CN101155584A - Methods for administering ixabepilone - Google Patents
Methods for administering ixabepilone Download PDFInfo
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- CN101155584A CN101155584A CNA2006800108077A CN200680010807A CN101155584A CN 101155584 A CN101155584 A CN 101155584A CN A2006800108077 A CNA2006800108077 A CN A2006800108077A CN 200680010807 A CN200680010807 A CN 200680010807A CN 101155584 A CN101155584 A CN 101155584A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract
Methods for administering ixabepilone to patients are provided, wherein ixabepilone has the formula (I). One aspect of the invention comprises the use of a Y-site or dual source administration technique that provides enhanced ixabepilone stability and allows for greater flexibility in infusion time and/or product preparation.
Description
Technical field
The present invention relates to administration Epothilones (epothilone) analog, i.e. the method for ipsapirone (ixabepilone).One aspect of the present invention comprises uses gamma-form (site) or double source medicine-feeding technology enhanced ipsapirone stability to be provided and to allow better adaptability in phase of inculcating and/or preparation of product phase.
Background technology
Epothilones A and B are separable naturally occurring chemical compounds from microorganism, sorangium cellulosum (Sorangiumcellulosm).Having been found that epothilone B has been brought into play is similar to paclitaxel (TAXOL
) the microtubule stabilizing effect and showed at the fast breeding cell, the cellular cytoxicity activity of cell that for example betides cancer and other hyperplasia cell diseases is (referring to Angew.Chem.Int.Ed.Engl., Vol.35, No.13/14 (1996) and D.M.Bollag, Exp.Opin.Invest.Drugs, 6 (7): 867-873 (1997).The application's assignee has had been found that a kind of superior active pharmaceutical preparation that is used as that has, and as the epothilone analogs of chemotherapeutics, promptly is the chemical compound with this structure especially,
The chemical name of this chemical compound is [1S-[1R
*, 3R
*(E), 7R
*, 10S
*, 11R
*, 12R
*, 16S
*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl) vinyl]-4-azepine-17 oxabicyclo [14.1.0] heptadecane-5, the 9-diketone, and be called as ipsapirone now.Ipsapirone is advocated in United States Patent (USP) 6,605,599, the U. S. application sequence No.09/084 that this patent was submitted based on May 26th, 1998,542, and on April 3rd, 2003 the continuation application U.S. sequence No.10/405 that submits, 886, the two all belongs to present assignee and quotes for referencial use at this.
Yet, ipsapirone before being used for the treatment of patient, but must be mixed with the compositions that patient is given in a kind of administration, for example, be mixed with a kind of be applicable to oral, Transdermal absorption, or the dosage form of (more typical) intravenous (IV) or other parenterals as chemotherapeutics.Yet, because there is controversial formulation problems in some chemical property ipsapirone.Ipsapirone is in fact than TAXOL
Have more water solublity, have more water solublity than epothilone B and other naturally occurring Epothilones and analog thereof equally.Yet its low relatively water solublity remains a difficult problem of drug development.In addition, Epothilones is easy to degrade in aqueous medium and is the pH-sensitivity.The sensitivity of acid medium made uses conventional obtainable infusion to become a difficult problem as 0.9% sodium chloride injection (normal saline) or 5% glucose injection administering ixabepilone because these diluent be typically based on water and have a wide in range tart pH scope.For example, the pH scope of 0.9% sodium chloride injection is 4.5-7.0, and the pH scope of 5% glucose injection is 3.5-6.5.
The use of the replacement method of the lasting herein research administering ixabepilone of the application is to solve the problem relevant with dissolubility with its stability.U.S. Patent application sequence No.60/572,279, apply on May 18th, 2004, a kind of nanoparticle formulations that is used for ipsapirone has been described, and U.S. Patent application sequence No.60/628,970, apply on November 18th, 2004, a kind of intestinal bag of ipsapirone that is used for has been described by the pearl preparation.These preparations have lot of advantages but they relate to the preparation technique of relative complex simultaneously.It will be appreciated that,, and/or do not relate to use non-ionic surface active agent, for example Cremophor in view of the sensitivity of ipsapirone to acid and/or water environment
, provide the method for administering ixabepilone and/or preparation to realize that enhanced stability is favourable, especially for tendency between the extended period administration inculcate agent.
Summary of the invention
The application's purpose relates to the method for administering ixabepilone.According to an aspect of the present invention, Epothilones flows to the intravenous infusion circuit from first source, and diluent (for example, infusion) is transferred to the vein circuit from second source.Diluent can optionally comprise patient's continuous feed or be transferred to flow of liquid in patient's the vein circuit, by ipsapirone (or ixabepilone solution) being pumped into or other modes are injected continuously and fed.Epothilones and diluent are kept physical separation in first and second sources respectively.Ipsapirone during the transmission the administration facility inner with mixing diluents forming pharmaceutical preparation, and to be defined as " mixing period " that be transferred to before the patient herein be in the stable phase of pharmaceutical preparation.
According to another aspect of the present invention, ipsapirone places in first container of pH control (for example, the buffering) solvent system with less percentage of water so that ixabepilone solution to be provided.The fluid channel fluid UNICOM of first container and central infusion line is used for the content of infusion line is flowed to patient.Also place second container with the central infusion line fluid communication with the diluent of dried administering ixabepilone solution, but keep physical separation with first container that contains ixabepilone solution.Ixabepilone solution and diluent mix (for example, contacting with each other) formation pharmaceutical preparation and are used for preparation is flowed to patient in central infusion line.Use this medication, before flowing to patient, the ixabepilone solution part can be relative than the short time, for example in the stable phase of pharmaceutical preparation with one of contact of diluent (can be main aqueous or water base for example).
According to a further aspect of the invention, a kind of method of using double source method administering ixabepilone described herein is provided, double source method is defined herein as the ipsapirone that is positioned at first source or container and is containing cosolvent, thinner (VRA), the pH-control solvent system of buffer agent and aqueous medium mixture mixes.Preferred co-solvents is Polyethylene Glycol (PEG 400), VRA be dehydrated alcohol (for example, ethanol), buffer agent is tromethane (tromethamine), aqueous medium is a water, and the volume ratio of component is about the dehydrated alcohol of 30-60%, the PEG 400 of 30-60%, be less than 1% buffer agent, and the water of 10-30%.In embodiments of the invention, freeze dried ipsapirone can be mixed in pH control solvent system and be present in first container or first source.PH control solvent system can comprise the composition media that is used for lyophilized ixabepilone.Diluent, (for example, saline or glucose) is positioned at second container or second source.Ixabepilone solution and diluent mix formation pharmaceutical preparation and use double source method described herein to flow to patient in administration device.
Other embodiments of the present invention and aspect are conspicuous for the those of ordinary skills that read following description.
Brief description
Consider additional accompanying drawing, advantage of the present invention, character and various feature will be more comprehensive.In the accompanying drawings:
Fig. 1 has described the dissolubility (mg/mL) of ipsapirone at PEG 400: EtOH (diluting with 1: 5 with saline or glucose) dicyandiamide solution, as the function of ethanol percent in the dicyandiamide solution.
Fig. 2 has described the function of the dissolubility (mg/mL) of ipsapirone when further with saline or glucose dilution as vectorial percentage by volume.
Fig. 3 has described total impurities as continuing 3 hours with 25mL/hr and the lasting function of 0.9% brinish liquid stream time inculcated in 24 hours of 0.5mL/hr with ixabepilone solution with 1.5mg/mL.What show simultaneously is total impurities as being contained in the function of time of inculcating the ipsapirone of the 0.4mg/mL in the bag.
It should be noted that these accompanying drawings are to be used to set forth the present invention but to be not limited thereto.
Detailed Description Of The Invention
It below is the definition of description used herein various terms of the present invention. Unless be particularly limited in addition, the definition of these terms is used in the whole specification separately or as the part of macoradical more.
" acid " refers to anyly contain hydrogen and can decompose the just hydrionic compound of generation in water and solvent, and lewis acid, include but are not limited to for example hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, three halogen acetic acids (for example, trifluoroacetic acid), hydrogen bromide, maleic acid, sulfonic acid is toluenesulfonic acid and camphorsulfonic acid for example, and propionic acid is (R)-chloropropionic acid for example, and phthalamic acid is N-[(R for example)-1-(1-naphthyl) ethyl] phthalamic acid, tartaric acid is L-TARTARIC ACID and dibenzyl-L-TARTARIC ACID for example, lactic acid, camphoric acid, aspartic acid, citronellic acid, BCl3，BBr
3, wait acid. Like this, this term comprises weak acid for example acetic acid and hydrogen sulfide, and strong acid is methanesulfonic acid for example, trifluoroacetic acid etc.
" administration device " refers to by intravenous administration medicine or fluid be flowed to a whole set of equipment of patient.
" mixing period " refers to a period of time, and the Ipsapirone (generally in solvent system) of given volume contacts with diluent and forms pharmaceutical preparation in during this period.
" aqueous medium " of Shi Yonging is meant and contains greater than 30% volume water herein, more preferably greater than 40% volume water, and more preferably greater than the liquid medium of 50% volume water, solvent or solvent system.Like this, " aqueous medium " can be the water of 100% volume but also can be the water that is mixed with one or more other solvents or reagent." non-water " medium is meant the medium that does not satisfy this definition.
" alkali " comprises hydroxide or alkoxide herein, hydride or such as the chemical compound that can accept proton in water or solvent of ammonia.Like this, the base of example include but not limited to, and alkali metal hydroxide and alkoxide (that is, and MOR, wherein M is the alkali metal of potassium, lithium or sodium for example, and R is hydrogen or alkyl as defined above, more preferably R is the C of straight or branched
1-5Alkyl, it comprises but not is restricted to, potassium hydroxide, potassium tert-butoxide, tert-pentyl alcohol potassium, sodium hydroxide, sodium tert-butoxide, Lithium hydrate or the like); Other hydroxide is magnesium hydroxide (Mg (OH) for example
2), calcium hydroxide (Ca (OH)
2), or barium hydroxide (Ba (OH)
2); Alkali metal hydride (be MH, wherein M as defined above, it comprises and is not restricted to, the hydride of sodium, potassium, lithium); Alkylating two silica-based nitrine (disilazide), for example, potassium hexamethyldisilazide and hexamethyl two silica-based amido lithiums; Carbonate is potassium carbonate (K for example
2CO
3), sodium carbonate (Na
2CO
3), potassium bicarbonate (KHCO
3) and sodium bicarbonate (NaHCO
3); Alkyl ammonium hydroxide is n-TBAH (TBAH) or the like for example.
" buffer agent " is meant the composition that the effective acidity that can hinder medium when adding acid or alkali or basicity change.Preferably, the scope of the pKa (the negative log value of acidity constant) of the buffer agent that uses of the present invention is 7-9.Buffer agent includes but are not limited to sodium phosphate like this, sodium citrate, diethanolamine, triethanolamine, the L-arginine, L-lysine, L-histidine, L-alanine, glycine, sodium carbonate, tromethane (a/k/a three [methylol] aminomethane or Tris), and their mixture.
" composition media " or " reconstruction media " is meant and is used for reformulating lyophilized ixabepilone, make ipsapirone be partially dissolved in solvent or the solvent system in the liquid medium fully or at least.
" cosolvent " is meant and is used for dissolving ipsapirone to form any pharmaceutically acceptable solvent (liquid) of ixabepilone solution.Preferred cosolvent is can be used in solvent dissolving ipsapirone and can dissolving with the miscible such ipsapirone of aqueous medium like this with the miscible cosolvent of water in aqueous medium according to the present invention.The preferred cosolvent of selecting makes the ipsapirone of the about 20mg of as many as be dissolvable in water in the solution of cosolvent/water of 1mL, and wherein 1mL solution may contain 10-30% volume water.Cosolvent includes but are not limited to ethanol, N,N-dimethylacetamide, propylene glycol, glycerol and Polyethylene Glycol, for example Liquid Macrogol and/or PEG400.
" surfactant " is meant pharmaceutically acceptable by reducing its surface tension with the expansion of increase chemical compound (as ipsapirone) or the surface-active agents of moistening character.Preferred surfactants is that these can be used for dissolving ipsapirone, or increases the surfactant of the dissolubility of ipsapirone in aqueous medium to about 20mg/mL (promptly extremely about 20mg ipsapirone is dissolved in the 1mL liquid medium).Surfactant comprises Cremophor
, Solutol HS 15
, polysorbate80, polysorbate20, poloxamer, ketopyrrolidine be N-alkyl pyrrolidone (for example N-Methyl pyrrolidone) and/or polyvinylpyrrolidone for example.
Term herein " degraded " is meant that the chemical constitution of ipsapirone changes over another kind of chemical compound or another kind of compound form (for example isomer, metabolite, or the like)." degraded " measures by the formation of impurity in ixabepilone solution or the preparation." degradation rate " is meant the percentage ratio that detects total impurities in ixabepilone solution or the preparation in the regular period.
Term as used herein " glucose " relates to infusion, promptly contains the fluid of glucose injection, preferred 5% glucose injection (USP).
Term " diluent " and " infusion " can be used alternatingly herein, are meant the fluid of drug conveying being given patient by parenteral.Preferable absorbent is saline or glucose according to the present invention.Yet very clear these notions of the present invention can be applied to other infusion.
The idiom of Shi Yonging " time period of prolongation " was meant greater than 4 hours herein, more preferably greater than 6 hours cycle, even more preferably greater than 10 to 24 hours or longer cycle.
" non-essence percent " as used herein, " non-real mass ", " less percent " or " less amount " is meant water in solvent system and/or the amount of adding the water of solvent system to, promptly this water yield contacts infusion period (the preferred as many as of selecting 10 hours with the ipsapirone of specified rate in solvent system, more preferably to 24 hours) time, water in the solvent system is considerably less can not to cause surpassing the degraded of 10% given ipsapirone, preferably, can not cause surpassing the degraded of 5% ipsapirone, even more have preferably, can not cause surpassing 3.5% degraded.
The preparation that " pharmaceutical preparation " or " preparation " that the present invention uses is meant ipsapirone wherein ipsapirone mixes with a kind of diluent or infusion.Usually ipsapirone will be lyophilized and reconstituted in the solvent system and will further form pharmaceutical preparation with the infusion dilution to form ixabepilone solution and this ixabepilone solution.
Term " pH regulator composition " is meant buffer agent, acid, and/or alkali, or their mixture (preferably further regulating the buffer agent of pH) with acid and/or alkali, and its selected pH value with the adjusting solvent is used for dissolving or reorganization ipsapirone.Like this, " pH regulator composition " is used in reference to buffer agent, the mixture of buffer agent, acid and/or alkali, the mixture of acid and/or alkali, and/or one or more buffer agents, acid, and/or the mixture of alkali.
Term " normal saline " is used to refer to the liquid that infusion promptly contains chloride injection agent (USP), preferred 0.9% sodium chloride injection (USP).
Term " stable phase " is meant one-period, wherein at room temperature in solvent system or the preparation degradation rate of the ipsapirone of specified rate be more preferably less than 5%, even be more preferably less than 3.5% less than 10%.
" thinner " (VRA) is meant any non-aqueous media or other reagent, or non-aqueous media and/or other combination of agents, adds in the ixabepilone solution that contains ipsapirone and cosolvent (or solubilizing agent) to improve the property inculcated of ixabepilone solution.
It should be noted that all numerical value of delivering are approximations herein, and test error or other insubstantial deviations may take place during further putting into practice.Like this, unless spell out, any numerical value of Zhu Zhanging all is approximation herein.
The working of an invention scheme
According to an embodiment, the present invention relates to the double source method of at least a administering ixabepilone.Use phrase " at least a double source " to be and drug conveying may be existed more than two sources in patient's vein (" the IV ") administration device because be expected at.But, can expect the source that has at least two to be supplied to IV administration circuit.In the method, the ipsapirone that offers IV administration circuit (this circuit is given patient with FLUID TRANSPORTATION) is from first source, and the diluent that offers the IV circuit is from second source.(it is pointed out that term " first source " and " second source " do not get rid of the existence that the three, the fourth class is originated, in administration device, term " first " and " second " only are used for these two kinds of sources are distinguished each other and come).Important consideration be the diluent in ipsapirone (or ixabepilone solution) and the second source in first source divide keep from, the ipsapirone in such first source can not be exposed to the degradation factor in the diluent.Ipsapirone discharges from first source, combines with being released to second-source diluent, forms pharmaceutical preparation.Like this, in administration device, form preparation (being the mixture of ipsapirone or ixabepilone solution and diluent).The time that the ipsapirone of specified rate contacts with diluent before flowing to patient (mixing cycle) is in the stable period of pharmaceutical preparation.Nature, " stable period " depends on the preparation of use, promptly it depends on the solvent system that is used to dissolve or rebuild ipsapirone, is used for the concrete diluent that IV transmits, and the percent of concrete solvent system and/or pH value in the diluent and water.
Available various container and equipment provide other parts of first and second sources and administration device.Frame for movement is flexible and can be changed.For example, ipsapirone can place first container or IV to give medicated bag, and diluent can place second container or IV to give medicated bag, and each container has pump and the IV circuit of oneself.The isolating IV circuit that produces from each container can connect into single flow path or central IV circuit flows to patient with the content in the IV circuit then by the Y-position connector.Alternatively, use a central IV administration circuit, it comprises gives patient with the diluent continuous feed, simultaneously ipsapirone is pumped into continuous feed and gives patient.It is well-known will giving patient's the induction system of inculcating from the drug administration that surpasses a source, can buy from the market, and describe to some extent in the document formerly.For example, various such systems can obtain from Baxter International Inc..The present invention can quote any such system and disclosed afterwards system herein, takes the circumstances into consideration the medication that is used for ipsapirone and enumerates herein.Use the example of such system and/or valve and/or joint to be described in hereinafter the United States Patent (USP), each quotes for referencial use at this: United States Patent (USP) 5,547,471; 5,385,547; 5,279,557; 5,200,090; 5,032,112; 4,456,105; 4,258,712; 4,256,104; 4,252,116; 4,250,879; 4,237,880; 4,237,879; 4,236,515; 4,223,695; 4,219,022; 4,094,318; 4,034,754; With 3,886,937.
The ipsapirone in first source dissolves in pharmacy acceptable solvent system, does not preferably contain the solvent system of non-ionic surface active agent.The applicant has been found that non-ionic surface active agent can replace with other solvent system, this solvent system is and uses and the miscible solubilizing agent of water or the solvent system of cosolvent, wherein have better dissolubility (typical high viscosity cosolvent) than ipsapirone, be used in combination with thinner with water.Use method of the present invention, if ipsapirone is set up in only containing the solution that makes the dissolved cosolvent of ipsapirone, the property inculcated (by the IV administration) will be difficult to accomplish and be very unrealistic.Like this, make the thinner of forming with containing any pharmaceutically acceptable non-aqueous media or reagent, adapt, and effectively improve the property inculcated of cosolvent and dissolving and rebuild freeze dried ipsapirone with cosolvent and ipsapirone.The solvent system that preferably is used for the double source administration contains one or more kinds of cosolvents and the typical combination that contains dehydrated alcohol such as alcoholic acid thinner.
According to another aspect of the present invention, the applicant has been found that ipsapirone has been kept advantages of higher stability in Polyethylene Glycol/dehydrated alcohol system compared with the solvent system that uses propylene glycol or glycerol.Freeze dried ipsapirone is with dehydrated alcohol and cosolvent propylene glycol, glycerol, and 50/50 mixture (by volume) of Liquid Macrogol and PEG400 is formed 2mg/mL.Solution at room temperature stores and illumination 6-8 hour.Each stability of formulation data is as shown in table 1.
Table 1
| The vehicle prescription | The ipsapirone degradation rate (%/hour) |
| Propylene glycol/dehydrated alcohol | 0.3 |
| Glycerol/dehydrated alcohol | 0.9 |
| Liquid Macrogol/dehydrated alcohol | 0.1 |
| PEG400/dehydrated alcohol | 0.1 |
The bearing reaction of table 1 goes out in these solvent systems, and those that use Polyethylene Glycol/dehydrated alcohol mixture are preferred keeping aspect ipsapirone stable in solution.
Between Liquid Macrogol/dehydrated alcohol system and PEG400/dehydrated alcohol system, yet, owing to the preferred latter of deliquescent reason.Particularly, 50/50 of Liquid Macrogol/dehydrated alcohol and PEG400/dehydrated alcohol mixture (by volume) respectively with 1: 5 ratio with the normal saline dilution of 5% glucose and 0.9% and add excessive ipsapirone.These solution (diluent that contains 20% volume) at room temperature stirred 3 hours, filtered and identified with HPLC.Solubility data is as shown in table 2.
Table 2
| The vehicle prescription | Infusion | Ipsapirone dissolubility (mg/mL) |
| Liquid Macrogol/ |
5% glucose | 0.41 |
| Liquid Macrogol/dehydrated alcohol | 0.9% normal saline | 0.39 |
| PEG400/ |
5% glucose | 0.44 |
| PEG400/dehydrated alcohol | 0.9% normal saline | 0.40 |
As can be seen, compared with using PEG300, ipsapirone is stronger in the diluent dissolubility with 5% glucose and 0.9% normal saline when using PEG400.(abbreviation used herein " PEG " is meant " Polyethylene Glycol ").
Although at above-mentioned solvent system, for example understand the mixture of the PEG/ dehydrated alcohol of 50/50 (by volume), the applicant can effectively use the more cosolvent and the VRA of wide region after measured.In certain embodiment, when the mixture of the cosolvent (or solubilizing agent) of every 30-70 percent by volume being prepared solvent system, can realize these advantages with the dehydrated alcohol of about 30-70 percent by volume.For example, herein accompanying drawing 1 has reflected that ipsapirone is containing useful normal saline or dextrose infusion fluid with the deliquescent result of study in the solvent system of the PEG 400 of the different proportion of 1: 5 dilution proportion and dehydrated alcohol.The HPLC of the filtering five equilibrium of the dissolubility of ipsapirone by mixing the solution that contains excess ixabepilone after 3 hours analyzes and measures.Can find out, this accompanying drawing reflect in this scope (30: 70 couples of 70: 30 PEG 400: EtOH), along with the increase dissolubility of dehydrated alcohol amount has very small increase.Yet preferably administration minimizes the side effect that is associated with the ethanol administration to avoid for patient's alcoholic acid amount during inculcating.Like this, increase dissolubility slightly when dehydrated alcohol increases, also there is shortcoming in it.Like this, when using PEG 400: alcoholic acid solvent system, the scope that the inventor has determined preferred cosolvent and dehydrated alcohol is 40: 60-60: 40, and further preferred ratio is the mixture of about 50: 50 volume ratios.
Preferably, the present invention's solvent system of being used for ipsapirone (is more preferably and does not contain Cremophor
Or do not contain Cremophor in fact
Solvent system) be pH control." solvent system of pH control ", meaning that the solvent prepared system can show the pH scope of selection, promptly is to be applicable within the desired pH scope of ipsapirone, in addition, when with diluent formulated in combination ipsapirone preparation, the pH of final preparation will drop within the desired scope.For example, having determined the pH that is applicable to the optimum stabilization of ipsapirone in solution and/or the preparation is about 7-9.Favourable, the pH that is used to make up ixabepilone solution will be within the scope of 6.0-9.5, more preferably within the scope of about 6.0-9.0, most preferably within the scope of about 7-9.In addition, the pH of preparation (for example, ixabepilone solution and diluent combination) will be within the scope of about 6.0-9.5, more preferably within the scope of about 6.5-9.0, most preferably within the scope of about 7-9.Be defined as finishing preparation in this pH scope, wherein saline and glucose are as diluent, and the pH of solvent system can drop within the scope of about 6.5-10, more preferably within the scope of about 7-9.5, most preferably within the scope of about 7-9.For example, when solvent system has 8.3 ± 1.0 pH scope, when the concentration of ipsapirone was 0.2-0.6mg/mL, the pH of pharmaceutical preparation will be within the scope of 6.1-9.3.
The pH of solvent system can control in several ways.For example, can and/or use for example one or more buffer agents of one or more pH regulator agent by selective solvent, acid and/or alkali are realized.One embodiment of the invention comprise the pH that uses buffer agent to regulate solvent system, use a spot of acid and/or alkali further to regulate pH with approaching as much as possible needed scope then, and the amount of need selecting is to reach needed pH scope.In one embodiment, diluent is saline or dextrose infusion fluid, solvent system comprises PEG 400 and dehydrated alcohol, and uses the 1N HCl of a kind of buffer agent of tromethane and trace and/or pH value that 1N NaOH regulates solvent system to reach 8.3 ± 1.0 pH scope.Preferred pH regulator agent may be depended on the cosolvent (or solubilizing agent) of use and the type and the amount of thinner.For example, as the PEG 400 that uses 50: 50: during the mixture of dehydrated alcohol, consider the dissolubility at this solvent system, tromethane will be a preferred reducing agents.
According to the selection of buffer agent and solvent system, it may be favourable adding a spot of water in solvent system.A spot of water provides several advantages, for example, avoids the solvent system muddiness, dissolves buffer agent and allows pH regulator, the compatibility of increase and infusion, and/or the viscosity of reduction solvent system.For example, the applicant has been found that when using PEG 400: the solvent system of dehydrated alcohol, add the water of as many as 30% volume, the more preferably water of as many as 25% volume, even the water that more preferably adds as many as 20% volume is with the dissolving buffer agent, this can be favourable, and the amount of this water continues prolongation should not cause the level of can not the accepting during cycle ipsapirone degraded inculcating.For example, one aspect of the present invention, buffered solvent system contain the PEG 400 of approximately equal amount: ethanol, and the water of about 20% volume of as many as ixabepilone solution cumulative volume will can not cause the ipsapirone degraded greater than 5% 24 hours infusion period.
According to another aspect of the present invention, freeze dried ipsapirone (referring to, for example, US Pat.6,670,384 introduce reference herein), recombinate so that ixabepilone solution to be provided with the solvent system of the pH-control that contains low amounts of water.Can prepare ixabepilone solution earlier, place first container of administration device then, perhaps directly in administration device, prepare.First container and central infusion line fluid communication flow to patient with the content of infusion line.The diluent that is used for the ipsapirone administration places second container, this container also with the central infusion line fluid communication, but keep separating with first container that contains ixabepilone solution." maintenance separates " or " physical separation " mean ipsapirone and are not exposed to diluent, and the degradation coefficient of diluent (for example, substantial water and/or acid condition) may cause the ipsapirone degraded whereby.Ixabepilone solution and diluent are combined to form pharmaceutical preparation and flow to patient in central infusion line.By this medication, ixabepilone solution may only be exposed to relatively short cycle of diluent (can be saline or glucose or other mainly be aqueous vehicle) before flowing to patient.
According to other aspects of the invention, be advantageously used in according to above description and provide the solvent system of ixabepilone solution as shown in table 3.
Table 3
| Composition | (amount g/mL) |
| PEG400 NF | 0.40-0.49 |
| Dehydrated alcohol USP | 0.28-0.35 |
| Tromethane USP | 0.00225-0.00275 |
| The 1N hydrochloric acid solution | In right amount to pH 8.3 ± 0.1 |
| The 1N sodium hydroxide solution | In right amount to pH 8.3 ± 0.1 |
| Inculcate water USP | In right amount to 0.993g (1.00mL) |
The inventor has also found herein, and for fear of the formation of ipsapirone supersaturated solution, the concentration of ipsapirone (after constituting with solvent system) was high approximately to 2mg/mL during ixabepilone solution was preferred, or more preferably from about high to 1.5 ± 0.1mg/mL.In order to illustrate, accompanying drawing 2 has shown the solubility in mg/mL as the ipsapirone of the function of the vehicle percentage by volume of glucose and two kinds of infusion of normal saline infusion.Accompanying drawing 2 reflected for avoiding the supersaturated solution of ipsapirone, preferred group become lyophilized ixabepilone to concentration for about 2mg/mL or still less, 1.5mg/mL or still less more preferably from about.
Accompanying drawing 3 has illustrated present invention surprising advantage aspect the access times of enhanced stability that realizes ixabepilone solution and preparation and prolongation.Particularly, accompanying drawing 3 has shown compared with method before according to the degradation rate (and stable period) that is used for two kinds of double source methods of administering ixabepilone of the present invention.Each ixabepilone solution of accompanying drawing 3, ipsapirone are dissolved in and contain the PEG 400 that had an appointment 50: 50: EtOH (solvent system of respectively doing for oneself 40% amount), about 20% water and be less than the concentration that forms about 1.5mg/mL in the buffer solvent system of 1% buffer agent.The buffer solvent system of this ipsapirone beats into 0.9% normal saline liquid stream 3 hours with 25mL/hr, beats into the saline liquid stream 24 hours with 0.5mL/hr, and (according to method before) constrains in and contain the inculcating in the bag of saline infusion.As can be seen, the latter, method before, total impurities may reach about 5% level in about 4 hours life cycle (or mixing cycle), and use method of the present invention, in the same solvent system, equally maybe can compare the impurity of level and just can observe up to about 24 hours life cycle.
One aspect of the present invention provides uses the ipsapirone manufacturing to be used for the treatment of the pharmaceutical preparation of cancer patient, wherein ipsapirone comes from first source and is fed to the IV circuit, and diluent comes from second source and is fed to the IV circuit, keep the physical separation state in each comfortable first and second source of ipsapirone and diluent whereby, and before flowing to patient, carry the back to mix and form pharmaceutical preparation, to the IV circuit from first and second sources.Pharmaceutical preparation can flow to patient in a prolongation cycle.Preferably, pharmaceutical preparation continue greater than 10 continuously or continuous in fact hour infusion period flow to patient.More preferably infusion period continues continuous hour of about 20-24.The ipsapirone of first source of supply can be a lyophilized ixabepilone, and it makes up in the solvent system that contains have an appointment 65-90% volume cosolvent and thinner mixture, and wherein mixture contains and has an appointment 70: 30-30: the cosolvent of 70 volumes: VRA.Solvent system can further contain pH regulator agent and a spot of aqueous medium.Preferably, cosolvent contains Polyethylene Glycol, Liquid Macrogol or 400 for example, more preferably, PEG400.Preferred thinner contains dehydrated alcohol, more preferably, and ethanol.Solvent system can contain the water of as many as 30% volume, for example, and 20% ± 5%.Preferred solvent systems does not contain or does not contain in fact polyoxyethylene castor oil, for example, contains and is less than 5 weight %, more preferably less than 1 weight %, still more preferably less than 0.1 weight %, does not most preferably contain polyoxyethylene castor oil.
Other aspects of the present invention provide the purposes of the pharmaceutical preparation of ipsapirone preparation treatment cancer patient.Wherein:
To produce ixabepilone solution, wherein first container and central infusion line fluid communication are used to carry the content of infusion line to give patient to the ipsapirone that first container provides in the pH of the water that contains small percentage control solvent system;
The diluent that second container provides also with the central infusion line fluid communication, but keep the physical separation state with first container that contains ixabepilone solution; And
Ixabepilone solution and diluent flow to central infusion line, and ipsapirone and diluent are combined to form pharmaceutical preparation and are used for pharmaceutical preparation is flowed to patient in central infusion line whereby.
PH control solvent system contains cosolvent or solubilizing agent, thinner, the mixture of pH regulator agent and water.Preferred co-solvents comprises propylene glycol, glycerol, Liquid Macrogol, and/or PEG400.Preferred thinner is a dehydrated alcohol.Preferred pH control solvent system does not contain non-ionic surface active agent or does not contain non-ionic surface active agent in fact.
Provide a kind of on the other hand with the pharmaceutical kit of ipsapirone administration to patient, comprise at least the first and second bottles, wherein first bottle contains a certain amount of lyophilized ixabepilone, and second bottle comprises the pH control solvent system that contains 65-90% volume cosolvent and thinner (VRA) mixture, wherein this mixture contains and has an appointment 70: 30-30: the cosolvent of 70 volumes: VRA, and solvent system further contains the buffer agent that is less than 1% weight and the water of 10-30 volume %.Pharmaceutical kit goes for inculcating to patient at an IV who prolongs the cycle administering ixabepilone, for example, continues to surpass continuously or continuous in fact 10 hours infusion period, or sustained continuous or 20-24 hour infusion period in fact continuously.PH control solvent system can further contain pH regulator agent and/or water.Preferred co-solvents comprises propylene glycol, glycerol, Liquid Macrogol and/or PEG400.Preferred thinner is a dehydrated alcohol.Preferably, pH control solvent system does not contain non-ionic surface active agent or does not contain non-ionic surface active agent in fact.
Practicality
Ipsapirone is a kind of microtubule stabilizer, therefore can be used for treating various cancers and other proliferative diseasees.Ipsapirone is especially effective to the treatment of malignant tumor, comprises breast carcinoma, colon cancer, and pulmonary carcinoma and cancer of pancreas, also the cancer that especially refractory is healed is effective.Yet this medicine can be used for treating other cancers, proliferative disease, neuron asynthesis, central nervous system disorder (for example Alzheimer), and other diseases.Relate to United States Patent (USP) Pat.6,686,380 and Pat.6,605,599, each quotes in full for referencial use at this, relate to having shown that ipsapirone can be used for treating other and refers to disease.
Further, ipsapirone can be used in combination and be used for the treatment of cancer and other proliferative diseasees with other anticarcinogen and cytotoxic reagent.The U.S. Patent application sequence No.10/091 that other reagent were like this submitted on March 5th, 2002 confirms in 061, is equivalent to U.S. Patent Publication and publishes 2003/0073677A1, and the assignee who transfers the application quotes for referencial use at this.Other reagent can be implemented by using three fens source side methods like this, for example, and use the application's principle, but another kind of and the bonded chemotherapeutics of ipsapirone are carried in the 3rd or other sources of also being used for other reagent.The effective dose of ipsapirone can be measured by persons skilled in the art.The U. S. application sequence No.10/055 that exemplary dosage amounts can be submitted on January 23rd, 2002 finds in 653, quotes for referencial use at this.Selectable, can single dose for the people according to the present invention, by separately continuously IV inculcate, with the form administration of independent separate dose, for example, every day is greater than once, continue a week or several weeks, can be from about 0.05mg/kg/ days to about 200mg/kg/ days ipsapirone.When in infusion when dilution preferred ipsapirone range of concentrations be the about 2.0mg/ml of about 0.01-, more preferably in the scope of the about 1.5mg/mL of about 0.05-, the scope of 0.2-about 0.8 most preferably from about.Although the present invention continues prolongation cycle advantageous particularly for infusion period, ipsapirone can reach 10 hours, to 6 hours, even administration to 1-4 hour the infusion period, and advantageously provide, for example, according to the induction system of medical supervision.Yet in one embodiment, the breast carcinoma of transfer can be by being administered to 100mg/m
2The ipsapirone treatment of dosage, more preferably from about 40 ± 20mg/m
2Dosage, be administered once in per 21 days, infusion period reaches 24 hours.Dosed administration can separate, and is still more frequent than per 21 days, and/or may repeat one or many if necessary.
Be to be understood that to change and will depend on various factors, comprise the activity of the particular compound of use, metabolic stability any concrete curee's given dose level and dose frequency, the action length of chemical compound, species, age, body weight, lean body mass (or fatty tissue percentage ratio), general health situation, sex and curee's diet, the mode of administration and time, excretion rate, the order of severity of drug combination and concrete disease etc.The curee comprises mammal, and is most preferably human, but also can be the patient of treatment to the mammal of other kinds of the imbalance of ipsapirone sensitivity.
At first, the water of amount that is equivalent to 15% volume of final batch volume is added in the proportion container.When mixing, add tromethane in the water and solution mixing at least 10 minutes to tromethane is dissolved.An amount of 1.2% the 1N HCl that is equivalent to final ingredients by weight is added in the proportion container.Continue to mix, PEG400 and the ethanol (40 volumes that are about final batch volume separately) that is similar to equivalent is added in the proportion container.If desired, regulate batch temperature and make temperature maintenance in 15-25 ℃ scope, and solution was mixed 15 minutes at least.Regulate pH value to 8.3 ± 0.1 of ingredients solution with 1N HCl and/or 1N NaOH.The interpolation make-up water reaches required final batch volume and solution was mixed 15 minutes at least.Final solution is by 0.22 suitable microfilter filter-sterilized.The sterile solution aliquot is packed into I type glass tubule then to be clogged and seals.The general composition of final solvent system is shown in following table 4, and 2-25 ℃ of storage.
Table 4
| Composition | (amount/mL) |
| PEG400 NF | 0.4488g |
| Dehydrated alcohol USP | 0.3160g |
| Tromethane USP | 0.0025g |
| The 1N hydrochloric acid solution | In right amount to pH 8.3 |
| The 1N sodium hydroxide solution | In right amount to pH 8.3 |
| Inculcate water USP | In right amount to 0.993g (1.00mL) |
By slowly the 10.7mL solvent system being injected in each bottle, the solvent system of embodiment 1 is used to rebuild two bottles of freeze dried ipsapirones, and every bottle contains the 16mg ipsapirone.Bottle rotated gently up to lyophilized products dissolve fully.When dissolving fully, the solution concentration of ipsapirone is 1.5mg/mL.
Minimum Y-joint on the ixabepilone solution inhalation syringe that 15mL is rebuild and the outlet of syringe and the IV circuit by use have 2mL or still less the extension set of priming volume be connected.The Y-joint is no more than 12 inches apart from the far-end of administration device.The IV circuit contains 0.9% sodium chloride infusion, the liquid stream of USP (normal saline).The speed that normal saline is set is 50mL/ hour and begin to flow at least.The syringe that contains the ipsapirone of reconstruction places one to inculcate pump and enable 0.5mL/ hour ipsapirone flow velocity.Use syringe, syringe pump and Y-joint are injected into the ixabepilone solution of rebuilding in the liquid stream of normal saline.
Ixabepilone potency and total impurities are monitored by analyzing with HPLC 24 hours infusion period.The result has shown that the degradation rate of ipsapirone was about 3.2% 24 hours infusion period, that is to say that detected total impurities accounts for about 3.2% of initial ipsapirone amount in ixabepilone solution.
The solution system of embodiment 1 is used to rebuild the ixabepilone concentration that a certain amount of lyophilized ixabepilone forms 1.5mg/mL.The ixabepilone solution of rebuilding is drawn in the syringe, and the outlet of syringe is respectively by with having 1.2 microns and 0.2 micron, and volume Blang's grace expansion equipment of being respectively the in-line filter of 4.3mL and 1.15mL priming is connected to the Y-joint of IV circuit.The IV circuit contains 0.9% sodium chloride infusion, USP (normal saline) fluid.Syringe contains the ipsapirone and the initial ipsapirone flow velocity of the reconstruction that places syringe pump.The speed of the ipsapirone rebuild is arranged to constant speed 2.22mL/ hour.Saline flow rate is variable from 6 to 96mL/ hours.Selectable, the flow velocity of the ixabepilone solution inculcated is arranged to 5mL/ hour and 17.8mL/ hour, and the speed of saline infusion is variable from 15 to 95mL/ hours.Keep that the concentration of ipsapirone is lower than about 0.4mg/mL in the preparation, the flow velocity of ipsapirone can reach 10mL/ hour, and brinish flow velocity is set to about 30mL/ hour.Greater than 10mL/ hour, brinish flow velocity should be set to about 3 times of ipsapirone flow velocity for the flow velocity of ipsapirone.For reaching flow velocity (usually greater than 60mL/ hour) faster, in use equipment, use 1.2 microfilter/extension set, but not less filter.
Claims (12)
1. ipsapirone is used for the treatment of application in patient's the pharmaceutical preparation of cancer in preparation, wherein ipsapirone is provided to the IV circuit by first source, and diluent is provided to the IV circuit by second source, keep physical separation in each comfortable first and second source of ipsapirone and diluent whereby, and after being transported to the IV circuit from first and second sources respectively, mix, before flowing to patient, to form pharmaceutical preparation.
2. according to the application of claim 1, wherein pharmaceutical preparation flows to patient in the time period that prolongs.
3. according to the application of claim 2, wherein pharmaceutical preparation flows to patient lasting inculcating above successive or successive basically 10 hours in the phase.
4. according to the application of claim 1, wherein the ipsapirone in first source of supply is the lyophilized ixabepilone of rebuilding in the solvent system of the mixture of cosolvent that contains the 65-90% volume of having an appointment and thinner (VRA), wherein mixture contains and has an appointment 70: 30-30: the cosolvent of 70 volumes: VRA, and this solvent system further contains pH regulator composition and a spot of aqueous medium.
5. according to the application of claim 4, wherein cosolvent comprises Liquid Macrogol or 400, and thinner comprises dehydrated alcohol.
6. according to the application of claim 4, wherein solvent system does not contain or is substantially free of the Oleum Ricini of polyoxyethyleneization.
7. ipsapirone is used for the treatment of application in patient's the pharmaceutical preparation of cancer in preparation, wherein:
Ipsapirone is provided in first container of solvent system of the pH control with small percentage water and forms ixabepilone solution, and wherein first container and central infusion line fluid communication are used for the content of infusion line is flowed to patient;
Diluent is provided in second container, its also with the central infusion line fluid communication, but keep physical separation with first container that contains ixabepilone solution; And
Ixabepilone solution and diluent are transported to central infusion line, and ixabepilone solution and diluent are combined to form pharmaceutical preparation in central infusion line whereby, are used for pharmaceutical preparation is flowed to patient.
8. according to the application of claim 7, wherein the solvent system of pH control contains cosolvent or solubilizing agent, thinner, pH regulator composition, and the mixture of the water of small percentage.
9. application according to Claim 8, cosolvent wherein is selected from propylene glycol, glycerol, Liquid Macrogol, and/or PEG400, and thinner comprises dehydrated alcohol.
10. application according to Claim 8, wherein the solvent system of pH control does not contain non-ionic surface active agent or is substantially free of non-ionic surface active agent.
11. be used for ipsapirone is administered into patient's pharmaceutical kit, contain at least the first and second bottles, wherein first bottle comprises a certain amount of lyophilized ixabepilone, and second bottle comprises the solvent system of pH control of the mixture of the cosolvent that contains the 65-90% volume of having an appointment and thinner (VRA), wherein mixture comprises 70: 30-30: the cosolvent of 70 volumes: VRA, and solvent system further contains the water less than the buffer agent of 1% weight and 10-30% volume.
12. according to the test kit of claim 11, be applicable in the time period that prolongs and give patient that wherein the solvent system of pH control does not contain non-ionic surface active agent or is substantially free of non-ionic surface active agent with the ipsapirone intravenous infusion.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US66690705P | 2005-03-31 | 2005-03-31 | |
| US60/666,907 | 2005-03-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101155584A true CN101155584A (en) | 2008-04-02 |
Family
ID=36763031
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800108077A Pending CN101155584A (en) | 2005-03-31 | 2006-03-30 | Methods for administering ixabepilone |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1863481A1 (en) |
| JP (1) | JP2008534610A (en) |
| CN (1) | CN101155584A (en) |
| NO (1) | NO20075090L (en) |
| WO (1) | WO2006105399A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103908432A (en) * | 2013-01-02 | 2014-07-09 | 博瑞生物医药技术(苏州)有限公司 | Ixabepilone albumin freeze-dried composition and preparation method thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009089138A1 (en) * | 2008-01-04 | 2009-07-16 | Bristol-Myers Squibb Company | Oral administration of ixabepilone |
| US8449886B2 (en) | 2008-01-08 | 2013-05-28 | Bristol-Myers Squibb Company | Combination of anti-CTLA4 antibody with tubulin modulating agents for the treatment of proliferative diseases |
| CN103402543B (en) * | 2010-12-16 | 2015-09-16 | 德克萨斯州立大学董事会 | For azole drugs preparation that parenteral is used and preparation method thereof and the using method for the treatment of to the disease of azole compounds sensitivity |
| JP6080312B2 (en) | 2011-04-28 | 2017-02-15 | プラットフォーム ブライトワークス トゥー， リミテッド | Improved parenteral formulations of lipophilic pharmaceutical agents and methods for preparing and using the same |
| CN115350155A (en) * | 2014-03-13 | 2022-11-18 | V·沃道里斯 | Bendamustine solid dispersions and continuous infusion |
-
2006
- 2006-03-30 JP JP2008504420A patent/JP2008534610A/en active Pending
- 2006-03-30 EP EP06749025A patent/EP1863481A1/en not_active Withdrawn
- 2006-03-30 CN CNA2006800108077A patent/CN101155584A/en active Pending
- 2006-03-30 WO PCT/US2006/011920 patent/WO2006105399A1/en active Application Filing
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2007
- 2007-10-09 NO NO20075090A patent/NO20075090L/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103908432A (en) * | 2013-01-02 | 2014-07-09 | 博瑞生物医药技术(苏州)有限公司 | Ixabepilone albumin freeze-dried composition and preparation method thereof |
| CN103908432B (en) * | 2013-01-02 | 2018-09-21 | 博瑞生物医药（苏州）股份有限公司 | A kind of freeze-dried composition and preparation method thereof of Ipsapirone albumin |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1863481A1 (en) | 2007-12-12 |
| JP2008534610A (en) | 2008-08-28 |
| WO2006105399A1 (en) | 2006-10-05 |
| NO20075090L (en) | 2007-12-04 |
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