CN101340933A - Factor xa inhibitor inclusion complex with cyclodextrin - Google Patents
Factor xa inhibitor inclusion complex with cyclodextrin Download PDFInfo
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- CN101340933A CN101340933A CNA2006800300033A CN200680030003A CN101340933A CN 101340933 A CN101340933 A CN 101340933A CN A2006800300033 A CNA2006800300033 A CN A2006800300033A CN 200680030003 A CN200680030003 A CN 200680030003A CN 101340933 A CN101340933 A CN 101340933A
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Abstract
An injectable Factor Xa inhibitor formulation is provided which includes the Factor Xa inhibitor razaxaban or apixaban, a solubilizing agent which is a substituted beta-cyclodextrin, preferably, sulfobutyl ether beta-cyclodextrin (SBE-CD) or hydroxypropyl-beta-cyclodextrin (HPB-CD), and water. A method for preventing or treating venous thrombosis, deep venous thrombosis and acute coronary syndrome employing the above formulation is also provided.
Description
The cross reference of related application
[0001] the application requires the benefit of priority of No. the 60/709th, 077, the U.S. Provisional Application submitted on August 17th, 2005, and it expressly all is incorporated herein by reference at this.
Technical field
[0002] the present invention relates to comprise the beta-schardinger dextrin-(factor Xa of solubilizing agent (Factor Xa) inhibitor formulations of β-cyclodextrin) of factor Xa inhibitor and replacement, factor Xa inhibitor inclusion complex (inclusion complex) with beta-schardinger dextrin-of replacement, the injectable formulation that comprises the beta-schardinger dextrin-of factor Xa inhibitor and replacement, be used for inhibitive factor Xa and prevention or treatment venous thromboembolism with the above-mentioned preparation of use, the method of venous thrombosis and acute coronary syndrome.
Background technology
[0003] United States Patent (USP) the 6th, 339, discloses amino benzoisoxazole No. 099
(after this being called Lei Zhashaban (Razaxaban)), it suppresses blood coagulation enzyme people factor Xa, thereby is useful for prevention or treatment venous thromboembolism and venous thrombosis.
[0004] Lei Zhashaban is a weak base, has the dissolubility that relies on pH, and when pH raise, its dissolubility showed reduction.The neutral form of Lei Zhashaban or free alkali (free base) have extremely low dissolubility, estimate under the room temperature that its dissolubility is below the 1 μ g/mL when pH6.8.And under normal gastric ph conditions, wherein the pH of stomach medium is～1-2, and Lei Zhashaban has～dissolubility of 3mg/mL with the form of its hydrochlorate.
[0005] the human body bullet vein dosage of Yu Qi Lei Zhashaban is about 50 milligrams.In order to obtain actual volume injected, the following volume injected of 20mL for example need have the solution of high drug level, as 2.5mg/mL.Having been found that by regulating pH (pH3-11) within the ideal pH scope to make the dissolubility of Lei Zhashaban be elevated to needed level.Pain when making the parenteral intravenous injection minimizes, and this pH scope is expected.
[0006] U.S. Patent Publication 2003/0191115A1 is (based on the U. S. application series number 10/245 of JIUYUE in 2002 submission on the 17th, 122) a series of factor Xa inhibitors are disclosed, it comprises 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide (after this being called apixaban), it has structure
Apixaban is weak base and indissoluble (being below about 1 μ g/mL when pH6.8 under the room temperature).
[0007] known cyclodextrin is used to increase the dissolubility of medicine.They work by forming inclusion complex with hydrophobic molecule.Regrettably, exist a lot of medicines, cyclodextrin to they complexing or can not or not produce obvious benefit, as by J.Szeftli, Cyclodextrns in Drug Formulations:Part II, Pharmaceutical Technology, 24-38, August, 1991 is disclosed.
[0008] people's such as Stella United States Patent (USP) the 5th, 134, No. 127 and the 5th, disclose that sulfoalkyl ether cyclodextrin (sulfoalkyl ether cyclodextrin) derivant and their are oral as being used for for 376, No. 645, intranasal or comprise intravenous injection and the application of the solubilizing agent of the water-insoluble drug of the parenteral administration of intramuscular injection.People such as Stella disclose the inclusion complex of water-insoluble drug and sulfoalkyl ether cyclodextrin derivant, and the pharmaceutical composition that contains same composition.The example of disclosed sulfoalkyl ether cyclodextrin derivant comprises the list-sulfobutyl ether (mono-sulfobutylether) of beta-schardinger dextrin-and single sulfopropyl ether (monosulfopropyl ether) of beta-schardinger dextrin-.The example of water-insoluble drug is illustrated in the 7th row, originates in the 25th row.
[0009] people's such as Kim United States Patent (USP) the 6th, 232, disclose for No. 304 at cyclodextrin such as beta-schardinger dextrin-sulfobutyl ether (SBE-CD) and HP-(hydroxypropyl-β-cyclodextrin, the inclusion complex of the tartrate of aryl-heteroaryl salt HPBCD) such as Ziprasidone (ziprasidone), and the application of this class inclusion complex in oral and parenteral administration.
[0010] people's such as Uekama United States Patent (USP) discloses for the 5th, 904, No. 929 and has contained medicine and as the through mucous membrane of mistake acidylate (peracylated) cyclodextrin of solubilizing agent and the pharmaceutical composition of percutaneous.The example of medicine comprises anticoagulant, be warfarin (warfarin), with the anti-stroke chemical compound, as lubetuzole or its oxide, riluzole (riluzole), N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine (aptiganel), eliprodil (eliprodil) and remacemide (remacemide).
[0011] people's such as Muller United States Patent (USP) discloses the clathrate (inclusion compound) that is formed by medicine that is insoluble in water and water unstable and beta-cyclodextrin derivative for the 6th, 407, No. 079.People such as Muller disclose the medicine that uses: the mol ratio of beta-cyclodextrin derivative is from about 1: 6 to 4: 1, particularly about 1: 2 to 1: 1.
Summary of the invention
[0012] according to the present invention, preparation is provided, it comprises thunderous Zha Shaban of factor Xa inhibitor (razaxaban) or apixaban, and solubilizing agent, this solubilizing agent is the beta-schardinger dextrin-that replaces.Have been found that, the beta-schardinger dextrin-that replaces increases to the dissolubility of factor Xa inhibitor to be enough to and allows to prepare 20mL to contain the 2.5mg/mL or the aqueous injectable preparation of multiple-factor Xa inhibitor more in the lower volume, makes and carry 50mg or more factor Xa inhibitor in the single bolus injection.
[0013] surprisingly and unexpectedly, have been found that, the beta-schardinger dextrin-of the thunderous Zha Shaban of factor Xa inhibitor and apixaban and replacement such as sulfobutyl ether-beta-cyclodextrin (sulfobutylether-β-cyclodextrin, SBE-CD) can be formulated as injectablely, it is transported to factor Xa inhibitor the muscle site under acceptable volume injected.
[0014] is used for the factor Xa inhibitor of this paper by following type definition.
Kind A
With its pharmaceutically acceptable salt,
R wherein
2Be alkyl or many alkylhalide groups, be preferably CF
3
R
1Be alkyl, be preferably CH
3With
X is a halogen, is preferably F.
[0015] the kind A that shows above is by United States Patent (USP) the 6th, 339, and disclosed classes of compounds covers in No. 099, and this patent is hereby incorporated by, and is included in United States Patent (USP) the 6th, 339, the open and/or general factor Xa inhibitor that covers in No. 099.
[0016] the preferred factor Xa that is used in the kind A of this paper is Lei Zhashaban, and it has structure
Kind B
With its pharmaceutically acceptable salt,
R wherein
3Be to be selected from
Alkyl
Or HO (alkylidene)
x(x is 1 to 4),
(R wherein
6And R
7Be identical or different, and be alkyl)
Be preferably
R
4Be selected from alkoxyl and halogen, be preferably methoxyl group; And
R
5Be
Wherein Q is 6 yuan of monocycles, and wherein 0,1 or 2 two key is present in the ring, and this ring is substituted with 0,1 or 2 R
5aGroup, its under each situation, be independently selected from H ,=O or alkyl and
Q
1Be C=O.
[0017] preferred R
5Group is
R wherein
5a, under each situation, be independently selected from H ,=O, CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH
2CH
2CH
2CH
3, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3And C (CH
3)
3With
R
5bBe H or alkyl, as CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH
2CH
2CH
2CH
3, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3And C (CH
3)
3
[0018] R
5Be preferably
[0019] the kind B that shows is above contained (comprising) by disclosed classes of compounds among the U.S. Patent Publication 2003/0191115A1, this patent is hereby incorporated by, and is included in the factor Xa inhibitor that U.S. Patent Publication 2003/0191115A1 is disclosed and/or generally contain.
[0020] be used for herein that the preferred factor Xa inhibitor in kind B is apixaban, it has structure
[0021] chemical compound within kind A and B scope is called as " factor Xa inhibitor (one or more) " in this article jointly.
[0022] in addition, according to the present invention, provide pharmaceutical preparation, its beta-schardinger dextrin-and pharmaceutically acceptable carrier thereof by factor Xa inhibitor and replacement forms.
[0023] in preferred embodiment, pharmaceutical preparation of the present invention will be the form of aqueous parenteral administration or injectable formulation.Yet pharmaceutical preparation of the present invention can be other dosage form, as freeze dried injectable forms, oral form (as tablet, capsule, elixir and similar dosage form), percutaneous or through mucous membrane form or suction form.
[0024] injectable formulation of the present invention will preferably clear, colorless be to pale yellow solution, and visual examination does not have particulate matter basically.
[0025] further, according to the present invention, be provided for using injectable factor Xa inhibitor and do not cause the method for unacceptable irritation, wherein preferably to the above-mentioned injectable formulation of patient's intramuscular administration of needs treatment at injection point.
[0026] still further according to the present invention, the method that is provided for suppressing blood coagulation enzyme people factor Xa and is used to prevent or treat venous thromboembolism, venous thrombosis and acute coronary syndrome, it comprises that the patient to the needs treatment uses the step of above-mentioned preparation, preferably use with the form of injection, no matter be at the muscle position or other site, can not cause improperly at injection point stimulates.
[0027] according to the present invention, the factor Xa inhibitor concentration of the injectable formulation of expectation is the result to 20mL bullet volume infused (maximal dose of 50mg is provided) restriction.The pH of injectable formulation of the present invention is an important consideration when determining the greatest hope dissolubility of factor Xa inhibitor, and it should be about 3 to about 11, this depends on employed concrete factor Xa inhibitor, so that pain on injection reduces to minimum.
[0028] considers all above-mentioned factors, according to the present invention, have been found that (hydroxypropyl-β-cyclodextrin HPB-CD) is the preferred solubilizing agent that is used for factor Xa inhibitor for the beta-schardinger dextrin-of replacement such as sulfobutyl ether beta-schardinger dextrin-(SBE-CD) and HP-.
[0029] factor Xa inhibitor Lei Zhashaban in the beta-schardinger dextrin-that replaces, as reaching under 11 the pH, has identical dissolubility at pH4.5 and higher pH.In fact, have been found that by pH to be reduced between about 3 and about 4, realized the rising of Lei Zhashaban dissolubility Lei Zhashaban-beta-schardinger dextrin-solution, and the injectable drug concentration and the volume that can obtain expecting, and can not cause stimulation or pain improperly at injection point.
[0030] by using acid buffer and alkali to obtain to comprise the expectation pH of the injectable formulation of the present invention of the thunderous Zha Shaban of kind A chemical compound.The lower limit of pH will be about 3.Because physiological restriction is as the stimulation at injection point, is lower than 3 pH and do not expect.The upper limit of pH will be about 11, so that the margin of safety about drug solubility to be provided.Yet, for injectable drug concentration and the volume that obtains to expect, preferably at about 3 pH that arrive within about 5 the scope.
[0031] by using pH that buffer regulates the aqueous injection about 6 within about 8 the scope, be preferably approximately 7, obtain comprising the expectation pH of the injectable formulation of the present invention of kind B chemical compound such as apixaban.
Detailed Description Of The Invention
[0032] kind A that shows above and the thunderous Zha Shaban of the factor Xa inhibitor of B and apixaban have poor water solublity and therefore are difficult to prepare as the aqueous injection.According to the present invention, have been found that beta-schardinger dextrin-solubilizing agent by usage factor Xa inhibitor and replacement, the water solublity of factor Xa inhibitor can be enough to be increased to makes it prepare as the aqueous injection.This is astonishing and beyond thought really, because the main body that has been found that miscible cosolvent system of water and water unmixing cosolvent system is unacceptable as the carrier of the thunderous Zha Shaban of injectable factor Xa inhibitor,, they are not enough under acceptable volume injected, provide the drug level of 2.5mg/mL at least because not making the dissolubility of factor Xa inhibitor increase to.On the other hand, aqueous injectable preparation of the present invention concentration with 2.5mg/mL at least in 20mL or volume is still less carried thunderous Zha Shaban of factor Xa inhibitor or apixaban, so that provide acceptable dosage, as 50mg or more Lei Zhashaban and 5mg or more apixaban with the single bolus injection.
[0033],, the factor Xa inhibitor preparation of the present invention of aqueous injection form regulates the buffer of pH to aspiration level for can comprising as will seeing hereinafter.
[0034] beta-schardinger dextrin-that is suitable for replacement herein be meant sulfobutyl ether beta-schardinger dextrin-(SBE-CD) and HP-(hydroxypropyl-β-cyclodextrin, HPB-CD), preferred SBE-CD.
[0035] term " bullet (bolus) " refers to comprise the single injection of medicine all dosage as used herein, and it was used as in one minute or shorter time in the short relatively time.
[0036] term is waited until serious stimulation at injection point or in " inadequate stimulus " or " unacceptable irritation " of muscle point is meant, it is unacceptable for the patient, and the patient comply with the generation adverse influence.
[0037] term refers to general Min. to slight stimulation at injection point or in " stimulation of minimizing " of muscle point, and it is acceptable for the patient, and can be to the patient comply with the generation adverse influence.
[0038] term " acute coronary syndrome " refers to stand possibility because the people of the chest pain that unstable angina pectoris outbreak or heart attack cause as used herein.
[0039] except as otherwise noted, as used herein alone or as the employed term of the part of another group " low-carbon alkyl ", " alkyl " or " alk " comprises straight chain and branched-chain hydrocarbons, it is included in 1 in the straight chain to 10 carbon, 1 to 8 carbon preferably, as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, isohesyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2, the 4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl, its various branched chain isomers and analog and such group, it comprises 1 to 4 substituent group, as halogen---and F for example, Br, Cl or I or CF
3, alkoxyl, aryl, aryloxy group, aryl (aryl) or diaryl, alkoxy aryl, alkenyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl alkoxy, hydroxyl, hydroxyalkyl, acyl group, aryl alkyl carbonyl oxygen, aryloxy alkyl, aryloxy group aryl, alkylamidoalkyl, alkanoylamino, aryl-amino-carbonyl, nitro, cyano group, thiol, alkylhalide group, three alkylhalide groups and/or alkylthio.
[0040] (alkylidene)
xBe included in the alkylidene of 1 to 4 carbon in the straight chain, it can randomly comprise 1,2 or 3 substituent group, and this substituent group comprises alkyl, alkenyl, halogen, cyano group, hydroxyl, alkoxyl, amino, alkylthio, ketone group (keto), C
3-C
6Cycloalkyl, alkyl-carbonyl-amino or alkyl-carbonyl oxygen base; This alkyl substituent can be the moieties of 1 to 4 carbon, its can with (CH
2) a carbon among the x connects.
[0041] (alkylidene)
xExample comprise
[0042] refers to chlorine, bromine, fluorine and iodine and CF as term " halogen " or " halogen " used herein alone or that use as the part of another group
3, preferred chlorine or fluorine.
[0043] term " many alkylhalide groups " refers to that as " alkyl " defined above group, it comprises 2 to 9 as used herein, and preferably 2 to 5 halogen substituent groups as F or Cl, are preferably F, as CF
3CH
2, CF
3Or CF
3CF
2CH
2
It is believed that [0044] factor Xa inhibitor will form coordination compound (complex) with the beta-schardinger dextrin-that replaces, this coordination compound can be dissolved in the water to generate injectable preparation.Yet the physical mixture of the beta-schardinger dextrin-of factor Xa inhibitor and replacement and the aqueous solution that directly forms (the solid preparation with the beta-schardinger dextrin-of factor Xa inhibitor and replacement does not dissolve again) are also within the scope of the invention.
[0045] coordination compound or physical mixture also can be pressed into tablet and maybe can be filled in the capsule.
[0046] factor Xa inhibitor preparation of the present invention can be used as aqueous solution and directly forms, perhaps as the dry reason mixture of the beta-schardinger dextrin-of factor Xa inhibitor and replacement, perhaps as its dried inclusion complex, this dried inclusion complex can be formed the injectable preparation of aqueous by reconstruct when adding entry.Alternatively, this aqueous injectable preparation can lyophilization and later on water by reconstruct.Therefore, according to factor Xa inhibitor preparation of the present invention can be pre-formed, original position forms or in vivo (in digestive tract or oral cavity) form.The present invention has considered above-mentioned all situations.
[0047] when the factor Xa inhibitor that uses in preparation of the present invention with the form of aqueous injection is the thunderous Zha Shaban of weak base, said preparation will comprise acid buffer, with the pH that regulates the aqueous injection about 3 to about 9 the scope, preferably about 3 to about 5 the scope.The example that is suitable for the acid buffer of this paper comprises sour example hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid and similarly acid, and organic acid such as oxalic acid, maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, ethyl sulfonic acid and similarly acid.Also can use the acid salt of above-mentioned acid.Preferred acid is tartaric acid, citric acid, phosphoric acid and hydrochloric acid.Citric acid most preferably.
[0048] injectable formulation of the present invention that comprises factor Xa inhibitor Lei Zhashaban can have about 3 pH to about 9 the scope, and preferably from about 3 to about 5 and more preferably from about 3 to about 3.4, and most preferably be about 3.2.During injection, if necessary, can regulate pH in preparation, as alkali-metal citrate such as sodium citrate or potassium citrate, alkali metal hydroxide such as NaOH, KOH or LiOH, be preferably NaOH, perhaps alkaline earth metal hydroxide such as Mg (OH) with alkali
2Or Ca (OH)
2, optimization citric acid sodium.
[0049] when factor Xa inhibitor is the form of free alkali such as factor Xa inhibitor apixaban, said preparation will comprise buffer with the pH that regulates the aqueous injection about 6 to about 8 the scope, be preferably about 7.
[0050] example that is suitable for these buffer of this paper comprises that phosphate buffer (is dihydric phosphate and sodium hydroxide, or the mixture of sodium hydrogen phosphate and sodium dihydrogen phosphate), with tris buffer (being the methylol aminoethane), described buffer can adjusting pH as implied above, so that stability to greatest extent to be provided.
[0051] in preparation aqueous injectable preparation of the present invention, the beta-schardinger dextrin-that replaces will be used, the mol ratio of itself and thunderous Zha Shaban of factor Xa inhibitor or apixaban is within about 5: 1 to 400: 1 scopes, preferably within about 10: 1 to about 100: 1 scopes.The cyclodextrin of employed each type needs different ratios, to obtain acceptable drug concentration.
[0052] in the preferred implementation of aqueous injection of the present invention, the beta-schardinger dextrin-that replaces will be SBE-CD, the mol ratio of thunderous Zha Shaban of employed SBE-CD and factor Xa inhibitor or apixaban at about 5: 1 to about 400: 1 scope, preferably about 10: 1 to about 80: 1 scope, more preferably be 12: 1 (based on the Lei Zhashaban concentration of 2.5mg/mL and the SBE-CD (120mg/mL) of 12%w/v).The amount that cyclodextrin exists is greater than the required amount of complexation factor Xa inhibitor, because extra cyclodextrin can help the dissolving of medicine.
[0053] the present invention another preferred embodiment in, to use SBE-CD, the mol ratio of itself and apixaban is within about 50: 1 to 100: 1 scope, preferably about 70: 1 to about 90: 1 scope, more preferably be about 75: 1 (based on the drug level of 1mg/mL medicine and the SBE-CD of 35%w/v (350mg/mL)).
[0054] still in another preferred implementation of the present invention, to use HP-(HPB-CD), the mol ratio of itself and apixaban at about 30: 1 to about 100: 1 scope, preferably about 40: 1 to about 70: 1 scope, more preferably be about 45: 1 (based on the drug level of 2.5mg/mL and the HPB-CD of 35%w/v (350mg/mL)).
[0055] factor Xa inhibitor is present in the amount in the aqueous injectable preparation, based on whole injectable formulations, and will be at about 0.1wt% to about 2wt% scope, preferably in the extremely about 1wt% scope of about 0.2wt%.
[0056] in preferred embodiment, factor Xa inhibitor will be present in the aqueous injectable preparation, so that about 1mg/mL to be provided the preparation to about 20mg/mL, preferably about 2mg/mL is to the preparation of about 10mg/mL, and more preferably about at least 2.5mg/mL reaches the preparation of about 8mg/mL.
[0057] in preferred embodiment, preparation of the present invention will provide 2.5mg Lei Zhashaban/mL or 2.5mg apixaban/mL, 5mg/mL and 7.5mg/mL.To preferably 10mL and 20mL for the Lei Zhashaban packing volume, and incite somebody to action preferably 2mL, 4mL and 10mL for apixaban.
[0058] preferred injection preparation is as follows:
(1) Lei Zhashaban---about 2.5mg/mL is provided the amount to the solution of about 8mg/mL.
(2) SBE-CD---its amount is the solution of about 50mg/mL to about 200mg/mL.
(3) acid buffer (being preferably citric acid)---its amount for about 0.5mg/mL to about 5mg/mL solution, being about 3 to about 5 with pH regulator.
(4) alkali of adjusting pH is preferably alkali-metal citrate, is preferably sodium citrate, and its amount is about 3 to 5 with pH regulator.
(5) water is an amount of, to 1mL.
[0059] can be prepared as follows Lei Zhashaban injectable formulation of the present invention: with citric acid or as described herein other bronsted lowry acids and bases bronsted lowry such as sodium citrate or as described herein other alkali dissolution in water for injection.The beta-schardinger dextrin-(being preferably SBE-CD) that replaces is dissolved in buffered aqueous solution.Then Lei Zhashaban is dissolved in the solution.Add the batch volumes (batch volume) of extra water for injection to obtain expecting.
[0060] solution that obtains of aseptic filtration for example, by 0.22 μ membrane filter, and is put into it in bottle.Clog and sealed vial, and can carry out terminal disinfection.
[0061] when the amount of the Lei Zhashaban that provides by coordination compound in water under the cyclodextrin concentration of 5-20%w/v when measured, aqueous injectable preparation of the present invention will provide the Lei Zhashaban amount of 2mg Lei Zhashaban/ml at least, be preferably 2.5mg Lei Zhashaban/ml at least.
[0062] another preferred injection preparation is as follows:
(1) apixaban---the amount of the solution from about 2.5mg/ml to about 8mg/ml is provided.
(2) HPB-CD---its amount is the solution of about 50mg/mL to about 500mg/mL.
(3) phosphate buffer (dihydric phosphate and sodium hydroxide, or sodium hydrogen phosphate and sodium dihydrogen phosphate)---its amount is about 6 to about 8 for the solution of about 0.5mg/mL to about 5mg/mL to regulate pH.
(4) water is an amount of, to 1mL.
[0063] factor Xa inhibitor apixaban injectable formulation of the present invention can be prepared as follows: phosphate buffer or TRIS buffer are dissolved in the water for injection.The beta-schardinger dextrin-(being preferably HPB-CD or SBE-CD) that replaces is dissolved in the buffered aqueous solution.Then Apixaban is dissolved in this solution.Add extra water for injection to obtain the batch volumes of expectation.
[0064] solution that obtains of aseptic filtration for example, by 0.22 μ membrane filter, and is put into it in bottle.Clog and sealed vial, and can carry out terminal disinfection.
[0065] when measuring the amount of the apixaban that provides by coordination compound under for the cyclodextrin concentration of 35%w/v in water, aqueous injection preparation of the present invention will provide 2mgapixaban/ml at least, preferably 2.5mg apixaban/ml at least.
[0066] preparation of the present invention is used to inhibitive factor Xa and prevention or treatment and factor Xa diseases associated, and it comprises venous thrombosis, venous thrombosis and acute coronary syndrome in the human patients.The preferred dose that injectable formulation of the present invention adopted will be to contain 2.5mg Lei Zhashaban/ml or 2.5mg apixaban/ml, perhaps give the Lei Zhashaban of 25 to 50mg dosage once a day, perhaps give 2 to 20ml the injection of the apixaban of 2.5 to 10mg dosage once a day.Although subcutaneous also effective with intravenous injection, this ejection preparation is preferably by intramuscular administration.
[0067] following examples are represented preferred implementation of the present invention.
Embodiment 1
[0068] be prepared as follows have following composition, visual examination do not have the Lei Zhashaban injection solution (2.67mg Lei Zhashaban/mL, 10.5mL/ bottle) of the clear, colorless of particulate matter substantially.
Table 1
As the quantitative composition of the Lei Zhashaban injection of free alkali, 25mg/ bottle (2.5mg/mL)
| Composition | The reason of using | The amount of every mL | Every bottle amount |
| Lei Zhashaban (Razaxaban) | Effective ingredient | 2.67 b | 28.06mg |
| CaptisolTM (SBE-CD) | Solubilizing agent | 120mg | 1260mg |
| Citric acid USP/EP (monohydrate) | Stabilizing agent (buffer) | 1.831mg | 19.23mg |
| Sodium citrate, USP/EP (dihydrate) | Stabilizing agent (buffer) | 0.379mg | 3.98mg |
| Water for injection, USP/EP | Solvent | In right amount to 1mL | In right amount to 10.5mL a |
aThe target packing volume is 10.5mL.This volume comprises the excessive filling of 0.5mL, is used for bottle-needle injection (VNS) and is detained.
bSuppose 100% purity.28.06mg Lei Zhashaban (hydrochlorate, MW=564.92) suitable with 26.25mg free alkali (MW=528.46).2.67mg Lei Zhashaban (hydrochlorate) is suitable with the 2.50mg free alkali.
[0069] the rustless steel proportion container adds water for injection USP/EP (WFI), and its amount equals about 85% of final batch volumes.
[0070] is accompanied by and continue mixes, the granular USP of citric acid monohydrate compound and sodium citrate USP/EP are joined proportion container and stir till obtaining the solution of finishing (completedsolution).
[0071] is accompanied by lasting the mixing, with sulfobutyl ether beta-schardinger dextrin--(Captisol
TM) (approximately 1.26kg) join proportion container and stir till obtaining completely solution.
[0072] Lei Zhashaban (approximately 28g) is joined proportion container, and continue to stir till the Lei Zhashaban dissolving and obtaining completely solution.
[0073] extra water for injection USP is joined in the above-mentioned solution, adjust to the final batch of size of 10.5L in the time of stirring.
[0074] sterilizing filter of above-mentioned bulk solution (bulk solution) by 0.22 μ M porosity is aseptically filled in the aseptic receiving vessel.10.5mL the above-mentioned solution of amount is aseptically filled in the aseptic 15cc flint 1 type tubular glass bottle (flint type 1 tubing glass vial), this bottle seals so that its sealing with the stopper asepsis plug of sterilization then.
[0075] the Lei Zhashaban injection solution for preparing above has about 3.1 pH to about 3.3 scopes in the time of 20 ℃-25 ℃, wherein the target pH in the time of 20 ℃-25 ℃ is 3.2, the bulk solution density that in the time of 23 ℃, has 1.047g/mL, and having the solution usefulness (solution potency) of about 2.42mg/mL to the about 2.58mg/mL scope as free alkali, its target usefulness as free alkali (target potency) is 2.5mg/mL.
Embodiment 2
[0076] use hydroxypropyl (HPB-CD), be prepared as follows have following composition, visual examination do not have the clear, colorless of particulate matter substantially to lurid apixaban injection solution (2.5mg medicine/mL, 2mL/ bottle).
Table 2
As the quantitative composition of the apixaban of free alkali, 5mg/ bottle (2.5mg/mL)
| Composition | The reason of using | The amount of every mL | Every bottle amount |
| Apixaban | Effective ingredient | 2.5mg | 5.5mg a |
| HPB-CD | Solubilizing agent | 350mg | 770mg |
| Sodium dihydrogen phosphate (monohydrate) | Stabilizing agent (buffer) | 0.83 | 1.826 |
| Sodium hydrogen phosphate (anhydrous) | Stabilizing agent (buffer) | 0.57mg | 1.254mg |
| Water for injection, USP/EP | Solvent | In right amount, to 1mL | In right amount, to 2.2mL a |
aThe target packing volume is 2.2mL.This volume comprises the excessive filling of 0.2mL, is used for bottle-needle injection (VNS) and is detained.
The Apixaban injection solution
[0077] be prepared as follows the 10mM phosphate buffer of pH～7:
[0078] 0.8001 gram sodium dihydrogen phosphate is dissolved in the 400mL water, and makes the volume dosage to 500mL (pH4.57).
[0079] 0.7099 gram sodium hydrogen phosphate is dissolved in the 400mL water, and makes the volume dosage to 500mL (pH9.2).The sodium hydrogen phosphate of 400mL 10mM is placed the 1L beaker and adds the 400mL sodium dihydrogen phosphate.Final pH is 7.01.
[0080] 17.5 gram HPB-CD is dissolved in the 10mM phosphate buffer of pH7 of 30mL, in solution, add 0.125 gram apixaban, and mixed solution is till solid is mixed into dissolving.The 10mM phosphate buffered solution that adds capacity is so that final volume is 50mL.
[0081] the sterilization filter of above-mentioned bulk solution by 0.22 μ m porosity is aseptically filled in the aseptic receiving vessel.In the 5cc vial that the aseptic threading of above-mentioned solution of 2.2mL amount is aseptic, then with aseptic this bottle that clogs of the stopper of sterilizing with its sealing.
[0082] pH that has in the time of 20 ℃-25 ℃ of the apixaban injection solution of above-mentioned preparation is about 7, this pH is target pH, in the time of about 23 ℃, has the bulk solution density of 1.102g/mL, with and have the solution usefulness of about 2.25mg/mL to the about 2.75mg/mL scope as free alkali, its target usefulness as free alkali is 2.5mg/mL.
Embodiment 3
[0083] use SBE-CD to be prepared as follows to have following composition, visual examination do not have the clear, colorless of particulate matter substantially to lurid apixaban injection solution (1mg apixaban/mL, 5.2mL/ bottle).
Table 3
As the quantitative composition of free alkali Apixaban injection, 5mg/ bottle (1mg/mL)
| Composition | The reason of using | The amount of every mL | Every bottle amount |
| Apixaban | Effective ingredient | 1mg | 5.2mg a |
| Captisol TM (SBE-CD) | Solubilizing agent | 350mg | 1820mg |
| Sodium dihydrogen phosphate (monohydrate) | Stabilizing agent (buffer) | 0.83mg | 4.32mg |
| Sodium hydrogen phosphate (anhydrous) | Stabilizing agent (buffer) | 0.57mg | 2.96mg |
| Water for injection, USP/EP | Solvent | In right amount, to 1mL | In right amount, to 5.2mL a |
aThe target packing volume is 5.2mL.This volume comprises the excessive filling of 0.2mL, is used for bottle-needle injection (VNS) and is detained.
[0084] restrains the 10mM phosphate buffer (as embodiment 2 preparations) that SBE-CD are dissolved in the pH7 of 30mL with 17.5.In this solution, add 0.05 gram apixaban and mixed solution till the solid dissolving.The 10mM phosphate buffer of the pH7 of adding capacity is so that final volume is 50mL.
[0085] the sterilization filter of above-mentioned bulk solution by 0.22 μ m porosity is aseptically filled in the aseptic receiving vessel.In the 10cc vial that the aseptic threading of above-mentioned solution of 5.2mL amount is aseptic, the stopper with sterilization seals its asepsis plug to seal this bottle then.
[0086] pH that the apixaban injection solution for preparing above has under 20 ℃-25 ℃ is about 7, this pH is target pH, in the time of about 23 ℃, has the bulk solution density of 1.102g/mL, with and have the solution usefulness of about 0.90mg/mL to the about 1.10mg/mL scope as free alkali, its target usefulness as free alkali is 1mg/mL.
Claims (37)
1. pharmaceutical preparation, it comprises the beta-schardinger dextrin-of factor Xa inhibitor and replacement.
2. as the preparation that claim 1 limited, it is the form of injectable formulation.
3. as the preparation that claim 1 limited, it further comprises buffer agent.
4. as the preparation that claim 1 limited, wherein said factor Xa inhibitor has structure:
Or its pharmaceutically acceptable salt,
R wherein
3Be selected from
R wherein
6And R
7Be identical or different, and be alkyl and
X is 1 to 4;
R
4Be selected from alkoxyl and halogen; With
R
5Be
Wherein Q is 6 yuan of monocycles, and wherein 0,1 or 2 two key is present in the described ring, and described ring is substituted with 0,1 or 2 R
5aGroup, described R
5aGroup under each situation, be independently selected from H ,=O or alkyl and
Q
1Be C=O.
5. as the preparation that claim 4 limited, wherein said factor Xa inhibitor R
5Have structure:
Or
R wherein
5a, under each situation, be independently selected from H ,=O, CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH
2CH
2CH
2CH
3, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3And C (CH
3)
3With
R
5bBe H or alkyl, described alkyl is CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH
2CH
2CH
2CH
3, CH
2CH (CH
3)
2, CH (CH
3) CH
2CH
3And C (CH
3)
3
6. as the preparation that claim 5 limited, R wherein
5Be
7. as the preparation that claim 4 limited, wherein said factor Xa inhibitor has structure:
(being also referred to as apixaban).
8. as the preparation that claim 1 limited, wherein said factor Xa inhibitor has structure:
Or its pharmaceutically acceptable salt,
R wherein
1It is alkyl;
R
2Be alkyl or many alkylhalide groups and
X is a halogen.
9. as the preparation that claim 8 limited, wherein said factor Xa inhibitor is Lei Zhashaban.
10. as the preparation that claim 1 limited, the beta-schardinger dextrin-of wherein said replacement is sulfobutyl ether beta-schardinger dextrin-(SBE-CD) or HP-(HPB-CD).
11. as the preparation that claim 9 limited, it comprises having at about 3 the aqueous injectable preparations of pH to about 5 scopes.
12. as the preparation that claim 11 limited, it comprises acid buffer.
13. as the preparation that claim 12 limited, wherein said acid buffer is tartaric acid or its salt, citric acid or its salt, hydrochloric acid or its salt, acetic acid or its salt, maleic acid or its salt, malic acid or its salt, sulphuric acid or its salt, toluenesulfonic acid or its salt, benzenesulfonic acid or its salt, LOMAR PWA EINECS 246-676-2 or its salt or ethyl sulfonic acid or its salt.
14., further comprise alkali as the preparation that claim 13 limited, arrive about 3 to about 5 scope with the pH that regulates described aqueous formulation, wherein said alkali is alkali-metal citrate, alkali metal hydroxide or alkaline earth metal hydroxide.
15. as the preparation that claim 2 limited, wherein use the beta-schardinger dextrin-of described replacement, the weight ratio of itself and factor Xa inhibitor at about 10: 1 to about 100: 1 scope.
16. as the preparation that claim 9 limited, wherein use described acid buffer, the weight ratio of itself and described Lei Zhashaban at about 2: 1 to about 10: 1 scope.
17. as the preparation that claim 9 limited, wherein said Lei Zhashaban exists with the amount that about 2mg Lei Zhashaban/mL to 10mg Lei Zhashaban/mL dosage is provided.
18. as the preparation that claim 9 limited, the beta-schardinger dextrin-of wherein said replacement is SBE-CD or HPB-CD, and is to exist to about 40: 1 scope at about 20: 1 with the weight ratio with Lei Zhashaban.
19. as the preparation that claim 2 limited, wherein said factor Xa inhibitor and described beta-schardinger dextrin-are in the form of inclusion complex.
20. as the preparation that claim 7 limited, it comprises having from about 6 the aqueous injectable preparations of pH to about 8 scopes.
21. as the preparation that claim 20 limited, it comprises buffer, this buffer is phosphate buffer or TRIS buffer.
22. as the preparation that claim 7 limited, wherein apixaban exists to provide from about 2 amounts to about 8mg medicine/mL dosage.
23. as the preparation that claim 7 limited, the beta-schardinger dextrin-of wherein said replacement is HPB-CD or SBE-CD, and is to exist to about 40: 1 scope at about 20: 1 with the weight ratio with apixaban.
24. Lei Zhashaban is in the beta-schardinger dextrin-that replaces or the inclusion complex of apixaban in the beta-schardinger dextrin-that replaces.
25. as the inclusion complex that claim 24 limited, the beta-schardinger dextrin-of wherein said replacement is sulfobutyl ether beta-schardinger dextrin-(SBE-CD) or HP-(HPB-CD).
26. an aqueous injectable preparation, it comprises the beta-schardinger dextrin-and the water of factor Xa inhibitor, replacement.
27. as the preparation that claim 26 limited, it comprises Lei Zhashaban, SBE-CD, citric acid, sodium citrate and water, described preparation has at about 3 pH to about 5 scopes.
28. as the preparation that claim 27 limited, it comprises: Lei Zhashaban, its amount can provide from about preparation of 2 to about 8mg/mL; SBE-CD, its amount about 100 to about 200mg/mL scope; Citric acid, its amount about 7 to about 9mg/mL scope; Sodium citrate, an amount of, with regulate pH about 3 to about 5 the scope; And water, an amount of, to 1mL.
29. as the preparation that claim 27 limited, wherein when the amount of the Lei Zhashaban that provides by described coordination compound in water when measuring under substituted beta-cyclodextrin concentration of 12%w/v, described inclusion complex provides the Lei Zhashaban content of 2mg Lei Zhashaban/mL at least.
30. as the preparation that claim 26 limited, it comprises apixaban, HPB-CD or SBE-CD, buffer and water, described preparation has at about 6 pH to about 8 scopes.
31. as the preparation that claim 30 limited, it comprises: apixaban, its amount can provide from about preparation of 2 to about 8mg/mL; HPB-CD, its amount about 100 to about 500mg/mL scope; The biphosphate sodium-hydrate, about 0.5 to about 2mg/mL scope; Sodium hydrogen phosphate, about 0.4 to about 1.5mg/mL scope, with regulate pH about 6 to about 8 the scope; And water, an amount of, to 2mL.
32. as the preparation that claim 30 limited, wherein when the amount of the apixaban that provides by described coordination compound in water when measuring under substituted beta-cyclodextrin concentration of 35w/v, described inclusion complex provides the apixaban content of 2mg apixaban/mL at least.
33. the aqueous injection, it comprises:
A) 25mg Lei Zhashaban (being free alkali)/bottle
2.5mg Lei Zhashaban (being free alkali)/mL
Lei Zhashaban hydrochlorate-about 28mg
The about 1260mg of SBE-CD-
Citric acid-about 19 is to 20mg
Sodium citrate-about 4mg
Water for injection-about 9.5 is to 10.5mL; Perhaps
B) about 5mg apixaban (being free alkali)/bottle
About 2.5mg apixaban (being free alkali)/mL
The about 5mg of Apixaban-
The about 700mg of HPB-CD
Sodium dihydrogen phosphate (monohydrate)-about 1.66mg
Sodium hydrogen phosphate (anhydrous)-about 1.14mg
Water for injection-about 2mL.
Can not cause the method for unacceptable irritation at injection point 34. a patient who is used for to needs treatments uses injectable factor Xa inhibitor, it comprises that the patient to the needs treatment uses the preparation that limits as claim 26.
35. as the method that claim 34 limited, wherein factor Xa inhibitor is Lei Zhashaban or apixaban.
36. the method for preventing or treating venous thrombosis, venous thrombosis or acute coronary syndrome, it comprises that the patient to the needs treatment uses the preparation that limits as claim 26.
37. as the method that claim 36 limited, wherein the preparation of being used comprises Lei Zhashaban or apixaban.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US70907705P | 2005-08-17 | 2005-08-17 | |
| US60/709,077 | 2005-08-17 | ||
| US11/464,519 | 2006-08-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101340933A true CN101340933A (en) | 2009-01-07 |
Family
ID=40214744
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800300033A Pending CN101340933A (en) | 2005-08-17 | 2006-08-16 | Factor xa inhibitor inclusion complex with cyclodextrin |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101340933A (en) |
| ZA (1) | ZA200800925B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102802608A (en) * | 2009-06-16 | 2012-11-28 | 美国辉瑞有限公司 | Dosage forms of apixaban |
| WO2014044113A1 (en) * | 2012-09-18 | 2014-03-27 | 上海恒瑞医药有限公司 | Pyrazol[3,4-c] pyridine derivative, preparation method and use in medicine thereof |
| CN104971355A (en) * | 2014-04-02 | 2015-10-14 | 上海现代药物制剂工程研究中心有限公司 | Rivaroxaban-containing composition and preparation method thereof |
| WO2020034989A1 (en) | 2018-08-14 | 2020-02-20 | 江苏恒瑞医药股份有限公司 | Injectable pharmaceutical composition and preparation method therefor |
| CN111514147A (en) * | 2020-05-12 | 2020-08-11 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium medicinal composition for acute decompensated heart failure symptoms and preparation method thereof |
-
2006
- 2006-08-16 CN CNA2006800300033A patent/CN101340933A/en active Pending
-
2008
- 2008-01-29 ZA ZA200800925A patent/ZA200800925B/en unknown
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102802608A (en) * | 2009-06-16 | 2012-11-28 | 美国辉瑞有限公司 | Dosage forms of apixaban |
| WO2014044113A1 (en) * | 2012-09-18 | 2014-03-27 | 上海恒瑞医药有限公司 | Pyrazol[3,4-c] pyridine derivative, preparation method and use in medicine thereof |
| CN104039788A (en) * | 2012-09-18 | 2014-09-10 | 上海恒瑞医药有限公司 | Pyrazol[3,4-c] pyridine derivative, preparation method and use in medicine thereof |
| CN104039788B (en) * | 2012-09-18 | 2015-10-14 | 上海恒瑞医药有限公司 | Pyrazolo [3,4-c] pyridine derivatives, its preparation method and in application pharmaceutically |
| CN104971355A (en) * | 2014-04-02 | 2015-10-14 | 上海现代药物制剂工程研究中心有限公司 | Rivaroxaban-containing composition and preparation method thereof |
| CN104971355B (en) * | 2014-04-02 | 2018-04-24 | 上海现代药物制剂工程研究中心有限公司 | Composition containing razaxaban and preparation method thereof |
| WO2020034989A1 (en) | 2018-08-14 | 2020-02-20 | 江苏恒瑞医药股份有限公司 | Injectable pharmaceutical composition and preparation method therefor |
| CN111514147A (en) * | 2020-05-12 | 2020-08-11 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium medicinal composition for acute decompensated heart failure symptoms and preparation method thereof |
| CN111514147B (en) * | 2020-05-12 | 2021-09-17 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium medicinal composition for acute decompensated heart failure symptoms and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200800925B (en) | 2009-06-24 |
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