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WO1998016252A1 - New pharmaceutical parenteral formulation of a thrombin inhibitor - Google Patents

New pharmaceutical parenteral formulation of a thrombin inhibitor 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
French (fr)
Inventor
Anna Lundgren
Urban Skantze
Original Assignee
Astra Aktiebolag
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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/en

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    • 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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Abstract

A pharmaceutical formulation of a thrombin inhibitor for parenteral use having an extended release effect, as well as a process for its preparation and the use of the formulation in arterial and/or venous thromboembolism, the extended release formulation comprising a thrombin inhibitor selected from the group consisting of melagatran, inogatran and their physicologically acceptable water soluble salts, and one or more block copolymer having the general formula: HO[C2H4O]a[C3H6O]b[C2H4O]aH, wherein each a independently is an integer 1 - 250 and b is an integer 1 - 250 and wherein the formulation has a solution-gelation transition temperature below 37 °C.

Description

NEW PHARMACEUTICAL PARENTERAL FORMULATION OF A THROMBIN INHIBITOR
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 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. Particularly for low molecular weight, water soluble drugs with a short half life, an extended release effect may be a prerequisite for subcutaneous or intramuscular treatment.
A wide range of measures are used to achieve extended release parenteral formulations.
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.).
All 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.
In Johnston et al. (Johnston, T.P. et al. J. of Parenteral Science & Technology, vol. 43, No. 6, 1989) and Pec et al. (Pec, E. A. et al. J. of Pharmaceutical Sciences, 81, 7, 1992) 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.
For low molecular weight compounds, diffusion is much more difficult to retard, which makes the viscosity properties (and the solution-gelation transition temperature) of the poloxamer vehicle particularly important for obtaining extended release effects in vivo. These parameters are determined by the overall composition of the formulation, such as the nature and concentration of the active compound, and the poloxamer, electrolytes, solvents, and surfactants, and it is not possible to predict the total effect on these parameters (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).
Guzman et al. International J. of Pharmaceutics, 80 (1992) p 119-127) illustrated how poloxamers can be used as extended release formulations for a model drug compound phenolsulfophtalein. Variations in gelation properties of the poloxamer formulations were found to be a function of the concentration of the model drug, as well as of the type and concentration of poloxamer and electrolyte.
Disclosure of the invention
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.
It has now surprisingly been found that 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
HO[C2H40]a [C3H60]b [C2H40]a H wherein a is an integer 1-250 and b is an integer 1-250, and wherein the additive(s) together with the trombin inhibitor in the formulation have a solution-gelation transition temperature below 37°C, provides an extended release effect in vivo after subcutaneous 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.
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. maleate, benzoate, salicylate, acetate, malate, succinate, gluconate, glycollate, lactate, tartrate, citrate, ascorbate, hexanoate, octanoate, decanoate, undecylenate, dodecylsulphate, oleate, stearate.
As additives are used poloxamers, which are block copolymers having the general formula
HO[C2H40]a [C3H6O]b [C2H4O]a H wherein a is an integer 1-250 and b is an integer 1-250.
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
HO[C2H40]a [C3H6O]b [C2H4O]a H
wherein 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
HO[C2H40]a [C3H6O]b [C2H4O]a H
wherein 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%. The 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.
Due to physiological considerations 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.
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
Example 1 (20 mg/ml Melagatran in 18/10% (w/w) of Poloxamer 407/188)
Melagatran 8.1 g
Poloxamer 407 72 g
Poloxamer 188 40 g
HCl to adjust pH to 5 qs
Water for injection to 400 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 μm 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 μm sterile filters and filled into sterile injection vials.
The solution-gelation transition temperature of the formulation was determined as 34°C.
In similar ways the following formulations were prepared:
Example 2 (30 mg/ml Melagatran in 25% (w/w) of Poloxamer 407)
Melagatran 450 mg Poloxamer 407 3.75 g
Water for inj ection to 15.0 g
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)
Melagatran 727 mg
Poloxamer 407 5.1 g
Poloxamer 188 5.1 g
HCl to adjust pH to 5 qs
Water for injection to 30.0 g
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
HCl to adjust pH to 5 q.s.
Water for injection to 30.0 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
HCl to adjust pH to 5 q.s.
Water for injection to 30.0 g
The solution-gelation transition temperature of the formulation was determined as 24°C. Biological experiments
Figure imgf000011_0001
Extended release
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.
Physiological saline vehicle Poloxamer vehicle
Time Mean plasma concentration Mean plasma concentration (minutes) (μmole/1) (μmole/1)
N=3 N=3
0 0.00 0.00
10 1.11 0.10
20 1.80 0.29
40 1.19 0.30
60 0.89 0.27
90 0.57 0.30
120 0.41 0.35
240 0.12 0.38
Data from humans Extended release
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
Time Mean plasma concentration Time Mean plasma concentration
N = 6 N = 6
(minutes) (μmole/litre) (minutes) (μmole/litre)
5 - xx) 5 0.084
10 - x) 10 0.23
15 - x) 15 0.43
20 0.25 20 - x)
30 -x) 30 0.59
40 0.36 40 -
45 -x) 45 0.55
60 0.40 60 0.49
90 0.41 90 0.37
120 0.34 120 0.28
150 0.28 150 - x)
180 0.23 180 0.19
210 - x) 210 0.15
240 0.16 240 0.12
300 0.10 300 0.085
360 0.063 360 - x)
480 0.028 480 0.024
600 0.016 600 - x)
720 0.011 720 - x)
The total area under the plasma concentration versus time curves are equal for the two formulations (AUC=88.3 μmole -L" - min.) x) not determined xx) below limit of quantitation
The data set out above from pigs and humans clearly demonstrate a significant and useful extended release effect achieved by the present invention.

Claims

Claims
1. An extended release formulation for parenteral administration of a water solution of a low molecular weight water soluble thrombin inhibitor with a short half life comprising a thrombin inhibitor selected from the group consisting of melagatran, inogatran and their physiologically acceptable water soluble salts, and one or more block copolymer having the general formula
HO[C2H4O]a [C3H60]b [C2H4O]aH
wherein each a independently is an integer 1-250 and b is an integer 1-250 and wherein the formulation have a solution-gelation transition temperature below 37°C.
2. A formulation according to claim 1, having at least one additional component which is an acidifying or alkalising agent, antimicrobial preservative, tonicity modifier, antioxidant and/or buffer.
3. A formulation according to claim 1 or 2, wherein the block copolymer has the general formula
HO[C2H40]a [C3H6O]b[C2H4O]aH
wherein each a independently is an integer 5-150 and b is an integer 15-75.
4. A formulation according to claims 1 or 2, wherein the additive is a block copolymer having the general formula
HO[C2H40]a[C3H6O]b[C2H40]aH wherein each a independently is an integer 70-105 and b is an integer 25-70.
5. A formulation according to any one of claims 1 to 4, wherein the additive is a block copolymer having the general formula
HO[C2H4O]a[C3H6O]b[C2H4O]aH
wherein each 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%.
6. A formulation according to any one of claims 1 to 4, wherein the additive is a block copolymer having the general formula
HO[C2H4O]a[C3H6O]b[C2H4O]aH
wherein each 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%o.
7. A formulation according to any of the preceding claims wherein the additive is a mixture of the block copolymers defined in claim 5 and claim 6.
8. A formulation according to any one of claims 1 to 7, wherein the additive(s) together with the thrombin inhibitor in the formulation have a solution-gelation transition temperature within the range 15-37°C.
9. A formulation according to claim 8, wherein the additive(s) together with the thrombin inhibitor in the formulation have a solution-gelation transition temperature within the range 25-35°C.
10. A formulation according to any one of claims 1 to 9 wherein the thrombin inhibitor is melagatran or a physiologically acceptable salt thereof.
11. A formulation according to any one of claims 1 to 10 wherein the concentration of the thrombin inhibitor is in the range 0.01 - 20 % (w/w) of the ready to use formulation.
12. A formulation according to claim 11 wherein the concentration of the additive(s) is 15 - 40 % (w/w) of the ready to use formulation.
13. An extended release formulation as defined in any of claims 1-12 for use in the prophylaxis and/or treatment in arterial and/or venous thromboembolism in mammals including man.
14. A process for the preparation of a formulation according to any of the preceding claims wherein the thrombin inhibitor and the additives are dissolved in water, the pH is adjusted and the resulting solution is sterilized, the separate steps being performed in any order.
15. 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 1-13.
16. Use of the components of the extended release formulation defined in any one of claims 1 to 13 for the manufacture of a medicament useful in the prophylaxis and /or treatment of arterial and /or venous thromboembolism.
PCT/SE1997/001652 1996-10-11 1997-10-01 New pharmaceutical parenteral formulation of a thrombin inhibitor WO1998016252A1 (en)

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 (en) 1996-10-11 1996-10-11 New pharmaceutical parenteral formulation of a thrombin inhibitor

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SE (1) SE9603724D0 (en)
WO (1) WO1998016252A1 (en)

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EP0955063A1 (en) * 1998-04-01 1999-11-10 Basf Aktiengesellschaft Use of aqueous compositions in medicaments for subcutaneous or intramuscular administration
WO2000076504A1 (en) * 1999-06-10 2000-12-21 Astrazeneca Ab Production of agglomerates of inogatran and the compound inogatran anhydrate
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WO2003101424A1 (en) * 2002-05-31 2003-12-11 Astrazeneca Ab Modified release pharmaceutical formulation
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US7273858B2 (en) 2002-05-31 2007-09-25 Astrazeneca Ab Salts
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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 (18)

* Cited by examiner, † Cited by third party
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EP0955063A1 (en) * 1998-04-01 1999-11-10 Basf Aktiengesellschaft Use of aqueous compositions in medicaments for subcutaneous or intramuscular administration
EP1527787A1 (en) * 1998-09-03 2005-05-04 AstraZeneca AB Immediate release tablet
US6683054B1 (en) * 1999-01-13 2004-01-27 Astrazeneca Ab Use of melagatran
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
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 (en) * 2002-05-31 2005-12-02 アストラゼネカ アクチボラグ Controlled release pharmaceutical formulations
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 (en) * 2002-05-31 2008-07-16 阿斯特拉曾尼卡有限公司 Modified release pharmaceutical formulation
JP2009298795A (en) * 2002-05-31 2009-12-24 Astrazeneca Ab Controlled-release type pharmaceutical formulation
WO2003101424A1 (en) * 2002-05-31 2003-12-11 Astrazeneca Ab Modified release pharmaceutical formulation
SG165162A1 (en) * 2002-05-31 2010-10-28 Astrazeneca Ab Modified release pharmaceutical formulation
CN101264051B (en) * 2002-05-31 2010-12-22 阿斯特拉曾尼卡有限公司 Modified release pharmaceutical formulation
RU2474416C2 (en) * 2002-05-31 2013-02-10 Астразенека Аб Time-release pharmaceutical composition and use thereof
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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SE9603724D0 (en) 1996-10-11

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