EP3003273A1 - Procédé de stabilisation de tigecycline - Google Patents

Procédé de stabilisation de tigecycline

Info

Publication number
EP3003273A1
EP3003273A1 EP14728902.9A EP14728902A EP3003273A1 EP 3003273 A1 EP3003273 A1 EP 3003273A1 EP 14728902 A EP14728902 A EP 14728902A EP 3003273 A1 EP3003273 A1 EP 3003273A1
Authority
EP
European Patent Office
Prior art keywords
tigecycline
solution
nitric acid
lactose
acid
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Withdrawn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
EP14728902.9A
Other languages
German (de)
English (en)
Inventor
Ivona JASPRICA
Sasa GRUBESIC
Anita BEVETEK MOCNIK
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.)
Xellia Pharmaceuticals ApS
Original Assignee
Xellia Pharmaceuticals ApS
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 Xellia Pharmaceuticals ApS filed Critical Xellia Pharmaceuticals ApS
Publication of EP3003273A1 publication Critical patent/EP3003273A1/fr
Withdrawn legal-status Critical Current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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K47/26—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
    • A61K9/08—Solutions
    • 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

Definitions

  • the present invention relates to a method for stabilizing Tigecycline using nitric acid or sulphuric acid.
  • the present invention furthermore relates to Tigecycline compositions comprising nitric acid or sulphuric acid as the only pH adjusting agent.
  • Tigecycline acts by inhibiting protein synthesis at the level of the bacterial ribosome.
  • Tigecycline is the active ingredient of the product Tygacil®, (Tigecycline) for injection, 50 mg/vial, developed by Wyeth Pharmaceuticals and approved in US in June 2005.
  • Tigecycline degrades by oxidation (prevalent form of degradation in basic conditions) and cpimcrization (prevalent form of degradation in acidic environment).
  • each Tygacil vial contains 50 mg of Tigecycline and 100 mg of lactose monohydrate with 6% overage.
  • the pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide.
  • the product does not contain preservatives,
  • CN101 167732 discloses experiments concerning Tigecycline formulations comprising hydrochloric acid, tartaric acid or lactic acid as pH-adj listing agents.
  • inorganic and organic acids are mentioned, including sulphuric and nitric acid, but there is no disclosure of or hints to the advantages of using sulphuric or nitric acids for stabilizing Tigecycline.
  • CN102697739 discloses the use of pH adjustment for obtaining stable Tigecycline formulations. The stability is achieved when the H is first adjusted down with TIG, II 2 S0 4 or II3PO 4 and then adjusted up with KOH or NaOH.
  • CN1 01 919816 discloses experiments concerning of Tigecycline powders having improved dissolution properties.
  • Tigecycline salts are mentioned including the sulphuric acid salt of Tigecycline.
  • sulphuric acid salt of Tigecycline there is no disclosure of or hints to the advantages of using sulphuric or nitric acids for stabilizing Tigecycline.
  • WO2006099258 discloses Tigecycline formulations. However, there is no disclosure of or hints to the advantages of using sulphuric or nitric acids for
  • WO201 2142958 discloses Tigecycline crystals and formulations comprising them. However, there is no disclosure of or hints to the advantages of using sulphuric or nitric acids for stabilizing Tigecycline.
  • AU2012327237 discloses Tigecycline compositions comprising one or more formulating agcnt(s) selected from a chelator, pyruvic acid, or a salt or ester thereof and ascorbic acid, and optionally one or more cxcipicnts, diluents or buffers.
  • US20090275660 discloses Tigecycline compositions comprising EDTA.
  • the pH- modifying agents that may be used includes acids and or/buffers that is required to prevent degradation from oxidation and/or epimerization of the stable parenteral formulation as described herein, and that which helps in modifying the pH of the said formulation from about 3.0 to about 5.0. Any acid/buffer which does not adversely affect the effectiveness of the drug formulations may be employed.
  • Acids may be exemplified as hydrochloric, succinic, L-(+)- lactic or L -tartaric acid, and the like.
  • Buffers may be selected from citrate, acetate or phosphate buffer and the like.
  • 1.0N hydrochloric acid/1. ON sodium hydroxide is used.
  • sulphuric or nitric acids for stabilizing Tigecycline,
  • the present invention covers formulations comprising Tigecycline and sulphuric or nitric acid.
  • the present invention concerns aqueous solutions comprising Tigecycline having acidic pH obtained by addition of sulphuric acid or nitric acid as the only pH adj sting agents. In one aspect, the present invention concerns aqueous solutions comprising Tigecycline and lactose having acidic pH obtained by addition of sulphuric acid or nitric acid as the only pH adjusting agents.
  • the pH of the basic or neutral aqueous solution containing lactose and Tigecycline is lowered by the addition of sulphuric acid or nitric acid.
  • the pH of an aqueous solution containing lactose and Tigecycline is made acidic by the addition of sulphuric acid or nitric acid.
  • the pH of the basic or neutral aqueous solution containing Tigecycline is adjusted to pi I 2.5 - 6.6
  • the pH of the basic or neutral aqueous solution containing Tigecycline is adjusted to pH 4-6, such as pH 4.5-5.5 or pi I 4.8-5.2
  • the pll of the basic or neutral aqueous solution containing lactose and Tigecycline is adjusted to pH 4-6, such as pi I 4.5-5.5 or pH 4.8-5.2
  • a lyophilized powder is provided, which upon dissolution in pure water provides an acidic pi I.
  • the lyophilized powder is prepared by lyophili/ation of the aqueous solutions of the present invention.
  • Tigecycline formulations are provided, which are prepared by reconstitution of the above lyophilized powder of the present invention.
  • an aqueous solution of Tigecyciine comprising Tigecyciine and lactose, which is prepared by addition of sulphuric acid or nitric acid in Tigecyciine solution in an amount which is sufficient to provide an acidic pH.
  • an aqueous Tigecyciine solution with pH adjusted in acidic range is provided, wherein the aqueous solution of Tigecyciine comprises lactose as the only bulking agent.
  • an aqueous lactose solution is first provided, in which Tigecyciine is dissolved followed by adjustment of pH by the addition of sulphuric or nitric acid to the so obtained Tigecyciine solution.
  • a method for stabilizing Tigecyciine comprises addition of sulphuric acid or nitric acid to an aqueous solution comprising Tigecyciine and obtaining an acidic pH.
  • a method for stabilizing Tigecyciine comprising the steps of;
  • step b) add sulphuric or nitric acid in the solution obtained in step a) to obtain acidic pH;
  • c) dissolve Tigecyciine in the solution obtained in step a) or b) and optionally, d) add nitric acid or sulphuric acid to the solution obtained in c) in order to obtain acidic H if needed.
  • the skilled artisan can calculate the amount of sulphuric or nitric acid to be added in order to achieve the targeted acidic pH according to the present invention based on the concentration of Tigecyciine in the solution and the concentration of the acid.
  • a method for stabilizing Tigecyciine is provided, further comprising lyophilization of the solution obtained in step c).
  • a method for stabilizing Tigecyciine comprising the steps of:
  • step a) prepare an aqueous solution comprising lactose and Tigecyciine; and b) adjust the pH of the solution in step a) to preferred range or value, such as pH 4-6 by sulphuric acid or nitric acid.
  • a method for stabilizing Tigecycline comprising the steps of:
  • step b) adjust the pH of the solution in step a) to preferred range or value, such as pH 4-6 by sulphuric or nitric acid;
  • a method for stabilizing Tigecycline consisting of the steps of:
  • step b) adjust the pH of the solution in step a) to preferred range or value, such as pH 4-6 by sulphuric or nitric acid;
  • the present invention provides the use of sulphuric acid or nitric acid as stabilizing agents in the preparation of Tigecycline.
  • the present invention is based on the surprising finding that sulphuric acid or nitric acid provides a stabilizing effect on an aqueous solution containing Tigecycline compared to many other tested acids.
  • the surprising findings are achieved when sulphuric acid or nitric acid is used to lower the pi I prior to lyophilization.
  • the stabilizing effect of nitric acid and sulphuric acid is obtained when the pi I is made acidic prior to lyophilization.
  • only one pH adjusting step is needed when preparing the formulation of the present invention.
  • only one pH adjusting agent is needed when preparing the formulation of the present invention,
  • the present aqueous solution of Tigecycline may be used as a bulk solution for the preparation of a lyophilized composition.
  • the lyophilized composition according to the present invention is in solid state, e.g. in form of a powder or a cake resulting from lyophilization of bulk solutions.
  • the lyophilized composition is thus prepared by lyophilization of an aqueous solution of the present invention according to methods well known to the skilled person.
  • the pH of the obtained solution is acidic. According to one embodiment, the pH of the solution obtained is within 4-6. According to one embodiment, the lyophilized composition of the present invention is dissolved in any suitable diluent to provide a formulation of Tigecycline ready for administration to a patient in need thereof. Suitable diluents include, but are not limited to 0,9% sodium chloride injection, lactated ringer's injection and 5% dextrose injection.
  • an aqueous solution comprising Tigecycline and sulphuric acid, and further characterized by having an acidic pH.
  • an aqueous solution comprising Tigecycline and nitric acid, and further characterized by having an acidic pH.
  • an aqueous solution comprising Tigecycline, lactose and sulphuric acid, and further characterized by having an acidic pH.
  • an aqueous solution comprising Tigecycline, lactose and nitric acid, and further characterized by having an acidic pH.
  • lactose is the only bulking agent in the solution of the invention.
  • an aqueous solution comprising Tigecycline, lactose and sulphuric acid, arid further characterized by having an acidic pH of 4-6.
  • an aqueous solution comprising Tigecycline, lactose and nitric acid, and further characterized by having an acidic pH of 4-6.
  • a solution consisting of water, Tigecycline, lactose and sulfuric acid, characterized by having an acidic pH.
  • a solution consisting of water, Tigecycline, lactose and sulfuric acid, characterized by having a pH of 4-6.
  • a solution consisting of water, Tigecycline, lactose and sulfuric acid, characterized by having a H of 5-6.
  • a solution is provided, consisting of water, Tigecycline, lactose and sulfuric acid, characterized by having a pH of 5.
  • a solution is provided, consisting of water, Tigec cline, lactose and nitric acid, characterized by having an acidic pH.
  • a solution consisting of water, Tigecycline, lactose and nitric acid, characterized by having a pH of 4-6.
  • a solution consisting of water, Tigecycline, lactose and nitric acid, characterized by having a pH of 5-6.
  • a solution is provided, consisting of water, Tigecycline, lactose and nitric acid, characterized by having a ⁇ I of 5.
  • a lyophilized powder is provided, wherein said powder is prepared by the lyophilization of an aqueous solution having a pi I between 4 and 6 comprising Tigecycline as the active ingredient, and lactose as the bulking agent and the H adjusting agent is selected from sulphuric acid and nitric acid.
  • a lyophilized powder is provided, wherein said powder is prepared by the lyophilization of an aqueous solution having a pH between 4 and 6 comprising Tigecycline as the active ingredient and the pH adjusting agent is selected from sulphuric acid and nitric acid.
  • composition is provided, wherein said composition is a lyophilized powder prepared by the lyophilization of an aqueous solution having an acidic pH comprising Tigecycline, lactose and sulphuric acid.
  • composition is provided, wherein said composition is a lyophilized powder prepared by the lyophilization of an aqueous solution having an acidic pH consisting of Tigecycline, lactose and sulphuric acid.
  • composition is provided, wherein said composition is a lyophilized powder prepared by the lyophilization of an aqueous solution having an acidic pH comprising Tigecycline, lactose and nitric acid.
  • a composition is provided, wherein said composition is a lyophilized powder prepared by the lyophilization of an aqueous solution having an acidic pH consisting of Tigecycline, lactose and nitric acid.
  • Tigecycline is meant to embrace any compound having the structure of formula I regardless of the charge of the molecule which varies by pH.
  • Tigecycline is present in bulk solutions, lyophilized powders arid in solutions made by dissolving the lyophilized powders in. pure water or other suitable diluents.
  • Tigecycline is also to be understood to embrace the active ingredient in Tygacil®.
  • Tigecycline epimer which inter alia is a degradation product of Tigecycline, is a com ound which may be represented by the following structure:
  • Tigecycline epimer is believed to be non-toxic, but it lacks the antibacterial activity of Tigecycline.
  • "Lactose” is the well known disaccharide sugar commonly used as an excipient in pharmaceuti represented by the structure:
  • the lactose excipient is in the form of lactose monohydrate. Lactose can be anhydrous or hydrated, but lactose mono hydrate is preferred,
  • Sulphuric acid is meant to embrace the aqueous solutions of sulphuric acid. It is preferred that the sulphuric acid is diluted to a concentration of 0.5M-2M.
  • Nitric acid is meant to embrace the aqueous solutions of nitric acid. It is preferred that the nitric acid is diluted to a concentration, of 0.5M-2M. "pH” is the conventional measurement unit for hydrogen ion activity in a solution at 25°C unless other temperature is specified.
  • neutral ⁇ ' as used herein is meant to cover solutions having pi I 7.
  • the preferred acidic pi I is 3-6 and the most preferred acidic pH is about 5.
  • pH adjusting agent is any agent capable of adjusting pH in a solution comprising Tigecycline, but “pi I adjusting agent” is not meant to cover Tigecyclme, Tigecycline HC1 or Tigecycline dillCl.
  • Suitable carbohydrate as used herein is any carbohydrate or sugar alcohol which can be used as an excipient together with Tigecycline.
  • Preferred carbohydrates include, but are not limited to, mannose, mannitol, sucrose, glucose and lactose. The most preferred carbohydrate is lactose.
  • Purified water as used herein is substantially pure and sterile water. E.g. water purified by distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms.
  • Aqueous solution as used herein means any solution in which water is the main solvent.
  • Bin solution is a solution comprising Tigecycline suitable for lyophili/.ation.
  • the Tigecycline formulations were prepared in the following manner: lactose monohydrate was dissolved in ultrapure water and predefined quantity of diluted acid solution was added (used acids include sulphuric, phosphoric, citric, succinic, tartaric, acetic, lactic, ascorbic, and nitric acid), Tigecycline was dissolved in obtained lactose mono ydrate solution and then solution pH was adjusted to the predefined value using respective diluted acid solution (final concentration of lactose in the solution was 50 mg/mL and Tigecycline 25 mg/mL). After pH adjustment, volume of the solution was made up to predefined value.
  • the Tigecycline formulations with lactose were prepared in the following manner: lactose monohydrate was dissolved in ultrapure water and a predefined quantity of a diluted acid solution was added (used acids include sulphuric and nitric acid). Tigecycline was dissolved in the obtained lactose monohydrate solution and then the pll of the solution was adjusted to the predefined value using the respective diluted acid solution (final concentration of lactose in the solution was 50 mg/mL, and Tigecycline 25 mg/mL). After pi I adjustment, volume of the solution was made up to predefined value.
  • Formulations containing Tigecycline and the respective acid are manufactured as follows: in ultrapure water Tigecycline was dissolved and then the solution pH. was adjusted to the predefined value using diluted sulphuric, nitric or hydrochloric acid solution (final concentration of Tigecycline in the solution was 25 mg/mL). After pll adjustment, the volume of the solution was made up to predefined value.
  • the formulation containing Tigecycline Hydrochloride API was prepared by dissolving the API in ultrapure water with resulting concentration of Tigecycline of 25 mg/raL. After dissolution of API, the volume of the solution was made up to predefined value.
  • Product solution containing 50 mg/niL of lactose monohydrate and 25 mg/niL of Tigecycline with pH adjusted to 5.0 using sulphuric acid and nitric acid were prepared and lyophilized together with formulations containing 25 mg/raL of Tigecyeline with pH adjusted to 5.0 using sulphuric acid, hydrochloric acid and nitric acid and formulation containing Tigecyeline Hydrochloride API.
  • pi T is measured in vial reconstituted with 5.3 mL of ultrapurc water

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

Abstract

La présente invention concerne un procédé pour stabiliser la tygecycline au moyen d'acide nitrique ou d'acide sulfurique. La présente invention concerne également des compositions de tygecycline comprenant de l'acide nitrique ou de l'acide sulfurique en tant qu'agent régulateur de pH unique.
EP14728902.9A 2013-05-31 2014-05-30 Procédé de stabilisation de tigecycline Withdrawn EP3003273A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NO20130759 2013-05-31
PCT/EP2014/061253 WO2014191552A1 (fr) 2013-05-31 2014-05-30 Procédé de stabilisation de tigecycline

Publications (1)

Publication Number Publication Date
EP3003273A1 true EP3003273A1 (fr) 2016-04-13

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ID=50897578

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14728902.9A Withdrawn EP3003273A1 (fr) 2013-05-31 2014-05-30 Procédé de stabilisation de tigecycline

Country Status (2)

Country Link
EP (1) EP3003273A1 (fr)
WO (1) WO2014191552A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101132775A (zh) † 2005-03-14 2008-02-27 惠氏公司 替加环素组合物及制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101167732A (zh) * 2007-10-22 2008-04-30 合肥信风科技开发有限公司 一种注射用替加环素冻干粉针的制备方法
CN102697739B (zh) * 2012-05-31 2014-10-29 丽珠医药集团股份有限公司 一种减少替加环素差向异构体化的粉针剂制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014191552A1 *

Also Published As

Publication number Publication date
WO2014191552A1 (fr) 2014-12-04

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