EP1863481A1

EP1863481A1 - Methods for administering ixabepilone

Info

Publication number: EP1863481A1
Application number: EP06749025A
Authority: EP
Inventors: Thomas A. Haby; Fahri T. Comezoglu; Vijay Naringrekar; Ismat Ullah
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2005-03-31
Filing date: 2006-03-30
Publication date: 2007-12-12
Also published as: WO2006105399A1; CN101155584A; JP2008534610A; NO20075090L

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

METHODS FOR ADMINISTERING IXABEPILONE

FIELD OF THE INVENTION

[0001] The present invention relates to methods of administering an epothilone analog, i.e., ixabepilone. 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.

BACKGROUND OF THE INVENTION [0002] Epothilones A and B are naturally-occurring compounds that can be isolated from the microorganism, Sorangium cellulosum. Epothilone B was found to exert microtubule-stabilizing effects similar to paclitaxel (TAXOL^®) and exhibit cytotoxic activity against rapidly proliferating cells, such as occur in cancer and other hyperproliferative cellular diseases (See 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 assignee of the present application has discovered an epothilone analog having advantageous activity for use as a pharmaceutical agent, particularly for use as a chemotherapeutic agent, namely, the compound having the structure,

This compound has the chemical name [IS-

[lR*,3R*(E),7R*,10S*,HR*,12R*,16S*]]-7,l l-dihydroxy-8,8,10,12,16- pentamethyl-3-[ 1 -methyl-2-(2-methyl-4-tlτiazolyl)ethenyl]-4-aza- 17 oxabicyclo[14.1.0]heptadecane-5,9-dione, and is now known as ixabepilone. Ixabepilone is claimed in US Pat. 6,605,599, based on US application Serial No. 09/084,542, filed May 26, 1998, and in continuation application US Serial No.

10/405,886, filed April 3, 2003, both of which are assigned to the present assignee and incorporated herein by reference. [0003] Before ixabepilone can be used to treat patients, however, it must be formulated into a composition that can be administered to patients, e.g., into a dosage form suitable for oral, transdermal, or (more typically for chemotherapeutic agents) intravenous (IV) or other parenteral administration. However, ixabepilone presents challenging formulation issues by reason of certain chemical properties. Ixabepilone is substantially more water soluble than TAXOL^®, and also more water soluble than epothilone B and other naturally-occurring epothilones and analogs. However, its relatively low-water solubility is still a challenge for pharmaceutical development. Additionally, ixabepilone is susceptible to degradation in aqueous medium and is pH- sensitive. This sensitivity to an acidic medium makes it challenging to administer ixabepilone using commonly available infusion fluids like 0.9% Sodium Chloride Injection (Normal Saline) or 5% Dextrose Injection, since these diluents are typically water-based and exhibit a wide pH range that is acidic. For example, 0.9% Sodium Chloride Injection has a pH range of 4.5 to 7.0, while 5% Dextrose Injection has a pH range of 3.5 to 6.5.

[0004] The applicant herein has continued to investigate the use of alternate methods of administering ixabepilone to address issues relating to its stability and solubility. US patent application Serial No. 60/572,279, filed May 18, 2004, describes a nanoparticulate formulation for ixabepilone, and US patent application Serial No. 60/628,970, filed November 18, 2004, describes an enteric-coated bead formulation for ixabepilone. These formulations provide many advantages but they also involve relatively complicated formulation technology. As may be appreciated, it may be advantageous to provide methods and/or formulations for administering ixabepilone that achieve enhanced stability in view of ixabepilone 's sensitivity to acidic and/or aqueous environments, and/or that do not involve use of nonionic surfactants, e.g., Cremophor^®, particularly for infusions intended to be administered over an extended period of time.

SUMMARY OF THE INVENTION [0005] The present invention is directed toward methods for administering ixabepilone. According to one aspect of the invention, the ixabepilone is delivered to an rv infusion line from a first source, and the diluent (e.g., infusion fluid) is delivered to the IV line from a second source. The diluent may optionally comprise a continuous feed to the patient or running stream of fluid in the IV line delivered to the patient, with the ixabepilone (or ixabepilone solution) being pumped or otherwise feed into the continuous feed. The ixabepilone and diluent are maintained in physical separation in the first and second sources, respectively. The ixabepilone becomes mixed with the diluent within the administration set during the course of delivery to form the pharmaceutical formulation, and the "admixed period" as defined herein before being delivered to the patient is within the stability period for the pharmaceutical formulation. [0006] According to another aspect of the invention, ixabepilone is placed in a first receptacle in a pH-controlled (e.g., buffered) solvent system having a minor percentage of water to provide an ixabepilone solution. The first receptacle is in fluid communication with a central infusion line for delivery of the contents of the infusion line to a patient. The diluent used for administration of the ixabepilone solution is placed in a second receptacle which also is in fluid communication with the central infusion line but is maintained in physical separation from the first receptacle containing the ixabepilone solution. The ixabepilone solution and diluent are admixed (e.g., in contact with each other) in the central infusion line to form a pharmaceutical formulation for delivery of the formulation to the patient. With this method of administration, a portion of the ixabepilone solution may be exposed to the diluent (e.g., which can be primarily aqueous or aqueous-based) for only a relatively short period of time before delivery to the patient, e.g., within the stability period for the pharmaceutical formulation. [0007] According to yet another aspect of the invention, there is provided a method for administering ixabepilone using the dual source methods described herein wherein the ixabepilone in the first source or receptacle is mixed in a pH- controlled solvent system comprising a mixture of co-solvent, viscosity reducing agent (VRA), buffer, and aqueous medium. Preferably the co-solvent is polyethylene glycol 400 (PEG 400), the VRA is dehydrated alcohol (e.g., ethanol), the buffer is tromethamine, the aqueous medium is water, and the constituents are present in a volume to volume ratio of about 30 to 60 percent dehydrated alcohol, 30 to 60 percent PEG 400, less than 1% buffer, and 10 to 30 percent water. In this embodiment of the invention, lyophilized ixabepilone may be mixed in the pH-controlled solvent system and contained in the first receptacle, or first source. The pH-controlled solvent system may comprise a constitution vehicle for a lyophilized ixabepilone. The diluent (e.g., saline or dextrose) is placed in the second receptacle or second source. The ixabepilone solution and diluent are admixed within the administration set to form a pharmaceutical formulation and are delivered to the patient using the dual source methods described herein.

[0008] Other embodiments and aspects of the invention may be apparent to one skilled in the field upon reading the description below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The advantages, nature and various features of the invention may appear more fully upon consideration of the accompanying drawings. In the drawings: [0010] Fig. 1 is a graph depicting the solubility of ixabepilone (mg/niL) in solvent systems of PEG 400:EtOH (diluted 1 :5 with saline or dextrose), as a function of the percent ethanol in the solvent system.

[0011] Fig. 2 is a graph depicting the solubility of ixabepilone (mg/mL) as a function of volume percent vehicle when further diluted with saline or dextrose. [0012] Fig. 3 is graph depicting the total impurities as a function of time for a 1.5 mg/mL ixabepilone solution infused into a running stream of 0.9% saline at both 25 mL/hr for 3 hours and 0.5 mL/hr for 24 hours. Also shown is the total impurities as a function of time for a 0.4 mg/mL ixabepilone solution when held in an infusion bag. [0013] It is to be understood that these drawings are for purposes of illustrating the concepts of the invention and are not limiting in nature.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The following are definitions of various terms used herein to describe the present invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group. [0015] "Acid" refers to any compound that contains hydrogen and dissociates in water or solvent to produce positive hydrogen ions, as well as Lewis acids, including but not limited to acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trihaloacetic acid {e.g., TFA), hydrogen bromide, maleic acid, sulfonic acids such as toluenesulfonic acids and camphorsulfonic acids, propionic acids such as (R)-chloropropionic acid, phthalamic acids such as N-[(R)-l-(l-naphthyl) ethyl] phthalamic acid, tartaric acids such as L-tartaric acid and dibenzyl-L-tartaric acid, lactic acids, camphoric acids, aspartic acids, citronellic acids, BCl₃, BBr₃, and so forth. Thus, the term includes weak acids such as ethanoic acid and hydrogen sulfide; strong organic acids such as methanesulfonic acid, trifluoroacetic acid; and so forth. [0016] "Administration set" means the complete set of equipment used to deliver medicine or fluids to a patient via intravenous administration. [0017] "Admixed period" means the period of time during which a given volume of ixabepilone (typically in a solvent system) is in contact with diluent to form a pharmaceutical formulation.

[0018] "Aqueous medium" when used herein is intended to refer to a liquid medium, solvent or solvent system containing greater than 30% water by volume, more preferably greater than 40% water by volume, and more preferably greater than 50% water by volume. Thus, an "aqueous medium" may be 100% by volume water but it also may be water mixed with one or more other solvents or agents. A "nonaqueous" medium is a medium that does not meet this definition. [0019] "Base" when used herein includes hydroxides or alkoxides, hydrides, or compounds such as ammonia, that accept protons in water or solvent. Thus, exemplary bases include, but are not limited to, alkali metal hydroxides and alkoxides {i.e., MOR, wherein M is an alkali metal such as potassium, lithium, or sodium, and R is hydrogen or alkyl, as defined above, more preferably where R is straight or branched chain C_1-5 alkyl, thus including, without limitation, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert-butoxide, lithium hydroxide, etc.); other hydroxides such as magnesium hydroxide (Mg(OH)₂), calcium hydroxide (Ca(OH)₂), or barium hydroxide

(Ba(OH)₂); alkali metal hydrides {i.e., MH, wherein M is as defined above, thus including, without limitation, sodium, potassium, and lithium hydrides); alkylated disilazides, such as, for example, potassium hexamethyldisilazide and lithium hexamethyldisilazide; carbonates such as potassium carbonate (K₂CO₃), sodium carbonate (Na₂CO₃), potassium bicarbonate (KHCO₃), and sodium bicarbonate (NaHCO₃); alkyl ammonium hydroxides such as n-tetrabutyl ammonium hydroxide (TBAH) and so forth.

[0020] "Buffer" means an ingredient which imparts an ability to resist change in the effective acidity or alkalinity of a medium upon the addition of increments of an acid or base. Preferably, a buffer used in the present invention will have a pKa (negative log of the acidity constant) in the range of about 7 to 9. A buffer thus includes but is not limited to sodium phosphate, sodium citrate, diethanolamine, triethanolamine, L-arginine, L-lysine, L-histidine, L-alanine, glycine, sodium carbonate, tromethamine (a/k/a tris[hydroxymethyl]aminomethane or Tris), and/or mixtures thereof. [0021] "Constitution vehicle" or "reconstitution vehicle" means a solvent or solvent system that may be used to reconstituted lyophilized ixabepilone such that the ixabepilone is completely or at least partially solubilized or dissolved in liquid medium.

[0022] "Co-solvent" means any pharmaceutically-acceptable solvent (liquid) that may be used to dissolve ixabepilone to form an ixabepilone solution. Preferred co- solvents according to the invention are water miscible co-solvents that may be used to dissolve ixabepilone in solution and which may be mixed with an aqueous medium such that the ixabepilone becomes solubilized in the aqueous medium. Preferably a co-solvent is selected such that up to about 20 mg of ixabepilone may be dissolved in a 1 mL solution of co-solvent/water, wherein the 1 mL solution may contain from 10- 30% water by volume. Co-solvents include but are not limited to ethanol, N₅N dimethylacetamide, propylene glycol, glycerol and polyethylene glycols, e.g., polyethylene glycol 300 and/or polyethylene glycol 400,

[0023] "Surfactant" means any pharmaceutically-acceptable surface active agent that may be used to increase a compound's (e.g., ixabepilone' s) spreading or wetting propertites by reducing its surface tension. Preferred surfactants are those surface active agents that may be used to solubilize ixabepilone, or increase ixabepilone 's solubility in aqueous medium up to about 20 mg/niL (e.g., up to about 20 mg of ixabepilone may be dissolved in 1 mL of liquid medium.) Surfactants include Cremophor^®, Solutol HS 15^®, polysorbate 80, polysorbate 20, poloxamer, pyrrolidones such as N-alkylpyrrolidone {e.g., N-methylpyrrolidone) and/or polyvinylpyrrolidone. [0024] The term "degradation" as used herein is intended to refer to a change in the chemical structure of ixabepilone to another compound or form of compound (e.g., including isomers, metabolites, and so forth). "Degradation" is determined by measuring the formation of impurities in an ixabepilone solution or formulation. "Degradation rate" thus refers to the percentage of total impurities detected in an ixabepilone solution or formulation over a given period of time.

[0025] The term "dextrose" when used herein with reference to an infusion fluid means a fluid comprising dextrose injection, preferably 5% Dextrose Injection (USP). [0026] The terms "diluent" and "infusion fluid" are used interchangeably herein to denote the fluid used to administer medicine to a patient via parenteral administration. Preferred diluents according to the invention are saline or dextrose. However, it should be understood that the concepts of the invention may be applied to other infusion fluids.

[0027] The phrase "extended period of time" as used herein is intended to denote periods of greater than 4 hours, more preferably greater than 6 hours, even more preferably periods of greater than 10 and up to 24 hours or longer.

[0028] "Insubstantial percentage", "insubstantial amount", "insubstantial quantity" "minor percentage", "minor amount", or "minor quantity" as used herein to denote the amount of water in and/or added to a solvent system means that the water in the solvent system is sufficiently low that it does not cause a degradation in a given quantity of ixabepilone of more than 10%, more preferably, it does not cause a degradation in ixabepilone of more than 5%, and even more preferably, it does not cause a degradation of more than 3.5%, when the solvent system with this quantity of water is in contact with the given quantity of ixabepilone for the duration of a selected infusion period (preferably for up to 10 hours, more preferably for up to 24 hours). [0029] "Pharmaceutical formulation" or "formulation" when used with reference to the instant invention means a formulation of ixabepilone wherein ixabepilone is mixed with a diluent or infusion fluid. Typically the ixabepilone will be lyophilized and reconstituted in a solvent system to form an ixabepilone solution and the ixabepilone solution will be further diluted with an infusion fluid to form the pharmaceutical formulation.

[0030] The term "pH-adjusting ingredient" denotes a buffer, acid, and/or base, or mixtures thereof (preferably a buffer, with the pH further adjusted with an acid and/or base), which is selected to adjust the pH of the solvent system used to solubilize and/or reconstitute ixabepilone. Thus, "pH-adjusting ingredient" is intended to denote a buffer, mixtures of buffers, an acid and/or base, mixtures of acids and/or bases, and/or mixtures of one or more buffers, acids, and/or bases. [0031] The term "saline" as used to refer to an infusion fluid means a fluid comprising Sodium Chloride Injection (USP), preferably about 0.9% Sodium Chloride Injection (USP).

[0032] The phrase "stability period" means the period of time wherein a given quantity of ixabepilone in a solvent system or formulation at room temperature will experience a degradation rate of less than 10%, more preferably less than 5%, and even more preferably less than 3.5%.

[0033] "Viscosity-reducing agent" (VRA) means any non-aqueous medium or other agent, or combinations of non-aqueous media and/or other agents, that may be added to an ixabepilone solution comprising ixabepilone and co-solvent (or solubilizer) in order to aid in the syringeability of the ixabepilone solution.

[0034] It should be understand that all numerical values reported herein are intended as approximations and experimental error or other insubstantial deviations may occur during a further reduction to practice. Thus, to the extent any numerical values are recited in the claims herein, it is intended for these numerical values to be approximations unless otherwise specifically indicated.

ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

[0035] According to one embodiment, the present invention is directed toward at least a dual source method for administering ixabepilone. The phrase "at least a dual source" is used because it is contemplated that there may be more than two sources in the intravenous ("IV") administration set used to deliver the medicine to the patient. However, at least two sources of supply to an IV administration line are contemplated. In this method, the ixabepilone is provided to the IV administration line (which delivers fluid to the patient) from a first source, and the diluent is provided to the IV line from a second source. (As noted, use of the terms "first source" and "second source" do not preclude the existence of third, fourth, and so on, sources, in the administration set - the terms "first" and "second" are used only to distinguish these two sources from each other.) The important consideration is that the ixabepilone (or ixabepilone solution) maintained in the first source is kept separate from the diluent in the second source, so that the ixabepilone while maintained in the first source is not exposed to degradation factors of the diluent. The ixabepilone is delivered from the first source and combined with the diluent delivered from the second source, to define the pharmaceutical formulation. Thus, the formulation (i.e., mixture of ixabepilone or ixabepilone solution and diluent) is formed within the administration set. The period of time in which a given amount of ixabepilone and diluent are in contact before being delivered to the patient (the "admixed period"), is within the stability period for that pharmaceutical formulation. Naturally, the "stability period" is dependent on the formulation used, i.e., it depends upon the solvent system used for dissolving or reconstituting the ixabepilone, the particular diluent used for the IV delivery, and also particularly the pH and percentage of water in the solvent system and/or diluent. [0036] Various containers and equipment may be used to provide the first and second sources and remainder of the administration set. The mechanical structure is flexible and can be varied. For example, the ixabepilone can be placed in a first container or IV administration bag, and the diluent can be placed in a second container or IV administration bag, each container having its own pump and IV line. Separate IV lines flowing from each container may then be coupled together via a Y- site connector to a single flow path or central IV line that then delivers the contents of the IV line to the patient. Alternatively, a central IV administration line may be used that comprises a continuous feed of diluent to the patient, with the ixabepilone being pumped into the continuous feed to the patient. Infusion delivery systems for administering medicine to patients from more than one source are well known, are commercially available, and have been described in the prior art. For example, various such systems are available from Baxter International Inc. It is contemplated the invention herein may invoke use of any such systems, as appropriate for ixabepilone and the methods of administration recited herein, as well as systems hereinafter developed. Examples of such systems and/or valves and/or junctions that may be used are described in the following US patents, each of which is incoiporated herein by reference: US Pat. 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; and 3,886,937. [0037] The ixabepilone in the first source may be dissolved in a pharmaceutically acceptable solvent system, preferably in a solvent system that does not comprise a non-ionic surfactant. Applicant has found that the non-ionic surfactant can be replaced with an alternative solvent system, i.e., a solvent system employing use of a water-miscible solubilizer or co-solvent, in which ixabepilone has greater solubility as compared with water (typically a high-viscosity co-solvent), in combination with a viscosity-reducing agent. With the methods of this invention, if ixabepilone were constituted in a solution consisting only of co-solvents used to solubilize the ixabepilone, syringeability (and administration via IV) would be impossible and/or highly impractical. Thus, the viscosity-reducing agent is employed which may comprise any non-aqueous medium or agent that is pharmaceutically-acceptable, compatible with the co-solvent and ixabepilone, and effective to improve the syringeability of the co-solvent and also dissolve and reconstitute the lyophilized ixabepilone. A preferred solvent system for the dual source administration comprises a combination of one or more of co-solvents with a viscosity-reducing agent which typically may comprise a dehydrated alcohol, such as ethanol. [0038] According to another aspect of the invention, the applicant has discovered that ixabepilone maintains higher stability when in a solvent system of polyethylene glycol/dehydrated alcohol, as compared with solvent systems using propylene glycol or glycerol. Lyophilized ixabepilone was constituted to 2 mg/mL with 50/50 mixtures (by volume) of dehydrated alcohol and the co-solvents propylene glycol, glycerol, polyethylene glycol 300 and polyethylene glycol 400. The solutions were stored at room temperature and light for between 6-8 hours. The stability data for each formulation is presented in Table 1. TABLE l

The results in Table 1 reflect that of these solvent systems, those using the polyethylene glycol/dehydrated alcohol mixtures were preferred with respect to maintaining ixabepilone' s stability in solution.

[0039] As between solvent systems of polyethylene glycol 300/dehydrated alcohol and polyethylene glycol 400/dehydrated alcohol, however, for solubility reasons it was determined that the latter are preferred. In particular, 50/50 mixtures (by volume) of polyethylene glycol 300/dehydrated alcohol and polyethylene glycol 400/dehydrated alcohol were each diluted 1 :5 with both 5% dextrose and 0.9% normal saline and excess ixabepilone was added. These solutions (containing 20% diluent by volume), were stirred for 3 hours at room temperature, filtered and assayed by HPLC. Solubility data is presented in Table 2.

TABLE 2

[0040] As can be seen, ixabepilone was more soluble in dilutions with both 5% dextrose and 0.9% saline when PEG 400 was used as compared with when PEG 300 was used. (The abbreviation "PEG" as used herein denotes "polyethylene glycol.") [0041] Although in the above solvent systems, 50/50 mixtures (by volume) of PEG/dehydrated alcohol are exemplified, applicant has determined that wider ranges of co-solvent and VRA may be used effectively. In certain embodiments, advantages are realized when the solvent systems are prepared using mixtures of about 30 to 70 percent by volume dehydrated alcohol for each 30 to 70 percent by volume co-solvent (or solubilizer). For example, Fig. 1 hereof reflects results of a study performed to analyze the solubility of ixabepilone in solvent systems containing different proportions of PEG 400 and dehydrated alcohol when diluted 1 :5 with saline or dextrose infusion fluids. Ixabepilone solubility was determined by HPLC analysis of a filtered aliquot of solution containing excess ixabepilone after 3 hours of mixing. As can be seen, this Figure reflects that within this range (30:70 vs. 70:30 of PEG 400:EtOH) there is a small increase in solubility as the amount of dehydrated alcohol is increased. However, it is preferred that the amount of ethanol administered to a patient during an infusion be minimized to avoid side effects associated with ethanol administration. Thus, while increasing the dehydrated alcohol slightly increases solubility, it also presents disadvantages. Thus, when a solvent system of PEG 400: ethanol is used, the inventors have determined that a preferred range of co-solvent to dehydrated alcohol is 40:60 to 60:40, and a further preferred ratio is a mixture at about 50:50 by volume each.

[0042] Preferably, this inventive solvent system for ixabepilone (which more preferably is a Cremophor^®-free or substantially Cremophor^®-free solvent system), is pH-controlled. By "pH controlled solvent system," it is meant that the solvent system has been prepared so that it will tend to exhibit a selected range of pH that is within a desired range of pH for ixabepilone and additionally, when combined with the diluent to define the ixabepilone formulation, the pH of the final formulation will fall within a desired range. For example, it has been determined that the pH of optimal stability for ixabepilone in solution and/or in the formulation is about 7-9. Advantageously, the pH of the solution used to constitute the ixabepilone will be within the range of 6.0 to 9.5, more preferably in the range of about 6.5 to 9.0, and most preferably in the range of about 7 to 9. Additionally, the pH of the formulation (e.g., ixabepilone solution and diluent combined) will be in the range of about 6.0 to 9.5, more preferably in the range of about 6.5 to 9.0, and most preferably in the range of about 7 to 9. It has been determined that to achieve a formulation pH in these ranges, wherein saline or dextrose is used as the diluent, the pH of the solvent system may fall within the range of about 6.5 to 10, more preferably in the range of about 7 to 9.5, and most preferably in the range of about 7-9. For example, when the solvent system has a pH in the range of 8.3+ 1.0, then the pH of the pharmaceutical formulation will be in the range of 6.1 to 9.3 at a concentration of ixabepilone at 0.2 to 0.6 mg/mL. [0043] The pH of the solvent system can be controlled in various ways. For example, this can be achieved via choice of solvents and/or use of one or more pH- adjusting ingredients such as one or more buffers, acid(s) and/or base(s). One embodiment of the invention comprises using a buffer to adjust the pH of the solvent system, then further adjusting the pH to as close to the desired range as possible using small amounts of acid and/or base, the quantities being selected as needed to reach the desired range of pH. In one embodiment, the diluent is a saline or dextrose infusion fluid, the solvent system includes PEG 400 and dehydrated alcohol, and a buffer of tromethamine is used together with trace quantities of IN HCl and/or IN NaOH to adjust the pH of the solvent system to a pH in the range of 8.3 ± 1.0. The preferred pH adjusting ingredient may depend upon the type and quantities of co-solvent (or solubilizer) and viscosity-reducing agent used. For example, when a 50:50 mixture of PEG 400: dehydrated alcohol is used, tromethamine is considered to be a preferred buffer in view of its degree of solubility in this solvent system. [0044] Depending on the selection of buffer and solvent system it may be advantageous to add in the solvent system a minor quantity of water. A minor quantity of water provides advantages in terms of, e.g., avoiding a haze in the solvent system, dissolving the buffer and allowing for pH adjustment, increasing compatibility with the infusion fluids, and/or reducing the viscosity of the solvent system. For example, applicant has discovered that when a solvent system of PEG 400:dehydrated alcohol is used, advantageously up to about 30% by volume water, more preferably up to about 25% by volume water, and even more preferably up to about 20% by volume water, may be added to dissolve the buffer, and this quantity of water should not cause an unacceptable level of degradation in ixabepilone over the course of an infusion lasting for an extended period of time. For example, in one aspect of the invention, a buffered solvent system comprising approximately equal amounts of PEG 400:EtOH, and an amount of water comprising up to about 20% by volume of the total volume of the ixabepilone solution, may not cause a degradation of ixabepilone of more than 5% over a 24 hour infusion period. [0045] According to another aspect of the invention, a lyophilized ixabepilone (see, e.g., US Pat. 6,670,384 incoiporated herein), is reconstituted with a pH- controlled solvent system having a minor percentage of water to provide an ixabepilone solution. The ixabepilone solution may be prepared first, then placed in a first receptacle of an administration set, or it may be prepared directly within the administration set. The first receptacle is in fluid communication with a central infusion line for delivery of the contents of the infusion line to a patient. The diluent used for administration of the ixabepilone is placed in a second receptacle which also is in fluid communication with the central infusion line but is maintained separate from the first receptacle containing the ixabepilone solution. By being "maintained separate" or "in physical separation" it is meant that the ixabepilone is not exposed to the diluent whereby the degradation factors of the diluent (e.g., substantially aqueous and/or acidic conditions) may cause the ixabepilone to degrade. The ixabepilone solution and diluent are combined in the central infusion line to form a pharmaceutical formulation for delivery of the formulation to the patient. With this method of administration, the ixabepilone solution may be exposed to the diluent (which may be saline or dextrose or other primarily aqueous vehicle) for only a relatively short period of time before delivery to the patient. [0046] According to further aspects of the invention, solvent systems advantageous for providing an ixabepilone solution according to the above description is depicted below in Table 3.

TABLE 3

[0047] The inventors herein also discovered that, to avoid the formation of a supersaturated solution of ixabepilone, the preferred concentration of ixabepilone in the ixabepilone solution (after constitution with the solvent system), is about up to 2 mg/niL, or more preferably about up to 1.5+ .1 mg/mL. To illustrate, Figure 2 shows the ixabepilone solubility in mg/mL as a function of volume percent vehicle for both dextrose and saline infusion fluids. Figure 2 reflects that to avoid supersaturated solutions of ixabepilone, it is preferred to constitute the lyophilized ixabepilone to a concentration of about 2 mg/mL or less, more preferably about 1.5 mg/mL or less. [0048] Figure 3 illustrates the surprising advantages of the instant invention in enabling improved stability and longer use times for ixabepilone solutions and formulations. In particular, Figure 3 shows the degradation rates (and stability periods) for two dual source methods of administering ixabepilone according to the invention as compared with previous methods. For each of the ixabepilone solutions of Figure 3, ixabepilone was dissolved to a concentration of about 1.5 mg/mL in a buffered solvent system comprising about 50:50 PEG 400:EtOH (each present in an amount of about 40% by volume of the solvent system), about 20% water, and less than 1% buffer. This buffered solvent system of ixabepilone was infused into a running stream of 0.9% normal saline at 25 mL/hr for 3 hours, infused into a running stream of saline at 0.5 mL/hr for 24 hours, and (according to previous methods) held in an infusion bag containing the saline infusion fluid. As can be seen, in the latter, previous method, the total impurities may reach the level of about 5% within about a four hour use time (or admixed period), whereas with the methods of this invention, the same or comparable level of impurities in the same solvent system may not be observed until approximately a 24 hour use time.

[0049] One aspect of this invention provides use of ixabepilone for the manufacture of a pharmaceutical formulation for the treatment of cancer in a patient, wherein the ixabepilone is supplied from a first source to an FV line and a diluent is supplied from second source to the IV line, whereby the ixabepilone and the diluent are maintained in physical separation in the first and second sources, respectively, and are admixed upon delivery from the first and second sources, respectively, to the IV line, to form the pharmaceutical formulation before being delivered to the patient. The pharmaceutical formulation can be delivered to the patient during an extended period of time. Preferably, the pharmaceutical formulation is delivered to the patient during an infusion period lasting for more than 10 continuous or substantially- continuous hours, and more preferably for an infusion period lasting for about 20 to 24 continuous hours. The ixabepilone in the first source of supply can be a lyophilized ixabepilone constituted in a solvent system comprising about 65-90% by volume of a mixture of co-solvent and viscosity-reducing agent (VRA), wherein the mixture comprises about 70:30 to 30:70 by volume co-solvent:VRA. The solvent system can further comprise a pH-adjusting ingredient and a minor amount of aqueous medium. Preferably, the co-solvent comprises polyethylene glycol, such as, for example, polyethylene glycol 300 or 400, and more preferably, polyethylene glycol 400. Preferably the viscosity-reducing agent comprises dehydrated alcohol, and more preferably, ethanol. The solvent system may comprise up to 30 % water by volume, for example, 20%±5%. Preferred is a solvent system that is free or substantially free of polyoxyethylated castor oil, for example, comprising less than 5 weight %, more preferably, less than 1 weight %, still more preferably less than 0.1 weight %, and most preferably free of the polyoxyethylated castor oil.

[0050] A further aspect of the invention provides use of ixabepilone for the manufacture of a pharmaceutical formulation for the treatment of cancer in a patient, wherein: ixabepilone is provided in a first receptacle in a pH-controlled solvent system having a minor percentage of water to define an ixabepilone solution, wherein the first receptacle is in fluid communication with a central infusion line for delivery of the contents of the infusion line to a patient; a diluent is provided in a second receptacle which also is in fluid communication with the central infusion line but is maintained in physical separation from the first receptacle containing the ixabepilone solution; and the ixabepilone solution and the diluent are delivered to the central infusion line whereby the ixabepilone solution and diluent are combined to form a pharmaceutical formulation within the central infusion line for delivery of the pharmaceutical formulation to the patient.

The pH-controlled solvent system comprises a mixture of co-solvent or solubilizer, viscosity-reducing agent, pH adjusting ingredient, and water. Preferred co-solvents include propylene glycol, glycerol, polyethylene glycol 300, and/or polyethylene glycol 400. A preferred viscosity-reducing agent is dehydrated alcohol. Preferably, the pH controlled solvent system does not comprise a non-ionic surfactant or is substantially free of a non-ionic surfactant.

[0051] Another aspect provides a pharmaceutical kit for administering ixabepilone to a patient comprising at least a first and a second vial, wherein the first vial comprises a quantity of lyophilized ixabepilone, and the second vial comprises a pH-controlled solvent system comprising about 65-90% by volume of a mixture of co-solvent and viscosity-reducing agent (VRA), wherein the mixture comprises about 70:30 to 30:70 by volume co-solvent:VRA, and the solvent system further comprises less than 1% by weight buffer, and 10 to 30 percent by volume water. The pharmaceutical kit may be adapted for use in administering an IV infusion of ixabepilone to a patient over an extended period of time, for example, an infusion period lasting for more than 10 continuous or substantially-continuous hours, or for an infusion period lasting from 20 to 24 continuous or substantially-continuous hours. The pH-controlled solvent system may further comprise pH adjusting ingredient and/or water. Preferred co-solvents include propylene glycol, glycerol, polyethylene glycol 300, and/or polyethylene glycol 400. A preferred viscosity-reducing agent is dehydrated alcohol. Preferably, the pH controlled solvent system does not comprise a non-ionic surfactant or is substantially free of a non-ionic surfactant.

UTILITY

[0052] Ixabepilone is a microtubule-stabiliziiig agent and thus useful in the treatment of a variety of cancers and other proliferative diseases. Ixabepilone is particularly useful in the treatment of carcinoma, including that of the breast, colon, lung, and pancreas, and also particularly useful in treating refractory cancers.

However, the medicine may be useful in treating many other cancers, proliferative diseases, neuronal connectivity defects, central nervous system disorders (such as Alzheimer's disease), and other diseases. Reference is made to U.S. Pat. 6,686,380 and US Pat. 6,605,599, each of which is incoiporated herein by reference as is fully set forth herein, for reference to other specific indications ixabepilone may be useful in treating. [0053] Furthermore, ixabepilone may be administered in combination with other anticancer and cytotoxic agents and treatments useful in the treatment of cancer or other proliferative diseases. Such other agents are identified in US Pat. application Serial No. 10/091,061, filed March 5, 2002, corresponding with US Pat. publication 2003/0073677 Al , assigned to the present assignee, which is incorporated herein by reference. Such other agents may be administered using a triparte source method, e.g., employing the concepts of the present invention, but also delivering another chemotherapeutic agent in combination with ixabepilone, using a third or further sources for the other agent(s). The effective amount of ixabepilone may be determined by one of ordinary skill in the art. Exemplary dosage amounts may be found in US patent application Serial No. 10/055,653, filed January 23, 2002, incorporated herein by reference. Alternatively, for a human of from about 0.05 mg/kg/day to about 200 mg/kg/day, ixabepilone according to the invention may be administered in a single dose, via a single continuous FV infusion, in the form of individual divided doses, e.g., more than one time per day, or over the course of a week or several weeks. A preferred concentration of ixabepilone when diluted in the infusion fluid is approximately in the range of about 0.01 to about 2.0 mg/mL, more preferably in the range of about 0.05 to about 1.5 mg/mL, and most preferably in the range of about 0.2 to about 0.8 mg/mL. Although the present invention is particularly advantageous for infusion periods lasting extended periods of time, the ixabepilone may be administered with infusion times of up to 10 hours, up to 6 hours, or even 1 to 4 hours, and advantages are provided, e.g., in terms of the logistics of medicine administration. In one embodiment, however, metastatic breast cancer may be treated by administering a dose of up to 100 mg/m² of ixabepilone, more preferably a dose of about 40± 20 mg/m², administered once every 21 days, with an infusion time of up to 24 hours. The dose administration may be split, however, administered more frequently than every 21 days, and/or may be repeated one or more times as needed. [0054] It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, lean mass (or percentage fat tissue), general health, sex, and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Subjects for treatment include mammals, most preferably humans, but other species of mammals subject to the disorders responsive to ixabepilone treatment potentially may be patients as well.

EXAMPLE 1

[0055] First, an amount of water equivalent to 15% by volume of the final batch volume is added to the batching vessel. While mixing, tromethamine is added to the water and the solution is mixed for a minimum of 10 minutes to dissolve the tromethamine. An amount of IN HCl equivalent to 1.2% of the final batch weight is added to the batching vessel. With constant mixing, approximately equal amounts of polyethylene glycol 400 and ethanol (each about 40 by volume of the final batch volume) are added to the batching vessel. If necessary, the batch temperature is adjusted so that a temperature is maintained in the range of 15-25°C, and the solution is mixed for a minimum of 15 minutes. The pH of the batch solution is then adjusted to 8.3 ± 0.1 with IN HCl and/or 1 N NaOH. Additional water is then added to reach the desired final batch volume and the solution is mixed for a minimum of 15 minutes. The resulting solution is sterilized by filtration though a suitable 0.22 micron filter. Aliquots of the sterile solution are aseptically filled into Type I glass vials which are then stoppered and sealed. The finished solvent system has approximately the composition shown in Table 4, below, and is stored at 2-25⁰C.

TABLE 4

EXAMPLE 2

[0056] The solvent system of Example 1 is used to constitute two vials of lyophilized ixabepilone, each vial containing 16 mg ixabepilone, by slowly injecting 10.7 niL of the solvent system into each vial. The vial is gently swirled until the lyophile is completely dissolved. When completely dissolved, the solution concentration of Ixabepilone is 1.5 mg/mL.

[0057] 15 mL of the constituted ixabepilone solution is withdrawn into a syringe and the outlet of the syringe is connected to the lowest Y-site on an FV line using an extension set with a priming volume of 2 mL or less. The Y-site is located not more than 12 inches from the distal end of the administration set. The IV line contains a running stream of 0.9% Sodium Chloride Injection, USP (Normal Saline). The rate of the Normal Saline is set to at least 50 mL/hour and flow is started. The syringe containing the constituted ixabepilone is placed into a syringe pump and an ixabepilone flow rate of 0.5 mL/hour is started. With the syringe, syringe pump, and

Y-site, the constituted ixabepilone solution is thus infused into the running stream of saline.

[0058] Ixabepilone potency and total impurities are monitored over a 24 hour infusion period using HPLC analysis. Results show that over the 24 hour infusion period, there is a degradation rate of about 3.2% for the ixabepilone, i.e., total impurities detected in the ixabepilone solution comprise about 3.2% of the starting quantity of ixabepilone.

EXAMPLE 3

[0059] The solvent system of Example 1 is used to constitute a quantity of lyophilized ixabepilone to an ixabepilone concentration of 1.5 mg/mL. The constituted ixabepilone solution is withdrawn into a syringe, and the outlet of the syringe is comiected to a Y-site on an IV line using Braun extension sets with in-line filters of 1.2 microns and 0.2 microns, and priming volumes of 4.3 mL and 1.15 mL, respectively. The FV line contains a running stream of 0.9% Sodium Chloride Injection, USP (Normal Saline). The syringe containing the constituted ixabepilone is placed into a syringe pump and an ixabepilone flow rate is started. The rate of the constituted ixabepilone is set at a constant rate of 2.22 mL/hr. The saline flow rate is varied from 6 to 96 mL/hr. Alternatively, the infused ixabepilone solution is set at rates of 5 mL/hr and 17.8 mL/hr, and the saline infusion rate is varied from about 15 to 95 mL/hr. To maintain the ixabepilone concentration in the formulation below about 0.4 mg/mL, for ixabepilone flow rates of up to 10 mL/hour, the saline flow rate is set at about 30 mL/hour. For ixabepilone flow rates of greater than 10 mL/hour, the saline flow rate is set at about 3 times the ixabepilone flow rate. For faster flow rates (generally greater than 60 mL/hour), the 1.2 micron filter/extension set is used in the administration set, rather than the smaller filter.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. Use of ixabepilone for the manufacture of a pharmaceutical formulation for the treatment of cancer in a patient, wherein the ixabepilone is supplied from a first source to an IV line and a diluent is supplied from second source to the IV line, whereby the ixabepilone and the diluent are maintained in physical separation in the first and second sources, respectively, and are admixed upon delivery from the first and second sources, respectively, to the IV line, to form the pharmaceutical formulation before being delivered to the patient.

2. The use according to claim 1, wherein the pharmaceutical formulation is delivered to the patient during an extended period of time.

3. The use according to claim 2, wherein the pharmaceutical formulation is delivered to the patient during an infusion period lasting for more than 10 continuous or substantially-continuous hours.

4. The use according to claim 1, wherein the ixabepilone in the first source of supply is a lyophilized ixabepilone constituted in a solvent system comprising about 65-90% by volume of a mixture of co-solvent and viscosity- reducing agent (VRA), wherein the mixture comprises about 70:30 to 30:70 by volume co-solvent: VRA, and the solvent system further comprises a pH-adjusting ingredient and a minor amount of aqueous medium.

5. The use according to claim 4 wherein the co-solvent comprises polyethylene glycol 300 or 400 and the viscosity-reducing agent comprises dehydrated alcohol.

6. The use according to claim 4 wherein the solvent system is free or substantially free of polyoxyethylated castor oil.

7. Use of ixabepilone for the manufacture of a pharmaceutical formulation for the treatment of cancer in a patient, wherein ixabepilone is provided in a first receptacle in a pH-controlled solvent system having a minor percentage of water to define an ixabepilone solution, wherein the first receptacle is in fluid communication with a central infusion line for delivery of the contents of the infusion line to a patient; a diluent is provided in a second receptacle which also is in fluid communication with the central infusion line but is maintained in physical separation from the first receptacle containing the ixabepilone solution; and the ixabepilone solution and the diluent are delivered to the central infusion line whereby the ixabepilone solution and diluent are combined to form a pharmaceutical formulation within the central infusion line for delivery of the pharmaceutical formulation to the patient.

8. The use according to claim 7, in which the pH-controlled solvent system comprises a mixture of co-solvent or solubilizer, viscosity-reducing agent, pH adjusting ingredient, and a minor percentage of water.

9. The use according to claim 8, wherein the co-solvent is selected from propylene glycol, glycerol, polyethylene glycol 300, and/or polyethylene glycol 400; and the viscosity-reducing agent comprises dehydrated alcohol.

10. The use according to claim 8, wherein the pH controlled solvent system does not contain a non-ionic surfactant or is substantially free of a non-ionic surfactant.

11. A pharmaceutical kit for administering ixabepilone to a patient comprising at least a first and a second vial, wherein the first vial comprises a quantity of lyophilized ixabepilone, and the second vial comprises a pH-controlled solvent system comprising about 65-90% by volume of a mixture of co-solvent and viscosity- reducing agent (VRA)₅ wherein the mixture comprises about 70:30 to 30:70 by volume co-solvent: VRA, and the solvent system further comprises less than 1% by weight buffer, and 10 to 30 percent by volume water.

12. The kit according to claim 11, adapted for use in administering an IV infusion of ixabepilone to a patient over an extended period of time, wherein the pH- controlled solvent system does not comprise a non-ionic surfactant or is substantially free of a non-ionic surfactant.