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WO1997039770A1 - New pharmaceutical formulation of a thrombin inhibitor for parenteral use - Google Patents

New pharmaceutical formulation of a thrombin inhibitor for parenteral use Download PDF

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Publication number
WO1997039770A1
WO1997039770A1 PCT/SE1997/000676 SE9700676W WO9739770A1 WO 1997039770 A1 WO1997039770 A1 WO 1997039770A1 SE 9700676 W SE9700676 W SE 9700676W WO 9739770 A1 WO9739770 A1 WO 9739770A1
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Prior art keywords
cyclodextrin
thrombin inhibitor
formulation
water
formulation according
Prior art date
Application number
PCT/SE1997/000676
Other languages
French (fr)
Inventor
Anna Lundgren
Ulla Stjernfelt
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 AU27195/97A priority Critical patent/AU2719597A/en
Publication of WO1997039770A1 publication Critical patent/WO1997039770A1/en

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    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
  • 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
  • an extended release formulation is desirable, especially when the administration is parenteral.
  • Parenteral extended release formulations allow a drug to be delivered in a dose resulting in
  • An extended release effect may be a prerequisite for subcutaneous or intramuscular treatment, particularly for low molecular weight, water soluble drugs with short half-life.
  • Retardation can be obtained by using viscous vehicles, or by means of reversible complex formation to a constituent of the formulation.
  • Cyclodextrins are enzymatically modified starches made of glucopyranose units. In this
  • the outer surface of the cyclodextrin is
  • thrombin inhibitor comprising a thrombin inhibitor which is melagatran, inogatran or a physiologically
  • 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),
  • Aze is (S)-azetidine-2-carboxylic acid
  • Cgl is (S)-cyclohexylglycine
  • Pab is l-amidino-4-aminomethyl benzene Pic is (S)-pipecolinic acid.
  • Water solubility in this context is defined as a solubility of more than 3.5 g / 100 g of water, in accordance with the solubility definition of Martindale (Martindale, The Extra
  • Physiologically acceptable salts are such as for instance but not restricted to salts from inorganic and organic acids, e.g. hydrobromide, hydrochloride, sulphate, nitrate; salts of
  • sulphonic acids e.g. methane sulphonate, ethane sulphonate, benzene sulphonate, toluene sulphonate, 'naphthalene-2-sulphonate, salts of carboxylic acids, e.g. maleate, benzoate, salicylate, salts of hydroxy acids, e.g. acetate, malate, succinate, gluconate, glycollate,
  • lactate tartrate, citrate, ascorbate, salts of fatty acids, e.g. hexanoate, octanoate, decanoate, undecylenate, dodecylsulphate, oleate, stearate.
  • fatty acids e.g. hexanoate, octanoate, decanoate, undecylenate, dodecylsulphate, oleate, stearate.
  • the additive is a cyclodextrin which may be either unsubstituted ⁇ -cyclodextrin, ⁇ - cyclodextrin, or ⁇ -cyclodextrin or substituted derivatives thereof.
  • Preferred unsubstituted cyclodextrin is the ⁇ -cyclodextrin.
  • the preferred substituted cyclodextrins according to the present invention are alkylated cyclodextrins.
  • the preferred alkylated cyclodextrins are O-alkylated cyclodextrins having alkyl (1-5C) groups.
  • the alkyl groups may be linear or branched, preferably linear with 1 to 4 carbon atoms.
  • the alkyl groups may be substituted by one or more hydroxy groups at position 2-5, preferably by a hydroxy group at the 2-position and/or the 3-position.
  • the most preferred alkyl group is the 2-hydroxypropyl.
  • hydroxypropyl substituted cyclodextrins are the hydroxypropyl- ⁇ - cyclodextrins and the hydroxypropyl- ⁇ -cyclodextrins. The most preferred are the hydroxypropyl- ⁇ -cyclodextrins.
  • the alkylated cyclodextrin is usually not a homogenous product but a mixture of alkylated cyclodextrin molecules with a various number of hydroxyl groups substituted.
  • the degree of substitution of the hydroxypropyl- ⁇ -cyclodextrins may theoretically vary
  • substitution is in the range of 2 to 4 hydroxypropyl groups per ⁇ -cyclodextrin molecule.
  • the concentration of the thrombin inhibitor is usually in the range 0.01 to 50% (w/w),
  • the concentration of cyclodextrin is 10 to 70 % (w/w) of the ready to use formulation.
  • the amount of thrombin inhibitor relative to the amount of cyclodextrin in the formulation according to the invention varies in the range 1 :7000 to 1 : 1 calculated by weight. Due to physiological considerations the pH of the formulation is preferably adjusted to
  • an acid such as but not restricted to acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, or an alkali, such as sodium hydroxide or any other physiologically suitable alkalising agent.
  • the formulation may contain antimicrobial preservatives, tonicity modifiers and/or antioxidants.
  • the formulation may be prepared 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, however,
  • humans are 0.001 to 50 mg/kg body weight, preferably 0.005 to 5 mg/kg.
  • the pharmaceutical formulation is suitable for prophylaxis and/or treatment in arterial as well as venous thromboembolism.
  • the formulation is to be used parenterally including intracutaneous, subcutaneous, intra lipomateus, intramuscular and intraperitoneal administration.
  • Working examples are to be used parenterally including intracutaneous, subcutaneous, intra lipomateus, intramuscular and intraperitoneal administration.
  • Example 1 [1.8% w/w (20 mg/ml) melagatran in 40% w/w of hydroxypropyl- ⁇ -cyclodextrin (HP ⁇ CD)]
  • the cyclodextrin is weighed and dissolved during stirring in the main part of the water.
  • Example 2 [1.9% w/w (22 mg/ml) inogatran in 40% w/w of hydroxypropyl- ⁇ -cyclodextrin
  • a dose of 5 mg of melagatran was administered subcutaneously to humans in a) the

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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)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

A pharmaceutical formulation of a trombin inhibitor for parenteral use having an extended release effect.

Description

NEW PHARMACEUTICAL FORMULATION OF A THROMBIN INHIBITOR FOR PARENTERAL USE
Field of invention
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.
Background of the invention
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 which are rapidly cleared from the body. To permit administration with
a low dosing frequence an extended release formulation is desirable, especially when the administration is parenteral.
Parenteral extended release formulations allow a drug to be delivered in a dose resulting in
a suitable plasma concentration for an extended period of time, with less frequent
administration and avoiding high peak concentrations. An extended release effect may be a prerequisite for subcutaneous or intramuscular treatment, particularly for low molecular weight, water soluble drugs with short half-life.
A wide range of means have been used to achieve parenteral extended release.
One approach has been to retard the diffusion of the drug out of the formulation. Retardation can be obtained by using viscous vehicles, or by means of reversible complex formation to a constituent of the formulation.
Cyclodextrins are enzymatically modified starches made of glucopyranose units. In this
process, three different cyclodextrines are formed, α-, β-, and γ-cyclodextrin with six, seven
and eight glucopyranose units, respectively. The outer surface of the cyclodextrin is
hydrophilic and the internal cavity is hydrophobic. Cyclodextrins are known to form
inclusion complexes with compounds or parts of compounds that fit into the ring cavity and
are attracted to the hydrophobic environment. Cyclodextrins, and in particular β-
cyclodextrins, have been used in many pharmaceutical formulations, e.g. to increase solubility and stability.In EP 149 197 the combination of a medicinal substance sparingly
soluble in water and a partially etherified β-cyclodextrin is disclosed with the object of
providing better solubility and stability.
The object of achieving extended release of various water-soluble drugs from oral and oily
parenteral formulations by cyclodextrin derivatives is disclosed in K. Uekama et al., Release
control of water-soluble drugs by β-cyclodextrin derivatives. Minutes Int. Symp. Cyclodextrines, 5th Ed. Sante, Paris, France 1990, pages 418-423, Conference Proceedings.
In WO 95/05197 the use of a cyclodextrin derivative for preparing an opioid analgesic
preparation for intramuscular or subcutaneous administration is described. However, the
problem of achieving extended release of parenteral formulations of water-soluble low
molecular weight compounds from low viscosity cyclodextrin solutions has not been
previously described.
Disclosure of the invention
It has now surprisingly been found that a formulation of a water solution of a thrombin
inhibitor comprising a thrombin inhibitor which is melagatran, inogatran or a physiologically
acceptable water-soluble salt thereof, and a cyclodextrin additive can be used for extending
the release of the thrombin inhibitor in vivo after parenteral administration.
Melagatran is the compound HOOC-CH2-(R)-Cgl-Aze-Pab (disclosed in EP 701 568) and
inogatran is the compound HOOC-CH2-(R)-Cha-Pic-Nag (disclosed in EP 618 926),
wherein
Aze is (S)-azetidine-2-carboxylic acid
Cgl is (S)-cyclohexylglycine
Cha is (S)-β-cyclohexyl alanine
Nag is noragmatine
Pab is l-amidino-4-aminomethyl benzene Pic is (S)-pipecolinic acid.
Water solubility in this context is defined as a solubility of more than 3.5 g / 100 g of water, in accordance with the solubility definition of Martindale (Martindale, The Extra
Pharmacopea, The Pharmaceutical press, London 1993).
Physiologically acceptable salts, are such as for instance but not restricted to salts from inorganic and organic acids, e.g. hydrobromide, hydrochloride, sulphate, nitrate; salts of
sulphonic acids, e.g. methane sulphonate, ethane sulphonate, benzene sulphonate, toluene sulphonate, 'naphthalene-2-sulphonate, salts of carboxylic acids, e.g. maleate, benzoate, salicylate, salts of hydroxy acids, e.g. acetate, malate, succinate, gluconate, glycollate,
lactate, tartrate, citrate, ascorbate, salts of fatty acids, e.g. hexanoate, octanoate, decanoate, undecylenate, dodecylsulphate, oleate, stearate.
The additive is a cyclodextrin which may be either unsubstituted α-cyclodextrin, β- cyclodextrin, or γ-cyclodextrin or substituted derivatives thereof.
Preferred unsubstituted cyclodextrin is the γ-cyclodextrin.
The preferred substituted cyclodextrins according to the present invention are alkylated cyclodextrins.
The preferred alkylated cyclodextrins are O-alkylated cyclodextrins having alkyl (1-5C) groups. The alkyl groups may be linear or branched, preferably linear with 1 to 4 carbon atoms. The alkyl groups may be substituted by one or more hydroxy groups at position 2-5, preferably by a hydroxy group at the 2-position and/or the 3-position. The most preferred alkyl group is the 2-hydroxypropyl.
The preferred of the hydroxypropyl substituted cyclodextrins are the hydroxypropyl- β- cyclodextrins and the hydroxypropyl-γ-cyclodextrins. The most preferred are the hydroxypropyl- β-cyclodextrins.
The alkylated cyclodextrin is usually not a homogenous product but a mixture of alkylated cyclodextrin molecules with a various number of hydroxyl groups substituted.
The degree of substitution of the hydroxypropyl-β-cyclodextrins may theoretically vary
from 1 to 21 hydroxypropyl groups per β-cyclodextrin molecule, with a preferred average
degree of substitution in the range of 1 to 7. The most preferred average degree of
substitution is in the range of 2 to 4 hydroxypropyl groups per β-cyclodextrin molecule.
The concentration of the thrombin inhibitor is usually in the range 0.01 to 50% (w/w),
preferably 0.1 to 25% (w/w) of the ready to use formulation.
The concentration of cyclodextrin is 10 to 70 % (w/w) of the ready to use formulation.
The amount of thrombin inhibitor relative to the amount of cyclodextrin in the formulation according to the invention varies in the range 1 :7000 to 1 : 1 calculated by weight. Due to physiological considerations the pH of the formulation is preferably adjusted to
between 3 and 10. For pH adjustment an acid is used, such as but not restricted to acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, or an alkali, such as sodium hydroxide or any other physiologically suitable alkalising agent.
The formulation may contain antimicrobial preservatives, tonicity modifiers and/or antioxidants.
The formulation may be prepared 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, however,
normally the sterilization is performed in the last step.
Suitable daily parenteral doses for the trombin inhibitor in the therapeutical treatment of
humans are 0.001 to 50 mg/kg body weight, preferably 0.005 to 5 mg/kg.
The pharmaceutical formulation is suitable for prophylaxis and/or treatment in arterial as well as venous thromboembolism.
The formulation is to be used parenterally including intracutaneous, subcutaneous, intra lipomateus, intramuscular and intraperitoneal administration. Working examples
Example 1 [1.8% w/w (20 mg/ml) melagatran in 40% w/w of hydroxypropyl-β-cyclodextrin (HPβCD)]
Melagatran 7.97 g
HPβCD 183.2 g
HCI to adjust pH to 5 qs
Adjust with water for inj. to 450.2 g
The cyclodextrin is weighed and dissolved during stirring in the main part of the water. The
weighed amount of melagatran is then added to the cyclodextrin solution and dissolved
during stirring. The pH of the dissolved solution is adjusted to 5 with 2 M HCI. The rest of the water is added to the final weight The solution is sterilized by filtration through 0.22
μm sterile filters and filled into sterile injection vials.
In a similar way the following formulations were prepared:
Example 2 [1.9% w/w (22 mg/ml) inogatran in 40% w/w of hydroxypropyl-γ-cyclodextrin
(HPγCD)]
Inogatran 0.329 g
HPγCD 6.88 g
HCI to adjust pH to 7.4 qs
Adjust with water for inj. to 17.52 g Example 3 [1.7% w/w (20 mg/ml) melagatran in 50% w/w of HPβCD)
Melagatran 0.518 g
HPβCD 15.0 g
HCI to adjust pH to 5 qs
Adjust with water for inj. to 30.0 g
Extended release
A dose of 5 mg of melagatran was administered subcutaneously to humans in a) the
cyclodextrin formulation of Example 1, and b) in a physiological saline solution.
The data in the Table shows a 3-fold decrease in absorption rate and a reduced peak plasma concentration for the cyclodextrin formulation as compared to the physiological saline
solution.
TABLE
Human data l
a) Cyclodextrin vehicle b) Physiological sali
Time Mean plasma concentration Time M Meeaann plasma concentration
N = 6 N = 6
(minutes) (μmole/litre) (minutes) (μmol
5 . ** 5 0.084
10 . * 10 0.23
15 . * 15 0.43
20 0.24 20 . *
30 . * 30 0.59
40 0.37 40 . *
45 . * 45 0.55
60 0.39 60 0.49
90 0.38 90 0.37
120 0.32 120 0.28
150 0.28 150 0.22
180 0.23 180 0.19
210 . * 210 0.15
240 0.15 240 0.12
300 0.10 300 0.085
360 0.063 360 . *
480 0.031 480 0.024
600 0.015 600 . *
720 0.010 720 . *
The total area under the plasma concentration versus time curves are equal for the two
-1 formulations (AUC=88.3 μmole L • min.)
*) not determined **) below limit of quantitation

Claims

Claims
1. An extended release formulation for parenteral administration of a water-soluble
thrombin inhibitor comprising a thrombin inhibitor which is melagatran, inogatran or a
physiologically accepatble water-soluble salt thereof and a water soluble cyclodextrin
additive for extending the release of the thrombin inhibitor.
2. A formulation according to claim 1 , wherein the cyclodextrin is a substituted cyclodextrin having alkyl-, or hydroxyalkyl groups.
3. A formulation according to claim 1 , wherein the cyclodextrin is hydroxypropyl
cyclodextrin.
4. A formulation according to any one of the preceding claims, wherein the cyclodextrin is
hydroxypropyl- β-cyclodextrin or hydroxypropyl-γ-cyclodextrin.
5. A formulation according to any one of the preceding claims, wherein the cyclodextrin is
2-hydroxypropyl-β-cyclodextrin.
6. A formulation according to any one of the preceding claims, wherein the thrombin
inhibitor is melagatran.
7. A formulation according to any one of the preceding claims, wherein the concentration of the thrombin inhibitor is in the range 0.01 to 50% (w/w) of the ready to use formulation.
8. A formulation according to any one of the preceding claims, wherein the concentration of cyclodextrin is 10 to 70% (w/w) of the ready to use formulation.
9. A formulation according to any one of the preceding claims for use in the prophylaxis
and/or treatment in arterial and/or venous thromboembolism in mammals including man.
10. A process for the preparation of a formulation according to any one of the preceding claims wherein the thrombin inhibitor and the cyclodextrin are dissolved in water, the pH is
adjusted and the resulting solution is sterilized or the separate steps are performed in any other order.
1 1. A method for the prophylaxis and/or treatment of arterial and/or venous
thromboembolism in mammals including man by administering to a host in need thereof of a formulation as defined in any of claims 1 to 9.
12. Use of a water-soluble thrombin inhibitor which is melagatran, inogatran or a
physiologically acceptable water-soluble salt thereof and a cyclodextrin additive for extending the release of the thrombin inhibitor as defined in any one of claims 1 to 9 for the
manufacture of an extended release medicament for prophylaxis and/or treatment of arterial and/or venous thromboembolism.
PCT/SE1997/000676 1996-04-24 1997-04-22 New pharmaceutical formulation of a thrombin inhibitor for parenteral use WO1997039770A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27195/97A AU2719597A (en) 1996-04-24 1997-04-22 New pharmaceutical formulation of a thrombin inhibitor for parenteral use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9601556A SE9601556D0 (en) 1996-04-24 1996-04-24 New pharmaceutical formulation of a thrombin inhibitor for parenteral use
SE9601556-5 1996-04-24

Publications (1)

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WO1997039770A1 true WO1997039770A1 (en) 1997-10-30

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AR (1) AR006664A1 (en)
AU (1) AU2719597A (en)
ID (1) ID17334A (en)
SE (1) SE9601556D0 (en)
WO (1) WO1997039770A1 (en)
ZA (1) ZA973062B (en)

Cited By (18)

* Cited by examiner, † Cited by third party
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WO2000012043A1 (en) * 1998-09-01 2000-03-09 Astrazeneca Ab Improved stability for injection solutions
WO2000041716A1 (en) * 1999-01-13 2000-07-20 Astrazeneca Ab New use of melagatran
WO2000067727A1 (en) * 1999-05-11 2000-11-16 Sanofi-Synthelabo Galenic formulations of antithrombotic agents for subcutaneous administration
WO2000076504A1 (en) * 1999-06-10 2000-12-21 Astrazeneca Ab Production of agglomerates of inogatran and the compound inogatran anhydrate
WO2001095932A1 (en) * 2000-06-10 2001-12-20 Astrazeneca Ab A COMBINATION PRODUCT COMPRISING MELAGATRAN AND A FACTOR VIIa INHIBITOR
WO2001095931A1 (en) * 2000-06-10 2001-12-20 Astrazeneca Ab A COMBINATION PRODUCT COMPRISING MELAGATRAN AND A FACTOR Xa INHIBITOR
US6462021B1 (en) 2000-11-06 2002-10-08 Astrazeneca Ab Use of low molecular weight thrombin inhibitor
WO2002094304A1 (en) * 2001-05-18 2002-11-28 Astrazeneca Ab The use of a gatran for the manufacture of a medicament for the treatment of pulmonary fibrosis
WO2003101423A1 (en) * 2002-05-31 2003-12-11 Astrazeneca Ab Immediate release pharmaceutical formulation
WO2003101424A1 (en) * 2002-05-31 2003-12-11 Astrazeneca Ab Modified release pharmaceutical formulation
US6716834B2 (en) 2000-05-16 2004-04-06 Astrazeneca Ab Thiochromane derivatives and their use as thrombin inhibitors
EP1527787A1 (en) * 1998-09-03 2005-05-04 AstraZeneca AB Immediate release tablet
US6989381B2 (en) 2000-08-22 2006-01-24 Pharmacia Corporation Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
US7273858B2 (en) 2002-05-31 2007-09-25 Astrazeneca Ab Salts
US7645751B2 (en) 2000-12-01 2010-01-12 Astrazeneca Mandelic acid derivatives and their use as thrombin inhibitors
US7820645B2 (en) 2006-12-06 2010-10-26 Astrazeneca Ab Crystalline forms
WO2013175494A3 (en) * 2012-04-10 2014-01-23 Rubicon Research Private Limited Controlled release pharmaceutical formulations of direct thrombin inhibitors
EP2982668A2 (en) 2002-12-03 2016-02-10 Pharmacyclics LLC 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors for the treatment of thromboembolic disorders

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Cited By (35)

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US6576245B1 (en) 1998-09-01 2003-06-10 Astrazeneca Ab Stability for injection solutions
US6998136B2 (en) 1998-09-01 2006-02-14 Astrazeneca Ab Stability for injection solutions
MY120822A (en) * 1998-09-01 2005-11-30 Astra Ab Stability for injection solutions
WO2000012043A1 (en) * 1998-09-01 2000-03-09 Astrazeneca Ab Improved stability for injection solutions
US6660279B2 (en) 1998-09-01 2003-12-09 Astrazeneca Ab Stability for injection solutions
EP1527787A1 (en) * 1998-09-03 2005-05-04 AstraZeneca AB Immediate release tablet
WO2000041716A1 (en) * 1999-01-13 2000-07-20 Astrazeneca Ab New use of melagatran
US6683054B1 (en) 1999-01-13 2004-01-27 Astrazeneca Ab Use of melagatran
WO2000067727A1 (en) * 1999-05-11 2000-11-16 Sanofi-Synthelabo Galenic formulations of antithrombotic agents for subcutaneous administration
FR2793418A1 (en) * 1999-05-11 2000-11-17 Synthelabo GALENIC FORMULATIONS OF ANTITHROMBOTIC AGENTS FOR SUBCUTANEOUS ADMINISTRATION
WO2000076504A1 (en) * 1999-06-10 2000-12-21 Astrazeneca Ab Production of agglomerates of inogatran and the compound inogatran anhydrate
US6531490B1 (en) 1999-06-10 2003-03-11 Astrazeneca Ab Production of agglomerates of inogatran and the compound inogatran anhydrate
US6716834B2 (en) 2000-05-16 2004-04-06 Astrazeneca Ab Thiochromane derivatives and their use as thrombin inhibitors
WO2001095931A1 (en) * 2000-06-10 2001-12-20 Astrazeneca Ab A COMBINATION PRODUCT COMPRISING MELAGATRAN AND A FACTOR Xa INHIBITOR
WO2001095932A1 (en) * 2000-06-10 2001-12-20 Astrazeneca Ab A COMBINATION PRODUCT COMPRISING MELAGATRAN AND A FACTOR VIIa INHIBITOR
US6989381B2 (en) 2000-08-22 2006-01-24 Pharmacia Corporation Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
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
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SE9601556D0 (en) 1996-04-24
ID17334A (en) 1997-12-18
AU2719597A (en) 1997-11-12
ZA973062B (en) 1997-10-24
AR006664A1 (en) 1999-09-08

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