WO2011062676A1 - Formulations of daptomycin - Google Patents
Formulations of daptomycin Download PDFInfo
- Publication number
- WO2011062676A1 WO2011062676A1 PCT/US2010/049322 US2010049322W WO2011062676A1 WO 2011062676 A1 WO2011062676 A1 WO 2011062676A1 US 2010049322 W US2010049322 W US 2010049322W WO 2011062676 A1 WO2011062676 A1 WO 2011062676A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- daptomycin
- long term
- term storage
- containing composition
- storage stable
- Prior art date
Links
- 229960005484 daptomycin Drugs 0.000 title claims abstract description 194
- 239000000203 mixture Substances 0.000 title claims abstract description 184
- 108010013198 Daptomycin Proteins 0.000 title claims abstract description 182
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 title claims abstract description 181
- 238000009472 formulation Methods 0.000 title abstract description 30
- 238000003860 storage Methods 0.000 claims abstract description 99
- 230000007774 longterm Effects 0.000 claims abstract description 64
- 230000007062 hydrolysis Effects 0.000 claims abstract description 20
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000011575 calcium Substances 0.000 claims abstract description 15
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 14
- 239000012530 fluid Substances 0.000 claims abstract description 13
- 239000012535 impurity Substances 0.000 claims description 77
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 57
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 34
- 239000001110 calcium chloride Substances 0.000 claims description 34
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 34
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 33
- 239000000920 calcium hydroxide Substances 0.000 claims description 33
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 33
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 30
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical group [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 21
- 239000001527 calcium lactate Substances 0.000 claims description 21
- 229960002401 calcium lactate Drugs 0.000 claims description 21
- 235000011086 calcium lactate Nutrition 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 15
- 229960005069 calcium Drugs 0.000 claims description 13
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 10
- 239000000347 magnesium hydroxide Substances 0.000 claims description 10
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 10
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 5
- 239000003002 pH adjusting agent Substances 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 18
- 239000007857 degradation product Substances 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 20
- 238000004458 analytical method Methods 0.000 description 19
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 15
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 15
- 229960002713 calcium chloride Drugs 0.000 description 15
- 229940074410 trehalose Drugs 0.000 description 15
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 235000001014 amino acid Nutrition 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- 239000004475 Arginine Substances 0.000 description 9
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 9
- 230000014759 maintenance of location Effects 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- -1 calcium source Chemical class 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000008380 degradant Substances 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 2
- DPVHGFAJLZWDOC-PVXXTIHASA-N (2r,3s,4s,5r,6r)-2-(hydroxymethyl)-6-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-3,4,5-triol;dihydrate Chemical compound O.O.O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DPVHGFAJLZWDOC-PVXXTIHASA-N 0.000 description 1
- 208000031729 Bacteremia Diseases 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 108010028921 Lipopeptides Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000194042 Streptococcus dysgalactiae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 208000037815 bloodstream infection Diseases 0.000 description 1
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 1
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940027278 hetastarch Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 201000007119 infective endocarditis Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940115920 streptococcus dysgalactiae Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229940074409 trehalose dihydrate Drugs 0.000 description 1
- 125000000647 trehalose group Chemical group 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K9/14—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Definitions
- Daptomycin is a lipopeptide antibiotic represented by the following structural formula (I)
- Daptomycin is used in the treatment of Methicillm-resistant Staphylococcus aureus (MRSA) and Methiciliin-susceptible Staphylococcus aureus (MSSA), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies equisirnilis, and Ertiero coccus faecal is (vancomycin-susceptible isolates only) in complicated skin infections and bloodstream infections (bacteremia), including right-sided infective endocarditis. Daptomycin is commercially available as CubicinTM for intravenous administration.
- MRSA Methicillm-resistant Staphylococcus aureus
- MSSA Methiciliin-susceptible Staphylococcus aureus
- Streptococcus pyogenes Streptococcus agalactiae
- Daptomycin exhibits premature degradation upon reeonstitution of the lyophilized product.
- the reconstituted daptomycin exhibits increased degradation after reeonstitution and is, therefore, not suitable for long-term storage in liquid form.
- Some of the main degradants of daptomycin are the hydrolysis product of daptomycin, the ⁇ -isomer of daptomycin and anhydro daptomycin.
- the hydrolysis product, (ring opening compound) appears as the main impurity at a Relative Retention Time (RRT) of about, 0.66
- the ⁇ -isomer of daptomycm appears as the main impurity at an R RT of about 0.97
- anhydro daptomycin appears as the main impurity at an RRT of about 1.1.
- the invention is generally directed to daptomycin-containing compositions that are long term storage stable, i.e. for a period of at least about 18 months or longer.
- the compositions include a source of calcium selected from among calcium chloride and calcium lactate and the concentration of daptomycin will be less than or equal to about 25 mg/mL.
- the compositions will have a pH of from about 6 to about 7.
- the compositions will include an alkaline hydroxide selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide. Still further aspects of the invention include methods of treatment, methods of preparing the compositions and kits.
- compositions will include an amino acid in an amount sufficient to maintain the pH of the composition at about 6 to about 7.
- compositions will include trehalose.
- One of the advantages of the inventive liquid compositions is that they are substantially free of impurities after at least 18 months.
- Substantially free of impurities refers to daptomycin- containing compositions in which total impurities are less than about 10 %, including less than about 5% of the hydrolysis product of daptomycin, less than about 5% of the ⁇ -isomer of daptomyein and less than 5% of anhydro-daptomycin, area-under-the-curve (“AUG”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223nm, after a period of at least about 18 months at a temperature of from about 5 °C to about, 25 °C.
- the formulations are ready for use or further dilution; storage as a lyophilized powder is no longer a necessity for commercial use of the drug.
- RRT is calculated by dividing the retention time of the peak of interest by the retention time of the main peak. Any peak with an RRT ⁇ 1 elutes before the main peak, and any peak with an RRT >1 elutes after the main peak.
- substantially free of impurities refers to daptomycm-containing compositions in which the total impurities are less than about 10 %, calculated as being based upon the original amount daptomycin (or salt thereof) being present in the composition or formulation.
- the total amount of impurities, i.e. > 10% includes less than about 5%, i.e. no more than about 1/3 thereof, of the hydrolysis product of daptomycin, less than about 5%, i.e. no more than about 1/3 thereof, of the ⁇ -isomer of daptomycin and less than 5%, i.e. no more than about 1/3 thereof, of anhydro-daptomycin.
- the amounts of impurities are calculated under-the-curve ("AUG”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after storage periods of at least about 18 months at a temperature of from about 5 °C to about 25 °C.
- the amount of time the compositions demonstrate long term storage stability is at least about 2 years.
- long term storage stable daptomycin-containing compositions including:
- daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL;
- compositions ha ve a pH of from about 6 to about 7, and total impurities are less than about 10 % area-under-the-curve (''AUG") as determined by high performance liquid chromatography (“HPLC”) at, a wavelength of 223nm, after at least about 18 months storage at a temperature of from about 5 °C to about 25 °C.
- HPLC high performance liquid chromatography
- the compositions described herein when the daptomycin- containing compositions described herein are referred to as having total impurities of less than about 10 %, the compositions will iiirther include less than about 5% of the hydrolysis product of daptomycin, less than about 5% of the ⁇ -isomer of daptomycin and less than 5% of anhydro- daptomycm (as calculated with reference to the original starting amount of daptomycin) after the same period of long term storage, i.e. about 18 months or longer under the conditions mentioned herein.
- the source of calcium is calcium chloride.
- the amount of calcium chloride is greater than 1 nig/ ' mL. In other aspects of the invention, the concentration of calcium chloride is from about 1.5 nig/ ' mL to about 17 mg/mL. In one embodiment, the concentration of calcium chloride is from about 4 mg/mL to about 16.2 mg/mL. In another embodiment, the concentration of calcium chloride is from about 8 mg/mL to about 12 mg/mL. Some preferred concentrations of calcium chloride include, for example, 8 mg/mL, 12 mg/mL or 16.2 mg/mL.
- the source of calcium is calcium lactate.
- the calcium lactate concentration is about 0.05M to about 0.3M.
- the concentration of calcium lactate is about 0.1M to about 0.25M. More preferably, the concentration of calcium lactate is about 0.1M.
- the compositions of the present invention can be kept at a pH of from about 6,25 to about 6.75, Preferably, the composition is maintained at a pH of from about 6.5 to about 6.75. In one embodiment, the pH is about 6.5. In another embodiment, the pH is about 6.75.
- the long term storage stable daptomycin-containing compositions include a pH adjusting agent which is present in an amount sufficient to adjust the pH of the compositions to the ranges set forth above, i.e. from about 6.25 to about 6.75, or to specific points in between such as about 6.5 or about 6.75.
- a pH adjusting agent is sodium hydroxide.
- Another preferred pH adjusting agent is calcium hydroxide.
- Alternative pH adjusters are those commonly used in the art, including HC1 and TRIS.
- daptomycin is predominantly ionized at pHs of from about 6.5 to about 7.0. As a result the molecule is considerably more stable and thus self association and degradation thereof is unexpectedly and substantially reduced for extended periods of time.
- the inventive compositions are maintained during storage and/ or prior to use at a temperature of from about 5 °C to about 15 °C. In another embodiment, the compositions are maintained at a temperature of from about 5 °C to about 10 °C. More preferably, the compositions are maintained at a temperature of about 5 °C, i.e. at about refrigerated temperatures and conditions.
- the amount of daptomycin included in the compositions of the present in vention is generally in concentrations of from about 1 mg/mL to about 25 mg/mL. In another embodiment of the invention, the daptomycin concentration is from about 5 mg/mL to about 20 mg/mL. In yet another embodiment, the daptomycin concentration is from about 7.5 mg/mL to about 15 mg/mL. In a further embodiment of the invention, the daptomycin concentration is from about 10 mg/mL to about 15 mg/mL. Preferably, the daptomycin concentration is about 10 mg/mL.
- compositions of the present invention can also include an alkaline hydroxide selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide.
- the alkaline hydroxide is calcium hydroxide.
- the alkaline hydroxide concentration is from about 0.5 mg/nil to about 1 mg/ml.
- the alkaline hydroxide concentration is about 0.68 mg/ml.
- A. further embodiment of the invention includes long term storage stable daptomycin-containmg compositions which include:
- daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL;
- compositions have a pH of from about 6 to about 7; and have the same stability profiles as already described, i.e. having total impurities of less than about 10 %, less than about 5% AUC of the hydrolysis product of daptomycin, less than about 5% AUG of the ⁇ -isomer of daptomycin and less than about 5% AUC" of anhydro-daptomycin, area-under-the-curve (“AUC") as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223nm, after at least about 18 months storage at a temperature of from about 5 °C to about 25 °C.
- HPLC high performance liquid chromatography
- compositions in accordance with the present invention include:
- daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL;
- compositions in this embodiment have a pH of about 6.5.
- the stability profile is the same as previously mentioned, i.e. having less than about 10 % total impurities, etc.
- a further embodiment of the invention includes daptomycin-containing compositions having similar long term stability profiles, but includes:
- daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 rng/'mL; b) calcium chloride at a concentration of about 16.2 mg/niL; and
- Another embodiment of the invention includes methods of treating a daptomycm sensitive disease in mammals.
- the methods include administering, to a mammal in need thereof, an effective amount of a daptomyein-contaimng composition described herein. Since the active ingredient portion of the inventive compositions is an FDA-approved drug, those of ordinary skill will recognize that the doses of daptomycin employed in this aspect of the invention will be the similar to those employed in any treatment regimens designed for daptomycin as marketed under the trade name CubieinTM.
- the patient package insert containing dosing information is incorporated herein by reference.
- the methods of treatment also include administering the inventive formulations for any purpose or physical condition for which daptomycm has been indicated as being useful.
- Another embodiment of the invention includes methods of preparing daptomyein-contaimng compositions described herein.
- the methods include reconstituting lyophilized daptomycin to a concentration of less than or equal to about 25 rng/mL in a pharmacologically acceptable fluid including a source of calcium selected from among calcium chloride and calcium lactate, and adjusting the pH of the composition to about 6.0 to about 7.0.
- the steps are carried out under pharmaceutically acceptable conditions for sterility and manufacturing.
- the reconstitution of the daptomycin can also be carried out with the buffer and a sufficient amount of an aqueous solution.
- a further aspect of the invention there are provided methods of controlling or preventing the formation of impurities in daptomycin-containing compositions during long term storage.
- the methods include combining an amount of daptomycin or a pharmaceutically acceptable salt thereof with a sufficient amount of a pharmacologically acceptable fluid including a source of calcium selected from among calcium chloride and calcium lactate so that a formulation or composition is formed wherein the amount daptomycin or pharmaceutically acceptable salt thereof included therein is at a concentration of less than or equal to about 25 mg/ml and the pH of the resultant formulation is from about 6,0 to about 7.0.
- steps in accordance therewith include transferring one or more pharmaceutically acceptable doses of the formulations into a suitable scalable container and storing the sealed container at a temperature of from about 5 °C to about 25 °C.
- daptornyein-containing formulations having less than about, 10 % total impurities area-under-the- curve ("AUC") as determined by high performance liquid chromatography (“HPLC”) at a wa velength of 223nm, after at least about 18 months of storage at a temperature of from about 5 °C to about 25 °C.
- the method described herein provides compositions or formulations in which the less than about 10% total impurities is comprised of less than about 5% AUC of the hydrolysis product of daptomycin, less than about 5% AUC of the ⁇ -isomer of daptomycin and less than about 5% AUC of anhydro-daptomycm, based on the initial amount daptomycin included in the composition.
- compositions of the present invention can be packaged in any suitable sterile vial or container fit for the sterile storage of a pharmaceutical such as daptomycin.
- Suitable containers can be glass vials, polypropylene or polyethylene vials or other special purpose containers and be of a size sufficient to hold one or more doses of daptomycin.
- a further aspect of the invention includes a kit containing the daptornyein-containing
- the kit will contain at least one pharmaceutically acceptable vial or container containing one or more doses of the daptornyein-containing compositions as well as other pharmaceutically necessary materials for storing and/or administering the drug, including instructions for storage and use, infusion bag or container with normal saline or D5W , additional diluents, if desired, etc. in accordance with another aspect of the invention, there are provided long term storage stable daptornyein-containing compositions including:
- daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/niL; and b) an alkaline hydroxide selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide, in an amount sufficient to maintain the composition at a pH of from about 6 to about 7.
- Total impurities of the daptomycin-containing compositions are less than about 10 % area-under-the-curve ("AUC") as determined by high performance liquid
- the daptomycm-contaming compositions described herein are referred to as having total impurities of less than about 10 %, the compositions will further include less than about 5% AUC of the hydrolysis product of daptomycin, less than about 5% AUC of the ⁇ -isorner of daptomycm and less than about 5% AUC of anhydro-daptomycin (as calculated with reference to the original starting amount of daptomycin) after the same period of long term storage, i.e.
- the amount of alkaline hydroxide is sufficient to maintain a pH of from about 6.5 to about 6.75.
- the amount of alkaline hydroxide is sufficient to maintain a pH of about 6.75.
- daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/ ' niL;
- compositions have the same stability profiles as already described, i.e., having less than about 10 % area-under-the-curve (“AUC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223nm, after at least about 18 months storage at a temperature of from about 5 °C to about 25 C C.
- AUC area-under-the-curve
- HPLC high performance liquid chromatography
- the amino acid is selected from among arginine, glycine, alanine, valine, methionine and histidine. More preferably, the amino acid is arginine. In other aspects of the present invention, the amino acid is present in an amount sufficient to maintain the pH of the compositions in the ranges set forth above, i.e. from about 6.5 to about 6.75. Preferably, the amount of amino acid is sufficient to maintain a pH of about 6.75.
- the inventive compositions are maintained during storage and/or prior to use at a temperature of from abou t 5 °C to about 15 °C, Preferably, the compositions are maintained at a temperature of from about 5 °C to about 10 °C. More preferably, the compositions are maintained at a temperature of about 5 °C, i.e. about refrigerated conditions.
- the amount of daptomycin included in the compositions of the present invention is generally concentrations of from about 1 mg/mL to about 25 mg/mL. In another embodiment of the invention, the daptomycin concentration is from about 10 mg/mL to about 25 mg/mL.
- the daptomycin concentration is about 7.5 mg/mL to about 15 mg/mL.
- the daptomycin concentration is about 10 mg/mL.
- Some preferred embodiments of the invention include daptomycin-containing compositions in which the total amount of impurities is less than about 8 % and more preferably less than about 6% area-under-the-eurve (“ADC”) as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223nm after a storage period of about 18 months at a temperature of from about 5 °C to about 25 °C.
- ADC area-under-the-eurve
- HPLC high performance liquid chromatography
- compositions of the present invention can be self preserved to maintain stability and sterility.
- the compositions can include one or more art recognized stabilizers and/or preservatives in amounts generally recognized as being effective for such purposes.
- the stabilizer can be selected from among trehalose, sucrose and hetastarch.
- the stabilizer is trehalose.
- the stabilizer content is less than 4 g/mL.
- the stabilizer content is from about 10 mg/mL to about 200 mg/mL. More preferably, the stabilizer content is from about 10 mg/mL to about 50 mg/mL.
- the compositions include a tonicifying agent, in amounts which preferably render the composition isotonic or substantially isotonic.
- Some preferred tonicifying agents include glycerin, sodium chloride, polyethylene glycol (PEG) 400, propylene glycol or injectable grade polyvinylpyrrolidone (PVP). More preferably, the tonicifying agent is polyethylene glycol (PEG) 400.
- the tonicifying agent content in the compositions is about 2.5% (v/v) to about 5.0% (v/v).
- the tonicifying agent content is about, 5% (v/v).
- A. further embodiment of the invention includes long term storage stable daptomycin-containmg compositions which include:
- daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL;
- an alkaline hydroxide selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide, in an amount sufficient to maintain the composition at a pH of from about 6 to about 7;
- a further embodiment of the invention provides a long term storage stable daptomycin- containing compositions, including a pharmacologically acceptable fluid which includes:
- daptomycin or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg/mL;
- Another embodiment of the invention includes methods of treating daptomycin sensitive disease in mammals.
- the methods include administering, to a mamrnal in need thereof, an effective amount of daptomycin-containing compositions described herein.
- the methods of treatment also include administering the inventive formulations for any purpose or physical condition for which daptomycin has been indicated as being useful.
- kits including lyophilized daptomycin, and
- pharmacologically suitable fluids with calcium hydroxide in an amount sufficient, to maintain the composition at a pH of about 6.75, arginine in an amount sufficient to maintain the composition at a pH of about 6,75, and about 5% trehalose.
- kits include the lyophilizate of daptomycin and about 5% trehalose and a pharmacologically suitable fluid with calcium hydroxide in an amount sufficient to maintain the composition at a pH of about 6.75 and arginine in an amount sufficient to maintain the composition at a pH of about 6.75.
- a pharmacologically suitable fluid including alkaline hydroxides selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide, in an amount sufficient to maintain the composition at a pH of from about 6 to about 7 and/or an amino acid in an amount sufficient to maintain the pH of the composition at about 6 to about 7,
- the lyophilizate includes daptomycin and 5% trehalose.
- the pharmacologically suitable fluid also contains trehalose.
- a pharmacologically suitable fluid including alkaline hydroxides selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide, in an amount sufficient to maintain the composition at a pH of from about 6 to about 7 and/or an amino acid in an amount sufficient to maintain the pH of the composition at about 6 to about 7 so that a formulation or composition is formed wherein the amount daptomycin or pharmaceutically acceptable salt thereof included therein is at a concentration of less than or equal to about 25 mg/rnl.
- Further optional steps in accordance therewith include transferring one or more pharmaceutically acceptable doses of the formulations into a suitable scalable container and storing the sealed container at, a temperature of from about 5 °C to about 25 °C.
- AUC area-under-the-curve
- HPLC high performance liquid chromatography
- compositions or formulations in which the less than about 10% total impurities is comprised of less than about 5% AUG of the hydrolysis product of daptomycin, less than about 5% AUC" of the ⁇ -isomer of daptomycin and less than about 5% AUG of anhydro-daptomycm, based on the initial amount daptomycin included in the composition.
- compositions of the present invention can be packaged in any suitable sterile vial or container fit for the sterile storage of a pharmaceutical such as daptomycin.
- Suitable containers can be glass vials, polypropylene or polyethylene vials or other special purpose containers and be of a size sufficient to hold one or more doses of daptomycin.
- a further aspect of the in vention includes a kit containing the daptomycin-containing
- the kit will contain at least one pharmaceutically acceptable vial or container containing one or more doses of the daptomycin-containing compositions as well as other pharmaceutically necessary materials for storing and/or administering the drug, including instructions for storage and use, infusion bag or container with normal saline or D 5 W, additional diluents, if desired, etc.
- Daptomycin-containing compositions were prepared by dissolving daptomyein in distilled water to obtain a daptomyein concentration of 10 mg/mL.
- the "control” sample was prepared by adding a sufficient amount ofNaOH to obtain a pH of 6,75.
- the "Ca(OH) 2 " sample was prepared by adding a sufficient amount of a 0,5% Ca(OH) 2 dispersion to obtain a pH of 6.75,
- the "arginine” sample was prepared by adding a sufficient amount of arginine to obtain a pil of 6.75.
- the "5% Trehalose” sample was prepared by adding Trehalose to a sample prepared in the same manner as the control to obtain a 5% (v/v) solution.
- the "5% PEG 400” sample was prepared by adding PEG 400 to a sample prepared in the same manner as the control to obtain a 5% (v/v) solution. The samples were stored at 5 °C.
- the samples were tested for impurities after initial preparation, and again as indicated in Table 1.
- the samples were tested via UPLC at a wavelength of 223nm, and the amount of daptomyein in the initial sample and the area % for ring opening products, ⁇ -daptomycin and total degradants were measured obtain the area-under-the-cirrve ("AUC") after storage.
- AUC area-under-the-cirrve
- the area % of total degradants was used to determine the change in area %.
- the test data is reported in Table 1 below.
- the daptomycin formulations are stable in solutions containing calcium hydroxide.
- Table 1 shows that daptomycin, when reconstituted at a concentration of about 10 mg/mL, in a solution containing an alkaline hydroxide, such as calcium hydroxide, in an amount sufficient to maintain the composition at a pH of about 6.75, and stored at 5 °C, had substantially no increase in total degradants.
- Table 1 shows that the samples formulated with an alkaline hydroxide, such as calcium hydroxide, in an amount sufficient to maintain the composition at a pH of about 6.75, had 1.46% total impurities after 4 months analysis at 5 °C.
- the data presented in Table 1 translates to daptomycin-containing compositions including an alkaline hydroxide having a shelf life of at least about 18 months under refrigerated conditions with levels of impurities within the levels required herein.
- the daptomvcin formulations are also stable in solutions containing arginine.
- the 5% trehalose solution also provided sufficient long-term stabilizing effects.
- Table 1 shows that the formulations made with arginine and trehalose had less than a 3% increase in total degradants at the end of four months analysis at 5°C.
- the data presented in Table 1 translates to daptomycin- containing compositions including an amino acid, or trehalose having a shelf life of at least about 18 months under refrigerated conditions with levels of impurities within the levels required herein.
- control sample which was pH adjusted with NaOH, and the sample containing PEG 400 did not provide such stabilizing effects.
- These samples exhibited an increase of more than 3.5% total degradant peak area compared to initial after 4 months analysis at, 5 °C. Daptomycin-containing compositions with such high levels of degradation would not, be suitable for long-term storage.
- Daptomycm-containing compositions were prepared by dissolving daptomycin ("DPT") in distilled water to obtain a daptomycin concentration of 10 mg/mL and by adding a sufficient amount of a 0.5% Ca(OH) 2 dispersion to obtain a pH of 6.75 or 6.5 as indicated in Table 2. The samples were stored at the temperatures indicated in Table 2 below.
- DPT daptomycin
- the Ca(OH) 2 stabilized the daptomyem-contairting solutions between pH 6.5 and 6.75.
- the area % of the total impurities increased about 0.95% at a pH of 6.75 over three months analysis at 5 °C. Such an increase projects a shelf-life of about 24 months under refrigerated conditions within the levels required herein.
- the area % of the total impurities increased about 2.04% at a pH of 6.5 over three months analysis at 5 °C, which projects a shelf-life of about 18 months under refrigerated conditions with levels of impurities within the levels required herein.
- Daptomycin-containing compositions were prepared by dissolving daptomycm ("DPT") in distilled water to obtain a daptomycin concentration of 10 mg/mL and by adding a filtrate of a 0.7 mg/rnl Mg(OH) 2 solution. 0.1M Ca(OH) 2 was added to the solutions to obtain a pH as indicated in Table 3. The samples were stored at the temperatures indicated in Table 3 below.
- DPT daptomycm
- the area % of the total impurities increased about 1.82% over three months storage and 3.1 8% after six months storage at 5 °C at a pH of 6.5, which also projects a shelf-life of about 1 8 months. It can be seen that these formulations are also therefore within the scope of the invention since they are expected to have long term stability and low r levels of impurities when stored for the time periods of at least about 18 months at temperatures below 25 °C.
- DPT Daptornyein
- Samples were tested for impurities after initial preparation, and at times indicated in Table 4 below.
- the samples were tested via HPLC, at a wavelength of 223nm, and the amount of daptornyein in the initial sample and the relative retention times ("RRT") for each of the hydrolysis product of daptornyein (0.66), the ⁇ -isomer of daptornyein (0.97) and anhydro- daptomycin (1.1 ) were added to obtain the total impurities area-under-the-curve (“AUC”) after storage.
- RRT relative retention times
- the sample with Ca(OH) 2 , CaCl 2 and pH 6.75 with NaOH exhibited an increase in the area % of the total impurities of about, 1.93% over three months analysis and 2.16% over five months analysis at, 5 °C. Such an increase projects a shelf-life of about 18 months under refrigerated conditions with levels of impurities within the levels required herein. This sample also exhibited little fluctuation in pH.
- the sample with Ca(OH) 2 and pH 7 with NaOH exhibited an increase in the area % of the total impurities of about 2.46% over three months storage and 3.98 % over five months storage at 5 °C.
- the sample with Ca(OH) 2 and pH 6.75 with NaOH exhibited an increase in the area % of the total impurities of about 2.4% over three months storage and 3.5% over five months storage at 5 °C.
- the sample with Ca(OH) 2 , Trehalose and pH 6.75 with NaOH exhibited an increase in the area % of the total impurities of about 2.51% over three months storage and 3.55% over five months storage at 5 °C. Daptomycin-containing compositions with such high levels of degradation would not be suitable for long-term storage.
- DPT Daptornyein
- Samples were tested for impurities after initial preparation, and at times indicated in Table 5.
- the samples were tested via UPLC, at a wavelength of 223nrn, and the amount of daptornyein in the initial sample and the relative retention times ("RRT") for each of the hydrolysis product of daptornyein (0.66), the ⁇ -isoraer of daptornyein (0.97) and anhydro-daptomvcm (1.1 ) were added to obtain the total impurities area-under-the-curve ("AUC”) after storage.
- RRT relative retention times
- the daptomycin-containing formulations including greater than 1 mg/mi CaCl;> and having a pH adjusted to about 6.75 with NaOH exhibited long-term storage stability.
- the area % of the total impurities increased about 1.34% at a pH of 6.75 over three months analysis at, 5 °C in the formulation including 4 mg/ml CaCl 2 .
- the area % of the total impurities increased about 0.94% at a pH of 6.75 over three months analysis at 5 °C in the formulation including 8 mg/ml CaCl 2 .
- the area % of the total impurities increased about 1.06% at a pH of 6.75 over three months analysis at 5 °C in the formulation including 12 mg/ml CaCl 2 .
- Such increases project a shelf-life of at least about, 24 months under refrigerated conditions with levels of impurities within the levels required herein. Additionally, these three samples exhibited limited fluctuation of pH.
- the area % of the total impurities increased about 4.34% at a pH of 6.75 over three months analysis at 5 °C in the formulation including 0.5 mg/ml CaCl 2 .
- the area % of the total impurities increased about 3.8% at a pH of 6.75 over three months analysis at 5 °C in the formulation including 1 mg/ml CaCl 2 .
- Daptomycin-containing compositions with such high levels of degradation would not be suitable for long-term storage.
- Daptomycin (“DPT") was dissolved in distilled water to obtain a daptomycin concentration of 10 mg/mL. Calcium chloride was added to the daptomycin-containing solution to obtain a concentration of 1.5 mg/mi calcium chloride. The pH was adjusted with 1 N NaOH as indicated in Table 6. The volume of the solution was adjusted to ImL with water. The samples were stored at the temperatures indicated in Table 6 below.
- Samples were tested for impurities after initial preparation, and as indicated in Table 6.
- the samples were tested via HPLC, at a wavelength of 223nm, and the amount of daptomycin in the initial sample and the relative retention times ("RRT") for each of the hydrolysis product of daptomycin (0.66), the ⁇ -isomer of daptomycm (0.97) and anhydro-daptomycin (1.1) were added to obtain the total impurities area-under-the-curve (“AUC”) after storage.
- RRT relative retention times
- the daptomycin-containing formulations including greater than 1 mg/ml CaCl 2 and having a pH adjusted to about 6.0 to 7.0 with NaOH exhibited long-term storage stability.
- the area % of the total impurities increased about 1.11 % over one month analysis at 5 °C at a pH of 6.0.
- the area % of the total impurities increased about, 1.03% over one month analysis at, 5 °C at, a pH of 6.25,
- the area % of the total impurities increased about 0.91% over one month analysis at 5 °C at a pH of 6.5.
- the area % of the total impurities increased about, 0.78% over one month analysis at 5 °C at a pH of 7.
- Daptomycin (“DPT) was dissolved in 0.1 M calcium lactate to obtain a daptomycin
- the daptomyem-containing formulations including O. IM calcium lactate and having a pH adjusted to about 6.5 with NaOH exhibited long-term storage stability.
- the area % of the total impurities increased about 1.81 % over three months analysis and 2.22% over four months analysis at 5 °C in the formulation including 0.3 M calcium lactate and having a pH adjusted to about 6.5 with NaOH.
- Such an increase projects a shelf-life of about 1 8 months under refrigerated conditions with le vels of impurities within the levels required herein.
- the area % of the total impurities increased about 2.93% over three months analysis and 3.41% over four months storage at 5 °C in the formulation including O. IM calcium lactate and having a pH adjusted to about 6.25 with NaOH. Daptomycin-containing compositions with such high levels of degradation would not be suitable for long-term storage.
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Abstract
Long term storage stable daptomycin-containing compositions are disclosed. The compositions include a pharmacologically acceptable fluid including daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL, and a calcium source. The formulations are surprisingly free of degradation products such as the hydrolysis product of daptomycin, the β-isomer of daptomycin and anhydro daptomycin after storage periods of at least about 18 months under refrigerated conditions.
Description
FORMULATIONS OF DAFTOMYCIN CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under under 35 U.S.C. §119(e) to U.S. Provisional Patent, Application No. 61/263,695, filed November 23, 2009, entitled "FORMULATIONS OF DAFTOMYCIN", and U.S. Provisional Patent Application No. 61/371,802, filed August 9, 2010, entitled "FORMULATIONS OF DAFTOMYCIN", the disclosures of each of which are incorporated by reference herein in their entirety.
BACKGROUND OF THE INVENTION
Daptomycin is a lipopeptide antibiotic represented by the following structural formula (I)
and is described, for example, in U.S. Patent No. 4,537,717, the contents of which are incorporated herein by reference.
Daptomycin is used in the treatment of Methicillm-resistant Staphylococcus aureus (MRSA) and Methiciliin-susceptible Staphylococcus aureus (MSSA), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies equisirnilis, and Ertiero coccus faecal is
(vancomycin-susceptible isolates only) in complicated skin infections and bloodstream infections (bacteremia), including right-sided infective endocarditis. Daptomycin is commercially available as Cubicin™ for intravenous administration.
Daptomycin exhibits premature degradation upon reeonstitution of the lyophilized product. The reconstituted daptomycin exhibits increased degradation after reeonstitution and is, therefore, not suitable for long-term storage in liquid form. Some of the main degradants of daptomycin are the hydrolysis product of daptomycin, the β-isomer of daptomycin and anhydro daptomycin. The hydrolysis product, (ring opening compound) appears as the main impurity at a Relative Retention Time (RRT) of about, 0.66, the β-isomer of daptomycm appears as the main impurity at an R RT of about 0.97 and anhydro daptomycin appears as the main impurity at an RRT of about 1.1. There is a need for daptomycin formulations with increased stability.
SUMMARY OF THE INVENTION
The invention is generally directed to daptomycin-containing compositions that are long term storage stable, i.e. for a period of at least about 18 months or longer. In several aspects of the invention, the compositions include a source of calcium selected from among calcium chloride and calcium lactate and the concentration of daptomycin will be less than or equal to about 25 mg/mL. In other aspects of the invention, the compositions will have a pH of from about 6 to about 7. In other aspects of the invention, the compositions will include an alkaline hydroxide selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide. Still further aspects of the invention include methods of treatment, methods of preparing the compositions and kits.
In other aspects of the invention, the compositions will include an amino acid in an amount sufficient to maintain the pH of the composition at about 6 to about 7. In other aspects of the invention, the compositions will include trehalose.
One of the advantages of the inventive liquid compositions is that they are substantially free of impurities after at least 18 months. Substantially free of impurities refers to daptomycin-
containing compositions in which total impurities are less than about 10 %, including less than about 5% of the hydrolysis product of daptomycin, less than about 5% of the β-isomer of daptomyein and less than 5% of anhydro-daptomycin, area-under-the-curve ("AUG") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223nm, after a period of at least about 18 months at a temperature of from about 5 °C to about, 25 °C. The formulations are ready for use or further dilution; storage as a lyophilized powder is no longer a necessity for commercial use of the drug.
DETAILED DESCRIPTION OF THE INVENTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
As used herein, RRT is calculated by dividing the retention time of the peak of interest by the retention time of the main peak. Any peak with an RRT <1 elutes before the main peak, and any peak with an RRT >1 elutes after the main peak.
As used herein, substantially free of impurities refers to daptomycm-containing compositions in which the total impurities are less than about 10 %, calculated as being based upon the original amount daptomycin (or salt thereof) being present in the composition or formulation. Preferably, the total amount of impurities, i.e. > 10% includes less than about 5%, i.e. no more than about 1/3 thereof, of the hydrolysis product of daptomycin, less than about 5%, i.e. no more than about 1/3 thereof, of the β-isomer of daptomycin and less than 5%, i.e. no more than about 1/3 thereof, of anhydro-daptomycin. The amounts of impurities are calculated under-the-curve ("AUG") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223 nm, after storage periods of at least about 18 months at a temperature of from about 5 °C to about 25 °C. In preferred aspects the amount of time the compositions demonstrate long term storage stability is at least about 2 years.
In accordance with one aspect of the invention, there are provided long term storage stable daptomycin-containing compositions, including:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL; and
b) a source of calcium selected from among calcium chloride and calcium lactate. The compositions ha ve a pH of from about 6 to about 7, and total impurities are less than about 10 % area-under-the-curve (''AUG") as determined by high performance liquid chromatography ("HPLC") at, a wavelength of 223nm, after at least about 18 months storage at a temperature of from about 5 °C to about 25 °C.
In most of the embodiments described herein, it will be understood that when the daptomycin- containing compositions described herein are referred to as having total impurities of less than about 10 %, the compositions will iiirther include less than about 5% of the hydrolysis product of daptomycin, less than about 5% of the β-isomer of daptomycin and less than 5% of anhydro- daptomycm (as calculated with reference to the original starting amount of daptomycin) after the same period of long term storage, i.e. about 18 months or longer under the conditions mentioned herein.
In some aspects of the invention, the source of calcium is calcium chloride. In some
embodiments, the amount of calcium chloride is greater than 1 nig/'mL. In other aspects of the invention, the concentration of calcium chloride is from about 1.5 nig/'mL to about 17 mg/mL. In one embodiment, the concentration of calcium chloride is from about 4 mg/mL to about 16.2 mg/mL. In another embodiment, the concentration of calcium chloride is from about 8 mg/mL to about 12 mg/mL. Some preferred concentrations of calcium chloride include, for example, 8 mg/mL, 12 mg/mL or 16.2 mg/mL.
In other aspects of the invention, the source of calcium is calcium lactate. In some aspects, the calcium lactate concentration is about 0.05M to about 0.3M. Preferably, the concentration of calcium lactate is about 0.1M to about 0.25M. More preferably, the concentration of calcium lactate is about 0.1M.
The compositions of the present invention can be kept at a pH of from about 6,25 to about 6.75, Preferably, the composition is maintained at a pH of from about 6.5 to about 6.75. In one embodiment, the pH is about 6.5. In another embodiment, the pH is about 6.75.
In other aspects of the invention, the long term storage stable daptomycin-containing compositions include a pH adjusting agent which is present in an amount sufficient to adjust the pH of the compositions to the ranges set forth above, i.e. from about 6.25 to about 6.75, or to specific points in between such as about 6.5 or about 6.75. One preferred pH adjusting agent is sodium hydroxide. Another preferred pH adjusting agent is calcium hydroxide. Alternative pH adjusters are those commonly used in the art, including HC1 and TRIS.
Without meaning to be bound by any theory or hypothesis, it is been surprisingly found that daptomycin is predominantly ionized at pHs of from about 6.5 to about 7.0. As a result the molecule is considerably more stable and thus self association and degradation thereof is unexpectedly and substantially reduced for extended periods of time.
In some aspects of the invention, the inventive compositions are maintained during storage and/ or prior to use at a temperature of from about 5 °C to about 15 °C. In another embodiment, the compositions are maintained at a temperature of from about 5 °C to about 10 °C. More preferably, the compositions are maintained at a temperature of about 5 °C, i.e. at about refrigerated temperatures and conditions.
The amount of daptomycin included in the compositions of the present in vention is generally in concentrations of from about 1 mg/mL to about 25 mg/mL. In another embodiment of the invention, the daptomycin concentration is from about 5 mg/mL to about 20 mg/mL. In yet another embodiment, the daptomycin concentration is from about 7.5 mg/mL to about 15 mg/mL. In a further embodiment of the invention, the daptomycin concentration is from about 10 mg/mL to about 15 mg/mL. Preferably, the daptomycin concentration is about 10 mg/mL.
The compositions of the present invention can also include an alkaline hydroxide selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide. Preferably, the
alkaline hydroxide is calcium hydroxide. In some aspects, the alkaline hydroxide concentration is from about 0.5 mg/nil to about 1 mg/ml. Preferably, the alkaline hydroxide concentration is about 0.68 mg/ml.
Without meaning to be bound by any theory or hypothesis, it is thought that, the presence of a counter ion, i.e., calcium source, alkaline hydroxide, amino acid, stabilizes daptomycin and slows down degradation.
A. further embodiment of the invention includes long term storage stable daptomycin-containmg compositions which include:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL; and
b) calcium chloride at a concentration of greater than 1 mg/mL. These compositions have a pH of from about 6 to about 7; and have the same stability profiles as already described, i.e. having total impurities of less than about 10 %, less than about 5% AUC of the hydrolysis product of daptomycin, less than about 5% AUG of the β-isomer of daptomycin and less than about 5% AUC" of anhydro-daptomycin, area-under-the-curve ("AUC") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223nm, after at least about 18 months storage at a temperature of from about 5 °C to about 25 °C.
Other compositions in accordance with the present invention include:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL; and
b) 0.1 M calcium lactate. Unlike the pH ranges recited immediately above, the compositions in this embodiment have a pH of about 6.5. The stability profile is the same as previously mentioned, i.e. having less than about 10 % total impurities, etc.
A further embodiment of the invention includes daptomycin-containing compositions having similar long term stability profiles, but includes:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 rng/'mL;
b) calcium chloride at a concentration of about 16.2 mg/niL; and
c) calcium hydroxide. The pH of these compositions is from about 6 to about 7 and the impurity profile is the same as that mentioned above.
Another embodiment of the invention includes methods of treating a daptomycm sensitive disease in mammals. The methods include administering, to a mammal in need thereof, an effective amount of a daptomyein-contaimng composition described herein. Since the active ingredient portion of the inventive compositions is an FDA-approved drug, those of ordinary skill will recognize that the doses of daptomycin employed in this aspect of the invention will be the similar to those employed in any treatment regimens designed for daptomycin as marketed under the trade name Cubiein™. The patient package insert containing dosing information is incorporated herein by reference. The methods of treatment also include administering the inventive formulations for any purpose or physical condition for which daptomycm has been indicated as being useful.
Another embodiment of the invention includes methods of preparing daptomyein-contaimng compositions described herein. The methods include reconstituting lyophilized daptomycin to a concentration of less than or equal to about 25 rng/mL in a pharmacologically acceptable fluid including a source of calcium selected from among calcium chloride and calcium lactate, and adjusting the pH of the composition to about 6.0 to about 7.0. The steps are carried out under pharmaceutically acceptable conditions for sterility and manufacturing. The reconstitution of the daptomycin can also be carried out with the buffer and a sufficient amount of an aqueous solution.
In a further aspect of the invention, there are provided methods of controlling or preventing the formation of impurities in daptomycin-containing compositions during long term storage. The methods include combining an amount of daptomycin or a pharmaceutically acceptable salt thereof with a sufficient amount of a pharmacologically acceptable fluid including a source of calcium selected from among calcium chloride and calcium lactate so that a formulation or composition is formed wherein the amount daptomycin or pharmaceutically acceptable salt thereof included therein is at a concentration of less than or equal to about 25 mg/ml and the pH
of the resultant formulation is from about 6,0 to about 7.0. Further optional steps in accordance therewith include transferring one or more pharmaceutically acceptable doses of the formulations into a suitable scalable container and storing the sealed container at a temperature of from about 5 °C to about 25 °C. As a result of carrying out these steps, it is possible to control or substantially prevent the formation of impurities which otherwise occur with daptornyein- containing compositions during long term storage so that the artisan is provided with
daptornyein-containing formulations having less than about, 10 % total impurities area-under-the- curve ("AUC") as determined by high performance liquid chromatography ("HPLC") at a wa velength of 223nm, after at least about 18 months of storage at a temperature of from about 5 °C to about 25 °C. The method described herein provides compositions or formulations in which the less than about 10% total impurities is comprised of less than about 5% AUC of the hydrolysis product of daptomycin, less than about 5% AUC of the β-isomer of daptomycin and less than about 5% AUC of anhydro-daptomycm, based on the initial amount daptomycin included in the composition.
The compositions of the present invention can be packaged in any suitable sterile vial or container fit for the sterile storage of a pharmaceutical such as daptomycin. Suitable containers can be glass vials, polypropylene or polyethylene vials or other special purpose containers and be of a size sufficient to hold one or more doses of daptomycin.
A further aspect of the invention includes a kit containing the daptornyein-containing
compositions described herein. As will be appreciated by those of ordinary skill, the kit will contain at least one pharmaceutically acceptable vial or container containing one or more doses of the daptornyein-containing compositions as well as other pharmaceutically necessary materials for storing and/or administering the drug, including instructions for storage and use, infusion bag or container with normal saline or D5W , additional diluents, if desired, etc. in accordance with another aspect of the invention, there are provided long term storage stable daptornyein-containing compositions including:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/niL; and
b) an alkaline hydroxide selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide, in an amount sufficient to maintain the composition at a pH of from about 6 to about 7. Total impurities of the daptomycin-containing compositions are less than about 10 % area-under-the-curve ("AUC") as determined by high performance liquid
chromatography ("HPLC") at a wavelength of 223nm, after storage for at least, about, 18 months at a temperature of from about, 5 °C to about 25 °C. As with the embodiments described above, it will be understood that when the daptomycm-contaming compositions described herein are referred to as having total impurities of less than about 10 %, the compositions will further include less than about 5% AUC of the hydrolysis product of daptomycin, less than about 5% AUC of the β-isorner of daptomycm and less than about 5% AUC of anhydro-daptomycin (as calculated with reference to the original starting amount of daptomycin) after the same period of long term storage, i.e. about 18 months or longer under the conditions mentioned herein. in some aspects of the invention, the amount of alkaline hydroxide is sufficient to maintain a pH of from about 6.5 to about 6.75. Preferably, the amount of alkaline hydroxide is sufficient to maintain a pH of about 6.75. in accordance with yet another aspect of the in vention, there are provided long term storage stable daptomycin-containing compositions including:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/'niL; and
b) an amino acid in an amount sufficient to maintain the pH of the composition at about 6 to about 7. These compositions have the same stability profiles as already described, i.e., having less than about 10 % area-under-the-curve ("AUC") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223nm, after at least about 18 months storage at a temperature of from about 5 °C to about 25 CC.
In some aspects of the invention, the amino acid is selected from among arginine, glycine, alanine, valine, methionine and histidine. More preferably, the amino acid is arginine.
In other aspects of the present invention, the amino acid is present in an amount sufficient to maintain the pH of the compositions in the ranges set forth above, i.e. from about 6.5 to about 6.75. Preferably, the amount of amino acid is sufficient to maintain a pH of about 6.75.
In some aspects of the invention, the inventive compositions are maintained during storage and/or prior to use at a temperature of from abou t 5 °C to about 15 °C, Preferably, the compositions are maintained at a temperature of from about 5 °C to about 10 °C. More preferably, the compositions are maintained at a temperature of about 5 °C, i.e. about refrigerated conditions.
The amount of daptomycin included in the compositions of the present invention is generally concentrations of from about 1 mg/mL to about 25 mg/mL. In another embodiment of the invention, the daptomycin concentration is from about 10 mg/mL to about 25 mg/mL.
Alternatively, it can be from about 5 mg/mL to about 20 mg/mL. In yet another embodiment, the daptomycin concentration is about 7.5 mg/mL to about 15 mg/mL. Preferably, the daptomycin concentration is about 10 mg/mL.
Some preferred embodiments of the invention include daptomycin-containing compositions in which the total amount of impurities is less than about 8 % and more preferably less than about 6% area-under-the-eurve ("ADC") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223nm after a storage period of about 18 months at a temperature of from about 5 °C to about 25 °C.
The compositions of the present invention can be self preserved to maintain stability and sterility. Alternatively, the compositions can include one or more art recognized stabilizers and/or preservatives in amounts generally recognized as being effective for such purposes. The stabilizer can be selected from among trehalose, sucrose and hetastarch. Preferably, the stabilizer is trehalose. In some aspects of the invention, the stabilizer content is less than 4 g/mL. Preferably, the stabilizer content is from about 10 mg/mL to about 200 mg/mL. More preferably, the stabilizer content is from about 10 mg/mL to about 50 mg/mL.
In other aspects of the invention, the compositions include a tonicifying agent, in amounts which preferably render the composition isotonic or substantially isotonic. Some preferred tonicifying agents include glycerin, sodium chloride, polyethylene glycol (PEG) 400, propylene glycol or injectable grade polyvinylpyrrolidone (PVP). More preferably, the tonicifying agent is polyethylene glycol (PEG) 400. In some aspects of the invention, the tonicifying agent content in the compositions is about 2.5% (v/v) to about 5.0% (v/v). Preferably, the tonicifying agent content is about, 5% (v/v).
A. further embodiment of the invention includes long term storage stable daptomycin-containmg compositions which include:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL;
b) an alkaline hydroxide selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide, in an amount sufficient to maintain the composition at a pH of from about 6 to about 7; and
c) an amino acid in an amount sufficient to maintain the pH of the composition at about 6 to about 7. The stability profile is the same as previously mentioned, i.e. having less than about 30 % total impurities, etc.
A further embodiment of the invention provides a long term storage stable daptomycin- containing compositions, including a pharmacologically acceptable fluid which includes:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg/mL;
b) calcium hydroxide in an amount sufficient to maintain the composition at a pH of about 6.75;
c) arginine in an amount sufficient to maintain the composition at a pH of about 6.75; and
d) 5% trehalose. The impurity profile is the same as that mentioned above.
Another embodiment of the invention includes methods of treating daptomycin sensitive disease in mammals. The methods include administering, to a mamrnal in need thereof, an effective
amount of daptomycin-containing compositions described herein. As described above, the methods of treatment also include administering the inventive formulations for any purpose or physical condition for which daptomycin has been indicated as being useful.
Another aspect of the invention provides kits including lyophilized daptomycin, and
pharmacologically suitable fluids with calcium hydroxide in an amount sufficient, to maintain the composition at a pH of about 6.75, arginine in an amount sufficient to maintain the composition at a pH of about 6,75, and about 5% trehalose.
Lyophilizates of daptomycin and about 5% trehalose are provided in another embodiment of the invention, in a further embodiment, kits include the lyophilizate of daptomycin and about 5% trehalose and a pharmacologically suitable fluid with calcium hydroxide in an amount sufficient to maintain the composition at a pH of about 6.75 and arginine in an amount sufficient to maintain the composition at a pH of about 6.75. in a further embodiment of the invention, there are provided methods of preparing daptomycm- containing compositions including reconstituting lyophilized daptomycin, to a concentration of less than or equal to about 25 mg/mL in a pharmacologically suitable fluid including alkaline hydroxides selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide, in an amount sufficient to maintain the composition at a pH of from about 6 to about 7 and/or an amino acid in an amount sufficient to maintain the pH of the composition at about 6 to about 7, In some aspects the lyophilizate includes daptomycin and 5% trehalose. In other aspects of the invention, the pharmacologically suitable fluid also contains trehalose. The steps are carried out under pharmaceutically acceptable conditions for sterility and manufacturing. The reconstitution of the daptomycin can also be carried out with the buffer and a sufficient amount of an aqueous solution.
In a further aspect of the invention, there are provided methods of controlling or preventing the formation of impurities in daptomycin-containing compositions during long term storage. The methods include combining an amount of daptomycin or a pharmaceutically acceptable salt thereof with a sufficient amount of a pharmacologically suitable fluid including alkaline
hydroxides selected from among calcium hydroxide, magnesium hydroxide and aluminum hydroxide, in an amount sufficient to maintain the composition at a pH of from about 6 to about 7 and/or an amino acid in an amount sufficient to maintain the pH of the composition at about 6 to about 7 so that a formulation or composition is formed wherein the amount daptomycin or pharmaceutically acceptable salt thereof included therein is at a concentration of less than or equal to about 25 mg/rnl. Further optional steps in accordance therewith include transferring one or more pharmaceutically acceptable doses of the formulations into a suitable scalable container and storing the sealed container at, a temperature of from about 5 °C to about 25 °C. As a result of carrying out these steps, it is possible to control or substantially prevent the formation of impurities which otherwise occur with daptomycin-containing compositions during long term storage so that the artisan is provided with daptomycin-containing formulations having less than about 10 % total impurities area-under-the-curve ("AUC") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223nm, after at least about 18 months of storage at a temperature of from about 5 °C to about 25 °C. The method described herein provides compositions or formulations in which the less than about 10% total impurities is comprised of less than about 5% AUG of the hydrolysis product of daptomycin, less than about 5% AUC" of the β-isomer of daptomycin and less than about 5% AUG of anhydro-daptomycm, based on the initial amount daptomycin included in the composition.
The compositions of the present invention can be packaged in any suitable sterile vial or container fit for the sterile storage of a pharmaceutical such as daptomycin. Suitable containers can be glass vials, polypropylene or polyethylene vials or other special purpose containers and be of a size sufficient to hold one or more doses of daptomycin.
A further aspect of the in vention includes a kit containing the daptomycin-containing
compositions described herein. As will be appreciated by those of ordinary skill, the kit will contain at least one pharmaceutically acceptable vial or container containing one or more doses of the daptomycin-containing compositions as well as other pharmaceutically necessary materials for storing and/or administering the drug, including instructions for storage and use, infusion bag or container with normal saline or D5W, additional diluents, if desired, etc.
EXAMPLES
The following examples serve to provide further appreciation of the invention but are not meant in any way to restrict the effective scope of the invention.
Example 1
Daptomycin-containing compositions were prepared by dissolving daptomyein in distilled water to obtain a daptomyein concentration of 10 mg/mL. The "control" sample was prepared by adding a sufficient amount ofNaOH to obtain a pH of 6,75. The "Ca(OH)2" sample was prepared by adding a sufficient amount of a 0,5% Ca(OH)2 dispersion to obtain a pH of 6.75, The "arginine" sample was prepared by adding a sufficient amount of arginine to obtain a pil of 6.75. The "5% Trehalose" sample was prepared by adding Trehalose to a sample prepared in the same manner as the control to obtain a 5% (v/v) solution. The "5% PEG 400" sample was prepared by adding PEG 400 to a sample prepared in the same manner as the control to obtain a 5% (v/v) solution. The samples were stored at 5 °C.
The samples were tested for impurities after initial preparation, and again as indicated in Table 1. The samples were tested via UPLC at a wavelength of 223nm, and the amount of daptomyein in the initial sample and the area % for ring opening products, β-daptomycin and total degradants were measured obtain the area-under-the-cirrve ("AUC") after storage. The area % of total degradants was used to determine the change in area %. The test data is reported in Table 1 below.
As shown in Table 1 , the daptomycin formulations are stable in solutions containing calcium hydroxide. Table 1 shows that daptomycin, when reconstituted at a concentration of about 10 mg/mL, in a solution containing an alkaline hydroxide, such as calcium hydroxide, in an amount sufficient to maintain the composition at a pH of about 6.75, and stored at 5 °C, had substantially no increase in total degradants. Table 1 shows that the samples formulated with an alkaline hydroxide, such as calcium hydroxide, in an amount sufficient to maintain the composition at a pH of about 6.75, had 1.46% total impurities after 4 months analysis at 5 °C. The data presented
in Table 1 translates to daptomycin-containing compositions including an alkaline hydroxide having a shelf life of at least about 18 months under refrigerated conditions with levels of impurities within the levels required herein.
The daptomvcin formulations are also stable in solutions containing arginine. The 5% trehalose solution also provided sufficient long-term stabilizing effects. Table 1 shows that the formulations made with arginine and trehalose had less than a 3% increase in total degradants at the end of four months analysis at 5°C. The data presented in Table 1 translates to daptomycin- containing compositions including an amino acid, or trehalose having a shelf life of at least about 18 months under refrigerated conditions with levels of impurities within the levels required herein.
As shown in Table 1 , the control sample, which was pH adjusted with NaOH, and the sample containing PEG 400 did not provide such stabilizing effects. These samples exhibited an increase of more than 3.5% total degradant peak area compared to initial after 4 months analysis at, 5 °C. Daptomycin-containing compositions with such high levels of degradation would not, be suitable for long-term storage.
Example 2
Daptomycm-containing compositions were prepared by dissolving daptomycin ("DPT") in distilled water to obtain a daptomycin concentration of 10 mg/mL and by adding a sufficient amount of a 0.5% Ca(OH)2 dispersion to obtain a pH of 6.75 or 6.5 as indicated in Table 2. The samples were stored at the temperatures indicated in Table 2 below.
Samples were tested for impurities after initial preparation, and again as indicated in Table 2. The samples were tested via HPLC, at a wavelength of 223nm, and the amount of daptomycin in the initial sample and the relative retention times f'RRT") for each of the hydrolysis product of daptomycin (0.66), the β-isomer of daptomycin (0.97) and anhydro-daptomycin (1.1) were added to obtain the total impurities area-under-the-curve ("AUC") after storage. The test data is reported in Table 2 below.
Table 2-Stability of Daptomycin (10 mg/mL) in presence of Ca(OH)2
As shown in Table 2, the Ca(OH)2 stabilized the daptomyem-contairting solutions between pH 6.5 and 6.75. The area % of the total impurities increased about 0.95% at a pH of 6.75 over three months analysis at 5 °C. Such an increase projects a shelf-life of about 24 months under refrigerated conditions within the levels required herein.
The area % of the total impurities increased about 2.04% at a pH of 6.5 over three months analysis at 5 °C, which projects a shelf-life of about 18 months under refrigerated conditions with levels of impurities within the levels required herein.
Example 3
Daptomycin-containing compositions were prepared by dissolving daptomycm ("DPT") in distilled water to obtain a daptomycin concentration of 10 mg/mL and by adding a filtrate of a 0.7 mg/rnl Mg(OH)2 solution. 0.1M Ca(OH)2 was added to the solutions to obtain a pH as indicated in Table 3. The samples were stored at the temperatures indicated in Table 3 below.
Samples were tested for impurities after initial preparation, and at times indicated in Table 3. The samples were tested via HPLC, at a wavelength of 223nm, and the amount of daptomycin in the initial sample and the relative retention times ("RET") for each of the hydrolysis product of daptomycin (0.66), the β-isomer of daptomycin (0.97) and anhydro-daptomycin (1.1) were added to obtain the total impurities area-under-the-curve ("AUG") after storage. The test data is reported in Table 3 below.
Table 3 -Stability of Daptomycin (10 mg/mL) in presence of Mg(OH)2 and Ca(OH)2
As shown in Table 3, the addition of Mg(OH)2 stabilized the daptomycin-containing solutions between pH 6,5 and 6.75, The area % of the total impurities increased about 1.61% over three months storage and 2.61% after six months storage at 5 °C at a pH of 6.75. Such an increase projects a shelf-life of about 18 months under refrigerated conditions.
The area % of the total impurities increased about 1.82% over three months storage and 3.1 8% after six months storage at 5 °C at a pH of 6.5, which also projects a shelf-life of about 1 8 months.
It can be seen that these formulations are also therefore within the scope of the invention since they are expected to have long term stability and lowr levels of impurities when stored for the time periods of at least about 18 months at temperatures below 25 °C.
Example 4
Daptornyein ("DPT") was dissolved in distilled water to obtain a daptornyein concentration of 10 mg/mL and Ca( ΟH )2 was added to obtain a Ca(OH)2 concentration of 0.68 mg/ml. The pH was adjusted with 0.1N NaOH to obtain a pH as indicated in Table 4 below. Samples were made isotonic with the addition of calcium chloride dihydrate or trehalose dihydrate as indicated in Table 4 below. The samples were stored at the temperatures indicated in Table 4 below.
Samples were tested for impurities after initial preparation, and at times indicated in Table 4 below. The samples were tested via HPLC, at a wavelength of 223nm, and the amount of daptornyein in the initial sample and the relative retention times ("RRT") for each of the hydrolysis product of daptornyein (0.66), the β-isomer of daptornyein (0.97) and anhydro- daptomycin (1.1 ) were added to obtain the total impurities area-under-the-curve ("AUC") after storage. The test data is reported in Table 4 below.
Table 4-Stability of Daptomycin (10 mg/mL) in presence of Ca(OH)2 and NaOH, with and without Tonicifying Agents
As shown in Table 4, the sample with Ca(OH)2, CaCl2 and pH 6.75 with NaOH exhibited an increase in the area % of the total impurities of about, 1.93% over three months analysis and 2.16% over five months analysis at, 5 °C. Such an increase projects a shelf-life of about 18 months under refrigerated conditions with levels of impurities within the levels required herein. This sample also exhibited little fluctuation in pH.
The sample with Ca(OH)2 and pH 7 with NaOH exhibited an increase in the area % of the total impurities of about 2.46% over three months storage and 3.98 % over five months storage at 5 °C. The sample with Ca(OH)2 and pH 6.75 with NaOH exhibited an increase in the area % of the
total impurities of about 2.4% over three months storage and 3.5% over five months storage at 5 °C. The sample with Ca(OH)2, Trehalose and pH 6.75 with NaOH exhibited an increase in the area % of the total impurities of about 2.51% over three months storage and 3.55% over five months storage at 5 °C. Daptomycin-containing compositions with such high levels of degradation would not be suitable for long-term storage.
Example 5
Daptornyein ("DPT") was dissolved in distilled water to obtain a daptornyein concentration of 10 rng/nxL. Calcium chloride was added to the daptomycin-containing solution in amounts indicated in Table 5 below. The pH was adjusted to 6.75 with NaOH as indicated in Table 5 below. The volume of the solution was adjusted to ImL with water. The samples were stored at the temperatures indicated in Table 5 below.
Samples were tested for impurities after initial preparation, and at times indicated in Table 5. The samples were tested via UPLC, at a wavelength of 223nrn, and the amount of daptornyein in the initial sample and the relative retention times ("RRT") for each of the hydrolysis product of daptornyein (0.66), the β-isoraer of daptornyein (0.97) and anhydro-daptomvcm (1.1 ) were added to obtain the total impurities area-under-the-curve ("AUC") after storage. The test data is reported in Table 5 below.
As shown in Table 5, the daptomycin-containing formulations including greater than 1 mg/mi CaCl;> and having a pH adjusted to about 6.75 with NaOH exhibited long-term storage stability. The area % of the total impurities increased about 1.34% at a pH of 6.75 over three months analysis at, 5 °C in the formulation including 4 mg/ml CaCl2. The area % of the total impurities increased about 0.94% at a pH of 6.75 over three months analysis at 5 °C in the formulation including 8 mg/ml CaCl2. The area % of the total impurities increased about 1.06% at a pH of 6.75 over three months analysis at 5 °C in the formulation including 12 mg/ml CaCl2. Such increases project a shelf-life of at least about, 24 months under refrigerated conditions with levels of impurities within the levels required herein. Additionally, these three samples exhibited limited fluctuation of pH.
As shown in Table 5, the area % of the total impurities increased about 4.34% at a pH of 6.75 over three months analysis at 5 °C in the formulation including 0.5 mg/ml CaCl2. The area % of the total impurities increased about 3.8% at a pH of 6.75 over three months analysis at 5 °C in the formulation including 1 mg/ml CaCl2. Daptomycin-containing compositions with such high levels of degradation would not be suitable for long-term storage.
Example 6
Daptomycin ("DPT") was dissolved in distilled water to obtain a daptomycin concentration of 10 mg/mL. Calcium chloride was added to the daptomycin-containing solution to obtain a concentration of 1.5 mg/mi calcium chloride. The pH was adjusted with 1 N NaOH as indicated in Table 6. The volume of the solution was adjusted to ImL with water. The samples were stored at the temperatures indicated in Table 6 below.
Samples were tested for impurities after initial preparation, and as indicated in Table 6. The samples were tested via HPLC, at a wavelength of 223nm, and the amount of daptomycin in the initial sample and the relative retention times ("RRT") for each of the hydrolysis product of daptomycin (0.66), the β-isomer of daptomycm (0.97) and anhydro-daptomycin (1.1) were added
to obtain the total impurities area-under-the-curve ("AUC") after storage. The test data is reported in Table 6 below.
Table 6-Stability of Daptomycin (10 mg/niL) in presence of CaCl2 and NaOH
As shown in Table 6, the daptomycin-containing formulations including greater than 1 mg/ml CaCl2 and having a pH adjusted to about 6.0 to 7.0 with NaOH exhibited long-term storage stability.
The area % of the total impurities increased about 1.11 % over one month analysis at 5 °C at a pH of 6.0. The area % of the total impurities increased about, 1.03% over one month analysis at, 5 °C at, a pH of 6.25, The area % of the total impurities increased about 0.91% over one month analysis at 5 °C at a pH of 6.5. The area % of the total impurities increased about, 0.78% over one month analysis at 5 °C at a pH of 7. These increases are comparable to the increases obsen'ed in Example 6 above. Such increases project, a shelf-life of at, least about 18 months under refrigerated conditions with levels of impurities within the levels required herein.
Additionally, these samples exhibited limited fluctuation of pH.
Example 7
Daptomycin ("DPT") was dissolved in 0.1 M calcium lactate to obtain a daptomycin
concentration of 10 mg/mL. The pH was adjusted as indicated in Table 7 with I N NaOH. The samples were stored at the temperatures indicated in Table 7 below.
Samples were tested for impurities after initial preparation, and as indicated in Table 7. The samples were tested via HPLC, at a wavelength of 223nm, and the amount of daptomycin in the initial sample and the relative retention times ("RRT") for each of the hydrolysis product of daptomycin (0.66), the β-isomer of daptomycin (0.97) and anhydro-daptomycin (1.1) were added to obtain the total impurities area-under-the-curve ("AUG") after storage. The test data is reported in Table 7 below.
Table 7-Stability of Daptomycin (10 mg/mL) with 0.1M Calcium Lactate and IN NaOH
As shown in Table 7, the daptomyem-containing formulations including O. IM calcium lactate and having a pH adjusted to about 6.5 with NaOH exhibited long-term storage stability. The area % of the total impurities increased about 1.81 % over three months analysis and 2.22% over four months analysis at 5 °C in the formulation including 0.3 M calcium lactate and having a pH adjusted to about 6.5 with NaOH. Such an increase projects a shelf-life of about 1 8 months under refrigerated conditions with le vels of impurities within the levels required herein.
The area % of the total impurities increased about 2.93% over three months analysis and 3.41% over four months storage at 5 °C in the formulation including O. IM calcium lactate and having a pH adjusted to about 6.25 with NaOH. Daptomycin-containing compositions with such high levels of degradation would not be suitable for long-term storage.
Claims
1. A long term storage stable daptomycin-containing composition, comprising a pharmacologically acceptable fluid comprising:
a) daptornyein or a pharmaceutically acceptabl e salt thereof at a concentration of less than or equal to about 25 mg/mL; and
b) a source of calcium selected from the group consisting of calcium chloride and calcium, lactate;
said daptomycin-containing composition having a pH of from about 6 to about 7, and wherein total impurities are less than about 10 % area-under-the-curve ("AUG") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223nm, after at least about 18 months of storage at a temperature of from about 5 °C to about 25 °C.
2. The long term storage stable daptomycin-containing composition of claim 1 , wherein the less than about 10% total impurities include less than about 5% of the hydrolysis product of daptornyein, less than about 5% of the β-isomer of daptornyein and less than about 5% of anhydro- daptornyein based on the amount of daptornyein included in said composition.
3. The long term storage stable daptomycin-containing composition of claim 1 , wherein the source of calcium is calcium chloride, and the calcium chloride concentration is greater than 1 mg/ml.
4. The long term storage stable daptomycin-containing composition of claim 3, wherein the calcium chloride concentration is from about 1.5 mg/mL to about 17 mg/niL.
5. The long term storage stable daptomycin-containing composition of claim 4, wherein the calcium chloride concentration is from about 4 mg/mL to about 16.2 mg/mL.
6. The long term storage stable daptomycin-containing composition of claim 5, wherein the calcium chloride concentration is from about 8 mg/mL to about 12 mg/mL.
7. The long term storage stable daptomycin-containing composition of claim 6, wherein the calcium chloride concentration is about 8 mg/mL.
8. The long term storage stable daptomycin-containing composition of claim 6, wherein the calcium chloride concentration is about 12 mg/mL,
9. The long term storage stable daptomycin-containing composition of claim 5, wherein the calcium chloride concentration is about 16.2 mg/mL,
10. The long term storage stable daptomycin-containing composition of claim 1 , wherein the source of calcium is calcium lactate, and the calcium lactate concentration is about 0.05M to about 0.3 M.
11. The long term storage stable daptomycin-containing composition of claim 10, wherein the source of calcium is calcium lactate, and the calcium lactate concentration is about 0.1 M to about 0.25M.
12. The long term storage stable daptomycin-containing composition of claim 11 , wherein the source of calcium is calcium lactate, and the calcium lactate concentration is about 0.1M.
13. The long term storage stable daptomycin-containing composition of claim 1 , further comprising a pH adjusting agent.
14. The long term storage stable daptomycin-containing composition of claim 13, wherein the pH adjusting agent is selected from the group consisting of sodium hydroxide and calcium hydroxide,
15. The long term storage stable daptomycin-containing composition of claim 1 , wherein the pH of the composition is from about 6.25 to about 6.75.
16. The long term storage stable daptomycin-contaimng composition of claim 15, wherein the pH of the composition is from about 6.5 to about 6.75.
17. The long term storage stable daptomycin-containing composition of claim 16, wherein the pH of the composition is about 6.5,
18. The long term storage stable daptomycin-containing composition of claim 16, wherein the pH of the composition is about 6,75.
19. The long term storage stable daptomycin-containing composition of claim 1 , wherein the composition is maintained at a temperature of from about 5 °C to about 15 °C.
20. The long term storage stable daptomycin-containing composition of claim 19, wherein the composition is maintained at a temperature of from about 5 °C to about 10 °C.
21. The long term storage stable daptomycin-containing composition of claim 20, wherein the composition is maintained at a temperature of about 5 °C.
22. The long term storage stable daptomycin-containing composition of claim 1 , wherein the daptomycin concentration is from about 1 mg/mL to about 25 mg/mL.
23. The long term storage stable daptomycin-containing composition of claim 22, wherein the daptomycin concentration is from about 5 mg/mL to about 20 mg/mL.
24. The long term storage stable daptomycin-containing composition of claim 23, wherein the daptomycin concentration is from about 7.5 mg/mL- to about 15 mg/mL.
25. The long term storage stable daptomycin-containing composition of claim 24, wherein the daptomycin concentration is about 10 mg/mL.
26. The long term storage stable daptomycin-containing composition of claim 1 , wherein said long term storage is at least about 2 years.
27. The long term storage stable daptomycin-containing composition of claim 1 , further comprising an alkaline hydroxide selected from the group consisting of calcium hydroxide, magnesium hydroxide and aluminum hydroxide,
28. The long term storage stable daptomycin-containing composition of claim 27, wherein the alkaline hydroxide is calcium hydroxide at a concentra tion of about 0.5 mg/ml to about 1 mg/ml.
29. The long term storage stable daptomycin-containing composition of claim 28, wherein the calcium hydroxide concentration is about 0.68 mg/ml.
30. A long term storage stable daptomycin-containing composition, comprising a
pharmacologically acceptable fluid comprising:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/mL; and
b) calcium chloride at a concentration of greater than 1 mg/mL;
said daptomycin-containing composition having a pH of from about 6 to about 7, and wherein total impurities are less than about 10 % area-under-the-curve ("AUG") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223nm, after at least about 18 months storage at a temperature of from about 5 °C to about 25 °C.
31. The long term storage stable daptomycin-containing composition of claim 30, wherein less than about 10% total impurities include less than about 5% of the hydrolysis product of daptomycin, less than about 5% of the β-isomer of daptomycin and less than about 5% of anhydro-daptomycin based on the amount of daptomycin included in said composition.
32. A long term storage stable daptomycin-containing composition, comprising a
pharmacologically acceptable fluid comprising: a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/niL; and
b) 0.1 M calcium lactate;
said daptomycin-containing composition having a pH of about 6.5, and
wherein total impurities are less than about 10 % area-under-the-curve ("AUC") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223nrn, after at least about 18 months storage at a temperature of from about, 5 °C to about 25 °C.
33. The long term storage stable daptomycin-containing composition of claim 32, wherein less than about 10% total impurities include less than about 5% of the hydrolysis product of daptomycin, less than about 5% of the β-isomer of daptomycin and less than about 5% of anhvdro-daptomycin based on the amount of daptomycin included in said composition.
34. A long term storage stable daptomycin-containing composition, comprising a pharmacologically acceptable fluid comprising:
a) daptomycin or a pharmaceutically acceptable salt thereof at a concentration of less than or equal to about 25 mg/rnL;
b) calcium chloride at a concentration of about 16.2 mg/rnL; and
c) calcium hydroxide at a concentration of about 0.68mg/'mL;
said daptomycin-containing composition having a pH of from about 6 to about 7, and wherein total impurities are less than about 10 % area-under-the-curve ("AUC") as determined by high performance liquid chromatography ("HPLC") at a wavelength of 223nm, after at least about 18 months storage at a temperature of from about 5 °C to about 25 °C.
35. The long term storage stable daptomycin-containing composition of claim 34, wherein less than about 10% total impurities include less than about 5% of the hydrolysis product of daptomycin, less than about 5% of the β-isomer of daptomycin and less than about 5% of anhydro-daptomycin based on the amount of daptomycin included in said composition.
36. A method of treating a daptomycin sensitive disease in mammals, comprising administering an effective amount of a long term storage stable daptomycin-containing composition of claim 1 to a mammal in need thereof.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10831938.5A EP2504020A4 (en) | 2009-11-23 | 2010-09-17 | Formulations of daptomycin |
JP2012539887A JP2013511522A (en) | 2009-11-23 | 2010-09-17 | Daptomycin preparation |
CA2774094A CA2774094A1 (en) | 2009-11-23 | 2010-09-17 | Formulations of daptomycin |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26369509P | 2009-11-23 | 2009-11-23 | |
US61/263,695 | 2009-11-23 | ||
US37180210P | 2010-08-09 | 2010-08-09 | |
US61/371,802 | 2010-08-09 |
Publications (1)
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WO2011062676A1 true WO2011062676A1 (en) | 2011-05-26 |
Family
ID=44059911
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2010/049322 WO2011062676A1 (en) | 2009-11-23 | 2010-09-17 | Formulations of daptomycin |
Country Status (5)
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US (1) | US20110124551A1 (en) |
EP (1) | EP2504020A4 (en) |
JP (1) | JP2013511522A (en) |
CA (1) | CA2774094A1 (en) |
WO (1) | WO2011062676A1 (en) |
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CN104511011A (en) * | 2013-09-29 | 2015-04-15 | 山东新时代药业有限公司 | Daptomycin aseptic powder and preparation method thereof |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004073654A2 (en) * | 2003-02-20 | 2004-09-02 | Santarus, Inc. | A novel formulation, omeprazole antacid complex-immediate release for rapid and sustained supression of gastric acid |
EP1586580A2 (en) * | 2000-01-20 | 2005-10-19 | Cubist Pharmaceuticals, Inc. | Process for the purification of daptomycin |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA901622B (en) * | 1989-03-06 | 1991-11-27 | Lilly Co Eli | An improved diluent formulation for daptomycin |
US7527807B2 (en) * | 2000-06-21 | 2009-05-05 | Cubist Pharmaceuticals, Inc. | Compositions and methods for increasing the oral absorption of antimicrobials |
US6716962B2 (en) * | 2000-07-17 | 2004-04-06 | Micrologix Biotech Inc. | Extractive purification of lipopeptide antibiotics |
WO2002059145A1 (en) * | 2000-12-18 | 2002-08-01 | Cubist Pharmaceuticals, Inc. | Methods for preparing purified lipopeptides |
JP2004525108A (en) * | 2000-12-18 | 2004-08-19 | キュービスト ファーマスーティカルズ インコーポレイテッド | Preparation method of purified lipopeptide |
US20060014674A1 (en) * | 2000-12-18 | 2006-01-19 | Dennis Keith | Methods for preparing purified lipopeptides |
US20070202051A1 (en) * | 2006-02-10 | 2007-08-30 | Pari Gmbh | Aerosols for sinunasal drug delivery |
-
2010
- 2010-09-17 EP EP10831938.5A patent/EP2504020A4/en not_active Withdrawn
- 2010-09-17 CA CA2774094A patent/CA2774094A1/en not_active Abandoned
- 2010-09-17 JP JP2012539887A patent/JP2013511522A/en active Pending
- 2010-09-17 WO PCT/US2010/049322 patent/WO2011062676A1/en active Application Filing
- 2010-09-17 US US12/885,009 patent/US20110124551A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1586580A2 (en) * | 2000-01-20 | 2005-10-19 | Cubist Pharmaceuticals, Inc. | Process for the purification of daptomycin |
WO2004073654A2 (en) * | 2003-02-20 | 2004-09-02 | Santarus, Inc. | A novel formulation, omeprazole antacid complex-immediate release for rapid and sustained supression of gastric acid |
Non-Patent Citations (2)
Title |
---|
MUANGSIRI ET AL.: "The Kinetics of the Alkaline Degradation of Daptomycin", J PHARM SCI, vol. 90, no. 8, August 2001 (2001-08-01), pages 1066 - 1075, XP008161425 * |
See also references of EP2504020A4 * |
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Also Published As
Publication number | Publication date |
---|---|
JP2013511522A (en) | 2013-04-04 |
EP2504020A1 (en) | 2012-10-03 |
EP2504020A4 (en) | 2013-05-29 |
CA2774094A1 (en) | 2011-05-26 |
US20110124551A1 (en) | 2011-05-26 |
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