Compositions Containing Cyclodextrin and Busulfan

Abstract

Pharmaceutical formulations containing busulfan and cyclodextrin are described. Methods of making the busulfan formulations and methods of using the formulations are also described. The formulation may include busulfan and a cyclodextrin in a clear, aqueous solution.

Description

[Technical field]

[0001] INCORPORATION BY REFERENCE TO ALL PRIOR APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 500,970, filed May 3, 2017, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to formulations containing busulfan and sulfoalkyl ether cyclodextrins, methods of making same, and methods of using same. [Background technology]

[0003] Busulfan [1,4-bis-(methanesulfonoxyl)butane] is an alkylating agent that is widely used for its antitumor properties and was characterized in the early 1950s by Galton et al. for the treatment of chronic myeloid leukemia (CML). Its poor water solubility, stability, and unpleasant side effects (significant gastric irritation, nausea, vomiting, etc.) mean that the bioavailability of oral dosage forms is highly variable. In addition, the drug is rapidly metabolized by the liver and can cause severe hepatotoxicity, which can be a dose-limiting toxicity in high-dose regimens. Certain solvents used to dissolve busulfan can cause liver damage, compromising patients' long-term treatment goals and quality of life. Summary of the Invention

[0004] Some embodiments relate to pharmaceutical compositions comprising a solid comprising busulfan and a cyclodextrin, wherein at least 25% of the busulfan in the composition is complexed with a cyclodextrin.

[0005] Some embodiments relate to pharmaceutical compositions comprising a clear aqueous solution comprising busulfan having a concentration in the range of about 0.3 mg / ml to about 3 mg / ml and a cyclodextrin, wherein the molar ratio of cyclodextrin to busulfan is less than 12.

[0006] Some embodiments relate to a pharmaceutical composition comprising a clear, aqueous solution comprising busulfan and a sulfoalkyl ether cyclodextrin.

[0007] Some embodiments relate to a reconstituted solution obtained by adding a pharma- ceutically acceptable solvent to a composition described herein.

[0008] Some embodiments relate to a sterile container comprising a composition described herein.

[0009] Some embodiments relate to a method of making a busulfan composition comprising: Mixing busulfan and organic solvent to obtain a clear solution; mixing the clear solution with cyclodextrin to obtain a first mixture; and drying the first mixture to obtain a busulfan composition; Includes.

[0010] Some embodiments relate to methods of treatment comprising reconstituting a pharmaceutical composition described herein and administering the reconstituted pharmaceutical composition to a subject in need thereof.

[0011] Some embodiments relate to methods of conditioning a subject for hematopoietic stem cell transplantation comprising administering to a subject in need thereof a composition described herein.

[0012] A method of conditioning a subject for a bone marrow transplant comprising administering to a subject in need thereof a composition described herein.

[0013] A method of treating leukemia, lymphoma, and myeloproliferative disorders comprising administering to a subject in need thereof a composition described herein. [Brief description of the drawings]

[0014] [Figure 1]FIG. 1 shows the results of a solubility study of busulfan in sulfoalkyl ether-β-cyclodextrin solutions. [Diagram 2] FIG. 2 shows the results of a stability study with three busulfan formulations. [Diagram 3] FIG. 3A is a graph showing the stability of the first busulfan formulation at 2-8°C, 25°C, and 40°C, and the stability of the third busulfan formulation at 2-8°C (RF) and 25°C, and FIG. 3B is a graph showing the stability of the second busulfan formulation at 2-8°C (RF), 25°C, and 40°C, and the stability of the third busulfan formulation at 2-8°C (RF) and 25°C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The term "pharmaceutical acceptable cation" refers to a cation that maintains the biological effectiveness and properties of a compound and is not biologically or otherwise undesirable in pharmaceutical use. Examples of cations include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, with ammonium, potassium, sodium, calcium, and magnesium cations being particularly preferred. Other types of cations can include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such cations are known in the art, as described in International Publication WO 87 / 05297 by Johnston et al., published September 11, 1987.

[0016] The term "pharmaceutically acceptable salt" refers to a salt that maintains the biological effectiveness and properties of the compounds of the preferred embodiments and is not biologically or otherwise undesirable. In many cases, the compounds of the preferred embodiments can form acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in International Publication WO 87 / 05297 by Johnston et al., published September 11, 1987.

[0017] The term "pharmaceutical acceptable solvent" as used herein means one or more compatible solid or liquid fill diluents or encapsulating agents suitable for administration to a mammal. The terms "compatible" or "acceptable" as used herein mean that the components of the composition are capable of being mixed with the subject compound, and with each other, in a manner that does not cause interactions that would significantly reduce the pharmaceutical effectiveness of the composition under normal conditions of use. Pharmaceutically acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably a mammal, being treated.

[0018] Some examples of substances that can be used as pharma- ceutically acceptable carriers or components thereof are cyclodextrins (e.g., SAE-CD, HAE-CD, and other cyclodextrin derivatives), sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEEN® S; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water, isotonic saline; and phosphate buffer solutions.

[0019] As used herein, a "major portion of busulfan" means at least (at least) about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the busulfan in the composition.

[0020] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (wherever described herein, a numerical range such as "1 to 20" refers to each integer within the given range, e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also includes the occurrence of the term "alkyl" where no numerical range is specified). The alkyl group may be a medium-sized alkyl having 1 to 9 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be a "C 1~4 By way of example only, "C 1~4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0021] A "sulfonyl" group refers to a "-SO2R" group, where R is hydrogen, C, 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0022] "Subject" as used herein means a human or non-human mammal, e.g., By this is meant dogs, cats, mice, rats, cows, sheep, pigs, goats, non-human primates, or birds, such as chickens, as well as any other vertebrate or invertebrate.

[0023] The term "mammal" is used in its ordinary biological sense, and thus specifically includes, but is not limited to, primates, including monkeys (chimpanzees, apes, and monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, and the like.

[0024] "Effective amount" or "therapeutically effective amount," as used herein, means an amount of a therapeutic agent effective to alleviate to some extent one or more of the symptoms of a disease or condition or reduce the likelihood of its onset, including curing the disease or condition. "Cure" means that the symptoms of the disease or condition are eliminated, although certain long-term or permanent effects may exist even after a cure has been achieved (such as extensive tissue damage).

[0025] "Treat", "treatment" or "treating" as used herein means administering a pharmaceutical composition to a subject for preventative and / or therapeutic purposes. The term "prophylactic treatment" means treating a subject who does not yet exhibit symptoms of a disease or condition but who is susceptible to or otherwise at risk for a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. "Therapeutic treatment" means administering treatment to a subject who is already suffering from a disease or condition.

[0026] The compositions and methods described herein can help reduce or eliminate the amount of toxic solvents, such as N,N-dimethylacetamide (DMA), and / or non-aqueous solvents, such as PEG, in busulfan formulations. The methods and compositions described herein can lead to higher drug loadings that require relatively lower amounts of cyclodextrin or cyclodextrin derivatives. The superior properties of the methods and compositions described herein help achieve improved drug tolerance, better drug stability, higher drug exposure, longer duration of treatment, and even more options due to flexible handling and improved stability.

[0027] The compositions and methods described herein provide high-dose parenteral busulfan therapy for the treatment of a variety of diseases while overcoming the problems of toxic solvent use and busulfan instability associated with existing busulfan compositions. The busulfan compositions described herein exhibit less drug precipitation over time compared to other commercially available busulfan formulations. The technology also offers the potential for extending use to the pediatric population due to reduced solvent toxicity.

[0028] Cyclodextrin The term "cyclodextrin" as used herein means α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or their respective derivatives, including derivatives in which one or more hydroxyls on the cyclodextrin core are replaced by alkyl ether, hydroxyalkyl ether, or sulfoalkyl ether substituents. Examples of cyclodextrin derivatives include, but are not limited to, the cyclodextrins listed in Tables A-D below. Preferably, the cyclodextrin is β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sulfoalkyl ether β-cyclodextrin.

[0029] Some exemplary sulfoalkyl ether (SAE)-CD derivatives include:

[0030] [Table 1]

[0031] Various embodiments of sulfoalkyl ether cyclodextrins include eicosa-O-(methyl)-6G-O-(4-sulfobutyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, and heptakis-O-[(1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(sulfomethyl)-β-cyclodextrin. Other known alkylated cyclodextrins containing a sulfoalkyl moiety include octakis-(S-sulfopropyl)-octathio-γ-cyclodextrin, octakis-O-[3-[(2-sulfoethyl)thio]propyl]-β-cyclodextrin, and octakis-S-(2-sulfoethyl)-octathio-γ-cyclodextrin.

[0032] In some embodiments, alkylated cyclodextrin compositions of the invention are sulfoalkyl ether-β-cyclodextrin compositions having an ADS of 2-9, 4-8, 4-7.5, 4-7, 4-6.5, 4.5-8, 4.5-7.5, 4.5-7, 5-8, 5-7.5, 5-7, 5.5-8, 5.5-7.5, 5.5-7, 5.5-6.5, 6-8, 6-7.5, 6-7.1, 6.5-7.1, 6.2-6.9, or 6.5 per alkylated cyclodextrin, with the remaining substituents being -H.

[0033] Some exemplary alkyl ether cyclodextrin (AE-CD) derivatives include:

[0034] [Table 2]

[0035] In the table, ME means methyl ether, EE means ethyl ether, PE means propyl ether, BE means butyl ether, PtE means pentyl ether, HE means hexyl ether and y means the average degree of substitution.

[0036] Some exemplary hydroxyalkyl ether (HAE)-CD derivatives include:

[0037] [Table 3]

[0038] In the table, HME means hydroxymethyl ether, HEE means hydroxyethyl ether, HPE means hydroxypropyl ether, HBE means hydroxybutyl ether, HPtE means hydroxypentyl ether, HHE means hydroxyhexyl ether, and z means the average degree of substitution.

[0039] The alkylated cyclodextrin can include an SAE-CD, an HAE-CD, an SAE-HAE-CD, an HANE-CD, an HAE-AE-CD, an HAE-SAE-CD, an AE-CD, an SAE-AE-CD, a neutral cyclodextrin, an anionic cyclodextrin, a cationic cyclodextrin, a halo-derivatized cyclodextrin, an amino-derivatized cyclodextrin, a nitrile-derivatized cyclodextrin, an aldehyde-derivatized cyclodextrin, a carboxylate-derivatized cyclodextrin, a sulfate-derivatized cyclodextrin, a sulfonate-derivatized cyclodextrin, a mercapto-derivatized cyclodextrin, an alkylamino-derivatized cyclodextrin, or a succinyl-derivatized cyclodextrin.

[0040] Some exemplary mixed ether cyclodextrin derivatives.

[0041] [Table 4-1]

[0042] [Table 4-2]

[0043] [Table 4-3]

[0044] The terms "sulfoalkyl ether cyclodextrin" and "SAE-CD" as used herein refer to 2~6 Alkylene)-SO3 - The sulfoalkyl derivative of cyclodextrin may be a single derivative or a mixture of derivatives. The cyclodextrin derivative may be a charged species due to the presence of a sulfonyl group. The sulfoalkyl ether cyclodextrin may be substituted at at least one of the primary hydroxyl groups of the cyclodextrin, or they may be substituted at both the primary hydroxyl group and the hydroxyl group at the 3-position. Substitution at the 2-position is also possible. An example of a sulfoalkyl ether cyclodextrin is sulfobutyl ether beta cyclodextrin.

[0045] In some embodiments, the cyclodextrin is a compound of formula 1:

[0046] [ka] or a pharma- ceutically acceptable salt thereof, wherein: p is 4, 5, or 6, and each R1 is selected from -OH or -O-(C1-C8 alkylene)-SO3T; each T is independently hydrogen or a pharma- ceutically acceptable cation; With the proviso that at least one R1 is -OH.

[0047] In some embodiments, each R1 is independently -OH or -O-(C1-C8 alkylene)-SO3T, provided that at least one R1 is -OH and at least one R1 is -O-(C1-C8 alkylene)-SO3T, where T is hydrogen or a pharma- ceutically acceptable cation. In some embodiments, at least one R1 is independently -OH or -O-(C 1~4 In some embodiments, at least one R is independently -O-(CH) g is a SO3T group, and g is 2 to 6 or 2 to 4. In some embodiments, at least one R1 is independently -OCH2CH2CH2SO3T or -OCH2CH2CH2CH2SO3T. In some embodiments, at least one R1 is -OCH2CH2CH2-OH. In some embodiments, each R1 is independently -OH or O-(C1-C6 alkyl)-OH, provided that at least one R1 is O-(C1-C6 alkyl)-OH. In some embodiments, T is independently hydrogen or sodium. In some embodiments, T is H. In some embodiments, T is Na + In some embodiments, each T is independently selected from alkali metals, alkaline earth metals, ammonium ions, and amine cations such as the, and combinations thereof. In some embodiments, each T is independently selected from Li + , Na + , K + , Ca +2 , Mg +2 , amines, and any combination thereof. In some embodiments, each T is independently an amine cation selected from (C1-C6)-alkylamines, piperidines, pyrazines, (C1-C6)-alkanolamines, ethylenediamines, and (C4-C8)-cycloalkanolamines.

[0048] In some embodiments, each R1 is independently -OH or -O-(C1-C8 alkyl), provided that at least one R1 is -OH and at least one R1 is -O-(C1-C8 alkyl). In some embodiments, each R1 is independently selected from methyl ether, ethyl ether, propyl ether, butyl ether, pentyl ether, and hexyl ether.

[0049] In some embodiments, each R1 is independently -OH or O-(C1-C6 alkyl)-OH, provided that at least one R1 is OH and at least one R1 is O-(C1-C6 alkyl)-OH. In some embodiments, at least one R1 is -O-(C1-C6 alkyl)-OH. In some embodiments, each R1 is independently selected from hydroxymethyl ether, hydroxyethyl ether, hydroxypropyl ether, hydroxybutyl ether, hydroxypentyl ether, and hydroxyhexyl ether.

[0050] In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0051] In some embodiments, the cyclodextrin derivatives, such as sulfoalkyl ether cyclodextrins, alkylated cyclodextrins, or hydroxyalkyl ether cyclodextrins, may have an average degree of substitution (ADS) per cyclodextrin of 2-9, 4-8, 4-7.5, 4-7, 4-6.5, 4.5-8, 4.5-7.5, 4.5-7, 5-8, 5-7.5, 5-7, 5.5-8, 5.5-7.5, 5.5-7, 5.5-6.5, 6-8, 6-7.5, 6-7.1, 6.5-7.1, 6.2-6.9, or 6.5, with the remaining substituents being -H.

[0052] Some embodiments provide compositions containing a single type of cyclodextrin derivative having the structure shown in formula (I), the composition as a whole having an average of at least 1 to 3n+6 alkylsulfonic acid moieties per cyclodextrin molecule. The compositions described herein also include compositions containing cyclodextrin derivatives having narrow or broad ranges of substitution, and high or low degrees of substitution. These combinations can be optimized to provide cyclodextrins with specific properties, as needed.

[0053] Exemplary SAE-CD derivatives include SBE4-β-CD, SBE7-β-CD, SBE11-β-CD, SBE7-γ-CD, and SBE5-γ-CD, which correspond to SAE-CD derivatives of formula I where p=5, 5, 5, 6, and 6, respectively, and there are an average of 4, 7, 11, 7, and 5 sulfoalkyl ether substituents, respectively. Other exemplary SAE-CD derivatives include derivatives of SAEx-R-CD (Formula 2), where SAE is sulfomethyl ether (SME), sulfoethyl ether (SEE), sulfopropyl ether (SPE), sulfobutyl ether (SBE), sulfopentyl ether (SPtE), or sulfohexyl ether (SHE), x (average or specific degree of substitution) is 1-18, 1-21, or 1-24, R (the ring structure of the parent cyclodextrin) is α, β, or γ, respectively, and CD is a cyclodextrin. The SAE functional group includes a cationic counterion as disclosed herein or as commonly used in the pharmaceutical industry as a counterion for any acidic group. Since the SAE-CD is a polyanionic cyclodextrin, it can be provided in a variety of salt forms. Suitable counterions for the SAE functional group include cationic organic atoms or molecules, and cationic inorganic atoms or molecules. SAE-CD may contain a single type of counterion or a mixture of different counterions. The properties of SAE-CD can be modified by changing the type of counterion present. For example, a first salt form of SAE-CD may have a greater electrostatic charge than a different second salt form of SAE-CD. The calcium salt form has been found to be more electronegative than the sodium salt form. Similarly, an SAE-CD with a first degree of substitution may have a greater electrostatic charge than a second SAE-CD with a different degree of substitution.

[0054] Some embodiments provide compositions of an SAE-CD, the SAE-CD having the structure: is a sulfobutyl ether derivative of beta cyclodextrin (SBE-β-CD) having the formula:

[0055] [ka] In the formula, each R is independently -H or -(CH2)4-SO3Na, and the average degree of substitution with -(CH2)4-SO3Na groups is 6 to 7.1.

[0056] Methods for making SAE-CD derivatives vary, but generally include the general steps of sulfoalkylation and subsequent isolation. The chemical property profile of the SAE-CD is established during the sulfoalkylation process. For example, varying the reaction conditions during the sulfoalkylation process can vary the average degree of substitution and average regiochemical distribution of the sulfoalkyl groups in the SAE-CD. The alkyl chain length of the sulfoalkyl functional group is determined by the sulfoalkylating agent used. The use of a particular alkalizing agent during the alkylation process will result in the formation of a particular SAE-CD salt, unless an ion exchange step is performed after the sulfoalkylation.

[0057] In general, known processes for the sulfoalkylation step include, for example: 1) exposing the underivatized parent cyclodextrin to an alkylating agent, such as an alkyl sultone or haloalkylsulfonate, under alkaline conditions; 2) optionally adding additional alkalizing agent to the reaction environment to consume excess alkylating agent; and 3) neutralizing the reaction environment with an acidifying agent. Most literature processes carry out the sulfoalkylation step in an aqueous medium, although some references disclose the use of pyridine, dioxane, or DMSO as the reaction solvent for sulfoalkylation. The literature discloses the use of an alkalizing agent to facilitate the sulfoalkylation reaction.

[0058] After completion of the sulfoalkylation step, isolation and purification of the SAE-CD is carried out.

[0059] Several different processes have been reported for the isolation of SAE-CD following sulfoalkylation and neutralization. Generally, an aqueous liquid containing SAE-CD is dried to remove water and form a solid. The literature also contains methods for removing water from aqueous solutions containing SAE-CD. Various methods have been proposed for the preparation of SAE-CD derivatives. Such methods include conventional freeze drying, spray drying, oven drying, vacuum oven drying, rotary evaporation under reduced pressure, vacuum drying, or vacuum drum drying. See, for example, Ma (STP Pharma. Sciences (1999), 9(3), 261-266), CAPTISOL® (sulfobutyl ether beta-cyclodextrin sodium; Pharmaceutical Excipients 2004; Eds. RC Rowe, PJ Sheskey, SCOwen; Pharmaceutical Press and American Pharmaceutical Association, 2004), and other references on the preparation of SAE-CD derivatives.

[0060] Suitable methods for making the SAE-CD feedstock used in making the SAE-CD compositions for use herein are described in U.S. Pat. Nos. 5,376,645, 5,874,418, and 5,134,127 to Stella et al.; U.S. Pat. No. 3,426,011 to Parmerter et al.; Lammers et al. (Reel. Trav. C. Mm. Pays-Bas (1972), 91(6), 733-742; Staerke (1971), 23(5), 167-171); Qu et al. (J Inclusion Phenom. Macro. Chem., (2002), 43, 213-221); U.S. Pat. No. 5,241,059 to Yoshinaga; U.S. Pat. No. 6,153,746 to Shah; U.S. Pat. No. 6,153,746 to Stella et al. al., PCT Publication No. WO 2005 / 042584; Adam et al. (J. Med. Chem. (2002), 45, 1806-1816); Zhang et al., PCT Publication No. WO 01 / 40316; Tarver et al. (Bioorganic & Medicinal Chemistry (2002), 10, 1819-1827); Ma (STP Pharma. Sciences (1999), 9(3), 261-266); Jung et al. (J Chromat. 1996, 755, 81-88); and Luna et al. (Carbohydr. Res. 1997, 299, 103-110), the entire disclosures of which are incorporated herein by reference.

[0061] The SAE-CD raw material may be included in the liquid feed used in the fluidized bed spray drying process described in U.S. Patent No. 8,049,003, which is incorporated by reference for the purpose of making SAE-CD compositions by the fluidized bed spray drying process. Other methods for removing water from aqueous solutions containing SAE-CD may include conventional freeze drying, spray drying, oven drying, vacuum oven drying, rotary evaporation under reduced pressure, vacuum drying, or vacuum drum drying. See, for example, Ma (STP Pharma. Sciences (1999), 9(3), 261-266), CAPTISOL® (sulfobutyl ether beta-cyclodextrin sodium; Pharmaceutical Excipients 2004; Eds. RC Rowe, PJ Sheskey, SCOwen; Pharmaceutical Press and American Pharmaceutical Association, 2004), the entire contents of which are incorporated by reference herein, and other references regarding the preparation of SAE-CD derivatives.

[0062] The SAE-CD compositions described herein may include a combination of derivatized cyclodextrin (SAE-CD) and underivatized cyclodextrin. For example, the SAE-CD compositions may be made to include underivatized cyclodextrin in an amount of 0-50% by weight of the total cyclodextrin present. Exemplary embodiments of SAE-CD compositions include those that include 0-5%, 5-50% by weight, less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, or less than 50% underivatized cyclodextrin.

[0063] Compositions Containing Busulfan and Cyclodextrin Some embodiments relate to a pharmaceutical composition comprising a clear, aqueous solution comprising busulfan and a cyclodextrin.

[0064] In some embodiments, the concentration of busulfan is greater than about 4 mg / ml. In some embodiments, the concentration of busulfan is about 0.5 mg / ml. In some embodiments, the concentration of busulfan is about 0.55 mg / ml. In some embodiments, the concentration of busulfan is greater than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.6, 6, 6.5, 7, 7.5, or 8 mg / ml. In some embodiments, the concentration of busulfan is less than about 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 mg / ml. In some embodiments, the concentration of busulfan may be within a range from any lower limit of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.6, 6, 6.5, 7, 7.5, or 8 mg / ml to any upper limit of about 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2, including any subset therebetween. Some of the lower limits listed above are greater than some of the upper limits listed, but one of skill in the art will recognize that a selected subset will require the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, the concentration of busulfan may be within the range of about 1-10 mg / ml, about 2-8 mg / ml, about 3-6 mg / ml, about 0.2-4 mg / ml, about 0.2-3 mg / ml, about 0.3-3 mg / ml, about 0.5-2 mg / ml, or about 0.4-1 mg / ml.

[0065] In some embodiments, the molar ratio of cyclodextrin to busulfan is less than about 25, 22, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1. In some embodiments, the molar ratio of cyclodextrin to busulfan is less than about 9.1. In some embodiments, the molar ratio of cyclodextrin to busulfan is less than about 9. In some embodiments, the molar ratio of cyclodextrin to busulfan is less than about 8. In some embodiments, the molar ratio of cyclodextrin to busulfan is less than about 7. In some embodiments, the molar ratio of cyclodextrin to busulfan is less than about 6. In some embodiments, the molar ratio of cyclodextrin to busulfan is less than about 5. In some embodiments, the molar ratio of cyclodextrin to busulfan is about 3.1. In some embodiments, the molar ratio of cyclodextrin to busulfan is greater than about 2, 3, 4, 5, or 6. In some embodiments, the molar ratio of cyclodextrin to busulfan is greater than about 3. In some embodiments, the molar ratio of cyclodextrin to busulfan is in the range of about 3 to about 5.2. In some embodiments, the molar ratio of cyclodextrin to busulfan can be in the range of from a lower limit of about 2, 3, 4, 5, or 6 to an upper limit of about 25, 22, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1, including any subset therebetween. Some of the lower limits listed above are greater than some of the upper limits listed, but one of skill in the art will recognize that a selected subset will require the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, the molar ratio of cyclodextrin to busulfan is within the range of about 3 to about 10, about 3 to about 9, about 3 to about 7, or about 3 to about 5.

[0066] In some embodiments, the mass ratio of cyclodextrin to busulfan is about 4. In some embodiments, the weight ratio of cyclodextrin to busulfan is about 2.5. In some embodiments, the weight ratio of cyclodextrin to busulfan is about 67.5. In some embodiments, the weight ratio of cyclodextrin to busulfan is about 80. In some embodiments, the weight ratio of cyclodextrin to busulfan is less than about 80, 70, 67.5, 65, 60, 55, 50, 45, 42.5, or 40. In some embodiments, the weight ratio of cyclodextrin to busulfan can be within a range from a lower limit of about 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 80 to an upper limit of about 90, 80, 70, 67.5, 65, 60, 55, 50, 45, 42.5, or 40, including any subset therebetween. Some of the lower limits recited above are greater than some of the upper limits recited, but one of skill in the art will recognize that a select subset will require the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, the mass ratio of cyclodextrin to busulfan is within the range of about 40 to about 80, about 40 to about 60, or about 32 to about 54.

[0067] Some embodiments relate to a pharmaceutical composition comprising a clear, aqueous solution comprising busulfan and a sulfoalkyl ether cyclodextrin.

[0068] In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is in the range of about 3 to about 12. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is less than 9.1. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 9. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 8. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 7. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 6. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 5. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 5.3. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is about 3.1. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 25, 22, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is greater than about 2, 3, 4, 5, or 6. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is greater than about 3. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is within the range of about 3 to about 5.2. In some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan can be within the range from any of a lower limit of about 2, 3, 4, 5, or 6 to any of an upper limit of about 25, 22, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1, including any subset therebetween.Some of the lower limits recited above are greater than some of the upper limits recited, but one of skill in the art will recognize that a select subset will require the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, the molar ratio of sulfoalkyl ether cyclodextrin to busulfan is within the range of about 3 to about 10, about 3 to about 9, about 3 to about 7, or about 3 to about 5.

[0069] Some embodiments relate to a pharmaceutical composition comprising a solid comprising busulfan and a cyclodextrin, wherein at least about 25% of the busulfan in the composition is a sulfoalkyl ether. It is complexed with cyclodextrin. In some embodiments, the solid is water soluble.

[0070] In some embodiments, a majority of the busulfan in the composition is complexed with a sulfoalkyl ether cyclodextrin. In some embodiments, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the busulfan in the composition is complexed with a sulfoalkyl ether cyclodextrin. In some embodiments, less than 100%, 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the busulfan in the composition is complexed with a sulfoalkyl ether cyclodextrin. In some embodiments, the amount of busulfan complexed to a sulfoalkyl ether cyclodextrin in the composition may range from any lower limit of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, to any upper limit of 100%, 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20%, including any subset therebetween. Some of the lower limits listed above are greater than some of the upper limits listed, but one of skill in the art will recognize that a selected subset will require the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, the amount of busulfan complexed to cyclodextrin is within the range of about 20% to about 95%, about 50% to about 99%, about 80% to about 99%, about 90% to about 99%, or about 60% to about 100%.

[0071] In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is in the range of about 3 to about 12. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is in the range of about 3 to about 10. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is less than 12. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is less than 9.1. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is less than 9. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 8. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 7. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 6. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 5. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 5.3. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is about 3.1. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is less than about 25, 22, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is greater than about 2, 3, 4, 5, or 6.In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan can range from any of a lower limit of about 2, 3, 4, 5, or 6 to any of an upper limit of about 25, 22, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1, including any subset between these upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, but one of skill in the art will recognize that a selected subset requires the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is greater than about 3. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is within the range of about 3 to about 5.2. In some embodiments, the molar fraction ratio of sulfoalkyl ether cyclodextrin to busulfan is within the range of about 3 to about 10, about 3 to about 9, about 3 to about 7, or about 3 to about 5.

[0072] Some embodiments relate to a reconstituted solution obtained by adding a pharma- ceutically acceptable solvent to a composition described herein, wherein the concentration of busulfan is in the range of about 0.3 mg / ml to about 3 mg / ml.

[0073] In some embodiments, the mass ratio of busulfan to cyclodextrin is greater than about 0.01.

[0074] In some embodiments, the mass ratio of busulfan to cyclodextrin is greater than about 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.45, 0.48, or 0.50. In some embodiments, the mass ratio of busulfan to cyclodextrin is less than about 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.025, or 0.01. In some embodiments, the mass ratio of busulfan to cyclodextrin is about 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, The range may be from any lower limit of about 31, 0.32, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.45, 0.48, or 0.50 to any upper limit of about 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.025, or 0.01, including any subset therebetween. Some of the lower limits listed above are greater than some of the upper limits listed, but one of skill in the art will recognize that a selected subset will require the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, the mass ratio of busulfan to cyclodextrin is within the range of about 0.01 to about 5, about 0.1 to about 2, or about 0.5 to about 1.

[0075] Some embodiments relate to a sterile container comprising a composition described herein.

[0076] In some embodiments, the composition has a moisture content of less than 20%. In some embodiments, the composition has a moisture content of less than 50%, 40%, 30%, 25%, 20%, 10%, or 5%. In some embodiments, the composition has a moisture content of more than 0.1%, 1%, 5%, or 10%. In some embodiments, the composition has a moisture content in the range of about 0.1% to about 50%, 1% to about 30%, or about 5% to about 25%.

[0077] The compositions described herein may have an osmolality suitable for parenteral injection. In some embodiments, the osmolality of the composition is about 100, 110, 120, 130, 140, From the lower limit of any of 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 320, 340, 360, 380, or 400 mOsm to about 600, 500, 480, 460, 440, 420, 400, 390, 380, 370, 380, 490, 500, 600, 700, 750, 800, 850, 900, 950, 10 ... The range may be up to any of the upper limits of 60, 350, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 180, 160, 140, 120, or 100 mOsm, and may include any subset between these upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, but one of skill in the art will recognize that the selected subset requires the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, the composition has an osmolality in the range of about 150 mOsm to about 600 mOsm, about 200 mOsmol / L to about 400 mOsm, about 200 to about 320 mOsm, or 285 to about 310 mOsm. In more specific embodiments, the composition may have an osmolality in the range of about 221 to about 280 mOsm. In one embodiment, the osmolality is about 270 mOsm. In some embodiments, the composition may have an osmolality close to that of human plasma. In some embodiments, the osmolality of the composition is greater than 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 320, 340, 360, 380, or 400 mOsm. In some embodiments, the osmolality of the composition is less than 600, 500, 480, 460, 440, 420, 400, 390, 380, 370, 360, 350, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 180, 160, 140, 120, or 100 mOsm.

[0078] In some embodiments, the cyclodextrin is a sulfubutyl ether cyclodextrin. In some embodiments, the cyclodextrin is a hydroxypropyl beta cyclodextrin. In some embodiments, the cyclodextrin is an alpha cyclodextrin. In some embodiments, the cyclodextrin is a sulfubutyl butyl ether alpha cyclodextrin. In some embodiments, the cyclodextrin is a sulfubutyl butyl ether gamma cyclodextrin. In some embodiments, the cyclodextrin is a sulfubutyl ether beta cyclodextrin with an ADS of about 2. In some embodiments, the cyclodextrin is a sulfubutyl ether beta cyclodextrin with an ADS of about 6.5.

[0079] In some embodiments, the compositions described herein comprise less than 30% (w / w) dimethylacetamide, hi some embodiments, the compositions comprise less than about 90%, 80%, 70%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.1%, or 0.05% (w / w) dimethylacetamide. In some embodiments, the dimethylacetamide in the composition may range from any lower limit of about 0%, 0.0001%, 0.001%, or 0.01% to any upper limit of about 90%, 80%, 70%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.1%, or 0.05% (w / w), including any subset between these upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, but one of ordinary skill in the art will recognize that a selected subset requires the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, dimethylacetamide in the composition may be in the range of about 0% to about 1%, about 0.0001% to about 1%, or 0.001% to about 0.05%.

[0080] In some embodiments, the pharmaceutical compositions described herein are free of dimethylacetamide. In some embodiments, the pharmaceutical compositions described herein are substantially free of dimethylacetamide. In some embodiments, the amount of dimethylacetamide in the pharmaceutical compositions described herein is less than about 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.6%, 0.5%, 0.3%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% by weight based on the total weight of the composition.

[0081] In some embodiments, the compositions described herein are free of polyethylene glycol (PEG) (e.g., PEG 400). In some embodiments, the pharmaceutical compositions described herein are substantially free of PEG (e.g., PEG 400). In some embodiments, the amount of PEG (e.g., PEG 400) in the pharmaceutical compositions described herein is less than about 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.8%, 0.6%, 0.5%, 0.3%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.01% by weight based on the total weight of the composition.

[0082] The term "pharmaceutical acceptable carrier" or "pharmaceutical acceptable excipient" includes any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such media and agents for pharmaceutical active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various auxiliary agents, such as those commonly used in the art, may be included. Considerations for including various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, the entire contents of which are incorporated herein by reference.

[0083] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of compound suitable for administration in a single dose to an animal, preferably a mammalian subject, in accordance with good clinical practice. However, the creation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per treatment period. Such dosage forms are contemplated to be administered once, twice, three or more times per day, and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours) or as a continuous infusion, and may be administered more than once during the treatment period, although single administration is not specifically excluded. Those skilled in the art will recognize that the formulations do not specifically contemplate the entire treatment period, and such determination is left to those skilled in the art of treatment rather than formulation.

[0084] The compositions useful as described above may be in any of a variety of forms suitable for a variety of routes of administration, such as oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. In some embodiments, the compositions described herein may be made in the form of a solid (e.g., lyophilized powder) that can be reconstituted with an appropriate liquid prior to administration. In some embodiments, the compositions described herein may be in the form of a liquid ready for administration. Those skilled in the art will appreciate that oral and nasal compositions include compositions made using available methods that are administered by inhalation. In some embodiments, the compositions described herein may be administered by any suitable infusion device, portable device, or wearable device. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers known in the art may be used. Pharmaceutically acceptable carriers include, for example, liquid fillers, diluents, hydrotropies, surfactants, and encapsulating agents. Pharmaceutically active substances that do not substantially interfere with the inhibitory action of the compound acetaminophen may be included as desired. The carrier used with the compound is in an amount sufficient to provide a practical amount of substance for administration per unit dose of the compound. Techniques and compositions for making dosage forms that are useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0085] A variety of oral dosage forms may be used, including liquid forms, including aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavoring agents.

[0086] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are known in the art. Oral compositions include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for preparing such compositions are known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL, RC-591, tragacanth, and sodium alginate, typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components such as sweeteners, flavorings, and colorings disclosed above.

[0087] The compositions described herein may, if desired, contain other pharmacoactive ingredients.

[0088] Liquid compositions formulated for topical eye drop use are formulated so that they can be administered topically to the eye. Comfort can be maximized as much as possible, but in some cases, formulation considerations (e.g., drug stability) may require less than optimal comfort. If comfort cannot be maximized, the liquid can be formulated so that the patient can tolerate topical eye drop use. In addition, liquids acceptable for eye drop use may be packaged for single use or may contain preservatives to prevent contamination during multiple uses.

[0089] For eye drop applications, the solution or medicament is often prepared using saline solution as the main vehicle. The eye drop solution can preferably be maintained at a comfortable pH with an appropriate buffer system. The formulation may contain conventional pharma- ceutically acceptable preservatives, stabilizers, and surfactants.

[0090] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. A useful surfactant is, for example, Tween® 80. Similarly, a variety of useful vehicles may be used in the ophthalmic formulations disclosed herein. These vehicles may include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0091] Tonicity adjusting agents may be added as necessary or convenient, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerin, or any other tonicity adjusting agent acceptable for ophthalmic use.

[0092] Various buffers and means for adjusting pH may be used as long as the resulting preparation is acceptable for ophthalmic use. In many compositions, pH is 4 to 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these preparations as needed.

[0093] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0094] Another excipient component that may be included in the ophthalmic formulation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents may be used instead or in combination.

[0095] For topical use, creams, ointments, gels, solutions, suspensions, etc. containing the compositions disclosed herein are employed. Topical formulations may generally include a pharmaceutical carrier, cosolvent, emulsifier, permeation enhancer, preservative system, and emollient.

[0096] For intravenous or intramuscular administration, the compositions described herein may be dissolved or dispersed in a pharma- ceutically acceptable diluent, such as saline or dextrose solution. To achieve the desired pH, suitable excipients may be included, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. Thus, buffers, including acetate buffer, citrate buffer, phosphate buffer, and borate buffer, may be used as necessary to adjust the pH of these formulations. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde sulfoxylate, thiourea, and disodium edetate. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates, such as dextrose, mannitol, and dextran. Additional acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0097] Compositions for intravenous or intramuscular administration may be provided to the caregiver in one or more solid forms to be reconstituted immediately prior to administration with a suitable diluent, such as sterile water, saline, or aqueous dextrose. In other embodiments, the compositions are provided as a solution that is ready for parenteral administration. In yet other embodiments, the compositions are provided as a solution that is further diluted prior to administration. In embodiments that involve administering a combination of a composition described herein with another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0098] The actual dose of the active compositions described herein will depend on the particular composition and condition to be treated, and the selection of the appropriate dose is well within the knowledge of one of ordinary skill in the art. In some embodiments, the daily dose may be about 0.25 mg / kg body weight to about 120 mg / kg body weight or more, about 0.5 mg / kg or less to about 100 mg / kg body weight, about 1.0 mg / kg body weight to about 80 mg / kg body weight, or about 1.5 mg / kg body weight to about 75 mg / kg body weight. Thus, when administered to a 70 kg human, the dose ranges are about 17 mg to about 8000 mg per day, about 35 mg or less to about 7000 mg or more per day, about 70 mg to about 6000 mg per day, about 100 mg to about 5000 mg per day, or about 200 mg to about 3000 mg per day.

[0099] In some embodiments, the compositions described herein may be administered as an intravenous infusion over a period of 15 minutes. In some embodiments, the compositions described herein may be administered as an intravenous infusion over a period of 5 minutes to about 30 minutes. The compositions described herein may be administered as single or repeated doses.

[0100] In some embodiments, the compositions may be administered by subcutaneous infusion. In some embodiments, the compositions described herein may be administered by subcutaneous infusion in combination with Hylenex® recombinant.

[0101] In some embodiments, for adult and adolescent patients weighing 50 kg or more, the dose of the active compositions described herein may be 1000 mg every 6 hours, or 650 mg every 4 hours, up to a maximum of 4000 mg per day. In some embodiments, for adult and adolescent patients weighing 50 kg or more, the dose of the active compositions described herein may be in the range of about 500 mg to 1500 mg every 6 hours, or in the range of about 300 mg to about 1000 mg every 4 hours. In some embodiments, for adult and adolescent patients weighing 50 kg or more, the maximum dose per day may be in the range of about 2000 mg to about 6000 mg.

[0102] In some embodiments, for adult and adolescent patients weighing less than 50 kg, the dose of the active compositions described herein may be 15 mg / kg every 6 hours, or 12.5 mg / kg every 4 hours, up to a maximum of 75 mg / kg per day. In some embodiments, for adult and adolescent patients weighing less than 50 kg, the dose of the active compositions described herein may be in the range of about 10 mg / kg to about 20 mg / kg every 6 hours, or 8 mg / kg to about 15 mg / kg every 4 hours. In some embodiments, for adult and adolescent patients weighing less than 50 kg, the maximum dose per day may be in the range of about 50 mg / kg to about 100 mg / kg.

[0103] In some embodiments, for children 2 to 12 years of age, the dose of the active compositions described herein may be 15 mg / kg every 6 hours, or 12.5 mg / kg every 4 hours, up to a maximum of 75 mg / kg per day. In some embodiments, for children 2 to 12 years of age, the dose of the active compositions described herein may be in the range of about 10 mg / kg to about 20 mg / kg every 6 hours, or 8 mg / kg to about 15 mg / kg every 4 hours ..., up to a maximum of 75 mg / kg per day. The maximum dose may be in the range of about 50 mg / kg to about 100 mg / kg.

[0104] In some embodiments, the minimum dosing interval may be 4 hours. In some embodiments, the minimum dosing interval may be about 1 hour to 8 hours. In some embodiments, the minimum dosing interval may be 1, 2, 3, 4, 5, 6, 7, or 8 hours.

[0105] Method of preparation Some embodiments relate to a method of making a busulfan composition comprising: Mixing busulfan and organic solvent to obtain a clear solution; mixing the clear solution with cyclodextrin to obtain a first mixture; removing the solvent from the first mixture to obtain a second mixture; and freeze-drying the second mixture to obtain a busulfan composition; Includes.

[0106] A variety of solvents may be used to initially dissolve the busulfan. In some embodiments, the organic solvent is selected from dimethylacetamide, polyethylene glycol, acetone, and any combination thereof. In some embodiments, the solvent is acetone. In some embodiments, the solvent is dimethylacetamide. In some embodiments, the solvent is dimethylsulfoxide. In some embodiments, the solvent is polyethylene glycol. In some embodiments, the solvent is dimethylacetamide and polyethylene glycol. In some embodiments, the organic solvent is not dimethylacetamide. In some embodiments, the organic solvent is not polyethylene glycol.

[0107] Some embodiments relate to a method of making a busulfan composition comprising: mixing busulfan with an organic solvent selected from dimethylacetamide, acetone, and any combination thereof to obtain a clear solution; mixing the clear solution with cyclodextrin to obtain a first mixture; and drying the first mixture to obtain a busulfan composition; Includes.

[0108] Some embodiments relate to a method of making a busulfan composition comprising: Mix busulfan and acetone to obtain a clear solution; mixing the clear solution with cyclodextrin to obtain a first mixture; and drying the first mixture to obtain a busulfan composition; Includes.

[0109] In some embodiments, removing the organic solvent comprises removing the organic solvent by a rotary evaporator. In some embodiments, drying the first mixture further comprises lyophilizing. In some embodiments, drying the first mixture further comprises freeze-drying.

[0110] In some embodiments, combining a cyclodextrin with the clear busulfan solution comprises combining the clear busulfan solution with a cyclodextrin solution. In some embodiments, the cyclodextrin solution is added to the clear busulfan solution. In some embodiments, the cyclodextrin solution is an aqueous cyclodextrin solution.

[0111] In some embodiments, the methods described herein include combining a busulfan composition with a parenterally acceptable solvent to form a busulfan concentrate.

[0112] In some embodiments, the methods described herein include diluting the busulfan concentrate with a pharma- ceutically acceptable diluent.

[0113] In some embodiments, the parenterally acceptable solvent is selected from water, saline, a cyclodextrin solution, and any combination thereof. In some embodiments, the parenterally acceptable solvent is selected from water, saline, a cyclodextrin solution, and any combination thereof. In some embodiments, the parenterally acceptable solvent is a sugar solution such as lactose, glucose, and sucrose, starch such as corn starch and potato starch, pyrogen-free water, isotonic saline, and phosphate buffer solution. In some embodiments, the parenterally acceptable solvent is a cyclodextrin solution, and the cyclodextrin may be any cyclodextrin described herein, including any of the cyclodextrins or cyclodextrin derivatives listed in Tables A-D.

[0114] In some embodiments, the pharma- ceutically acceptable diluent is selected from water, saline, a cyclodextrin solution, and any combination thereof. In some embodiments, the pharma-ceutically acceptable diluent is selected from water, saline, a cyclodextrin solution, and any combination thereof. In some embodiments, the pharma-ceutically acceptable diluent is a sugar solution, such as lactose, glucose, and sucrose, starch, such as corn starch and potato starch, pyrogen-free water, isotonic saline, and phosphate buffer solution. In some embodiments, the pharma-ceutically acceptable diluent is a cyclodextrin solution, where the cyclodextrin may be any cyclodextrin described herein, including any of the cyclodextrins or cyclodextrin derivatives listed in Tables A-D.

[0115] In some embodiments, the second mixture is a clear solution.

[0116] In some embodiments, the parenterally acceptable solvent is a cyclodextrin solution. In some embodiments, the parenterally acceptable solvent is a sulfobutyl ether cyclodextrin solution. In some embodiments, the cyclodextrin solution has a concentration of greater than about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg / ml. In some embodiments, the cyclodextrin solution has a concentration of less than about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg / ml. In some embodiments, the cyclodextrin (e.g., sulfobutyl ether cyclodextrin) solution has a concentration that can range from a lower limit of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg / ml to an upper limit of about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg / ml, including any subset therebetween. Some of the lower limits listed above are greater than some of the upper limits listed, but one of skill in the art will recognize that a selected subset requires the selection of an upper limit that is greater than the selected lower limit. For example, in some embodiments, the cyclodextrin (e.g., sulfobutyl ether cyclodextrin) solution has a concentration in the range of about 10 to 500 mg / ml, about 50 to about 300 mg / ml, about 80 to about 200 mg / ml, or about 100 to 150 mg / ml.

[0117] Some embodiments relate to methods of combining busulfan with a sulfoalkyl ether cyclodextrin.

[0118] Treatment method Some embodiments relate to methods of treatment comprising reconstituting a pharmaceutical composition described herein and administering the reconstituted pharmaceutical composition to a subject in need thereof.

[0119] In some embodiments, reconstituting comprises adding a parenterally acceptable solvent to the pharmaceutical composition. In some embodiments, reconstituting comprises adding a pharma- ceutically acceptable diluent to the pharmaceutical composition. In some embodiments, the parenterally acceptable solvent or pharma- ceutically acceptable diluent is selected from water, saline, a cyclodextrin solution, and any combination thereof. In some embodiments, the parenterally acceptable solvent or pharma- ceutically acceptable diluent is a sugar solution such as lactose, glucose, and sucrose, starch such as corn starch and potato starch, pyrogen-free water, isotonic saline, and phosphate buffer solution. In some embodiments, the parenterally acceptable solvent or pharma- ceutically acceptable diluent is a cyclodextrin solution, and the cyclodextrin may be any cyclodextrin described herein, including any of the cyclodextrins or cyclodextrin derivatives listed in Tables A-D.

[0120] When the pharmaceutical compositions described herein are used to treat various diseases, they can provide better drug tolerance, higher drug exposure, longer duration of treatment, flexible handling, and improved stability compared to other commercially available compositions containing busulfan.

[0121] Some embodiments relate to methods of conditioning a subject for hematopoietic stem cell transplantation comprising administering to a subject in need thereof a composition described herein.

[0122] Some embodiments relate to a method of conditioning a subject for bone marrow transplantation, comprising administering to a subject in need thereof a composition as described herein. The method may further comprise the additional step of administering to the subject an immunosuppressant and / or an additional dose of T cell depleted bone marrow cells. The above method is also useful for treating hemoglobinopathies and / or preventing rejection of an organ or tissue transplant in a subject, as described herein.

[0123] Some embodiments relate to methods of treating leukemia, lymphoma, and myeloproliferative disorders comprising administering to a subject in need thereof a composition described herein. Cancer cells may be eradicated from the body by administering the busulfan-based compositions described herein. The busulfan compositions and methods of making the same described herein represent a novel and more effective tool for administering higher doses of therapeutic agents while reducing the risk of toxic solvents associated with the administered therapeutic agents.

[0124] In some embodiments, the composition is administered intravenously or intramuscularly. In some embodiments, the composition or a dilution thereof is administered as an intravenous drip. In some embodiments, the composition or a dilution thereof is administered as an intravenous push or bolus.

[0125] In some embodiments, the adult dose of busulfan is about 0.2, 0.5, or 10 mg / kg of body weight. In some embodiments, the adult dose is greater than about 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, or 1.4 mg / kg of body weight. In some embodiments, the adult dose is less than about 0.8, 1, 1.2, 1.4, 1.6, 1.8, or 2 mg / kg of body weight. In some embodiments, the adult dose of busulfan is about 0.2 to 2.0, about 0.4 to about 1.5, or about 0.6 to about 1 mg / kg of body weight. In some embodiments, the busulfan composition is administered intravenously via a central venous catheter as a 2-hour infusion every 6 hours for 4 consecutive days for a total of 16 doses.

[0126] Intravenous administration kit Some embodiments include kits comprising a cyclodextrin (e.g., a sulfoalkyl ether cyclodextrin) and busulfan. Some embodiments include kits comprising a cyclodextrin (e.g., a sulfoalkyl ether cyclodextrin) and busulfan, wherein at least a majority of the busulfan is complexed with the cyclodextrin. Some embodiments include kits comprising 1) a cyclodextrin (e.g., a sulfoalkyl ether cyclodextrin) and busulfan, and 2) a pharma- ceutically acceptable solvent or diluent for reconstituting a busulfan composition, wherein at least a majority of the busulfan is complexed with the cyclodextrin. In some embodiments, the kits are for use in parenteral administration. In some embodiments, the kits are for use in intravenous administration.

[0127] In one embodiment, busulfan and cyclodextrin, with the majority of the busulfan complexed with the cyclodextrin, are provided in a first sterile container. In some embodiments, a pharma- ceutically acceptable solvent used to reconstitute the busulfan solution is provided in a second sterile container. In some embodiments, the pharma-ceutically acceptable solvent is an aqueous cyclodextrin solution provided in a separate container. In the case of a solid for reconstitution, a composition containing busulfan and cyclodextrin is first made using the methods described herein and then lyophilized to a powder that is added to the container. In some embodiments, the solid is a sterile crystalline product. In other embodiments, the solid is a lyophilizate. Non-limiting examples of agents that aid in lyophilization include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. One embodiment includes a non-sterile solid that is irradiated either before or after introduction into the container.

[0128] In the case of liquids, the busulfan compositions described herein may be dissolved or dispersed in a diluent or pharma- ceutically acceptable solvent and ready for administration. In another embodiment, the solution or dispersion may be further diluted prior to administration. Some embodiments include providing the liquid in an IV bag. The liquid may be frozen to enhance stability.

[0129] In one embodiment, the container contains other ingredients such as a pH adjuster, a solubilizing agent, or a dispersing agent. Non-limiting examples of pH adjusters include NaOH, sodium carbonate, sodium acetate, HCl, and citric acid.

[0130] In alternative embodiments, the busulfan composition and the cyclodextrin to be used for reconstitution may be provided in a single sterile container. In some embodiments, the busulfan composition and the cyclodextrin to be used for reconstitution may be provided in separate containers. Each container may contain a solid, a solution, or a dispersion. In such embodiments, the two containers may be provided in a single package or may be provided separately. In one embodiment, the compositions described herein are provided as solids while the parenterally acceptable solvent (e.g., water, saline, and cyclodextrin solution) is provided as a solution ready for reconstitution. In one embodiment, the compositions described herein are provided as solids while the parenterally acceptable agent (e.g., cyclodextrin) is initially provided as a solid ready for reconstitution. In one such embodiment, a solution of the parenterally acceptable agent described herein is used as a diluent with the parenterally acceptable agent to reconstitute the other solid composition. EXAMPLES

[0131] Example 1. Phase solubility data for Captisol® containing busulfan The phase solubility of busulfan was studied in sulfobutylether-β-cyclodextrin (Captisol®) solutions and the results are shown in Figure 1. Busulfan was added to various Captisol® solutions and the mixtures were measured by HPLC to determine the amount of busulfan dissolved in solution after equilibrium was reached at room temperature. It was also found that busulfan solutions (1 mg / ml busulfan in 200 mg / ml Captisol® solution and 2 mg / ml busulfan in 400 mg / ml Captisol® solution) exhibited greater than 90% stability after the solutions were kept at ambient temperature for 3 days.

[0132] Example 2. Captisol®-containing Busulfan Formulation A busulfan formulation was made by first dissolving busulfan in an organic solvent (e.g., acetone) and then mixing it with an aqueous Captisol® solution. This mixture was then added to a rotary evaporator to remove the organic solvent. After removal of the acetone solvent, the solution remained clear. This solution was then lyophilized to remove all water and produce a freeze-dried Captisol®-containing busulfan powder. In one freeze-dried sample, a weight ratio of busulfan to Captisol was achieved of 4:170, meaning that the concentration of busulfan was about 40 mg and the Captisol® solution was about 1.7 g. The lyophilized busulfan formulation was then reconstituted and diluted with Captisol® solution (100-150 mg / ml) to obtain the infusion concentration. In one reconstituted sample, the busulfan powder quickly dissolved to form a clear solution with a busulfan concentration in the range of about 0.5 mg / ml to 2 mg / ml. During the reconstitution process, a 5 mg / ml solubilized busulfan solution was achieved with a lower Captisol® loading compared to directly mixing the busulfan with the Captisol® solution.

[0133] Example 3. Stability of Captisol®-containing Busulfan Formulations The stability of several busulfan solutions was studied over time, and Figure 2 shows the amount of precipitation for three busulfan compositions. A first busulfan composition was made using freeze-drying / lyophilization of a busulfan Captisol® solution followed by reconstitution of the lyophilized mixture with Captisol® solution, a second busulfan composition was made by mixing busulfan and Captisol® in a sodium chloride solution, and a third busulfan composition was Bulsulfex® (Otsuka Pharmaceuticals; Tokyo, Japan: each vial of BUSULFEX contains 60 mg (6 mg / mL) busulfan, which is dissolved in 3.3 mL of N,N-dimethylacetamide (DMA) and 6.7 mL of polyethylene glycol 400, NF). The stability data showed that the first and second Captisol®-containing busulfan compositions exhibited less precipitation than the Bulsulfex® samples, and that busulfan precipitation was delayed even further in the first busulfan formulation than in the second busulfan composition. Both the first and second busulfan compositions exhibited better stability than the Bulsulfex® samples, with the first busulfan composition made by freeze-drying followed by reconstitution with additional Captisol® exhibiting the greatest stability.

[0134] Example 4. Testing of Captisol®-containing Busulfan Formulations Busulfan stability was studied in several formulations at three different temperatures. The first busulfan formulation was made using freeze-drying / lyophilization of Busulfan Captisol® powder containing 60 mg busulfan and 5.25 g Captisol®, followed by reconstitution of the lyophilized mixture with Captisol® solution. The second busulfan formulation was made using freeze-drying / lyophilization of Busulfan Captisol® powder containing 60 mg busulfan and 5.25 g Captisol®, followed by reconstitution of the lyophilized mixture with saline diluent. The third busulfan composition was Bulsilvex® (Pierre Fabre Oncologie, Boulogne, France) reconstituted with 0.9% saline to a final busulfan concentration of 0.55 mg / ml. The container used for preparation was a PP syringe (Becton Dickinson, Franklin Lakes, NJ). The sample solution was divided into aliquots into smaller containers, so that the solution was maintained under the defined storage conditions throughout the evaluation period. At each of the storage temperatures, samples were processed and analyzed by HPLC-UV. Busulfan was detected by absorbance at 281 nm. In isocratic mode, the mobile phase consisted of acetonitrile (ACN), H2O, and trifluoroacetic acid (TFA) (ratio: 650 / 350 / 1, vol / vol / vol) was run through the system at a flow rate of 2 mL / min. At time zero (T0), the initial concentration (C0) of the active substance was 100%. The content for each analysis time was therefore determined based on C0.

[0135] FIG. 3A shows the stability of the first busulfan formulation at 2-8° C., 25° C., and 40° C., and the stability of the third busulfan formulation at 2-8° C. (RF) and 25° C.; FIG. 3B shows the stability of the second busulfan formulation at 2-8° C. (RF), 25° C., and 40° C., and the stability of the third busulfan formulation at 2-8° C. (RF) and 25° C. The stability data in both FIG. 3A and FIG. 3B show that Captisol®-containing busulfan compositions, including compositions reconstituted with Captisol® solution and saline solution, were more stable than the Bulsilvex® samples, which did not contain any Captisol®.

[0136] Example 5. Testing of Captisol®-containing Busulfan Formulations Patients received test doses of Captisol®-containing busulfan and IV Bulsulfex® (Otsuka Pharmaceuticals; Tokyo, Japan: each vial of BUSULFEX contains 60 mg (6 mg / mL) busulfan, dissolved in 3.3 mL of N,N-dimethylacetamide (DMA) and 6.7 mL of polyethylene glycol 400, NF) at 0.8 mg / kg, with the two drug products alternated after adequate washout. The PK of Captisol®-containing busulfan will be studied and compared to IV Bulsulfex® at the test doses. The safety and tolerability of high-dose Captisol®-containing busulfan will also be studied and compared to the IV Bulsulfex® sample.

[0137] Example 6. Dosage regimen experiment Patients with chemotherapy-sensitive relapsed or primary refractory lymphoma undergoing first autologous hematopoietic stem cell transplant receive a test dose of Captisol®-containing busulfan (0.8 mg / kg) IV as a 2-hour continuous infusion on one day between days -14 and -11. Busulfan exposure is determined as the area under the concentration-time curve (AUC) using six whole blood samples taken at defined intervals after the end of the infusion. Based on the test PK, the remaining busulfan dose is calculated to achieve a total AUC of 20,000 μM·min. One-quarter of this dose is administered as a 3-hour infusion on day -8, during which a second PK analysis is performed. The same daily dose of Bu is administered on days -7, -6, and -5, unless the PK results on day -8 indicate that the total AUC is outside the target ±20%. If the secondary PK results predict a total AUC less than 16000 μM min or greater than 24000 μM min, the busulfan infusion on days -6 and -5 will be modified. Etoposide 1.4 g / m 2 was administered as a 4-hour infusion on day -4, followed by cyclophosphamide 2.5 g / m on days -3 and -2. 2 Administered at 100 mg / day.

[0138] Six serial blood samples are collected after administration of the test dose (test PK) and on day -8 (confirmatory PK). Busulfan concentrations are measured to determine busulfan exposure as AUC using WinNonlin software and to recommend doses based on individualized PK. The target daily AUC over the course of the conditioning regimen is calculated as (20000 μM·min-test PK AUC) / 4. The conditioning regimen daily dose is calculated as (test PK dose / study PK AUC)*target daily AUC.

Claims

[Claim 1] 1. A pharmaceutical composition comprising: Busulfan; and Cyclodextrin, wherein at least 25% of the busulfan in the composition is complexed with the cyclodextrin; The pharmaceutical composition, wherein the cyclodextrin is a sulfoalkyl ether cyclodextrin.

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