CN103826608A - Formulations of deoxycholic acid and salts thereof - Google Patents
Formulations of deoxycholic acid and salts thereof Download PDFInfo
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- CN103826608A CN103826608A CN201180072842.2A CN201180072842A CN103826608A CN 103826608 A CN103826608 A CN 103826608A CN 201180072842 A CN201180072842 A CN 201180072842A CN 103826608 A CN103826608 A CN 103826608A
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The present application is directed to an aqueous pharmaceutical composition comprising from about 0.4% w/v to less than about 2% w/v of a salt of deoxycholic acid, wherein the composition is maintained at a pH from about 8.1 to about 8.5 such that the composition is stabilized against precipitation. Also disclosed herein, are methods for stabilizing an aqueous pharmaceutical composition comprising from about 0.4% w/v to less than about 2% w/v of a salt of deoxycholic acid against precipitation, said method comprising maintaining pH of the solution from about 8.1 to about 8.5.
Description
Invention field
The present invention relates to contain the very aqueous pharmaceutical preparations of the deoxycholic acid of low concentration (" DCA ") salt, wherein said preparation is remained on to DCA and precipitate the pH substantially being suppressed.In a preferred embodiment, pharmaceutical composition is cushioned to keep the upper acceptable pH of physiology, so that compositions is suitable for injection.
Background
The bibliographical information of delivering recently in the time being injected into fatty deposits in body, DCA aqueous solution have fat remove character (referring to, WO2005/117900 and WO2005/112942, US2005/0261258; US2005/0267080; US2006/127468; And US2006/0154906).The DCA that is injected into fatty tissue reduces fat cell so that the aesthetic result of expectation to be provided by cytolytic mechanism.
Although DCA aqueous formulation has benefit, find optionally to contain the DCA(of low concentration in the aqueous solution of benzylalcohol, be less than or about 2%w/v; ) after storing a period of time, form precipitate.Surprisingly, find, although the pH of solution without any remarkable change, DCA concentration is lower, settling velocity is higher.Very the precipitation of low concentration is commercialization problem, because precipitate is avoided for DCA subcutaneous injection.
In each therapeutic scheme, a small amount of aqueous formulation multiple injection of the clinical trial utilization of current DCA aqueous formulation is entered to limit the different parts of the fatty deposits being treated.
Be apparent that, for the DCA aqueous formulation of such treatment with to precipitate by DCA the problem causing overlapping.In other words, when storing DCA aqueous solution initial limpid after a period of time, commercially relevant DCA concentration is formed to precipitate, although the pH of these solution is approximately 7.50 with approximately between 8.0---substantially higher than the pKa of deoxycholic acid.
Therefore, exist the aqueous solution of stablizing low concentration deoxycholic acid or its salt during the storage period of at least 2 months in case precipitation.
Abstract of invention
Have surprisingly been found that, about 0.4%w/v to be less than about 2%w/v concentration deoxycholic acid saline solution can by pH value of solution is adjusted to higher than approximately 8 and preferably from physiology acceptable pH approximately 8.1 to approximately 8.5 stablized.Preferably by utilizing buffer agent that pH is remained within the scope of this.
Correspondingly, in one of its composition aspect, the present invention relates to substantially by the aqueous formulation forming below: about 0.4%w/v is to being less than the dexycholate of about 2%w/v concentration and the benzylalcohol of anticorrosion effective dose optionally, and said preparation is by being stablized the pH regulator of the clear solution forming at first in case precipitate to approximately 8.1 to approximately 8.5 pH.In another embodiment, the present invention relates to substantially by the aqueous formulation forming below: about 0.5%w/v is to the dexycholate of about 1%w/v concentration and the benzylalcohol of anticorrosion effective dose optionally, said preparation is by being stablized the pH regulator of the clear solution of formation at first in case precipitate to approximately 8.1 to approximately 8.5 pH.
In another embodiment, the present invention relates to substantially by the aqueous formulation forming below:
Be buffered to the aseptic aqueous solution of pH approximately 8.3;
The dexycholate of about 0.5%w/v or about 1%w/v;
The optionally benzylalcohol of anticorrosion effective dose; With
The sodium chloride of about 1%w/v,
Wherein compositions is stable to precipitating.
Also openly the waterborne compositions of stabilized deoxy cholate is in case the method precipitating between the storage life herein, and wherein the concentration of dexycholate is the amount of effective cracking adipose cell, condition be the amount of dexycholate be about 0.4%w/v to being less than 2%w/v, the method comprises:
Form the deoxycholic acid saline solution higher than the initial pH of its pKa; By extremely approximately 8.1 to approximately 8.5 pH of the pH regulator of aqueous solution; Optionally comprise that the buffer of sufficient quantity is to be maintained at about pH 8.1 to approximately 8.5.
The method that also discloses cracking adipose cell herein, comprises and gives described cell according to compositions of the present invention.
Accompanying drawing summary
Fig. 1 shows (67X amplification), water and 0.9%w/v benzylalcohol and do not have the waterborne compositions of NaTDC only to contain the precipitate of trace, and it is presumably bioprene pipeline granule.
Fig. 2 shows (67X amplification), the precipitate that the waterborne compositions of water, 0.5%w/v NaTDC and 0.9%w/v benzylalcohol contains significant quantity, and it is presumably dexycholate crystal.
Fig. 3 shows (67X amplification), and the precipitate that the waterborne compositions of water, 1%w/v NaTDC and 0.9%w/v benzylalcohol contains significant quantity, although be less than the precipitate of 0.5%w/v NaTDC.As before, precipitate is presumably dexycholate crystal.
Fig. 4 shows (67X amplification), the precipitate that the waterborne compositions of water, 2%w/v NaTDC and 0.9%w/v benzylalcohol contains significant quantity, but be substantially less than the precipitate of observing in Fig. 2 and 3.
Describe in detail
As used herein, some term has with the undefined meaning.
The indication of all numeral, for example, pH, temperature, time, concentration and molecular weight, comprise scope, is approximation, it changes (+) or (-) with 0.1 increment.Although should be appreciated that not necessarily and clearly state, add term " about " before all numeral indications.Except the less increment of " X " is as " X+0.1 " or " X-0.1 ", term " about " also comprises exact value " X ".Although it is also understood that not necessarily and clearly state, reagent described herein is only exemplary, and its equivalent is known in the art.
As used herein, term " comprises " and is intended to refer to that compositions and method comprise the component of enumerating, but do not get rid of other component.
When limiting compositions and method, " substantially by ... composition " will refer to get rid of active component." active component " is such material, its be intended to the diagnosis of disease, cure, alleviate, treat or prevent in the structure or any function that pharmacological activity or other direct effect are provided or affect human body.Therefore, for example, substantially by as the compositions that form of component that limits herein by trace contaminant and the pharmaceutically acceptable carrier do not got rid of from Isolation and purification method, as phosphate buffered saline (PBS), antiseptic and analog, still will get rid of enzyme as phosphatase and protein.The unrestriced example of such protein is heparin, albumin and analog.
" by ... composition " will refer to get rid of the trace element that exceedes other composition and the basic method steps that gives compositions of the present invention.
By each embodiment limiting in these excessive terms in scope of the present invention.
As used herein, term " dexycholate " or " its salt " refer to (4R)-4-((3R, 5R, 10S, 12S, 13R, 17R)-3,12-dihydroxy-10,13-dimethyl 16 hydrogen-1H-ring penta [a] phenanthrene-17-yl) pharmaceutically acceptable salt of valerate, there is alkali metal or ammonium ion as cation.Preferred as alkali salt, sodium salt more preferably.
NaTDC or (4R)-4-((3R, 5R, 10S, 12S, 13R, 17R)-3,12-dihydroxy-10,13-dimethyl 16 hydrogen-1H-ring penta [a] phenanthrene-17-yl) name that can submit to for 17th according in Decembers, 2010 of natrium valericum is called disclosed method preparation in the PCT/US2010/061150 of " deoxycholic acid purification process ".
As used herein, term " aqueous pharmaceutical preparations " refers to the compositions of deoxycholic acid in water or its salt, is applicable to giving patient, preferably gives patient from syringe by subcutaneous injection.
As used herein, term " buffer agent " refers to the aqueous solution of the mixture that comprises weak acid and its conjugate base or weak base and its conjugate acid.The pH that buffer agent has solution in the time adding a small amount of acid or alkali changes very little character.In number of chemical application, buffer solution is as pH is remained on to the means that approach steady state value.The example of suitable buffer agent comprise phosphate buffer and those buffer agents of known in the literature (referring to, for example, Troy, D.B., ed.(2005)
Remington:The Science and Practice of Pharmacy, the 21st edition, Lippincott Williams & Wilkins).
As used herein, term " alkali " refers to multiple common water soluble compound, molecule or the ion in solution with the pH that is greater than 7.Such compound, molecule or ion can obtain proton from acid and maybe can abandon and sour unshared electron pair.The example of suitable alkali comprises metal carbonate and bicarbonate, for example sodium carbonate, calcium carbonate, magnesium carbonate, zinc carbonate, sodium bicarbonate and analog; And metal hydroxides, for example sodium hydroxide, potassium hydroxide and analog, as known in the literature those (referring to, for example, Troy, D.B., ed.(2005) Remington:The Science and Practice of Pharmacy, the 21st edition, Lippincott Williams & Wilkins).
As used herein, term " metal carbonate " refers to CO
3 2-slaine.For example, sodium carbonate, calcium carbonate, magnesium carbonate, zinc carbonate and analog.
As used herein, term " alkali metal bicarbonate salt " refers to HCO
3 -slaine ".For example, sodium bicarbonate and analog.
As used herein, the slaine of refer to-O of term " metal hydroxides " Η.For example, sodium hydroxide, potassium hydroxide and analog.
As used herein, term " sterilized water " or " water for injection " refer to aseptic, the pyrogen-free water formulation for injecting, and it is bacteriostatic agent, antimicrobial or the buffer agent that adds not.Generally speaking, the osmolarity of additive amounts to 112mOsm/ liter at least (normal osmolarity-280mOsm/ of extracellular fluid rise 2/5).
As used herein, term " benzylalcohol " refers to compound
As used herein, term " precipitation " refers to the formation of solid in solution and easily distinguishes over gel formation.
As used herein, term " solution " refers to the mixture of homogenizing substantially---comprise that two or more are dissolved in the material of solvent.
As used herein, term " substantially suppress precipitation " and " suppressing precipitation " refer to suppress great majority or whole visible precipitations with maintenance homogeneity scope the time from least 1 month at least 1 year.
As used herein, term " homogeneous relative standard deviation " or " H
e" refer to that the absolute value of meansigma methods is divided by the value of homogeneous standard deviation acquisition.Be less than 10 H
erefer to extraordinary homogeneity.
Preparation
The chemistry of pharmaceutical composition and the knowledge of physical stability about the expectation medium for sending are valuable.In more over a long time, the storage period of the product that the stability of compositions is introduced indication to the market.Preferably, in the time giving patient, the active ingredient in pharmaceutical composition is in the concentration of needs.
In the following discussion, enumerate NaTDC only for the object of example, and be to be understood that other pharmaceutically acceptable salt of deoxycholic acid can use with sodium salt exchange.
Current patient that NaTDC is given comprises by subcutaneous injection and gives low concentration (with the clinical method of dissolved fat, <2%w/v) deoxycholic acid saline solution, wherein the amount of dexycholate is enough to cracking adipose cell (about 0.4%w/v and Geng Gao).In such concentration, as shown, low concentration is useful to effectively removing with safety of fatty deposits in health.But, observe precipitate and formed at relatively low like this deoxycholic acid na concn in aqueous medium.This precipitation causes the even limited storage period at cold temperature (3-5 ℃) deoxycholic acid sodium water solution.In one embodiment, sodium salt can be replaced by another kind of alkali metal salt.
This unstability of deoxycholic acid sodium water solution can be by evading as follows: prepare the approximately 5% deoxycholic acid sodium water solution to about 16%w/v concentration and make practitioner dilute deoxycholic acid sodium solution pharmaceutical composition a moment before using.Although this dilution process effectively obtains storage stability and effective patient dose, if especially need to be no more than the aseptic injectable solution of about 2mL as conventional using method, it is not desirable.And current clinical program comprises that each treatment reaches 50 injections period.
Find, the about 0.4%w/v of concentration range can be stablized by the pH of regulator solution to the aqueous formulation of the NaTDC that is less than about 2%w/v.The present invention relates to substantially by the aqueous formulation forming below: the about 0.4%w/v of concentration range is to being less than the dexycholate of about 2%w/v and pharmaceutically acceptable excipient optionally, as the benzylalcohol of anticorrosion effective dose and/or pH regulator buffer agent, wherein described preparation is maintained at about to 8.1 to approximately 8.5 pH.
In another embodiment, by aqueous formulation lyophilizing, so that stable compositions to be provided, said composition is easily again dissolved and is made into original concentration by adding appropriate water.In this embodiment, the present invention includes the compositions of lyophilizing as above, it optionally further contains lyophilization aid.
In one embodiment, aqueous formulation is containing the dexycholate of the 0.5%w/v that has an appointment.In another embodiment, aqueous formulation is containing the dexycholate of the 1%w/v that has an appointment.
In another embodiment, the water utilizing in aqueous formulation is sterilized water.Still in another embodiment, the benzylalcohol of anticorrosion effective dose is that the pH of about 0.9%w/v benzylalcohol and preparation is approximately 8.3.In one embodiment, described salt is alkali metal salt.In another embodiment, described salt is sodium salt.
In one embodiment, pharmaceutical preparation disclosed herein is applicable to being injected into people.Injecting method can be the injection of any type, as subcutaneous injection, and the injection of other form.
Of the present invention one preferred aspect, the suppressed time at least about six months of the precipitation of dexycholate in aqueous formulation.On the other hand, precipitate suppressed at least about year.Again on the one hand, precipitate the suppressed time at least about 2 years.
Expection is when in different temperatures, and for example, in the time that ambient temperature or cold temperature store, preparation can have the storage period of increase.In some embodiments, the temperature at approximately 17 ℃ to approximately 27 ℃ by composition stores.In some embodiments, the temperature of preparation is elevated to the temperature of approximately 25 ℃ to approximately 37 ℃.In other embodiments, preparation is stored in to the temperature of approximately 2 ℃ to approximately 8 ℃.
In some embodiments, the pH scope approximately 8.1 to approximately 8.5 of preparation.In one embodiment, the pH of compositions is approximately 8.1, or alternatively, approximately 8.2, or alternatively, approximately 8.3, or alternatively, approximately 8.4, or alternatively, approximately 8.5.In a preferred embodiment, the pH of preparation is approximately 8.3.
In one embodiment, by using alkali to establish pH.Expect that any alkali can be used for increasing the pH of compositions, condition is that it does not react with NaTDC and will not be harmful to patient.In some embodiments, alkali is selected from metal carbonate, alkali metal bicarbonate salt, metal hydroxides or its mixture.The example of alkali includes but not limited to, is selected from following alkali: sodium carbonate, calcium carbonate, magnesium carbonate, zinc carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide or its mixture.In one embodiment, alkali is sodium hydroxide.
In some cases, can be by using buffer agent the pH of compositions to be remained on to the pH of expectation between the storage life.Various buffer agents are that the known any buffer agent that has buffer capacity at the pH expecting with expection can be used for preparation disclosed herein in this area.In one embodiment, buffer agent is phosphate buffer.Can determine in compositions that phosphatic amount is to provide pH and the salinity of expectation.In one embodiment, compositions comprises about 10mM phosphate buffer.In a preferred embodiment, compositions comprises about 10mM sodium hydrogen phosphate buffer agent.
In some embodiments, compositions comprises that at least one excipient has desirable properties as the dissolubility, the conservatory compositions that increase or isosmotic solution is provided to assist to obtain.Such excipient is known in this area.In one embodiment, compositions comprises about 1%w/v sodium chloride.In another embodiment, compositions comprises about 0.9%w/v benzylalcohol.In some embodiments, compositions comprises about 0.9%w/v benzylalcohol and about 1%w/v sodium chloride.
In some embodiments, the pH of compositions is by establishing with alkali and optionally by keeping with buffer agent.
In a preferred embodiment, the invention provides the compositions of stabilisation, comprising:
The phosphate buffer of approximately 8.3 pH;
The NaTDC of about 0.5%w/v or about 1%w/v;
The benzylalcohol of anticorrosion effective dose; With
The sodium chloride of about l%w/v,
Wherein by composition stable in case precipitation.
In other embodiment, phosphate buffer is 10mM sodium hydrogen phosphate buffer agent.
In one embodiment, the benzylalcohol of anticorrosion effective dose is about 0.9%w/v.
Preparation disclosed herein comprises that in water, about 0.4%w/v is to the dexycholate that is less than about 2%w/v, and it remains on the pH that is enough to substantially suppress dexycholate precipitation.The precipitation capacity of compositions or homogeneity can utilize several different methods to measure.For example, it can be by utilizing light scattering to carry out quantitative measurement with spectrophotometer lighting compositions.Or alternatively, homogeneity can be by observing solution vision clarity and observation measurements with eye.In some embodiments, compositions has the homogeneity relative standard deviation who is less than approximately 5%.Alternatively, compositions has and is less than approximately 4%, or alternatively, approximately 3%, or alternatively, approximately 2%, or alternatively, approximately 1% homogeneity relative standard deviation.
In another embodiment, the present invention relates to substantially by the compositions forming below:
Be buffered to the aseptic aqueous solution of approximately 8.3 pH;
The NaTDC of about 0.5%w/v or 1%w/v;
About 0.9%w/v benzylalcohol; With
The sodium chloride of about 1%w/v,
Wherein compositions is stable to precipitation.
In another embodiment, the present invention relates to by the compositions forming below:
Be buffered to the aqueous solution of approximately 8.3 pH;
The NaTDC of about 0.5%w/v or about 1%w/v;
About 0.9%w/v benzylalcohol; With
The sodium chloride of about 1%w/v,
Wherein compositions is stable to precipitation.
In some embodiments, the solution of this paper does not comprise lipid, phospholipid or phosphatidylcholine.In some embodiments, solution herein comprises the lipid that reaches 5%w/w, w/v or v/v, phospholipid particularly, or phosphatidylcholine more specifically.Preferably, the amount of the lipid of use is less than the amount of NaTDC or another kind of dexycholate.
In some embodiments, aqueous pharmaceutical compositions of the present invention can further comprise and is selected from the second following therapeutic agent: antimicrobial, vasoconstrictor, antithrombotic agents, anticoagulant, foam inhibitor, antiinflammatory, analgesic, dispersant, anti-dispersant, penetration enhancer, steroid class, tranquillizer, muscle relaxant and diarrhea.In some embodiments, solution is containing in the container that reaches 500mL solution.Such container can be the container that syringe or syringe can loads.
In some embodiments, preparation further comprises the known molecule that causes fat death by orthogonal mechanism.Such molecule comprises neuropeptide tyrosine (NPY) antagonist, and it includes but not limited to, npy receptor antagonist, 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, with S.A.0204(Sanofi Aventis), S-2367(Shiongli), for dihydropyridine and the dihydrogen pyridine derivative of npy receptor antagonist, for the bicyclic compound of npy receptor antagonist, carbazole npy receptor antagonist, with be npy receptor antagonist tricyclic compound (referring to, for example, WO2006/133160 and U.S.6,313,128).Also consider that the short apoptosis peptide of Fat Selection is as CKGGRAKDC peptide, its be positioned at fat vascular system (referring to, Kolonin M.G. etc., Nat.Med., 2004,10 (6): 625-32).
Another aspect of the present invention relates to mixing-in fat and melts cholic acid, as, deoxycholic acid (DCA) and the agent of killing adipose cell.On the one hand, the present invention considers to cause that by orthogonal mechanism the dead molecule of fat improves the method for the aesthetic effect of deoxycholic acid salt injection by being mixed into dexycholate infusion (injectate).The example of such material standed for molecule includes but not limited to, the short apoptosis peptide of neuropeptide tyrosine (NPY) antagonist and Fat Selection.Owing to may needing adipose cell to kill to mediate the effect of expectation, having the effect that fat kills the agent of ability can have the molecule that effective adipose cell kills effect and improve by adding.In addition, need to enter vascular system and can approach these albumen with the molecule (apoptosis peptide as short in some, it is in conjunction with the albumen of expressing in blood capillary tube chamber side) killing, because dexycholate can cause vascular leakage.Therefore, such agent can be with the dexycholate generation synergism that produces potentially more effective method to mediate body contouring in the treatment phase still less.
The example of NPY antagonist includes but not limited to, npy receptor antagonist, 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 Aventis), S-2367(Shiongli), for dihydropyridine and the dihydrogen pyridine derivative of npy receptor antagonist, for the bicyclic compound of npy receptor antagonist, carbazole npy receptor antagonist, with the tricyclic compound that is npy receptor antagonist.Referring to, for example, WO2006/133160 and U.S.6,313,128.
The short apoptosis peptide of exemplary Fat Selection includes but not limited to, is positioned at the CKGGRAKDC peptide of fat vascular system.Referring to, Kolonin M.G. etc., Nat.Med.June10 (6): 625-32(2004).
NaTDC or (4R)-4-((3R, 5R, 10S, 12S, 13R, 17R)-3,12-dihydroxy-10,13-dimethyl 16 hydrogen-lH-ring penta [a] phenanthrene-17-yl) name that can submit to for 17th according in Decembers, 2010 of natrium valericum is called disclosed method preparation in the PCT/US2010/061150 of " deoxycholic acid purification process ".Technical staff can prepare other dexycholate equally.
Method
Openly the aqueous formulation of stabilized deoxy cholate is in case the method precipitating between the storage life herein, and wherein its concentration or salt are the amounts of effective cracking adipose cell, condition be the weight range of salt be about 0.4%w/v to being approximately less than 2%w/v, the method comprises:
Be formed on the deoxycholic acid saline solution higher than the initial pH of its pKa;
By extremely approximately 8.1 to approximately 8.5 pH of the pH regulator of aqueous solution; Optionally comprise that the buffer agent of q.s is to be maintained at about pH 8.1 to approximately 8.5.
In one aspect of the invention, method disclosed herein preferably at least about six months following period of time substantially stabilized deoxy cholate preparation in case precipitation.On the other hand, the preparation of the method stabilized deoxy cholate is in case precipitate at least about one-year age.Again on the one hand, the preparation of the method stabilized deoxy cholate is in case precipitate at least about two years.
The pH that has found solution can suppress in water the about 0.4%w/v of concentration to the deoxycholic acid or its salt precipitation that are less than about 2%w/v, to allow deoxycholic acid or its salt to remain in solution.In one embodiment, pH is by utilizing alkali to establish.Expect that any alkali can be used for increasing the pH of compositions, if it not with deoxycholic acid or its reactant salt.In some embodiments, alkali is selected from metal carbonate, alkali metal bicarbonate salt and metal hydroxides or its mixture.The example of alkali includes but not limited to be selected from following alkali: sodium carbonate, calcium carbonate, magnesium carbonate, zinc carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide or its mixture.In one embodiment, alkali is sodium hydroxide.
In some embodiments, pH is approximately 8.1 to approximately 8.5.In one embodiment, the pH of compositions is approximately 8.1, or alternatively, approximately 8.2, or alternatively, approximately 8.3, or alternatively, approximately 8.4, or alternatively, approximately 8.5.In a preferred embodiment, the pH of aqueous solution is approximately 8.3.
In some cases, the pH of compositions can utilize buffer agent to keep.Numerous buffers can be used for preparation disclosed herein at any buffer agent known in the art and that expection has buffer capacity at the pH expecting.In one embodiment, buffer agent is phosphate buffer.Provide pH and the needed phosphatic amount of salinity of expectation can utilize method well known in the art to calculate.In one embodiment, compositions comprises about 10mM phosphate buffer.In another embodiment, phosphate buffer is 10mM sodium hydrogen phosphate buffer agent.
In some cases, pH is by utilizing alkali to establish and optionally by utilizing buffer agent to keep.
In one embodiment, method disclosed herein provides the preparation that is applicable to being injected into people.Injecting method can be the injection of any type, as subcutaneous injection, and the injection of other form.Therefore, in some embodiments, aqueous solution comprises sterilized water or water for injection (WFI).
On the one hand, one or more excipient can be used for keeping dissolubility or increase to be present in the keeping quality of the dexycholate in preparation.In one embodiment, the method comprises and adds about 1%w/v benzylalcohol.In some embodiments, said preparation also comprises that at least one excipient is to assist acquisition isosmotic solution.Such excipient is well known in the art.In one embodiment, the method comprises and adds about 1%w/v sodium chloride.In some embodiments, the method comprises and adds 1%w/v benzylalcohol and 1%w/v sodium chloride.In some embodiments, the method comprises and adds 0.9%w/v benzylalcohol and 0.9%w/v sodium chloride.Utilize method disclosed herein, will comprise that the aqueous solution that is less than about 2%w/v dexycholate remains on the pH that is enough to substantially suppress dexycholate precipitation.The amount of precipitation or compositions homogeneity can utilize several different methods to measure.For example, it can be by throwing light on to measure light scattering and then quantitative measurement with spectrophotometer.Or alternatively, homogeneity can be by observing the vision clarity of solution and observation measurements with eye simply.In some embodiments, the method provides pharmaceutical composition, and it has the homogeneity relative standard deviation who is less than approximately 5%.Alternatively, be less than approximately 4%, or alternatively, approximately 3%, or alternatively, approximately 2%, or alternatively, approximately 1% homogeneity relative standard deviation.
Storage temperature can help to keep the dissolubility of dexycholate in preparation.In some embodiments, storage temperature is approximately 17 ℃ to approximately 27 ℃.In some embodiments, storage temperature is approximately 25 ℃ to approximately 37 ℃.In other embodiments, storage temperature is approximately 2 ℃ to approximately 8 ℃.
Consider that the concentration of dexycholate is about 0.5%w/v in preparation, or about 0.7%w/v alternatively, or about 1%w/v alternatively, or about 1.2%w/v alternatively, or about 1.4%w/v alternatively, or be less than alternatively about 2%w/v.In a preferred embodiment, dexycholate is NaTDC.Another preferred embodiment in, compositions comprises 0.5%w/v NaTDC.Another preferred embodiment in, compositions comprises 1%w/v NaTDC.
In one embodiment, aqueous formulation is divided into multiple independent solution, that is separated gives adipose cell.For example, by aqueous formulation be divided into 5,10,15,20,25 or 30 independent solution and, in some cases, reach 50 independent solution.
In a preferred embodiment, dexycholate is NaTDC.Because method of the present invention comprises subcutaneous injection, syringe is also provided, it comprises chamber, plunger and entry needle, wherein chamber comprises preparation of the present invention.Preferably, chamber is enough to hold at least 2mL, and is preferably no more than 4mL preparation.
In another embodiment, the invention provides from shielded commercially available 9-α, the DCA of 17-beta-dihydroxy-5-α-androstane-3-one is synthetic, as shown in diagram below 1.
Diagram 1:DCA's is synthetic
By commercially available 9-α, the 9-α of 17-beta-dihydroxy-5-α-androstane-3-one, 17-β hydroxyl is differentially protected with hydroxy-protective group, this hydroxy-protective group can be reproduced and other hydroxyl keeps removing under protected condition at one of hydroxyl.Differentiated protection is like this known as orthogonally protect and utilizes reagent and the reaction condition known.In an example, hydroxyl is protected is acetyl group, and other hydroxyl protected be benzyl.Each group can optionally be removed under the complete reaction condition of other hydroxy-protective group keeping.
The 9-Alpha-hydroxy of the relatively three-dimensional protection of expection can be protected because remove the reaction of considering before this group may be suppressed in this position due to steric hindrance.In any case the protection of this hydroxyl guarantees that this group keeps complete until remove hydroxyl by dehydration and expect fully.
By the 9-α of orthogonally protect; the 3-ketone groups of 17-beta-dihydroxy-5-α-androstane-3-one---compound 1---with conventional reducing agent as sodium borohydride reduction; so that 3-Alpha-hydroxy derivant to be provided, then by this derivant with another orthogonally protect radical protection so that compound 2 to be provided.
Then the hydroxy-protective group of the 17-position of compound 2 is optionally removed, then the hydroxyl of regeneration is like this oxidized as Cr03 with suitable oxidising agent, so that 17-ketone derivatives to be provided---compound 3.By the 17-ketone groups in compound 3 in the ketal condition of standard as with 1; under the reaction of 2-dihydroxy ethane or 1,3-dihydroxypropane, as ketal protection, to produce compound 4(, it shows and 1; the ketal of 2-dihydroxy ethane forms, only for the object of example).
While needs after the dehydration of this hydroxyl carrying out the alpha-hydroxy deprotection of 9-as under the condition of acid catalyzed removal, the undersaturated derivant of 9,10----compound 5 is provided.The generation of 12-ketone group by compound 5 with oxidising agent as chromic acid or TBHP(tert-butyl hydrogen peroxide) and the allylic of NaOCl be oxidized, so that compound 6 to be provided.Referring to, for example, U.S. Patent Application Serial 61/348,686.Alternatively, allylic oxidation completes by the CuI as catalyst that utilizes the TBHP of approximately 2 to 5 equivalents and approximately 0.3 to 0.5 equivalent.Reaction is carried out about 40-55 hour at 40 ℃ at solvent in as acetonitrile.Portion-wise addition TBHP causes more effective oxidation slowly.The mixture that the product forming contains compound 6 and corresponding allyl alcohol.Then product mixtures is oxidized to produce compound 6 with PCC.
Compound 6 in standard conditions as 10%Pd/C and H
2under hydrogenation compound 7 is provided.12-ketone group in compound 7 uses reagent as LiA (OBu
t)
3the reduction that H carries out provides 12-hydroxy derivatives---compound 8.Under the Wei Tixi of standard condition as utilized the olefination of ethyl triphenyl phosphonium bromide compound 8 in the situation that having alkali as potassium tert-butoxide that compound 9 is provided.Exist in lewis acidic situation alkyl acrylate to provide compound 10 as the interpolation of acrylic acid methyl ester., wherein R is that alkyl is as methyl.In compound 10 reduction of two keys under the hydrogenation conditions of standard as Pd/C and H
2again carry out, compound 11 is provided.With alkali as 3-OR after LiOH hydrolysis
3deprotection DCA is provided---compound 12.
By DCA rough compound 12() further carry out purification by methanol wash and from ethanol recrystallize.Used CH
2c1
2middle 2mol%MeOH(25 volume) dilute and be heated to 35-37 ℃, continue 1 hour.Allow slurry to be cooled to 28-30 ℃ and filtration.By filter cake CH
2c1
2(5 volume) washs and is dried at 40 ℃ under vacuum, so that DCA to be provided.
DCA is dissolved in to 10%DI water/EtOH(12 volume), on celite polishing filter and with 10%DI water/EtOH(3 volume) wash.15 volumes of filtrate that produce are joined to DI water (30 volume) neutralization thin white slurry is provided.By slurry keep 24 hours, filter, with DI water (20 volume) wash and under vacuum 40 ℃ be dried so that DCA to be provided.
DCA changes into pharmaceutically acceptable salt to be undertaken by normal condition as NaTDC.Alternatively, the pharmaceutically acceptable salt of DCA is also undertaken by normal condition as NaTDC changes into DCA.
In another embodiment, the preparation that the invention provides stabilisation comprises:
Have approximately 8.1 to approximately 8.5 pH buffering aqueous solution and further comprise approximately 0.5% NaTDC and approximately 0.9% benzylalcohol,
Wherein by said preparation stabilisation in case precipitation, NaTDC is prepared according to diagram 1.
In another embodiment, the invention provides the preparation of stabilisation, comprising:
Have approximately 8.1 to approximately 8.5 pH buffering aqueous solution and further comprise approximately 1% NaTDC and approximately 0.9% benzylalcohol,
Wherein by said preparation stabilisation in case precipitation, NaTDC is prepared according to diagram 1.
Embodiment
In the other places of embodiment and description, abbreviation has the following meaning:
Mg=milligram
ML=milliliter
Mm=millimeter
MM=mM
The T=time
UV=ultraviolet
V/v=volume/volume
W/v=weight/volume (g/mL)
W/w=w/w
WFI=water for injection
MOsm=m osmole
By reference to following examples, the present invention is further appreciated, and it is example of the present invention purely that embodiment is intended to.
Embodiment 1
The precipitation relying on from the concentration of deoxycholic acid sodium solution
The precipitate of evaluating the deoxycholic acid sodium solution of variable concentrations after storing for 1 week forms.Result is described in Fig. 1-4, and be presented in the aqueous solution that only contains water and 0.9%w/v benzylalcohol approximately 0.5% and about 1%(w/v) deoxycholic acid na concn, the precipitate of significant quantity forms, to such an extent as to it will suppress this solution and be used as hypodermic compositions.By the visual inspection to Fig. 1-4, as the table of making below, gradable evaluation precipitation capacity.
Table 1
Precipitation grade evaluation " 0 " refers to clear solution, and " 10 " refer to show the easily mixture of visible a large amount of precipitations of naked eyes.
Such observed result demonstration, in the concentration range of test, deposited phenomenon is subject in fact the impact of deoxycholic acid salinity.In order to find out the impact of pH on precipitation, measure the pH of solution, as provided in table 2, its pH that shows solution is substantially the same, especially for 1% and 2% solution.The dissolubility against the current of NaTDC---solution (2%) that wherein rarer solution (0.5% or 1%) is denseer provides more precipitations---is surprising observed result and proves that deposited phenomenon is not directly related with pH, because the pH of solution is substantially the same again, especially for 1% and 2% solution.
Table 2
Correspondingly, the present invention shows, from rare---0.4% to being less than 2%(w/v)---the surprising precipitation of deoxycholic acid saline solution is suppressed to such solution by increase pH value of solution and can be used for hypodermic degree.
Embodiment 2
There is and do not have NaTDC (API) preparation of benzylalcohol
1. prepare NaTDC (0.5% and 1%) compositions, comprise sodium phosphate (10mM), sodium chloride (75-90mM), benzylalcohol (0.9%), deoxycholic acid, pH8.3.
2. utilize free acid form, that is, deoxycholic acid, is prepared as follows and does not have the grade of the NaTDC of benzylalcohol to ooze compositions.
A.100mL10mg/mL the preparation that grade is oozed batch
Only, after preparing alkaline solution with 70mL water, 142mg disodium hydrogen phosphate,anhydrous and 267 μ L10M NaOH, 1.0g deoxycholic acid (DCA) is joined to solution.API need to enter solution for approximately 20 minutes.The pH of solution is 11.1.Known quick interpolation HCl causes some precipitations, so 225 μ L1M HCl are added to solution is transferred to pH8.3 lentamente.Allow solution to mix extra 15 minutes.After volume is transferred to 100mL by water, find that osmolality is 51mOsm.Add 859mg NaCl that osmolality is transferred to 305mOsm.
So the solution of preparation is optionally lyophilized to provide freeze-drying prods, and this freeze-drying prods can again dissolve and be made into original concentration by adding appropriate sterilized water.Correspondingly, the present invention also provides the freeze-drying prods of solution disclosed herein.
B.1000mL10mg/mL the preparation that grade is oozed batch
In the time being increased to ten times, above part a() result not do not amplify completely in proportion.In 900mL water, add 1.4g disodium hydrogen phosphate,anhydrous, 8.6g NaCl and 2.7mL10M NaOH.Then add 10.0gDCA and allow to be mixed to limpid 30 minutes.The pH of solution is 10.4.Slowly add 1.5mL1M HCl and allow and mix 5 minutes.Final pH is 8.1.Have to add other 20 μ L10M NaOH so that pH is transferred to 8.3.Volume is transferred to 1000mL by water, osmolality 314mOsm.
Based on adding the observed result that pH changes during 1M HCl, determine for 1000mL10mg/mL API batch, just the 1M HCl of 1.0mL should add immediately, then uses lentamente small size acidometric titration.Addition sequence for the suggestion of 1000mL10mg/mL API is described in table 3.
C.100mL5mg/mL the preparation that grade is oozed batch
Only, after preparing alkaline solution with 70mL water, 142mg disodium hydrogen phosphate,anhydrous and 134 μ L10M NaOH, 1.0g deoxycholic acid (DCA) is joined to solution.API need to enter solution for approximately 20 minutes.The pH of solution is 10.7.Known quick interpolation HCl causes some precipitations, so 115 μ L1M HCl are added to solution is transferred to pH8.3 lentamente.Allow solution to mix extra 15 minutes.After volume is transferred to 100mL by water, find that osmolality is 39mOsm.Add 859mg NaCl that osmolality is transferred to 294mOsm.
D.1000mL5mg/mL the preparation that grade is oozed batch
In the time being increased to ten times, above part c() result not do not amplify completely in proportion.In 900mL water, add 1.4g disodium hydrogen phosphate,anhydrous, 8.6g NaCl and 1.3mL10M NaOH.Then add 5.0gDCA and allow to be mixed to limpid 30 minutes.PH is 8.6.After just adding 350 μ L1M HCl, pH drops to 8.0.Have to add other 25 μ L10M NaOH so that pH is transferred to 8.4.Volume is transferred to 1000mL by water, osmolality 305mOsm.Based on adding the observed result that pH changes during 1M HCl, to determine for 1000mL5mg/mL API batch, solution should be used small size 1M HCl titration lentamente.Addition sequence for the suggestion of 1000mL5mg/mL API is described in table 3.
The 1000mL that table 3. etc. ooze is without the addition sequence (from left to right) of the preparation of benzylalcohol
Claims (15)
1. the stable waterborne compositions of precipitation, it is substantially by forming below: about 0.4%w/v, to the dexycholate and the pharmaceutically acceptable excipient that are less than about 2%w/v, is wherein maintained at about described compositions 8.1 to approximately 8.5 pH.
2. compositions claimed in claim 1, wherein said dexycholate exists to the amount of about 1%w/v with about 0.5%w/v.
3. claim 1 or compositions claimed in claim 2, wherein said dexycholate exists with the amount of about 0.5%w/v.
4. claim 1 or compositions claimed in claim 2, wherein said dexycholate exists with the amount of about 1%w/v.
5. the compositions described in any one in claim 1 to 4, wherein said excipient is solvent, buffer agent, antiseptic, lyophilization aid or its any combination.
6. compositions claimed in claim 5, wherein said excipient is solvent, as sterilized water.
7. compositions claimed in claim 5, wherein said excipient is antiseptic, as benzylalcohol.
8. compositions claimed in claim 7, wherein said antiseptic is 0.9% benzylalcohol.
9. the compositions described in any one in claim 1 to 8, wherein said compositions has approximately 8.3 pH.
10. the compositions described in any one in claim 1 to 9, wherein said salt is alkali metal salt.
11. compositions claimed in claim 10, wherein said alkali metal salt is sodium.
The stable waterborne compositions of 12. precipitation, it is substantially by forming below:
Be buffered to the aseptic aqueous solution of approximately 8.3 pH;
The NaTDC of about 0.5%w/v;
About 0.9%w/v benzylalcohol; With
The sodium chloride of about 1%w/v.
The stable waterborne compositions of 13. precipitation, it is substantially by forming below:
Be buffered to the aqueous solution of approximately 8.3 pH;
The NaTDC of about 1%w/v;
About 0.9%w/v benzylalcohol; With
The sodium chloride of about 1%w/v.
Compositions in 14. claim 1 to 13 described in any one, wherein said deoxycholic acid is synthetic according to following diagram:
The method of 15. cracking adipose cells, comprises and gives the compositions described in any one in described cell claim 1 to 14.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107865964A (en) * | 2016-09-22 | 2018-04-03 | 李京洛 | Hypo-osmoticity lipolysis composition and preparation method thereof |
| CN116617160A (en) * | 2023-07-25 | 2023-08-22 | 山东则正医药技术有限公司 | Aqueous suspension, preparation method, freeze-dried powder, application and fat reduction injection |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US8101593B2 (en) | 2009-03-03 | 2012-01-24 | Kythera Biopharmaceuticals, Inc. | Formulations of deoxycholic acid and salts thereof |
| US20170119794A1 (en) * | 2015-11-04 | 2017-05-04 | Kythera Biopharmaceuticals, Inc. | Treatments of accumulated fat with deoxycholic acid and salts thereof |
| KR101841193B1 (en) * | 2016-09-22 | 2018-03-22 | 이경락 | Composition for hypotonic lipolysis and manufacturing method thereof |
| JP7042531B2 (en) * | 2018-04-16 | 2022-03-28 | ペンミックス リミテッド | Pharmaceutical composition containing deoxycholic acid |
| KR102172439B1 (en) | 2018-12-05 | 2020-10-30 | 송미희 | Composition for lipolysis and injection composition comprising the same |
| KR102064864B1 (en) | 2019-02-08 | 2020-01-10 | (주)제테마 | Topical injectable composition |
| KR102111346B1 (en) | 2019-08-20 | 2020-05-22 | 아영창 | Aqueous composition with sodium deoxycholate having improved stability against precipitation |
| KR20220026068A (en) | 2020-08-25 | 2022-03-04 | 강명범 | Composition for lipolysis and injection composition comprising the same |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348360A (en) * | 1998-07-24 | 2002-05-08 | 柳署弘 | Preparation of aqueous clear solution dosage forms with bile acids |
| US6417179B1 (en) * | 1998-10-13 | 2002-07-09 | Craig G. Burkhart | Ear wax solution |
| US20050048126A1 (en) * | 2000-12-22 | 2005-03-03 | Barrett Rabinow | Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2754709B1 (en) | 1996-10-23 | 1999-03-05 | Sanofi Sa | COSMETIC COMPOSITION CONTAINING AN ANTAGONIST OF GAMMA NEUROPEPTIDE RECEPTORS AND ALPHA 2 ANTAGONISTS THAT MAY BE INCORPORATED IN SUCH A COMPOSITION |
| DE10361067A1 (en) * | 2003-12-22 | 2005-07-14 | Aventis Pharma Deutschland Gmbh | Medicinal lipolysis of fat accumulations |
| US7754230B2 (en) | 2004-05-19 | 2010-07-13 | The Regents Of The University Of California | Methods and related compositions for reduction of fat |
| ES2372499T3 (en) * | 2004-05-19 | 2012-01-20 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | USE OF A DETERGENT FOR NON-SURGICAL FAT DISPOSAL. |
| US20060127468A1 (en) * | 2004-05-19 | 2006-06-15 | Kolodney Michael S | Methods and related compositions for reduction of fat and skin tightening |
| CA2610022A1 (en) | 2005-06-06 | 2006-12-14 | Georgetown University | Compositions and methods for lipo modeling |
| TW201011755A (en) | 2008-09-10 | 2010-03-16 | Skymedi Corp | Flash memory system and its data recovery method |
| JP5420946B2 (en) * | 2009-03-23 | 2014-02-19 | 富士フイルム株式会社 | Minoxidil aqueous composition containing bile acids |
| EP2645099A1 (en) * | 2012-03-30 | 2013-10-02 | Phares Pharmaceutical Research N.V. | Biorelevant compositions |
-
2011
- 2011-08-23 IN IN2188CHN2014 patent/IN2014CN02188A/en unknown
- 2011-08-23 NZ NZ620040A patent/NZ620040A/en unknown
- 2011-08-23 JP JP2014527128A patent/JP5919597B2/en active Active
- 2011-08-23 CN CN201810403291.7A patent/CN108743522A/en active Pending
- 2011-08-23 WO PCT/US2011/048806 patent/WO2013028177A1/en active Application Filing
- 2011-08-23 MX MX2014001495A patent/MX350390B/en active IP Right Grant
- 2011-08-23 CA CA2842177A patent/CA2842177C/en active Active
- 2011-08-23 CN CN201810400642.9A patent/CN108619089A/en active Pending
- 2011-08-23 SG SG2014013205A patent/SG2014013205A/en unknown
- 2011-08-23 CN CN201180072842.2A patent/CN103826608A/en active Pending
- 2011-08-23 EA EA201490175A patent/EA029305B1/en unknown
- 2011-08-23 KR KR1020197030233A patent/KR102073536B1/en active IP Right Grant
- 2011-08-23 KR KR1020187032491A patent/KR102034606B1/en active IP Right Grant
- 2011-08-23 KR KR1020207002722A patent/KR20200013103A/en not_active Application Discontinuation
- 2011-08-23 AU AU2011375432A patent/AU2011375432B2/en active Active
- 2011-08-23 KR KR1020177016779A patent/KR101919269B1/en active IP Right Grant
- 2011-08-23 MY MYPI2014000197A patent/MY184277A/en unknown
- 2011-08-23 KR KR1020147006855A patent/KR101751585B1/en active IP Right Review Request
- 2011-08-23 UA UAA201400641A patent/UA113522C2/en unknown
-
2014
- 2014-01-20 IL IL230547A patent/IL230547A/en active IP Right Grant
- 2014-01-30 CR CR20140053A patent/CR20140053A/en unknown
- 2014-02-10 ZA ZA2014/01027A patent/ZA201401027B/en unknown
-
2016
- 2016-04-27 AU AU2016202661A patent/AU2016202661B2/en active Active
- 2016-06-16 PH PH12016501175A patent/PH12016501175B1/en unknown
-
2018
- 2018-04-23 AU AU2018202807A patent/AU2018202807B2/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348360A (en) * | 1998-07-24 | 2002-05-08 | 柳署弘 | Preparation of aqueous clear solution dosage forms with bile acids |
| US6417179B1 (en) * | 1998-10-13 | 2002-07-09 | Craig G. Burkhart | Ear wax solution |
| US20050048126A1 (en) * | 2000-12-22 | 2005-03-03 | Barrett Rabinow | Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug |
Non-Patent Citations (3)
| Title |
|---|
| ADAM M. ROTUNDA ET AL.: "《Randomized Double-Blind Clinical Trial of Subcutaneously Injected Deoxycholate Versus a Phosphatidylcholine–Deoxycholate Combination for the Reduction of Submental Fat》", 《DERMATOLOGIC SURGERY》 * |
| ADAM M. ROTUNDA ET AL.: "《Randomized Double-Blind Clinical Trial of Subcutaneously Injected Deoxycholate Versus a Phosphatidylcholine–Deoxycholate Combination for the Reduction of Submental Fat》", 《DERMATOLOGIC SURGERY》, vol. 35, 31 December 2009 (2009-12-31) * |
| KYTHERA BIOPHARMACEUTICALS: "《Evaluation of Safety and Efficacy of ATX-101 in the Reduction of Submental Fat》", 《NCT01294644》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107865964A (en) * | 2016-09-22 | 2018-04-03 | 李京洛 | Hypo-osmoticity lipolysis composition and preparation method thereof |
| CN116617160A (en) * | 2023-07-25 | 2023-08-22 | 山东则正医药技术有限公司 | Aqueous suspension, preparation method, freeze-dried powder, application and fat reduction injection |
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