WO1998016252A1 - Novelle formulation pharmaceutique parenterale d'un inhibiteur de thrombine - Google Patents

Novelle formulation pharmaceutique parenterale d'un inhibiteur de thrombine Download PDF

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Publication number
WO1998016252A1
WO1998016252A1 PCT/SE1997/001652 SE9701652W WO9816252A1 WO 1998016252 A1 WO1998016252 A1 WO 1998016252A1 SE 9701652 W SE9701652 W SE 9701652W WO 9816252 A1 WO9816252 A1 WO 9816252A1
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WO
WIPO (PCT)
Prior art keywords
formulation
formulation according
thrombin inhibitor
integer
additive
Prior art date
Application number
PCT/SE1997/001652
Other languages
English (en)
Inventor
Anna Lundgren
Urban Skantze
Original Assignee
Astra Aktiebolag
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 Astra Aktiebolag filed Critical Astra Aktiebolag
Priority to AU46410/97A priority Critical patent/AU4641097A/en
Publication of WO1998016252A1 publication Critical patent/WO1998016252A1/fr

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Classifications

    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • 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 new pharmaceutical formulation of thrombin inhibitors for parenteral use, which is an extended release formulation.
  • the invention also relates to a process for the manufacture of such a formulation and, the use of the new formulation in medicine.
  • Thrombin inhibitors are effective for treatment of a number of diseases characterized by hypercoagulation.
  • the compounds melagatran and inogatran are low- molecular weight, water soluble thrombin inhibitors with short half lives. To permit administration at a low frequency an extended release formulation is useful.
  • Parenteral extended release formulations allow a drug to be delivered at controlled rate resulting in a satisfactory plasma concentration for an extended period of time, with less frequent administration, avoiding high peak blood concentrations.
  • an extended release effect may be a prerequisite for subcutaneous or intramuscular treatment.
  • One approach is to retard the diffusion of the drug out of the formulation. This can be achieved, for example by using a vehicle with increased viscosity.
  • Another approach is to make a suspension of the drug, or a suitable salt of the drug, which is insoluble in the vehicle and only sparsely soluble in the surrounding tissue after injection; the rate of dissolution of the drug is retarded and thereby the uptake of the drug.
  • Poloxamers are nonionic polyoxyethylene-polyoxypropylene copolymers primarily used in pharmaceutical formulations as emulsifying, stabilising, or solubilizing agents (Tarcha, P, J., Polymers for controlling drug delivery, CRC press 1991.).
  • poloxamers are chemically similar in composition differing only in the relative amount of ethylene and propylene oxide units and in the total molecular weight of the polymer. Some poloxamers are thermo-reversible in the temperature range around body temperature. A water solution of the compound is in the liquid state below the solution-gelation transition temperature, and a semi-solid gel above this temperature. Parameters that determine the formation and the viscosity of the gel can be the type of poloxamer used, the concentration of the poloxamer as well as the overall composition of the formulation (Schmolka I.R. Artificial Skin I. Preparation and properties of Pluronic F 127 gels for treatment of burns. J. Biomed. Mater. Res., 6 571, 1972). The potential use of poloxamers in drug delivery systems for extended release has previously been illustrated (US Patent No 4 474 752).
  • US 5 306 501 discloses certain poloxamers as a drug delivery system for drug injection for certain classes of drugs.
  • the composition of the US 5 306 501 is said to provide a physiologically acceptable media having a buffered pH and an osmotically balanced vehicle so as to provide an isotonic mixture having iso-osmotic and pH properties which are similar to that of body fluids, such as blood plasma.
  • WO 95/151 82 discloses certain poloxamers in pharmaceutical composition either alone or in combination with an antibiotic for the treatment of infections.
  • US 5 306 501 and WO 95/15182 do not refer to the application of poloxamer in pharmaceutical formulations in order to obtain an extended release effect. This is mentioned in US 4 474 752 which, however, refers to substantially different structures, which are substituted derivatives of ethylene diamine.
  • Poloxamer 407 is suggested as a vehicle for obtaining in vivo extended release of the high molecular weight compounds inulin and urease.
  • the highly viscous poloxamer matrix retards the diffusion of the large molecules through the formulation and extended release is obtained.
  • the solution-gelation transition temperature and the viscosity in vivo in a poloxamer- containing extended release pharmaceutical formulation are determined by the overall composition of the formulation where the nature and concentration of the active compound, the poloxamer as well as e.g. additional electrolytes, surfactants, solvents, and pH regulating agents are of major importance.
  • the effect on viscosity parameters and the solution-gelation transition temperature due to interaction between a particular compound, and the formulation components is not predictable and thus not the in vivo extended release effect.
  • a formulation comprising a water solution of a low molecular weight, water soluble thrombin inhibitor with a short half life selected from the group consisting of melagatran, inogatran and their physiologically acceptable water soluble salts and an additive selected from the group consisting of a block copolymer having the general formula
  • Melagatran is the compound HOOC-CH 2 -(R)-Cgl-Aze-Pab (disclosed in EP 701 568) and inogatran is the compound HOOC-CH 2 -(R)-Cha-Pic-Nag (disclosed in EP 618 926), wherein Aze is (S)-azetidine-2-carboxylic acid
  • Cgl is (S)-cyclohexylglycine Cha is (S)- ⁇ -cyclohexyl alanine Nag is noragmatine
  • Pab is l-amidino-4-aminomethyl benzene Pic is (S)-pipecolinic acid.
  • Physiologically acceptable salts may be any of the following salts of inorganic and organic acids, namely hydrobromide, hydrochloride, sulphate, nitrate, salts from sulphonic acids, e.g. methane sulphonate, ethane sulphonate, benzene sulphonate, toluene sulphonate, 'naphthalene-2-sulphonate, salts from carboxylic acids, e.g.
  • poloxamers which are block copolymers having the general formula
  • the additive(s) could be a single poloxamer or a mixture of two or more poloxamers.
  • the preferred poloxamers have the general formula defined above wherein a is an integer 5 -150 and b is an integer 15-75.
  • the most preferred poloxamers have the general formula defined above wherein a is an integer 70-105 and b is an integer 25-70.
  • Poloxamer 188 is a block copolymer having the general formula
  • a is approximately 79 and b is approximately 28, having a molecular weight in the range of 7689-9510 and with a mass fraction of polyoxyethylene of approximately 81%.
  • Poloxamer 407 is a block copolymer having the general formula
  • a is approximately 98 and b is approximately 67, having a molecular weight in the range of 9840-14600 and with a mass fraction of polyoxyethylene of approximately 73%.
  • concentration of the thrombin inhibitor is preferably in the range 0.01-20% (w/w), and more preferably 0.1-10% (w/w) of the ready to use formulation.
  • the concentration of the poloxamer is preferably 15-40 % (w/w), and more preferably 20- 35% (w/w) but most preferably 25-30% (w/w) of the ready to use formulation.
  • the solution-gelation transition temperature of the ready to use formulation is below 37°C, preferably in the range 15-37° C and most preferably in the range 25-35°C.
  • a pH between 3-10 is preferred. If necessary the pH is adjusted with an acidifying agent, such as for instance acetic acid, ascorbic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid or tartaric acid, or an alkalising agent, such as sodium hydroxide.
  • an acidifying agent such as for instance acetic acid, ascorbic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid or tartaric acid
  • an alkalising agent such as sodium hydroxide
  • the formulation may contain further additional components, such as antioxidants, antimicrobial preservatives, tonicity modifiers and/or buffer components.
  • the formulation is prepared conveniently by dissolving the solid components in water, adjusting the pH and sterilizing the resulting solution.
  • the order in which the components are dissolved and at which stage the pH adjustment or sterilization is performed is not critical and may be choosen according to what is most suitable.
  • Suitable daily parenteral doses for the thrombin inhibitor in the therapeutical treatment of humans are 0.001-50 mg/kg body weight, preferably 0.005-5 mg/kg.
  • the pharmaceutical formulation is intended for prophylaxis and/or treatment in arterial as well as venous thromboembolism.
  • the formulation is intended for parenteral use, including intracutaneous, subcutaneous, intra lipomateus, intra muscular and intraperitoneal administration.
  • Working examples including intracutaneous, subcutaneous, intra lipomateus, intra muscular and intraperitoneal administration.
  • Example 1 (20 mg/ml Melagatran in 18/10% (w/w) of Poloxamer 407/188)
  • Poloxamer 407 72 g
  • the poloxamers are weighed and slowly added to the main part of the water during intense stirring. When the poloxamers are dissolved the solution is filtered through 0.45 ⁇ m sterile filters. The weighed amount of melagatran is added to and dissolved in the poloxamer solution. The pH of the solution is adjusted to 5 with HCl and the rest of the water is added to the final weight. The solution is sterilized by filtration through 0.22 ⁇ m sterile filters and filled into sterile injection vials.
  • the solution-gelation transition temperature of the formulation was determined as 34°C.
  • the solution-gelation temperature of the formulation was determined as 17°C.
  • Example 3 24 mg/ml Melagatran in 17/17 % (w/w) of Poloxamer 407/188)
  • the solution-gelation transition temperature of the formulation was determined as 32°C.
  • Example 4 (12 mg/ml Melagatran in 16% (w/w) of Poloxamer 407) Melagatran 363 mg
  • Poloxamer 407 4.8 g
  • the solution-gelation transition temperature of the formulation was determined as 30°C.
  • Example 5 (24 mg/ml Melagatran in 18% (w/w) of Poloxamer 407) Melagatran 727 mg Poloxamer 407 5.4 g
  • the solution-gelation transition temperature of the formulation was determined as 24°C.
  • a dose of 30 mg of melagatran was administered subcutaneously to pigs in the poloxamer- containing formulation of Example 2 and in a physiological saline solution.
  • Data shows an obvious extended release effect and a reduced peak plasma concentration for the formulation according to the invention as compared to the formulation comprising a physiological saline solution.
  • the plasma concentration was followed during the first 4 hours.
  • Time Mean plasma concentration Mean plasma concentration (minutes) ( ⁇ mole/1) ( ⁇ mole/1)
  • a dose of 5 mg of melagatran was administered subcutaneously to humans in the poloxamer-containing formulation of Example 1, and in a physiological saline solution.
  • Data shows a 3-fold decrease in absorption rate and a reduced peak plasma concentration for the formulation according to the invention as compared to the formulation comprising a physiological saline solution.
  • Poloxamer vehicle Physiological saline vehicle

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

Formulation pharmaceutique d'un inhibiteur de thrombine pour utilisation parentérale, avec effet de diffusion prolongée, ainsi que procédé de préparation et d'utilisation de cette formulation dans le traitement des thrombo-embolies artérielles et/ou veineuses. La formulation à diffusion prolongée contient un inhibiteur de thrombine sélectionné dans un groupe composé de melagatran, d'inogatran et de leurs sels solubles à l'eau physiologiquement acceptables, et un ou plusieurs copolymères séquencés définis par la formule générale HO[C2H4O]a[C3H6O]b[C2H4O]aH, dans laquelle chaque a représente indépendamment un nombre entier de 1 à 250 et b est un nombre entier de 1 à 250, la température de transition solution-gélification de la formulation étant inférieure à 37 °C.
PCT/SE1997/001652 1996-10-11 1997-10-01 Novelle formulation pharmaceutique parenterale d'un inhibiteur de thrombine WO1998016252A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46410/97A AU4641097A (en) 1996-10-11 1997-10-01 New pharmaceutical parenteral formulation of a thrombin inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9603724-7 1996-10-11
SE9603724A SE9603724D0 (sv) 1996-10-11 1996-10-11 New pharmaceutical parenteral formulation of a thrombin inhibitor

Publications (1)

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WO1998016252A1 true WO1998016252A1 (fr) 1998-04-23

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SE (1) SE9603724D0 (fr)
WO (1) WO1998016252A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0955063A1 (fr) * 1998-04-01 1999-11-10 Basf Aktiengesellschaft Utilisations de compositions aqueuses dans des médicaments pour une administration sous-cutanée ou intramusculaire
WO2000076504A1 (fr) * 1999-06-10 2000-12-21 Astrazeneca Ab Production d'agglomerats d'inogatran et compose d'anhydrate d'inogatran
US6462021B1 (en) 2000-11-06 2002-10-08 Astrazeneca Ab Use of low molecular weight thrombin inhibitor
US6479078B1 (en) * 1999-07-02 2002-11-12 Astrazeneca Ab Substantially crystalline form of melagatran
WO2003101424A1 (fr) * 2002-05-31 2003-12-11 Astrazeneca Ab Formulation pharmaceutique à libération modifiée
US6683054B1 (en) * 1999-01-13 2004-01-27 Astrazeneca Ab Use of melagatran
EP1527787A1 (fr) * 1998-09-03 2005-05-04 AstraZeneca AB Comprimés à libération immédiate
US7273858B2 (en) 2002-05-31 2007-09-25 Astrazeneca Ab Salts
US7803954B2 (en) 2000-12-01 2010-09-28 Astrazeneca Ab Mandelic acid derivatives and their use as thrombin inhibitors
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2233816A1 (de) * 1971-07-14 1973-02-01 Basf Wyandotte Corp Stabilisierte blutzusammensetzung
WO1993011152A1 (fr) * 1991-12-04 1993-06-10 Aktiebolaget Astra Nouveaux derives de peptides
US5306501A (en) * 1990-05-01 1994-04-26 Mediventures, Inc. Drug delivery by injection with thermoreversible gels containing polyoxyalkylene copolymers
WO1994029336A1 (fr) * 1993-06-03 1994-12-22 Astra Aktiebolag Nouveaux derives peptidiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2233816A1 (de) * 1971-07-14 1973-02-01 Basf Wyandotte Corp Stabilisierte blutzusammensetzung
US5306501A (en) * 1990-05-01 1994-04-26 Mediventures, Inc. Drug delivery by injection with thermoreversible gels containing polyoxyalkylene copolymers
WO1993011152A1 (fr) * 1991-12-04 1993-06-10 Aktiebolaget Astra Nouveaux derives de peptides
WO1994029336A1 (fr) * 1993-06-03 1994-12-22 Astra Aktiebolag Nouveaux derives peptidiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DIALOG INFORMATION SERVICES, File 155, MEDLINE, Dialog Accession No. 05731289, Medline Accession No. 90095751, JOHNSTON TP et al., "Inulin Disposition Following Intramuscular Administration of an Inulin/Poloxamer Gel Matrix"; & J. PARENTER SCI. TECHNOL., (UNITED STATES), Nov-Dec. 1989, 43(6), p. 279-86. *
DIALOG INFORMATION SERVICES, File 155, MEDLINE, Dialog Accession No. 07242053, Medline Accession No. 93020237, PEC E.A. et al., "Biological Activity of Urease Formulated in Poloxamer 407 After Intraperitoneal Injection in the Rat"; & J. PHARM. SCI., (UNITED STATES), Jul. 1992, 81(7), p. 626-30. *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0955063A1 (fr) * 1998-04-01 1999-11-10 Basf Aktiengesellschaft Utilisations de compositions aqueuses dans des médicaments pour une administration sous-cutanée ou intramusculaire
EP1527787A1 (fr) * 1998-09-03 2005-05-04 AstraZeneca AB Comprimés à libération immédiate
US6683054B1 (en) * 1999-01-13 2004-01-27 Astrazeneca Ab Use of melagatran
WO2000076504A1 (fr) * 1999-06-10 2000-12-21 Astrazeneca Ab Production d'agglomerats d'inogatran et compose d'anhydrate d'inogatran
US6531490B1 (en) 1999-06-10 2003-03-11 Astrazeneca Ab Production of agglomerates of inogatran and the compound inogatran anhydrate
US6479078B1 (en) * 1999-07-02 2002-11-12 Astrazeneca Ab Substantially crystalline form of melagatran
US6462021B1 (en) 2000-11-06 2002-10-08 Astrazeneca Ab Use of low molecular weight thrombin inhibitor
US7803954B2 (en) 2000-12-01 2010-09-28 Astrazeneca Ab Mandelic acid derivatives and their use as thrombin inhibitors
JP2005536472A (ja) * 2002-05-31 2005-12-02 アストラゼネカ アクチボラグ 調節放出型の医薬配合物
US7202236B2 (en) * 2002-05-31 2007-04-10 Astrazeneca Ab Modified release pharmaceutical formulation
US7273858B2 (en) 2002-05-31 2007-09-25 Astrazeneca Ab Salts
CN100402025C (zh) * 2002-05-31 2008-07-16 阿斯特拉曾尼卡有限公司 改性释放的药物制剂
JP2009298795A (ja) * 2002-05-31 2009-12-24 Astrazeneca Ab 調節放出型の医薬配合物
WO2003101424A1 (fr) * 2002-05-31 2003-12-11 Astrazeneca Ab Formulation pharmaceutique à libération modifiée
SG165162A1 (en) * 2002-05-31 2010-10-28 Astrazeneca Ab Modified release pharmaceutical formulation
CN101264051B (zh) * 2002-05-31 2010-12-22 阿斯特拉曾尼卡有限公司 改性释放的药物制剂
RU2474416C2 (ru) * 2002-05-31 2013-02-10 Астразенека Аб Фармацевтическая композиция с модифицированным высвобождением и ее применение
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

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Publication number Publication date
AU4641097A (en) 1998-05-11
SE9603724D0 (sv) 1996-10-11

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