a simple formulation, suitable for parenteral administration comprising primarily of the active trans-isomer of vitamin Kl in its pure form.
  • Yet another object of the present invention is to provide a simple, commercially viable process for preparation of an injectable formulation of vitamin Kl .
  • the present invention relates to stable pharmaceutical compositions comprising a desired diastereomer of phytonadione.
  • the formulation specifically an injectable composition, contains the desired trans-isomer, in an amount of at least 50% of the total weight of active ingredient.
  • the desired trans isomer is at least about 75% of the total weight of the active ingredient in the formulation.
  • the present invention comprises a composition composed of the desired trans-isomer (phytonadione); and substantially free of other diastereomers, geometrical isomers and impurities.
  • the present invention sets forth a simple composition for vitamin K suitable for parenteral administration; wherein the formulation when administered to a human subject exhibits pharmacokinetic properties such as Cmax and AUC, comparable with the marketed formulation but are achieved by a significant reduction in the therapeutic dose.
  • the present invention provides a 5 to 50 percent dose reduction of the active ingredient and yet achieves the desired pharmacokinetic profile required to observe the therapeutic effect.
  • the present invention sets forth a safe and commercially viable process for preparation of an injectable composition for vitamin K that is sufficiently stable to provide an acceptable shelf life.
  • FIG. -1 is a chromatogram of the marketed injectable formulation, manufactured by Hospira, by using API assay method in United States Pharmacopoeia (USP).
  • FIG. -2 is a chromatogram of the marketed injectable formulation, manufactured by Hospira, by using USP method for phytonadione injectable emulsion.
  • FIG. - 3 is a chromatogram of the marketed injectable formulation, manufactured by Hospira, by using a chiral column.
  • FIG. - 4 is a chromatogram of the injectable formulation, developed according to an embodiment of the present invention, by using a chiral column.
  • FIG. - 5 is a linear plot of mean baseline corrected plasma concentrations versus time.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising primarily of the desired, active diastereomer of vitamin Kl in its pure form.
  • the formulation also contains suitable excipients which imparts to the novel formulation its desired properties.
  • the present invention relates to an injectable emulsion pharmaceutical compositions, suitable for parenteral administration, comprising desired diastereomer, 2-Methyl-3- [(2E,7R,11R)-3,7,1 l ,15-tetramethyl-2-hexadecenyl]-l,4-naphthalene-dione (phytonadione).
  • active ingredient means all stereoisomers, including geometric isomers of vitamin Kl and their salts.
  • trans isomer or “desired isomers” means a Vitamin Kl isomer having 2'trans-7R, 11R configuration and known chemically as 2-Methyl- 3-[(2E,7R, 11 R)-3,7, 11,15-tetramethyl-2-hexadecenyl]- 1 ,4-naphthalene-dione.
  • emulsion or "emulsion formulation” means a colloidal dispersion of two immiscible liquids in the form of droplets, whose diameter, iri general, is less than 1 micron.
  • An emulsion is denoted by the symbol O/W if the continuous phase is an aqueous solution and by W/O if the continuous phase is oil.
  • Other examples of emulsions such as 0/W/O include oil droplets contained within aqueous droplets dispersed in a continuous oil phase.
  • oil means a general sense to identify hydrocarbon derivatives, carbohydrate derivatives, or similar organic compounds that are liquid at body temperatures, e.g., about 37 °C and are pharmacologically acceptable in injectable compositions. It includes glycerides or non-glycerides. These are generally non-polar compounds that are not immediately miscible with water.
  • oil component and “non-aqueous phase” are used interchangeably and refers to oil, or a combination of multiple oils and oil soluble pharmaceutically acceptable excipients.
  • AUCo-t means the area under the plasma concentration versus time curve, from time 0 to the last measurable concentration as calculated by the linear trapezoidal method.
  • AUC means the area under the plasma concentration versus time curve from time 0 to infinity.
  • the present invention provides an injectable formulation of Vitamin Kl, wherein the desired trans isomer is the predominant isomer of the active agent.
  • the desired trans isomer is present in an amount of at least 50 percent by weight of the active ingredient.
  • the desired trans isomer constitutes about 70 to 80% by weight of the active ingredient and more preferably, the trans isomer is present in an amount of more than 90 percent by weight of the active ingredient.
  • the final formulation typically contains the desired trans isomer in the range of 10 mg / ml or 2 mg /ml of the formulation Further, according to one embodiment of the present invention, the quantity of the trans isomer in the active ingredient is measured by using chiral columns.
  • the column chromatography was performed using chiral column, Chiral Pak AD-H (250 X 4.6 mm, 5 mum), and using acetonitrile and 0.1 percent formic acid in water (960 :40 v/v) as mobile phase with a flow rate of 3 mL/min.
  • the USP method is not capable of separating the desired trans isomer from others.
  • compositions of the invention are both chemically and physically stable and have the globule size in the sub-micron range.
  • a "sub-micron size” refers to globule or droplet in the emulsion that has an average diameter of less than 1 micron as measured by conventional sizing techniques such as laser light scattering spectrometry.
  • the emulsion contains droplets of the drug compositions that have an average diameter of less than 500, 450, 400, 350, 300 or 250 nm. Oil droplets of sub-micron size are desired for the safe passage of these droplets in, the capillary blood vessel in the circulation. In some defined aspects droplets are less than 5 microns in diameter.
  • compositions of the invention may need to be prepared in a sterilized formulation.
  • An effective method of sterilization that is well-known in the art is filtration through a 0.2 micron sized filter membrane.
  • the droplets of the emulsion compositions of the invention have an average diameter that is less than 0.2-micron (200 nm).
  • the emulsion droplets have an average diameter of less than about 150, 100, 75, 50, 25, 20, 15, or 10 nm.
  • the present formulation is presented as an emulsion suitable for parenteral administration. Typically, any emulsion is made up of an oil phase, an aqueous phase and emulsifiers.
  • the oil phase of the emulsion comprises medium or long chain triglyceride which can be used either alone or in combination with one or more vegetable oils.
  • Any injectable vegetable oil such as soybean oil, corn oil, saffiower oil, sesame oil, olive oil, castor oil of a mixture thereof may be used for the oil phase.
  • polyehtoxylated fatty acid derivatives are preferred.
  • an aqueous phase is prepared by dissolving or mixing water soluble excipients in water.
  • the aqueous phase may contain suitable tonicity adjusting agents such as dextrose, sodium chloride etc.
  • suitable antimicrobial preservative such as benzyl alcohol, phenols, formaldehyde, quaternary ammonium compounds etc.
  • suitable antioxidants such as ascorbic acid, tocopherols, butylated hydroxytoluene, butylated hydroxyl anisole etc.
  • the composition may also contain suitable pH adjusting agents or buffers.
  • the judicious selection of the excipients makes the formulation simple, convenient and easy to manufacture and helps to achieve the desired properties of the formulation such as efficacy, stability and desired pharmaceutical appearance.
  • Another embodiment of the present invention relates to a method for preparing an injectable formulation of Vitamin Kl .
  • the, formulations of the present invention are prepared as emulsions and the method comprises the steps of:
  • the present invention relates to a reduced dose pharmaceutical composition
  • a reduced dose pharmaceutical composition comprising at least 50% of trans isomer of Vitamin Kl .
  • the reduction in the dose could be from 5 to 50 percent than the standard approved dosage of 2.5 to 25 mg or more.
  • the composition could be provided in the form ampules or glass vials.
  • the formulations prepared as an emulsion are summarised in Table 1.
  • the aqueous phase was prepared by dissolving water soluble excipients in water.
  • the oil soluble excipients were dissolved in polyoxyethylated fatty acid derivative.
  • the oil phase and the aqueous phase were mixed in a homogenizer.
  • the pH was adjusted using hydrochloric acid and/or sodium hydroxide.
  • the resulting emulsion was filtered and was filled in suitable vials.
  • BHT Butylated Hydroxytoluene

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant de la vitamine Kl et le procédé de préparation de celle-ci. En particulier, la présente invention concerne des compositions pharmaceutiques injectables stables comprenant un diastéréomère souhaité de phytonadione en une quantité qui n'est pas inférieure à 50 % du poids total du principe actif.
PCT/IN2015/000356 2014-09-12 2015-09-11 Compositions pharmaceutiques de vitamine kl Ceased WO2016038626A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2911MU2014 2014-09-12
IN2911/MUM/2014 2014-09-12

Publications (1)

Publication Number Publication Date
WO2016038626A1 true WO2016038626A1 (fr) 2016-03-17

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PCT/IN2015/000356 Ceased WO2016038626A1 (fr) 2014-09-12 2015-09-11 Compositions pharmaceutiques de vitamine kl

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023119230A1 (fr) 2021-12-22 2023-06-29 L'oreal Compositions de modulation de la voie de coagulation et de la voie de nicotinamide-adénine dinucléotide et leurs procédés d'utilisation
CN116990402A (zh) * 2023-06-25 2023-11-03 南京汉欣医药科技有限公司 一种测定维生素k1注射液中异构体含量的分析方法
CN117064849A (zh) * 2023-07-10 2023-11-17 南京臣功制药股份有限公司 一种维生素k1注射液及其制备方法
CN117860668A (zh) * 2023-12-06 2024-04-12 中润药业有限公司 一种维生素k1注射液及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2708419A1 (de) * 1977-02-26 1978-08-31 Basf Ag Verwendung von 1,2-butandiol-1- methylaether als loesungsmittel fuer pharmazeutische zubereitungen
WO2011153513A2 (fr) * 2010-06-03 2011-12-08 Latitude Pharma Composition de nano-émulsion contenant de la vitamine k
CN103462887A (zh) * 2013-08-09 2013-12-25 张蕊 一种维生素k1注射液及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2708419A1 (de) * 1977-02-26 1978-08-31 Basf Ag Verwendung von 1,2-butandiol-1- methylaether als loesungsmittel fuer pharmazeutische zubereitungen
WO2011153513A2 (fr) * 2010-06-03 2011-12-08 Latitude Pharma Composition de nano-émulsion contenant de la vitamine k
CN103462887A (zh) * 2013-08-09 2013-12-25 张蕊 一种维生素k1注射液及其制备方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALBERTO CAVAZZINI ET AL: "Recent applications in chiral high performance liquid chromatography: A review", ANALYTICA CHIMICA ACTA, ELSEVIER, AMSTERDAM, NL, vol. 706, no. 2, 25 August 2011 (2011-08-25), pages 205 - 222, XP028326070, ISSN: 0003-2670, [retrieved on 20110922], DOI: 10.1016/J.ACA.2011.08.038 *
BERGER T A ET AL: "Two minute separation of the cis- and trans-isomers of vitamin K1 without heptane, chlorinated solvents, or acetonitrile.", CHROMATOGRAPHIA, vol. 76, no. 3, 17 January 2013 (2013-01-17), pages 109 - 115, XP002753487, DOI: 10.1007/s10337-013-2392-z *
LOWENTHAL J ET AL: "COMPARISON OF THE ACTIVITY OF THE CIS AND TRANS ISOMER OF VITAMIN K-1 IN VITAMIN K DEFICIENT AND COUMARIN ANTICOAGULANT PRE TREATED RATS", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, US, vol. 209, no. 3, 1 January 1979 (1979-01-01), pages 330 - 333, XP009147207, ISSN: 0022-3565 *
SCIENTIFIC COMMITTEE ON CONSUMER HEALTH: "Opinion on Vitamin K1 (Phytonadione)", 23 March 2010 (2010-03-23), pages 1 - 31, XP002753486, ISSN: 1831-4767, Retrieved from the Internet <URL:http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_014.pdf> [retrieved on 20160126], DOI: 10.2772/23121 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023119230A1 (fr) 2021-12-22 2023-06-29 L'oreal Compositions de modulation de la voie de coagulation et de la voie de nicotinamide-adénine dinucléotide et leurs procédés d'utilisation
CN116990402A (zh) * 2023-06-25 2023-11-03 南京汉欣医药科技有限公司 一种测定维生素k1注射液中异构体含量的分析方法
CN117064849A (zh) * 2023-07-10 2023-11-17 南京臣功制药股份有限公司 一种维生素k1注射液及其制备方法
CN117860668A (zh) * 2023-12-06 2024-04-12 中润药业有限公司 一种维生素k1注射液及其制备方法和应用

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