WO2014032956A1 - Tigecycline formulations - Google Patents
Tigecycline formulations Download PDFInfo
- Publication number
- WO2014032956A1 WO2014032956A1 PCT/EP2013/066841 EP2013066841W WO2014032956A1 WO 2014032956 A1 WO2014032956 A1 WO 2014032956A1 EP 2013066841 W EP2013066841 W EP 2013066841W WO 2014032956 A1 WO2014032956 A1 WO 2014032956A1
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- WO
- WIPO (PCT)
- Prior art keywords
- tigecycline
- lactose
- composition
- formulations
- solution
- Prior art date
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Classifications
-
- 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
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Definitions
- Tigecycline is a glycylcycline antibiotic which belongs to the tetracycline family and may be illustrated by the following formula:
- Tigecycline is (4S,4aS,5aR, 12aS)-9-[2-(tert- butylamino)acetamido]-4,7-bis(dimethylamino)-l ,4,4a,5,5a,6,l l , 12a-octahydro- 3, 10, 12, 12a-tetrahydroxy-l , l l-dioxo-2-naphthacenecarboxamide, also known under the CAS number 220620-09-7.
- Tigecycline is due to the substance's ability to inhibit bacterial protein translation. Tigecycline is thus useful in the prevention and treatment of bacterial infections, such as infections caused by e.g. S. pneumoniae and L. pneumophila.
- Tigecycline is the active ingredient of the product Tygacil®, a drug approved by FDA in 2005 which then did not contain any exipients or preservatives.
- Tigecycline degrades by oxidation (prevalent form of degradation in basic conditions) and epimerization (prevalent form of degradation in acidic
- each Tygacil vial contains 50 mg of Tigecycline and 100 mg of lactose monohydrate with 6% overage.
- the pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide.
- the product does not contain preservatives.
- the present invention concerns new formulations comprising Tigecycline and lactose.
- the formulations according to the present invention can be in liquid state, e.g. bulk solutions prior to lyophilization.
- the formulations according to the present invention can be in solid state, e.g. powder/cake resulting from lyophilization of bulk solutions.
- the formulations according to the present invention have a pH of 7.2 to 7.7.
- the formulations in solid state will provide a solution with pH ranging from 7.2 to 7.7 if reconstituted in water for injection.
- compositions of the present invention are provided, in addition to various embodiments of a method for stabilizing solutions comprising Tigecycline.
- Tigecycline is meant to embrace any compound having the structure of formula I regardless of the charge of the molecule which varies by pH.
- a Tigecycline formulation according to the present invention comprises "Tigecycline” both as present in a vial before reconstitution as well as present after reconstitution and after further dilution. Tigecycline is also to be understood to embrace the active ingredient in Tygacil®.
- an aqueous solution comprising Tigecycline and lactose, and further characterized by having a pH of 7.2 to 7.7. Lactose is the only excipient in the solution of the invention.
- an aqueous solution consisting of water, Tigecycline, lactose and a pH adjusting agent, characterized by having a pH of 7.2- 7.7.
- a lyophilized powder is provided, wherein said powder is prepared by the lyophilization of an aqueous solution having a pH of 7.2-7.7 comprising Tigecycline as the active ingredient, and lactose as the only excipient.
- a pharmaceutical composition wherein said composition is a lyophilized powder prepared by the lyophilization of an aqueous solution having a pH of 7.2-7.7 comprising Tigecycline as the active ingredient, and lactose as the only excipient.
- Tigecycline epimer which inter alia is a degradation product of Tigecycline, is a compound which may be represented by the following structure:
- Tigecycline epimer is believed to be non toxic, but it lacks the antibacterial activity of Tigecycline.
- “Lactose” is the well known disaccharide sugar commonly used as an excipient in pharmaceutical formulations, and may be represented by the structure:
- Lactose is stabilizing Tigecycline when used as an excipient.
- the lactose excipient is in the form of lactose mo no hydrate.
- pH is the conventional measurement unit of hydrogen ion activity in a solution at 25 °C unless other temperature is specified.
- pH of 7.2-7.7 is meant to include pH 7.2, pH 7.3, pH 7.4, pH 7.5, pH 7.6 and pH 7.7. Further included is any pH between any of these; e.g. pH 7.23, pH 7.35, pH 7.39 etc.
- pH adjusting agent is according to the present invention to be understood as any substance capable of changing the pH of a Tigecycline solution.
- suitable pH adjusting agents is e.g. acids like diluted hydrochloric acid, bases like sodium hydroxide, and buffers like acetate, citrate, succinate, tartrate, phosphate and acetate buffers
- Water for injection as used herein is substantially pure and sterile water. E.g. water purified by distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms.
- Aqueous solution as used herein means any solution in which water is the main solvent.
- Bulk solution is any solution suitable for lyophilization. Bulk solutions usually comprise drug formulations which are lyophilized in vials.
- Tigecycline epimer was performed using the GL Science Intersil ODS-3 column. Elution was performed by using a gradient consisting of mobile phase A and a mobile phase B.
- Mobile phase A consisted of acetonitrile and a solution of dipotassium hydrogen phosphate and ethylenediaminetetraacetic acid tetrasodium salt (pH adjusted to 7.5) in a volume ratio of 5 :95
- mobile phase B consisted of acetonitrile and a solution of dipotassium hydrogen phosphate and ethylene- diaminetetraacetic acid tetrasodium salt (pH adjusted to 7.5 as well) in a volume ratio of 50:50).
- the run time was 70 minutes starting from 15% B and ending at 100% B, with the detection wavelength set to 248 nm.
- the epimer concentration was expressed as the percentage of the Tigecycline theoretical content per vial (53 mg) in sample analyzed by HPLC.
- IP Inverted position of the vial during storage (product was in contact with rubber stopper)
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- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Abstract
The present invention regards compositions comprising Tigecycline and lactose as well as a method for stabilizing Tigecycline containing solutions.
Description
Tigecycline formulations
Background
Tigecycline is a glycylcycline antibiotic which belongs to the tetracycline family and may be illustrated by the following formula:
Formula I
The chemical name of Tigecycline is (4S,4aS,5aR, 12aS)-9-[2-(tert- butylamino)acetamido]-4,7-bis(dimethylamino)-l ,4,4a,5,5a,6,l l , 12a-octahydro- 3, 10, 12, 12a-tetrahydroxy-l , l l-dioxo-2-naphthacenecarboxamide, also known under the CAS number 220620-09-7.
The antibacterial activity of Tigecycline is due to the substance's ability to inhibit bacterial protein translation. Tigecycline is thus useful in the prevention and treatment of bacterial infections, such as infections caused by e.g. S. pneumoniae and L. pneumophila.
Furthermore, Tigecycline is the active ingredient of the product Tygacil®, a drug approved by FDA in 2005 which then did not contain any exipients or preservatives.
The stability of Tigecycline molecule has been discussed in several publications. Tigecycline degrades by oxidation (prevalent form of degradation in basic conditions) and epimerization (prevalent form of degradation in acidic
environment).
According to the current Tygacil® label, each Tygacil vial contains 50 mg of Tigecycline and 100 mg of lactose monohydrate with 6% overage. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. The product does not contain preservatives.
Summary of the invention
The present invention concerns new formulations comprising Tigecycline and lactose. The formulations according to the present invention can be in liquid state, e.g. bulk solutions prior to lyophilization. The formulations according to the present
invention can be in solid state, e.g. powder/cake resulting from lyophilization of bulk solutions.
In liquid state, the formulations according to the present invention have a pH of 7.2 to 7.7.
The formulations in solid state will provide a solution with pH ranging from 7.2 to 7.7 if reconstituted in water for injection.
As will appear from the enclosed claims and the detailed description of the present invention, various embodiments of the compositions of the present invention are provided, in addition to various embodiments of a method for stabilizing solutions comprising Tigecycline.
Detailed description
"Tigecycline" is meant to embrace any compound having the structure of formula I regardless of the charge of the molecule which varies by pH. Thus, a Tigecycline formulation according to the present invention comprises "Tigecycline" both as present in a vial before reconstitution as well as present after reconstitution and after further dilution. Tigecycline is also to be understood to embrace the active ingredient in Tygacil®.
According to one aspect of the invention, an aqueous solution is provided, comprising Tigecycline and lactose, and further characterized by having a pH of 7.2 to 7.7. Lactose is the only excipient in the solution of the invention.
According to another aspect, an aqueous solution is provided, consisting of water, Tigecycline, lactose and a pH adjusting agent, characterized by having a pH of 7.2- 7.7. According to another aspect of the present invention, a lyophilized powder is provided, wherein said powder is prepared by the lyophilization of an aqueous solution having a pH of 7.2-7.7 comprising Tigecycline as the active ingredient, and lactose as the only excipient. According to yet another aspect of the present invention, a pharmaceutical composition is provided, wherein said composition is a lyophilized powder prepared by the lyophilization of an aqueous solution having a pH of 7.2-7.7 comprising Tigecycline as the active ingredient, and lactose as the only excipient. Tigecycline epimer, which inter alia is a degradation product of Tigecycline, is a compound which may be represented by the following structure:
Tigecycline epimer is believed to be non toxic, but it lacks the antibacterial activity of Tigecycline.
"Lactose" is the well known disaccharide sugar commonly used as an excipient in pharmaceutical formulations, and may be represented by the structure:
Lactose is stabilizing Tigecycline when used as an excipient. According one embodiment of the invention, the lactose excipient is in the form of lactose mo no hydrate.
"pH" is the conventional measurement unit of hydrogen ion activity in a solution at 25 °C unless other temperature is specified.
"pH of 7.2-7.7" is meant to include pH 7.2, pH 7.3, pH 7.4, pH 7.5, pH 7.6 and pH 7.7. Further included is any pH between any of these; e.g. pH 7.23, pH 7.35, pH 7.39 etc.
"pH adjusting agent" is according to the present invention to be understood as any substance capable of changing the pH of a Tigecycline solution. A non-limiting list of suitable pH adjusting agents is e.g. acids like diluted hydrochloric acid, bases like sodium hydroxide, and buffers like acetate, citrate, succinate, tartrate, phosphate and acetate buffers
"Water for injection" as used herein is substantially pure and sterile water. E.g. water purified by distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms.
"Aqueous solution" as used herein means any solution in which water is the main solvent. "Bulk solution" is any solution suitable for lyophilization. Bulk solutions usually comprise drug formulations which are lyophilized in vials.
Experimental
The following table represents adjustment of pH in the bulk solutions.
Table 1. pH of bulk solutions in different stages of compounding.
In this experiment, bulk solutions comprising 25 mg/mL of Tigecycline and 50 mg/mL of Lactose monohydrate were lyophilized in 10 mL vials. The pH of the formulation was adjusted using Diluted hydrochloric acid to the target value as specified for the bulk solutions prior to lyophilization (see Table 1). After lyophilization, the finished product vials were stored in inverted position (product was in contact with the rubber stopper) during 3 months at specified temperatures and in the specified relative humidity (RH) as stated in Table 2. Determination of epimer level in Tigecycline for injection 50 mg/vial finished product was monitored during the storage using the appropriate in house developed HPLC method.
Analysis of Tigecycline epimer was performed using the GL Science Intersil ODS-3 column. Elution was performed by using a gradient consisting of mobile phase A and a mobile phase B. Mobile phase A consisted of acetonitrile and a solution of dipotassium hydrogen phosphate and ethylenediaminetetraacetic acid tetrasodium salt (pH adjusted to 7.5) in a volume ratio of 5 :95, while mobile phase B consisted of acetonitrile and a solution of dipotassium hydrogen phosphate and ethylene-
diaminetetraacetic acid tetrasodium salt (pH adjusted to 7.5 as well) in a volume ratio of 50:50). The run time was 70 minutes starting from 15% B and ending at 100% B, with the detection wavelength set to 248 nm. The epimer concentration was expressed as the percentage of the Tigecycline theoretical content per vial (53 mg) in sample analyzed by HPLC.
Table 2. Content of Tigecycline epimer in lyophilized samples during 3 months storage.
LEGEND:
IP = Inverted position of the vial during storage (product was in contact with rubber stopper)
Claims
1. Composition in liquid state comprising Tigecycline and lactose
characterized by a pH of 7.2 to 7.7
2. Composition according to claim 1 wherein the composition is an aqueous solution.
3. Composition according to claim 1 or 2, wherein the composition is a bulk solution.
4. Composition according to claim 1 , 2 or 3, consisting essentially of
Tigecycline, lactose, water and optionally a pH adjusting agent.
5. Composition in solid state prepared by lyophilization of the composition according to claim 1 , 2, 3 or 4.
6. Composition in solid state comprising Tigecycline and lactose characterized by providing an aqueous solution having a pH of 7.2-7.7 if dissolved in water for injection.
7. Composition according to claim 6, consisting essentially of Tigecycline, lactose and salts from a pH-adjusting agent.
8. Method for stabilizing solutions comprising Tigecycline characterized by adjusting the pH to 7.2-7.7
9. Method according to claim 8, wherein the pH is adjusted by HC1.
10. Method according to claim 8, wherein the solution further comprises lactose.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261694461P | 2012-08-29 | 2012-08-29 | |
| US61/694,461 | 2012-08-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014032956A1 true WO2014032956A1 (en) | 2014-03-06 |
Family
ID=48979747
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2013/066841 WO2014032956A1 (en) | 2012-08-29 | 2013-08-12 | Tigecycline formulations |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2014032956A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105079816A (en) * | 2015-08-17 | 2015-11-25 | 江苏豪森药业股份有限公司 | Tigecycline pharmaceutical composition and preparation method thereof |
| IT202100031133A1 (en) * | 2021-12-13 | 2023-06-13 | Zambon Spa | Pharmaceutical composition including tigecycline |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090275660A1 (en) * | 2008-05-01 | 2009-11-05 | Chauhan Bhaskar | Stable parenteral formulations of tigecycline |
| US20100035845A1 (en) * | 2008-08-06 | 2010-02-11 | Wyeth | Tigecycline formulations |
-
2013
- 2013-08-12 WO PCT/EP2013/066841 patent/WO2014032956A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090275660A1 (en) * | 2008-05-01 | 2009-11-05 | Chauhan Bhaskar | Stable parenteral formulations of tigecycline |
| US20100035845A1 (en) * | 2008-08-06 | 2010-02-11 | Wyeth | Tigecycline formulations |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105079816A (en) * | 2015-08-17 | 2015-11-25 | 江苏豪森药业股份有限公司 | Tigecycline pharmaceutical composition and preparation method thereof |
| IT202100031133A1 (en) * | 2021-12-13 | 2023-06-13 | Zambon Spa | Pharmaceutical composition including tigecycline |
| WO2023110739A1 (en) | 2021-12-13 | 2023-06-22 | Zambon S.P.A. | Pharmaceutical composition comprising tigecycline |
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