WO2013028177A1 - Formulations of deoxycholic acid and salts thereof - Google Patents
Formulations of deoxycholic acid and salts thereof Download PDFInfo
- Publication number
- WO2013028177A1 WO2013028177A1 PCT/US2011/048806 US2011048806W WO2013028177A1 WO 2013028177 A1 WO2013028177 A1 WO 2013028177A1 US 2011048806 W US2011048806 W US 2011048806W WO 2013028177 A1 WO2013028177 A1 WO 2013028177A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- salt
- deoxycholic acid
- sodium
- precipitation
- Prior art date
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- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 title claims abstract description 130
- 229960003964 deoxycholic acid Drugs 0.000 title claims abstract description 111
- 239000000203 mixture Substances 0.000 title claims abstract description 111
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 150000003839 salts Chemical class 0.000 title claims abstract description 49
- 238000009472 formulation Methods 0.000 title description 32
- 238000001556 precipitation Methods 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 35
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 32
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 25
- 239000000872 buffer Substances 0.000 claims description 19
- 239000011780 sodium chloride Substances 0.000 claims description 16
- 239000003755 preservative agent Substances 0.000 claims description 11
- 210000001789 adipocyte Anatomy 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 230000002335 preservative effect Effects 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- -1 alkali metal salt Chemical class 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
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- 230000000087 stabilizing effect Effects 0.000 abstract description 4
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 101710151321 Melanostatin Proteins 0.000 description 11
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- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 11
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 229940009976 deoxycholate Drugs 0.000 description 8
- 239000008363 phosphate buffer Substances 0.000 description 8
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- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
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- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 4
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 4
- CIWXXQSJBGNZNJ-UHFFFAOYSA-N BMS-192548 Chemical compound COC1=CC2=C(C(O)=C1)C(=O)C1=C(O)C3(O)C(=O)C(C(C)=O)=C(O)CC3(O)CC1=C2 CIWXXQSJBGNZNJ-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 description 4
- 229940075564 anhydrous dibasic sodium phosphate Drugs 0.000 description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 description 4
- 235000010216 calcium carbonate Nutrition 0.000 description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 4
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 4
- 239000001095 magnesium carbonate Substances 0.000 description 4
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 4
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical group O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 4
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- 229910000010 zinc carbonate Inorganic materials 0.000 description 4
- 235000004416 zinc carbonate Nutrition 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
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- 239000003638 chemical reducing agent Substances 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- JHYNXXDQQHTCHJ-UHFFFAOYSA-M ethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC)C1=CC=CC=C1 JHYNXXDQQHTCHJ-UHFFFAOYSA-M 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000005907 ketalization reaction Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000011179 visual inspection Methods 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
- A61K9/08—Solutions
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to aqueous pharmaceutical formulations containing very low concentrations of a salt of deoxycholic acid (“DCA”), wherein the formulation is maintained at a pH such that precipitation of DCA is substantially inhibited.
- DCA deoxycholic acid
- the pharmaceutical composition is buffered to maintain a physiologically acceptable pH such that the composition is suitable for injection.
- aqueous solutions of a salt of deoxycholic acid at concentrations of from about 0.4% w/v to less than about 2% w/v can be stabilized by adjusting the pH of the solution to above about 8 and preferably from a physiologically acceptable pH from about 8.1 to about 8.5.
- the pH is preferably maintained within this range by using buffers.
- this invention is directed to aqueous formulations consisting essentially of a salt of deoxycholic acid at a concentration of from about 0.4% w/v to less than about 2% w/v and optionally a preservative effective amount of benzyl alcohol which formulations are stabilized against precipitation by adjusting the pH of the initially formed clear solution to a pH of from about 8.1 to about 8.5.
- this invention is directed to an aqueous formulation consisting essentially of a salt of deoxycholic acid at a concentration of from about 0.5% w/v to about 1% w/v and optionally a preservative effective amount of benzyl alcohol which formulations are stabilized against precipitation by adjusting the pH of the initially formed clear solution to a pH of from about 8.1 to about 8.5.
- this invention is directed to an aqueous formulation consisting essentially of: a sterile aqueous solution buffered to a pH of about 8.3;
- composition is stable against precipitation.
- Also disclosed herein is a method for stabilizing an aqueous composition of a salt of deoxycholic acid against precipitation during storage wherein the concentration of the deoxycholic acid salt is an amount effective to lyse fat cells provided that the amount of the deoxycholic acid salt ranges from about 0.4%> w/v to less than 2% w/v, which method comprises: forming an aqueous solution of a deoxycholic acid salt at an initial pH above its pKa; adjusting the pH of the aqueous solution to a pH of from about 8.1 to about 8.5; and optionally including a sufficient amount of buffer to maintain the pH at from about 8.1 to about 8.5.
- a method to lyse a fat cell comprising administering to said cell a composition according to this invention.
- Fig. 1 illustrates (67 X enhancement) that an aqueous composition of water and 0.9 % w/v benzyl alcohol and no sodium deoxycholate contains only a trace of precipitate, which is presumed to be bioprene tubing particles.
- Fig. 2 illustrates (67 X enhancement) that an aqueous composition of water, 0.5 % w/v sodium deoxycholate and 0.9 % w/v benzyl alcohol contains significant amounts of precipitate which is presumed to be deoxycholate crystals.
- Fig. 3 illustrates (67 X enhancement) that an aqueous composition of water, 1 % w/v sodium deoxycholate and 0.9 % w/v benzyl alcohol contains significant amounts of precipitate, albeit less than that of 0.5 % w/v sodium deoxycholate. As before, the precipitate is presumed to be deoxycholate crystals.
- Fig. 4 illustrates (67 X enhancement) that an aqueous composition of water, 2 % w/v sodium deoxycholate and 0.9 % w/v benzyl alcohol contains significant amounts of precipitate but substantially less than that observed in Figs. 2 and 3.
- compositions and methods shall mean excluding any active ingredients.
- An "active ingredient” is a substance intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body.
- a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like but would exclude enzymes such as phosphatases, and proteins.
- Non- limiting examples of such proteins are heparin, albumin, and the like
- compositions of this invention consisting of excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this invention.
- salt of deoxycholic acid or "a salt thereof refers to pharmaceutically acceptable salts of (4R)-4-((3R,5R,10S,12S,13R,17R)-3,12-dihydroxy- 10, 13-dimethylhexadecahydro- 1 H-cyclopenta[a]phenanthren- 17-yl)pentanoate having an alkali metal or an ammonium ion as the cation.
- alkali metal salts with sodium salts being more preferred.
- Sodium deoxycholate or sodium (4R)-4-((3R,5R, 105,125,13R,17R)-3,12-dihydroxy- 10, 13-dimethylhexadecahydro- lH-cyclopenta[a]phenanthren- 17-yl)pentanoate can be prepared according to the methods disclosed in PCT/US2010/061150 titled “Methods for the Purification of Deoxycholic Acid," filed on December 17, 2010.
- the term "aqueous pharmaceutical formulation” refers to a composition of a deoxycholic acid or a salt thereof in water suitable for administration to a patient preferably via subcutaneous injection from a syringe.
- buffer refers to an aqueous solution comprising a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid.
- a buffer has the property that the pH of the solution changes very little when a small amount of acid or base is added to it. Buffer solutions are used as a means of keeping pH at a nearly constant value in a wide variety of chemical applications. Examples of suitable buffers include phosphate buffers and those known in the literature (see, for example, Troy, D.B., ed. (2005)
- base refers to various typically water-soluble
- suitable bases include metal carbonates and bicarbonates, for example sodium carbonate, calcium carbonate, magnesium carbonate, zinc carbonate, sodium bicarbonate and the like; and metal hydroxides, for example sodium hydroxide, potassium hydroxide, and the like, such as those known in the literature (see, for example, Troy, D.B., ed. (2005) Remington: The Science and Practice of Pharmacy, 21 st ed., Lippincott Williams & Wilkins).
- metal carbonates refers to the metal salt of CO 3 " .
- metal bicarbonates refers to the metal salt of HCO 3 " .
- metal bicarbonate For example, sodium bicarbonate, and the like.
- metal hydroxides refers to the metal salt of ⁇ .
- sterile water or "water for injection” refer to a sterile, nonpyrogenic preparation of water for injection which contains no bacteriostat, antimicrobial agent or added buffer.
- the osmolar concentration of additives totals at least 112 mOsm/liter (two-fifths of the normal osmolarity of the extracellular fluid -280 mOsm/liter).
- benzyl alcohol refers to the compound
- precipitation refers to the formation of a solid in a solution and is readily differentiated from gel formation.
- solution refers to a substantially homogeneous mixture comprising two or more substances dissolved in a solvent.
- substantially inhibit precipitation and “inhibits precipitation” means to inhibit most or all visible precipitation so as to maintain homogeneity for a period of time ranging from at least 1 month to at least 1 year.
- the term "relative standard deviation for homogeneity” or "3 ⁇ 4" refers to the value obtained by dividing the standard deviation of the homogeneity by the absolute value of the mean. An 3 ⁇ 4 less than 10 indicates very good homogeneity.
- sodium deoxycholate is recited for illustrative purposes only and it is understood that other pharmaceutically acceptable salts of deoxycholic acid can be used interchangeably with the sodium salt.
- concentrations ranging from about 0.4% w/v to less than about 2% w/v can be stabilized by adjusting the pH of the solution.
- This invention is directed to an aqueous formulation consisting essentially of a salt of deoxycholic acid at a concentration ranging from about 0.4% w/v to less than about 2% w/v and optionally a pharmaceutically acceptable excipient such as a preservative effective amount of benzyl alcohol and/or a pH adjusting buffer, wherein said formulation is maintained at a pH of about 8.1 to about 8.5.
- the aqueous formulation is lyophilized to provide for a stable composition which is ready to be reconstituted by addition of the appropriate amount of water.
- this invention comprises lyophilized compositions as described above which optionally further contain a lyophilization aid.
- the aqueous formulation contains about 0.5% w/v of a salt of deoxycholic acid. In another embodiment, the aqueous formulation contains about 1% w/v of a salt of deoxycholic acid.
- the water employed in the aqueous formulation is sterile water.
- the preservative effective amount of benzyl alcohol is about 0.9% w/v benzyl alcohol and the pH of the formulation is about 8.3.
- said salt is an alkali metal salt. In another embodiment, said salt is a sodium salt.
- the pharmaceutical formulations disclosed herein are suitable for injection into a human.
- the method of injection can be any type of injection, such as subcutaneous injection, as well as other forms of injection.
- the precipitation of the salt of deoxycholic acid in the aqueous formulation is inhibited for a period of at least about six months. In another aspect, the precipitation is inhibited for a period of at least about one year. In yet another aspect, the precipitation is inhibited for a period of at least about two years.
- the formulation when stored at various temperatures, for example at ambient or cold temperatures, the formulation can have an increased shelf life.
- the formulation when stored at various temperatures, for example at ambient or cold temperatures, the formulation can have an increased shelf life.
- the composition is stored at a temperature of from about 17 °C to about 27 °C. In some embodiments, the temperature of the formulation is increased to a temperature of about 25 °C to about 37 °C. In other embodiments, the formulation is stored at a temperature of from about 2 °C to about 8 °C.
- the pH of the formulation ranges from about 8.1 to about 8.5. In one embodiment, the pH of the composition is about 8.1, or alternatively, about 8.2, or alternatively, about 8.3, or alternatively, about 8.4, or alternatively, about 8.5. In a preferred embodiment, the pH of the formulation is about 8.3.
- the pH is established by the use of a base. It is contemplated that any base can be used to increase the pH of the composition provided that it does not react with the sodium deoxycholate and will not cause harm to the patient.
- the base is selected from the group consisting of metal carbonates, metal bicarbonates, metal hydroxides, or a mixture thereof. Examples of bases include, but are not limited to, a base selected from the group consisting of sodium carbonate, calcium carbonate, magnesium carbonate, zinc carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide or a mixture thereof. In one embodiment, the base is sodium hydroxide.
- the pH of the composition may be maintained at the desired pH during storage with the use of a buffer.
- a buffer Various buffers are known in the art and it is contemplated that any buffer having buffering capacity at the desired pH can be used in the formulations disclosed herein.
- the buffer is a phosphate buffer.
- the amount of phosphate in the composition can be determined to provide a desired pH and salt concentration.
- the composition comprises about 10 mM phosphate buffer. In a preferred embodiment, the composition comprises about 10 mM dibasic sodium phosphate buffer.
- the composition comprises at least one excipient to aid in achieving a composition with desired properties, such as increased solubility, preservability or to provide an isotonic solution.
- excipients are known in the art.
- the composition comprises about 1% w/v sodium chloride.
- the composition comprises about 0.9% w/v benzyl alcohol.
- the composition comprises about 0.9% w/v benzyl alcohol and about 1% w/v sodium chloride.
- the pH of the composition is established by use of a base and optionally maintained by use of a buffer.
- this invention provides a stabilized composition
- a stabilized composition comprising: a phosphate buffer of a pH of about 8.3;
- composition wherein the composition is stabilized against precipitation.
- the phosphate buffer is 10 mM dibasic sodium phosphate buffer.
- the preservative effective amount of benzyl alcohol is about 0.9% w/v.
- the formulations disclosed herein comprise from about 0.4% w/v to less than about 2% w/v of a salt of deoxycholic acid in water maintained at a pH sufficient to substantially inhibit precipitation of the salt of deoxycholic acid.
- the amount of precipitation or homogeneity of the composition can be measured using various methods. For example, it can be measured quantitatively using light scattering by illuminating the composition with a spectrophotometer. Or alternatively, the homogeneity can be measured qualitatively by observing the visual clarity of the solution with the eye. In some embodiments, the composition has a relative standard deviation for homogeneity of less than about 5%.
- the composition has a relative standard deviation for homogeneity of less than about 4%, or alternatively, about 3%, or alternatively, about 2%, or alternatively, about 1%.
- this invention is directed to a composition consisting essentially of: a sterile aqueous solution buffered to a pH of about 8.3;
- composition is stable against precipitation.
- this invention is directed to a composition consisting of: an aqueous solution buffered to a pH of about 8.3;
- composition is stable against precipitation.
- the solutions herein do not include lipids, phospholipids, or phosphatidylcholine. In some embodiments, the solutions herein include up to 5% w/w, w/v, or v/v lipids, specifically phospholipids, or more specifically phosphatidylcholine. Preferably, the amount of lipids used is less than that of sodium deoxycholate or another salt of deoxycholic acid .
- the aqueous pharmaceutical composition of the invention can further comprise a second therapeutic agent selected from the group consisting of: antimicrobial agents, vasoconstrictors, anti-thrombotic agents, anti-coagulation agents, suds- depressants, anti-inflammatory agents, analgesics, dispersion agents, anti-dispersion agents, penetration enhancers, steroids, tranquilizers, muscle relaxants, and anti-diarrhea agents.
- a solution is in a container that contains up to 500 mL of solution. Such container can be a syringe or syringe-loadable container.
- the formulations further comprise a molecule known to cause fat to die by an orthogonal mechanism.
- NPY neuropeptide Y
- Such molecules include neuropeptide Y (NPY) antagonists including, but not limited to, NPY receptor antagonists, such as BIBP-3226 (Amgen), BIBO-3304 (Boehringer Ingleheim), BMS-192548 and AR-H040922 (Bristol- Myers Squibb), LY-357897 (Eli Lilly), 1229U91 and GW438014S (GlaxoSmithKline), JNJ- 5207787 (Johnson & Johnson), Lu-AA-44608 (Lundbeck), MK-0557 (Merck NPY), NGD- 95-1 (Neurgogen), NLX-E201 (Neurologix), CGP-71683 (Novartis), PD- 160170 (Pfizer), SR-120819A, BIIE0246, and S.A.0204 (Sanofi Avent
- fat selective pro-apoptotic peptides such as the CKGGRAKDC peptide that homes to white fat vasculature (See, Kolonin M.G. et al, Nat. Med., 2004, 10(6): 625-32).
- Another aspect of the invention relates to mixing adipo-ablative bile acids, such as, deoxycholic acid (DCA) with agents that kill fat cells.
- DCA deoxycholic acid
- this invention contemplates a means to enhance the aesthetic effects of deoxycholate injections by mixing into the deoxycholate injectate a molecule that causes fat to die by an orthogonal mechanism.
- candidate molecules include, but are not limited to, neuropeptide Y (NPY) antagonists and fat selective pro-apoptotic peptides. Since fat cell killing may be required to mediate the desired effects, the effects of an agent with fat killing ability can be enhanced via the addition of a molecule with potent fat cell killing effects.
- molecules that require access to the vasculature to kill can gain access to these proteins because deoxycholate may cause vascular leakage.
- deoxycholate may cause vascular leakage.
- such agents can be synergistic with deoxycholate potentially creating a more potent means to mediate body contouring in fewer therapeutic sessions.
- NPY antagonists include, but are not limited to, NPY receptor antagonists, such as BIBP-3226 (Amgen), BIBO-3304 (Boehringer Ingleheim), BMS-192548 and AR-H040922 (Bristol-Myers Squibb), LY-357897 (Eli Lilly), 1229U91 and GW438014S (GlaxoSmithKline), JNJ-5207787 (Johnson & Johnson), Lu-AA-44608 (Lundbeck), MK- 0557 (Merck NPY), NGD-95-1 (Neurgogen), NLX-E201 (Neurologix), CGP-71683
- NPY receptor antagonists such as BIBP-3226 (Amgen), BIBO-3304 (Boehringer Ingleheim), BMS-192548 and AR-H040922 (Bristol-Myers Squibb), LY-357897 (Eli Lilly), 1229U91 and GW438014S (Glaxo
- Exemplary fat selective pro-apoptotic peptides includes, but is not limited to, CKGGRAKDC peptide that homes to white fat vasculature. See, Kolonin M.G. et al., Nat. Med. June 10(6):625-32 (2004).
- Sodium deoxycholate or sodium (4R)-4-((3R,5R, 105,125,13R,17R)-3,12-dihydroxy- 10, 13-dimethylhexadecahydro- lH-cyclopenta[a]phenanthren- 17-yl)pentanoate can be prepared according to the methods disclosed in PCT/US2010/061150 titled “Methods for the Purification of Deoxycholic Acid," filed on December 17, 2010. Other salts of deoxycholic acid can be prepared likewise by the skilled artisan.
- adjusting the pH of the aqueous solution to a pH of from about 8.1 to about 8.5; and optionally including a sufficient amount of buffer to maintain the pH at from about 8.1 to about 8.5.
- methods disclosed herein substantially stabilize the formulation of deoxycholic acid salt against precipitation over a period of time preferably for at least about six months.
- the methods stabilize the formulation of deoxycholic acid salt against precipitation for a period of at least about one year.
- the methods stabilize the formulation of deoxycholic acid salt against precipitation for a period of at least about two years.
- the pH of the solution can inhibit the precipitation of deoxycholic acid or a salt thereof at concentrations of from about 0.4% w/v to less than about
- the pH is established by the use of a base. It is contemplated that any base can be used to increase the pH of the composition provided that it does not react with deoxycholic acid or a salt thereof.
- the base is selected from the group consisting of metal carbonates, metal bicarbonates, and metal hydroxides, or a mixture thereof. Examples of bases include, but are not limited to, a base selected from the group consisting of sodium carbonate, calcium carbonate, magnesium carbonate, zinc carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide or a mixture thereof. In one embodiment, the base is sodium hydroxide.
- the pH ranges from about 8.1 to about 8.5.
- the pH of the composition is about 8.1, or alternatively, about 8.2, or alternatively, about 8.3, or alternatively, about 8.4, or alternatively, about 8.5.
- the pH of the aqueous solution is about 8.3.
- the pH of the composition may need to be maintained with the use of a buffer.
- a buffer is know in the art and it is contemplated that any buffer having buffering capacity at the desired pH can be used in the formulations disclosed herein.
- the buffer is a phosphate buffer.
- the amount of phosphate required to provide a desired pH and salt concentration can be calculated using methods well known in the art.
- the composition comprises about 10 mM phosphate buffer.
- the phosphate buffer is 10 mM dibasic sodium phosphate buffer.
- the pH is established by use of a base and optionally maintained by use of a buffer.
- the methods disclosed herein provide formulations which are suitable for injection into a human.
- the method of injection can be any type of injection, such as subcutaneous injection, as well as other forms of injection. Therefore, in some embodiments, the aqueous solution comprises sterile water or water for injection (WFI).
- WFI water for injection
- the method comprises adding about 1% w/v benzyl alcohol.
- the formulation also comprises at least one excipient to aid in achieving an isotonic solution. Such excipients are known in the art.
- the method comprises adding about 1% w/v sodium chloride. In some embodiments, the method comprises adding both 1% w/v benzyl alcohol and 1% w/v sodium chloride. In some embodiments, the method comprises adding both 0.9% w/v benzyl alcohol and 0.9% w/v sodium chloride.
- an aqueous solution comprising less than about 2% w/v of deoxycholic acid salt is maintained at a pH sufficient to substantially inhibit precipitation of deoxycholic acid salt.
- the amount of precipitation or homogeneity of the composition can be measured using various methods. For example, it can be measured quantitatively by measuring the light scattering via illumination by a spectrophotometer. Or alternatively, the homogeneity can be measured qualitatively by simply observing the visual clarity of the solution with the eye.
- the method provides a
- composition having a relative standard deviation for homogeneity of less than about 5%.
- the relative standard deviation for homogeneity of less than about 4% or alternatively, about 3%, or alternatively, about 2%, or alternatively, about 1%.
- the storage temperature can assist in maintaining the solubility of deoxycholic acid salt in the formulation.
- the storage temperature is from about 17 °C to about 27 °C. In some embodiments, the storage temperature is about 25 °C to about 37 °C. In other embodiments, the storage temperature is from about 2 °C to about 8 °C.
- the concentration of the salt of deoxycholic acid in the formulation is about 0.5% w/v, or alternatively about 0.7% w/v, or alternatively about 1% w/v, or alternatively about 1.2% w/v, or alternatively about 1.4% w/v, or alternatively less than about 2% w/v.
- the salt of deoxycholic acid is sodium deoxycholate.
- the composition comprises 0.5% w/v of sodium deoxycholate.
- the composition comprises 1% w/v of sodium deoxycholate.
- the aqueous formulation is split into a plurality of individual solutions which are separately administered to the fat cells.
- the aqueous formulation is split into 5, 10, 15, 20, 25 or 30 separate solutions and, in some cases, up to 50 separate solutions.
- the salt of deoxycholic acid is sodium deoxycholate.
- a syringe comprising a chamber, a plunger and an injection needle wherein the chamber comprises a formulation of this invention.
- the chamber is sufficient to hold at least 2 mL and preferably no more than 4 mL of the formulation.
- this invention provides a synthesis of DCA from protected commercially available 9-a,17-P-dihydroxy-5-a-androstan-3-one as shown in scheme 1 below.
- the 9- ⁇ ,17- ⁇ hydroxyl groups of commercially available 9-a,17-P-dihydroxy-5-a- androstan-3-one are differentially protected with hydroxyl protecting groups which can be removed under conditions where one of the hydroxyl groups is regenerated while the other hydroxyl group remains protected.
- Such differential protection is referred to as orthogonal protection and uses well known reagents and reaction conditions.
- one hydroxy group is protected as an acetyl group, whereas the other hydroxy group is protected as a benzyl group.
- Each group can be selectively removed under reaction conditions that retain the other hydroxyl protecting group intact.
- the relatively sterically protected 9-a-hydroxyl group may not need to be protected as the reactions contemplated prior to elimination of that group are likely inhibited at this position due to steric hindrance. Regardless, protection of this hydroxyl group adequately insures that the group remains intact until elimination of the hydroxyl group via dehydration is desired.
- the 17-keto group in compound 3 is protected as a ketal under standard ketalization conditions such as reaction with 1 ,2-dihydroxyethane or 1,3-dihydroxypropane to give compound 4 (which illustrates ketal formation with the 1 ,2-dihydroxyethane for illustrative purposes only).
- the reaction is carried out in a solvent such as acetonitrile at 40 °C for about 40-55 hours.
- a solvent such as acetonitrile
- the slow portionwise addition of TBHP results in more efficient oxidation.
- the product formed contains a mixture of compound 6 and the corresponding allylic alcohol.
- the product mixture is then oxidized with PCC to give compound 6.
- Compound 12 (crude DCA) was further purified with methanol wash and recrystallized from ethanol. It was diluted with 2 mol% MeOH in CH 2 C1 2 (25 vol) and heated to 35-37 °C for 1 hour. The slurry was allowed to cool to 28-30 °C and filtered. The filter cake was washed with CH 2 C1 2 (5 vol) and dried under vacuum at 40 °C to afford DCA.
- DCA was dissolved in 10% DI water/ EtOH (12 vol), polish filtered over celite and washed with 10% DI water/ EtOH (3 vol). The resulting 15 volume filtrate was added to DI water (30 vol) and a thin white slurry was afforded. The slurry was held for 24 hours, filtered, washed with DI water (20 vol) and dried under vacuum at 40 °C to afford DCA.
- deoxycholate proceeds via conventional conditions.
- conversion of a pharmaceutically acceptable salt of DCA such as sodium deoxycholate to DCA also proceeds via conventional conditions.
- this invention provides a stabilized formulation comprising: a buffered aqueous solution having a pH of about 8.1 to about 8.5 and further comprising about 0.5%> of sodium deoxycholate and about 0.9%> of benzyl alcohol, wherein the formulation is stabilized against precipitation, and the sodium deoxycholate is prepared according to scheme 1.
- this invention provides a stabilized formulation comprising: a buffered aqueous solution having a pH of about 8.1 to about 8.5 and further comprising about 1% of sodium deoxycholate and about 0.9%> of benzyl alcohol, wherein the formulation is stabilized against precipitation, and the sodium deoxycholate is prepared according to scheme 1.
- the precipitation rating estimates that "0” refers a clear solution and that "10” refers to a mixture exhibiting substantial precipitation readily visible to the naked eye.
- this invention provides that the surprising precipitation from dilute, 0.4% to less than 2% (w/v), salt of deoxycholic acid solutions are inhibited, to the extent that such solutions are useful for subcutaneous injections, by increasing the solution pH.
- a composition of sodium deoxycholate (0.5%> and 1% ) was prepared comprising sodium phosphate (10 mM), sodium chloride (75-90 mM), benzyl alcohol (0.9%>), deoxycholic acid, pH 8.3.
- the solution so prepared could optionally be lyophilized to provide for a lyophilized product which could be reconstituted by addition of the appropriate amount of sterile water. Accordingly, this invention also provides for lyophilized products of the solutions disclosed herein.
- b. Preparation of 1000 mL isotonic batches at 10 mg/niL
- the results from section a (above) did not scale up perfectly when multiplied ten fold. To 900 mL of water, 1.4g anhydrous dibasic sodium phosphate, 8.6 g NaCl, and 2.7 mL 10 M NaOH were added. 10.0 g of DCA was then added and allowed to mix to clarity for 30 minutes. The pH of the solution was 10.4.
- DCA deoxycholic acid
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KR1020177016779A KR101919269B1 (ko) | 2011-08-23 | 2011-08-23 | 데옥시콜린산 및 그의 염들의 제형물들 |
SG2014013205A SG2014013205A (en) | 2011-08-23 | 2011-08-23 | Formulations of deoxycholic acid and salts thereof |
CN201810400642.9A CN108619089A (zh) | 2011-08-23 | 2011-08-23 | 脱氧胆酸和其盐的制剂 |
PCT/US2011/048806 WO2013028177A1 (en) | 2011-08-23 | 2011-08-23 | Formulations of deoxycholic acid and salts thereof |
BR112014000547-8A BR112014000547B1 (pt) | 2011-08-23 | 2011-08-23 | Composição aquosa estável em precipitação |
CN201810403291.7A CN108743522A (zh) | 2011-08-23 | 2011-08-23 | 脱氧胆酸和其盐的制剂 |
EA201490175A EA029305B1 (ru) | 2011-08-23 | 2011-08-23 | Составы дезоксихолевой кислоты и ее солей |
NZ620040A NZ620040A (en) | 2011-08-23 | 2011-08-23 | Formulations of deoxycholic acid and salts thereof |
KR1020187032491A KR102034606B1 (ko) | 2011-08-23 | 2011-08-23 | 데옥시콜린산 및 그의 염들의 제형물들 |
KR1020207002722A KR20200013103A (ko) | 2011-08-23 | 2011-08-23 | 데옥시콜린산 및 그의 염들의 제형물들 |
KR1020197030233A KR102073536B1 (ko) | 2011-08-23 | 2011-08-23 | 데옥시콜린산 및 그의 염들의 제형물들 |
CA2842177A CA2842177C (en) | 2011-08-23 | 2011-08-23 | Formulations of deoxycholic acid and salts thereof |
UAA201400641A UA113522C2 (xx) | 2011-08-23 | 2011-08-23 | Склади дезоксихолевої кислоти та її солей |
MX2014001495A MX350390B (es) | 2011-08-23 | 2011-08-23 | Formulaciones de acido desoxicolico y sales del mismo. |
JP2014527128A JP5919597B2 (ja) | 2011-08-23 | 2011-08-23 | デオキシコール酸およびその塩類の製剤 |
IN2188CHN2014 IN2014CN02188A (ko) | 2011-08-23 | 2011-08-23 | |
AU2011375432A AU2011375432B2 (en) | 2011-08-23 | 2011-08-23 | Formulations of deoxycholic acid and salts thereof |
KR1020147006855A KR101751585B1 (ko) | 2011-08-23 | 2011-08-23 | 데옥시콜린산 및 그의 염들의 제형물들 |
MYPI2014000197A MY184277A (en) | 2011-08-23 | 2011-08-23 | Formulations of deoxyccholic acid and salts thereof |
CN201180072842.2A CN103826608A (zh) | 2011-08-23 | 2011-08-23 | 脱氧胆酸和其盐的制剂 |
IL230547A IL230547A (en) | 2011-08-23 | 2014-01-20 | Formulations of deoxycholic acid and saline |
CR20140053A CR20140053A (es) | 2011-08-23 | 2014-01-30 | Formulaciones de ácido desoxicólico y sales del mismo |
ZA2014/01027A ZA201401027B (en) | 2011-08-23 | 2014-02-10 | Formulations of deoxycholic acid and salts thereof |
AU2016202661A AU2016202661B2 (en) | 2011-08-23 | 2016-04-27 | Formulations of deoxycholic acid and salts thereof |
PH12016501175A PH12016501175A1 (en) | 2011-08-23 | 2016-06-16 | Formulations of deoxycholic acid and salts thereof |
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KR (5) | KR20200013103A (ko) |
CN (3) | CN103826608A (ko) |
AU (3) | AU2011375432B2 (ko) |
BR (1) | BR112014000547B1 (ko) |
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EA (1) | EA029305B1 (ko) |
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WO2019203511A1 (ko) * | 2018-04-16 | 2019-10-24 | 주식회사 펜믹스 | 데옥시콜릭산을 포함하는 약학 조성물 |
US11179404B2 (en) | 2009-03-03 | 2021-11-23 | Allergan Sales, Llc | Formulations of deoxycholic acid and salts thereof |
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MX2018005628A (es) * | 2015-11-04 | 2018-08-01 | Kythera Biopharmaceuticals Inc | Tratamientos de grasa acumulada con acido desoxicolico y sales del mismo. |
US20180078621A1 (en) * | 2016-09-22 | 2018-03-22 | Kyoung Lack Lee | Composition for hypotonic lipolysis and manufacturing method thereof |
KR101841193B1 (ko) * | 2016-09-22 | 2018-03-22 | 이경락 | 저장성 지방 분해 조성물 및 그의 제조 방법 |
KR102172439B1 (ko) | 2018-12-05 | 2020-10-30 | 송미희 | 지방 분해용 조성물 및 이를 포함하는 주사제 조성물 |
KR102064864B1 (ko) | 2019-02-08 | 2020-01-10 | (주)제테마 | 국소 주사용 조성물 |
KR102111346B1 (ko) | 2019-08-20 | 2020-05-22 | 아영창 | 침전으로부터 안정한 소듐디옥시콜레이트를 포함하는 수용액상 조성물 |
KR20220026068A (ko) | 2020-08-25 | 2022-03-04 | 강명범 | 지방 분해용 주사제 조성물 |
CN116617160A (zh) * | 2023-07-25 | 2023-08-22 | 山东则正医药技术有限公司 | 水性混悬液及制备方法、冻干粉及应用、脂肪消减注射剂 |
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US11179404B2 (en) | 2009-03-03 | 2021-11-23 | Allergan Sales, Llc | Formulations of deoxycholic acid and salts thereof |
WO2019203511A1 (ko) * | 2018-04-16 | 2019-10-24 | 주식회사 펜믹스 | 데옥시콜릭산을 포함하는 약학 조성물 |
KR20190120712A (ko) * | 2018-04-16 | 2019-10-24 | 주식회사 펜믹스 | 데옥시콜릭산을 포함하는 약학 조성물 |
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