WO2009109741A1 - Solution de clopidogrel destinée à l’administration orale - Google Patents

Solution de clopidogrel destinée à l’administration orale Download PDF

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Publication number
WO2009109741A1
WO2009109741A1 PCT/GB2009/000527 GB2009000527W WO2009109741A1 WO 2009109741 A1 WO2009109741 A1 WO 2009109741A1 GB 2009000527 W GB2009000527 W GB 2009000527W WO 2009109741 A1 WO2009109741 A1 WO 2009109741A1
Authority
WO
WIPO (PCT)
Prior art keywords
clopidogrel
solution
solution according
agent
salt
Prior art date
Application number
PCT/GB2009/000527
Other languages
English (en)
Inventor
Ingrid Maria Soderberg
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 WO2009109741A1 publication Critical patent/WO2009109741A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • This invention relates to a clopidogrel containing solution, a method of use thereof and a method of manufacture.
  • Clopidogrel is an enantiopure carboxylic ester of S- configuration.
  • the pharmaceutically accepted salt clopidogrel hydrogen sulphate is an ADP receptor antagonist that is known to inhibit platelet aggregation in human patients.
  • the systemic name for clopidogrel is (+)- (s)-methyl 2-(2-chlorophenyl)-2-(6,7- dihydrothienol[3,2-C]pyridine -5 (4H)-yl)acetate or
  • clopidogrel is only commercially available for use in a solid dosage form, such as in tablet form.
  • a liquid oral dosage form of clopidogrel Whilst it is possible to create a "suspension" form of clopidogrel (i.e. it is not fully soluble in liquid) , typically via suspending crushed tablets, such a suspension has a very short shelf life and there is currently no commercial form of clopidogrel in suspension which has a sufficiently long shelf life to be commercially and pharmaceutically acceptable.
  • a clopidogrel liquid solution with a long shelf life would be more cost effective to manufacture and the logistic chain from the manufacturer to the patient would be significantly improved.
  • a liquid solution is preferable to a solid dosage where a patient needs dose titration to obtain a correct maintenance treatment dose of clopidogrel.
  • a clopidogrel solution suitable for oral administration, said solution containing a pharmaceutically acceptable salt of clopidogrel and a substantially non-aqueous agent in which the clopidogrel salt is substantially or completely soluble.
  • the resulting clopidogrel containing oral solution is said to be non-aqueous in form and is defined as containing less than approximately 8% weight of water.
  • the final solution may not be completely anhydrous since some of the components of the liquid solution are also not anhydrous .
  • any suitable salt of clopidogrel can be used for the clopidogrel solution.
  • the pharmaceutically acceptable salt of clopidogrel is clopidogrel hydrogen sulphate (same as clopidogrel bisulphate) .
  • the clopidogrel salt is clopidogrel bisulphate.
  • the salt is preferably in a powder form prior to mixing with the non-aqueous agent.
  • the non-aqueous agent is a polyol and further preferably the polyol is glycerol.
  • the non-aqueous agent typically provides the clopidogrel solution with a long shelf life (i.e. of at least two-three months) .
  • the solution includes a polar solvent to increase the solubility of the clopidogrel salt and/or any other compound included in the final formulation of the solution, such as an anti-oxidant and/or sweetener.
  • a polar solvent to increase the solubility of the clopidogrel salt and/or any other compound included in the final formulation of the solution, such as an anti-oxidant and/or sweetener.
  • the polar solvent is propylene glycol. It is particularly advantageous in that its use helps to dissolve other compounds in the final formulation, such as a sweetener and increases the total solvent power of the solution.
  • the solution includes one or more of the following agents, a preservative, a viscosity modifying agent, an antioxidant and/or a sweetener.
  • the preservative agent is used to inhibit microbial growth in the solution
  • the viscosity modifying agent typically reduces or adjusts the viscosity of the solution to make it sufficiently pourable in use
  • the anti-oxidant prevents oxidisation of the solution ingredients
  • the sweetening agent typically makes the solution palatable to a patient.
  • the above agent(s) are substantially soluble in a nonaqueous solution.
  • the solution contains all of the abovementioned agents.
  • the solution includes ethanol which acts as both a preservative and a viscosity modifying agent.
  • the sweetener that can be used in the solution is neohesperidine dihydrochalcone (NHDC) .
  • NHDC has low water solubility and is therefore suitable for use in a non-aqueous formulation.
  • NHDC is compatible with clopidogrel salts.
  • the anti-oxidant agent that can be used in the solution is butylated hydroxyanisole (BHA) .
  • BHA butylated hydroxyanisole
  • the anti-oxidant could be propyl gallat, tocopherol and/or the like.
  • the solution contains at least one flavouring agent.
  • a flavouring agent for example, Raspberry Flavour 545724E can be used.
  • the flavouring produces acceptable organoleptic properties to the solution.
  • the formulation of the clopidogrel solution includes ethanol, glycerol, clopidogrel bisulphate, NHDC, BHA and a flavouring agent.
  • a pharmaceutically acceptable dosage of the clopidogrel salt is used in the solution.
  • the dosage is 75mg of clopidogrel salt in a 5ml substantially non-aqueous solution.
  • the dosage is typically a suitable amount for inhibiting platelet aggregation.
  • a method of manufacturing a clopidogrel solution including mixing a pharmaceutically acceptable salt of clopidogrel with a substantially non-aqueous agent until the clopidogrel salt is substantially dissolved.
  • the method further includes adding any or any combination of one or more preservatives, viscosity modifying agents , sweeteners, flavourings, anti-oxidants and/or the like.
  • the method of manufacture takes place at room temperature (i.e. approx. 20-25 0 C) and pressure (i. e. approx l atm) .
  • the solution constituents can be mixed together via any suitable mixing means.
  • a method of use of a clopidogrel solution is used to manufacture a medicament of the treatment of inhibiting platelet aggregation in patients.
  • Aqueous containing agents are preferably avoided in the solution of the present invention since research shows that any water in the final solution will hydrolyse clopidogrel and the hydrolysis products will precipitate out and, over time, the clopidogrel will be completely degraded. Thus, non-aqueous agents are preferred for use in the solution to increase the stability of the solution.
  • the present invention provide a pharmaceutically effective, safe and simple to administer dosage form that will benefit a patient group that have problems in swallowing and therefore limits the usage of a conventional solid dosage form.
  • Figure 1 is a graph illustrating the stability of clopidogrel in different solutions where the aqueous part of the solution is acidified to pH 1 ;
  • Figure 2 is a graph illustrating the results of a stability study with liquid maltitol (Lycasin) ; and Figure 3 is a graph illustrating the stability of clopidogrel as a % SA versus time.
  • FIG 1 there is shown a graph which illustrates the stability of clopidogrel in different aqueous solutions; namely:
  • the clopidogrel samples were each analysed after 0, 2 and 8 weeks of storage at 50 0 C, unless otherwise stated, with regard to the remaining amount of Clopidogrel hydrogen sulphate present in the samples at each time (%SA — percentage of the stated amount of the single dose in the original sample of 75mg/ml) .
  • the study was undertaken at an accelerated rate by storing the samples at 50 0 C, rather than the recommended storage conditions of 25°C.
  • the results shown in figure 1 clearly show that the three samples (3 lower lines of the graph above the water control) containing the higher levels o f water (i.e. 40% glycerol) showed an increase in degradation of the Clopidogrel hydrogen sulphate over time compared to the three samples (3 higher lines of the graph) containing the lower levels of water (i.e. 80% glycerol) .
  • the results show that the stability of clopidogrel in solution increased with decreasing water content of the solution.
  • the present invention provides a substantially non-aqueous liquid formulation of clopidogrel using pharmaceutically accepted excipients. Since the components /excipients of the clopidogrel liquid formulation are not completely anhydrous, the resulting non-aqueous liquid solution of the present invention is defined as a solution containing less than 8% (w/w) by weight of water.
  • Example 1 An example of a formulation of a clopidogrel solution is provided in Example 1 below.
  • the stability study of figure 2 was undertaken at 50 0 C, with a 100% water control at pH 1 ; a solution of 80% glycerol and 20% ethanol; and a solution of 80% glycerol, 10% ethanol and 10% Lycasin (maltitol) .
  • the samples were again part of an accelerated stability study in that the samples were stored at 50 0 C and samples were taken at 0, 2, 4, 6 and 8 weeks, with the remaining amount of Clopidogrel hydrogen sulphate present in the samples assessed at each time (%SA — percentage of the stated amount of the single dose in the original sample of 75mg/ml) .
  • the results show that the solution containing the Lycasin degraded faster over time than the solution which did not contain Lycasin.
  • Example 2 An example of a further clopidogrel solution is provided in Example 2 below.
  • raspberry flavour (10mg/ 5ml) gave acceptable organoleptic properties. Stability studies undertaken showed that raspberry flavour 545724E was compatible with Clopidogrel Hydrogen Sulphate and other excipients of the above formulation. Further experimentation of the formulation in example 2 showed that the solution underwent a subtle colour change with time during storage. As such a further formulation was derived which included an anti-oxidant in the form of Butylated Hydroxyanisole (BHA) and this formulation is detailed in Example 3 below. It is to be noted that other suitable antioxidants could include Butulated Hydroxytoluene (BHT) , propyl gallat or tocopherol in place of BHA.
  • BHA Butylated Hydroxyanisole
  • Ethanol (A) is added to a main mixing vessel;
  • Glycerol (A) is added to the main vessel and mixed using a propeller mixer until dispersed;
  • Clopidogrel bisulphate is then added into the vessel and is mixed with the mixer until dispersed. It is noted that clopidogrel powder will not dissolve at this stage.
  • the clopidogrel weighing vessel is rinsed with ethanol (B) .
  • Water is preferably not used for rinsing at any stage since the final solution is water sensitive.
  • Glycerol (B) is added to the main vessel and mixed using the mixer until substantially homogenous.
  • Neohesperidine Dihydrochalcone is added to the separate vessel and mixed using a high shear mixer until dissolved.
  • BHA is added to the separate vessel and mixed using the high shear mixer until dissolved.
  • the raspberry flavouring is added to the separate vessel and mixed using the propeller mixer until dispersed.
  • the solution in the separate vessel is then transferred to the main vessel and mixed using the propeller mixer until dispersed.
  • step 10 The final weight of the solution in step 10 is then adjusted using glycerol (C) to the required amount and mixed with a propeller mixer.
  • C glycerol
  • Figure 3 illustrates the stability of the formulation give in example 3 versus time. It can be seen that there is little degradation of the final Clopidogrel solution over time, thereby providing a pharmaceutically acceptable oral product.

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

Abstract

La présente invention concerne une solution de clopidogrel qui est adaptée pour être administrée aux patients par voie orale. La solution comprend un sel pharmaceutiquement acceptable de clopidogrel et un agent sensiblement non aqueux dans lequel le sel de clopidogrel est sensiblement ou complètement soluble.
PCT/GB2009/000527 2008-03-07 2009-02-25 Solution de clopidogrel destinée à l’administration orale WO2009109741A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0804242.6A GB0804242D0 (en) 2008-03-07 2008-03-07 Clopidogrel solution
GB0804242.6 2008-03-07

Publications (1)

Publication Number Publication Date
WO2009109741A1 true WO2009109741A1 (fr) 2009-09-11

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Application Number Title Priority Date Filing Date
PCT/GB2009/000527 WO2009109741A1 (fr) 2008-03-07 2009-02-25 Solution de clopidogrel destinée à l’administration orale

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GB (1) GB0804242D0 (fr)
WO (1) WO2009109741A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023012479A1 (fr) 2021-08-03 2023-02-09 Liqmeds Worldwide Limited Solution pharmaceutique orale de clopidogrel

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1105102B1 (fr) * 1998-08-20 2003-01-02 Sanofi-Synthelabo Composition pharmaceutique injectable a base d'un sel pharmaceutiquement acceptable du clopidogrel ou de ticlopidine
US20050049275A1 (en) * 2002-08-02 2005-03-03 Entire Interest Racemization and enantiomer separation of clopidogrel
US20070003628A1 (en) * 2005-05-10 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel formulations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1105102B1 (fr) * 1998-08-20 2003-01-02 Sanofi-Synthelabo Composition pharmaceutique injectable a base d'un sel pharmaceutiquement acceptable du clopidogrel ou de ticlopidine
US20050049275A1 (en) * 2002-08-02 2005-03-03 Entire Interest Racemization and enantiomer separation of clopidogrel
US20070003628A1 (en) * 2005-05-10 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel formulations

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023012479A1 (fr) 2021-08-03 2023-02-09 Liqmeds Worldwide Limited Solution pharmaceutique orale de clopidogrel

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