CA2752784A1 - Daptomycin formulation - Google Patents
Daptomycin formulation Download PDFInfo
- Publication number
- CA2752784A1 CA2752784A1 CA 2752784 CA2752784A CA2752784A1 CA 2752784 A1 CA2752784 A1 CA 2752784A1 CA 2752784 CA2752784 CA 2752784 CA 2752784 A CA2752784 A CA 2752784A CA 2752784 A1 CA2752784 A1 CA 2752784A1
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- Prior art keywords
- daptomycin
- product
- vials
- steps
- impurities
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a process for production of a parenteral composition comprising daptomycin.
Description
FIELD OF THE INVENTION
The present invention relates to an improved process for the production of a parenteral formulation comprising daptomycin represented by the chemical name N-decanoy 1-L-tryptophy l-D-asparaginy l-L-asparty l- L-threony Iglycy l-L-orn ithy l-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamy1-3-anthraniloyl-L-alanine sl-lactone. Daptomycin can be presented by the formula I:
n >~H.
. . NH- CONH-'IN~ C
NH
NH O:H
,, rd H't HO.OC H'1 J
IN ~
a /
J
'IC-C
(I) BACKGROUND
Daptomycin is a lipopeptide antibiotic with activity against gram-positive organisms. Daptomycin is produced by fermentation of Strepromyces roseosporus and then purification of the fermentation broth. The mechanism of action for daptomycin is that it binds to bacterial membranes and causes a rapid depolarization of the membrane potential. This loss of membrane potential causes inhibition of protein, DNA and RNA synthesis, resulting in bacterial cell death. Daptomycin is approved for complicated skin and skin structure infections (cSSSI) and Staphylococcus aureus bloodstream infections (bacteraemia). Daptomycin is marketed by Cubist Pharmaceuticals under the trademark Cubicin Daptomycin was first described in the mid 1980's in several patents and journals;
US 4,537,717 and Debono M. et al, Journal of Antibiotics, 1986, Vol. XL, No 6, 761-777. Since then there have been several publications regarding improved fermentation processes and purification processes.
In US 4,885,243 an improved fermentation process for making daptomycin is described. This method describes the feeding of decanoic fatty acid or ester or salts thereof to a fermentation broth of Strepromyces roseosporus. During fermentation, the decanoic fatty acid will be inserted into the molecule to form the decanoic side chain of daptomycin.
In the prior art, several purification processes for purifying daptomycin has been described. US 4,874,843 describes a method for purifying daptomycin in which the fermentation broth was filtered and added to a chromatographic column containing HP-20 resin. After elution, the semipurified daptomycin was passed through a column containing HP-20ss resin and then added to another column containing HP-20 resin. In addition to these steps, attempts to increase the purity with several additional chromatographic steps without any success are described. The `843 patent further teach that by using a non-functional resin and an aqueous solution and including a step where water are physically removed and then rewet the resin with a polar organic solvent, the purity of the product is increased from 80%
to 93%. This process is time consuming and not very well suitable for industrial production.
The US RE 39071 patent describes the two major impurities found in the production of daptomycin, the anhydro-daptomycin and the beta-isomer of daptomycin. The US
RE 39071 further states that by using the method described in example 1-3 you will have a daptomycin product comprising less than 6% of the two mentioned impurities. Example 3 describes a method where intermediate quality of daptomycin is further purified in a method comprising four chromatographic steps and additional desalting, concentration and freeze drying steps. In the chromatographic steps acetonitrile is used for washing and elution and in addition you have to perform the method with chilled solutions and in a chilled room.
US 6,696,412 patent discloses a method for purifying daptomycin by utilizing an anion exchange chromatography step where a modified buffer is used for elution and by utilizing a microfiltration step where daptomycin forms micelles. They further stated that low pH and refrigerated conditions was used to retard the degradation of purified daptomycin. The highly purified daptomycin product is defined in the patent to be daptomycin with a purity level of 95-97%.
Kirsch et al, Pharmaceutical Research, 6: 387-393, 1989, stated that anhydro -daptomycin and the 0-isomer were produced during the purification process of daptomycin. Kirsch described methods to minimize the levels of anhydro-daptomycin and the (3-isomer through manipulation of pH conditions and temperature conditions. Kirsch also described the equilibrium that exists between daptomycin, anhydro-daptomycin and the (3-isomer.
Cubist Pharmaceuticals is the brand owner of the product Cubicin . To be able to get a pharmaceutical product in to the market you have to apply for a marketing authorization by the government. In Europe you can apply for marketing authorization through the European Medicines Agency, your application has to be supported by lots of documentation about your product. In the documentation Cubist Pharmaceutical submitted to the European Medicines Agency is a scientific discussion. In this documentation Cubist Pharmaceuticals states that to minimize the potential degradation of daptornycin during the manufacturing of the finished dosage form, refrigerated conditions were used and lyophilization was performed under nitrogen atmosphere.
SUMMARY OF THE INVENTION
The prior art teaches that daptomycin is in an equilibrium with anhydro-daptomycin and (3-isomer. The prior art also teaches that there could be additional impurities in the purified daptomycin, such as other degradation products and impurities formed during fermentation. Another important impurity is the ring-opened daptomycin lactone hydrolyse product. The structures for daptomycin, anhydro-daptomycin, (3-isomer and daptomycin lacton-hydrolyse product are shown in Fig 1.
The prior art teaches that to minimize the potential degradation of daptomycin, the preparation of vials for lyophilization should be performed under refrigerated conditions.
However, contrary to the prior art teaching, the present inventors have experience that when preparing vials for lyophilization at 5 C, problems inapproperate for industrial scale production occurs, such as time-consuming wetting of daptomycin followed by foaming.
It turns out being difficult to get the daptomycin in solution due to wetting problems resulting in a need for vigorous stirring which again creates foaming. Foaming furthermore acts as a barrier for further wetting of additional quantity of daptomycin.
In addition, vigorous stirring might degrade the product.
Surprisingly and in spite of the prior art teaching of preparing daptomycin vials for lyophilization at refrigerated temperature, the present inventors discovered that preparation of vials at room-temperature surprisingly did not significantly affect the level of impurities in the lyophilized product.
In one aspect, our invention describes a manufacturing process for lyophilized daptomycin in which the process steps preceding lyophilization are performed at room temperature. The invention allows a technically convenient process in which the development of the daptomycin impurities is similar to a refrigerated process.
The present invention relates to an improved process for the production of a parenteral formulation comprising daptomycin represented by the chemical name N-decanoy 1-L-tryptophy l-D-asparaginy l-L-asparty l- L-threony Iglycy l-L-orn ithy l-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamy1-3-anthraniloyl-L-alanine sl-lactone. Daptomycin can be presented by the formula I:
n >~H.
. . NH- CONH-'IN~ C
NH
NH O:H
,, rd H't HO.OC H'1 J
IN ~
a /
J
'IC-C
(I) BACKGROUND
Daptomycin is a lipopeptide antibiotic with activity against gram-positive organisms. Daptomycin is produced by fermentation of Strepromyces roseosporus and then purification of the fermentation broth. The mechanism of action for daptomycin is that it binds to bacterial membranes and causes a rapid depolarization of the membrane potential. This loss of membrane potential causes inhibition of protein, DNA and RNA synthesis, resulting in bacterial cell death. Daptomycin is approved for complicated skin and skin structure infections (cSSSI) and Staphylococcus aureus bloodstream infections (bacteraemia). Daptomycin is marketed by Cubist Pharmaceuticals under the trademark Cubicin Daptomycin was first described in the mid 1980's in several patents and journals;
US 4,537,717 and Debono M. et al, Journal of Antibiotics, 1986, Vol. XL, No 6, 761-777. Since then there have been several publications regarding improved fermentation processes and purification processes.
In US 4,885,243 an improved fermentation process for making daptomycin is described. This method describes the feeding of decanoic fatty acid or ester or salts thereof to a fermentation broth of Strepromyces roseosporus. During fermentation, the decanoic fatty acid will be inserted into the molecule to form the decanoic side chain of daptomycin.
In the prior art, several purification processes for purifying daptomycin has been described. US 4,874,843 describes a method for purifying daptomycin in which the fermentation broth was filtered and added to a chromatographic column containing HP-20 resin. After elution, the semipurified daptomycin was passed through a column containing HP-20ss resin and then added to another column containing HP-20 resin. In addition to these steps, attempts to increase the purity with several additional chromatographic steps without any success are described. The `843 patent further teach that by using a non-functional resin and an aqueous solution and including a step where water are physically removed and then rewet the resin with a polar organic solvent, the purity of the product is increased from 80%
to 93%. This process is time consuming and not very well suitable for industrial production.
The US RE 39071 patent describes the two major impurities found in the production of daptomycin, the anhydro-daptomycin and the beta-isomer of daptomycin. The US
RE 39071 further states that by using the method described in example 1-3 you will have a daptomycin product comprising less than 6% of the two mentioned impurities. Example 3 describes a method where intermediate quality of daptomycin is further purified in a method comprising four chromatographic steps and additional desalting, concentration and freeze drying steps. In the chromatographic steps acetonitrile is used for washing and elution and in addition you have to perform the method with chilled solutions and in a chilled room.
US 6,696,412 patent discloses a method for purifying daptomycin by utilizing an anion exchange chromatography step where a modified buffer is used for elution and by utilizing a microfiltration step where daptomycin forms micelles. They further stated that low pH and refrigerated conditions was used to retard the degradation of purified daptomycin. The highly purified daptomycin product is defined in the patent to be daptomycin with a purity level of 95-97%.
Kirsch et al, Pharmaceutical Research, 6: 387-393, 1989, stated that anhydro -daptomycin and the 0-isomer were produced during the purification process of daptomycin. Kirsch described methods to minimize the levels of anhydro-daptomycin and the (3-isomer through manipulation of pH conditions and temperature conditions. Kirsch also described the equilibrium that exists between daptomycin, anhydro-daptomycin and the (3-isomer.
Cubist Pharmaceuticals is the brand owner of the product Cubicin . To be able to get a pharmaceutical product in to the market you have to apply for a marketing authorization by the government. In Europe you can apply for marketing authorization through the European Medicines Agency, your application has to be supported by lots of documentation about your product. In the documentation Cubist Pharmaceutical submitted to the European Medicines Agency is a scientific discussion. In this documentation Cubist Pharmaceuticals states that to minimize the potential degradation of daptornycin during the manufacturing of the finished dosage form, refrigerated conditions were used and lyophilization was performed under nitrogen atmosphere.
SUMMARY OF THE INVENTION
The prior art teaches that daptomycin is in an equilibrium with anhydro-daptomycin and (3-isomer. The prior art also teaches that there could be additional impurities in the purified daptomycin, such as other degradation products and impurities formed during fermentation. Another important impurity is the ring-opened daptomycin lactone hydrolyse product. The structures for daptomycin, anhydro-daptomycin, (3-isomer and daptomycin lacton-hydrolyse product are shown in Fig 1.
The prior art teaches that to minimize the potential degradation of daptomycin, the preparation of vials for lyophilization should be performed under refrigerated conditions.
However, contrary to the prior art teaching, the present inventors have experience that when preparing vials for lyophilization at 5 C, problems inapproperate for industrial scale production occurs, such as time-consuming wetting of daptomycin followed by foaming.
It turns out being difficult to get the daptomycin in solution due to wetting problems resulting in a need for vigorous stirring which again creates foaming. Foaming furthermore acts as a barrier for further wetting of additional quantity of daptomycin.
In addition, vigorous stirring might degrade the product.
Surprisingly and in spite of the prior art teaching of preparing daptomycin vials for lyophilization at refrigerated temperature, the present inventors discovered that preparation of vials at room-temperature surprisingly did not significantly affect the level of impurities in the lyophilized product.
In one aspect, our invention describes a manufacturing process for lyophilized daptomycin in which the process steps preceding lyophilization are performed at room temperature. The invention allows a technically convenient process in which the development of the daptomycin impurities is similar to a refrigerated process.
In another aspect, this invention describes a method for production of vials comprising lyophilized daptomycin in which the process steps preceding lyophilization are performed at room-temperature. Such steps may comprise dissolution of daptomycin in a pharmaceutically acceptable liquid, pH
adjustment, filtration, filling of vials etc.
The levels of impurities are measured by standard HPLC methods well known for the skilled person in the art.
Brief description of the drawings Fig. I shows the structures of daptomycin, anhydro-daptomycin, the R-isomer and the daptomycin lacton-hydrolyse product.
Fig.2 shows an overview of the manufacturing process, e.g. the process used to prepare the vials tested resulting in the measurements outlined in figure 3-5.
Fig. 3 shows the development of the two most important impurities when manufactured at 10 C and 25 C.
Fig. 4 shows the development of the total amount of impurities when manufactured at 10 C and 25 C.
Fig. 5 shows the development of the total purity in the composition when manufactured at 10 C and 25 C
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the invention involves dissolution of daptomycin in water at room temperature using very gentle stirring, such as e.g. slowly stirring.
The term "room-temperature" as used herein means a temperature in the interval about 20 C-28 C e.g. about 25 C.
One embodiment of the manufacturing process according to the invention is schematically represented in Fig. 2.
Examples Daptomycin products were prepared according to the present invention following the process shown in figure 2.
Initial tests of the impurity profile and stability trials of the lyophilized formulation have been performed. As can be seen from the data, there is very little difference in the impurity profile between refrigerated and non-refrigerated process. Thus the product is surprisingly pure and stable even if the process steps preceding lyophilization is performed at room temperature.
The results are shown in figure 3-5.
adjustment, filtration, filling of vials etc.
The levels of impurities are measured by standard HPLC methods well known for the skilled person in the art.
Brief description of the drawings Fig. I shows the structures of daptomycin, anhydro-daptomycin, the R-isomer and the daptomycin lacton-hydrolyse product.
Fig.2 shows an overview of the manufacturing process, e.g. the process used to prepare the vials tested resulting in the measurements outlined in figure 3-5.
Fig. 3 shows the development of the two most important impurities when manufactured at 10 C and 25 C.
Fig. 4 shows the development of the total amount of impurities when manufactured at 10 C and 25 C.
Fig. 5 shows the development of the total purity in the composition when manufactured at 10 C and 25 C
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the invention involves dissolution of daptomycin in water at room temperature using very gentle stirring, such as e.g. slowly stirring.
The term "room-temperature" as used herein means a temperature in the interval about 20 C-28 C e.g. about 25 C.
One embodiment of the manufacturing process according to the invention is schematically represented in Fig. 2.
Examples Daptomycin products were prepared according to the present invention following the process shown in figure 2.
Initial tests of the impurity profile and stability trials of the lyophilized formulation have been performed. As can be seen from the data, there is very little difference in the impurity profile between refrigerated and non-refrigerated process. Thus the product is surprisingly pure and stable even if the process steps preceding lyophilization is performed at room temperature.
The results are shown in figure 3-5.
Claims (5)
1. A process for the preparation of lyophilized daptomycin, characterized in performing the following steps:
a) dissolving daptomycin in a suitable solvent;
b) optionally adjusting pH to about 4.5 - 5.0;
c) filtrating the solution obtained in the step a) or optionally step b);
d) transferring the product of c) into vials;
e) subjecting the vials of d) for lyophilisation; and wherein the steps a) - d) is performed at room temperature.
a) dissolving daptomycin in a suitable solvent;
b) optionally adjusting pH to about 4.5 - 5.0;
c) filtrating the solution obtained in the step a) or optionally step b);
d) transferring the product of c) into vials;
e) subjecting the vials of d) for lyophilisation; and wherein the steps a) - d) is performed at room temperature.
2. Process according to claim 1, wherein the solvent used in step a) is water.
3. Process according to claim 1, wherein the steps preceding step e) is performed at a temperature in the range of 20 - 28 °C.
4. Process according to claim 1, wherein the pH is adjusted by the addition of sodium hydroxide.
5. Lyophilized daptomycin prepared according to any of the claims 1-3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38473210P | 2010-09-21 | 2010-09-21 | |
| US61/384732 | 2010-09-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2752784A1 true CA2752784A1 (en) | 2012-03-21 |
Family
ID=45874472
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2752784 Abandoned CA2752784A1 (en) | 2010-09-21 | 2011-09-20 | Daptomycin formulation |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2752784A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2887953A4 (en) * | 2012-08-23 | 2016-05-25 | Agila Specialties Private Ltd | Improved daptomycin injectable formulation |
| CN115590825A (en) * | 2022-10-20 | 2023-01-13 | 安士制药(中山)有限公司（Cn） | Daptomycin for injection and preparation method thereof |
-
2011
- 2011-09-20 CA CA 2752784 patent/CA2752784A1/en not_active Abandoned
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2887953A4 (en) * | 2012-08-23 | 2016-05-25 | Agila Specialties Private Ltd | Improved daptomycin injectable formulation |
| EP3287138A1 (en) * | 2012-08-23 | 2018-02-28 | Agila Specialties Private Limited | Improved daptomycin injectable formulation |
| CN115590825A (en) * | 2022-10-20 | 2023-01-13 | 安士制药(中山)有限公司（Cn） | Daptomycin for injection and preparation method thereof |
| CN115590825B (en) * | 2022-10-20 | 2024-02-02 | 安士制药（中山）有限公司 | Daptomycin for injection and preparation method thereof |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |
Effective date: 20140922 |