WO2009112800A1 - Composition de losartan - Google Patents

Composition de losartan Download PDF

Info

Publication number
WO2009112800A1
WO2009112800A1 PCT/GB2009/000531 GB2009000531W WO2009112800A1 WO 2009112800 A1 WO2009112800 A1 WO 2009112800A1 GB 2009000531 W GB2009000531 W GB 2009000531W WO 2009112800 A1 WO2009112800 A1 WO 2009112800A1
Authority
WO
WIPO (PCT)
Prior art keywords
losartan
composition according
composition
agents
suspension
Prior art date
Application number
PCT/GB2009/000531
Other languages
English (en)
Inventor
Carl David Tiernery
Original Assignee
Rosemont 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 Rosemont Pharmaceuticals Ltd filed Critical Rosemont Pharmaceuticals Ltd
Publication of WO2009112800A1 publication Critical patent/WO2009112800A1/fr

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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to a losartan composition, a method of use thereof and a method of manufacture.
  • Losartan is an active agent which is metabolised by cytochrome P450 enzymes in the human body to form an active carboxylic acid metabolite that is responsible for angiotension II receptor antagonism. Losartan containing drugs are therefore often used to treat high blood pressure.
  • the systemic name for losartan is [2-butyl-4-chloro- l -( ⁇ 4- [2-(2H- l ,2,3,4-tetrazol-5- yl)phenyl]phenyl ⁇ methyl) -lH-imidazol-5-yl] -methanol or
  • Losartan potassium a pharmaceutically acceptable salt of losartan
  • a solid dosage form which can be difficult for some patient's to swallow, or a liquid solution form as disclosed in WO2007016352.
  • the losartan in the liquid solution form is typically completely dissolved in an aqueous solution to form a particle free solution.
  • losartan solutions a problem with known losartan solutions is that the losartan tends to degrade over time to form dimer degradation products.
  • losartan potassium has a bitter taste which is difficult to mask even with strong flavourings or sweetening agents.
  • a further aim of the present invention to provide a method of manufacturing an improved losartan composition for oral administration.
  • a losartan composition suitable for oral administration said composition containing a pharmaceutically acceptable salt of losartan and a carrier agent, the losartan salt forming a suspension with said carrier agent.
  • the losartan suspension formed has a significantly improved flavour and the bitter taste is significantly reduced.
  • the suspension is substantially more stable than losartan solutions .
  • the term "suspension” used herein is where the losartan salt is substantially homogenously dispersed or “suspended" in the carrier agent. This is contrasted with prior art losartan “solutions” wherein the losartan salt is substantially dissolved in a carrier agent.
  • Any suitable salt of losartan can be used for the losartan suspension.
  • the pharmaceutically acceptable salt of losartan used is losartan potassium.
  • the pH of the composition is less than 7.
  • the carrier agent is at a pH of less than 7.
  • one or more pH modifying or buffering agents can be included in the composition with the carrier agent to adjust and/or maintain the pH below 7 and to an optimum pH value.
  • the acidic pH of the final composition reduces the solubility of the losartan in the carrier agent, thereby forming the suspension.
  • the one or more pH modifying agents can include any or any combination of citric acid, sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate and/or the like.
  • the pH modifying agents are used in such suitable amounts to provide the composition with an optimum pH.
  • Preferably the one or more pH modifying agents are provided at a concentration of 7mmol. Further preferably the concentration of the one or more pH modifying agents is between 70-90mmol. Most preferably the concentration of the pH modifying agent is 90mmol.
  • the pH range of the final suspension is between 2-6, further preferably the pH range is 3.5-6 and yet further preferably the pH range is 3.5-4.5. In a preferred embodiment the pH of the final suspension is pH 4.0.
  • a wetting agent is included in the composition to aid dispersion of the losartan salt. This is preferable if the pH of the final suspension is 3 or below since at this pH the losartan salt can be difficult to disperse to form a substantially homogenous suspension.
  • wetting agents examples include a sorbiton fatty ester, such as for example Tween 80 (polysorbate 80) .
  • Tween 80 polysorbate 80
  • Other surfactants or combinations of surfactants could also be used.
  • an anti-foaming agent is included in the composition to minimise the amount of foam produced during manufacture of the composition.
  • the anti-foaming agent preferably includes a silicon based agent, such as for example simethicone emulsion
  • one or more suspension agents are provided as the carrier agent or used in addition to the carrier agent.
  • the suspension agent preferably acts to thicken the suspension to prevent settling of the losartan salt from the suspension.
  • the one or more suspension agents include any or any combination of microcrystalline cellulose, carboxymethycellulose, carmellose sodium, Magnesium Aluminium Silicate (Veegum K), Xantham Gum, and/or any alternative salts thereof and/or the like.
  • the Veegum K is used in a larger amount than the other suspension agent or agents.
  • a combination of suspension agents is typically found to reduce the concentration of the agents required in the composition.
  • Preferred combinations include: a) Avicel RC591 (microcrystalline cellulose + carboxymethycellulose) with carmellose sodium; b) Veegum K with carboxymethycellulose sodium; or c) Veegum K with Xantham Gum.
  • an optimum concentration of suspension agents include Veegum K at approximately 0.7%w/v combined with Xanthum Gum at approximately 0.4%w/v. (w/v —weight of the final volume of the composition) .
  • the combination and concentration of the suspension agents chosen typically provide a fluid or liquid pourable suspension which minimises the tendency of losartan to settle out of the suspension.
  • the carrier agent in one embodiment is an aqueous carrier agent, such as for example water or purified water.
  • one or more anti-microbial agents are included in the composition.
  • sodium benzoate can be used at it is effective at the optimum pH of the composition.
  • the anti-microbrial agent could include any or any combination of benzoic acid, methyl hydroxybenzoate, propyl hydroxybenzoate, other analogues of the hydroxybenzoates and/or the like.
  • sweetener agents Preferably one or more sweetener agents, flavouring agents, anti-oxidant agents, preservative agents and/or the like are included in the composition.
  • a pharmaceutically acceptable dosage of the losartan salt is used in the composition.
  • the dosage is 50mg of losartan potassium in a 5ml aqueous solution.
  • a method of manufacturing a losartan composition suitable for oral administration including the steps of mixing a pharmaceutically acceptable salt of losartan with a suitable carrier agent so that the losartan salt forms a suspension with the carrier agent.
  • the target pH of the composition is less than 7 and, if the composition is not less than 7 or unlikely to be less than 7, one or more pH modifiers are added to the composition before or after said losartan salt.
  • the composition can be mixed together using any suitable mixing means .
  • the components of the composition can be mixed together in any order, although it is preferable that the pH modifiers or buffer components are added before the losartan salt to ensure the losartan remains as a suspension rather than a solution. If the losartan salt is added before the pH modifiers or buffers, it is likely that the losartan salt will dissolve into solution rather than forming a suspension. On subsequent addition of the pH modifiers or buffers, the losartan salt will precipitate out of the solution to form a suspension but the losartan salt may be of a different particle size.
  • the losartan salt is added to the composition in particulate or granular form.
  • the particle size of the losartan potassium used to produce the composition is preferably between 14-150 ⁇ m
  • the method of manufacture takes place at room temperature (i.e. approx 20-25 0 C) and pressure (i.e. approx. 1 bar) .
  • a losartan suspension for the manufacture of a medicament for the treatment of lowering blood pressure in a patient.
  • the patient is preferably a human patient.
  • the present invention provides a pharmaceutically effective, safe and simple to administer oral liquid dosage form that will benefit a patient group that have problems in swallowing.
  • Figure 1 is a graph illustrating the stability of losartan in suspension at different pH values.
  • Each suspension was given a batch number (D454-1/011A, D454-1/011B and D454-1/001C) and was stored in a suitable container at room temperature (25 0 C). Samples were taken at 0, 2, 4, 8 and 12 weeks to determine the %SA (percentage of the stated amount of the single dose in the original sample of 50mg/5ml of losartan potassium). The results of the stability- test are shown in Figure 1 and Table 2 and Table 3 below:
  • polysorbate 80 as a wetting agent aided the dispersion of the losartan salt in the formulation but was found not to be critical for forming the suspension. In addition, other wetting agents could be used if required. In order to determine the actual amount of the losartan salt present in the suspension, the following assay was undertaken using losartan potassium as the pharmaceutically acceptable salt.
  • Losartan potassium at a concentration of 1.0%w/v (5mg/ 5ml) was added to 90mmol of citrate phosphate buffer solutions at different pH and mixed until dispersed to form a suspension. The samples were then filtered and filtrate was analysed to determine the amount of losartan that had dissolved into solution. The amounts of losartan potassium in solution at the various pH's are shown in Table 4 below.
  • Purified water (A) is added to the main manufacturing vessel.
  • the citric acid monohydrate is added to the main vessel and mixed until dissolved.
  • the sodium dihydrogen phosphate dihydrate is added to the main vessel and mixed until dissolved.
  • the sodium benzoate is added to the main vessel and mixed until dissolved.
  • the Tween 80 is added to the main vessel and mixed until dispersed.
  • the losartan potassium is added to the main vessel and mixed until a homogeneous suspension is produced.
  • the Simethicone emulsion (Q7-2587 30%) is added to the main vessel and mixed until dispersed.
  • Veegum K and xanthan gum are added to a separate container and mixed until a uniform powder mixture is produced.
  • the powder blend produced at stage 8 is slowly added to the main vessel and mixed until dispersed and a homogeneous thickened suspension is produced.
  • the liquid maltitol is added to the main vessel and mixed until dispersed.
  • Acesulfame k is added to the main vessel and mixed until dissolved.
  • the compound orange spirit is added to the main vessel and mixed until dispersed.
  • target pH is 4.0. If the pH is outside the range of 3.8 - 4.2 the pH is adjusted until it is within this range by adding either 10%w/w citric acid monohydrate solution to lower pH or 10%w/w solution of disodium hydrogen phosphate anhydrous to increase the pH.
  • Purified water (B) is then added to make to the final volume and mixed until dispersed.
  • the finished product is filled into amber glass bottles (to reduce any reaction with sunlight) which are closed with suitable closures.
  • Polysorbate 80 (Tween 80) 1.0g
  • Polysorbate 80 (Tween 80) 1.0g

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

Abstract

La présente invention concerne une composition de losartan qui peut être administrée par la voie orale. La composition contient un sel de losartan pharmaceutiquement acceptable et un agent vecteur. Le sel de losartan forme une suspension avec l’agent vecteur.
PCT/GB2009/000531 2008-03-12 2009-02-25 Composition de losartan WO2009112800A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0804536.1A GB0804536D0 (en) 2008-03-12 2008-03-12 Losartan composition
GB0804536.1 2008-03-12

Publications (1)

Publication Number Publication Date
WO2009112800A1 true WO2009112800A1 (fr) 2009-09-17

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2009/000531 WO2009112800A1 (fr) 2008-03-12 2009-02-25 Composition de losartan

Country Status (2)

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GB (1) GB0804536D0 (fr)
WO (1) WO2009112800A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2557944A1 (fr) * 2010-04-15 2013-02-20 Chromocell Corporation Composés, compositions, et procédés de réduction ou d'élimination de l'amertume
US9706790B2 (en) 2011-10-20 2017-07-18 Chromocell Corporation Compounds, compositions, and methods for reducing or eliminating bitter taste
WO2020039262A1 (fr) * 2018-08-18 2020-02-27 Ftf Pharma Private Limited Solution d'agents pharmaceutiques pour forme posologique orale
US11890273B2 (en) 2020-10-09 2024-02-06 Scienture, Inc. Losartan liquid formulations and methods of use

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070026026A1 (en) * 2005-08-01 2007-02-01 David Delmarre Oral liquid losartan compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070026026A1 (en) * 2005-08-01 2007-02-01 David Delmarre Oral liquid losartan compositions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MERCK & CO., INC: "COZAAR: Losartan Potassium Tablets", INTERNET ARTICLE, December 2005 (2005-12-01), pages 3 - 18, XP002529970, Retrieved from the Internet <URL:http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020386s045lbl.pdf> [retrieved on 20090610] *
SEBURG ET AL: "Photosensitized degradation of losartan potassium in an extemporaneous suspension formulation", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 42, no. 4, 11 October 2006 (2006-10-11), NEW YORK, NY, US, pages 411 - 422, XP005657182, ISSN: 0731-7085 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2557944A1 (fr) * 2010-04-15 2013-02-20 Chromocell Corporation Composés, compositions, et procédés de réduction ou d'élimination de l'amertume
EP2557944A4 (fr) * 2010-04-15 2014-06-11 Chromocell Corp Composés, compositions, et procédés de réduction ou d'élimination de l'amertume
US8865779B2 (en) 2010-04-15 2014-10-21 Chromocell Corporation Compounds, compositions, and methods for reducing or eliminating bitter taste
US9408407B2 (en) 2010-04-15 2016-08-09 Chromocell Corporation Compounds, compositions, and methods for reducing or eliminating bitter taste
US9872514B2 (en) 2010-04-15 2018-01-23 Chromocell Corporation Compounds, compositions, and methods for reducing or eliminating bitter taste
US9706790B2 (en) 2011-10-20 2017-07-18 Chromocell Corporation Compounds, compositions, and methods for reducing or eliminating bitter taste
WO2020039262A1 (fr) * 2018-08-18 2020-02-27 Ftf Pharma Private Limited Solution d'agents pharmaceutiques pour forme posologique orale
GB2591389A (en) * 2018-08-18 2021-07-28 Ftf Pharma Private Ltd Pharmaceuticals solution for oral dosage
US11738020B2 (en) 2018-08-18 2023-08-29 Ftf Pharma Private Limited Stable liquid vigabatrin pharmaceutical composition for oral dosage
US12016857B2 (en) 2018-08-18 2024-06-25 Ftf Pharma Private Limited Stable liquid vigabatrin pharmaceutical composition for oral dosage
US11890273B2 (en) 2020-10-09 2024-02-06 Scienture, Inc. Losartan liquid formulations and methods of use

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Publication number Publication date
GB0804536D0 (en) 2008-04-16

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