OA18955A - Phosphaplatin liquid formulations - Google Patents
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- OA18955A OA18955A OA1201800390 OA18955A OA 18955 A OA18955 A OA 18955A OA 1201800390 OA1201800390 OA 1201800390 OA 18955 A OA18955 A OA 18955A
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- pharmaceutical composition
- liquid pharmaceutical
- pyrodach
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- 239000000203 mixture Substances 0.000 title claims abstract description 84
- 239000007788 liquid Substances 0.000 title claims abstract description 60
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 40
- 201000011510 cancer Diseases 0.000 claims abstract description 26
- 239000000243 solution Substances 0.000 claims description 156
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 56
- 238000009472 formulation Methods 0.000 claims description 52
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 51
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 33
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 27
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 27
- 235000011180 diphosphates Nutrition 0.000 claims description 23
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 9
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims description 9
- 239000012062 aqueous buffer Substances 0.000 claims description 8
- 239000008363 phosphate buffer Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- -1 pyrophosphate anion Chemical class 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 201000010536 head and neck cancer Diseases 0.000 claims description 5
- 201000000849 skin cancer Diseases 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- NHWZQIYTQZEOSJ-UHFFFAOYSA-N carbonic acid;phosphoric acid Chemical compound OC(O)=O.OP(O)(O)=O NHWZQIYTQZEOSJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- 210000000988 Bone and Bones Anatomy 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 150000004982 aromatic amines Chemical class 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 230000002496 gastric Effects 0.000 claims description 3
- 230000002489 hematologic Effects 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 150000003385 sodium Chemical group 0.000 claims 1
- 239000002245 particle Substances 0.000 description 35
- 102100002078 DACH1 Human genes 0.000 description 25
- 101700026669 DACH1 Proteins 0.000 description 25
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 25
- 239000000539 dimer Substances 0.000 description 21
- 239000012535 impurity Substances 0.000 description 21
- 229940048084 Pyrophosphate Drugs 0.000 description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000004166 bioassay Methods 0.000 description 12
- 239000007853 buffer solution Substances 0.000 description 12
- 239000010452 phosphate Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000008057 potassium phosphate buffer Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- 239000001488 sodium phosphate Substances 0.000 description 8
- 101700023105 3L21 Proteins 0.000 description 7
- 239000002158 endotoxin Substances 0.000 description 7
- 229910000162 sodium phosphate Inorganic materials 0.000 description 7
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000003139 buffering Effects 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000010979 pH adjustment Methods 0.000 description 6
- 235000011008 sodium phosphates Nutrition 0.000 description 6
- 239000012523 bacterial endotoxin Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- FQENQNTWSFEDLI-UHFFFAOYSA-J Tetrasodium pyrophosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 230000036512 infertility Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000001264 neutralization Effects 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229940048086 sodium pyrophosphate Drugs 0.000 description 4
- 231100000803 sterility Toxicity 0.000 description 4
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 4
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 4
- 229940061607 Dibasic Sodium Phosphate Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drugs Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000003301 hydrolyzing Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-L phosphate Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 210000004369 Blood Anatomy 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N Citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 206010017758 Gastric cancer Diseases 0.000 description 2
- 208000005017 Glioblastoma Diseases 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 229940045641 Monobasic Sodium Phosphate Drugs 0.000 description 2
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 2
- 108009000071 Non-small cell lung cancer Proteins 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 2
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- 108009000491 Small cell lung cancer Proteins 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- 240000006802 Vicia sativa Species 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 230000001580 bacterial Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000008366 buffered solution Substances 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 239000001187 sodium carbonate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012064 sodium phosphate buffer Substances 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- VZWGHDYJGOMEKT-UHFFFAOYSA-J tetrasodium;phosphonato phosphate;decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O VZWGHDYJGOMEKT-UHFFFAOYSA-J 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N Cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- 229940111685 Dibasic potassium phosphate Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L Dipotassium phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N Isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N N-Butylamine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N Propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
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- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045985 antineoplastic drugs Platinum compounds Drugs 0.000 description 1
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- 239000000337 buffer salt Substances 0.000 description 1
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- 239000003560 cancer drug Substances 0.000 description 1
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- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
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- 239000012153 distilled water Substances 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
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- 238000011031 large scale production Methods 0.000 description 1
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Abstract
Pharmaceutical compositions of phosphaplatin compounds, in particular buffered stable liquid formulations of pyrodach-2 ready for use in the treatment of various cancers, and methods of preparation are disclosed.
Description
PHOSPHAPLATIN LIQUID FORMULATIONS
CROSS REFERENCE TO RELATED APPLICATIONS
This application daims the benefït under 35 U.S.C. § ll9(e) of U.S. Provisional Application No. 62/319,047, filed on April 6, 2016, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present ' invention relates to pharmaceutical compositions of phosphaplatin compounds useful as anticancer agents, in particular stable liquid fonnulations ready for use in the treatment of various cancers.
BACKGROUND OF THE INVENTION
Monomeric phosphaplatin complexes hâve demonstrated great potential for treatment of a variety of diseases, including a broad range of cancers. See, e.g., WO 2009/021082, WO 201 1/153365, and WO 2012/096722. Like many therapeutically useful platinum compounds, phosphaplatin complexes are usually administered parenterally, e.g., intravenous (“i.v.” or “iv”) injections. Drugs for parentéral administration are typically formulated as liquids. or as lyophilized solids which require reconstitution with a stérile vehicle prior to administration. Liquid formulations are highly préférable to lyophilized formulations because a) they are more economical and simpler to manufacture, and b) they are much easier to administer as they do not require reconstitution with a stérile vehicle prior to use. The pH of liquid drug fonnulations for iv administration are typically formulated at a pH range near the physiological range of blood pH (7.3-7.4) to avoid the clinical challenges associated with administration of a drug formulation whose pH differs significantly from that of blood. Liquid fonnulations that are stable and easily stored at the ambient température are highly préférable to liquid or lyophilized fonnulations, which must be stored at refrigerated or frozen conditions. Due to the possible dégradation of monomeric phosphaplatin complexes in aqueous solutions, especially under acidic conditions, préparation of stable ready-to-use liquid formulations of these compounds remains a challenge.
SUMMARY OF THE INVENTION
The present invention, in one aspect, provides liquid pharmaceutical compositions comprising a phosphaplatin compound and an aqueous buffer solution having pH at or above
7, with a preferred pH range of 7-9. The buffer solution is an aqueous solution comprising a phosphate sait, a carbonate/bicarbonate sait, or a combination thereof.
In some embodiments, the phosphaplatin compound is a pyrophosphato-platinum (II) complex having a formula of (I) or (II):
O
R1 ZO-P'OH
Pt O R2Z R H OH 0 (I),
O O-^OH O . / OH 0 (Π), or a sait thereof, wherein R1 and R2 are each independently selected from NH3, substituted or unsubstituted aliphatic amines, and substituted or unsubstituted aromatic amines; and wherein R3 is selected from substituted or unsubstituted aliphatic or aromatic 1,2-diamines.
In some more preferred embodiments, the phosphaplatin compound is selected from the group consisting of pyrophosphato)platinum(II) (“trans-pyrodach-2”), pyrodach-2 and (S,S)-pyrodach-2, and pyrophosphato)platinum(II) (“cis-pyrodach-2”).
trans-1,2-cyclohexanediamine-(dihydrogen either of the two enantiomers (R,R)cis-1,2-cyclohexanediamine-(dihydrogen
(R.R)-pyrodach-2
(S,S)-pyrodach-2
czx-pyrodach-2
The most preferred embodiments of the formulations demonstrate the potential for muiti-year stability at the ambient température. The formulations afford a stérile concentrated solution of (R,R)-pyrodach-2 that is easily diluted in standard i.v. fluids used in
i.v. administration of cancer drugs or a stérile solution at a suitable concentration in a vial ready for use on a patient.
In another aspect, the present invention provides processes for making liquid formulations, in particular ready-to-use formulations, of phosphaplatin compounds in a buffer solution as described here, the process comprising the steps of: a) dissolving a phosphaplatin compound in an aqueous buffer comprising a sufficient amount of hydroxide base such that the pH remains at or above 7; b) optionally adding a hydroxide base to adjust the pH to a desired range, and c) filtering the solution to obtain a liquid formulation.
In another aspect, the present invention is directed to use of a stable liquid formulation according to any embodiment disclosed herein in the treatment of a cancer.
These and other aspects of the present invention will be better appreciated by reference to the following drawing, detailed description and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I illustrâtes the potency of capped l mg/mL (R,R)-pyrodach-2 solutions in various buffers stored in stability chambers controlled at 25°C/60%RH, as monitored by HPLC.
FIG. 2 illustrâtes the potency of capped l mg/mL (R,R)-pyrodach-2 solutions in various buffers stored in stability chambers controlled at 40°C/75%RH, as monitored by HPLC.
FIG. 3 illustrâtes the potency of capped l mg/mL (R,R)-pyrodach-2 solutions in a 10 mM potassium phosphate buffer at various pH’s stored in stability chambers controlled at 25°C/60%RH as monitored by HPLC.
FIG. 4 illustrâtes the potency of capped l mg/mL (R,R)-pyrodach-2 solutions in a 10 mM potassium phosphate buffer at various pH’s stored in stability chambers controlled at 40°C/75%RH as monitored by HPLC.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides a pharmaceutical composition comprising a phosphaplatin compound and an aqueous buffer solution having pH at or above 7.
In one embodiment of this aspect, sometimes preferred, the pharmaceutical composition is a ready-to-use liquid formulation suitable for parentéral administration.
In some embodiments of this aspect, the concentration of the phosphaplatin compound is about 20 mg/mL or less.
In some embodiments of this aspect, the concentration of the phosphaplatin compound is between about l and about 10 mg/mL.
In some embodiments of this aspect, the concentration of the phosphaplatin compound is between about l and about 6 mg/mL.
In another embodiment of this aspect, the concentration of the phosphaplatin compound is about 5 mg/mL.
In another embodiment of this aspect, the buffer comprises a sait of phosphate or bicarbonate / carbonate.
In some embodiments, the buffer comprises phosphate family ions, i.e., phosphate (PO43'), hydrogen phosphate (HPO42), and/or dihydrogen phosphate (H2PO4 ).
In some embodiments, the buffer comprises carbonate family ions, i.e, bicarbonate (HCO3 ) and carbonate (CO3 2').
In some embodiments, the buffer comprises both phosphate family ions (PO.?’, HPO42', and/or H2PO4' ions) and carbonate family ions (i.e., HCO3’ and CO3 2').
In some embodiments of this aspect, the buffer sait concentration is between about l mM and about 100 mM.
In some embodiments of this aspect, the buffer sait concentration is between about 5 mM and about 50 mM.
In some embodiments of this aspect, the buffer sait concentration is about IO mM.
In some embodiments of this aspect, the pH of the liquid pharmaceutical composition is in the range of about 7.0 to about 9.0.
In some embodiments of this aspect, the pH of the liquid pharmaceutical composition is in the range of about 7.0 to about 8.0.
In some embodiments of this aspect, the buffer contains sodium or potassium phosphate salts, or a combination thereof.
In some embodiments of this aspect, the buffer contains potassium phosphate; the concentration of the phosphaplatin compound is 5 mg/mL and the pH is in the range of about 7.0 to about 8.0.
In some embodiments of this aspect, the buffer concentration is about 10 mM.
In some embodiments of this aspect, the buffer comprises a pyrophosphate sait.
In some embodiments of this aspect, the molar ratio of pyrophosphate anion to the phosphaplatin compound is at least 0.1 to l.
In some embodiments of this aspect, the molar ratio of pyrophosphate ion to the phosphaplatin compound is about 0.2 to l
In some embodiments of this aspect, the molar ratio of pyrophosphate ion to the phosphaplatin compound is about 0.4 to I.
In some embodiments of this aspect, the concentration of the phosphaplatin compound is about 5 mg/mL, the pyrophosphate concentration is about 5.2 mM, and the pH is in the range of about 7.0 to about 8.0.
In some embodiments of this aspect, the phosphaplatin compound is a pyrophosphatoplatinum (II) complex having a formula of (I) or (II):
Rk /
R2 ZO-P'OH Pt\ z° (I)
(II), or a sait thereof, wherein R1 and R2 are each independently selected from NH3, substituted or unsubstituted aliphatic amines, and substituted or unsubstituted aromatic amines; and wherein R3 is selected from substituted or unsubstituted aliphatic or aromatic 1,2-diamines.
In some preferred embodiments, R1 and R2 in formula (I) are each independently selected from NH3, methyl amine, ethyl amine, propyl amine, isopropyl amine, butyl amine, cyclohexane amine, aniline, pyridine, and substituted pyridine; and R3 in formula (II) is 10 selected from ethylenediamine and cyclohexanediamine.
In some more preferred embodiments of this aspect, the phosphaplatin compound is a l,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(H) (“pyrodach-2”) complex selected from the group consisting of:
O O O aNH2.....,o-P<OH /%11¾ „O-PCOH X\T--NH2, lO-pOH 'NH2 °^OH °’hCOH (R,R)-trans-pyrodach-2 (S,S)-trans-pyrodach-2 cis-pyrodach-2
In one preferred embodiment of this aspect, the phosphaplatin compound is a trans-
1,2-cycIohexanediamine-(dihydrogen pyrophosphato)platinum(II) (“trans-pyrodach-2”) complex.
In another preferred embodiment of this aspect, the phosphaplatin compound is (R.R)20 trans- l,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) (“(R,R)-transpyrodach-2”).
In another preferred embodiment of this aspect, the phosphaplatin compound is (S,S)trans-1,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) (“(S,S)-transpyrodach-2”).
In another preferred embodiment of this aspect, the phosphaplatin compound is cis-
1,2-cyclohexanediamine-(dihydrogen pyrophosphato)-platinum(II) (“cis-pyrodach-2”).
In some embodiments, the present invention provides liquid pharmaceutical compositions of phosphaplatin according to any reasonable combinations of the embodiments described herein.
In another aspect, the présent invention provides a liquid pharmaceutical composition according to any embodiment disclosed herein, or any combination thereof, for use in the treatment of a disease or disorder.
In some embodiments, the disease or disorder is a cancer.
In some embodiments, the cancer includes, but is not limited to, those selected from gynecological cancers, genitourinary cancers, lung cancers, head-and-neck cancers, skin cancers, gastrointestinal cancers, breast cancers, bone and chondroital cancers, and hematological cancers.
In some embodiments, the cancer is selected from the group consisting of ovarian cancer, testicular cancer, small-cell lung cancer, non-small-cell lung cancer, head-and-neck cancers, skin cancer, pancreatic cancer, breast cancer, liver cancer, stomach cancer, bone cancer, glioblastoma cancer, and colon cancer.
In another aspect, the présent invention provides use of a liquid pharmaceutical composition according to any embodiment disclosed herein, or any combination thereof, for use in the manufacture of a médicament for the treatment of a disease or disorder. The disease or disorder includes a cancer, including but not limited to any of gynecological cancers, genitourinary cancers, lung cancers, head-and-neck cancers, skin cancers, gastrointestinal cancers, breast cancers, bone and chondroital cancers, and hematological cancers. More spécifie non-Iimiting examples include ovarian cancer, testicular cancer, small-cell lung cancer, non-small-cell lung cancer, head-and-neck cancers, skin cancer, pancreatic cancer, breast cancer, liver cancer, stomach cancer, bone cancer, glioblastoma cancer, and colon cancer.
In another aspect, the présent invention provides a process of preparing a liquid pharmaceutical composition of phosphaplatin compound according to any embodiments disclosed herein, or any combination thereof, the process comprises: a) dissolving a phosphaplatin compound in an aqueous buffer comprising a sufficient amount of hydroxide base such that the pH remains at or above 7; b) optionally adding a hydroxide base to adjust the pH to a desired range, and c) filtering the solution to obtain a liquid formulation.
In one embodiment of this aspect, the aqueous buffer is a phosphate buffer, a carbonate/biocarbonate buffer, or a combination thereof.
In another embodiment of this aspect, the pH of the liquid formulation is in the range of about 7.0 to about 9.0.
In another embodiment of this aspect, the process further includes adding a sufficient amount of a pyrophosphate sait to stabilize the phosphaplatin compound in the liquid formulation.
In another embodiment of this aspect, said filtering is conducted under stérile conditions.
In another embodiment of this aspect, the process further comprises step d) filling the solution into a vial, stoppering and capping the vial in a stérile environment so that the formulation is ready for use.
In another embodiment of this aspect, the liquid formulation obtained is a formulation according to any one of the embodiments described herein, or any combination thereof.
When the term “about” is applied to a parameter, such as pH, concentration, or the like, it indicates that the parameter can vary by ±10%, preferably within ±5%, and more preferably within ±5%. As would be understood by a person skilled in the art, when a parameter is not critical, a number is often given only for illustration purpose, instead of being limiting.
The term “a,” “an,” or “the,” as used herein, represents both singular and plural forms. In general, when either a singular or a plural form of a noun is used, it dénotés both singular and plural forms of the noun.
The present invention is equally applicable to ail of the stereoisomers of pyrodach-2 complexes, as a person skilled in the art would understand, though the following detailed description uses only the (R,R)-pyrodach-2 isomer (or “PT-112”) as a non-limiting example to illustrate certain aspects of the present invention.
(R,R)-Pyrodach-2 is a diacid, which displays a low solubility in water. The pKa values of the two acid groups in (R,R)-pyrodach-2 are approximately 2.6 and 4.4 (Inorg. Chem. 47, 7942 (2008)). Thus, simple dissolution of (R,R)-pyrodach-2 affords an acidîc solution. Under acidic aqueous conditions (R,R)-pyrodach-2 rapidly undergoes hydrolytic dégradation. At higher pHs, where the acid groups of (R,R)-pyrodach-2 are ionized, the solubility of (R,R)-pyrodach-2 increases. In addition, deprotonation of the acid groups in (R,R)-pyrodach-2 dramatically reduces the rate of hydrolytic dégradation. The two pKa values of (R,R)-pyrodach-2 indicate that an aqueous solution of (R,R)-pyrodach-2 in the physiological pH range of 7.0-7.5 will hâve no buffering capacity. Thus, controlling the pH of an aqueous solution in the physiological pH range, much less the accurate and reproducible préparation of aqueous (R,R)-pyrodach-2 solutions in this pH range by pH adjustment of an aqueous solution of (R,R)-pyrodach-2 with hydroxide base, is extremely difficult. Hence, the development of aqueous formulations of (R,R)-pyrodach-2 with controlled pH stability in the physiological pH range of 7 - 7.5 preferably requires the use of a buffer. This présents a unique challenge as the pyrophosphate ligand in (R,R)-pyrodach-2 is kinetically labile in solution and can potentially undergo reaction with anions present in many buffers. Table I summarizes the decrease in potency measured by HPLC of aqueous I mg/mL (R,R)-pyrodach-2 solutions in a variety of buffers at ambient température. The HPLC System and conditions used to monitor stability are summarized in Table 2.
Table l
| Buffer | Buffer conc. (mM) | pH | Decrease in Potency | |||
| 4 days | 7 days | 11 days | 14 days | |||
| Acetate | 20 mM | 5.32 | - | 13.5% | - | - |
| Citric acid | 20 mM | 6.51 | l.9% | 3.9% | - | |
| Triethanolamine | 20 mM | 7.97 | l.9% | 5.7% | *· | |
| L-arginine | 20 mM | 7.72 | 4.0% | 10% | ||
| NH4HCO3 | lOOmM | 7.94 | - | - | 47.1% | |
| NH4HCO3 | 50 mM | 7.83 | - | - | 18.0% | |
| NH4HCO3 | 20 mM | 7.68 | 8.0% |
Table 2
| Column | Waters Symmetry Cl8, 4.6 x 250 mm, 5 pm particle size |
| Column température | Ambient |
| Flow rate | 1 mg/mL |
| Injection volume | 25pL |
| Mobile Phase | 15% Acetonitrile / 85% 5mM Tetrabutylammonium hydrogen sulfate + 10 mM Na2HPO4 |
| Détection | UV |
To develop a stable ready-to-use aqueous formulation of (R,R)-pyrodach-2 with a pH controlled in the range of 7.0-8.0, screening of buffers for their lack of reactivity towards (R,R)-pyrodach-2 in an aqueous solution resulted in identification of phosphate and bicarbonate / carbonate buffers as most préférable. Température was observed to impact stability, with poorer stability observed at higher températures. Buffer concentration was also found to impact (R,R)-pyrodach-2 solution stability, with poorer stability observed at higher buffer concentrations; while impact of the cation associated with the buffer (e.g., potassium vs. sodium, etc.) was found to be minimal, if any. In a bicarbonate / carbonate buffer system, pH was found to hâve a significant impact on (R,R)-pyrodach-2 stability, with decreased stability observed at a higher pH, where the concertation ratio of carbonate ion to bicarbonate ion increases. In contrast, in phosphate buffers, pH was found to hâve minimal impact on (R,R)-pyrodach-2 stability when the pH was above 7. Below pH 7, dégradation was observed to resuit in formation of a dimeric species ((R,R)-pyrodach-2 dimer), which is highly insoluble and précipitâtes from the solution. Given the potential for dégradation în the presence of carbonate ion in a bicarbonate ! carbonate buffer system and for the potential loss în buffer capacity due to équilibration with CO2 in the atmosphère or head space of a container, phosphate offers a superior buffering system for manufacture of a buffered aqueous ready-to-use (R,R)-pyrodach-2 formulation with the pH controlled in the physiological range of 7 - 7.5, particularly in a large scale manufacturing setting.
“Pyrodach-2 Dimer”
Freezing an aqueous formulation is one way to retard the rate of dégradation and improve the stability of a drug substance formulated in aqueous media. The impact of a freeze-thaw cycle on the stability of (R,R)-pyrodach-2 in a variety of buffers was evaluated. Data summarized in Table 3 shows a higher level of dégradation with higher buffer concentrations. In addition, a higher level of dégradation is observed with the sodium sait in comparison to the potassium sait in the phosphate buffer Systems in consistence with the observation of sélective précipitation of disodium phosphate during freezing, which results in a significant decrease in pH during freezing, a phenomenon not observed on a potassium phosphate buffer (Archives of Biochemistry and Biophysics 384, 398, 2000). Hence, use of potassium salts îs preferable to use of sodium salts in phosphate buffered (R,R)-pyrodach-2 formulations.
Table 3
| 1 mg/mL (R,R)-pyrodach-2 solution in | Solution pH | Change in purity after freeze thaw cycle |
| 10 mM Na Phosphate | 7.02 | 99.5% |
| 100 mM Na Phosphate | 6.98 | 96.3% |
| 1 mg/mL (R,R)-pyrodach-2 | Solution pli | Change in |
| 10 mM K Phosphate | 7.01 | 99.7% |
| 100 mM K Phosphate | 7.02 | 99.1% |
| 10 mM Na Carbonate | 10.84 | 99.1% |
| 100 mM Na Carbonate | 11.39 | 93.7% |
| 10 mM Na Bicarbonate | 8.18 | 99.5% |
| 100 mM Na Bicarbonate | 8.06 | 98.8% |
The solubîlity of (R,R)-pyrodach-2 in aqueous buffered solution at pH 7 - 7.5 indicates that solutions of at least 20 mg/mL can easily be achieved. However, the clinical use of platinum oncolytic agents like (R,R)-pyrodach-2 indicates that a concentration of 5 mg/mL is highly désirable for a ready-to-use aqueous formulation. Buffering capacity modeling shows that a 10 mM concentration of phosphate or bicarbonate provides sufficient buffering capacity and acceptable pH control for a 5 mg/mL (R,R)-pyrodach-2 aqueous solution.
The rapid hydrolytic dégradation of (R,R)-pyrodach-2, in particular the formation of the highly insoluble dimeric impurity both on dissolution of (R,R)-pyrodach-2 in water or in a buffer medium such as phosphate buffer when the pH is below neutral, precludes large scale manufacture of an aqueous ready-to-use formulation of (R,R)-pyrodach-2, adjusted to the physiological pH range of 7-7.5, by simply adding base to a slurry of (R,R)-pyrodach-2 in water or adding a buffer solution to effect dissolution followed by adjustment to the desired pH range. Rather, effective control of dégradation and impurity formation requires dissolution of the (R,R)-pyrodach-2 under conditions of near neutral or basic pH. We hâve found that this can be achieved by adding (R,R)-pyrodach-2 to a solution of buffer and adding hydroxide base sufficient to neutralize ail of the added (R,R)-pyrodach-2. Once ail of the solids hâve dissolved, the solution pH is adjusted into the final desired range by the addition of small amount of hydroxide. In this manner the dissolution of the drug substance is conducted under conditions of near neutral or basic pH.
A scalable and commercially viable process for the manufacture of a ready-to-use formulation of (R,R)-pyrodach-2 in 10 mM buffer adjusted to a pH of 7.0 - 7.5 comprises the steps of: a) preparing a 10 mM aqueous solution of buffer; b) adding sufficient hydroxide base to effect neutralization of the added (R,R)-pyrodach-2 to reach a pH of about 7; c) adding (R,R)-pyrodach-2 and allowing it to dissolve; d) if necessary adding additional hydroxide to adjust the pH into a range of about 7.0 - 7.5; and e) filtering the solution under stérile conditions, filling the solution into glass vials, and covering it with a stopper and/or a cap. Stability data on two large batches of 5 mg/mL (R,R)-pyrodach-2 in lOmM potassium phosphate buffer were generated. One such batch at pH=7.2 was evaluated at both 25°C/60%RH and refrigerated (2-8°C) conditions, with data summarized in Table 4 and Table 5, respectively. While slow dégradation is observed over 24 months at 25°C/60%RH, 5 under refrigerated conditions the formulation displays excellent stability over the same or even longer (36 months) period (see Table 5). Similar observations hâve been made for the ready-to-use liquid formulation at pH 7.4, as illustrated in Table 6 and Table 7.
Table 4 (R,R)-Pyrodach-2 Ready-to-use Aqueous Formulation Stability at 25°C/60%RH (5 mg/mL (R,R)-pyrodach-2 in 10 mM Potassium Phosphate Buffer at pH 7.2) filled in 10 mL vials
| Parameter | Initia! | 1 Month | 2 Month | 3 Month | 4 Month | 6 Month |
| Appearance | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates |
| Assay (Potency) | 99.8% | 96.5% | 99.5% | 98.2% | 97.9% | 97.5% |
| Total Related Substances | 2% | 2% | 2% | 2% | 2% | 3% |
| (DACH) Ptdiaquo (~RRT 0.3) | 0.16% | 0.15% | 0.09% | 0.19% | 0.13% | 0.15% |
| (DACH) Ptmonoaquo (~RRT 0.7) | 0.98% | 0.75% | 0.96% | 0.73% | 1.05% | 1.03% |
| (DACH) Ptdichloride (RRT 1.3-1.6) | ND | ND | ND | ND | ND | ND |
| RRT 3.1-3.2 | ND | 0.22% | 0.32% | 0.37% | 0.38% | 0.40% |
| PT-112 Dimer (-RRT4.0) | 0.19% | 0.33% | 0.36% | 0.37% | 0.36% | 0.37% |
| RRT 0.41 | ND | ND | ND | ND | ND | ND |
| RRT 0.46 | ND | ND | ND | ND | ND | ND |
| RRT 0.50 | ND | ND | 0.05% | 0.08% | 0.09% | 0.15% |
| RRT 0.58 | 0.13% | 0.13% | 0.15% | 0.18% | 0.20% | 0.21% |
| RRT 0.67 | 0.05% | 0.06% | 0.09% | 0.06% | 0.07% | 0.07% |
| RRT 0.86 | ND | ND | ND | ND | ND | 0.05% |
| RRT 3.46 | ND | ND | ND | ND | 0.05% | ND |
| RRT 3.65 | ND | ND | 0.08% | 0.11% | 0.13% | 0.24% |
| RRT 4.97 | ND | ND | ND | ND | ND | 0.05% |
| pH | 7.2 | 7.2 | 7.2 | 7.3 | 7.1 | 7.2 |
| Sterility | Stérile | NT | NT | NT | NT | Stérile |
| Particulate | 219 particles | NT | NT | NT | NT | 20 particles |
| Parameter | Initial | 1 Month | 2 Month | 3 Month | 4 Month | 6 Month |
| Matter (Light Obscuration)1 | per container | per container | ||||
| 11 particles per container | NT | NT | NT | NT | 3 particles per container | |
| Bacterial Endotoxin (Kinetic Turbidimetric) | <0.35 EU/mL | NT | NT | NT | NT | <0.35 EU/mL |
Table 4 (cont'd)
| Parameter | Initial | 9 Month | 12 Month | 15 Month | 18 Month | 24 Month |
| Appearance | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates |
| Assay (Potency) | 99.8% | 96.8% | 96.8% | 98.1% | 99.0% | 97.5% |
| Total Related Substances | 2% | 3% | 3% | 3% | 4% | 5% |
| (DACH) Ptdiaquo (~RRT 0.3) | 0.16% | 0.16% | 0.18% | 0.14% | 0.14% | 0.15% |
| (DACH) Ptmonoaquo (-RRT0.7) | 0.98% | 1.10% | 0.91% | 0.84% | 1.04% | 0.83% |
| (DACH) Ptdichloride (RRT 1.3-1.6) | ND | ND | ND | ND | ND | ND |
| RRT 3.1-3.2 | ND | 0.30% | 0.44% | 0.41% | 0.40% | 0.41% |
| PT-112 Dimer (~RRT 4.0) | 0.19% | 0.39% | 0.33% | 0.29% | 0.30% | 0.36% |
| RRT 0.41 | ND | ND | 0.05% | 0.07% | 0.06% | 0.12% |
| RRT 0.46 | ND | ND | ND | ND | ND | 0.10% |
| RRT 0.50 | ND | 0.19% | 0.26% | 0.37% | 0.36% | 0.70% |
| RRT 0.58 | 0.13% | 0.27% | 0.26% | 0.26% | 0.29% | 0.17% |
| RRT 0.67 | 0.05% | 0.10% | 0.13% | 0.07% | 0.11% | 0.07% |
| RRT 0.86 | ND | 0.05% | 0.05% | ND | 0.14% | ND |
| RRT 3.46 | ND | ND | ND | ND | ND | 0.07% |
| RRT 3.65 | ND | 0.39% | 0.52% | 0.63% | 0.75% | 1.24% |
| RRT 4.97 | ND | 0.08% | 0.20% | 0.28% | 0.43% | 0.73% |
| PH | 7.2 | 7.2 | 7.2 | 7.3 | 7.2 | 7.2 |
| Sterility | Stérile | NT | Stérile | NT | NT | Stérile |
| Particulate Matter (Light | 219 particles per container | NT | 36 particles per container | NT | NT | 81 particles per container |
| Parameter | Initial | 9 Month | 12 Month | 15 Month | 18 Month | 24 Month |
| Obscuration) | ||||||
| 11 particles per container | NT | 2 particles per container | NT | NT | 4 particles per container | |
| Bacterial Endotoxin (Kinetic Turbidimetric) | <0.35 EU/mL | NT | <0.35 EU/mL | NT | NT | <0.35 EU/mL |
ND = Not detected; NT = Not tested
Table 5 (R,R)-Pyrodach-2 Ready-to-use Aqueous Formulation Stability 2-8°C (5 mg/mL (R,R)5 pyrodach-2 in 10 mM Potassium Phosphate Buffer at pH 7.2) filled in 10 mL vials
| Parameter | Initial | 1 Month | 2 Month | 3 Month | 4 Month | 6 Month | 9 Month |
| Appearance | Clear, colorless solution free of particulate s | Clear, colorless solution free of particulat es | Clear, colorless solution free of particulat es | Clear, colorless solution free of particulat es | Clear, colorless solution free of particulat es | Clear, colorless solution free of particulate s | Clear, colorless solution free of particulat es |
| Assay (Potency) | 99.8% | 97.7% | 100.1% | 98.2% | 98.6% | 98.4% | 97.8% |
| Total Related Substances | 2% | 1% | 1% | 2% | 2% | 2% | 2% |
| (DACH) Pt-diaquo (-RRT0.3) | 0.16% | 0.17% | 0.09% | 0.18% | 0.13% | 0.18% | 0.14% |
| (DACH) Ptmonoaquo(~RRT 0.7) | 0.98% | 0.84% | 0.91% | 0.82% | 0.88% | 0.91% | 1.05% |
| (DACH) Pt-dichloride (RRT 1.3-1.6) | ND | ND | ND | ND | ND | ND | ND |
| RRT 3.1-3.2 | ND | ND | ND | 0.08% | 0.07% | 0.10% | 0.10% |
| PT-112 Dimer (~RRT 4.0) | 0.19% | 0.21% | 0.25% | 0.31% | 0.27% | 0.28% | 0.29% |
| RRT 0.46 | ND | ND | ND | ND | ND | ND | ND |
| RRT 0.50 | ND | ND | ND | ND | 0.05% | ND | ND |
| RRT 0.56 | 0.13% | 0.11% | 0.10% | 0.12% | 0.13% | 0.12% | 0.16% |
| RRT 0.68 | 0.05% | ND | 0.06% | 0.05% | ND | 0.05% | 0.06% |
| RRT 3.54 | ND | ND | ND | ND | ND | ND | ND |
| PH | 7.2 | 7.2 | 7.2 | 7.2 | 7.3 | 7.3 | 7.2 |
| Sterilîty | Stérile | NT | NT | NT | NT | Stérile | NT |
| Particulate Matter (Light Obscuration) | 219 particles per container | NT | NT | NT | NT | 150 particles per container | NT |
I3
| Parameter | Initial | 1 Month | 2 Month | 3 Month | 4 Month | 6 Month | 9 Month |
| 11 partiales per container | NT | NT | NT | NT | 8 particles per container | NT | |
| Bacterîal Endotoxin (Kinetic Turbidimetric) | <0.35 EU/mL | NT | NT | NT | NT | <0.35 EU/mL | NT |
Table 5 (cont'd)
| Parameter | Initial | 12 Month | 15 Month | 18 Month | 24 Month | 30 Month | 36 Month |
| Appearance | Clear, colorless solution free of particulat es | Clear, colorless solution free of particulat es | Clear, colorless solution free of particula tes | Clear, colorless solution free of particula tes | Clear, colorless solution free of particulat es | Clear, colorless solution free of particulat es | Clear, colorless solution free of particula tes |
| Assay (Potency) | 99.8% | 97.8% | 98.7% | 100.3% | 97.1% | 98.2% | 97.8% |
| Total Related Substances | 2% | 2% | 2% | 2% | 2% | 2% | 3% |
| (DACH) Pt-diaquo (-RRT0.3) | 0.16% | 0.20% | 0.15% | 0.15% | 0.17% | 0.14% | 0.12% |
| (DACH) Ptmonoaquo (~RRT 0.7) | 0.98% | 1.02% | 0.92% | 0.93% | 0.82% | 0.96% | 1.16% |
| (DACH) Ptdichloride (RRT 1.31.6) | ND | ND | ND | ND | ND | ND | ND |
| RRT 3.1-3.2 | ND | 0.16% | 0.22% | 0.19% | 0.22% | 0.31% | 0.30% |
| PT-112 Dimer (~RRT 4.0) | 0.19% | 0.29% | 0.29% | 0.31% | 0.31% | 0.33% | 0.36% |
| RRT 0.46 | ND | ND | ND | NO | 0.06% | ND | 0.07% |
| RRT 0.50 | ND | 0.06% | 0.07% | 0.07% | 0.22% | 0.17% | 0.23% |
| RRT 0.56 | 0.13% | 0.16% | 0.19% | 0.19% | 0.09% | 0.19% | 0.11% |
| RRT 0.68 | 0.05% | 0.10% | 0.06% | 0.07% | 0.05% | 0.08% | 0.09% |
| RRT 3.54 | ND | ND | ND | 0.05% | 0.11% | 0.10% | 0.14% |
| pH | 7.2 | 7.2 | 7.2 | 7.3 | 7.2 | 7.2 | 7.2 |
| Sterilîty | Sterife | Stérile | NT | NT | Stérile | Stérile | NT |
| Particulate Matter (Light Obscuration) | 219 particles per container | 236 particles per container | NT | NT | 41 particles per container | 62 particles per container | NT |
| 11 particles per container | 4 particles per container | NT | NT | 12 particles per container | 6 particles per container | NT |
I4
| Parameter | Initial | 12 Month | 15 Month | 18 Month | 24 Month | 30 Month | 36 Month |
| Bacterial Endotoxin (Kinetîc Turbidimetric) | <0.35 EU/mL | <0.35 EU/mL | NT | NT | <0.35 EU/mL | <0.35 EU/mL | NT |
ND = Not detected; NT = Not tested
Table 6 (R,R)-Pyrodach-2 Ready-to-use Aqueous Formulation Stability at 25°C/60%RH (5 mg/mL (R,R)-pyrodach-2 in 10 mM Potassium Phosphate Buffer at pH 7.4) filled in 10 mL vials
| Parameter | Initial | 1 Month | 3 Month | 6 Month | 9 Month | 12 Month |
| Appearance | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates |
| Assay (Potency) | 98.1% | 98.4% | 99.2% | 96.7% | 98.2% | 98.0% |
| Total Related Substances | 2% | 3% | 3% | 3% | 4% | 4% |
| (DACH) Pt-diaquo (~RRT 0.3) | 0.16% | 0.16% | 0.15% | 0.19% | 0.14% | 0.11% |
| (DACH) Ptmonoaquo (~RRT 0.7) | 0.84% | 1.12% | 0.92% | 0.30% | 0.79% | 0.92% |
| (DACH) Ptdichloride (RRT 1.3-1.6) | ND | ND | ND | ND | ND | ND |
| RRT 3.1-3.2 | 0.11% | 0.56% | 0.77% | 0.86% | 0.84% | 0.82% |
| PT-112 Dimer (RRT 4.0) | 0.34% | 0.35% | 0.33% | 0.36% | 0.34% | 0.30% |
| RRT 0.42 | ND | ND | ND | 0.06% | 0.08% | 0.10% |
| RRT 0.46 | ND | ND | ND | 0.09% | 0.08% | 0.07% |
| RRT 0.50 | 0.06% | 0.07% | 0.11% | 0.31% | 0.39% | 0.38% |
| RRT 0.56 | 0.08% | 0.15% | 0.20% | 0.09% | 0.11% | 0.19% |
| RRT 0.68 | 0.09% | 0.21% | 0.11% | 0.16% | 0.11% | 0.11% |
| RRT 0.86 | ND | 0.06% | 0.05% | 0.07% | 0.06% | 0.05% |
| RRT 3.29 | ND | ND | ND | ND | ND | ND |
| RRT 3.41 | ND | ND | ND | ND | 0.08% | ND |
| RRT 3.44 | ND | ND | ND | ND | ND | ND |
| RRT 3.58 | ND | ND | 0.14% | 0.37% | 0.65% | 0.70% |
| RRT 4.95 | ND | ND | ND | 0.06% | 0.21% | 0.34% |
| PH | 7.4 | 7.4 | 7.4 | 7.4 | 7.4 | 7.5 |
| Sterility | Stérile | NT | NT | Stérile | NT | Stérile |
| Particuiate Matter (Light Obscuration}1 | 30 particles per container | NT | NT | 87 particles per container | NT | 118 particles per container |
| Parameter | Initial | 1 Month | 3 Month | 6 Month | 9 Month | 12 Month |
| 11 partides per container | NT | NT | 3 partides per container | NT | 7 partides per container | |
| Bacterial Endotoxin (Kinetic Turbidimetric)1 | <0.35 EU/mL | NT | NT | <0.35 EU/mL | NT | <0.35 EU/mL |
Table 6 (cont'd)
| Parameter | Initial | 15 Month | 18 Month | 21 Month | 24 Month |
| Notebook Reference | 1245-6-46 | 1245-14-36 | 1245-14-49 | 1245-14-59 | 1245-14-76 |
| Appearance | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates |
| Assay (Potency) | 98.1% | 96.8% | 96.9% | 96.3% | 94.6% |
| Total Related Substances | 2% | 4% | 5% | 6% | 6% |
| Indîvidual Related Substances | B «a | ||||
| (DACH) Pt-diaquo (~RRT 0.3} | 0.16% | 0.13% | 0.12% | 0.11% | 0.11% |
| (DACH) Ptmonoaquo (~RRT 0.7) | 0.84% | 0.92% | 0.78% | 1.13% | 0.85% |
| (DACH) Ptdichloride (RRT 1.31.6) | ND | ND | ND | ND | ND |
| RRT 3.1-3.2 | 0.11% | 0.78% | 0.73% | 0.75% | 0.72% |
| PT-112 Dimer (~RRT 4.0) | 0.34% | 0.28% | 0.29% | 0.28% | 0.28% |
| RRT 0.42 | ND | 0.12% | 0.15% | 0.16% | 0.18% |
| RRT 0.46 | ND | 0.08% | 0.13% | 0.12% | 0.12% |
| RRT 0.50 | 0.06% | 0.44% | 0.59% | 0.60% | 0.70% |
| RRT 0.56 | 0.08% | 0.20% | 0.09% | 0.17% | 0.17% |
| RRT 0.68 | 0.09% | 0.11% | 0.08% | 0.12% | 0.13% |
| RRT 0.86 | ND | 0.05% | 0.05% | ND | 0.05% |
| RRT 3.29 | ND | ND | ND | ND | 0.06% |
| RRT 3.41 | ND | ND | ND | 0.07% | ND |
| RRT 3.44 | ND | ND | 0.12% | 0.05% | 0.05% |
| RRT 3.58 | ND | 0.78% | 1.06% | 1.12% | 1.07% |
| RRT 4.95 | ND | 0.51% | 0.69% | 0.89% | 1.12% |
| _______Eü_______ | 7.4 | 7.5 | 7.5 | 7.4 | 7.4 |
| ________Sterîlity________ | Stérile | NT | NT | NT | TBD |
| ___ Parameter | Initial | 15 Month | 18 Month | 21 Month | 24 Month |
| Particulate Matter (Light Obscuration) | 30 particles per container | NT | NT | NT | TBD |
| 11 particles per container | NT | NT | NT | TBD | |
| Bacterial Endotoxîn (Kinetic Turbidimetric) | <0.35 EU/mL | NT | NT | NT | TBD |
Table 7 (R,R)-Pyrodach-2 Ready-to-use Aqueous Formulation Stability at 2-8 °C (5 mg/mL (R,R)pyrodach-2 in 10 mM Potassium Phosphate Buffer at pH 7.4) filled in 10 mL vials
| Parameter | Initial | 1 Month | 3 Month | 6 Month | 9 Month | 12 Month |
| Appearance | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates |
| Assay (Potency) | 98.1% | 98.7% | 99.7% | 98.2% | 100.2% | 98.7% |
| Total Related Substances | 2% | 2% | 2% | 2% | 2% | 2% |
| (DACH) Pt-diaquo (-RRT0.3) | 0.16% | 0.15% | 0.14% | 0.17% | 0.14% | 0.12% |
| (DACH) Ptmonoaquo (~RRT 0.7) | 0.84% | 1.04% | 0.92% | 0.28% | 0.81% | 0.96% |
| (DACH) Ptdichloride (RRT 1.3-1.6) | ND | ND | ND | ND | ND | ND |
| RRT 3.1-3.2 | 0.11% | 0.13% | 0.25% | 0.38% | 0.39% | 0.48% |
| PT-112 Dîmer (“RRT 4.0) | 0.34% | 0.33% | 0.37% | 0.36% | 0.33% | 0.34% |
| RRT 0.46 | ND | ND | ND | 0.06% | 0.05% | ND |
| RRT 0.50 | 0.06% | 0.06% | 0.06% | 0.18% | 0.18% | 0.15% |
| RRT 0.56 | 0.08% | 0.10% | 0.12% | 0.06% | 0.07% | 0.16% |
| RRT 0.68 | 0.09% | 0.19% | 0.11% | 0.16% | 0.08% | 0.11% |
| RRT 0.86 | ND | 0.05% | ND | 0.05% | 0.05% | 0.05% |
| RRT 3.58 | ND | ND | ND | ND | 0.07% | ND |
| pH | 7.4 | 7.4 | 7.4 | 7.4 | 7.4 | 7.4 |
| Sterrlity | Stérile | NT | NT | Stérile | NT | Stérile |
| Particulate Matter (Light Obscuration] | 30 particles per container | NT | NT | 83 particles per container | NT | 124 particles per container |
| 11 particles per container | NT | NT | 1 particles per container | NT | 6 particles per container | |
| Bacterial | <0.35 | NT | NT | < 0.3S | NT | <0.35 |
| Parameter | Initial | 1 Month | 3 Month | 6 Month | 9 Month | 12 Month |
| Endotoxin (Kinetic Turbidimetric)1 | EU/mL | EU/mL | EU/mL |
ND - Not detected, or <0.05% area NT = Not Tested
Table 7 (cont'd)
| Parameter | Initial | 15 Month | 18 Month | 21 Month | 24 Month |
| Appearance | Clear, colorless solution free of participâtes | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates | Clear, colorless solution free of particulates |
| Assay (Potency) | 98.1% | 98.0% | 97.5% | 97.4% | 96.5% |
| Total Related Substances | 2% | 3% | 2% | 3% | 3% |
| (DACH) Pt-diaquo (-RRT 0.3) | 0.16% | 0.14% | 0.13% | 0.12% | 0.11% |
| (DACH) Ptmonoaquo (~RRT 0.7) | 0.84% | 0.94% | 0.76% | 1.07% | 0.93% |
| (DACH) Ptdichloride (RRT 1.3-1.6) | ND | ND | ND | ND | ND |
| RRT 3.1-3.2 | 0.11% | 0.59% | 0.58% | 0.67% | 0.65% |
| PT-112 Dimer (~RRT 4.0) | 0.34% | 0.34% | 0.33% | 0.35% | 0.33% |
| RRT 0.46 | ND | ND | 0.09% | 0.07% | 0.08% |
| RRT 0.50 | 0.06% | 0.16% | 0.26% | 0.23% | 0.25% |
| RRT 0.56 | 0.08% | 0.17% | 0.06% | 0.12% | 0.12% |
| RRT 0.68 | 0.09% | 0.12% | 0.08% | 0.14% | 0.11% |
| RRT 0.86 | ND | 0.06% | 0.05% | 0.05% | 0.06% |
| RRT 3.58 | ND | 0.07% | 0.10% | 0.10% | 0.14% |
| PH | 7.4 | 7.4 | 7.4 | 7.4 | 7.4 |
| Sterility | Stérile | NT | NT | NT | TBD |
| Particulate Matter (Light Obscuration) | 30 particles per container | NT | NT | NT | TBD |
| 11 particles per container | NT | NT | NT | TBD | |
| Bacterial Endotoxin (Kinetic Turbidimetric) | < 0.35 EU/mL | NT | NT | NT | TBD |
ND = Not detected, or <0.05% area
NT = Not Tested
Stability data on a batch of 5 mg/mL (R,R)-pyrodach-2 in 10 mM bicarbonate buffer (pH 8.6) at 25°C/60%RH, 2-8°C and -20°C are summarized in Table 8, Table 9, and Table 10, respectively.
Surprisingly, the addition of a small amount of pyrophosphate ion has been found to 5 dramatically improve the thermal stability of ready-to-use aqueous formulations of (R,R)pyrodach-2. The addition not only retards the rate of dégradation as a function of température, but it also serves to decrease the concentration of several impurities, including (DACH)Pt-Cli, an impurity which can be présent in (R,R)-pyrodach-2 based on the route of manufacture (WO2013176764 Al), (R,R)-pyrodach-2 dimer, and the impurity that forms în 10 (R,R)-pyrodach-2 fbrmulated in phosphate buffer and elutes at RRT ~ 3.1-3.2 in the HPLC system described in Example 3.
The ability of added pyrophosphate to reduce the concentration of (R,R)-pyrodach-2 dimer is particularly advantageous because this impurity is readily formed in aqueous solution of (R,R)-pyrodach-2 below 7, is highly insoluble, and can, at very low 15 concentrations, precipitate from aqueous (R,R)-pyrodach-2 solutions. For example, in a 5 mg/mL ready-to-use formulation of (R,R)-pyrodach-2 manufactured according to Example 6 where the initial concentration of (R,R)-pyrodach-2 dimer was ~0.6 area %, the dimer was observed to begin to precipitate as a crystalline solid between 6 and 9 months of storage at 28°C, with crystallization observed in ail sample vials by 12 months of storage.
Table 8 (R,R)-Pyrodach-2 Ready-to-use Aqueous Formulation Stability 25°C/60%RH (5 mg/mL (R,R)-pyrodach-2 in 10 mM Bicarbonate Buffer at pH 8.6) filled in 10 mL vials
| 12 month | Clear solution with no visible p articulât es | 98.4% | 92.23% | 0.14% | 2.20% | %98 0 | 0.32% | 0.97% | 0.06% | 0.37% | 0.06% | 0.06% | 0.12% | 0.05% | 1.07% | 0.15% | 1.02% | 9.07 | |
| 9 month | Clear solution with no visible particulates | 100.3% | 93.82% | νΊ 0 | 1.88% | X® Û' X O | 0.32% | 0.43% | 0.05% | 0.32% | ND | 0.07% | 0.10% | 0.06% | 0.88% | a1' O | 0.66% | 9.08 | |
| 6 month | Clear solution with no visible particulates | 99.2% | 95.03% | 0.22% | 1.29% | 0.80% | o*rj 0 | 0.82% | ND | 0.15% | 0.07% | 1 ND | 0.05% | ND | N? cr | 0.08% | 0.36% | 8.93 | |
| 4 month | Clear solution with no visible particulates | 103.0% | 95.98% | 0.16% | O | •V.O O | 0.17% | 0.73% | ND | 0.17% | ND | ND | ND | ND | 0.58% | 0.06% | 0.20% | 8.90 | |
| 3 month | Clear solution with no visible particulates | 101.6% | θ'0C | 0.27% | 0.76% | | 0.78% | 0.25% | 0.92% | ND | 0.17% | 1 ND | ND | ND | ND | 0.40% | 0.06% | 0.14% | 10 6 | |
| 2 month | Clear solution with no visible particulates | 100.4% | 96.45% | 0.19% | 0.56% | | 0.79% | 0.26% | 0.97% | ND | 0.12% | ND | ND | ND | θ'· O | 0.31% | ND | 0.07% | 8.73 | |
| 1 month | Clear solution with no visible part iculatcs | θ'· 3* 0C | 97.44% | 0.16% | 0.21% | 0.75% | 0.1 5% | 1.03% | ND | ND | ND | ND | ND | ND | 0.08% | ND | ND | oc oc | |
| 3 week | Clear solution with no visible particulates | 100,3% | 97.33% | 0.16% | 0.15% | 0.76% | 0.12% | 1 1.26% | ND | ND | ND | ND | ON | ND | 0.06% | ND | ND | oc | |
| 2 week | Clear solution with no visible particulates | 99.9% | 97.77% | 0.12% | 0.10% | O*·*· O | ND | 1.17% | ND | ND | ND | ND | ND | ND | ND | ND | ND | 8.64 | |
| 1 week | Clear solution with no visible particulates | 101.7% | X? c**· s* | 0.1 1% | 0.05% | 0.78% | 0.06% | 1 1.12% | ND | ND | ND | ND | ND | ND | ND | ND | ND | 8.57 | |
| Initial | Clear solution with no visible particulates | 100.3% | 98.04% | 0.11% | ND | 0.62% | ND | 1.05% | ND | ND | ND | ND | ND | ND | ND | ND | ON | 8.60 | |
| Parametcr | Appearance | Potency (Assay) | Purity (% Area) | Unknown Impurities | M © L. flÉ | RRT - 0.42 | RRT - 0.49 | RRT ~ 0.59 | RRT ~ 0.73 | M 90 7 S | RRT - 2.85 | © © 7 B | m 7 i | © H i i | RRT ~ 3.45 | RRT - 3.74 | RRT ~ 4.27 | RRT - 4.99 | Hd |
ND — Not Detected, or < 0.05%; NT — Not Tested; RRT = Relative Rétention time
Table 9 (R,R)-Pyrodach-2 Ready-to-use Aqueous Formulation Stability 2-8°C (5 mg/mL (R,R)-pyrodach-2 in 10 mM Bicarbonate Buffer at pH 8.6) filled in 10 mL vials
| 12 month | Clear solution with no visible particulate s | 100.3% | 96.64% | 0.13% | 0.05% | 0.47% | 0.64% | 0.27% | 0.98% | ND | %61O | 0.28% | 8.97 | |
| 9 month | Clear solution with no visible particulate s | 102.2% | X? r*“i & | 0.15% | ND | 0.33% | 0.58% | 0.24% | 0.43% | 0.05% | 0.13% | 0.16% | 9.07 | |
| 6 month | Clear solution with no visible particulate 1 s 1 | 100.4% | 97.56% | 0.23% | ND | 0.23% | 0.65% | 0.21% | 0.90% | ND | ND | 0.09% | 8.84 | |
| 4 month | Clear solution with no vis ible particulate s | 103.5% | 98.07% | 0.15% | ND | 0.16% | 0.68% | 0.09% | 0.72% | 0.05% | 0.05% | ND | 8.83 | |
| 3 month | Clear solution with no visible particulate ___L_ | 102.3% | 5^ & | 0.29% | ND | 0.13% | 0.53% | 0.15% | 0.89% | 0.06% | 0.05% | ND | ΜΊ G OC | |
| 2 month | Clear solution with no visible particulate s | 102.4% | 97.58% | è'- Ol O | ND | 0.11% | 1 0.62% | 0.15% | 1.03% | ND | ND | 0.06% | 8.76 | |
| 1 month | Clear solution with no visible particulate ___________?____________1 | 99.1% | 97.85% | 0.14% | ND | 0.05% | 0.55% | 0.08% | 1.14% | ND | ND | ND | OC | |
| 3 week | Clear solution with no visible particulate s | 100.0% | 97.91% | 0.14% | ND | ND | 0.56% | 0.07% | 1.11% | ND | ND | ND | 8.67 | |
| o CM | Clear solution with no visible particulate s | 100.5% | ? & | 0.12% | ND | ND | 0.63% | 0.06% | 1.14% | ND | ND | ND | 8.65 | |
| 1 week | Clear solution with no visible particulate s | 101.9% | sŒ tr· ri o oc O | 2 o | ND | ND | 0.60% | ND | 1.11% | ND | ND | ND | 8.57 | |
| Initial | Clear solution with no visible particulate s | 100.3% | 98.04% | 0.11% | ND | ND | 0.62% | ND | 1.05% | ND | ND | ND | 8.60 | |
| Parameter | Appearance | Potcncy (Assay) | Purity (% Area) | Lnknown Impurities | σ' M O i Ë ai | RRT-035 | RRT-0.41 | RRT-0.49 | θ' VJ ? § | RRT-0.73 | RRT-1.51 | □C rsi Z i | Ί· 1*3 s | pH |
ND - Not Detected, or < 0,05%; NT = Not Tested; RRT = Relative Rétention time
Table 10 (R,R)-Pyrodach-2 Ready-to-use Aqueous Formulation Stability -20“C (5 mg/mL (R,R)-pyrodach-2 in 10 mM Bicarbonate Buffer at pH 8.6) filled in 10 mL vials
| I 12 month I | Clear solution with yellowbrown précipitât io n upon équilibrât io n | «6.1% | 90.94% | 0.13% | 5.26% | ND | 1.19% | 0.27% | 0.43% | 0.88% | 0.25% | 0.08% | 0.09% | 0.05% | 0.06% | %cro | O*' C C | %60 0 | 0.14% | OC OC | |
| 0 | NT | Z | H Z | NT | NT | F Z | NT | F Z | XN | NT | NT | NT | F Z | XN | NT | NT | NT | NT | NT | F Z | |
| s·· | |||||||||||||||||||||
| I 6 month | Clear solution with yellow precipilatio n upon équilibrai io n1 | oû o | 96.36% | 0.23% | 0.45% | Q Z | ti' | 0.15% | O Z | 0.84% | 0.22% | ND | ND | 0.08% | ND | 0.06% | 0.05% | ND | 0.09% | pl o6 | |
| I 4 month | NT | NT I | NT | F Z | NT | NT | H Z | NT | NT | F Z | NT | NT | NT | NT | NT | NT | NT | NT | NT | H Z | |
| month | NT | XN | NT | F Z | NT | I XN | NT | NT | | XN | NT | 1 XN | NT | H Z | NT | NT | NT | NT | | XN | F Z | H Z | |
| 2 | NT | Z | NT I | | IN | | XN | NT I | Z | F Z | H Z | NT I | NT I | NT I | I XN | NT I | NT I | Z | 1 XN | NT 1 | NT I | Z | |
| C O | yellow lut ion ith no isible iculates ______________________________________________________________________________________________________________________1 | Wj | £ ce | 16% | | e*© | O © | £ | © © | 12% | | 12% | | Q | Q | Û | d | ND | | ,s O’' w, q | | %900 | 1 QN | 0.08% | | ||
| - | Pale so wi vi parti | Ch | £ | 6 | d | d | d | d | d | — | d | d | 00 | ||||||||
| | 3 week | NT _______________________________________________________________________________________________________________________________________________________________________________________________1 | __NI__ | ___NJ___ | Z | NT | | NT | | NT | | NT | | H Z | F Z | Z | NT J | NT | | NT | | NT | | NT [ | NT | | NT | | NT j | H Z | |
| g C4 | NT | | NT | | NT | | NT | | NT | | NT | | NT | | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | F Z | |
| | | | NT | Z | XN | F Z | XN | XN , | H Z | F Z | XN | Z | XN | NT | NT | Z | NT | | NT | | NT | | NT | | NT | | Z | |
| ?lear lut ion Ih no siblc iculates | *1 | O | 11% I | ''ID | Û | θ'1 «N | Q | û 2 | 05% | Q 2 | ND | ND | ND | ND | ON | ND | ND | ND | © C | ||
| — | C > > £ | o | » | d | d | OC | |||||||||||||||
| eu | |||||||||||||||||||||
| Q | |||||||||||||||||||||
| Parameter | g s X 2 2. | ? te < £ ? | & < C | 1 s ! | RK 1-0.29 | RK Γ-0.41 | ffrO-.IMH | RRT - 0.49 | KRI -0.59 | RR 1 - 0.62 | J g | HR I - 1.69 | C M l ΐ | M © - ? | IN i - X X | RR I - 3.24 | d — g | KRI —3.33 | t ï | l £ 2 | n. |
| s |
ND Not Detected, or < 0.05%; NT — Not Tested; RRT = Relative Rétention time 1 Appeared to resolubilize with manual agitation and brief sonication 2 Not able to resolubilize with manual agitation and brief sonication
Comparison of stability data for a 5 mg/mL concentration (R,R)-pyrodach-2 solution in 10 mM potassium phosphate buffer adjusted to pH 7.0 - 7.5 at 25oC/60%RH in Table 4 with that of a same concentration formulation containing ~0.5 molar équivalent of added pyrophosphate in Table 1l, shows the addition of pyrophosphate ion dramatically retards the rate of (R,R)-pyrodach-2 dégradation such that the stability of the formulation with pyrophosphate at 25oC is comparable / superior to that of the formulation without the added pyrophosphate stored at refrigerated conditions. Stability data on the formulation with added pyrophosphate at 40oC/75%RH in Table 12 is even more dramatic. Kinetic / design of experiment studies were utilized to demonstrate the effect of pyrophosphate on buffered aqueous ready-to-use formulations of (R,R)-pyrodach-2 (Example 9).
The data further demonstrate that addition of a buffering sait such as phosphate or carbonate i bicarbonate is unnecessary to achieve pH control but rather the buffering capacity of pyrophosphate in the physiological pH range is sufficient to control pH in an aqueous formulation of (R,R)-pyrodach-2. From a clinical perspective, maintaining the amount of pyrophosppate ion at a minimum in an aqueous formulation of (R,R)-pyrodach-2 is désirable. A ratio of l molar équivalent of pyrophosphate ion to (R,R)-pyrodach-2 was found to provide sufficient stability to aqueous (R,R)-pyrodach-2 solutions at physiological pH such that a formulated ready-to-use formulation would hâve a commercial shelf-life of several years on storage at standard long-term International Committee on Harmonization (ICH) storage conditions of 25°C/60%RH (i.e. ambient température). More optimally a molar ratio of-0.5 mole of pyrophosphate ion to (R,R)-pyrodach-2 was found to provide acceptable stability for an aqueous ready-to-use formulation of (R,R)-pyrodach-2. Most preferably the formulation consists of a 5 mg/mL aqueous solution of (R,R)-pyrodach-2 in pyrophosphate adjusted to pH 7-7.5. Further, the inclusions of pyrophosphate ion in the formulation, or as the exclusive buffering agent, éliminâtes the potential for précipitation of impurities and in particuiar the highly insoluble (R,R)-pyrodach-2 dimer impurity from an aqueous ready-to-use formulations of (R,R)-pyrodach-2.
Table 11 (R,R)-Pyrodach-2 Ready-to-use Aqueous Formulation Stability 25°C/60%RH (5 mg/mL (R,R)-pyrodach-2 in lOmM Sodium Phosphate Buffer, 5.2 mM Sodium Pyrophosphate at pH 7.5) filled in 10 mL vials
| Parameter | Initial | 1 Month | 2 Months | 3 Months | 6 Months | 9 Months |
| Appcarancc | Clear Colorless Solution Free of Particubtes | Clear Colorless Solution Free of Particubtes | Clear Colorless Solution Free of Particulates | Clear Colorless Solution Free of Particubtes | Clear Colorless Solution Free of Particubtes | Clear Colorless Solution Free of Particubtes |
| Potency (Assay) | 102.0% | 102.2% | 103.8% | 101.4% | 102.8% | 101.7% |
| Indisidual Rclatcd Substances | ||||||
| RRT0.28-0.29 | 0.14% | 0.10% | 0.20% | 0.17% | 0.17% | 0.18% |
| RRT 0.50-0 .SI | 0.08% | 0.08% | 0.15% | 0.11% | 0.12% | 0.21% |
| RRT0.S8 | 0.34% | 0.39% | 0.38% | 0.43% | 0.44% | 0.42% |
| RRT 0.73-0.74 | 0.83% | 0.71% | 0.92% | 0.88% | 0.81% | 0.27% |
| RRT 0.92 | 0.05% | ND | ND | ND | ND | ND |
| RRT 1.57 | 0.12% | ND | ND | ND | ND | ND |
| ΡΓ-112 Dimer | 0.16% | ND | ND | ND | ND | ND |
| Total Relatcd Substances | 1.7% | 1.3% | 1.6% | 1.6% | 1.5% | 1.20% |
| pH | 7.5 | 7.6 | 7.6 | 7.6 | 7.6 | 7.6 |
Table 12 (R,R)-Pyrodach-2 Ready-to-use Aqueous Formulation Stability 40°C/75%RH (5 mg/mL (R,R)-pyrodach-2 in lOmM Sodium Phosphate Buffer, 5.2 mM Sodium
Pyrophosphate at pH 7.5) filled in 10 mL vials
| Parameter | Initial | 1 Month | 2 Months | 3 Months | 6 Months |
| Appcarancc | Clear Colorless Solution Free of Particulates | Clear Colorless Solution Free o f Particulates | Clear Colorless Solution Free of Particulates | Clear Colorless Solution Free of Particulates | Clear Co lo ries s Solution Free of Particulates |
| Potency (Assay) | 102.0% | 101.6% | 103.8% | 101.5% | 102.8% |
| Indisidual Rclatcd Substances | |||||
| RRT 0.28-0.29 | 0.14% | 0.10% | 0.19% | 0.16% | 0.17% |
| RRT 0.50-0.51 | 0.08% | 0.10% | 0.19% | 0.16% | 0.22% |
| RRT 0.58 | 0.34% | 0.41% | 0.41% | 0.48% | 0.47% |
| RRT 0.73-0.74 | 0.83% | 0.68% | 0.88% | 0.86% | 0.81% |
| RRT 0.92 | 0.05% | ND | ND | ND | ND |
| RRT 1.57 | 0.12% | ND | ND | ND | ND |
| RRT 3.66-3.71 | ND | ND | 0.07% | 0.11% | 0.18% |
| PT-1 1 2 Dimer | 0,16% | ND | ND | ND | ND |
| Total Rclatcd Substances | 1.7% | 1.3% | 1.7% | 1.8% | i .9% |
| pH | 7.5 | 7.6 | 7.6 | 7.5 | 7.5 |
Evidence that added pyrophosphate reverses the formation of PT-II2 dimer in aqueous formulations of PT-H2 was shown in the following experiment. A 5 mg/mL aqueous solution of PT-U2 was prepared by dissolving PT-H2 in 10 mM potassium phosphate buffer containing added potassium hydroxide such that the final solution pH was -6.5. The solution was allowed to stir at ambient température for about 24 hours during which time the PT-112 dimer level increased from about 0.33% in the API to about 1.02% in the formulated solution. On subséquent pH adjustment of a portion of the solution to -pH 7.5 with potassium hydroxide, the concentration of dimer was observed to progressively decrease over a 7 day period at ambient température accompanied by a corresponding increase in the RRT 3.1-3.2 impurity. However on pH of a portion of the solution with potassium hydroxide to ~pH 7.5 and the addition of 0.5 eq. of pyrophosphate, the level of dimer was observed to progressively decrease to effectively non-detectable level after 9 days at ambient température. The decrease was not accompanied by the formation of the RRT 3.1-3.2 impurity; nor the formation of any new impurities, rather an increase in the concentration of PT-112 was observed.
Example 1
Impact of Buffer Strength
Buffer solution préparation mM sodium phosphate, pH 7
-200 mL of 10 mM sodium phosphate, dibasic adjusted with -177 mL of 10 mM sodium phosphate, monobasic
-Final pH 7.02
100 mM sodium phosphate, pH 7
-200 mL of 100 mM sodium phosphate, dibasic and adjusted with —138 mL of 100 mM sodium phosphate, monobasic
-Final pH 6.98
ΙΟ mM potassium phosphate, pH 7
-200 mL of 10 mM potassium phosphate, dibasic adjusted with ~126 mL of 10 mM potassium phosphate, monobasic
-Final pH 7.01
100 mM potassium phosphate, pH 7
-200 mL of 100 mM potassium phosphate, dibasic adjusted with -125 mL of 10 mM potassium phosphate, monobasic
-Final pH 7.02 mM sodium carbonate
-No pH adjustment performed
-Final pH 10.84
100 mM sodium carbonate
-No pH adjustment performed
-Final pH H.39 mM sodium bicarbonate
-No pH adjustment performed
-Final pH 8.18
100 mM sodium bicarbonate
-No pH adjustment performed
-Final pH 8.06 (R,R)-Pyrodach-2 was dissolved in each of these buffers to préparé at l mg/mL solution. The potency of capped solutions stored in stability chambers controlled at 25°C/60%RH and 40°C/75%RH was monitored by HPLC. See FIG. I and FIG. 2.
Example 2
Impact of pH on Phosphate Buffer Solution Stability
Buffer solution préparation mM potassium phosphate. pH 6.5
-50 mL of 10 mM potassium phosphate, dibasic adjusted with -145 mL of 10 mM potassium phosphate, monobasic
-Final pH 6.50 mM potassium phosphate, pH 7
-200 mL of 10 mM potassium phosphate, dibasic adjusted with —126 mL of 10 mM potassium phosphate, monobasic
-Final pH 7.01 mM potassium phosphate, pH 7.5
-50 mL of 10 mM potassium phosphate, dibasic adjusted with -14 mL of 10 mM potassium phosphate, monobasic
-Final pH 7.50 mM potassium phosphate, pH 8.0
-50 mL of 10 mM potassium phosphate, dibasic adjusted with -4 mL of 10 mM potassium phosphate, monobasic
-Final pH 8.00 mM potassium phosphate. pH 8.5
-50 mL of 10 mM potassium phosphate, dibasic adjusted with -1 mL of 10 mM potassium phosphate, monobasic
-Final pH 8.49 mM potassium phosphate. pH 9.0
-90 mL of 10 mM potassium phosphate, dibasic adjusted with < l mL of 10 mM 5 potassium phosphate, monobasic
-Final pH 9.02 (R,R)-pyrodach-2 was dissolved in each of these buffers to préparé at l mg/mL solution. The potency of capped solutions stored in stability chambers controlled at 10 25°C/60%RH and 40°C775%RH was monitored by HPLC, from which the data reported at
T=3 days for pH 7.0 buffered solution are shown in FIG. 3 and FIG. 4, respectively.
Example 3
HPLC System
| Parameter | Condition |
| Column | Waters XSelect HSS T3, 4.6 mm x 100 mm, 3.5 pm |
| Stroke Volume | 100 pL |
| Column Température | 10.0°C± 2.0°C |
| Sample Température | Ambient |
| Mobile Phase A | 50 mM Sodium Phosphate, pH 2.0 |
| Mobile Phase B | 100% Acetonitrile |
| Diluent | 20 mM Sodium Pyrophosphate |
| Injection Volume | 6 pL |
| Run Time | 24 minutes |
| Détection Wavelength | 205 nm |
| Time (Minutes) | Flow Rate (mL/min) | % Mobile Phase A | % Mobile Phase B |
| 0.00 | 1.5 | 100.0 | 0.0 |
| 4.93 | 1.5 | 100.0 | 0.0 |
| 14.53 | 1.5 | 90.0 | 10.0 |
| 16.53 | 1.5 | 100.0 | 0.0 |
| 24.00 | 1.5 | 100.0 | 0.0 |
Example 4 (R,R)-pyrodach-2 Ready-to-use Formulation 5 mg/mL in 10 mM Sodium Bicarbonate pH 9.0-9.5 (Pharmatek (R,R)-pyrodach-2 Prototype Stability Protocol) • Transfer 1680.0 mg ± 0.5 mg of sodium bicarbonate to a 2-L volumétrie flask.
• Fill flask to approximately 75% volume with water, swirl as needed to dissolve ail solids.
• Volumetrically transfer 32.0 mL of l N NaOH to flask.
• Dilute to volume with water and mix well.
• Record pH of final solution. This is the diluent.
• Transfer 7653.1 mg ± 0.5 mg of (R,R)-pyrodach-2 to a compounding vessel.
• Transfer 1500 mM of the diluent to the vessel and stir to dissolve solids.
• Record pH of final solution.
• Pass entîre solution through a 0.22 pm stérile filter membrane into a stérile collection vessel.
• Calculate (R,R)-pyrodach-2 solution concentration
Wt of (R,R)-pyrodach-2, mg ([(R,R)-pyrodach-2], mg/mL * (R,R)-pyrodach-2 purity l500mL • Conduct the following in a laminar flow hood; fill 10-mL stérile Type i borosilicate glass vials with a fill volume of 10-mL, stopper the vials with 20 mm stérile rubber stoppers and crimp-sealed with 20 mm crimp tops.
• Place vials in 25°C/60%RH, 2-8°C and -20°C stability chambers. HPLC method in Example 3 to monîtor purity and impurities.
Example 5 (R,R)-pyrodach-2 15 mg/mL Ready-to-use Formulation
V is the required final volume of solution to be made • Dissolve V x 11.4 mg sodium phosphate, tribasîc (dodecahydrate) + V x 4.26 mg sodium, dibasic (anhydrous) in V mL of distilled water. Stir until buffer salts are dissolved.
• To the stirred buffer solution add V x 15 mg quantity of (R,R)-pyrodach-2; stir on a magnetic stirrer until the solid (R,R)-pyrodach-2 dissolves completely ( 10 -30 minutes) • Record the solution pH.
• Adjust the pH, if needed, to 7.0 - 7.4 by the adding V x l .8 mg of sodium phosphate, tribasic (dodecahydrate) with stirring to dissolve, record the final pH.
• To make a (R,R)-pyrodach-2 solution of a lower concentration, dilute the above 15 mg/mL (R,R)-pyrodach-2 solution with an appropriate amount of vehicle.
Example 6 (R,R)-Pyrodach-2 Ready-to-use Formulation 5 mg/mL in 10 mM Potassium Phosphate pH
7.2-7.5 • Transfer 4564.6 mg ± 0.5 mg of potassium phosphate dibasic, trihydrate to a 2-L volumétrie flask.
• Fill flask to approximately 75% volume with water, swirl as needed to dissolve ail solids.
• Volumetrically transfer 32.0 mL of IN K.OH to flask.
• Dilute flask to volume with water and mix well.
• Record pH of final solution. This is the diluent.
• Transfer 7653.1 mg ± 0.5 mg of (R,R)-pyrodach-2 to a compounding vessel.
• Transfer 1500 mL of the diluent to the vessel and stir to dissolve solids.
• Record pH of final solution.
• Pass entire solution through a 0.22 pm stérile filter membrane into a stérile collection vessel.
• Calculate (R,R)-pyrodach-2 solution concentration
Wt of (R,R)-pyrodach-2, mg ([(R.R)-pyrodach-2], mg/mL *
Example 7 (R,R)-pyrodach-2 Ready-to-use Formulation 5 mg/mL in 10 mM Sodium Phosphate, 5.2 mM Sodium Pyrophosphate pH 7.5 • Transfer 1419.6 mg± 14.0 mg of dibasic sodium phosphate anhydrous to a l-L volumétrie flask.
• Transfer 2298.5 mg ± 23.0 mg of tetrasodium pyrophosphate decahydrate into the same l-L volumétrie flask.
• Fill flask to approximately 75% volume with stérile water for injection, swîrl as needed to dissolve ail solids.
• Volumetrically transfer 8.0 mL of IN NaOH to flask.
• Dilute flask to volume with water and mix well.
• Record the pH of final solution. This is the vehicle.
• Déterminé the tare weight of a 500-mL compounding vessel with stir bar.
• Transfer 2500.1 mg ± 25.0 mg of (R,R)-pyrodach-2 to the vessel.
• Transfer 450.0 g ± 0.1 g of the vehicle to the vessel and stir to dissolve solids.
• Détermine the initial pH of the solution.
• Slowly adjust the pH of the solution to 7.5 ±0.1 by adding additional IN NaOH.
• Détermine the gross solution weight and dilute the solution weight to 500.0 g ± 0.1 g by adding additional vehicle into the compounding vessel. Density = 1.00 g/mL • Stir the final solution for an additional 5 minutes.
• Détermine the pH of final solution.
• Pass the entire solution through a 0.22 pm PVDF Stericup filter into a stérile collection vessel.
• Conduct the following in a laminar flow hood; fill 10-mL stérile tubing vials with 10 mL of solution, stoppered with a stérile Flurotec stopper, and crimp-capped with a flip-off seal.
• Place vials in 40°C/75%RH and 25°C/60%RH stability chambers. HPLC method in Example 3 to monitor purity and impurities.
Example 8 (R,R)-pyrodach-2 Ready-to-use Formulation 5 mg/mL in 5.2 mM Sodium Pyrophosphate pH 7.5 • Transfer 2298.5 mg ± 23.0 mg of tetrasodium pyrophosphate decahydrate into a l-L volumétrie flask.
• Fill flask to approximately 75% volume with stérile water for injection, swirl as needed to dissolve ail solids.
• Volumetrically transfer 14.5 mL of IN NaOH to flask.
• Dilute flask to volume with water and mix well.
• Record the pH of final solution. This is the vehicle.
• Détermine the tare weight of a 500-mL compounding vessel with stir bar.
• Transfer 2500.1 mg ± 25.0 mg of (R,R)-pyrodach-2 to the vessel.
• Transfer 450.0 g ± 0.1 g of the vehicle to the vessel and stir to dissolve solids.
• Déterminé the initial pH of the solution.
• Slowly adjust the pH of the solution to 7.5 ± 0.1 by adding additional 0.1N NaOH.
• Détermine the gross solution weight and dilute the solution weight to 500.0 g ± 0.1 g by adding additional vehicle into the compounding vessel. Density = l .00 g/mL.
• Stir the final solution for an additional 5 minutes.
• Determine the pH of final solution.
• Pass the entire solution through a 0.22 pm PVDF Stericup filter into a stérile collection vessel.
• Conduct the following in a laminar flow hood; fill 10-mL stérile tubing vials with mL of solution, stoppered with a stérile Flurotec stopper, and crimp-capped with a flip-off seaL • Place vials in 40°C/75%RH and 25°C/60%RH stability chambers. HPLC method in Example 3 to monitor purity and impurities.
Example 9
Design of Experiment Study on Pyrophosphate Ion Stabilization
The formulations used for the Design of Experiment study are listed in Table 11. The stability évaluation under the highly stressing température of 60 °C demonstrate that the addition of very small amounts of pyrophosphate ion, including as little as -0.25 molar équivalent relative to the (R,R)-pyrodach-2 present, provides a dramatic decrease in the overall rate of (R,R)-pyrodach-2 dégradation and in impurity appearance. Notably the data show that pyrophosphate ion results in the progressive disappearance of several impurities initially present in the aqueous solution resulting from impurities in the (R,R)-pyrodach-2 or which hâve formed during solution préparation. Specifically the presence of pyrophosphate results in the rapîd disappearance of the (R,R)-pyrodach-2 dimer impurity and the RRT-3.1-
3.2 impurity.
Table 11 (R,R)-Pyrodach-2 Pyrophosphate Design of Experiments Formulations
| Formulation No. | Phosphate concentration | Pyrophosphate concentration | pH |
| I | lOmM | 10.305 mM | 6.5 |
| 2 | lOmM | 10.305 mM | 7.5 |
| 3 | none | 10.305 mM | 7.5 |
| 4 | none | 10.305 mM | 6.5 |
| 5 | lOmM | 5.153 mM | 6.5 |
| 6 | lOmM | 5.153 mM | 7.5 |
| 7 | none | 5.153 mM | 7.5 |
| 8 | none | 5.153 mM | 6.5 |
| 9 | 10 mM | none | 6.5 |
| 10 | lOmM | none | 7.5 |
| H | 10 mM | l .0305 mM | 6.5 |
| 12 | 10 mM | l .0305 mM | 7.5 |
| 13 | 10 mM | 2.577 mM | 7.5 |
| 14 | none | _ 5.l35mM | 8.5 |
Example 10 (R,R)-pyrodach-2 Ready-to-use Aqueous Formulation (5 mg/mL (R,R)-pyrodach-2 in 10 mM Phosphate Buffer at pH 7) filled in 10 mL vials
To a 36 ml glass beaker equipped with mechanical mixer was add 24645.5 g of stérile water for injection. With agitation 47.03 gm of dibasic potassium phosphate USP was added and the solids allowed to dissolve. To the stirred solution was added 253.8 gm of 1.00 N potassium hydroxide. Stérile water for injection USP (900.0 gm) was used as a rinse to facilitate both additions. With vigorous agitation, (R,R)-pyrodach-2 (201.87 gm) was slowly added and agitation continued until all of the solids dissolved. Stérile water for injection USP (900.0 gm) was used as a rinse to facilitate the addition. The pH was determined to be 6.7. A total of 85 mL of 1.00 N potassium hydroxide was added in 5.0 mL aliquots to adjust the pH to 7.3. The solution was stérile filtered through 0.22 μ Millipore Millipack filter and aseptically filled, 10 ml top a vial in 10 mL in 10 cc Wheaton clear molded vails, stoppered with a 20 mm stopper and crimp seal capped.
The foregoing examples and description of certain preferred embodiments should be taken as illustrating, rather than as limiting, the present invention. As would be readily appreciated by a person skilled in the art, numerous variations and combinations of the features set forth above may be utilized without departing from the present invention.
Claims (34)
- What is claimed is:1. A liquid pharmaceutical composition comprising a phosphaplatin compound and an aqueous buffer solution having pH at about or above 7.
- 2. The liquid pharmaceutical composition of claim l, wherein the liquid pharmaceutical composition is a ready-to-use liquid formulation suitable for parentéral administration.
- 3. The liquid pharmaceutical composition of claim l or 2, wherein concentration of the phosphaplatin compound is about 20 mg/mL or less.
- 4. The liquid pharmaceutical composition of claim 3, wherein the concentration of the phosphaplatin compound is between about l and about 10 mg/mL.
- 5. The liquid pharmaceutical composition of claim 3, wherein the concentration of the phosphaplatin compound is between about 1 and about 6 mg/mL.
- 6. The liquid pharmaceutical composition of claim 3, wherein the concentration of the phosphaplatin compound is about 5 mg/mL.
- 7. The liquid pharmaceutical composition of any one of claims 1 to 6, wherein the buffer comprises a sait of phosphate or bicarbonate / carbonate.
- 8. The liquid pharmaceutical composition of claim 7, wherein the buffer sait concentration is between about I mM and about 100 mM.
- 9. The liquid pharmaceutical composition of claim 7, wherein the buffer sait concentration is between about 5 mM and about 50 mM.
- 10. The liquid pharmaceutical composition of claim 7, wherein the buffer sait concentration is about 10 mM.
- 11. The liquid pharmaceutical composition of any one of claims 1 to 10, wherein the pH is in the range of about 7.0 to about 9.0.
- 12. The liquid pharmaceutical composition of claim 11, wherein the pH is in the range of 7.0 - 8.0.
- 13. The liquid pharmaceutical composition of claim 11, wherein the buffer is a sodium or potassium sait.
- 14. The liquid pharmaceutical composition of claim 11, wherein the buffer is potassium phosphate; the concentration of the phosphaplatin compound is about 5 mg/mL and the pH is between about 7.0 and about 8.0.
- 15. The liquid pharmaceutical composition of claim 14, wherein the buffer concentration is about 10 mM.
- 16. The liquid pharmaceutical composition of any one of daims I to 15, wherein the buffer comprises a pyrophosphate sait.
- 17. The liquid pharmaceutical composition of claim 16, wherein the molar ratio of pyrophosphate anion to the phosphaplatin compound is at least about 0.1 to about l.
- 18. The liquid pharmaceutical composition of claim 17, wherein the molar ratio of pyrophosphate ion to the phosphaplatin compound is about 0.2 to about l
- 19. The liquid pharmaceutical composition of claim 17, wherein the molar ratio of pyrophosphate ion to the phosphaplatin compound is about 0.4 to about I.
- 20. The liquid pharmaceutical composition of claim 1, wherein the concentration ofthe phosphaplatin compound is about 5 mg/mL, the pyrophosphate concentration is about5.2 mM, and the pH is in the range of about 7.0 to about 8.0.
- 21. The liquid pharmaceutical composition of any one of daims 1 to 20, wherein the phosphaplatin compound is pyrophosphato-platinum (II) complex having a formula of (I) or (II):Ri /O-PZ-OH 'Pt OZ r(Π), or a sait thereof, wherein R1 and R2 are each independently selected from NH3, substituted or unsubstituted aliphatic amines, and substituted or unsubstituted aromatic amines; and wherein R3 is selected from substituted or unsubstituted aliphatic or aromatic 1,2-diamînes.
- 22. The liquid pharmaceutical composition of any one of daims 1 to 21, wherein the phosphaplatin compound is a trans-l,2-cydohexanediamine-(dihydrogen pyrophosphato)platinum(II) (“trans-pyrodach-2”) complex.
- 23. The liquid pharmaceutical composition of any one of daims 1 to 22, wherein the phosphaplatin compound is (R,R)-trans-l ,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) (“(R,R)-trans-pyrodach-2”).
- 24. The liquid pharmaceutical composition of any one of daims 1 to 22, wherein the phosphaplatin compound is (S,S)-trans-l,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) (“(S,S)-trans-pyrodach-2”).
- 25. The liquid pharmaceutical composition of any one of claims l to 21, wherein the phosphaplatin compound is cis-l,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) (“cis-pyrodach-2”).
- 26. A liquid pharmaceutical composition according to any one of claims l to 25 for use in the treatment of a disease or disorder.
- 27. A liquid pharmaceutical composition according to any one of claims l to 25 for use in the treatment of a cancer selected from the group consisting of gynecological cancers, genitourinary cancers, lung cancers, head-and-neck cancers, skin cancers, gastrointestinal cancers, breast cancers, bone and chondroital cancers, and hematological cancers,
- 28. A process of preparing a liquid pharmaceutical composition of phosphaplatin compound, the process comprising: a) dissolving a phosphaplatin compound in an aqueous buffer comprising a sufficient amount of hydroxide base such that the pH remains at or above 7; b) optionally adding a hydroxide base to adjust the pH to a desired range, and c) filtering the solution to obtain a liquid formulation.
- 29. The process of claim 28, wherein the aqueous buffer is a phosphate buffer, a carbonate/biocarbonate buffer, or a combination thereof.
- 30. The process of daim 28 or 29, wherein the pH of the liquid formulation is in the range of about 7.0 to about 9.0.
- 31. The process of any one of claims 28 to 30, further comprising adding a sufficient amount of a pyrophosphate sait to stabilize the phosphaplatin compound in the liquid formulation.
- 32. The process of any one of claims 28 to 31, wherein said filtering isconducted under stérile conditions.
- 33. The process of claim any one of claims 28 to 32, further comprising d) filling the solution into a vial, stoppering and capping the vial in a stérile environment so that the formulation is ready for use.
- 34. The process of any one of claims 28 to 33, wherein the liquid formulation obtained is a formulation according to any one of claims l to 27.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62/319047 | 2016-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA18955A true OA18955A (en) | 2019-10-28 |
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