RU2787621C2 - Composition containing cyclodextrin and busulfan - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: pharmaceutical compositions are described, containing busulfan and cyclodextrin. The composition may include busulfan and cyclodextrin in a transparent aqueous solution. A method for the production of a busulfan composition and a method for the use of a composition are also described.

EFFECT: invention provides a stable composition with a higher busulfan load.

41 cl, 3 dwg, 4 tbl, 4 ex

Description

INCLUSION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application No. 62/500,970, filed May 3, 2017, the contents of which are incorporated herein by reference in their entirety.

Technical field

[0002] The present invention relates to formulations containing busulfan and sulfoalkyl ether cyclodextrin, a method for their preparation and a method for their use.

State of the art

[0003] Busulfan [1,4-bis-(methanesulfonoxy)butane], is an alkylating agent widely used for its antitumor properties, which 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 (including significant gastric irritation, nausea, and vomiting) mean that oral dosage forms exhibit significant variability in bioavailability. In addition, the drug is rapidly metabolized in the liver and may cause marked hepatotoxicity, which may be a dosage limiting factor in high dose regimens. Certain diluents used to dissolve busulfan can cause liver damage and compromise long-term treatment goals and the patient's quality of life.

SUMMARY OF THE INVENTION

[0004] Some implementation options relate to a pharmaceutical composition containing a solid that contains: busulfan; and cyclodextrin; where at least 25% of busulfan in the composition forms a complex with cyclodextrin.

[0005] Some implementation options relate to a pharmaceutical composition containing a clear aqueous solution that includes busulfan, where the concentration of busulfan is from about 0.3 mg/ml to about 3 mg/ml; and cyclodextrin, where the molar ratio of cyclodextrin to busulfan is less than 12.

[0006] Some implementation options relate to a pharmaceutical composition containing a clear aqueous solution that contains busulfan; and sulfoalkyl ether cyclodextrin.

[0007] Some embodiments relate to a reconstituted solution obtained by adding a pharmaceutically acceptable solvent to the composition described herein.

[0008] Some embodiments refer to a sterilized container containing the composition described herein.

[0009] Some embodiments relate to a method for preparing a busulfan composition, including:

combining busulfan and an organic solvent to obtain a clear solution;

combining the clear solution with the cyclodextrin to form a first mixture; and

drying the first mixture to obtain a busulfan composition.

[0010] Some implementation options relate to a method of treatment, including; restoring the pharmaceutical composition described herein; and administering the reconstituted pharmaceutical composition to a subject in need thereof.

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

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

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

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 illustrates the results of a phase solubility study of busulfan in sulfoalkylether-β-cyclodextrin solutions.

[0015] Figure 2 illustrates the results of a stability study using three busulfan formulations.

[0016] Figure 3A illustrates the stability of the first busulfan formulation at 2-8°C, 25°C and 40°C, as well as the third busulfan formulation at 2-8°C (RT) and 25°C; and Figure 3B shows the stability of the second busulfan formulation at 2-8°C (RT), 25°C and 40°C and the third busulfan formulation at 2-8°C (RT) and 25°C.

DETAILED DESCRIPTION

[0017] The term "pharmaceutically acceptable cation" refers to cations that retain the biological efficacy and properties of the compound and are not biologically or otherwise undesirable for use in a pharmaceutical formulation. Examples of cations include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; especially preferred are the ammonium, potassium, sodium, calcium and magnesium cations. Other types of cations may include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such cations are known in the art as described in WO 87/05297 by Johnston et al., published September 11, 1987 (incorporated herein by reference in its entirety).

[0018] The term "pharmaceutically acceptable salt" refers to salts that retain the biological efficacy and properties of compounds according to preferred embodiments and that are not biologically or otherwise undesirable. In many instances, compounds according to preferred embodiments are capable of forming acidic and/or basic salts due to the presence of amino and/or carboxyl groups or the like. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids 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; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts may 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, especially such as isopropylamine, trimethylamine, diethylamine , triethylamine, tripropylamine and ethanolamine. Many such salts are known in the art, as described in International Publication 87/05297, Johnston et al., published September 11, 1987 (incorporated herein by reference).

[0019] The term "pharmaceutically acceptable solvent" as used herein means one or more compatible solid or liquid excipients, diluents or encapsulating agents that are suitable for administration to a mammal. The term "compatible" or "acceptable", as used herein, means that the components of the composition are capable of being mixed with the target compound and with each other, such that no interaction occurs that significantly reduces the pharmaceutical effectiveness of the composition in cases of normal use. Pharmaceutically acceptable carriers should, of course, be of sufficiently high purity and low enough toxicity to be suitable for administration, preferably to the animal, preferably mammal, to be treated.

[0020] Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are cyclodextrins (eg 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 tweens; wetting agents such as sodium lauryl sulfate; dyes; flavors; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0021] As used herein, "most busulfan" refers to at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% busulfan in the composition.

[0022] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (ie contains no double or triple bonds). The alkyl group may contain from 1 to 20 carbon atoms (whenever encountered herein, a numerical range such as "1 to 20" refers to each integer in that range; for example, "1 to 20 carbon atoms "means that an alkyl group may consist of 1 carbon, 2 carbons, 3 carbons, etc., up to and including 20 carbons, although this definition also covers the term "alkyl" where no numerical range is indicated) . The alkyl group may also 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 referred to as "C _1-4 alkyl" or similar designations. By way of example only, "C _1-4 alkyl" means that the alkyl chain contains from one to four carbon atoms, i. e. the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0023] A "sulfonyl" group refers to a "-SO ₂ R" group in which R is selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _{6 -10} aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl as defined herein.

[0024] As used herein, "subject" means a non-human human or mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or a bird, such as a chicken, and any other vertebrate or invertebrate.

[0025] The term "mammal" is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, higher apes, lower apes) and humans, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs or the like.

[0026] As used herein, "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent that is effective to reduce, to some extent, or reduce the likelihood of one or more symptoms of a disease or condition, and includes curing the disease or condition. "Cure" means that the symptoms of the disease or condition are eliminated; however, some long-term or permanent effects may exist even after treatment (eg extensive tissue damage).

[0027] As used herein, the term "treat", "treatment" or "treatment" refers to the administration of a pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet have symptoms of a disease or condition, but who is susceptible to or otherwise at risk for a particular disease or condition, whereby treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to providing treatment to a subject already suffering from a disease or condition.

[0028] The compositions and methods described herein may be useful in reducing or eliminating the amount of a toxic solvent such as N,N-dimethylacetamide (DMA) and/or a non-aqueous solvent such as PEG in busulfan. The method and compositions described herein can result in a higher drug load requiring relatively less cyclodextrin a or cyclodextrin derivative. The superior properties of the method and composition described herein help to achieve improved drug tolerance, better drug stability, higher drug exposure, longer duration of therapy, as well as more options with flexible regulation and improved stability.

[0029] The compositions and methods described herein provide high dose parenteral therapy with busulfan for the treatment of a variety of diseases while addressing the problems of toxic solvent usage and busulfan instability associated with existing busulfan formulations. The busulfan formulation described herein exhibits less drug precipitation over time compared to other commercially available busulfan formulations. The present technology also provides an opportunity for expanded use in the pediatric population due to reduced solvent toxicity.

Niklo dextrin

[0030] As used herein, the term “cyclodextrin” refers to α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or their respective derivatives, including derivatives in which one or more hydroxyl groups on the core of the cyclodextrin are replaced by an alkyl ether, hydroxyalkyl ether, or sufloalkyl ether . Examples of a cyclodextrin derivative may 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 ester of β-cyclodextrin.

[0031] Some exemplary sulfoalkyl ether (SAE)-CD derivatives include:

where x denotes the average degree of substitution. In some embodiments, the alkylated cyclodextrins are formed as salts.

[0032] Various embodiments of the sulfoalkyl ether cyclodextrin 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 sulfoalkylthio and sulfoalkylthioalkyl ether derivatives such as octakis-(S-sulfopropyl)-octathio-γ-cyclodextrin, octakis-O-[3-[(2-sulfoethyl)thio]propyl]- β-cyclodextrin] and octakis-S-(2-sulfoethyl)-octathio-γ-cyclodextrin.

[0033] According to some embodiments, the alkylated cyclodextrin composition of the present invention is a sulfoalkyl ether β cyclodextrin composition having an ADS of 2 to 9, 4 to 8, 4 to 7.5, 4 to 7, 4 to 6.5 , 4.5 to 8, 4.5 to 7.5, 4.5 to 7, 5 to 8, 5 to 7.5, 5 to 7, 5.5 to 8, 5, 5 to 7.5, 5.5 to 7, 5.5 to 6.5, 6 to 8, 6 to 7.5, 6 to 7.1, 6.5 to 7.1, from 6.2 to 6.9, or 6.5 per alkylated cyclodextrin, and the remaining substituents are -H.

[0034] Some exemplary alkylethercyclodextrin (AE-CD) derivatives include:

[0035] where ME is methyl ether, EE is ethyl ether, PE is propyl ether, BE is butyl ether, PtE is pentylethyl, HE is hexyl ether, and y is medium substitution.

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

[0037] where HME is hydroxymethyl ether, HEE is hydroxyethyl ether, HPE is hydroxypropyl ether, HBE is hydroxybutyl ether, HPtE is hydroxypentyl ether, HHE is hydroxyhexyl ether, and z is medium substitution.

[0038] Alkylated cyclodextrin may include SAE-CD, HAE-CD, SAE-HAE-CD, HANE-CD, HAE-AE-CD, HAE-SAE-CD, AE-CD, SAE-AE-CD, neutral cyclodextrin, анионный циклодекстрин, катионный циклодекстрин, галоген-дериватизированный циклодекстрин, амино-дериватизированный циклодекстрин, нитрил-дериватизированный циклодекстрин, альдегид-дериватизированный циклодекстрин, карбоксилат-дериватизированный циклодекстрин, сульфат-дериватизированный циклодекстрин, сульфонат-дериватизированный циклодекстрин, меркапто-дериватизированный циклодекстрин, алкиламино-дериватизированный циклодекстрин or succinyl-derivatized cyclodextrin.

[0039] Some exemplary cyclodextrin mixed ether derivatives include.

[0040] As used herein, the terms "cyclodextrin sulfoalkyl ether" and "SAE-CD" refer to a cyclodextrin derivative containing a sulfoalkyl ether substituent such as (C _2-6 alkylene)-SO ₃ ^- . The sulfoalkyl derivative of the cyclodextrin may be a single derivative or a mixture of derivatives. Because cyclodextrin derivatives contain sulfonyl groups, they can be charged. The sulfoalkyl ester of the cyclodextrin may either be substituted on at least one of the primary hydroxyl groups of the cyclodextrin or be substituted on both the primary hydroxyl groups and the hydroxyl group at the 3-position. Substitution in position 2 is also possible. Examples of the sulfoalkyl ester of cyclodextrin include sulfobutyl ether of β-cyclodextrin.

[0041] In some embodiments, the cyclodextrin is a compound of formula 1:

or a pharmaceutically acceptable salt thereof, where:

p is 4, 5 or 6 and each R ₁ is selected from -OH or -O-(C ₁ -C ₈ alkylene)-SO ₃ T, and

each T is independently hydrogen or a pharmaceutically acceptable cation,

with the proviso that at least one R ₁ is —OH.

[0042] In some embodiments, each R ₁ is independently -OH or -O-(C ₁ -C ₈ alkylene)-SO ₃ T, provided that at least one R ₁ is OH and at least one R ₁ is -O-(C ₁ -C ₈ alkylene)-SO ₃ T, where T is hydrogen or a pharmaceutically acceptable cation. In some embodiments, at least one R ₁ is independently -OH or -O-(C _1-4 alkylene)-SO ₃ T. In some embodiments, at least one R ₁ is independently -O-(CH ₂ )gSO ₃ T, where g is 2 to 6 or 2 to 4. In some embodiments, at least one R ₁ is independently -OCH ₂ CH ₂ CH ₂ SO ₃ T or -OCH ₂ CH ₂ CH ₂ CH ₂ SO ₃ T. In some embodiments, at least one R ₁ is —OCH ₂ CH ₂ CH ₂ —OH. In some embodiments, each R ₁ is independently -OH or O-(C ₁ -C ₆ alkyl)-OH, provided that at least one R ₁ is O-(C ₁ -C ₆ 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 metal, alkaline earth metal, ammonium ions, and amine cations, and combinations thereof. In some embodiments, each T is independently selected from Li ⁺ , Na ⁺ , K ⁺ , Ca ⁺² , Mg ⁺² , amine, and any combination thereof. In some embodiments, each T is independently an amine cation selected from (C ₁ -C ₆ )-alkylamines, piperidine, pyrazine, (C ₁ -C ₆ )-alkanolamine, ethylenediamine, and (C ₄ -C ₈ )-cycloalkanolamine.

[0043] In some embodiments, each R ₁ is independently -OH or -O-(C ₁ -C ₈ alkyl), provided that at least one R ₁ is OH and at least one R ₁ is -O-(C ₁ -C ₈ alkyl). In some embodiments, each R ₁ is independently selected from methyl ether, ethyl ether, propyl ether, butyl ether, pentyl ether, and hexyl ether.

[0044] In some embodiments, each R ₁ is independently -OH or O-(C ₁ -C ₆ alkyl)-OH, provided that at least one R ₁ is OH and at least one R ₁ is is O-(C ₁ -C ₆ alkyl)-OH. In some embodiments, at least one R ₁ is -O-(C ₁ -C ₆ alkyl)-OH. In some embodiments, each R ₁ is independently selected from hydroxymethyl ether, hydroxyethyl ether, hydroxypropyl ether, hydroxybutyl ether, hydroxypentyl ether, and hydroxyhexyl ether.

[0045] In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6.

[0046] In some embodiments, a cyclodextrin derivative, such as a sulfoalkyl ether cyclodextrin, an alkylated cyclodextrin, or a hydroxyalkyl ether cyclodextrin, may have an average degree of substitution (ADS) of 2 to 9, 4 to 8, 4 to 7.5, 4 up to 7, from 4 to 6.5, from 4.5 to 8, from 4.5 to 7.5, from 4.5 to 7, from 5 to 8, from 5 to 7.5, from 5 to 7, 5.5 to 8, 5.5 to 7.5, 5.5 to 7, 5.5 to 6.5, 6 to 8, 6 to 7.5, 6 to 7.1 , 6.5 to 7.1, 6.2 to 6.9, or 6.5 per cyclodextrin, and the remaining substituents are -H.

[0047] According to some embodiments, compositions are provided containing a single kind of cyclodextrin derivative having the structure represented in formula (I), where the composition as a whole contains an average of at least 1 to 3n + 6 alkylsulfonic acid residues per cyclodextrin molecule. The compositions described herein also include compositions containing cyclodextrin derivatives having a narrow or wide range of degrees of substitution and a high or low degree of substitution. These combinations can be optimized as necessary to obtain cyclodextrins having specific properties.

[0048] 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 on average 4, 7, 11, 7 and 5 sulfoalkyl ether substituents are present, respectively. Other exemplary SAE-CD derivatives include those of formula 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 (ring structure of the original cyclodextrin) is α, β or γ, respectively; and CD is cyclodextrin. The SAE functional group includes a cationic counterion as described herein, or a group commonly used in the pharmaceutical industry as a counterion to any acidic group. Since SAE-CD is a polyanionic cyclodextrin, it can be presented in various salt forms. Suitable counterions for the SAE functional group(s) include cationic organic atoms or molecules and cationic inorganic atoms or molecules. SAE-CD may include one type of counterion or a mixture of different counterions. The properties of SAE-CD can be changed by changing the type of counterion present. For example, a first salt form of SAE-CD may have a higher electrostatic charge than another 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 having a first degree of substitution may have a higher electrostatic charge than a second SAE-CD having a different degree of substitution.

[0049] In some embodiments, SAE-CD compositions are provided wherein SAE-CD is a beta-cyclodextrin sulfobutyl ether (SBE-β-CD) derivative having the following structure:

where each R is independently -H or -(CH ₂ ) ₄ -SO ₃ Na and the average degree of substitution with groups -(CH ₂ ) ₄ -SO ₃ Na is from 6 to 7.1.

[0050] SAE-CD derivatization methods vary, but generally involve general sulfoalkylation steps followed by isolation. The chemistry profile of SAE-CD is established at the sulfoalkylation step. For example, changing the reaction conditions during sulfoalkylation can change the average degree of substitution and the average regiochemical distribution of sulfoalkyl groups in SAE-CD. The alkyl chain length of the sulfoalkyl functional group is determined according to the sulfoalkylating agent used. Also, the use of a particular alkalizing agent during the alkylation may result in the formation of a particular SAE-CD salt, unless the ion exchange step was performed after the sulfoalkylation.

[0051] In general, known sulfoalkylation step processes include, for example: 1) exposing the underivatized starting cyclodextrin to an alkylating agent under alkaline conditions, such as an alkyl sultone or haloalkyl sulfonate, 2) optionally adding an additional alkalizing agent to the reaction medium to consume excess alkylating agent; and 3) neutralizing the reaction medium with an acidifying agent. The vast majority of the processes described in the literature include carrying out the stage of sulfoalkylation in aqueous media; however, some references disclose the use of pyridine, dioxane, or DMSO as the reaction solvent for the sulfoalkylation. The literature describes the use of an alkalizing agent to accelerate the sulfoalkylation reaction.

[0052] At the end of the sulfoalkylation step, SAE-CD is isolated and purified.

[0053] Several different processes for isolating SAE-CD after sulfoalkylation and neutralization have been described. In general, an aqueous liquid containing SAE-CD is dried to remove water to form a solid. Various methods have been proposed in the literature for removing water from an aqueous solution containing SAE-CD. Such methods include conventional freeze drying, spray drying, oven drying, vacuum oven drying, reduced pressure rotary evaporation, vacuum drying or vacuum drum drying. See, for example, Ma (S.T.P. Pharma. Sciences (1999), 9(3), 261-266), CAPTISOL® (sodium beta-cyclodextrin sulfobutyl ether; Pharmaceutical Excipients 2004; Eds. R.C. Rowe, P.J. Sheskey, S.C. Owen; Pharmaceutical Press and American Pharmaceutical Association, 2004) and other references regarding the derivatization of SAE-CD.

[0054] Suitable methods for preparing a SAE-CD starting material for preparing an SAE-CD composition for use as described herein are disclosed in US Pat. U.S. Pat. No. 3,426,011 to Parmerter et al.; Lammers et al. (Reel. Trav. CMm. 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); US patent No. 5244059 issued to Yoshinaga; US Pat. No. 6,153,746 to Shah; PCT International Publication No. WO 2005/042584 issued by Stella et al; Adam et al. (J. Med. Chem. (2002), 45, 1806-1816); PCT International Publication No. WO 01/40316 to Zhang et al.; Tarver et al. (Bioorganic & Medicinal Chemistry (2002), 10, 1819-1827); Ma (S.T.P. 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 full descriptions of which are incorporated herein by reference.

[0055] The SAE-CD starting material can be included in the liquid feed used in the fluid bed spray drying process as described in US Pat. layer. Other methods for removing water from an aqueous solution containing SAE-CD may include conventional freeze drying, spray drying, oven drying, vacuum oven drying, reduced pressure rotary evaporation, vacuum drying, or vacuum tumble drying. See, e.g., Ma (S.T.P. Pharma. Sciences (1999), 9(3), 261-266), CAPTISOL® (sodium beta-cyclodextrin sulfobutyl ether; Pharmaceutical Excipients 2004; Eds. R.C. Rowe, P.J. Sheskey, S.C. Owen; Pharmaceutical Press and American Pharmaceutical Association, 2004), which is incorporated herein by reference in its entirety, and other references relating to derivatization of SAE-CD.

[0056] The SAE-CD composition described herein may also include a combination of a derivatized cyclodextrin (SAE-CD) and a non-derivatized cyclodextrin. For example, the composition of SAE-CD can be obtained so as to include non-derivatized cyclodextrin in an amount of from 0 to less than 50 wt. %. of the total amount of cyclodextrin present. Typical embodiments of SAE-CD compositions include compositions that contain 0-5 wt. %, 5-50 wt. %, less than 5%, less than 10%, less than 20%, less than 30%, less than 40% or less than 50% of non-derivatized cyclodextrin.

Compositions containing busulfan and cyclodextrin

[0057] Some embodiments relate to a pharmaceutical composition comprising a clear aqueous solution that contains busulfan; and cyclodextrin.

[0058] 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 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 up to any upper limit of approx. 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 and covers any subset between the upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, the concentration of busulfan may be 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.

[0059] 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 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 from about 3 to about 5 ,2. In some embodiments, the molar ratio of cyclodextrin to busulfan can range from any lower limit of about 2, 3, 4, 5, or 6 to any 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 and covers any subset between the upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, the molar ratio of cyclodextrin to busulfan is from about 3 to about 10, from about 3 to about 9, from about 3 to about 7, or from about 3 to about 5.

[0060] In some embodiments, the weight ratio of cyclodextrin to busulfan is about 42.5. 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. According to in some embodiments, the weight ratio of cyclodextrin to busulfan may be from any lower limit of about 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 80 to any upper limit of about 90, 80, 70 , 67.5, 65, 60, 55, 50, 45, 42.5 or 40 and covers any subset between the upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, the weight ratio of cyclodextrin to busulfan is from about 40 to about 80, from about 40 to about 60, or from about 32 to about 54.

[0061] Some implementation options relate to a pharmaceutical composition containing a clear aqueous solution that includes busulfan; and sulfoalkyl ether cyclodextrin.

[0062] In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is from about 3 to about 12. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is less than 9.1. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is less than about 9. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is less than about 8. In some embodiments, the cyclodextrin sulfoalkyl ether to busulfan molar ratio is less than about 7. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is less than about 7. In some embodiments, in embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is less than about 6. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is less than about 5. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is less than about 5.3. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is about 3.1. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether 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 sulfoalkyl ether to busulfan is greater than about 2, 3, 4, 5, or 6. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is greater than about 3. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is from about 3 to about 5.2. In some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan can range from any lower limit of about 2, 3, 4, 5, or 6 to any 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 and covers any subset between the upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, the molar ratio of cyclodextrin sulfoalkyl ether to busulfan is from about 3 to about 10, from about 3 to about 9, from about 3 to about 7, or from about 3 to about 5.

[0063] Some embodiments relate to a pharmaceutical composition comprising a solid that contains busulfan; and cyclodextrin; wherein at least about 25% of the busulfan in the composition forms a complex with a sulfoalkyl ester of the cyclodextrin. In some embodiments, the solid is water soluble.

[0064] In some embodiments, most of the busulfan in the composition is complexed with the sulfoalkyl ester of the 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 busulfan in the composition forms a complex with the cyclodextrin sulfoalkyl ether. 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% busulfan in the composition forms a complex with the cyclodextrin sulfoalkyl ether. In some embodiments, the amount of busulfan in the composition that forms a complex with the sulfoalkyl ester of the cyclodextrin can 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% up to any upper limit of 100%, 99%, 95%, 90%, 85% , 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, or 20%, and covers any subset between the upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, the amount of busulfan complexed with the cyclodextrin is from about 20% to about 95%, from about 50% to about 99%, from about 80% to about 99%, from about 90% to about 99%. % or from about 60% to about 100%.

[0065] In some embodiments, the mole fraction ratio of cyclodextrin sulfoalkyl ether to busulfan is from about 3 to about 12. In some embodiments, the mole fraction ratio of cyclodextrin sulfoalkyl ether to busulfan is from about 3 to about 10. In some embodiments, the mole fraction ratio cyclodextrin sulfoalkyl ether to busulfan is less than 12. In some embodiments, the molar fraction ratio of cyclodextrin sulfoalkyl ether to busulfan is less than 9.1. In some embodiments, the cyclodextrin sulfoalkyl ether to busulfan mole fraction ratio is less than 9. In some embodiments, the cyclodextrin sulfoalkyl ether to busulfan mole fraction ratio is less than about 8. In some embodiments, the cyclodextrin sulfoalkyl ether mole fraction to busulfan ratio is less than about 7. In some embodiments, the mole fraction ratio of cyclodextrin sulfoalkyl ether to busulfan is less than about 6. In some embodiments, the ratio of mole fraction of cyclodextrin sulfoalkyl ether to busulfan is less than about 5. In some embodiments, the ratio of mole fraction of cyclodextrin sulfoalkyl ether to busulfan is less than about 5 ,3. In some embodiments, the mole fraction ratio of cyclodextrin sulfoalkyl ether to busulfan is about 3.1. In some embodiments, the mole fraction ratio of cyclodextrin sulfoalkyl ether 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 mole fraction ratio of cyclodextrin sulfoalkyl ether to busulfan is greater than about 2, 3, 4, 5, or 6. In some embodiments, the mole fraction ratio of cyclodextrin sulfoalkyl ether to busulfan can be from any lower limit of about 2, 3, 4, 5 or 6 to any 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 and covers any subset between the upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, the mole fraction ratio of cyclodextrin sulfoalkyl ether to busulfan is greater than about 3. In some embodiments, the mole fraction ratio of cyclodextrin sulfoalkyl ether to busulfan is from about 3 to about 5.2. In some embodiments, the mole fraction ratio of cyclodextrin sulfoalkyl ether to busulfan is from about 3 to about 10, from about 3 to about 9, from about 3 to about 7, or from about 3 to about 5.

[0066] Some embodiments relate to a reconstituted solution obtained by adding a pharmaceutically acceptable solvent to the composition described herein, where the concentration of busulfan is from about 0.3 mg/ml to about 3 mg/ml.

[0067] In some embodiments, the weight ratio of busulfan to cyclodextrin is greater than about 0.01.

[0068] In some embodiments, the weight 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 weight 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 weight ratio of busulfan to cyclodextrin may be from any lower limit of 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 up 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 and covers any subset between the upper and lower limits . Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, the weight ratio of busulfan to cyclodextrin is from about 0.01 to about 5, from about 0.1 to about 2, or from about 0.5 to about 1.

[0069] Some embodiments refer to a sterilized container containing the composition described herein.

[0070] 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 greater than 0.1%, 1%, 5%, or 10%. In some embodiments, the composition has a moisture content in the range of from about 0.1% to about 50%, from 1% to about 30%, or from about 5% to about 25%.

[0071] The composition described herein may have an osmolarity suitable for parenteral administration. In some embodiments, the osmolarity of the composition may be from any lower limit of about 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 up to any upper limit of about 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 and covers any subset between the upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, the composition has an osmolarity ranging from about 150 mOsm to about 600 mOsm, from about 200 mOsm/L to about 400 mOsm, from about 200 to about 320 mOsm, or from 285 to about 310 mOsm. In more specific embodiments, the composition may have an osmolarity in the range of about 221 to about 280 mOsm. In one embodiment, the osmolarity is about 270 mOsm. In some embodiments, the composition may have an osmolarity close to that of human plasma. In some embodiments, the osmolarity 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 osmolarity 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.

[0072] In some embodiments, the cyclodextrin is a sulfobutyl ether cyclodextrin. In some embodiments, the cyclodextrin is hydroxypropyl betacyclodextrin. In some embodiments, the cyclodextrin is alphacyclodextrin. In some embodiments, the cyclodextrin is a sulfobutyl ether of alphacyclodextrin. In some embodiments, the cyclodextrin is gammacyclodextrin sulfobutyl ether. In some embodiments, the cyclodextrin is a betacyclodextrin sulfobutyl ether having an ADS of about 2. In some embodiments, the cyclodextrin is a betacyclodextrin sulfobutyl ether having an ADS of about 6.5.

[0073] In some embodiments, the composition described herein includes less than 30% (w/w) dimethylacetamide. In some embodiments, the composition comprises 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 can 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%, 0.05% (wt./wt.) and covers any subset between the upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, dimethylacetamide in the composition can be from about 0% to about 1%, from about 0.0001% to about 1%, or from 0.001% to about 0.05%.

[0074] In some embodiments, the pharmaceutical composition described herein does not contain dimethylacetamide. In some embodiments, the pharmaceutical composition described herein is substantially free of dimethylacetamide. In some embodiments, the amount of dimethylacetamide in a pharmaceutical composition 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.

[0075] In some embodiments, the composition described herein does not contain polyethylene glycol (PEG) (eg, PEG 400). In some embodiments, the pharmaceutical composition described herein is substantially free of PEG (eg, PEG 400). In some embodiments, the amount of PEG (e.g., PEG 400) in the pharmaceutical composition 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 total weight compositions.

[0076] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any possible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and retarding absorption agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional carrier or agent is incompatible with the active ingredient, it is intended to be used in therapeutic compositions. In addition, various adjuvants may be included, such as those commonly used in the art. Recommendations for the inclusion of various components 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, which is hereby incorporated by reference in its entirety.

[0077] The compositions described herein are preferably presented in unit dosage form. As used herein, the term "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably a mammal, in a single dose in accordance with good medical practice. However, the receipt of a single or unit dosage form does not mean that the dosage form is administered once a day or once per course of therapy. It is contemplated that such dosage forms are administered one, two, three or more times per day and may be administered as an infusion over a period of time (eg, from about 30 minutes to about 2-6 hours) or administered as a continuous infusion, and can be given more than once during the course of therapy, although a single administration is not specifically excluded. One of skill in the art will appreciate that formulation is not specifically intended for the entire course of therapy, and such decisions are left to the judgment of one skilled in the art of treatment rather than being limited by formulation.

[0078] Suitable compositions as described above may be in any of a variety of suitable forms for a variety of routes of administration, e.g., oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular or other parenteral routes of administration. In some embodiments, the composition described herein may be in the form of a solid (eg, a lyophilized powder) that may be reconstituted with a suitable liquid prior to administration. In some embodiments, the composition described herein may be in liquid form ready for administration. The person skilled in the art will understand that oral and nasal compositions include compositions that are administered by inhalation and are made using available methodologies. In some embodiments, the composition described herein may be administered via any suitable infusion device, portable device, or wearable device. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be used. Pharmaceutically acceptable carriers include, for example, liquid fillers, diluents, hydrotropic agents, surfactants, and encapsulating agents. Optional pharmaceutically active substances may be included that do not substantially interfere with the inhibitory activity of the acetaminophen compound. The amount of carrier used in conjunction with the compound is sufficient to provide the required amount of substance to be administered per unit dose of the compound. Methods and compositions for preparing dosage forms suitable for 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).

[0079] Various oral dosage forms can be used, including liquid forms. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents , dyes and flavors.

[0080] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Oral compositions include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspension, 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 methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more of the ingredients such as sweeteners, flavors and colors described above.

[0081] the Compositions described herein may optionally include other medicinal active substances.

[0082] A liquid composition that is prepared for topical ophthalmic use can be prepared so that it can be administered topically to the eye. Comfort can be maximized, although formulation considerations (eg, drug stability) can sometimes be considered less than optimal comfort. In the event that comfort cannot be maximized, the fluid may be prepared to be patient-tolerable for topical ophthalmic application. In addition, the ophthalmologically acceptable liquid may either be packaged for single use or contain a preservative to prevent contamination from repeated use.

[0083] For ophthalmic use, solutions or medicaments are often prepared using physiological saline as the main carrier. Ophthalmic solutions can preferably be maintained at comfortable pH values with a suitable buffer system. The compositions may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0084] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercury, phenylmercuric acetate, and phenylmercuric nitrate. A suitable surfactant is, for example, Tween 80. Similarly, various suitable carriers can be used in the ophthalmic formulations disclosed herein. These carriers include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamers, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0085] Tonicity regulators can be added as needed or convenient. These include, but are not limited to, salts such as sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmologically acceptable tonicity regulator.

[0086] Various buffers and pH adjustment agents can be used if the resulting preparation is ophthalmologically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

[0087] Ophthalmologically acceptable antioxidants include, but are not limited to, sodium metabisulphite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0088] Other auxiliary components that can be included in ophthalmic preparations are chelating agents. A suitable chelating agent is disodium edetate, although other chelating agents may also be used in place of or in combination with it.

[0089] For topical use, creams, ointments, gels, solutions or suspensions, etc. containing the composition described herein are used. Compositions for topical application may typically consist of a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative system, and an emollient.

[0090] For intravenous or intramuscular administration, the compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent such as saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. Accordingly, buffers including acetate buffers, citrate buffers, phosphate buffers and borate buffers can be used to adjust the pH of these formulations as needed. Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite adduct, sodium formaldehyde, sulfoxylate, thiourea, and disodium edetate. Other non-limiting examples of suitable adjuvants found in the final intravenous composition may include sodium or potassium phosphates, 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 also be included to provide a bacteriostatic or fungistatic solution, including but not limited to phenylmercury nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0091] Compositions for intravenous or intramuscular administration may be provided to caregivers in the form of one or more solids, which is reconstituted with a suitable diluent, such as sterile water, saline, or dextrose in water, shortly before administration. In other embodiments, the compositions are provided in a solution ready for parenteral administration. In other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a composition described herein and another agent, the combination may be provided to caregivers as a mixture, or caregivers may mix the two agents prior to administration, or the two agents may be administered separately .

[0092] The actual dose of the active compositions described herein depends on the particular composition and on the condition being treated; the principle of selecting an appropriate dose is within the knowledge of a person skilled in the art. In some embodiments, the daily dose may be from about 0.25 mg/kg to about 120 mg/kg or more based on body weight, from about 0.5 mg/kg or less to about 100 mg/kg, from about 1.0 mg/kg to about 80 mg/kg based on body weight, or about 1.5 mg/kg to about 75 mg/kg based on body weight. Thus, for administration to a 70 kg human, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day.

[0093] In some embodiments, the composition described herein may be administered as a 15-minute intravenous infusion. In some embodiments, the composition described herein may be administered as an intravenous infusion over 5 minutes to 30 minutes. The composition described herein may be administered as a single or multiple dose.

[0094] In some embodiments, the composition may be administered by subcutaneous infusion. In some embodiments, the composition described herein may be administered by subcutaneous infusion in combination with recombinant Hylenex®.

[0095] In some embodiments, for adult and adolescent patients weighing 50 kg or more, the dosage 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 patients and adolescents weighing 50 kg or more, the dosage of the active compositions described herein may be from about 500 mg to 1500 mg every 6 hours, or from about 300 mg to about 1000 mg every 4 hours. In some embodiments, for adult patients and adolescents weighing 50 kg or more, the maximum daily dose may be from about 2000 mg to about 6000 mg.

[0096] In some embodiments, for 50 kg adult and adolescent patients, the dosage 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. kg per day. In some embodiments, for adult patients and adolescents weighing less than 50 kg, the dosage of the active compositions described herein may be from about 10 mg/kg to about 20 mg/kg every 6 hours, or from 8 mg/kg to about 15 mg /kg every 4 hours. In some embodiments, for adult patients and adolescents weighing less than 50 kg, the maximum daily dose may be from about 50 mg/kg to about 100 mg/kg.

[0097] In some embodiments for children 2 to 12 years of age, the dosage 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 dosage of the active compositions described herein may be from about 10 mg/kg to about 20 mg/kg every 6 hours, or from 8 mg/kg to about 15 mg/kg every 4 hours. In some embodiments, for children 2 to 12 years of age, the maximum dose per day may be from about 50 mg/kg to about 100 mg/kg.

[0098] In some embodiments, the minimum dosing interval may be 4 hours. In some embodiments, the minimum dosing interval may be from 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.

How to obtain

[0099] Some embodiments relate to a method for preparing a busulfan composition, including:

combining busulfan and an organic solvent to obtain a clear solution;

combining the clear solution with the cyclodextrin to form a first mixture;

removing the solvent from the first mixture to form a second mixture; and

freeze-drying the second mixture to obtain a busulfan composition.

[0100] Various solvents can 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 dimethyl sulfoxide. 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.

[0101] Some implementation options relate to a method for obtaining a composition of busulfan, including:

combining busulfan and an organic solvent to obtain a clear solution, where the organic solvent is selected from dimethylacetamide, acetone, and any combination thereof;

combining the clear solution with the cyclodextrin to form a first mixture; and

drying the first mixture to obtain a busulfan composition.

[0102] Some implementation options relate to a method for obtaining a composition of busulfan, including:

combining busulfan and acetone to obtain a clear solution;

combining the clear solution with the cyclodextrin to form a first mixture; and

drying the first mixture to obtain a busulfan composition.

[0103] In some embodiments, removing the organic solvent includes removing the organic solvent using a rotary evaporator. In some embodiments, drying the first mixture further comprises lyophilization. In some embodiments, drying the first mixture further comprises freeze drying.

[0104] In some embodiments, combining the cyclodextrin with the clear busulfan solution comprises combining the clear busulfan solution with the 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.

[0105] In some embodiments, the method described herein comprises combining a busulfan composition with a parenterally acceptable vehicle to form a busulfan concentrate.

[0106] In some embodiments, the method described herein comprises diluting the busulfan concentrate with a pharmaceutically acceptable diluent.

[0107] In some embodiments, the parenterally acceptable solvent is selected from water, saline, cyclodextrin solution, and any combination thereof. In some embodiments, the parenterally acceptable solvent is selected from water, saline, cyclodextrin solution, and any combination thereof. In some embodiments, the parenterally acceptable solvent is a solution of a sugar such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; pyrogen-free water; isotonic saline; and phosphate buffer solutions. In some embodiments, the parenterally acceptable solvent is a cyclodextrin solution, and the cyclodextrin can be any cyclodextrin described herein, including any cyclodextrin or cyclodextrin derivatives listed in Tables A-D.

[0108] In some embodiments, the pharmaceutically acceptable diluent is selected from water, saline, cyclodextrin solution, and any combination thereof. In some embodiments, the pharmaceutically acceptable diluent is selected from water, saline, cyclodextrin solution, and any combination thereof. In some embodiments, the pharmaceutically acceptable diluent is a solution of a sugar such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; pyrogen-free water; isotonic saline; and phosphate buffer solutions. In some embodiments, the pharmaceutically acceptable diluent is a cyclodextrin solution, and the cyclodextrin may be any cyclodextrin described herein, including any cyclodextrin or cyclodextrin derivatives listed in Tables A-D.

[0109] In some embodiments, the second mixture is a clear solution.

[0110] 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 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 any 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 up to any 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 and covers any subset between the upper and lower limits. Some of the lower limits listed above are greater than some of the upper limits listed, one skilled in the art will appreciate that a selected subset will require an upper limit to be selected that is greater than the selected lower limit. For example, in some embodiments, the cyclodextrin (e.g., sulfobutyl ether cyclodextrin) solution has a concentration 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.

[0111] Some embodiments relate to a process for combining busulfan and a sulfoalkyl ester of cyclodextrin.

Method of treatment

[0112] Some implementation options relate to a method of treatment, including the restoration of the pharmaceutical composition described herein; and administering the reconstituted pharmaceutical composition to a subject in need thereof.

[0113] In some embodiments, reconstitution includes adding a parenterally acceptable solvent to the pharmaceutical composition. In some embodiments, reconstitution includes adding a pharmaceutically acceptable diluent to the pharmaceutical composition. In some embodiments, the parenterally acceptable diluent or pharmaceutically acceptable diluent is selected from water, saline, cyclodextrin solution, and any combination thereof. In some embodiments, the parenterally acceptable diluent or pharmaceutically acceptable diluent is a solution of a sugar such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; pyrogen-free water; isotonic saline; and phosphate buffer solutions. In some embodiments, the parenterally acceptable diluent or pharmaceutically acceptable diluent is a cyclodextrin solution, and the cyclodextrin can be any cyclodextrin described herein, including any cyclodextrin or cyclodextrin derivatives listed in Tables A-D.

[0114] When the pharmaceutical compositions described herein are used to treat a variety of diseases, improved drug tolerance, higher drug exposure, longer duration of therapy, flexible regulation, and improved stability are achieved compared to other commercially available compositions containing busulfan. .

[0115] Some embodiments relate to a method of conditioning a subject for hematopoietic stem cell transplantation, comprising administering a composition described herein to a subject in need thereof.

[0116] Some embodiments relate to a method of conditioning a subject for bone marrow transplantation, comprising administering a composition described herein to a subject in need thereof. Said method may further comprise an additional step or steps of administering an immunosuppressant and/or administering to the subject an additional dose or doses of bone marrow T cell depleted cells. The above methods are also suitable for treating hemoglobinopathies and/or inhibiting organ or tissue transplant rejection in a subject, as described herein.

[0117] Some embodiments relate to a method of treating leukemia, lymphoma, and a myeloproliferative disorder, comprising administering a composition described herein to a subject in need thereof. Cancer cells can be killed in the body by administering the busulfan-based compositions described herein. The busulfan formulations and method for preparing them described herein provide a novel and more effective tool for administering higher doses of such therapy while reducing the risk of toxic solvent exposure associated with the administered therapy.

[0118] In some embodiments, the composition is administered intravenously or intramuscularly. In some embodiments, the composition or dilution thereof is administered as an intravenous infusion. In some embodiments, the composition or dilution thereof is administered as an intravenous stream or bolus.

[0119] In some embodiments, the adult dose amount of busulfan is about 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, or 1.4 mg per kg of body weight. In some embodiments, the adult dose amount is greater than about 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, or 1.4 mg per kg of body weight. In some embodiments, the adult dose amount is less than about 0.8, 1, 1.2, 1.4, 1.6, 1.8, or 2 mg per kg of body weight. In some embodiments, the adult dose amount of busulfan is about 0.2 to 2.0, about 0.4 to about 1.5, or about 0.6 to about 1 mg per kg of body weight. In some embodiments, the busulfan composition is administered intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days, for a total of 16 doses.

IV kits

[0120] Some embodiments include a kit containing a cyclodextrin (eg, a sulfoalkyl ether of cyclodextrin) and busulfan. Some embodiments include a kit containing a cyclodextrin (eg, a sulfoalkyl ester of cyclodextrin) and busulfan, wherein at least a majority of the busulfan is complexed with the cyclodextrin. Some embodiments include a kit containing 1) a cyclodextrin (eg, a sulfoalkyl ester of cyclodextrin) and busulfan, wherein at least a majority of the busulfan is complexed with the cyclodextrin; and 2) a pharmaceutically acceptable solvent or diluent for reconstituting the busulfan composition. In some embodiments, the kits are used for parenteral administration. In some embodiments, the kits are used for intravenous administration.

[0121] According to one embodiment, busulfan and cyclodextrin, where most of the busulfan forms a complex with cyclodextrin, are provided in a first sterile container. In some embodiments, the pharmaceutically acceptable solvent that is used to reconstitute the busulfan solution is provided in a second sterile container. In some embodiments, the pharmaceutically acceptable diluent is an aqueous solution of cyclodextrin provided in a separate container. In the case of solids for reconstitution, the composition containing busulfan and cyclodextrin is first prepared using the method described herein and then lyophilized into a powder for addition to a container. In some embodiments, the solids are sterile crystalline products. In another embodiment, the solids are a lyophilized powder. Non-limiting examples of lyophilization aids include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. One implementation option includes non-sterile solids, which are irradiated either before or after introduction into the container.

[0122] In the case of a liquid, the busulfan composition described herein may be dissolved or dispersed in a diluent or pharmaceutically acceptable solvent ready for administration. In another embodiment, the solution or dispersion may be further diluted prior to administration. Some embodiments include providing fluid in an IV bag. The liquid may be frozen to improve stability.

[0123] In one embodiment, the container includes 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.

[0124] In an alternative embodiment, the busulfan composition and the cyclodextrin used for reconstitution may be provided in the same sterile container. In some embodiments, the busulfan composition and the cyclodextrin used for reconstitution may be provided in separate containers. Each container may contain a solid, solution or dispersion. In such embodiments, the two containers may be provided in one package or may be provided separately. In one embodiment, the composition described herein is provided as a solid while the parenterally acceptable solvent (eg, water, saline, and cyclodextrin solution) is provided as a solution ready for reconstitution. In one embodiment, the composition described herein is provided as a solid, while the parenterally acceptable agent (eg, cyclodextrin) is provided first as a solid ready for reconstitution. In one such embodiment, a solution of a parenterally acceptable agent described herein is used as a parenterally acceptable diluent to reconstitute another solid composition.

Examples

Example 1 Busulfan phase solubility data. included in Captisol® (Captisol®-enabled Busulfan)

[0125] The phase solubility of busulfan was studied in solutions of sulfobutyl ether-β-cyclodextrin (Captisol®) and the results are shown in FIG. 1. Busulfan was added to various Captisol® solutions and the mixture was measured by HPLC to determine the amount of busulfan dissolved in the solution after reaching equilibrium at room temperature. It was also noted that the busulfan solution (1 mg/mL busulfan in 200 mg/mL Captisol® solution and 2 mg/mL busulfan in 400 mg/mL Captisol® solution) was more than 90% stable after storage of the solutions for 3 days at room temperature. temperature.

Example 2 Composition of busulfan. included in Captisol® (Captisol®-enabled Busulfan)

[0126] The composition of busulfan was obtained first by dissolving busulfan in an organic solvent (eg, acetone) and then by combining it with an aqueous solution of Captisol®. The mixture was then added to a rotary evaporator to remove the organic solvent. The solution remained clear after removal of the acetone solvent. The solution was then lyophilized to remove all water and a lyophilized powder of busulfan included in Captisol® was obtained. In one lyophilized sample, the ratio of busulfan to Captisol by weight reached 4:170, which means that the concentration of busulfan was approximately 40 mg and the Captisol® solution was approximately 1.7 g. mg/ml) to achieve the infusion concentration. In one reconstituted sample, the busulfan powder rapidly dissolved to form a clear solution with a busulfan concentration ranging from about 0.5 mg/mL to 2 mg/mL. It was noted that in the reconstitution step, 5 mg/ml solubilized busulfan solution was achieved at a lower loading of Captisol® compared to the direct combination of busulfan and Captisol® solution.

Example 3 Stability of the busulfan formulation. included in Captisol® (Captisol®-enabled Busulfan)

[0127] Studied the stability over time of several solutions of busulfan and in Fig. 2 shows the precipitation amount of three busulfan formulations. The first composition of busulfan was obtained using freeze-drying/lyophilization of a solution of busulfan in Captisol® followed by recovery of the lyophilized mixture with a solution of Captisol®; the second composition of busulfan was obtained by combining busulfan and Captisol® in a solution of sodium chloride; and the third busulfan formulation was Bulsulfex® (Otsuka Pharmaceutical; Tokyo, Japan). Each vial of BUSULFEX contains 60 mg (6 mg/ml) busulfan and busulfan was dissolved in N,N-dimethylacetamide (DMA) sample solution, 3.3 ml and polyethylene glycol 400, NF 6.7 ml. The stability data showed that the first and second busulfan formulations included in Captisol® had less settling than the Bulsulfex® sample; and busulfan precipitation was delayed even more in the first busulfan formulation than in the second busulfan formulation. The first and second busulfan formulations showed better stability than the Bulsulfex® sample, with the first busulfan-based formulation obtained by lyophilization followed by reconstitution with additional Captisol® showing the highest stability.

Example 4 Study of the composition of busulfan. included in Captisol® (Captisol®-enabled Busulfan)

[0128] The stability of busulfan was investigated in several formulations at three different temperatures. The first formulation of busulfan was prepared using freeze-drying/lyophilization of busulfan and Captisol® powder, which contained 60 mg of busulfan and 5.25 g of Captisol®, followed by reconstitution of the lyophilized mixture with Captisol® solution. A second formulation of busulfan was prepared using lyophilization of busulfan and Captisol® powder, which contained 60 mg of busulfan and 5.25 g of Captisol®, followed by reconstitution of the lyophilized mixture with saline diluent. The third formulation of busulfan was Bulsilvex® (Pierre Fabre Oncologie, Boulogne, France) reconstituted using 0.9% saline to give a final concentration of 0.55 mg/mL for busulfan. The containers used for preparation were PP syringes (Becton Dickinson, Franklin Lakes, NJ). The sample solutions were aliquoted into smaller containers to ensure that the solutions remained under specific storage conditions throughout the evaluation period. For each storage temperature, a sample was processed and analyzed by HPLC-UV. Busulfan was detected by absorbance at 281 nm. In isocratic mode, a mobile phase consisting of acetonitrile (ACN), H2O and trifluoroacetic acid (TFA) (proportions: 650/350/1, v/v/v) was passed through the system at a flow rate of 2 ml/min. At zero time (T ₀ ) the initial concentration (C ₀ ) of the active substance was 100%. Thus, the content for each analysis time was determined based on C ₀ .

[0129] Figure 3A shows the stability of the first busulfan formulation at 2-8°C, 25°C and 40°C, and the third busulfan formulation at 2-8°C (RT) and 25°C; and Figure 3B shows the stability of the second busulfan formulation at 2-8°C (RT), 25°C and 40°C and the third busulfan formulation at 2-8°C (RT) and 25°C. The stability data in both Figures 3A and 3B show that the busulfan formulations included in Captisol®, including formulations reconstituted using Captisol® solution and saline, were more stable than the Bulsilvex® sample that did not contain Captisol®.

Example 5 Study of the composition of busulfan. included in Captisol® (Captisol®-enabled Busulfan)

[0130] Patients received test doses of busulfan included in Captisol® and IV Bulsulfex® (Otsuka Pharmaceutical; Tokyo, Japan). Each vial of BUSULFEX contained 60 mg (6 mg/ml) of busulfan and busulfan dissolved in N,N-dimethylacetamide (DMA), 3.3 ml and polyethylene glycol 400, NF 6.7 ml) in an amount of 0.8 mg/ kg, with the two drug products alternating after sufficient washout. The PK of the busulfan included in Captisol® was studied and compared with IV Bulsulfex® at the test dose. The safety and tolerability of the high doses of busulfan included in Captisol® has also been studied and compared with Bulsulfex® Sample IV.

Example 6 Dosage Study

[0131] Patients with chemosensitive relapsed or primary refractory lymphoma who underwent first autologous hematopoietic stem cell transplantation received a test dose of busulfan included in Captisol® (0.8 mg/kg) via intravenous administration, administered as a 2-hour continuous infusion per day between days -14 and -11. Busulfan exposure was determined as the area under the concentration-time curve (AUC) using six whole blood samples obtained at regular intervals after the end of the infusion. Based on the PK test, the remaining dose of busulfan was calculated to achieve a total AUC of 20,000 µM⋅min. One fourth of this dose was given as a 3 hour infusion on day -8 during which a second PK analysis was performed. The same daily dose of Bu was administered on days -7, -6, and -5 until the FC results of day -8 showed total AUC outside the target value of ± 20%. Busulfan infusion on days -6 and -5 was modified if the second PK results predicted total AUC to be less than 16,000 μM⋅min or greater than 24,000 μM⋅min. Etoposide 1.4 g/m ² was administered on day -4 for a 4 hour infusion, followed by cyclophosphamide 2.5 g/m ² /day on days -3 and -2.

[0132] Six serial blood samples were taken after the test dose (PK test) and on day -8 (PK confirmation). Busulfan concentrations were measured to determine busulfan exposure as AUC using the WinNonlin software and to recommend individual dosing based on PK. The target daily AUC during the conditioning regimen was calculated as (20,000 µM⋅min - test PK AUC)/4. The daily conditioning dose was calculated as (test dose PK/test PK AUC)*Target daily AUC.

Claims (73)

1. A pharmaceutical composition containing a solid that contains: busulfan; and cyclodextrin; where at least about 25% of busulfan in the composition forms a complex with cyclodextrin, where the molar ratio of cyclodextrin to busulfan is less than 12, where the cyclodextrin or sulfoalkyl ester of cyclodextrin is a compound of formula 1 or a mixture thereof:

or a pharmaceutically acceptable salt thereof, where: p is 4, 5 or 6; each R ₁ is independently -OH or -O-(C ₁ -C ₈ alkylene)-SO ₃ T, -O-(C ₁ -C ₈ alkyl) and -O-(C ₁ -C ₆ alkyl)-OH , and T is hydrogen or a pharmaceutically acceptable cation, with the proviso that at least one R ₁ is -OH. 2. Pharmaceutical composition according to claim 1, characterized in that at least 50% of the busulfan in the composition forms a complex with cyclodextrin. 3. Pharmaceutical composition according to claim 1, characterized in that at least 90% of the busulfan in the composition forms a complex with cyclodextrin. 4. Pharmaceutical composition according to any one of paragraphs. 1-3, characterized in that the molar ratio of cyclodextrin to busulfan is from about 3 to about 10. 5. Pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that the molar ratio of cyclodextrin to busulfan is less than about 9. 6. Pharmaceutical composition according to any one of paragraphs. 1-5, characterized in that the molar ratio of cyclodextrin to busulfan is less than about 5. 7. Pharmaceutical composition according to any one of paragraphs. 1-6, characterized in that the composition has a moisture content of less than 20%. 8. Pharmaceutical composition containing a clear aqueous solution that contains: busulfan, where the concentration of busulfan is from about 0.3 mg/ml to 4 mg/ml; and cyclodextrin, where the molar ratio of cyclodextrin to busulfan is less than about 12, where the cyclodextrin or sulfoalkyl ether of cyclodextrin is a compound of formula 1 or a mixture thereof:

or a pharmaceutically acceptable salt thereof, where: p is 4, 5 or 6; each R ₁ is independently -OH or -O-(C ₁ -C ₈ alkylene) -SO ₃ T, -O-(C ₁ -C ₈ alkyl) and -O-(C ₁ -C ₆ alkyl) -OH , and T is hydrogen or a pharmaceutically acceptable cation, with the proviso that at least one R ₁ is -OH. 9. A pharmaceutical composition according to claim 8, characterized in that the molar ratio of cyclodextrin to busulfan is less than about 10. 10. Pharmaceutical composition according to claim 8 or 9, characterized in that the concentration of busulfan is from about 0.5 mg/ml to about 2 mg/ml. 11. Pharmaceutical composition according to any one of paragraphs. 8-10, characterized in that the concentration of busulfan is approximately 0.55 mg/ml. 12. Pharmaceutical composition according to any one of paragraphs. 8-11, characterized in that at least about 50% of the busulfan in the composition forms a complex with cyclodextrin sulfoalkyl ether. 13. Pharmaceutical composition according to any one of paragraphs. 1-12, characterized in that each R ₁ is independently -OH or -O-(C ₁ -C ₈ alkylene) -SO ₃ ^¯ -T, provided that at least one R ₁ is -O-( C ₁ -C ₈ alkylene) -SO ₃ ^¯ -T. 14. Pharmaceutical composition according to claim 13, characterized in that at least one R ₁ is -OCH ₂ CH ₂ CH ₂ CH ₂ SO ₃ T or -OCH ₂ CH ₂ CH ₂ SO ₃ T. 15. Pharmaceutical composition according to any one of paragraphs. 13, 14, characterized in that T is independently hydrogen or sodium. 16. Pharmaceutical composition according to claim 13, characterized in that each R ₁ is independently -OH or O-(C ₁ -C ₆ alkyl) -OH, provided that at least one R ₁ is O-(C ₁ -C ₆ alkyl)-OH. 17. Pharmaceutical composition according to claim 16, characterized in that at least one R ₁ is -OCH ₂ CH ₂ CH ₂ -OH. 18. Pharmaceutical composition according to claim 13, characterized in that each R ₁ is independently -OH or O-(C ₁ -C ₈ alkyl), provided that at least one R ₁ is O-(C ₁ - C ₈ alkyl). 19. Pharmaceutical composition according to any one of paragraphs. 1-18, wherein p is 5. 20. Reconstituted pharmaceutical composition in the form of a solution obtained by adding a pharmaceutically acceptable solvent to the composition according to any one of paragraphs. 1-7, where the concentration of busulfan is from about 0.3 mg/ml to 4 mg/ml, where the pharmaceutically acceptable solvent is a cyclodextrin solution, a sodium chloride solution, or a combination thereof. 21. The reconstituted pharmaceutical composition according to claim 20, characterized in that the pharmaceutically acceptable solvent is a sodium chloride solution. 22. The reconstituted pharmaceutical composition according to claim 20, characterized in that the pharmaceutically acceptable solvent is a cyclodextrin solution. 23. A sterilized container for storing busulfan containing a composition according to any one of paragraphs. 1-12. 24. A method for obtaining a busulfan composition, including: combining busulfan and an organic solvent to obtain a clear solution; combining the clear solution with the cyclodextrin to form a first mixture; removing the organic solvent from the first mixture to form a second mixture; and drying the second mixture to obtain a busulfan composition, where the cyclodextrin or sulfoalkyl ester of cyclodextrin is a compound of formula 1 or a mixture thereof:

or a pharmaceutically acceptable salt thereof, where: p is 4, 5 or 6; each R ₁ is independently -OH or -O-(C ₁ -C ₈ alkylene)-SO ₃ T, -O-(C ₁ -C ₈ alkyl) and -O-(C ₁ -C ₆ alkyl)-OH , and T is hydrogen or a pharmaceutically acceptable cation, with the proviso that at least one R ₁ is -OH. 25. The method according to p. 24, characterized in that the organic solvent is selected from dimethylacetamide, acetone, and any combination thereof. 26. The method according to p. 24, characterized in that the organic solvent is acetone. 27. The method according to p. 24, characterized in that the organic solvent is dimethylacetamide. 28. The method according to p. 24, characterized in that the organic solvent is removed by evaporation. 29. The method according to p. 24 or 25, characterized in that the drying of the second mixture includes lyophilization. 30. The method according to any one of paragraphs. 24-29, characterized in that combining the clear solution with the cyclodextrin comprises combining the clear solution with the cyclodextrin solution. 31. The method according to p. 30, characterized in that the cyclodextrin solution is an aqueous solution. 32. The method according to any one of paragraphs. 24-31, further comprising combining the busulfan composition with a parenterally acceptable solvent. 33. The method of claim 32, wherein the parenterally acceptable solvent is selected from water, saline, cyclodextrin solution, and any combination thereof. 34. A method for the treatment of leukemia, lymphoma or myeloproliferative disorders, including: restoration of the pharmaceutical composition according to any one of paragraphs. 1-7; and administering the reconstituted pharmaceutical composition to a subject in need thereof. 35. The method of claim 34, wherein reconstitution comprises adding a parenterally acceptable solvent to the pharmaceutical composition. 36. The method of claim 35 wherein the parenterally acceptable solvent is selected from water, saline solution, cyclodextrin solution, and any combination thereof. 37. The method of claim 36 wherein the parenterally acceptable solvent is a cyclodextrin solution having a concentration of from about 50 mg/mL to about 200 mg/mL. 38. The method of conditioning a subject for transplantation of hematopoietic stem cells, including the introduction of a composition according to any one of paragraphs. 1-19 to the subject in need of it. 39. The method of conditioning a subject for bone marrow transplantation, including the introduction of a composition according to any one of paragraphs. 1-19 to the subject in need of it. 40. A method for the treatment of leukemia, lymphoma and myeloproliferative disorders, including the introduction of a composition according to any one of paragraphs. 1-19 to the subject in need of it. 41. The method according to any one of paragraphs. 38-40, characterized in that the composition is administered intravenously or intramuscularly.

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