WO2011055379A1 - A stable injectable pharmaceutical composition of aceclofenac and process for preparing thereof - Google Patents
A stable injectable pharmaceutical composition of aceclofenac and process for preparing thereof Download PDFInfo
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- WO2011055379A1 WO2011055379A1 PCT/IN2010/000310 IN2010000310W WO2011055379A1 WO 2011055379 A1 WO2011055379 A1 WO 2011055379A1 IN 2010000310 W IN2010000310 W IN 2010000310W WO 2011055379 A1 WO2011055379 A1 WO 2011055379A1
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- Prior art keywords
- aceclofenac
- arginine
- solution
- aqueous solution
- pharmaceutical composition
- Prior art date
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- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical group OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 title claims abstract description 127
- 229960004420 aceclofenac Drugs 0.000 title claims abstract description 126
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 43
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 239000004475 Arginine Substances 0.000 claims abstract description 88
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 88
- 239000007864 aqueous solution Substances 0.000 claims abstract description 48
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 31
- 239000000243 solution Substances 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 235000009697 arginine Nutrition 0.000 description 75
- 229960003121 arginine Drugs 0.000 description 75
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 11
- 229960001680 ibuprofen Drugs 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 7
- 238000004108 freeze drying Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- 229930064664 L-arginine Natural products 0.000 description 4
- 235000014852 L-arginine Nutrition 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000001116 FEMA 4028 Substances 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 3
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 3
- 229960004853 betadex Drugs 0.000 description 3
- 238000010668 complexation reaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 230000003381 solubilizing effect Effects 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- -1 aceclofenac compound Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 101150071146 COX2 gene Proteins 0.000 description 1
- 101100114534 Caenorhabditis elegans ctc-2 gene Proteins 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 101150000187 PTGS2 gene Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229960003589 arginine hydrochloride Drugs 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to a stable injectable pharmaceutical composition of aceclofenac and process for its preparation.
- Aceclofenac is a non-steroidal anti-inflammatory drug which in the form of white or almost white, crystalline powder. Chemically aceclofenac is 2-[2-[2-[(2,6- dichlorophenyl)amino]phenyl]acetyl]oxyacetic acid with molecular formula of C 16 Hi 3 Cl 2 N0 4 and molecular weight of 354.18472 g mol. The mode of action of aceclofenac is largely based on the inhibition of prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclooxygenase, which is involved in the production of prostaglandins.
- U.S. Patent 1 Application No. 20090156670A1 relates to a nonaqueous liquid parenteral aceclofenac formulation, capable of pharmaceutical application, comprising an aceclofenac component in a form of a non-water-soluble aceclofenac salt, in a solubilized or dissolved form in a solvent liquid wherein said solvent liquid comprises, a) a nonaqueous solubilizer component effective to stabilize aceclofenac and diclofenac that forms by conversion of the aceclofenac component thereto, said nonaqueous solubilizer component being substantially inert with respect to said conversion; and b) an aceclofenac salt stabilizer component effective to inhibit precipitation of aceclofenac free acid. It also discloses that the presented pharmaceutical compositions are stable upon storage at room temperature and at refrigerated temperatures.
- Nisharani S. Ranpise et al., Pharmaceutical Development and Technology, June 2009 describe the inclusion complexation of aceclofenac with ⁇ -cyclodextrin by grinding, microwave and spray-drying techniques & provide an improvement of water solubility and in vitro dissolution rate of aceclofenac by complexation with ⁇ - cyclodextrin and hydroxypropyl-P-cyclodextrin.
- U.S. Patent No. 6727286 provides a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen with a molar ratio of arginine to ibuprofen, which is less than 1:1, as well as a method of making the same. It also discloses a method of treating a condition chosen from pain, inflammation, fever, and/or other conditions alleviated by ibuprofen comprising administering the above said pharmaceutical composition.
- Non aqueous injectable pharmaceutical compositions of lipophilic " water-insoluble drugs like aceclofenac frequently consist of mixtures of water, organic cosolvents and surfactants.
- Limitations in using non aqueous solvents for injectable compositions include possible drug precipitation, pain, inflammation and hemolysis upon injection. As such no aqueous injectable preparation of aceclofenac is commercially available.
- As aqueous solution is readily adaptable for formulating & also because of instability of
- aceclofenac pharmaceutical composition which uses aqueous solution of aceclofenac.
- Prior art also discloses pharmaceutical composition of an aqueous solution of arginine and ibuprofen comprising a molar ratio of arginine to ibuprofen, which is less than 1 :1 .
- ibuprofen is very slightly soluble in water and readily soluble in 5 ethanol. Also it is readily soluble and stable in alkaline pH.
- aceclofenac is practically insoluble in water & its solubility in alkaline medium is less than 10 mg ml.
- aceclofenac is instable in alkaline medium as it gets converted to diclofenac by hydrolysis. So making a formulation of aceclofenac by solubilizing aceclofenac instead of ibuprofen with arginine in line with the teachings
- Aceclofenac is less soluble in aqueous medium as compared to ibuprofen. Additionally a formulation of aceclofenac with arginine would give rise to a formulation with alkaline pH in which the aceclofenac would be instable unlike ibuprofen which is stable at alkaline pH. Moreover, we have observed that solution preparations of aceclofenac are highly
- a stable injectable pharmaceutical composition of dofenac can be prepared by solubilizing aceclofenac in arginine at a pH of about 20 6:5 to about 8.7 & subsequently lyophilizing the prepared aceclofenac solution.
- the aqueous solubility of aceclofenac can be enhanced by mixing it with arginine in a specified molar ratio, which can be used to prepare the said pharmaceutical composition of aceclofenac.
- It is a object of the present inventio to provide a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar . 30 ratio of arginine to aceclofenac in the range of about 1.1:1 to about 3.4.1, having pH of about 6 5 to about 8.7, wherein the said aqueous solution is lyophilized.
- It is an object of the present invention' to provide a stable injectable pharmaceutical composition comprising an aqueous solution of arginine 1 and aceclofenac in the molar i
- It is an another object of the present invention to provide a process to prepare a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1 : 1 to about 3.4: 1, having pH of about 6.5 to about 8.7, wherein the said aqueous solution is lyophilized.
- It is yet another object of the present invention to provide a process to prepare a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1: 1 to about 3.4: 1, having pH of about 6.5 to about 7.5, wherein the said aqueous solution is lyophilized.
- the present invention relates to a stable injectable pharmaceutical composition * comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1: 1 to about 3.4: 1, having pH of about 6.5 to about 8.7, wherein the said aqueous solution is lyophilized.
- the present invention relates to a stable injectable pharmaceutical composition
- a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1 : 1 to about 3.4:1, having pH of about 6.5 to about 7.5, wherein the said aqueous solution is lyophilized.
- the present invention also relates to a process for preparing a stable! injectable f ; ⁇ ⁇ . s ⁇ ; ⁇ . ' ⁇ I . ⁇ ⁇ ' ! ⁇ ' ⁇ ' . ! . ' ⁇ i ⁇ ⁇ : ⁇ . ' 7 i ⁇
- composition cpin prising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1 1 : 1 to about 3.4: 1, having pH of about 6.5 to about 8.7 comprising:
- the present invention also relates to a process for preparing a stable injectable pharmaceutical composition
- a process for preparing a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1 :1 to about 3.4: 1, having pH of about 6.5 to about 7.5 comprising:
- stable refers to chemical stability of aceclofenac in pharmaceutical composition wherein there is no change in assay values of aceclofenac when kept at 40°C/75%RH or 30°C/75%RH or 25°C/60%RH for 1 month.
- a stable injectable pharmaceutical composition of aceclofenac can be prepared by solubilizing aceclofenac in arginine at a pH of about 6.5 to about 8.7 & subsequently lyophilizing the prepared aceclofenac solution.
- the aqueous solubility of aceclofenac can be enhanced by mixing it with arginine in a specified molar ratio, which can be used to prepare the said pharmaceutical composition of aceclofenac.
- the present invention relates to a stable injectable pharmaceutical composition
- a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1:1 to about 3.4: 1, having pH of about 6.5 to about 8.7, wherein the said aqueous solution is lyophilized.
- the present invention relates to a stable injectable pharmaceutical composition
- a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1 : 1 to about 3.4: 1, having pH of about 6.5 to about 7.5, wherein the said aqueous solution is lyophilized.
- the present invention also relates to a process for preparing a stable injectable pharmaceutical composition
- a process for preparing a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1: 1 to about 3.4: 1, having pH of about 6.5 to about 8.7 comprising:
- the present invention also relates to a process for preparing a stable injectable pharmaceutical composition
- a process for preparing a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1 : 1 to 0 about 3.4: 1, having pH of about 6.5 to about 7.5 comprising: ⁇ ]
- the therapeutic effective amount of aceclofenac is in the range from about 100 mg to about 300 mg per day.
- Arginine is a conditionally nonessential amino acid, meaning most of the time it can be manufactured by the human body, and does not need to be obtained directly through the diet.
- the L-form is one of the 20 most common natural amino acids.
- the present invention utilizes arginine or its pharmaceutically acceptable salt forms, preferably L-arginine or arginine hydrochloride, more preferably L-arginine for solubilization.
- the therapeutic effective amount of arginine that may be used is in the range from about 2 gm to about 8 gm per day.
- One embodiment of the present invention relates to provide a stable injectable pharmaceutical composition
- a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac, wherein a molar ratio of arginine to aceclofenac is from about 1.1 :1 to about 3.40: 1, more preferably about 1.22: 1 to about 2,04:1.
- the said molar ratio of arginine to aceclofenac ensures the solubility of aceclofenac in the aqueous solution.
- the molar ratio of arginine to aceclofenac is below the said limit, aceclofenac is in insoluble form and when it is above the said limit, arginine would in insoluble form after reconstitution.
- the molar ratio of arginine to aceclofenac is from about 1.1:1 to about 3.40:1, more preferably about 1.22:1 to about 2.04: 1.
- Another embodiment of the present invention relates to adjusting pH of the 3 ⁇ solution of arginine and aceclofenac to about 6.5 to about 8.7, preferably about 6.5 to about 7.5.
- aceclofenac does not form solution with arginine due to its insolubility at pH of less than 6.5 and in alkaline medium at pH greater than about 8.7, aceclofenac is unstable due to ; its hydrolysis.
- the solution stability study of the solution of arginine and aceclofenac before lyophilization by adjusting the pH in between about 6.5 to about 8.7 shows degradation of aceclofenac and unstable formulation.
- lyophilization is a dehydration process and is typically used to preserve a perishable material or make the material more convenient for transport.
- adjusting the pH of the solution of arginine and aceclofenac in between about 6.5 to about 8.7 and subsequently lyophilizing it results in minimum degradation of aceclofenac during lyophilization process as well as upon reconstitution of the lyophilized pharmaceutical composition.
- the present invention relates to provide a stable injectable pharmaceutical composition
- a stable injectable pharmaceutical composition comprising an aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1:1 to about 3.4:1, having pH of about 6.5 to about 8.7, wherein the said aqueous solution is lyophilized.
- the present pharmaceutical composition of aceclofenac may include one or more pharmaceutically acceptable excipients such as buffers like disodium hydrogen phosphate, sodium dihydrogen phosphate or mixtures thereof, solubilizers, stabilizers, antioxidants which will be apparent to the skilled person.
- pharmaceutically acceptable excipients such as buffers like disodium hydrogen phosphate, sodium dihydrogen phosphate or mixtures thereof, solubilizers, stabilizers, antioxidants which will be apparent to the skilled person.
- the pharmaceutical composition as described herein may be prepared by different techniques.
- one embodiment of the present invention may relate to dissolving L-arginine in water fqr injection.
- disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate or mixtures thereof with L-arginine solution.
- aceclofenac Adding aceclofenac to this mixture and dissolving it with stirring.
- required volume was made up by water for injection and adjusting the pH of about 6.5 to about 8.7.
- Such methods provide the present stable injectable pharmaceutical compositions of aceclofenac.
- the stable injectable pharmaceutical compositibn of aceclofenac may, be prepared as given in table 1.
- Hifenac® is marketed by Intas Pharma in India & is available in 1 ml ampoule containing 150 mg Aceclofenac /ml and is meant for intramuscular administration in a ready to use form.
- results as shown in table 3 indicate that the aqueous solution of arginine and aceclofenac in the molar ratio of arginine to aceclofenac in the range of about 1.1 : 1 to about 3.4:1, having pH of about 6.5 to about 8.7, is unstable before lyophilization. It shows degradation of aceclofenac, when kept at 2°C to 8°C, 25°C/60%RH, 30°C/65%RH and 40°C/75%RH for 15 days without lyophilization.
- the stable injectable pharmaceutical composition may also be prepared by different molar ratios of arginine to aceclofenac as shown in table 4.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| UAA201206779A UA103955C2 (ru) | 2009-11-05 | 2010-05-14 | Стойкая инъекционная фармацевтическая композиция ацеклофенака и способ ее получения |
| RU2012122654/15A RU2012122654A (ru) | 2009-11-05 | 2010-05-14 | Стабильная фармацевтическая инъекционная композиция ацеклофенака и способ ее получения |
| PH1/2012/501121A PH12012501121A1 (en) | 2009-11-05 | 2010-05-14 | A stable injectable pharmaceutical composition of aceclofenac and process for preparing thereof |
| ZA2012/03711A ZA201203711B (en) | 2009-11-05 | 2012-05-22 | A stable injectable pharmaceutical composition of aceclofenac and process for preparing thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2564MU2009 | 2009-11-05 | ||
| IN2564/MUM/2009 | 2009-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011055379A1 true WO2011055379A1 (en) | 2011-05-12 |
Family
ID=43969651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2010/000310 WO2011055379A1 (en) | 2009-11-05 | 2010-05-14 | A stable injectable pharmaceutical composition of aceclofenac and process for preparing thereof |
Country Status (5)
| Country | Link |
|---|---|
| PH (1) | PH12012501121A1 (no) |
| RU (1) | RU2012122654A (no) |
| UA (1) | UA103955C2 (no) |
| WO (1) | WO2011055379A1 (no) |
| ZA (1) | ZA201203711B (no) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5708024A (en) * | 1994-06-29 | 1998-01-13 | Novartis Corporation | Salts of 2- (2,6-dichlorophenyl)amine!phenylacetoxyacetic acid with organic basic cations |
| WO2004024186A2 (en) * | 2002-09-11 | 2004-03-25 | Nitromed, Inc. | Treatment of cyclooxygenase-3 mediated diseases and disorders |
| KR20050005894A (ko) * | 2003-07-07 | 2005-01-15 | 진양제약주식회사 | 신규 아세클로페낙의 아미노산염 및 이 염을 유효성분으로함유하는 약학적 제제 |
| WO2006000228A2 (en) * | 2004-06-29 | 2006-01-05 | Nycomed Danmark Aps | Manufacturing of quick release pharmaceutical compositions of water insoluble drugs and pharmaceutical compositions obtained by the process of the invention |
| CN101205193A (zh) * | 2007-12-14 | 2008-06-25 | 王文菊 | 一种醋氯芬酸与有机碱形成的盐类化合物及其组合物及用途 |
-
2010
- 2010-05-14 WO PCT/IN2010/000310 patent/WO2011055379A1/en active Application Filing
- 2010-05-14 UA UAA201206779A patent/UA103955C2/ru unknown
- 2010-05-14 RU RU2012122654/15A patent/RU2012122654A/ru not_active Application Discontinuation
- 2010-05-14 PH PH1/2012/501121A patent/PH12012501121A1/en unknown
-
2012
- 2012-05-22 ZA ZA2012/03711A patent/ZA201203711B/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5708024A (en) * | 1994-06-29 | 1998-01-13 | Novartis Corporation | Salts of 2- (2,6-dichlorophenyl)amine!phenylacetoxyacetic acid with organic basic cations |
| WO2004024186A2 (en) * | 2002-09-11 | 2004-03-25 | Nitromed, Inc. | Treatment of cyclooxygenase-3 mediated diseases and disorders |
| KR20050005894A (ko) * | 2003-07-07 | 2005-01-15 | 진양제약주식회사 | 신규 아세클로페낙의 아미노산염 및 이 염을 유효성분으로함유하는 약학적 제제 |
| WO2006000228A2 (en) * | 2004-06-29 | 2006-01-05 | Nycomed Danmark Aps | Manufacturing of quick release pharmaceutical compositions of water insoluble drugs and pharmaceutical compositions obtained by the process of the invention |
| CN101205193A (zh) * | 2007-12-14 | 2008-06-25 | 王文菊 | 一种醋氯芬酸与有机碱形成的盐类化合物及其组合物及用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| UA103955C2 (ru) | 2013-12-10 |
| ZA201203711B (en) | 2013-03-27 |
| PH12012501121A1 (en) | 2018-01-24 |
| RU2012122654A (ru) | 2013-12-10 |
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