CN108619089A - The preparation of deoxycholic acid and its salt - Google Patents

The preparation of deoxycholic acid and its salt Download PDF

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CN108619089A
CN108619089A CN201810400642.9A CN201810400642A CN108619089A CN 108619089 A CN108619089 A CN 108619089A CN 201810400642 A CN201810400642 A CN 201810400642A CN 108619089 A CN108619089 A CN 108619089A
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composition
solution
dexycholate
composition described
natdc
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罗伯特·埃米尔·阿德热
杰弗里·多格拉斯·韦伯斯特
罗伯特·M·莫里亚蒂
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Kythera Biopharmaceuticals LLC
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
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    • 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
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Abstract

This application involves aqueous pharmaceutical compositions, include the dexycholate of about 0.4%w/v to less than about 2%w/v, wherein composition to be maintained to the pH of about 8.1 to about 8.5, to stablize composition to prevent precipitation.Also disclosed herein is the method for stabilized aqueous pharmaceutical composition, the composition includes the dexycholate of about 0.4%w/v to less than about 2%w/v to prevent precipitation, and the method includes the pH of solution is maintained at about 8.1 to about 8.5.

Description

The preparation of deoxycholic acid and its salt
The application, which is on 2 13rd, 2014 entrance National Phase in China, application No. is the 201180072842.2, applyings date to be August in 2011 23 days, entitled " preparation of deoxycholic acid and its salt " application for a patent for invention divisional application.
Invention field
The present invention relates to the aqueous pharmaceutical preparations containing very low concentration of deoxycholic acid (" DCA ") salt, wherein by the system Agent is maintained at DCA and precipitates the pH substantially inhibited.In a preferred embodiment, pharmaceutical composition is buffered to keep physiology Upper acceptable pH, so that composition is suitable for injecting.
Background
For the document report delivered recently when internal injection is into fatty deposits, DCA aqueous solutions have fatty removal Matter is (referring to WO 2005/117900 and WO 2005/112942, US2005/0261258；US2005/0267080；US2006/ 127468；And US2006/0154906).The DCA for being injected into adipose tissue reduces fat cell to carry by cytolytic mechanism For desired aesthetic implications.
Although DCA aqueous formulations have benefit, however, it has been found that optionally in the aqueous solution containing benzylalcohol low concentration DCA (that is, being less than or about 2%w/v；) sediment is formed after some time of storage.Surprisingly it has been discovered that although solution PH do not have it is any significantly change, DCA concentration is lower, and settling velocity is higher.Very low concentration of precipitation is commercialization problem, because Sediment is taboo for DCA hypodermic injections.
In each therapeutic scheme, the clinical test of current DCA aqueous formulations utilizes a small amount of aqueous formulation multiple injection Into limiting the different parts of treated fatty deposits.
It is evident that the DCA aqueous formulations for such treatment are be overlapped with the problem of being caused by DCA precipitations.That is Initially limpid DCA aqueous solutions commercially relevant DCA concentration will form sediment after storing a period of time, although these The pH of solution is between about 7.50 and about 8.0 --- it is substantially higher than the pKa of deoxycholic acid.
Accordingly, there exist stablize during the storage period of at least two moon the aqueous solution of low concentration deoxycholic acid or its salt to prevent Precipitation.
Abstract of invention
It has surprisingly been found that about 0.4%w/v to less than the deoxycholic acid saline solution of about 2%w/v concentration can be with By the way that pH value of solution is adjusted to greater than about 8 and is preferably stablized from about 8.1 to about 8.5 physiologically acceptable pH. PH is kept in the range preferably by buffer.
Correspondingly, one of in terms of its composition, the present invention relates to the aqueous formulations being substantially made up of：About The benzylalcohol of the dexycholate of 0.4%w/v to less than about 2%w/v concentration and optionally preservative effective amount, said preparation is by will most The pH of the clear solution just formed is adjusted to the pH of about 8.1 to about 8.5 and is obtained stablizing to prevent precipitation.In another embodiment In, the present invention relates to the aqueous formulations being substantially made up of：About 0.5%w/v to about 1%w/v concentration dexycholate The optionally benzylalcohol of preservative effective amount, said preparation is by adjusting the pH of the clear solution originally formed to about 8.1 to about 8.5 PH and obtain stablize to prevent precipitation.
In another embodiment, the present invention relates to the aqueous formulations being substantially made up of：
It is buffered to the aseptic aqueous solution of pH about 8.3；
The dexycholate of about 0.5%w/v or about 1%w/v；
The optionally benzylalcohol of preservative effective amount；With
The sodium chloride of about 1%w/v,
Wherein composition is stable to precipitation.
Also disclosed herein is the water-based compositions of stabilized deoxy cholate to prevent the method precipitated during storage, wherein deoxidation courage The concentration of hydrochlorate is the amount of effective cracking adipocyte, and condition is that the amount of dexycholate is about 0.4%w/v to less than 2%w/ V, this method include：
Form the deoxycholic acid saline solution of the initial pH higher than its pKa；The pH of aqueous solution is adjusted to about 8.1 to about 8.5 pH；With optionally include sufficient quantity buffer solution pH is maintained at about 8.1 to about 8.5.
Also disclosed herein is the methods of cracking adipocyte, including give the cell composition according to the present invention.
Brief description
Fig. 1 shows (67X amplifications), water and 0.9%w/v benzylalcohols and the water-based composition of NaTDC does not contain only trace The sediment of amount is presumably bioprene pipeline particles.
Fig. 2 shows (67X amplifications), and the water-based composition of water, 0.5%w/v NaTDCs and 0.9%w/v benzylalcohols contains The sediment of significant quantity is presumably deoxycholic acid salt crystal.
Fig. 3 shows (67X amplifications), and the water-based composition of water, 1%w/v NaTDCs and 0.9%w/v benzylalcohols contains aobvious The sediment of work amount, although less than the sediment of 0.5%w/v NaTDCs.As before, sediment is presumably deoxycholic acid Salt crystal.
Fig. 4 shows (67X amplifications), and the water-based composition of water, 2%w/v NaTDCs and 0.9%w/v benzylalcohols contains aobvious The sediment of work amount, but the sediment observed in substantially less than Fig. 2 and 3.
Detailed description
As used herein, certain terms have the meaning defined below.
All digital indications, for example, pH, temperature, time, concentration and molecular weight, including range, it is approximation, with 0.1 increment and change (+) or (-).Although it should be appreciated that not necessarily clearly stating, add before all digital indications Upper term " about ".In addition to " X " relatively little increment such as " X+0.1 " or " X-0.1 ", term " about " also include exact value " X ".Should also Understand, although not necessarily clearly stating, reagent described herein is only exemplary, equivalent this field Know.
As used herein, term " comprising " is intended to refer to composition and method includes the component enumerated, but is not excluded for other groups Point.
When for limiting composition and method, " substantially by ... form ", which will refer to, excludes active constituent." activity at Point " it is such substance, it is intended to provide pharmacological activity or other in the diagnosis in disease, healing, mitigation, treatment or prevention Directly act on or influence the structure of human body or any function.Thus, for example, the group being substantially grouped as by group as defined herein The trace contaminant from Isolation and purification method and pharmaceutically acceptable carrier, such as phosphate buffer salt will be not excluded for by closing object Water, preservative and analog, but enzyme such as phosphatase and protein will be excluded.The unrestricted example of such protein is liver Element, albumin and analog.
" by ... form " the basic of the composition that is micro- and giving the present invention that exclusion is more than other ingredients will be referred to Method and step.
It is within the scope of the invention by the embodiment each limited in these excessive terms.
As used herein, term " dexycholate " or " its salt " refer to (4R) -4- ((3R, 5R, 10S, 12S, 13R, 17R) - 3,12- dihydroxy -10,13- dimethyl, ten hexahydro -1H- rings penta [a] phenanthrene -17- bases) valerate pharmaceutically acceptable salt, tool There are alkali metal or ammonium ion as cation.Preferred as alkali salt, sodium salt are more preferable.
NaTDC or (4R) -4- ((3R, 5R, 10S, 12S, 13R, 17R) -3,12- dihydroxy -10,13- dimethyl Ten hexahydro -1H- rings penta [a] phenanthrene -17- bases) natrium valericum can according to submit on December 17th, 2010 it is entitled " deoxycholic acid purify It is prepared by method disclosed in the PCT/US2010/061150 of method ".
As used herein, term " aqueous pharmaceutical preparations " refers to the composition of deoxycholic acid or its salt in water, is suitable for administering to suffer from Person preferably gives patient from syringe by being subcutaneously injected.
As used herein, term " buffer " refers to including weak acid and its conjugate base or weak base and the mixture of its conjugate acid Aqueous solution.There is buffer the pH of the solution when a small amount of acid or alkali is added to change very small property.In a variety of Chemical activators, Buffer solution is used as pH being maintained close to the means of steady state value.The example of suitable buffer includes phosphate buffer and text Those of known buffer is (see, e.g., Troy, D.B., ed. (2005) in offering
Remington:The Science and Practice of Pharmacy, the 21st edition, Lippincott Williams&Wilkins)。
As used herein, term " alkali " refer to it is a variety of it is common in the solution have more than 7 pH water soluble compound, point Son or ion.Such compound, molecule or ion can obtain proton from acid or can abandon the unshared electron pair with acid.Properly The example of alkali include metal carbonate and bicarbonate, such as sodium carbonate, calcium carbonate, magnesium carbonate, zinc carbonate, sodium bicarbonate and Analog；And metal hydroxides, such as 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 Version, Lippincott Williams＆Wilkins).
As used herein, term " metal carbonate " refers to CO3 2-Metal salt.For example, sodium carbonate, calcium carbonate, magnesium carbonate, Zinc carbonate and analog.
As used herein, term " alkali metal bicarbonate salt " refers to HCO3 -Metal salt ".For example, sodium bicarbonate and analog.
As used herein, term " metal hydroxides " refers to-The metal salt of O Η.For example, sodium hydroxide, potassium hydroxide and Analog.
As used herein, term " sterile water " or " water for injection " refer to sterile, the pyrogen-free water formulation for injection, Not bacteriostatic agent, antimicrobial or the buffer of addition.In general, the osmolarity of additive amounts at least 112mOsm/ It rises (the 2/5 of the normal osmolarity -280mOsm/ liters of extracellular fluid).
As used herein, term " benzylalcohol " refers to compound
As used herein, term " precipitation " refers to the formation of solid in solution and is easy to distinguish over gel-forming.
As used herein, term " solution " refers to the mixture of substantially homogeneous --- it is dissolved in solvent including two or more Substance.
As used herein, it is most of or all visible heavy to refer to inhibition for term " substantially inhibiting precipitation " and " inhibiting precipitation " It forms sediment to keep homogeney range from least one moon at least 1 year time.
As used herein, term " relative standard deviation of homogeney " or " HE" refer to the absolute value divided by homogeney of average value The value that standard deviation obtains.H less than 10ERefer to extraordinary homogeney.
Preparation
The knowledge of chemically and physically stability about the pharmaceutical composition in the expectation medium for delivering is valuable Value.In longer period, the stability of composition will indicate the storage period for the product introduced to the market.It is preferred that when giving patient When, the concentration of active ingredient in pharmaceutical composition in needs.
In the following discussion, the purpose that NaTDC is given for example only is enumerated, and should understand that deoxycholic acid Other pharmaceutically acceptable salts can exchange use with sodium salt.
It is current NaTDC is given patient with the clinical method of dissolved fat include by be subcutaneously injected give it is low Concentration (that is,<2%w/v) deoxycholic acid saline solution, the amount of wherein dexycholate are enough to crack adipocyte (about 0.4%w/ V and higher).In such concentration, as having been displayed, low concentration is to have to the effectively and safely removal of fatty deposits in body Benefit.However, it has been observed that sediment is formed in aqueous medium in sodium deoxycholate concentration relatively low in this way.The precipitation causes Even in the limited storage period of cold temperature (3-5 DEG C) deoxycholic acid sodium water solution.In one embodiment, sodium salt can be by Another alkali metal salt is replaced.
This unstability of deoxycholic acid sodium water solution can be by evading as follows：About 5% is prepared to about 16%w/v concentration Deoxycholic acid sodium water solution and make practitioner before the use a moment dilution sodium deoxycholate solution pharmaceutical composition.Although should Dilution process effectively obtains storage stability and effective patient dose, but especially if necessary as conventional application method The no more than about aseptic injectable solution of 2mL is not ideal.Moreover, current clinical program includes reaching in each treatment period 50 injections.
It has been found that the aqueous formulation of the NaTDC of concentration range about 0.4%w/v to less than about 2%w/v can pass through tune It saves the pH of solution and is stablized.The present invention relates to the aqueous formulations being substantially made up of：Concentration range about 0.4%w/v To less than dexycholate and the optionally pharmaceutically acceptable excipient of about 2%w/v, as preservative effective amount benzylalcohol and/ Or pH adjusts buffer, wherein the preparation to be maintained to the pH of about 8.1 to about 8.5.
In another embodiment, aqueous formulation is lyophilized to provide stable composition, the composition is easy to pass through Suitable water is added and re-dissolves and is made into original concentration.In this embodiment, the present invention includes freeze-drying as described above Composition, optionally further contain lyophilization aid.
In one embodiment, aqueous formulation contains the dexycholate of about 0.5%w/v.In another embodiment In, aqueous formulation contains the dexycholate of about 1%w/v.
In another embodiment, the water utilized in aqueous formulation is sterile water.Still in another embodiment, The benzylalcohol of preservative effective amount is that the pH of about 0.9%w/v benzylalcohols and preparation is about 8.3.In one embodiment, the salt is alkali Metal salt.In another embodiment, the salt is sodium salt.
In one embodiment, pharmaceutical preparation disclosed herein is suitble to be injected into people.Injecting method can be any class The injection of type, such as hypodermic injection and the injection of other forms.
The precipitation of dexycholate is suppressed at least about six months in the preferred aspect of the present invention, aqueous formulation Time.On the other hand, precipitation is suppressed at least about year.In another aspect, precipitation be suppressed at least about 2 years when Between.
It is expected that when in different temperatures, such as in environment temperature or cold temperature storage, preparation can have increased storage Phase.In some embodiments, composition is stored in about 17 DEG C to about 27 DEG C of temperature.In some embodiments, it will make The temperature of agent is increased to about 25 DEG C to about 37 DEG C of temperature.In other embodiments, by formulation storage at about 2 DEG C to about 8 DEG C Temperature.
In some embodiments, the pH ranges about 8.1 to about 8.5 of preparation.In one embodiment, the pH of composition It is about 8.1, or optionally, about 8.2, or optionally, about 8.3, or optionally, about 8.4, or optionally, about 8.5.Preferred real It applies in mode, the pH of preparation is about 8.3.
In one embodiment, pH is established by using alkali.It is expected that any alkali can be used for increasing the pH of composition, condition It is that it does not react with NaTDC and will not be harmful to patient.In some embodiments, alkali is selected from metal carbonate, metal Or mixtures thereof bicarbonate, metal hydroxides.The example of alkali includes but not limited to alkali selected from the following：Sodium carbonate, carbonic acid Or mixtures thereof calcium, magnesium carbonate, zinc carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide.In one embodiment, alkali is Sodium hydroxide.
In some cases, can the pH of composition be maintained at by desired pH by using buffer during storage.It is various Buffer is known in the art and it is contemplated that there is desired pH any buffer of buffer capacity can be used for being disclosed herein Preparation.In one embodiment, buffer is phosphate buffer.It can determine that phosphatic amount is to provide the phase in composition The pH and salinity of prestige.In one embodiment, composition includes about 10mM phosphate buffer.In preferred embodiment In, composition includes about 10mM disodium hydrogen phosphate buffers.
In some embodiments, composition includes at least one excipient has desirable properties as increased to assist obtaining Dissolubility, keeping quality composition or provide isotonic solution.Such excipient is known in the art.Implement at one In mode, composition includes about 1%w/v sodium chloride.In another embodiment, composition includes about 0.9%w/v benzylalcohols. In some embodiments, composition includes about 0.9%w/v benzylalcohols and about 1%w/v sodium chloride.
In some embodiments, the pH of composition is established by using alkali and is protected optionally by buffer is used It holds.
In a preferred embodiment, the present invention provides stabilized composition, including：
The phosphate buffer of about 8.3 pH；
The NaTDC of about 0.5%w/v or about 1%w/v；
The benzylalcohol of preservative effective amount；With
The sodium chloride of about l%w/v,
Wherein composition is stablized to prevent precipitation.
In other embodiment, phosphate buffer is 10mM disodium hydrogen phosphate buffers.
In one embodiment, the benzylalcohol of preservative effective amount is about 0.9%w/v.
Preparation disclosed herein includes the dexycholate of about 0.4%w/v to less than about 2%w/v in water, is maintained at foot With the pH for substantially inhibiting dexycholate to precipitate.The precipitation capacity or homogeney of composition can utilize a variety of methods to measure.For example, It can by with spectrophotometer lighting compositions using light scattering come quantitative measurment.Or optionally, homogeney can be by with eye Observe solution vision clarity and observational measurement.In some embodiments, composition has opposite less than about 5% homogeney Standard deviation.Optionally, composition, which has, is less than about 4%, or optionally, and about 3%, or optionally, about 2%, or optionally, about 1% homogeney relative standard deviation.
In another embodiment, the present invention relates to the compositions being substantially made up of：
It is buffered to the aseptic aqueous solution of about 8.3 pH；
The NaTDC of about 0.5%w/v or 1%w/v；
About 0.9%w/v benzylalcohols；With
The sodium chloride of about 1%w/v,
Wherein composition is stable to precipitation.
In another embodiment, the present invention relates to the compositions being made up of：
It is buffered to the aqueous solution of about 8.3 pH；
The NaTDC of about 0.5%w/v or about 1%w/v；
About 0.9%w/v benzylalcohols；With
The sodium chloride of about 1%w/v,
Wherein composition is stable to precipitation.
In some embodiments, the solution of this paper does not include lipid, phosphatide or phosphatidyl choline.In some embodiments In, the solution of this paper includes the lipid up to 5%w/w, w/v or v/v, specifically phosphatide, or more specifically phosphatidyl choline.It is preferred that Ground, the amount of the lipid used are less than the amount of NaTDC or another dexycholate.
In some embodiments, aqueous pharmaceutical compositions of the invention can further comprise the second treatment selected from the following Agent：Antimicrobial, vasoconstrictor, antithrombotic agents, anti-coagulants, foam inhibitor, anti-inflammatory agent, antalgesic, dispersant, anti-dispersion Agent, penetration enhancer, steroid, tranquillizer, muscle relaxant and antidiarrheic.In some embodiments, solution containing up to In the container of 500mL solution.Such container can be the container that syringe or syringe can load.
In some embodiments, preparation further comprises the known molecule for causing fatty death by orthogonal mechanism.This The molecule of sample includes neuropeptide tyrosine (NPY) antagonist comprising but be not limited to, npy receptor antagonist, 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 Aventis), S-2367 (Shiongli), it is npy receptor antagonist Dihydropyridine and dihydrogen pyridine derivative, the bicyclic compound for npy receptor antagonist, carbazole npy receptor antagonist and be The tricyclic compound of npy receptor antagonist (see, e.g., WO 2006/133160 and U.S.6,313,128).Also consider fat Selectivity rush apoptosis peptide such as CKGGRAKDC peptides, be located at fat vascular system (referring to, Kolonin M.G. etc., Nat.Med., 2004,10(6):625-32)。
Another aspect of the present invention is related to mixing-in fat ablation cholic acid, e.g., deoxycholic acid (DCA) and kill adipocyte Agent.On the one hand, the present invention considers to cause fat by orthogonal mechanism by being mixed into dexycholate infusion (injectate) The molecule of fat death and the method for improving the aesthetic effect of deoxycholic acid salt injection.The example of such candidate molecule includes But it is not limited to, the rush apoptosis peptide of neuropeptide tyrosine (NPY) antagonist and Fat Selection.Due to may need adipocyte kill with Desired effect is mediated, the effect of the agent with fatty kill ability can be imitated by being added to kill with effective adipocyte The molecule answered and improve.In addition, it is necessary into vascular system with kill molecule (such as certain rush apoptosis peptides, in conjunction with expression exist The albumen of capillary tube chamber side) these albumen are close to, because dexycholate can cause vascular leakage.Therefore, such With the dexycholate for potentially generating more effective way synergistic effect can occur for agent to be mediated in less treatment phase Body contouring.
The example of NPY antagonists includes but not limited to npy receptor antagonist, 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 Aventis), S-2367 (Shiongli), dihydropyridine and dihydropyridine for npy receptor antagonist Derivative, the bicyclic compound for npy receptor antagonist, carbazole npy receptor antagonist and be npy receptor antagonist tricyclic Compound.See, e.g., WO 2006/133160 and U.S.6,313,128.
The rush apoptosis peptide of illustrative Fat Selection includes but not limited to be located at the CKGGRAKDC peptides of fat vascular system. Referring to the, Nat.Med.June 10 such as Kolonin M.G. (6):625-32(2004).
NaTDC or (4R) -4- ((3R, 5R, 10S, 12S, 13R, 17R) -3,12- dihydroxy -10,13- dimethyl Ten hexahydro-lH- rings penta [a] phenanthrene -17- bases) natrium valericum can according to submit on December 17th, 2010 it is entitled " deoxycholic acid purify It is prepared by method disclosed in the PCT/US2010/061150 of method ".Technical staff can equally prepare other dexycholates.
Method
The aqueous formulation of stabilized deoxy cholate is disclosed herein to prevent the method precipitated during storage, wherein its concentration or salt It is the amount of effective cracking adipocyte, condition is that the amount ranging from about 0.4%w/v of salt includes to 2%w/v, this method is approximately less than：
It is formed higher than the deoxycholic acid saline solution of the initial pH of its pKa；
The pH of aqueous solution is adjusted to the pH of about 8.1 to about 8.5；With optionally include sufficient amount buffer pH to be protected It holds about 8.1 to about 8.5.
In one aspect of the invention, method disclosed herein preferably at least about six months following period of time substantially The preparation of stabilized deoxy cholate is to prevent precipitation.On the other hand, the preparation of this method stabilized deoxy cholate to prevent precipitate at least About one-year age.In another aspect, the preparation of this method stabilized deoxy cholate is to prevent precipitation at least about two years.
It has been found that the pH of solution can inhibit the deoxycholic acid or its salt of concentration about 0.4%w/v to less than about 2%w/v in water Precipitation, to allow deoxycholic acid or its salt to keep in the solution.In one embodiment, pH is established by using alkali.In advance Phase any alkali can be used for increase composition pH, as long as it not with deoxycholic acid or its reactant salt.In some embodiments, alkali Selected from or mixtures thereof metal carbonate, alkali metal bicarbonate salt and metal hydroxides.The example of alkali includes but not limited to be selected from Alkali below：Or mixtures thereof sodium carbonate, calcium carbonate, magnesium carbonate, zinc carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide. In one embodiment, alkali is sodium hydroxide.
In some embodiments, pH is about 8.1 to about 8.5.In one embodiment, the pH of composition is about 8.1, Or optionally, about 8.2, or optionally, about 8.3, or optionally, about 8.4, or optionally, about 8.5.In a preferred embodiment, The pH of aqueous solution is about 8.3.
In some cases, the pH of composition can need to keep using buffer.Numerous buffers are known in the art With it is contemplated that desired pH have buffer capacity any buffer can be used for preparation disclosed herein.In an embodiment In, buffer is phosphate buffer.There is provided desired pH and the required phosphatic amount of salinity can utilize this field ripe The method known calculates.In one embodiment, composition includes about 10mM phosphate buffer.In another embodiment In, phosphate buffer is 10mM disodium hydrogen phosphate buffers.
In some cases, pH is established by using alkali and is kept optionally by using buffer.
In one embodiment, method disclosed herein provides the preparation for being suitble to be injected into people.Injecting method can be Any kind of injection, such as hypodermic injection and the injection of other forms.Therefore, in some embodiments, aqueous solution includes Sterile water or water for injection (WFI).
On the one hand, one or more excipient can be used for keeping solubility or increase the dexycholate being present in preparation Keeping quality.In one embodiment, this method includes that about 1%w/v benzylalcohols are added.In some embodiments, said preparation Further include at least one excipient to assist obtaining isotonic solution.Such excipient is well known in the art.At one In embodiment, this method includes that about 1%w/v sodium chloride is added.In some embodiments, this method includes that 1%w/v is added Benzylalcohol and 1%w/v sodium chloride.In some embodiments, this method includes that 0.9%w/v benzylalcohols and 0.9%w/v chlorinations is added Sodium.To include being maintained at less than about the aqueous solutions of 2%w/v dexycholates and being enough substantially to press down using method disclosed herein The pH of dexycholate precipitation processed.The amount or composition homogeney of precipitation can utilize a variety of methods to measure.For example, it can pass through use Spectrophotometer illuminates to measure light scattering and then quantitative measurment.Or optionally, homogeney can be molten by simply being observed with eye The vision clarity of liquid and observational measurement.In some embodiments, this method provides pharmaceutical composition, has and is less than about 5% homogeney relative standard deviation.Optionally, it is less than about 4%, or optionally, about 3%, or optionally, about 2% or optional Ground, about 1% homogeney relative standard deviation.
Storage temperature can assist in keeping the solubility of dexycholate in preparation.In some embodiments, storage temperature It is about 17 DEG C to about 27 DEG C.In some embodiments, storage temperature is about 25 DEG C to about 37 DEG C.In other embodiments, Storage temperature is about 2 DEG C to about 8 DEG C.
Consider a concentration of about 0.5%w/v of dexycholate in preparation, or optionally about 0.7%w/v, or optionally about 1%w/v, or optionally about 1.2%w/v, or optionally about 1.4%w/v, or it is alternatively less than about 2%w/v.It is being preferably implemented In mode, dexycholate is NaTDC.In another preferred embodiment, composition includes 0.5%w/v deoxidations Sodium taurocholate.In another preferred embodiment, composition includes 1%w/v NaTDCs.
In one embodiment, aqueous formulation is divided into multiple individual solution, separated gives its to adipocyte. For example, by aqueous formulation be divided into 5,10,15,20,25 or 30 independent solution and, in some cases, up to 50 independent solution.
In a preferred embodiment, dexycholate is NaTDC.Due to the method for the present invention includes hypodermic injection, Also provide syringe comprising room, plunger and injection needle, wherein room include the preparation of the present invention.Preferably, room be sufficient to accommodate to Few 2mL, and preferably more than 4mL preparations.
In another embodiment, the present invention is provided from shielded commercially available 9- α, 17- beta-dihydroxies- The DCA of 5- α-androstane-3-one is synthesized, as shown in following diagram 1.
Diagram 1：The synthesis of DCA
By commercially available 9- α, 9- α, 17- the β hydroxyl hydroxyl protections of 17- beta-dihydroxies -5- α-androstane-3-one Group is differentially protected, and can be reproduced the hydroxy-protective group and the protected condition of other hydroxyls holding in one of hydroxyl Lower removal.Such differentiated protection is referred to as orthogonal protection and utilizes well known reagent and reaction condition.In an example In, a hydroxyl is protected as acetyl group, and other hydroxyls are protected as benzyl.Each group can keep other hydroxyls to protect It is selectively removed under the shield complete reaction condition of group.
It is expected that the 9- Alpha-hydroxies of relatively three-dimensional protection can need not be protected, because of the reaction considered before removing the group It may be in the position suppressed due to steric hindrance.Anyway, the protection of the hydroxyl fully ensures that the group keeps complete straight It is desired to hydroxyl is removed by dehydration.
The 3- ketone groups of 9- α, 17- beta-dihydroxy-5- α-androstane-3-one --- compound 1 --- of orthogonal protection are used Conventional reducing agent such as sodium borohydride reduction, to provide 3- Alpha-hydroxy derivatives, then by the derivative with another orthogonal guarantor Radical protection is protected to provide compound 2.
Then the hydroxy-protective group of the positions 17- of compound 2 is optionally removed, then uses hydroxyl regenerated in this way Suitable oxidising agent such as Cr03Oxidation, to provide 17- ketone derivatives --- compound 3.By the 17- ketone groups in compound 3 Standard ketalization condition such as with 1,2- dihydroxyethanes or 1, under the reaction of 3- dihydroxypropanes as ketal protect, To generate compound 4 (it shows that the ketal with 1,2- dihydroxyethanes is formed, the purpose being given for example only).
9- alpha-hydroxy deprotections are carried out when needing under conditions of after the hydroxyls dehydrate in such as acid catalyzed removal, are carried For the undersaturated derivatives of 9,10- --- compound 5.The generation of 12- ketone groups by compound 5 and oxidising agent such as chromic acid or TBHP (tert-butyl hydrogen peroxide) and the allylic oxidations of NaOCl are completed, to provide compound 6.It is special see, e.g., the U.S. Sharp application serial no 61/348,686.Optionally, allylic oxidations are by using the TBHP of about 2 to 5 equivalents and about 0.3 to 0.5 The CuI as catalyst of equivalent is completed.Reaction carries out about 40-55 hours in solvent such as acetonitrile at 40 DEG C.Slowly divide Criticizing addition TBHP causes more effectively to aoxidize.The product of formation contains the mixture of compound 6 and corresponding allyl alcohol.Then Product mixtures PCC is aoxidized to generate compound 6.
Compound 6 is in standard conditions such as 10%Pd/C and H2Under hydrogenation provide compound 7.12- ketone groups in compound 7 With reagent such as LiA (OBut)3The reduction that H is carried out provides 12- hydroxy derivatives --- compound 8.Under the conditions of the Wei Tixi of standard Such as compound 9 is provided using the olefination of three phenyl-bromide Phosphonium of second base compound 8 there are alkali such as potassium tert-butoxide. The addition of alkyl acrylate such as methyl acrylate provides compound 10 there are lewis acid, and wherein R is alkyl Such as methyl.The reduction of double bond such as Pd/C and H under the hydrogenation conditions of standard in compound 102It carries out again, compound 11 is provided. With 3-OR after alkali such as LiOH hydrolysis3Deprotection provide DCA --- compound 12.
Compound 12 (crude DCA) is further washed with methanol to purify and be recrystallized from ethyl alcohol.Used CH2C12 Middle 2mol%MeOH (25 volume) dilutes and is heated to 35-37 DEG C, continues 1 hour.Slurry is allowed to be cooled to 28-30 DEG C and mistake Filter.By filter cake CH2C12(5 volume) washs and under vacuum in 40 DEG C of drying, to provide DCA.
DCA is dissolved in 10%DI water/EtOH (12 volume), on celite polishing filtering and with 10%DI water/ EtOH (3 volume) is washed.15 volumes of filtrate of generation are added to DI water (30 volume), the thin white slurry of offer is provided.It will Slurry is kept for 24 hours, filtering, is washed with DI water (20 volume) and is dried under vacuum at 40 DEG C to provide DCA.
DCA is converted to pharmaceutically acceptable salt such as NaTDC and is carried out by normal condition.Optionally, the medicine of DCA Acceptable salt such as NaTDC is converted to DCA and is carried out also by normal condition on.
In another embodiment, the stabilized preparation of present invention offer includes：
The aqueous solution of the buffering of pH with about 8.1 to about 8.5 and further comprise about 0.5% NaTDC peace treaty 0.9% benzylalcohol,
Wherein said preparation is stabilized to prevent precipitation, NaTDC is prepared according to diagram 1.
In another embodiment, the present invention provides stabilized preparation, including：
The aqueous solution of the buffering of pH with about 8.1 to about 8.5 and the NaTDC peace treaty for further comprising about 1% 0.9% benzylalcohol,
Wherein said preparation is stabilized to prevent precipitation, NaTDC is prepared according to diagram 1.
Embodiment
In embodiment and the other places of specification, abbreviation has the following meaning:
Mg=milligrams
ML=milliliters
Mm=millimeters
MM=mMs
The T=times
UV=ultraviolet lights
V/v=volume/volumes
W/v=weight/volumes (g/mL)
W/w=w/ws
WFI=waters for injection
MOsm=m osmoles
By reference to following embodiment, the present invention is further appreciated, embodiment be intended to purely be the present invention example.
Embodiment 1
From the precipitation of the concentration dependant of sodium deoxycholate solution
The sediment of the sodium deoxycholate solution of evaluation various concentration is formed after storage in 1 week.As a result it retouches in figures 1-4 State, and be shown in about 0.5% and about 1% (w/v) in the aqueous solution only containing water and 0.9%w/v benzylalcohols NaTDC it is dense Degree, the sediment of significant quantity are formed, so that it will inhibit the solution to be used as hypodermic composition.By to Fig. 1's -4 Visual inspection, such as following manufactured table, gradable evaluation precipitation capacity.
Table 1
Settling ratings evaluation " 0 " refers to clear solution, and " 10 " refer to the readily visible mixture largely precipitated of display naked eyes.
Such observation is the results show that in the concentration range of test, and deposited phenomenon is substantially by deoxycholic acid salinity Influence.In order to find out influences of the pH to precipitation, the pH of solution is measured, as provided in table 2, shows that the pH of solution is basic It is upper identical, especially for 1% and 2% solution.The solubility against the current of NaTDC --- wherein diluter solution (0.5% or 1%) denseer solution (2%) provides more precipitations --- be surprising observation result and also confirm it is heavy Shallow lake phenomenon is not directly related with pH, because the pH of solution is again substantially the same, especially for 1% and 2% solution.
Table 2
Correspondingly, the present invention is shown, from dilute --- 0.4% to less than 2% (w/v) ---, deoxycholate solution makes us Surprised precipitation is suppressed to such solution by increase pH value of solution and can be used for hypodermic degree.
Embodiment 2
With and without NaTDC (API) preparation of benzylalcohol
1. prepare NaTDC (0.5% and 1%) composition, including sodium phosphate (10mM), sodium chloride (75-90mM), Benzylalcohol (0.9%), deoxycholic acid, pH 8.3.
2. utilizing free acid form, that is, deoxycholic acid, the following isotonic combination for preparing the not NaTDC of benzylalcohol Object.
A.100mL the preparation of the isotonic batch of 10mg/mL
It, will only after preparing alkaline solution with 70mL water, 142mg Anhydrous Disodium Phosphate and 267 μ L 10M NaOH 1.0g deoxycholic acids (DCA) are added to solution.API needs about 20 minutes to enter solution.The pH of solution is 11.1.It is known quick Addition HCl causes some precipitations, so being slowly added into 225 μ L 1M HCl solution is transferred to pH 8.3.Allow solution mixed Close additional 15 minutes.After volume is transferred to 100mL with water, it is found that osmolality is 51mOsm.It is added Osmolality is transferred to 305mOsm by 859mg NaCl.
The solution so prepared is optionally lyophilized to provide freeze-drying prods, which can be suitable by being added Sterile water and re-dissolve and be made into original concentration.Correspondingly, the present invention also provides the freeze-drying prods of solution disclosed herein.
B.1000mL the preparation of the isotonic batch of 10mg/mL
When increasing to ten times, the result from part a (above) without scaling up completely.Add into 900mL water Enter 1.4g Anhydrous Disodium Phosphate, 8.6g NaCl and 2.7mL 10M NaOH.Then be added 10.0g DCA and allowing mix to Limpid 30 minutes.The pH of solution is 10.4.It is slowly added to 1.5mL 1M HCl and allows mixing 5 minutes.Final pH is 8.1. Other 20 μ L 10M NaOH must not be added without so that pH is transferred to 8.3.Volume is transferred to 1000mL, weight molar concentration infiltration with water Concentration 314mOsm.
Based on the observation that pH changes during 1M HCl are added as a result, determining for 1000mL 10mg/mL API batches, just The 1M HCl of good 1.0mL should be added immediately, then slowly use small size acidometric titration.For building for 1000mL 10mg/mL API The addition sequence of view is described in table 3.
C.100mL the preparation of the isotonic batch of 5mg/mL
It, will only after preparing alkaline solution with 70mL water, 142mg Anhydrous Disodium Phosphate and 134 μ L 10M NaOH 1.0g deoxycholic acids (DCA) are added to solution.API needs about 20 minutes to enter solution.The pH of solution is 10.7.It is known quick Addition HCl causes some precipitations, so being slowly added into 115 μ L 1M HCl solution is transferred to pH 8.3.Allow solution mixed Close additional 15 minutes.After volume is transferred to 100mL with water, it is found that osmolality is 39mOsm.It is added Osmolality is transferred to 294mOsm by 859mg NaCl.
D.1000mL the preparation of the isotonic batch of 5mg/mL
When increasing to ten times, the result from part c (above) without scaling up completely.Add into 900mL water Enter 1.4g Anhydrous Disodium Phosphate, 8.6g NaCl and 1.3mL 10M NaOH.Then 5.0g DCA are added and allow to mix to clear Clear 30 minutes.PH is 8.6.It is added after just 350 μ L 1M HCl, pH drops to 8.0.Other 25 μ L 10M must not be added without NaOH by pH to be transferred to 8.4.Volume is transferred to 1000mL, osmolality 305mOsm with water.Based on addition 1M The observation that pH changes during HCl is as a result, determine that solution should slowly use small size 1M for 1000mL 5mg/mL API batches HCl is titrated.For 1000mL 5mg/mL API suggestion addition sequence described in table 3.
The addition sequence (from left to right) of preparations of the isotonic 1000mL of table 3. without benzylalcohol

Claims (19)

1. the water-based composition stable for the precipitation by hypodermic injection cracking adipocyte, it includes：0.4%w/v is to small Dexycholate in 2%w/v and pharmaceutically acceptable excipient, wherein the composition is maintained at 8.1 to 8.5 pH。
2. composition described in claim 1, wherein the dexycholate exists with the amount of 0.5%w/v to 1%w/v.
3. the composition described in claim 1 or claim 2, wherein the dexycholate exists with the amount of 0.5%w/v.
4. the composition described in claim 1 or claim 2, wherein the dexycholate exists with the amount of 1%w/v.
5. composition any one of Claims 1-4, wherein the excipient is solvent, buffer, preservative, jelly Dry auxiliary agent or any combination thereof.
6. the composition described in claim 5, wherein the excipient is sterile water.
7. the composition described in claim 5, wherein the excipient is preservative.
8. the composition described in claim 7, wherein the preservative is 0.9% benzylalcohol.
9. composition described in any item of the claim 1 to 8, wherein the composition has 8.3 pH.
10. the composition described in any one of claim 1 to 9, wherein the salt is alkali metal salt.
11. composition according to any one of claims 10, wherein the alkali metal salt is sodium.
12. stable water-based composition is precipitated, it includes：
It is buffered to the aseptic aqueous solution of 8.3 pH；
The NaTDC of 0.5%w/v；
0.9%w/v benzylalcohols；With
The sodium chloride of 1%w/v.
13. stable water-based composition is precipitated, it includes：
It is buffered to the aqueous solution of 8.3 pH；
The NaTDC of 1%w/v；
0.9%w/v benzylalcohols；With
The sodium chloride of 1%w/v.
14. application of the composition in preparing the drug for cracking adipocyte described in any one of claim 1 to 13.
15. the composition described in claim 5, wherein the preservative is benzylalcohol.
16. the application described in claim 14, wherein the drug passes through subcutaneous administrations.
17. composition described in claim 1, by 0.4%w/v to less than 2%w/v dexycholate and can pharmaceutically connect The excipient composition received, wherein the composition to be maintained to 8.1 to 8.5 pH.
18. the composition described in claim 12, by as follows at being grouped as：
It is buffered to the aseptic aqueous solution of 8.3 pH；
The NaTDC of 0.5%w/v；
0.9%w/v benzylalcohols；With
The sodium chloride of 1%w/v.
19. the composition described in claim 13, by as follows at being grouped as：
It is buffered to the aqueous solution of 8.3 pH；
The NaTDC of 1%w/v；
0.9%w/v benzylalcohols；With
The sodium chloride of 1%w/v.
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Applicant before: Kesera biopharmaceutical Co., Ltd

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