WO1996014084A1 - A storage stable water solution for infusion containing a thrombin inhibitor - Google Patents

A storage stable water solution for infusion containing a thrombin inhibitor Download PDF

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Publication number
WO1996014084A1
WO1996014084A1 PCT/SE1995/001228 SE9501228W WO9614084A1 WO 1996014084 A1 WO1996014084 A1 WO 1996014084A1 SE 9501228 W SE9501228 W SE 9501228W WO 9614084 A1 WO9614084 A1 WO 9614084A1
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WO
WIPO (PCT)
Prior art keywords
hooc
nag
pic
cha
solution according
Prior art date
Application number
PCT/SE1995/001228
Other languages
French (fr)
Inventor
Ulla Stjernfelt
Mats Sundgren
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
Priority to DK95938085T priority Critical patent/DK0789585T3/en
Priority to PL95320342A priority patent/PL320342A1/en
Priority to BR9509634A priority patent/BR9509634A/en
Priority to US08/557,189 priority patent/US5830865A/en
Priority to DE69522702T priority patent/DE69522702T2/en
Priority to MX9703339A priority patent/MX9703339A/en
Priority to JP8515235A priority patent/JPH10508598A/en
Priority to AU38846/95A priority patent/AU695719B2/en
Application filed by Astra Aktiebolag filed Critical Astra Aktiebolag
Priority to SK535-97A priority patent/SK53597A3/en
Priority to NZ295492A priority patent/NZ295492A/en
Priority to EE9700218A priority patent/EE9700218A/en
Priority to AT95938085T priority patent/ATE205399T1/en
Priority to EP95938085A priority patent/EP0789585B1/en
Publication of WO1996014084A1 publication Critical patent/WO1996014084A1/en
Priority to IS4468A priority patent/IS4468A/en
Priority to NO19972065A priority patent/NO322048B1/en
Priority to FI971949A priority patent/FI971949A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides

Definitions

  • the present invention relates to a new improved storage stable intravenous formulation for infusion of thrombin inhibitors, especially of the peptidic thrombin inhibitors HOOC-CH 2 -(R)Cha-Pic-Nag and HOOC-CH2-(R)Cgl -Aze- Pab, respectively, to a process for the preparation of said formulation and to a method for treatment by administration of said formulations.
  • Thrombin inhibitors are expected to be effective drugs in a number of diseases characterised by hypercoagulation. Their therapeutic use will be facilitated if stable formulations are available, i.e. formulations having a long shelf-life when stored at room-temperature.
  • Example PI a water solution for parenteral administration is disclosed, said formulation is an acetate buffer-solution of HOOC-CH2-(R)Cha- Pic-Nag x 2HBr for parenteral use of pH 3-7, which is within the physiologically acceptable pH range suitable for injections directly into the human body.
  • This solution also includes additives such as sodium chloride to get an isotonic solution.
  • Example P2 in this document describes a solution for parenteral administration, namely a water solution of an active compound and sodium chloride, which is adjusted with NaOH to pH 3-9, preferably 5-7.
  • the stability of peptides is generally a problem in the pharmaceutical industry. Pharmaceutical formulations, especially with a low concentration of peptides, often loose activity during storage.
  • Each peptide is different with regard to pharmacological properties.
  • consideration can not only be taken to the pharmacological properties of the peptide but also other aspects must be considered such as the industrial manufacture, easy and convenient storage and handling for the hospital staff and safety for the patient The results of these aspects are not predictable when testing different formulations and each peptide often has a unique solution regarding stability.
  • peptides generally are more susceptible to degradation in an acidic or basic environment than in a neutral solution.
  • peptidic thrombin inhibitors HOOC-CH2-(R)-Cha-Pic- Nag and HOOC-CH2-(R)Cgl-Aze-Pab their storage stability is improved in acidic aqueous solutions.
  • the scope of the present invention is a storage stable concentrated, water solution for intraveneous infusion of an active thrombin inhibitor having the formula
  • Y is (R)-Cha-Pic-Nag or (R)-Cgl-Aze-Pab and having a pH in the range from 1.0 to 2.5, which solution does not require special storage conditions but can be stored at room temperature, i.e. between 15-30°C, preferably between 18-28°C, tentatively 25°C.
  • the stable water solution of the present invention which is a concentrated water solution of a thrombin inhibitor, is adjusted with a physiologically acceptable organic or inorganic acid, preferably an inorganic mineral acid such as hydrochloric acid, hydrobromic acid etc., for obtaining the desired pH.
  • a physiologically acceptable organic or inorganic acid preferably an inorganic mineral acid such as hydrochloric acid, hydrobromic acid etc.
  • the hydro chloric acid is most particularly preferred.
  • the formulation is a straight forward one without any stabilising additives.
  • the pharmaceutical formulation is easy to handle and to dose. Therefore said formulation suitably should be provided in containers intended for parenteral use, such as plastic or glass containers, e.g. vials, ampoules or prefilled syringes, and be added to infusion bags or bottles i.e. the storage stable concentrated water solution must be diluted before the administration to the patients.
  • containers intended for parenteral use such as plastic or glass containers, e.g. vials, ampoules or prefilled syringes, and be added to infusion bags or bottles i.e. the storage stable concentrated water solution must be diluted before the administration to the patients.
  • the solutions do not require additives such as buffer salts, isotonic salts or co-solvents for stability reasons.
  • the stable solution may also contain preservatives, i.e. in order to prevent microbiological growth.
  • the solution is aimed to be added to a solution for intravenous infusion such as physiological saline or other electrolytes, glucose, mannitol, dextran etc. or a combination thereof, and parenterally administered.
  • the solution may be manufactured with the active peptidic thrombin inhibitors HOOC-CH 2 -(R)-Cha-Pic-Nag and HOOC-CH 2 -(R)Cgl-Aze-Pab, respectively, as commonly used salts or in their base form.
  • the solution of the present invention will be stable enough to permit room temperature storage for extended periods.
  • a commercial product should preferably have an storage period of at least two years, at the end of which period at least 95% of the active compound should remain, that is the total amount of degradation products should be less than 5% .
  • the preferred concentrations of HOOC-CH2-(R)-Cha-Pic-Nag may vary within broad ranges between 0.001-200 mg/ml, preferably 0.1-100 mg/ml, more particularly preferred 10-100 mg/ml.
  • the preferred concentrations of HOOC- CH2-(R)Cgl-Aze-Pab may vary within broad ranges between 0.001-300 mg/ml, preferably 0.1-200 mg/ml , more particularly preferred 1-100 mg/ml.
  • This invention also relates to a process for the prepartion of a storage stable water solution, which comprises dissolving in water the active thrombin inhibitors HOOC-CH 2 -(R)Cha-Pic-Nag or HOOC-CH 2 -(R)Cgl-Aze-Pab, respectively, adjusting the pH of the obtained solution from 1.0 to 2.5, preferably from 1.5 to 2.0, or to a specific desired value, e.g. 1.0, 1.5, 2.0, 2.5.
  • Suitable volumes when using ampoules, vials or syringes are 0.1-100 ml, preferably 1-10 ml.
  • the two active thrombin inhibitors HOOC-CH2-(R)Cha-Pic-Nag and HOOC-
  • CH2-(R)Cgl-Aze-Pab are both possible to dissolve in water at room temperature.
  • a stability indicating method using reversed-phase liquid chromatography in an ion-pair mode and UV-detection at 210 and 238 ntn was developed for HOOC- CH2-(R)Cha-Pic-Nag and HOOC-CH2-(R)Cgl -Aze-Pab, respectively.
  • a standard solution of thrombin inhibitors 0.018-0.022 mg/mL was prepared, in mobile phase.
  • the sample solution was diluted to a concentration of about 0.02 mg/ml with mobile phase.
  • the column was equilibrated with mobile phase until a stable baseline was obtained.
  • the standard and sample were injected at suitable intervals.
  • the retention time for the active thrombin inhibitors HOOC-CH2- (R)Cha-Pic-Nag and HOOC-CH2-(R)Cgl -Aze-Pab are about 4 and 12 minutes for the methods, respectively.
  • the pH of the solutions was measured potentiometrically without prior dilution using a Radiometer PHM Reference pH meter with a glass electrode (GK2401C electrode).
  • This example presents the results from a stability study at 25°C of a prior known acetate buffer solution containing the hydrobromide salt of HOOC-CH 2 -(R)Cha- Pic-Nag in two different concentrations and having pH 5.0 at the beginning of the study.
  • This example presents the results from a stability study at 25°C of HOOC-CH 2 - (R)Cha-Pic-Nag as a free base in the same concentration as Example 1 (ii) above, and starting at a pH about 5.
  • the purpose of this study was to compare the stability of HOOC-CH 2 -(R)Cha-Pic-Nag as a free base and as a salt thereof.
  • This example presents the result from a stability study at 25°C of buffer solutions of HOOC-CH2-(R)Cha-Pic-Nag at different pHs between 3 to 9.
  • This example presents the result from a stability study at 25°C of HOOC-CH2- (R)Cha-Pic-Nag in two different concentrations at pH about 1.5, namely from 1.5 to 1.6.
  • This example presents the result from a stability study at 25°C of HOOC-CH 2 - (R)Cha-Pic-Nag in two different concentrations at pH 2.0.
  • the purpose with this study is to compare the degradation of different pH in the range from 1.0 to 2.5 by comparing (i) with Example 4 (i).
  • This example presents the results from a stability study at 25°C of HOOC-CH2- (R)-Cgl-Aze-Pab as free base.
  • This example presents the result from a stability study at 25°C of HOOC-CH2-(R)- Cgl-Aze-Pab as buffer-solution and as water-solution, respectively, at different pHs.

Abstract

This invention relates to a storage stable concentrated water-solution for infusion having a pH in the range from 1.0 to 2.5 and containing an active thrombin inhibitor having the formula: HOOC-CH2-Y, wherein Y is (R)-Cha-Pic-Nag or (R)-Cgl-Aze-Pab, as a salt or as a free base thereof, a process for their preparation and to a method for treatment of a patient in need of said formulation.

Description

O 96/14084 PCI7SE95/01228
A storage stable water solution for infusion containing a thrombin inhibitor
Field of the invention
The present invention relates to a new improved storage stable intravenous formulation for infusion of thrombin inhibitors, especially of the peptidic thrombin inhibitors HOOC-CH2-(R)Cha-Pic-Nag and HOOC-CH2-(R)Cgl -Aze- Pab, respectively, to a process for the preparation of said formulation and to a method for treatment by administration of said formulations.
Background of the invention
Thrombin inhibitors are expected to be effective drugs in a number of diseases characterised by hypercoagulation. Their therapeutic use will be facilitated if stable formulations are available, i.e. formulations having a long shelf-life when stored at room-temperature.
In WO 93/111528, Example PI, a water solution for parenteral administration is disclosed, said formulation is an acetate buffer-solution of HOOC-CH2-(R)Cha- Pic-Nag x 2HBr for parenteral use of pH 3-7, which is within the physiologically acceptable pH range suitable for injections directly into the human body. This solution also includes additives such as sodium chloride to get an isotonic solution.
The active compound HOOC-CH2-(R)-Cgl-Aze-Pab is disclosed in PCT/SE94/00535, filed 2 June 1994 and not yet published. Example P2 in this document describes a solution for parenteral administration, namely a water solution of an active compound and sodium chloride, which is adjusted with NaOH to pH 3-9, preferably 5-7. The stability of peptides is generally a problem in the pharmaceutical industry. Pharmaceutical formulations, especially with a low concentration of peptides, often loose activity during storage.
Each peptide is different with regard to pharmacological properties. When preparing a pharmaceutical formulation of a specific peptide, consideration can not only be taken to the pharmacological properties of the peptide but also other aspects must be considered such as the industrial manufacture, easy and convenient storage and handling for the hospital staff and safety for the patient The results of these aspects are not predictable when testing different formulations and each peptide often has a unique solution regarding stability.
It is well known that peptides generally are more susceptible to degradation in an acidic or basic environment than in a neutral solution. However, unexpectedly it has been found that for the peptidic thrombin inhibitors HOOC-CH2-(R)-Cha-Pic- Nag and HOOC-CH2-(R)Cgl-Aze-Pab their storage stability is improved in acidic aqueous solutions.
Disclosure of the invention
The scope of the present invention is a storage stable concentrated, water solution for intraveneous infusion of an active thrombin inhibitor having the formula
HOOC-CHz-Y wherein Y is (R)-Cha-Pic-Nag or (R)-Cgl-Aze-Pab and having a pH in the range from 1.0 to 2.5, which solution does not require special storage conditions but can be stored at room temperature, i.e. between 15-30°C, preferably between 18-28°C, tentatively 25°C.
Thus, the stable water solution of the present invention, which is a concentrated water solution of a thrombin inhibitor, is adjusted with a physiologically acceptable organic or inorganic acid, preferably an inorganic mineral acid such as hydrochloric acid, hydrobromic acid etc., for obtaining the desired pH. The hydro chloric acid is most particularly preferred. The formulation is a straight forward one without any stabilising additives.
In an acidic solution the solubility of the two different drugs, respectively, increases and a more concentrated solution can be produced, which means that small containers which are easy to handle can be used.
It is of importance that the pharmaceutical formulation is easy to handle and to dose. Therefore said formulation suitably should be provided in containers intended for parenteral use, such as plastic or glass containers, e.g. vials, ampoules or prefilled syringes, and be added to infusion bags or bottles i.e. the storage stable concentrated water solution must be diluted before the administration to the patients.
An additional improvement is that the solutions do not require additives such as buffer salts, isotonic salts or co-solvents for stability reasons. However, the stable solution may also contain preservatives, i.e. in order to prevent microbiological growth. The solution is aimed to be added to a solution for intravenous infusion such as physiological saline or other electrolytes, glucose, mannitol, dextran etc. or a combination thereof, and parenterally administered.
The solution may be manufactured with the active peptidic thrombin inhibitors HOOC-CH2-(R)-Cha-Pic-Nag and HOOC-CH2-(R)Cgl-Aze-Pab, respectively, as commonly used salts or in their base form.
The solution of the present invention will be stable enough to permit room temperature storage for extended periods. A commercial product should preferably have an storage period of at least two years, at the end of which period at least 95% of the active compound should remain, that is the total amount of degradation products should be less than 5% . The preferred concentrations of HOOC-CH2-(R)-Cha-Pic-Nag may vary within broad ranges between 0.001-200 mg/ml, preferably 0.1-100 mg/ml, more particularly preferred 10-100 mg/ml. The preferred concentrations of HOOC- CH2-(R)Cgl-Aze-Pab may vary within broad ranges between 0.001-300 mg/ml, preferably 0.1-200 mg/ml , more particularly preferred 1-100 mg/ml.
This invention also relates to a process for the prepartion of a storage stable water solution, which comprises dissolving in water the active thrombin inhibitors HOOC-CH2-(R)Cha-Pic-Nag or HOOC-CH2-(R)Cgl-Aze-Pab, respectively, adjusting the pH of the obtained solution from 1.0 to 2.5, preferably from 1.5 to 2.0, or to a specific desired value, e.g. 1.0, 1.5, 2.0, 2.5. Suitable volumes when using ampoules, vials or syringes are 0.1-100 ml, preferably 1-10 ml.
The two active thrombin inhibitors, HOOC-CH2-(R)Cha-Pic-Nag and HOOC-
CH2-(R)Cgl-Aze-Pab, respectively, are both possible to dissolve in water at room temperature.
Examples
Analytical methods used in the examples below
Stability assay
A stability indicating method using reversed-phase liquid chromatography in an ion-pair mode and UV-detection at 210 and 238 ntn was developed for HOOC- CH2-(R)Cha-Pic-Nag and HOOC-CH2-(R)Cgl -Aze-Pab, respectively.
A standard solution of thrombin inhibitors, 0.018-0.022 mg/mL was prepared, in mobile phase. The sample solution was diluted to a concentration of about 0.02 mg/ml with mobile phase. The column was equilibrated with mobile phase until a stable baseline was obtained. The standard and sample were injected at suitable intervals. The retention time for the active thrombin inhibitors HOOC-CH2- (R)Cha-Pic-Nag and HOOC-CH2-(R)Cgl -Aze-Pab are about 4 and 12 minutes for the methods, respectively.
EH
The pH of the solutions was measured potentiometrically without prior dilution using a Radiometer PHM Reference pH meter with a glass electrode (GK2401C electrode).
The following examples illustrate but do not limit in any way the invention.
Example 1
This example presents the results from a stability study at 25°C of a prior known acetate buffer solution containing the hydrobromide salt of HOOC-CH2-(R)Cha- Pic-Nag in two different concentrations and having pH 5.0 at the beginning of the study.
( i ) HOOC-CH2-(R)Cha-Pic-Nag x 2HBr buffer solution (0.04 me/ml), pH 5
Composition:
HOOC-CH2-(R)Cha-Pic-Nag x 2HBr 0.04 mg Sodium hydroxide 1 M to pH 5 q.s.
Acetate buffer 0.05 M (incl. NaCl, 9 mg/ml) to 1 ml Stability
Time pH Temperature Degradation
(months) (° Q (area % of active compound)
0 5.0 25 -
3 5.0 25 0.73
6 - 25 1.41
14 5.4 25 5.80
( ϋ ) HOOC-CH2-(R)Cha-Pic-Nag x 2HBr buffer solution (9 mg/ml), pH 5
Composition:
HOOC-CH2-(R)Cha-Pic-Nag x 2HBr 9 mg
Sodium hydroxide 1 M to pH 5 q.s.
Acetate buffer 0.05 M (incl. NaCl, 9mg/ml) to 1 ml
Stability
Time pH Temperature Degradation
(months) (° C) (area % of active compound)
0 5.0 25 -
6 5.2 25 1.70
14 5.3 25 3.68 Conclusion
This storage study indicates that storage at room temperature, 25°C, for 2 years will not be acceptable depending on the large amount of degradation of the active compound.
Example 2
This example presents the results from a stability study at 25°C of HOOC-CH2- (R)Cha-Pic-Nag as a free base in the same concentration as Example 1 (ii) above, and starting at a pH about 5. The purpose of this study was to compare the stability of HOOC-CH2-(R)Cha-Pic-Nag as a free base and as a salt thereof.
HOOC-CH2-(R)Cha-Pic-Nag buffer solution (9 mg/ml), pH 5
Composition:
HOOC-CH2-(R)Cha-Pic-Nag as free base 9 mg
Hydrochloric acid 1 M to pH 5 q.s.
Acetate buffer 0.05 M (incl. NaCl, 9mg/ml) to 1 ml
Stability
Time PH Temperature Degradation
(months) (° C) (area % of active compound)
0 4.9 25 -
3 5.0 25 0.85
6 5.1 25 1.70
15 5.3 25 4.31 Conclusion
This study shows that there is no big difference in storage stability at room temperature, 25°C, by using HOOC-CH2-(R)Cha-Pic-Nag as a salt or as a free base (cf. Example 1).
Example 3
This example presents the result from a stability study at 25°C of buffer solutions of HOOC-CH2-(R)Cha-Pic-Nag at different pHs between 3 to 9.
( i ) HOOC-CH2-(R)Cha-Pic-Nag buffer solutions (9 mg/ml) at different pHs
Composition:
HOOC-CH2-(R)Cha-Pic-Nag as free base 9 mg Hydrochloric acid (1 M) to pH q.s.
Acetate buffer 0.05 M (incl. NaCl, 9 mg/ml) to 1 ml
Stability
Time pH Temperature Degradation (months) (° Q (area % of active compound)
0 3.0 25 -
4.0 -
5.0 -
3 3.6 25 0.75
4.2 0.78
5.0 0.85
6 3.8 25 1.30
4.4 1.48
5.1 1.70 ii ) HOOC-CH2-(R)Cha-Pic-Nag x 2 HC1 buffer solutions (1 mg/ml) at different pHs
Composition: HOOC-CH2-(R)Cha-Pic-Nag x 2 HC1 1 g Buffer solution* to l ml
* (for pH 4, 5 and 6 acetate buffer, for pH 8 phosphate buffer, for pH 9 carbonate buffer)
Stability
Time pH Temperature Degradation
(months) (° C) (area % of active compound)
3 4 25 1.1
5 25 1.3
6 25 2.4
8 25 10.8
9 25 12.2
Conclusion This study shows that the degradation of HOOC-CH2-(R)Cha-Pic-Nag decreases at lower pH, independently of base or salt form.
Example 4
This example presents the result from a stability study at 25°C of HOOC-CH2- (R)Cha-Pic-Nag in two different concentrations at pH about 1.5, namely from 1.5 to 1.6. HOOC-CH2-(R)Cha-Pic-Nag water solution (0.4 mg/ml), pH 1.5
Composition:
HOOC-CH2-(R)Cha-Pic-Nag as free base 0.4 mg
Hydrochloric acid 1 M to pH 1.5 q.s.
Water to 1 ml
Stability
Time pH Temperature Degradation
(months) (° C) (area % of active compound)
0 1.5 25 -
3 1.5 25 0.27
6 1.6 25 0.58
12 1.6 25 1.36
( ii ) HOOC-CH2-(R)Cha-Pic-Nag water solution (66 mg/ml), pH 1.5
Composition:
HOOC-CH2-(R)Cha-Pic-Nag as free base 66 mg Hydrochloric acid 1 M to pH 1.5 q.s. Water to l ml Stability
Time PH Temperature Degradation
(months) (° C) (area % of active compound)
0 1.6 25 -
3 1.6 25 0.31
6 1.6 25 0.65
12 1.8 25 1.40
Conclusion
This study shows that the degradation of HOOC-CH2-(R)Cha-Pic-Nag decreases at this low pH.
Example 5
This example presents the result from a stability study at 25°C of HOOC-CH2- (R)Cha-Pic-Nag in two different concentrations at pH 2.0. The purpose with this study is to compare the degradation of different pH in the range from 1.0 to 2.5 by comparing (i) with Example 4 (i).
( i ) HOOC-CH2-(R)Cha-Pic-Nag water solution (0.4 mg/ml), pH 2
Composition:
HOOC-CH2-(R)Cha-Pic-Nag as free base 0.4 mg Hydrochloric acid (1 M) to pH 2 q.s. Water to l ml Stability
Time PH Temperature Degradation
(months) (° C) (area % of active compound)
0 2.0 25 -
3 2.0 25 0.46
6 2.0 25 0.91
12 2.2 25 2.05
( ii ) HOOC-CH2-(R)Cha-Pic-Nag water solution (26 mg/ml), pH 2
Composition:
HOOC-CH2-(R)Cha-Pic-Nag as free base 26 mg Hydrochloric acid 1 M to pH 2 q.s. Water to l ml
Stability
Time PH Temperature Degradation
(months) (° Q (area % of active compound)
0 2.1 25 -
3 2.1 25 0.45
6 2.1 25 0.94
12 2.4 25 1.93 Conclusion
This study shows that the degradation is decreased at this low pH.
Example 6
This example presents the results from a stability study at 25°C of HOOC-CH2- (R)-Cgl-Aze-Pab as free base.
HOOC-CH2-(R)-Cgl-Aze-Pab buffer solution (0.04 mg/ml) , pH 6
Composition:
HOOC-CH2-(R)-Cgl-Aze-Pab as free base 0.04 mg Sodium hydroxide (1 M) to pH 6 q.s. Acetate buffer (0.05 M) (incl. NaCl 9 mg/ml) to l ml
Stability
Time pH Temperature Degradation
(months) (° C) (area % of active compound)
0 5.9 25 1.07
1 5.9 25 1.30
3 6.0 25 1.50
6 6.0 25 2.10 Conclusion
This storage study shows that extended storage periods at 25°C for this pH 6 formulation gives substantial degradation.
Example 7
This example presents the result from a stability study at 25°C of HOOC-CH2-(R)- Cgl-Aze-Pab as buffer-solution and as water-solution, respectively, at different pHs.
HOQC-CH2-(R)-Cgl-Aze-Pab buffer solutions C12.9 mg/ml) at different pHs
Composition:
( i ) HOOC-CH2-(R)-Cgl-Aze-Pab as a free base 12.9mg
Hydrochloric acid 1 M to pH q.s. Acetate buffer 0.05 M (incl. NaCl, 9 mg/ml) to 1 ml
Stability
Time pH Temperature Degradation (months) (° C) (area % active compound)
1 3.7 25 0.59
5.1 0.55
6.2 0.74
3 3.5 25 0.51
5.2 0.46
6.3 0.79
6 4.3 25 0.58
5.4 0.70
6.3 0.98 ( ii ) HOOC-CH2-(R)-Cgl-Aze-Pab water solutions (12.9 mg/ml) at different pH
Composition:
HOOC-CH2-(R)-Cgl-Aze-Pab as free base 12.9 mg
Hydrochloric acid 1 M to pH q.s.
Water to 1 ml
Stability
Time pH Temperature Degradation
(months) (° C) (area % of active compound)
0 3.5 25 0.48
5.4 0.56
6.2 0.70
1 3.5 25 0.52
5.4 0.69
6.2 0.66
3 3.5 25 0.61
5.4 0.72
6.2 1.00
Conclusion
This study shows that the degradation of HOOC-CH2-(R)-Cgl- Aze-Pab decreases at lower pH, with or without buffer systems. Example 8
This example presents the result from a stability study at 50°C of HOOC-CH2-(R)-
Cgl-Aze-Pab as water-solution, at different pHs.
HOOC-CH2-(R)-Cgl-Aze-Pab water solutions (12.0 mg/ml) at different pHs
Composition:
( i ) HOOC-CH2-(R)-Cgl-Aze-Pab as a free base 12.0 mg
Hydrochloric acid 1 M or NaOH 1 M to pH q.s.
Water to 1 ml
Stability
Time pH Temperature Major degradation (weeks) (° q product
(area % active compound)
0 2 50 0.57
4 0.42
7 0.44
9 2.41
2 2 50 0.47
4 0.48
7 3.31
9 25.6
4 2 50 0.50
4 0.58
7 6.76
9 33.8 Conclusion
This study shows that also at elevated temperature the degradation of HOOC- CH2-(R)-Cgl-Aze-Pab decreases at lower pH.
Final conclusions
The studies above show that at room temperature, 25°C, the degradation of the active thrombin inhibitors HOOC-CH2-(R)Cha-Pic-Nag and HOOC-CH2-(R)-Cgl- Aze-Pab, respectivily, independently as a free base or as a salt and independently of concentration of active compound, decreases at lower pH.
Furthermore, the studies show that water solutions of said thrombin inhibitors having a pH in the range from 1.0 to 2.5, are more storage stable at room temperatur for extended periods.

Claims

1. A storage stable concentrated water solution for infusion having a pH in the range from 1.0 to 2.5 and containing an active thrombin inhibitor having the formula
HOOC-CH2-Y wherein Y is (R)-Cha-Pic-Nag or (R)-Cgl- Aze-Pab, as a salt or as a free base thereof.
2. The solution according to claim 1 wherein the thrombin inhibitor is HOOC-CH2-(R)-Cha-Pic-Nag as the free base.
3. The solution according to claim 1 the thrombin inhibitor is HOOC-CH2- (R)-Cgl-Aze-Pab as the free base.
4. The solution according to claim 1 wherein the pH is from 1.5 to 2.0.
5. The solution according to any one of the claims 1, 2 or 4 wherein the concentration of active thrombin inhibitor is between 0.001 to 200 mg/ml.
6. The solution according to any one of the claims 1, 3 or 4 wherein the concentration of active thrombin inhibitor is between 0.001 to 300 mg/ml.
7. The solution according to any one of the claims 1, 2, 4 or 5 consisting of the active compound HOOC-CH2-(R)-Cha-Pic-Nag, water and an inorganic mineral acid.
8. The solution according to any of the claims 1, 3, 4 or 6 consisting of the active compound HOOC-CH∑-Cgl-Aze-Pab, water and an inorganic mineral acid.
9. The solution according to claims 7 or 8, wherein the inorganic mineral acid is hydrochloric acid.
10. The solution according to any one of claims 1-9, in which after storage at room temperature for at least two years at least 95% of the active compound remains.
11. A process for preparing a storage stabil concentrated water solution according to any one of the preceeding claims 1-10 which comprises dissolving the active thrombin inhibitor in water, adjusting of the solution pH to the range 1.0 to 2.5.
12. A process according to claim 11, wherein hydrochloric acid is used to adjust pH.
13. Use of a storage stable concentrated water solution according to any one of claims 1-10 for inhibition of thrombin.
14. A method for the treatment of a patient in need of a thrombin inhibitor by administration intravenously by infusion the storage stable concentrated water- solution according to any one of claims 1-10.
15. A method for stabilizing an active thrombin inhibitor having the formula
HOOC-CH2-Y wherein Y is (R)-Cha-Pic-Nag or (R)-Cgl-Aze-Pab, as a salt or as a free base thereof, comprising dissolving said thrombin inhibitor in water and adjusting the obtained solution with a physiologically acceptable organic or inorganic acid for obtaining a pH from 1.0 to 2.5.
PCT/SE1995/001228 1994-11-08 1995-10-19 A storage stable water solution for infusion containing a thrombin inhibitor WO1996014084A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
SK535-97A SK53597A3 (en) 1994-11-08 1995-10-19 A storage stable water solution for infusion containing a thrombin inhibitor
PL95320342A PL320342A1 (en) 1994-11-08 1995-10-19 Thrombin inhibitor containing infusion solution, stable during storage
NZ295492A NZ295492A (en) 1994-11-08 1995-10-19 Storage stable aqueous infusion for iv administration comprising a thrombin inhibitor
DE69522702T DE69522702T2 (en) 1994-11-08 1995-10-19 A STABLE AQUEOUS INFUSION SOLUTION CONTAINING A THROMBIN INHIBITOR
MX9703339A MX9703339A (en) 1994-11-08 1995-10-19 A storage stable water solution for infusion containing a thrombin inhibitor.
JP8515235A JPH10508598A (en) 1994-11-08 1995-10-19 Storage-stable aqueous solutions containing thrombin inhibitors
AU38846/95A AU695719B2 (en) 1994-11-08 1995-10-19 A storage stable water solution for infusion containing a thrombin inhibitor
DK95938085T DK0789585T3 (en) 1994-11-08 1995-10-19 Storage stable water solution for infusion containing a thrombin inhibitor
BR9509634A BR9509634A (en) 1994-11-08 1995-10-19 Storage-stable concentrated aqueous solution for infusion, use of the same and preparation procedures for the treatment of a patient in need of a thrombin inhibitor and stabilization of an active thrombin inhibitor
US08/557,189 US5830865A (en) 1994-11-08 1995-10-19 Storage stable water solution for infusion containing a thrombin inhibitor
EE9700218A EE9700218A (en) 1994-11-08 1995-10-19 Aqueous solution for injection containing a thrombin inhibitor
AT95938085T ATE205399T1 (en) 1994-11-08 1995-10-19 A STORAGE-Stable AQUEOUS INFUSION SOLUTION CONTAINING A THROMBIN INHIBITOR
EP95938085A EP0789585B1 (en) 1994-11-08 1995-10-19 A storage stable water solution for infusion containing a thrombin inhibitor
IS4468A IS4468A (en) 1994-11-08 1997-04-21 Aqueous solution for injection which is stable during storage and contains a thrombin inhibitor
NO19972065A NO322048B1 (en) 1994-11-08 1997-05-05 Storage stable aqueous solution for infusion containing a thrombin inhibitor, process for preparing such a water solution and use thereof.
FI971949A FI971949A (en) 1994-11-08 1997-05-07 Storage-resistant aqueous solution containing thrombin inhibitor for infusion

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9403831A SE504185C2 (en) 1994-11-08 1994-11-08 Storage-stable aqueous solution for infusion of thrombin inhibitors
SE9403831-2 1994-11-08

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WO1996014084A1 true WO1996014084A1 (en) 1996-05-17

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US (1) US5830865A (en)
EP (1) EP0789585B1 (en)
JP (1) JPH10508598A (en)
KR (1) KR100416677B1 (en)
CN (1) CN1090508C (en)
AT (1) ATE205399T1 (en)
AU (1) AU695719B2 (en)
BR (1) BR9509634A (en)
CA (1) CA2203396A1 (en)
CZ (1) CZ287256B6 (en)
DE (1) DE69522702T2 (en)
DK (1) DK0789585T3 (en)
EE (1) EE9700218A (en)
ES (1) ES2163528T3 (en)
FI (1) FI971949A (en)
HU (1) HU217073B (en)
IL (1) IL115879A (en)
IS (1) IS4468A (en)
MX (1) MX9703339A (en)
MY (1) MY112593A (en)
NO (1) NO322048B1 (en)
NZ (1) NZ295492A (en)
PL (1) PL320342A1 (en)
PT (1) PT789585E (en)
RU (1) RU2164803C2 (en)
SE (1) SE504185C2 (en)
SK (1) SK53597A3 (en)
TR (1) TR199501391A2 (en)
TW (1) TW407057B (en)
WO (1) WO1996014084A1 (en)
ZA (1) ZA959377B (en)

Cited By (3)

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WO1997023499A1 (en) * 1995-12-21 1997-07-03 Astra Aktiebolag Prodrugs of thrombin inhibitors
US6462021B1 (en) 2000-11-06 2002-10-08 Astrazeneca Ab Use of low molecular weight thrombin inhibitor
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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US6984627B1 (en) * 1993-06-03 2006-01-10 Astrazeneca Ab Peptide derivatives
SE9301916D0 (en) * 1993-06-03 1993-06-03 Ab Astra NEW PEPTIDES DERIVATIVES
SE9802974D0 (en) * 1998-09-03 1998-09-03 Astra Ab New crystalline forms
US7345093B2 (en) * 2004-04-27 2008-03-18 Formatech, Inc. Methods of enhancing solubility of compounds
CA2781529C (en) * 2009-09-23 2017-10-24 Indu Javeri Methods for the preparation of liposomes comprising docetaxel
US20110070294A1 (en) * 2009-09-23 2011-03-24 Javeri Indu Methods for the Administration of Drugs Using Liposomes
US10143652B2 (en) 2009-09-23 2018-12-04 Curirx Inc. Methods for the preparation of liposomes

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WO1993011152A1 (en) * 1991-12-04 1993-06-10 Aktiebolaget Astra New peptide derivatives

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023499A1 (en) * 1995-12-21 1997-07-03 Astra Aktiebolag Prodrugs of thrombin inhibitors
US5965692A (en) * 1995-12-21 1999-10-12 Astra Ab Prodrugs of thrombin inhibitors
US6262028B1 (en) 1995-12-21 2001-07-17 Astrazeneca Ab Prodrugs of thrombin inhibitors
US7354905B2 (en) 1995-12-21 2008-04-08 Astrazeneca Ab Prodrugs of thrombin inhibitors
US6462021B1 (en) 2000-11-06 2002-10-08 Astrazeneca Ab Use of low molecular weight thrombin inhibitor
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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SE9403831D0 (en) 1994-11-08
CZ129497A3 (en) 1998-02-18
SE504185C2 (en) 1996-12-02
FI971949A0 (en) 1997-05-07
EP0789585B1 (en) 2001-09-12
NO322048B1 (en) 2006-08-07
CN1162921A (en) 1997-10-22
TR199501391A2 (en) 1996-06-21
RU2164803C2 (en) 2001-04-10
JPH10508598A (en) 1998-08-25
CZ287256B6 (en) 2000-10-11
NO972065L (en) 1997-05-05
EP0789585A1 (en) 1997-08-20
BR9509634A (en) 1998-01-06
DK0789585T3 (en) 2001-11-12
MX9703339A (en) 1997-07-31
SE9403831L (en) 1996-05-09
AU3884695A (en) 1996-05-31
ZA959377B (en) 1996-05-08
IS4468A (en) 1997-04-21
DE69522702T2 (en) 2002-07-11
KR100416677B1 (en) 2004-06-16
CN1090508C (en) 2002-09-11
MY112593A (en) 2001-07-31
AU695719B2 (en) 1998-08-20
US5830865A (en) 1998-11-03
HUT77560A (en) 1998-06-29
EE9700218A (en) 1998-02-16
HU217073B (en) 1999-11-29
PL320342A1 (en) 1997-09-29
SK53597A3 (en) 1998-07-08
ES2163528T3 (en) 2002-02-01
TW407057B (en) 2000-10-01
IL115879A (en) 2001-08-08
CA2203396A1 (en) 1996-05-17
NO972065D0 (en) 1997-05-05
NZ295492A (en) 1998-06-26
FI971949A (en) 1997-05-07
ATE205399T1 (en) 2001-09-15
KR970706844A (en) 1997-12-01
DE69522702D1 (en) 2001-10-18
PT789585E (en) 2002-01-30
IL115879A0 (en) 1996-01-31

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