WO2014041425A1 - Daptomycin formulations and uses thereof - Google Patents
Daptomycin formulations and uses thereof Download PDFInfo
- Publication number
- WO2014041425A1 WO2014041425A1 PCT/IB2013/002191 IB2013002191W WO2014041425A1 WO 2014041425 A1 WO2014041425 A1 WO 2014041425A1 IB 2013002191 W IB2013002191 W IB 2013002191W WO 2014041425 A1 WO2014041425 A1 WO 2014041425A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- formulation
- daptomycin
- lyophilized daptomycin
- lyophilized
- Prior art date
Links
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- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000003164 beta-aspartyl group Chemical group 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- GTZCVFVGUGFEME-IWQZZHSRSA-N cis-aconitic acid Chemical compound OC(=O)C\C(C(O)=O)=C\C(O)=O GTZCVFVGUGFEME-IWQZZHSRSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
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- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- WVRIJHGUJNXDRZ-UHFFFAOYSA-N ethane-1,1-diamine Chemical compound CC(N)N WVRIJHGUJNXDRZ-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- AIJZIRPGCQPZSL-UHFFFAOYSA-N ethylenetetracarboxylic acid Chemical compound OC(=O)C(C(O)=O)=C(C(O)=O)C(O)=O AIJZIRPGCQPZSL-UHFFFAOYSA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940089491 hydroxycitric acid Drugs 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
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- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
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- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- IDSXLJLXYMLSJM-UHFFFAOYSA-N morpholine;propane-1-sulfonic acid Chemical compound C1COCCN1.CCCS(O)(=O)=O IDSXLJLXYMLSJM-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- UFSCUAXLTRFIDC-UHFFFAOYSA-N oxalosuccinic acid Chemical compound OC(=O)CC(C(O)=O)C(=O)C(O)=O UFSCUAXLTRFIDC-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000003168 reconstitution method Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ODBLHEXUDAPZAU-UHFFFAOYSA-N threo-D-isocitric acid Natural products OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- 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
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
- A61K47/02—Inorganic compounds
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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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the presently disclosed subject matter relates to lyopbilized
- daptomycin formulations having improved reconstitution times and methods of preparing thereof.
- the presently disclosed subject matter also relates to methods of treating a bacterial infection in a subject by using the lyophilized daptomycin formulations.
- Daptomycin (I) is a cyclic lipopeptide derived from a natural product of Streptomyces roseosporus.
- the daptomycin comprises an asparagine (Asn) residue in the D configuration.
- Daptomycin has been used for treating complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following gram- positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).
- Staphylococcus aureus including methicillin-resistant isolates
- Streptococcus pyogenes Streptococcus agalactiae
- Daptomycin has also been used for treating Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-re sistant isolates.
- bacteremia Staphylococcus aureus bloodstream infections
- Daptomycin's bactericidal effects stem from its ability to rapidly depolarize the membrane potential of gram-positive bacteria, which causes inhibition of DNA, KNA and protein synthesis, and results in cell death.
- the bactericidal effect of daptomycin is rapid, with greater than 99.9% of both MRS A and MSSA bacteria dead in less than one hour.
- Daptomycin has also been used for biofilm treatment including catheter-related bloodstream infections (CRBSI) due to gram-positive bacteria.
- CBSI catheter-related bloodstream infections
- daptomycin may be used for central venous catheter salvage for 5.
- Daptomycin is commercially available as CUBICIN ® ("the CUBICIN® product", Cubist Pharmaceuticals, Inc., Lexington, MA) and is supplied as a sterile, lyophilized powder.
- CUBICIN* is reconstituted in sodium chloride for parenteral injection. Stability studies have shown that the reconstituted solution is stable in a vial for 12 hours at room temperature and up to 48 hours if stored under refrigeration at 2 to 8°C. However, after this time, or at higher temperatures, daptomycin begins to degrade.
- a major shortcoming of the commercially available daptomycin is that the reconstitution time of the CUBICIN ® product is long and is typically in the range of about 15 to 45 minutes depending on the reconstitution procedure. This reconstitution time is not ideal in a therapeutic setting with respect to ease and efficiency of administration. Such long reconstitution time also increases the risk of inadvertent incomplete dissolution prior to administration and additionally increases the likelihood that the daptomycin will degrade prior to patient administration.
- daptomycin degradation products There are a number of daptomycin degradation products that have been identified.
- the major degradants of daptomycin are anhydro-daptomycin derivatives in which an a-aspartyl group is transpeptidated to an anhydrosuccinamido group, ⁇ - isomer of daptomycin in which the compound contains a ⁇ -aspartyl group instead of an a-aspartyl group and the lactone hydrolysis product of daptomycin in which one of the esters moieties is hydrolysed.
- the degradation pathway of daptomycin is described in U.S. Patent Publication No. 2007/191280.
- High performance liquid chromatography (HPLC) of the reconstituted lyophilized powder can be used to determine the level of daptomycin relative to daptomycin degradants. Such comparison can thereby provide an indication of the stability of the daptomycin in the formulation.
- International Patent Publication No. WO2011/063419 discloses solid daptomycin preparations with improved reconstitution times and stability profiles relative to the CUBICI * product. This is achieved when sugars, such as sucrose, and a phosphate buffer are introduced into the formulation.
- the formulations have a pH of about 6.5 to about 7.5.
- the sugars used can be non-reducing sugars and are included in the formulations in an amount of about 2.5% w/v to about 25% w/v. For example, the sugars are included in amounts of 15% w/v and 20% w/v.
- daptomycin formulations having improved reconstitution times and methods of preparing thereof. Also provided are methods of treating a bacterial infection in a subject by using the lyophilized daptomycin formulations. The presently disclosed subject matter further provides methods of treating or preventing a biofilm by using the lyophilized daptomycin formulations.
- the presently disclosed subject matter provides a lyophilized daptomycin formulation comprising an additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof, and combinations thereof.
- the lyophilized daptomycin formulation includes from about 200 mg to about 600 mg of daptomycin.
- the lyophilized daptomycin formulation includes fro m about 0.01 mM to about 500 mM of the additive.
- the pharmaceutically acceptable antioxidant is ascorbic acid.
- the pharmaceutically acceptable organic acid can be selected from the group consisting of monocarboxylic organic acids, dicarboxylic organic acids, hydro xyl substituted dicarboxylic organic acids, tricarboxylic organic acids, hydroxyl substituted tricarboxylic organic acids, tetracarboxylic organic acids, and
- the pharmaceutically acceptable organic acid is a hydroxyl substituted tricarboxylic organic acid.
- the hydroxyl substituted tricarboxylic organic acid is citric acid.
- the pharmaceutically acceptable glucose derivative is acetyl glucosamine.
- the lyophilized daptomycin formulation can be reconstituted in a pharmaceutically acceptable diluent In one embodiment, the lyophilized daptomycin formulation is reconstituted in a pharmaceutically acceptable diluent in less than about 5 minutes.
- the concentration of daptomycin in the reconstituted lyophilized daptomycin formulation can be from about 20 mg/mL to about 100 rag/mL.
- the concentration of the additive in the reconstituted lyophilized daptomycin formulation can be from about 1 mM to about 500 mM. In one embodiment, the concentration of the additive in the reconstituted lyophilized daptomycin formulation is about 237.5 mM. In one embodiment, the concentration of the additive in the reconstituted lyophilized daptomycin formulation is about 300 mM. In certain embodiments, the concentration of the additive in the reconstituted lyophilized daptomycin formulation is from about 1 mg/mL to about 500 mg/mL.
- the pH of the reconstituted lyophilized daptomycin formulation can be from about 4.0 to about 5.0. In one embodiment, the pH of the reconstituted lyophilized daptomycin formulation is about 4.7.
- the diluent can be selected from the group consisting of sterile water for injection, bacteriostatic water for injection, 0.45% sodium chloride solution for injection, 0.9% sodium chloride solution for injection, Ringer's solution, lactated Ringer's solution, and combinations thereof. In one embodiment, the diluent is 0.9% sterile sodium chloride solution for injection. In another embodiment, the diluent is sterile water for injection.
- the presently disclosed subject matter also provides a method of treating a bacterial infection in a subject The method includes administering to a subject in need thereof, an effective amount of the above-disclosed lyophilized daptomycin formulation. Additionally, the presently disclosed subject matter provides a method of treating or preventing a biofilm. The method includes exposing a surface of a device to a solution of an effective amount of the above-disclosed lyophilized daptomycin formulation.
- the presently disclosed subject matter further provides methods for preparing lyophilized daptomycin formulations.
- the method includes (a) forming an aqueous solution of daptomycin and an additive, which is selected from the group consisting of pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof, and combinations thereof; (b) adjusting the pH to about 4.0 to about 5.0; and (c) lyophilising the solution to obtain a lyophilisate.
- the method includes (a) forming an aqueous solution of daptomycin at a pH of about 4.0 to about 5.0; (b) dissolving an additive selected from the group consisting of pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof, and combinations thereof in the aqueous solution of the daptomycin; (c) adjusting the pH to about 4.0 to about 5.0; and (d) lyophilising the solution to obtain a powder.
- the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
- Osmolality of a solution means the number of osmoles of solute per kilogram of solvent. Osmolality is a measure of the osmotic pressure exerted by a real solution across a semi-permeable membrane. It can be measured by use of a property of the solution that is dependent only on the particle concentration. These properties include vapour pressure depression, freezing point and boiling point depression, osmotic pressure collectively referred to as colligative properties. The osmolality of a solution is typically determined most accurately and conveniently by measuring freezing point depression.
- the term 'lyophilized means a stabilizing process used to remove a solvent from tissue, blood, serum, pharmaceutical formulations, or other biological substances; at low temperatures through a process of sublimation (primary drying) and then desorption (secondary drying).
- a lyophilized formulation can be reconstituted in a simple manner to give a ready-to-use solution which contains no visible particles by addition of a diluent.
- the presently disclosed subject matter provides a lyophilized daptomycin formulation including an additive.
- the additive can be a
- antioxidant a pharmaceutically acceptable organic acid and a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable glucose derivative and a pharmaceutically acceptable salt thereof, and a combination thereof.
- the lyophilized daptomycin formulation of the presently disclosed subject matter displays rapid reconstitution times in a pharmaceutically acceptable diluent. Furthermore, the inclusion of an additive in the daptomycin formulations does not adversely affect the stability of the formulations with respect to the
- additives suitable for use in the formulations of the presently disclosed subject matter can be pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids or salts thereof, pharmaceutically acceptable antioxidants, pharmaceutically acceptable glucose derivatives or salts thereof, or combinations thereof.
- antioxidants suitable for use in the formulations of the presently disclosed subject matter can be pharmaceutically acceptable antioxidants.
- Suitable antioxidants include, but are not limited to, ascorbic acid, monothioglycerol, L- cysteine, thioglycolic acid, sodium metabisulfite, sodium EDTA, monoethanolamine genu " sate, sodium formaldehyde sulfoxylate and sodium bisulfite.
- the antioxidant is ascorbic acid.
- organic acids suitable for use in the presently disclosed subject matter include, but are not limited to, monocarboxylic organic acids, dicarboxylic organic acids, hydro xyl substituted dicarboxylic organic acids, tricarboxylic organic acids, and tetracarboxylic organic acids.
- the dicarboxylic organic acid is a hydroxyl substituted dicarboxylic organic acid.
- the tricarboxylic organic acid is a hydroxyl substituted tricarboxylic organic acid.
- Monocarboxylic organic acids suitable for use in the presently disclosed subject matter include, but are not limited to, acetic acid, lactic acid, thiolactic acid, glycolic acid, butyric acid, isobutyric acid, glyceric acid, oxaloacetic acid, pyruvic acid, propionic acid, valeric acid, pivalic acid and benzoic acid.
- the monocarboxylic acid is acetic acid.
- the pharmaceutically acceptable salt of a monocarboxylic organic acid is sodium acetate.
- the pharmaceutically acceptable salt of a monocarboxylic organic acid is potassium acetate.
- Dicarboxylic organic acids suitable for use in the presently disclosed subject matter include, but are not limited to, malonic acid, succinic acid, adipic acid, maleic acid and glutaric acid.
- the dicarboxylic organic acid is succinic acid.
- Hydroxyl substituted dicarboxylic organic acids suitable for use in the presently disclosed subject matter include, but are not limited to, glucaric acid, a- hydroxyglutaric acid, gluconic acid, malic acid and tartaric acid.
- the hydroxyl substituted dicarboxylic organic acid is tartaric acid.
- Tricarboxylic organic acids suitable for use in the presently disclosed subject matter include, but are not limited to, aconitic acid and oxalosuccinic acid.
- Hydroxyl substituted tricarboxylic organic acids suitable for use in the presently disclosed subject matter include, but are not limited to, citric acid, isocitric acid, homocitric acid and hydroxycitric acid.
- the hydroxyl substituted tricarboxylic organic acid is citric acid.
- Tetracarboxylic organic acids suitable for use in the presently disclosed subject matter include, but are not limited to, edetic acid, ethylene tetracarboxylic acid and ethylene glycol tetraacetic acid.
- edetic acid ethylene tetracarboxylic acid
- ethylene glycol tetraacetic acid ethylene glycol tetraacetic acid.
- tetracarboxylic organic acids include, but are not limited to, di sodium edetate and tetrasodium edetate.
- the tetracarboxylic organic acid is edetic acid. In another embodiment, the
- pharmaceutically acceptable salt of a tetracarboxylic organic acid is disodium edetate.
- the additives suitable for use in the formulations of the presently disclosed subject matter can be pharmaceutically acceptable glucose derivatives or salts thereof
- the glucose derivative is acetyl glucosamine.
- the salt may be formed in situ by the addition of a pharmaceutically acceptable base to an acid solution. Alternatively, the salt may be added directly to the formulation.
- the cation of the salt includes, but is not limited to, sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium (such as triethylammonium), alkoxyammonium (such as ethanol ammonium and
- ethanediaminium choline
- amino acids such as arginine, lysine or histidine
- the lyophilized daptomycin formulations of the presently disclosed subject matter can include 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 and 500 mM, or a range including any of two of those integers, of an additive.
- the lyophilized daptomycin formulation includes from about 0.01 mM to about 500 mM of an additive.
- the lyophilized daptomycin formulation can include fro m about 0.05 mM to about 450 mM, from about 0.05 mM to about 300 mM, or from about 0.05 mM to about 100 mM, of an additive.
- the additive is a combination of a pharmaceutically acceptable antioxidant, a pharmaceutically acceptable organic acid, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable glucose derivative, and/or a pharmaceutically acceptable salt thereof.
- concentration of the additive is the sum of the concentrations of the antioxidant, the organic acid, the salt thereof, the glucose derivative, and/or the salt thereof expressed in terms of minimolar (mM) or mass per volume (mg/mL).
- the salt is the conjugate base of the organic acid so as to form a buffer solution.
- the additive is used at a concentration that does not destabilise the daptomycin and preferably aids stability of the daptomycin.
- the stability of daptomycin will depend on the intended shelf life of the
- the daptomycin formulations of the presently disclosed subject matter are at least as stable as the CUBICIN* lyophilized powder.
- the CUBICIN* product includes 250, 350 or 500 mg of daptomycin.
- the lyophilized daptomycin formulations of the presently disclosed subject matter include from about 200 mg to about 600 mg of daptomycin. In some embodiments, the lyophilized daptomycin formulations include from about 200 mg to about 300 mg of daptomycin. In one embodiment, the lyophilized daptomycin formulations include about 250 mg of daptomycin. In some embodiments, the lyophilized daptomycin formulations include from about 300 mg to about 400 mg of daptomycin. In one embodiment, the lyophilized daptomycin formulations include about 350 mg of daptomycin. In certain embodiments, the lyophilized daptomycin formulations include from about 450 mg to about 550 mg of daptomycin. In one embodiment, the lyophilized daptomycin formulations include about 500 mg of daptomycin.
- optional components can be included in the lyophilized daptomycin formulations.
- Such optional components include, but are not limited to, buffering agents, stabilisers, solubilisers, crystallisation inhibitors, surfactants and tonicifying agents.
- the lyophilized daptomycin formulations of the presently disclosed subject matter can optio nally include one or more buffering agents.
- Suitable buffering agents include, but are not limited to, phosphate buffers, sulfonic acids and Tris buffers.
- Specific buffers include sodium or potassium salts of phosphoric acid (such as di sodium hydro gen phosphate), 2 - ⁇ N-morpholino)ethanesulfonic acid (MES), N-[tris(hydroxymemyl)memyl]-2-ammoethanesulfonic acid (TES), N-(2- hydroxyethyl)piperazine-N' -(2-ethanesulfonic acid) (HEPES), 3-(N,N-Bis[2- hydroxyethl]amino)-2-hydroxypropanesulfonic acid (DIPSO), 2-hydroxy-3- [trishydroxymemyl)memylamine ⁇ -l-propanesulfonic acid (TAPSO), N-(2- acetamido)2 - amino ethanesulfonic acid (ACES), 1,4-piperazinediethanesulfonic acid (PIPES), 3- (N-morpholino)propanesulfonic acid (MOPS), ⁇ -h.ydr
- the lyophilized daptomycin formulations of the presently disclosed subject matter can optionally include one or more stabilisers.
- Suitable stabilising agents include, but are not limited to, sugars (such as sucrose, trehalose and dextran), amino acids (such as arginine, glycine and histidine), polyvinylpyrrolidones
- polyols such as mannitol and polymeric polyol surfactants, e.g., Pluronic®.
- the lyophilized daptomycin formulations of the presently disclosed subject matter display rapid reconstitution times in a pharmaceutically acceptable diluent.
- the lyophilized daptomycin formulations are reconstituted in a pharmaceutically acceptable diluent in less than about 5 minutes.
- the lyophilized daptomycin formulations are reconstituted in a pharmaceutically acceptable diluent in less than about 4 minutes.
- the lyophilized daptomycin formulations are reconstituted in a pharmaceutically acceptable diluent in less than about 3 minutes.
- the lyophilized daptomycin formulations are reconstituted in a pharmaceutically acceptable diluent in less than about 2 minutes. In yet another embodiment, the lyophilized daptomycin formulations are reconstituted in a pharmaceutically acceptable diluent in less than about 1 minute.
- the lyophilized daptomycin formulations of the presently disclosed subject matter have improved reconstitution times compared to the CUBICIN® product.
- the CUBICIN* product is reconstituted in 0.9% sterile sodium chloride for injection.
- the lyophilized daptomycin formulations of the presently disclosed subject matter can be reconstituted with one or more pharmaceutically acceptable diluents to provide a solution suitable for administration.
- compositions of the presently disclosed subject matter include, but are not limited to, sterile water for injection, bacteriostatic water for injection, 0.45% sodium chloride solution for injection and 0.9% sodium chloride solution for injection, Ringer's solution and lactated Ringer's solution.
- sterile water for injection bacteriostatic water for injection
- 0.45% sodium chloride solution for injection 0.45% sodium chloride solution for injection and 0.9% sodium chloride solution for injection
- Ringer's solution and lactated Ringer's solution.
- the lyophilized daptomycin formulations are reconstituted in 0.9% sterile sodium chloride solution for injection.
- formulations are reconstituted in sterile water for injection.
- the lyophilized daptomycin formulations of the presently disclosed subject matter can be reconstituted by adding the pharmaceutically acceptable diluent(s) to the lyophilized daptomycin formulation to provide the desired
- the volume of the pharmaceutically acceptable diluent(s) added to the lyophilized daptomycin formulation is from about 5 mL to about 15 mL. In some embodiments, the volume of the pharmaceutically acceptable diluent(s) added to the lyophilized daptomycin formulation is from about 8 mL to about 12 mL. In one embodiment, the volume of the pharmaceutically acceptable diluent(s) added to the lyophilized daptomycin formulation is about 10 mL.
- the lyophilized daptomycin formulations of the presently disclosed subject matter can be reconstituted by any suitable methods known to one of ordinary skill in the art.
- 10 mL of 0.9% sterile sodium chloride for injection is added slowly to a vial including 500 mg of the lyophilized daptomycin formulation of the presently disclosed subject matter.
- the resultant mixture is rotated to ensure all of the formulation is wetted and then allowed to stand undisturbed for about 2 minutes.
- the vial is then gently rotated or swirled intermittently as needed, to obtain a completely reconstituted solution.
- the reconstitution method includes quickly adding a diluent to a vessel including a lyophilized daptomycin formulation of the presently disclosed subject matter, followed by swirling of the vessel if required.
- the diluent is added in a period of about 1 -60 seconds. In some embodiments, the diluent is added in a period of about 1-30 seconds. In one embodiment, the diluent is added in less than about 20 seconds.
- the vessel including the daptomycin is swirled for about 1 minute and allowed to stand for about 3-5 minutes until clear.
- the CUBICIN* product includes 50 mg/mL daptomycin.
- the daptomycin formulations of the presently disclosed subject matter include daptomycin at a concentration of from about 20 mg/mL to about 100 mg/mL, e.g., from about 20 mg/mL to about 30 mg/mL, fro m about 30 mg/mL to about 40 mg/mL, from about 40 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 60 mg/mL, from about 60 mg/mL to about 70 mg/mL, from about 70 mg/mL to about 80 mg/mL, from about 80 mg/mL to about 90 mg/mL, or from about 90 mg/mL to about 100 mg/mL.
- the daptomycin formulations upon reconstitution in a pharmaceutically acceptable diluent, when provided in a vial, include daptomycin at a concentration of about
- the daptomycin formulations when provided in a vial, include daptomycin at a concentration of about 62.5 mg/mL.
- the reconstituted daptomycin formulation can be further diluted in a pharmaceutically acceptable diluent for administration to a subject.
- Pharmaceutically acceptable diluents include, but are not limited to, sterile water for injection, bacteriostatic water for injection, 0.45% sodium chloride solution for injection, 0.9% sodium chloride solution for injection, Ringer's solution and lactated Ringer's solution.
- the final daptomycin concentration is from about 2.5 to about 20 mg/mL.
- the daptomycin formulations of the presently disclosed subject matter include an additive at a concentration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 and 500 mM, or a range including any of two of those integers.
- the presently disclosed daptomycin formulations upon reconstitution in a pharmaceutically acceptable diluent, include an additive at a concentration of from about 1 mM to about 500 mM, from 1 mM to about 250 mM, or from about 1 mM to about 150 mM.
- the concentration of the additive in the reconstituted daptomycin formulations can be from 1 mM to about 50 mM, from about 50 mM to about 100 mM (e.g., from about 80 mM to about 120 mM), from about 100 mM to about 150 mM, from about 150 mM to about 200 mM, from about 200 mM to about 250 mM (e.g.
- the concentration of the additive in the reconstituted lyophilized daptomycin formulation is about 237.5 mM. In certain embodiments, the concentration of the additive in the reconstituted lyophilized daptomycin formulation is about 300 mM. In some embodiments, the concentration of the additive in the reconstituted lyophilized daptomycin formulation is about 500 mM.
- the additive is ascorbic acid.
- the concentration of ascorbic acid in the reconstituted lyophilized daptomycin formulation is about 237.5 mM. Additionally or alternatively, the concentration of ascorbic acid in the reconstituted lyophilized daptomycin formulation is about 300 mM.
- the additive is succinic acid.
- the concentration of succinic acid in the reconstituted formulation is from about 1 mM to about 500 mM, from about 1 mM to about 250 mM, or from about 80 mM to about 120 mM.
- the additive is tartaric acid.
- the concentration of tartaric acid in the reconstituted formulation is from about 1 mM to about 500 mM, from about 1 mM to about 250 mM, or from about 80 mM to about 120 mM.
- the additive is citric acid.
- the concentration of citric acid in the reconstituted formulation is from about 1 mM to about 500 mM, from about 1 mM to about 250 mM, or from about 25 mM to about 75 mM. In one embodiment, the concentration of citric acid in the reconstituted formulation is about 237.5 mM. Additionally or alternatively, the concentration of citric acid in the reconstituted formulation is about 300 mM. The concentration of citric acid in the reconstituted formulation can also be about 500 mM.
- the additive is edetic acid.
- concentration of edetic acid in the reconstituted formulation is from about 1 to about 500 mM, from about 1 to about 250 mM, or from about 50 mM to about 100 mM.
- the additive is acetyl glucosamine.
- concentration of acetyl glucosamine in the reconstituted lyophilized daptomycin formulation is about 237.5 mM. Additionally or alternatively, the concentration of acetyl glucosamine in the reconstituted lyophilized daptomycin formulation is about 300 mM.
- the presently disclosed daptomycin formulations upon reconstitution in a pharmaceutically acceptable diluent, include an additive at a concentration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 and 500 mg/mL, or a range including any of two of those integers.
- the presently disclosed daptomycin formulations upon reconstitution in a pharmaceutically acceptable diluent, include an additive at a concentration of from about 1 mg/mL to about 500 mg/mL, , from about 1 mg/mL to about 250 mg/mL, or from about 1 mg/mL to about 100 mg/mL.
- the concentration of the additive in the reconstituted daptomycin formulations can be from about 1 mg/mL to about 50 mg/mL (e.g., from about 10 mg/mL to about 50 mg/mL, from about 20 mg/mL to about 50 mg/mL, from about 30 mg/mL to about 50 mg/mL, or from about 40 mg/mL to about 50 mg/mL), from about 50 mg/mL to about 100 mg/mL (e.g.
- the additive is ascorbic acid.
- the concentration of ascorbic acid in the reconstituted lyophilized daptomycin formulation is about 41.8 mg/mL. Additionally or alternatively, the concentration of ascorbic acid in the reconstituted lyophilized daptomycin formulation is about 52.8 mg/mL.
- the additive is succinic acid.
- concentration of succinic acid in the reconstituted formulation is from about 1 mg/mL to about 500 mg/mL, fro m about 1 mg/mL to about 250 mg/mL, or from about 1 mg/mL to about 50 mg/mL.
- the additive is tartaric acid.
- concentration of tartaric acid in the reconstituted formulation is from about 1 mg/mL to about 500 mg/mL, from about 1 mg/mL to about 250 mg/mL, or from about 1 mg/mL to about 50 mg/mL.
- the additive is citric acid.
- the concentration of citric acid in the reconstituted formulation can be from about 1 mg/mL to about 500 mg/mL, from about 1 mg/mL to about 250 mg/mL, or from about 1 mg/mL to about 50 mg/mL. In one embodiment, the concentration of citric acid in the reconstituted lyophilized daptomycin formulation is about 45.6 mg/mL. Additionally or
- the concentration of citric acid in the reconstituted lyophilized daptomycin formulation is about 57.6 mg/mL.
- the concentration of citric acid in the reconstituted lyophilized daptomycin formulation can also be about 96.1 mg/mL.
- the additive is edetic acid.
- concentration of edetic acid in the reconstituted formulation is from about 1 mg/mL to about 500 mg/mL, from about 1 mg/mL to about 250 mg/mL, or from about 1 mg/mL to about 50 mg/mL.
- the additive is acetyl glucosamine.
- the concentration of acetyl glucosamine in the reconstituted lyophilized daptomycin formulation is about 52.5 mg/mL. Additionally or alternatively, the concentration of acetyl glucosamine in the reconstituted lyophilized daptomycin formulation is about 66.4 mg/mL.
- the pH of the presently disclosed daptomycin formulations is in the range of from about 4.0 to about 7.0. In one embodiment, the pH is in the range of from about 4.0 to about 5.0.
- the purity of the daptomycin in the lyophilized daptomycin formulations of the presently disclosed subject matter can be measured by any means known to one of ordinary skill in the art, including nuclear magnetic resonance (NMR), or high performance liquid chro moatography coupled with UV (HPLC/UV) or mass spectrometry (HPLC/MS).
- NMR nuclear magnetic resonance
- HPLC/UV high performance liquid chro moatography coupled with UV
- HPLC/MS mass spectrometry
- the purity of the lyophilized daptomycin formulations is measured by reconstitution in a pharmaceutically acceptable diluent followed by analysis employing HPLC/UV.
- the HPLC/UV process utilised for measuring the purity of the lyophilized daptomycin formulations can be any method known to one of ordinary skill in the art, e.g., using appropriate HPLC/UV machines typically encountered in the industry, such as the HPLC/UV process described in US Patent 2007/191280 Al .
- the purity of daptomycin in a reconstituted solution of a lyophilized daptomycin formulation of the presently disclosed subject matter can be determined by HPLC/UV followed by analysis of the peak area (the area-under-the curve-(AUC)) at a wavelength of 223 nm for individual peaks of the chromatogram.
- the amount of daptomycin can be measured with respect to the total amount of impurities present.
- the relative amount of daptomycin with respect to three of the known daptomycin degradants, specifically the anhydro-daptomycin, the ⁇ -isomer of daptomycin and the lactone hydrolysis pro duct of daptomycin can be determined.
- the lyophilized daptomycin formulations of the presently disclosed subj ect matter include daptomycin in a purity that is higher than that of CUBICI * product as detennined by HPLC/UV analysis of the reconstituted solution at a wavelength of 223 nm.
- the lyophilized daptomycin formulations of the presently disclosed subject matter include total impurities in an amount of less than that of the CUBICIN ® product as determined by HPLC/UV analysis of the reconstituted solution at a wavelength of 223 nm.
- the presently disclosed subject matter further provides a method of a bacterial infection in a subject.
- the method includes administering to a subject in need thereof, an effective amount of a lyophilized daptomycin formulation including an additive selected from the gro up consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and
- the presently disclosed subject matter further provides a method of treating or preventing a biofilm.
- the method includes exposing a surface of a device to a solution of an effective amount of a lyophilized daptomycin formulation including an additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and
- the presently disclosed subject matter provides a method for preparing the presently disclosed lyophilized daptomycin formulation.
- the lyophilized daptomycin formulation can be lyophilized from any solvent known to be suitable in the art. Acceptable solvents include, but are not limited to, water, aqueous butanol and aqueous ethanol.
- the lyophilisation process utilised to prepare the presently disclosed lyophilized daptomycin formulations can be any method known to one of ordinary skill in the art using appropriate freeze drying machines typically encountered in the industry. Exemplary lyophilisation processes include those described in "Lyophilization: Introduction and Basic Principles" by Thomas A Jennings, InterPharm Press, 1999.
- the method includes: (a) forming an aqueous solution of the daptomycin and the additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof,
- the method includes: (a) fonning an aqueous solution of the daptomycin at a pH of about 4.0 to about S.0; (b) dissolving the additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and a pharmaceutically acceptable salts thereof, and combinations thereof in the aqueous solution of the daptomycin; (c) adjusting the pH to about 4.0 to about 5.0; and (d) lyophilising the solution to obtain a powder.
- the method includes: (a) forming an aqueous tertiary-butanol solution of the daptomycin at a pH of 4.0 to 5.0; (b) dissolving an additive selected from the group insisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and a pharmaceutically acceptable salts thereof, and combinations thereof in the aqueous/butanol solution of the daptomycin; (c) adjusting the pH to about 4.0 to about 5.0; and (d) lyophilising the solution to obtain a powder.
- Table 1 provides examples of daptomycin formulation solutions that were subsequently lyophilized to produce lyophilized formulations of the presently disclosed subject matter including an additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof, and combinations thereof.
- Reconstitution time was determined by injecting 7 mL of 0.9% sterile sodium chloride for injection to a vial including 350 mg of the lyophilized
- the resultant mixture was swirled for about 1 minute and allowed to stand.
- the reconstitution time is the time required from addition of the diluent to total dissolution of the daptomycin formulation.
- Table 2 provides reconstitution times of the lyophilized daptomycin formulations including an additive in 0.9% sterile sodium chloride for injection. Initial reconstitution times, and reconstitution after 1, 3 or 6 months of storage at 5°C, 25°C and 40°C for the compositions are provided. The pH of the reconstituted lyophilized daptomycin formulations is 4.7. The reconstitution times of the
- the lyophilized daptomycin formulations of the presently disclosed subject matter were tested for daptomycin stability as a relative measure of daptomycin degradant impurity levels.
- the lyophilized daptomycin formulations were reconstituted in 0.9% sterile sodium chloride for injection the resultant solutions analysed by HPLC/UV.
- the amount of daptomycin and impurities in the solution were determined by % peak area at a wavelength of 223 nm.
- the total amount of impurities was calculated from the % peak area at a wavelength of 223 nm for all peaks other than that of daptomycin.
- the data are presented in the following Tables 4-9.
- Table 4 displays the amount of total impurities, represented as % peak area, for each composition at 1, 2, 3 and 6 months after storage at 5, 25 and 40°C. The difference from the initial value is shown in parentheses.
- Table 5 displays the amount of the anhdyro daptomycin impurities, represented as % peak area, for each composition at 1, 2, 3 and 6 months after storage at 5, 25 and 40°C. The difference from the initial value is shown in parentheses.
- Table 6 displays the amount of the hydrolysis daptomycin impurities, represented as % peak area, for each composition at 1, 2, 3 and 6 months after storage at 5, 25 and 40°C. The difference from the initial value is shown in parentheses.
- Table 7 displays the amount of the ⁇ -isomer daptomycin impurities, represented as % peak area, for each composition at 1, 2, 3 and 6 months after storage at S, 25 and 40°C. The difference from the initial value is shown in parentheses.
- the effect of pH on the stability of the lyophilized daptomycin formulations including citric acid were tested as a relative measure of daptomycin degradant impurity levels.
- the lyophilized daptomycin formulations, including 350 mg daptomycin, 56 mg citric acid, and sodium hydroxide sufficient to adjust the pH of the lyophilisation solution, were reconstituted in 0.9% sterile sodium chloride for injection and the resultant solutions analysed by HPLC/UV.
- Table 8 displays the amount of daptomycin impurities, represented as % peak area, for each composition upon initial preparation and after storage at 25°C for 3 months. The difference from the initial value is shown in parentheses.
- Table 9 displays the total amount of all daptomycin impurities, represented as % peak area, for each composition upon initial preparation and after storage at 25°C for 3 months. The difference from the initial value is shown in parentheses.
- the osmolalites of the presently disclosed lyophilized daptomycin formulations including citric acid (175 mM, 237.5 mM, 300 mM or 500 mM), 5 ascorbic acid (237.5 mM or 300 mM) and 62.5 mg/mL daptomycin were assessed.
- Table 10 provides the osmolalities of the lyophilized daptomycin formulations including ascorbic acid, citric acid in either sterile water for injection ("WFI") or a 0.9% sodium chloride solution for injection.
- the pH of the reconstituted lyophilized daptomycin formulations was in the range of 4.45 to 4.74.
- the osmolalities of the 10 CUBICIN® product and of a benchmark sucrose daptomycin formulation were included for comparison.
- the osmolalites of the ascorbic acid daptomycin formulations were lower than those of the citric acid daptomycin formulations.
- the reconstitution times, osmolalities, color appearances and stabilities of the presently disclosed lyophilized daptomycin formulations e.g., including ascorbic acid, citric acid, and acetyl glucosamine as an additive and 62.5 mg/mL daptomycin, were assessed.
- Reconstitution time was determined by injecting 7 mL of a 0.9% sodium chloride solution to a vial containing 350 mg/vial of lyophilized daptomycin. The resultant mixture was swirled for one minute and allowed to stand. The reconstitution time is the time required for addition of the diluent to total dissolution of the lyophilized daptomycin formulation.
- Table 11 provides the average reconstitution times of the lyophilized daptomycin formulations including ascorbic acid, citric acid, and acetyl glucosamine in a 0.9% sodium chloride solution for injection.
- the pH of the reconstituted lyophilized daptomycin formulations was in the range of 4.45 to 4.74.
- Table 12 provides the osmolalities of the lyophilized daptomycin formulations including ascorbic acid, citric acid and acetyl glucosamine. These formulations were reconstituted with a 0.9% sterile sodium chloride solution for injection and WFI. The osmolalities of the CUBICIN® product and of a benchmark sucrose daptomycin formulation were included for comparison, as shown in Table 13.
- Table 14 provides the initial color appearances of the lyophilized daptomycin formulations including ascorbic acid, citric acid and acetyl glucosamine at a 50 mg/mL bolus or 10 mg/mL infusion solution exposed to a temperature of ambient laboratory temperature (about 20°C) and a lighting condition of ambient laboratory lighting (about 400 lux).
- the color appearances of the CUBICIN® product and a benchmark sucrose daptomycin formulation were included for comparison.
- the lyophilized daptomycin formulations including ascorbic acid (237.5 mM and 300 mM), citric acid (237.5 mM and 300 mM), or acetyl glucosamine (237.5 mM and 300 mM), and 62.5 mg/mL daptomycin were tested for daptomycin stability as a relative measure of daptomycin degradant impurity level.
- the amount of daptomycin and impurities in the solution were determined by the % peak area at a wavelength of 223 nm, Table 15 displays the amount of daptomycin impurities, represented as % peak area, for each composition upon initial preparation and after storage at 25°C and 40°C for 2, 3 and 6 months. The difference from the initial value was shown in parentheses.
- the impurities of the CUBICIN ® product and a benchmark sucrose daptomycin formulation were included for comparison.
- Impurity 1 increased by about 0.2% for both 237.5 mM and 300 mM 5 lyophilised ascorbic acid daptomycin formulations, by about 0.02% for both 237.5 mM and 300 mM lyophilised acetyl glucosamine daptomycin formulations, while remained stable for both 237.5 mM and 300 mM lyophilised citric acid daptomycin formulations, which was comparable to benchmark Sucro se daptomycin formulation and the CUBICIN® product. All other major impurities remained stable without significant increases. The ⁇ -isomer daptomycin impurity remained stable for almost all formulations.
- Impurity 1 & ⁇ -isomer daptomycin impurities remained stable for the citric acid formulations, however increased up to 0.2% & 0.1%, respectively, for the ascorbic acid formulations, compared to the initial value.
- Hydrolysis impurity increased up to 0.14% for the citric acid formulations (0.14% for the 237.5 mM formulation, and 0.1% for the 300 mM formulation). Hydrolysis impurity increased up to 0.23% for the ascorbic acid formulations (0.23% for the 237.5 mM formulation, and 0.18% for the 300 mM formulation). Hydrolysis impurity increased up to 0.17% for the acetyl glucosamine formulations (0.14% for the 237.5 mM formulation, and 0.17% for the 300 mM formulation). Anhydro daptomycin impurities increased up to 0.39% for the citric acid formulations and up to 0.29% for the ascorbic acid formulations, which was comparable to the Sucrose formulation. The rate of increase for anhydro daptomycin impurities was the lowest for the 300 mM ascorbic acid formulation. The rates of increase for all other major impurities were approximately double for ascorbic acid formulations compared to citric acid formulations.
- citric acid lyophilized daptomycin formulations would tolerate heat excursions better than ascorbic acid lyophilized daptomycin formulations and acetyl glucosamine lyophilized daptomycin formulations.
- the impurity amounts or stability for the 237.5 mM formulations were comparable to the 300 mM formulations, e.g. , the 237.5 mM formulation was not significantly different fro m the 300 mM formulation for citric acid. In some examples, a 237.5 mM formulation concentration is preferred at least because it has lower osmolality, and it is possibly easy to register lower the amounts of the additives.
- Example 4
- the color appearances of the presently disclosed lyophilized daptomycin formulations e.g., including ascorbic acid (237.5 mM and 300 mM) or citric acid (237.5 mM and 300 mM) and 62.5 mg/mL daptomycin at 50 mg/mL IV bolus or 10 mg/mL IV infusion at initial, 4, 24, and 48 hours exposed to room temperature and lighting conditions of about 400 lux, were assessed.
- the color appearances for the CUBICIN® product and for a benchmark sucrose daptomycin formulation were included for comparison.
- the lyophilized daptomycin formulations and the benchmark sucrose daptomycin formulation were reconstituted in both 0.9% NaCl and WFI.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (23)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ706286A NZ706286A (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
ES13837694.2T ES2552754T1 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
MA37956A MA37956A1 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and their uses |
MX2015003164A MX366122B (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof. |
US14/427,618 US9655946B2 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
BR112015005400-5A BR112015005400B1 (en) | 2012-09-11 | 2013-09-11 | LYOPHILIZED DAPTOMYCIN FORMULATION, RECONSTITUTED DAPTOMYCIN FORMULATION, METHOD FOR TREATMENT A BIOFILM AND METHOD FOR PREPARING A LYOPHILIZED DAPTOMYCIN FORMULATION |
EP13837694.2A EP2895187A4 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
DE13837694.2T DE13837694T1 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
CA2884484A CA2884484C (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
AU2013316779A AU2013316779A1 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
DK13837694.2T DK2895187T1 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and applications thereof |
EP22169277.5A EP4066849A1 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
SG11201506113WA SG11201506113WA (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
IL237652A IL237652B (en) | 2012-09-11 | 2015-03-10 | Daptomycin formulations and uses thereof |
TNP2015000090A TN2015000090A1 (en) | 2012-09-11 | 2015-03-10 | Daptomycin formulations and uses thereof |
SA515360129A SA515360129B1 (en) | 2012-09-11 | 2015-03-11 | Daptomycin formulations and uses thereof |
ZA2015/02310A ZA201502310B (en) | 2012-09-11 | 2015-04-07 | Daptomycin formulations and uses thereof |
HK15107795.5A HK1207006A1 (en) | 2012-09-11 | 2015-08-12 | Daptomycin formulations and uses thereof |
CY20152200004T CY2200004T2 (en) | 2012-09-11 | 2015-11-20 | DAPTOMYCIN PREPARATION AND USES THEREOF |
US15/492,111 US20170216396A1 (en) | 2012-09-11 | 2017-04-20 | Daptomycin formulations and uses thereof |
US15/903,764 US10357535B2 (en) | 2012-09-11 | 2018-02-23 | Daptomycin formulations and uses thereof |
AU2018217322A AU2018217322B2 (en) | 2012-09-11 | 2018-08-17 | Daptomycin formulations and uses thereof |
US16/849,387 US20200237858A1 (en) | 2012-09-11 | 2020-04-15 | Daptomycin formulations and uses thereof |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261699570P | 2012-09-11 | 2012-09-11 | |
US61/699,570 | 2012-09-11 | ||
US201361839699P | 2013-06-26 | 2013-06-26 | |
US61/839,699 | 2013-06-26 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/427,618 A-371-Of-International US9655946B2 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
US15/492,111 Continuation US20170216396A1 (en) | 2012-09-11 | 2017-04-20 | Daptomycin formulations and uses thereof |
Publications (1)
Publication Number | Publication Date |
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WO2014041425A1 true WO2014041425A1 (en) | 2014-03-20 |
Family
ID=50277707
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2013/002191 WO2014041425A1 (en) | 2012-09-11 | 2013-09-11 | Daptomycin formulations and uses thereof |
Country Status (20)
Country | Link |
---|---|
US (4) | US9655946B2 (en) |
EP (2) | EP2895187A4 (en) |
AU (2) | AU2013316779A1 (en) |
BR (1) | BR112015005400B1 (en) |
CA (1) | CA2884484C (en) |
CL (1) | CL2015000608A1 (en) |
CY (1) | CY2200004T2 (en) |
DE (1) | DE13837694T1 (en) |
DK (1) | DK2895187T1 (en) |
ES (1) | ES2552754T1 (en) |
HK (1) | HK1207006A1 (en) |
HU (1) | HUE13837694T1 (en) |
IL (1) | IL237652B (en) |
MX (1) | MX366122B (en) |
NZ (3) | NZ706286A (en) |
SA (1) | SA515360129B1 (en) |
SG (1) | SG11201506113WA (en) |
TN (1) | TN2015000090A1 (en) |
WO (1) | WO2014041425A1 (en) |
ZA (1) | ZA201502310B (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018073269A1 (en) | 2016-10-21 | 2018-04-26 | Xellia Pharmaceuticals Aps | Liquid formulations of daptomycin |
WO2019043008A1 (en) | 2017-08-31 | 2019-03-07 | Xellia Pharmaceuticals Aps | Daptomycin formulations |
US11008316B2 (en) | 2012-09-11 | 2021-05-18 | Genzyme Corporation | Glucosylceramide synthase inhibitors |
US11058745B1 (en) | 2018-10-04 | 2021-07-13 | Good Health, Llc | Stable liquid pharmaceutical compositions of daptomycin |
US11857512B2 (en) | 2020-07-24 | 2024-01-02 | Genzyme Corporation | Pharmaceutical compositions comprising venglustat |
US12083115B2 (en) | 2020-02-03 | 2024-09-10 | Genzyme Corporation | Methods for treating neurological symptoms associated with lysosomal storage diseases |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ706286A (en) * | 2012-09-11 | 2018-05-25 | Hospira Australia Pty Ltd | Daptomycin formulations and uses thereof |
CN110339342A (en) * | 2018-04-03 | 2019-10-18 | 江苏恒瑞医药股份有限公司 | Salt or the composition of saliferous of a kind of Daptomycin and preparation method thereof |
EP4117625A1 (en) | 2020-03-12 | 2023-01-18 | Baxter International Inc. | Daptomycin formulations containing a combination of sorbitol and mannitol |
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 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020111311A1 (en) * | 2000-12-18 | 2002-08-15 | Chandrika Govardhan | Daptomycin and related analogs in crystalline form |
WO2011063419A2 (en) | 2009-11-23 | 2011-05-26 | Cubist Pharmaceuticals Inc. | Lipopeptide compositions and related methods |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5560906A (en) * | 1995-03-27 | 1996-10-01 | Oral Technology Laboratories, Inc. | Non-alcoholic antimicrobial mouthwash for removal of dental plaque |
CN1530136A (en) * | 1998-09-25 | 2004-09-22 | ������ҩ������˾ | Medicine feeding method for antibiotics |
US6696412B1 (en) | 2000-01-20 | 2004-02-24 | Cubist Pharmaceuticals, Inc. | High purity lipopeptides, Lipopeptide micelles and processes for preparing same |
US7468428B2 (en) * | 2004-03-17 | 2008-12-23 | App Pharmaceuticals, Llc | Lyophilized azithromycin formulation |
CN1616083A (en) * | 2004-09-01 | 2005-05-18 | 魏雪纹 | Daptomycin freeze-dried preparation for injection and preparing method |
JP2008546429A (en) * | 2005-05-31 | 2008-12-25 | キュービスト ファーマシューティカルズ, インコーポレイテッド | Daptomycin for biofilm processing and catheter rescue |
EP2504020A4 (en) * | 2009-11-23 | 2013-05-29 | Eagle Pharmaceuticals Inc | Formulations of daptomycin |
CA2881121A1 (en) * | 2012-08-23 | 2014-03-27 | Agila Specialties Private Limited | Improved daptomycin injectable formulation |
NZ706286A (en) * | 2012-09-11 | 2018-05-25 | Hospira Australia Pty Ltd | Daptomycin formulations and uses thereof |
-
2013
- 2013-09-11 NZ NZ706286A patent/NZ706286A/en unknown
- 2013-09-11 EP EP13837694.2A patent/EP2895187A4/en not_active Withdrawn
- 2013-09-11 AU AU2013316779A patent/AU2013316779A1/en not_active Abandoned
- 2013-09-11 BR BR112015005400-5A patent/BR112015005400B1/en active IP Right Grant
- 2013-09-11 SG SG11201506113WA patent/SG11201506113WA/en unknown
- 2013-09-11 NZ NZ74134213A patent/NZ741342A/en unknown
- 2013-09-11 WO PCT/IB2013/002191 patent/WO2014041425A1/en active Application Filing
- 2013-09-11 DK DK13837694.2T patent/DK2895187T1/en unknown
- 2013-09-11 CA CA2884484A patent/CA2884484C/en active Active
- 2013-09-11 DE DE13837694.2T patent/DE13837694T1/en active Pending
- 2013-09-11 US US14/427,618 patent/US9655946B2/en active Active
- 2013-09-11 EP EP22169277.5A patent/EP4066849A1/en active Pending
- 2013-09-11 ES ES13837694.2T patent/ES2552754T1/en active Pending
- 2013-09-11 NZ NZ742241A patent/NZ742241A/en unknown
- 2013-09-11 MX MX2015003164A patent/MX366122B/en active IP Right Grant
-
2015
- 2015-03-10 TN TNP2015000090A patent/TN2015000090A1/en unknown
- 2015-03-10 IL IL237652A patent/IL237652B/en active IP Right Grant
- 2015-03-11 CL CL2015000608A patent/CL2015000608A1/en unknown
- 2015-03-11 SA SA515360129A patent/SA515360129B1/en unknown
- 2015-04-07 ZA ZA2015/02310A patent/ZA201502310B/en unknown
- 2015-08-12 HK HK15107795.5A patent/HK1207006A1/en unknown
- 2015-11-11 HU HUE13837694A patent/HUE13837694T1/en unknown
- 2015-11-20 CY CY20152200004T patent/CY2200004T2/en unknown
-
2017
- 2017-04-20 US US15/492,111 patent/US20170216396A1/en not_active Abandoned
-
2018
- 2018-02-23 US US15/903,764 patent/US10357535B2/en active Active
- 2018-08-17 AU AU2018217322A patent/AU2018217322B2/en active Active
-
2020
- 2020-04-15 US US16/849,387 patent/US20200237858A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020111311A1 (en) * | 2000-12-18 | 2002-08-15 | Chandrika Govardhan | Daptomycin and related analogs in crystalline form |
WO2011063419A2 (en) | 2009-11-23 | 2011-05-26 | Cubist Pharmaceuticals Inc. | Lipopeptide compositions and related methods |
Non-Patent Citations (1)
Title |
---|
See also references of EP2895187A4 |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11008316B2 (en) | 2012-09-11 | 2021-05-18 | Genzyme Corporation | Glucosylceramide synthase inhibitors |
US12060349B2 (en) | 2012-09-11 | 2024-08-13 | Genzyme Corporation | Glucosylceramide synthase inhibitors |
WO2018073269A1 (en) | 2016-10-21 | 2018-04-26 | Xellia Pharmaceuticals Aps | Liquid formulations of daptomycin |
US10933019B2 (en) | 2016-10-21 | 2021-03-02 | Xellia Pharmaceuticals Aps | Liquid formulations of daptomycin |
WO2019043008A1 (en) | 2017-08-31 | 2019-03-07 | Xellia Pharmaceuticals Aps | Daptomycin formulations |
AU2018322769B2 (en) * | 2017-08-31 | 2021-12-02 | Xellia Pharmaceuticals Aps | Daptomycin formulations |
RU2770366C2 (en) * | 2017-08-31 | 2022-04-15 | Кселлия Фармасьютикалз Апс | Daptomycin preparations |
US11759497B2 (en) | 2017-08-31 | 2023-09-19 | Xellia Pharmaceuticals Aps | Daptomycin formulations |
US12053502B2 (en) | 2017-08-31 | 2024-08-06 | Xellia Pharmaceuticals Aps | Daptomycin formulations |
US11058745B1 (en) | 2018-10-04 | 2021-07-13 | Good Health, Llc | Stable liquid pharmaceutical compositions of daptomycin |
US12083115B2 (en) | 2020-02-03 | 2024-09-10 | Genzyme Corporation | Methods for treating neurological symptoms associated with lysosomal storage diseases |
US11857512B2 (en) | 2020-07-24 | 2024-01-02 | Genzyme Corporation | Pharmaceutical compositions comprising venglustat |
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