WO2019094819A2 - Intravenous delivery systems for chemotherapy drugs - Google Patents

Intravenous delivery systems for chemotherapy drugs Download PDF

Info

Publication number
WO2019094819A2
WO2019094819A2 PCT/US2018/060160 US2018060160W WO2019094819A2 WO 2019094819 A2 WO2019094819 A2 WO 2019094819A2 US 2018060160 W US2018060160 W US 2018060160W WO 2019094819 A2 WO2019094819 A2 WO 2019094819A2
Authority
WO
WIPO (PCT)
Prior art keywords
delivery system
intravenous delivery
cyclodextrin
intravenous
diluent
Prior art date
Application number
PCT/US2018/060160
Other languages
French (fr)
Other versions
WO2019094819A3 (en
Inventor
Salah U. Ahmed
Yanming Zu
Tahseen A. Chowdhury
Mukta RAHMAN
Hetalben Prajapati
Gaus M. KHAN
Original Assignee
Abon Pharmaceuticals, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abon Pharmaceuticals, Llc filed Critical Abon Pharmaceuticals, Llc
Publication of WO2019094819A2 publication Critical patent/WO2019094819A2/en
Publication of WO2019094819A3 publication Critical patent/WO2019094819A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present disclosure relates to intravenous delivery systems for chemotherapy drugs, e.g., irritating chemotherapy drugs. More specifically, the present disclosure is related to an intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprising, (a) a lyophilized mass comprising the irritating chemotherapy drug; and (b) a diluent capable of dispersing the mass; wherein the diluent disperses the mass when combined with the mass, wherein when the mass and diluent are combined with an intravenous infusion fluid to form an intravenous solution comprising the drug, and wherein the intravenous solution comprising the drug provides for reduced injection site reaction when administered to a subject.
  • a chemotherapy drug e.g., an irritating chemotherapy drug
  • a diluent capable of dispersing the mass
  • the diluent disperses the mass when combined with the mass, wherein when the mass and diluent are combined with an intravenous infusion fluid to form an intravenous solution
  • a flare reaction One type of injection site reactions is a local reaction, called a flare reaction. Symptoms of the flare reaction include tenderness, redness, burning, and pain at the site of the injection or along the vein. The other type of injection site reactions is a more severe reaction and is caused by extravasation, a leakage of an irritating chemotherapy drug from the blood vessel at the site of injection. Symptoms of the more severe extravasation reaction may initially be the same as the local flare reaction, and subsequently further include pain, edema, blistering, necrosis and severe skin damage.
  • Chemotherapy drugs can be classified, according to their potential to cause inflammation and/or damage to the tissue surrounding the injection site, into five categories of vesicants, exfoliants, irritants, inflammitants, and neutrals.
  • Irritating chemotherapy drugs include, but not limited to vesicants, exfoliants, irritants, and inflammitants.
  • Vesicants are drugs with the highest potential to cause tissue destruction. Varying degrees of pain, edema, erythema, blistering and necrosis may occur.
  • Carmustine is cell-cycle phase nonspecific, bifunctional, alkylating agent. It alkylates DNA and RNA, cross-links DNA, and inhibits several enzymes by carbamoylation. Carmustine is currently marketed under the brand name of BiCNU in the United States of America.
  • BiCNU ® (carmustine for injection) is indicated for the treatment of brain tumors and various other malignant neoplasms.
  • Each package of BiCNU ® includes a vial containing 100 mg lyophilized carmustine and a vial containing 3 mL sterile diluent of Dehydrated Alcohol Injection, USP.
  • the recommended dose of BiCNU ® as a single agent in previously untreated patients is 150 to 200 mg/m 2 intravenously every 6 weeks.
  • Prescribing information instructs that BiCNU ® lyophile be dissolved with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP), then aseptically diluted with 27 mL Sterile Water for Injection, USP.
  • the resulting solution contains 3.3 mg of BiCNU ® /lmL in 10% ethanol.
  • the solution is further diluted with Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
  • the reconstituted solution can be administered to a subject by slow intravenous infusion over at least two hours. Administration of BiCNU ® over a period of less than two hours can lead to pain and burning at the site of injection.
  • Carmustine is recognized as a vesicant. Therefore, the injection side reactions of BiCNU ® include both the local flare reaction and the more severe extravasation reaction if extravasated.
  • the local flare reaction such as burning at the injection site, or along the course of the vein, is common during carmustine administration, even when the reconstituted drug solution is administered by slow intravenous infusion over more than two hours.
  • side effects also include cardiovascular effect of hypotension, and dermatology/skin effect of flushing. See, e.g., Carmustine, BC Cancer Agency Cancer Drug Manual, Revised: April 2007, 1 September 2010, 1 August 2011).
  • the present disclosure provides intravenous delivery systems for chemotherapy drugs, e.g., irritating chemotherapy drugs, that may alleviate the injection site local flare reaction during drug administration.
  • the present invention also provides intravenous delivery systems for chemotherapy drugs, e.g., irritating chemotherapy drugs, that may alleviate the injection site more severe extravasation reaction if extravasated.
  • the disclosure is directed to an intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprising, (a) a lyophilized mass comprising the chemotherapy drug; and (b) a diluent capable of dispersing the mass; wherein the diluent disperses the mass when combined with the mass, wherein when the mass and diluent are combined with an intravenous infusion fluid to form an intravenous solution comprising the drug, and wherein the intravenous solution comprising the drug provides for reduced injection site reaction when administered to a subject.
  • the irritating chemotherapy drug is carmustine.
  • the disclosure is directed to an intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprising, (a) an chemotherapy drug; (b) a solubilizer; and (c) a diluent free of non-aqueous solvent capable of dispersing the composition;
  • the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof; and wherein the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex
  • the intravenous delivery system for the chemotherapy drug e.g., the irritating chemotherapy drug
  • further comprises a stabilizer wherein the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
  • polar amino acids such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan
  • globular proteins such as albumin, and combinations thereof.
  • the chemotherapy drug e.g., carmustine
  • a solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin, and globular proteins, such as albumin, and combinations thereof.
  • the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
  • polar amino acids such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan
  • globular proteins such as albumin, and combinations thereof.
  • the disclosure is directed to an intravenous delivery system
  • a lyophilized mass comprising (i) carmustine, and (ii) a polymeric carrier selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof; and (b) a diluent capable of dispersing the mass, wherein the diluent comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
  • a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
  • the disclosure is directed to an intravenous delivery system
  • the disclosure is directed to an intravenous delivery system
  • the disclosure is directed to an intravenous solution, comprising:
  • an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
  • the disclosure is directed to an intravenous solution, comprising:
  • a diluent capable of dispersing the mass comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof, and (d) an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
  • a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof
  • an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
  • the disclosure is directed to an intravenous solution, comprising:
  • a diluent capable of dispersing the mass comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof, and (e) an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
  • a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof
  • an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
  • the disclosure is directed to an intravenous solution, comprising:
  • the disclosure is directed to a method of administering a
  • chemotherapy drug e.g., an irritating chemotherapy drug
  • the method comprising, (a) obtaining a lyophilized mass comprising a chemotherapy drug; (b) dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass, is compatible with an intravenous infusion fluid and is suitable for intravenous administration; (c) combining the dispersed mass in diluent of (b) with an intravenous infusion fluid to form an intravenous solution comprising the drug; and (d) administering the intravenous solution comprising the drug to a patient in need thereof.
  • the disclosure is directed to a method of making an intravenous solution comprising a chemotherapy drug, e.g., an irritating chemotherapy drug, the method comprising, (a) obtaining a lyophilized mass comprising a chemotherapy drug; (b) dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass, is compatible with an intravenous infusion fluid and is suitable for intravenous administration; (c) combining the dispersed mass in diluent of (b) with the intravenous infusion fluid to form an intravenous solution comprising the chemotherapy drug.
  • a chemotherapy drug e.g., an irritating chemotherapy drug
  • the disclosure is directed to a lyophilized composition for use in an intravenous solution, the composition comprising: (a) a chemotherapy drug; and (b) a solubilizer; wherein the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof; and wherein the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-
  • the solubilizer is a globular protein, and the globular protein is albumin.
  • the solubilizer is sulfobutyl ether ⁇ -cyclodextrin sodium.
  • the solubilizer is the combination of sulfobutyl ether ⁇ -cyclodextrin sodium and albumin.
  • the lyophilized composition further comprises a stabilizer.
  • the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
  • the stabilizer is cysteine.
  • the stabilizer is albumin.
  • the disclosure is directed to a lyophilized composition for use in an intravenous solution, the composition comprising: (a) carmustine and albumin; (b) carmustine and sulfobutyl ether ⁇ -cyclodextrin sodium; (c) carmustine, sulfobutyl ether ⁇ -cyclodextrin sodium and albumin, or (d) carmustine, sulfobutyl ether ⁇ -cyclodextrin sodium and cysteine.
  • the ratio of carmustine to albumin is 1 : 1 to 1 :50
  • the ratio of carmustine to sulfobutyl ether ⁇ -cyclodextrin sodium is 1 : 10 to 1 :30
  • the ratio of carmustine : sulfobutyl ether ⁇ -cyclodextrin sodium : albumin is 1 : 10: 1 to 1 :30:5
  • the ratio of carmustine : sulfobutyl ether ⁇ -cyclodextrin sodium : cysteine is 1 : 10: 1 to 1 :30:5.
  • the lyophilized composition further comprises a stabilizer.
  • the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
  • the stabilizer is cysteine.
  • the disclosure is directed to an intravenous delivery system
  • compositions as described herein comprising: (a) the lyophilized compositions as described herein, and (b) a diluent capable of dispersing the chemotherapy drug and solubulizer, wherein (a) and (b) form the intravenous delivery system.
  • the intravenous delivery system comprises, (a) carmustine, (b)a solubilizer selected from sulfobutyl ether ⁇ -cyclodextrin sodium, albumin, or combinations thereof; and (c) a diluent capable of dispersing the carmustine and solubilizer; wherein (a), (b) and (c) form the intravenous delivery system.
  • the intravenous delivery system further comprises a stabilizer.
  • the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and a globular protein, and combinations thereof.
  • the stabilizer is cysteine. In some embodiments, the stabilizer is a globular protein, and the globular protein is albumin. In some embodiments, diluent is water, saline solution, or dextrose aqueous solution.
  • the disclosure is directed to an intravenous solution comprising (a) the intravenous delivery system as described herein, and (a) intravenous infusion fluid, wherein (a) and (b) form the intravenous solution.
  • the present invention provides intravenous delivery systems for chemotherapy drugs, e.g., irritating chemotherapy drugs, that may alleviate the injection site local flare reaction, such as tenderness, redness, burning, and pain at the site of the injection or along the vein during drug administration.
  • chemotherapy drugs e.g., irritating chemotherapy drugs
  • Injection site reactions during intravenous administration of chemotherapy drugs, e.g., irritating chemotherapy drugs, for cancer patients are particularly vulnerable, as subjects in need of chemotherapy agents already exhibit many physical and psychological problems.
  • Applicants describe herein systems and formulations for alleviating or reducing the injection site reactions, such as the local flare reaction and/or the more sever extravasation reaction during drug administration, which can benefit the subjects, e.g., cancer patients, receiving the chemotherapy drugs.
  • the present invention also provides intravenous delivery systems for a chemotherapy drug, e.g., an irritating chemotherapy drug, that may alleviate the injection site more severe extravasation reaction if extravasated, such as tenderness, redness, burning, and pain at the site of the injection or along the vein, edema, blistering, necrosis and severe skin damage.
  • a chemotherapy drug e.g., an irritating chemotherapy drug
  • such intravenous delivery system for a chemotherapy drug comprises a lyophilized mass of a chemotherapy drug, and a diluent, capable of dispersing the lyophilized drug, and compatible with intravenous infusion fluids such as 0.9% Sodium Chloride Injection or 5% Dextrose, USP for intravenous administration.
  • a chemotherapy drug e.g., an irritating chemotherapy drug
  • intravenous infusion fluids such as 0.9% Sodium Chloride Injection or 5% Dextrose, USP for intravenous administration.
  • such intravenous delivery system for a chemotherapy drug comprises a lyophilized mass which comprises a chemotherapy drug lyophilized with a polymeric carrier and/or a biocompatible amphiphilic carrier, and a diluent, capable of dispersing the co-lyophilized drug-polymeric/amphiphilic carrier, and compatible with intravenous infusion fluids such as 0.9% Sodium Chloride Injection or 5% Dextrose, USP for intravenous administration.
  • the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof.
  • the chemotherapy drug is carmustine.
  • the chemotherapy drug is romidepsin.
  • the intravenous system comprises co-administering a second
  • the intravenous system comprises a chemotherapy drug and an antiemetic drug. In some embodiments, the intravenous system comprises carmustine and an antiemetic drug.
  • the antiemetic drug is a 5-HT receptor antagonist or an adopamine blocker.
  • the antiemetic drug is selected from the group consisting of odansetron (Zofiran), palonosetron (Aloxi), procholoperazine (Compazine), lorazepam (Ativan), aoreoitant (Emend), dolastetron (Anzemet), or granistetron (Kytril).
  • the disclosure is directed to an intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprising, (a) an chemotherapy drug; (b) a solubilizer; and (c) a diluent free of non-aqueous solvent capable of dispersing the composition;
  • the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof; and wherein the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex
  • the intravenous delivery system for the chemotherapy drug further comprises a stabilizer, wherein the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
  • the stabilizer can be in the lyophilized mass with the chemotherapy drug and the solubilizer. In some embodiments, the stabilizer can be in the diluent.
  • the chemotherapy drug e.g., carmustine
  • a solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin, and globular proteins, such as albumin, and combinations thereof.
  • the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
  • polar amino acids such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan
  • globular proteins such as albumin, and combinations thereof.
  • the chemotherapy drug e.g., carmustine
  • a solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin, and globular proteins, such as albumin, and combinations thereof.
  • the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
  • polar amino acids such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan
  • globular proteins such as albumin, and combinations thereof.
  • any of the intravenous solutions described herein further comprise an intravenous infusion fluid.
  • the intravenous infusion fluid comprises about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
  • the salt is sodium chloride.
  • the sodium chloride is about 0.8% to about 1.0% sodium chloride.
  • the sugar is glucose or dextrose.
  • the sugar is dextrose at a concentration of about 2% to about 5% (w/v) dextrose.
  • Carmustine is freely soluble in ethanol, and slightly soluble in water (4.1 mg/mL).
  • a globular protein, albumin significantly increased the aqueous solubility of carmustine.
  • a cyclic oligosaccharides with at least 6 pyranose units, sulfobutyl ether ⁇ -cyclodextrin sodium tremendously increased the aqueous solubility of carmustine.
  • the combination of a cyclic oligosaccharides with at least 6 pyranose units and a globular protein provided a synergistic effect on the aqueous solubility of carmustine.
  • carmustine is not generally stable. Generally, an unopened vial of the
  • carmustine lyophile must be stored in a refrigerator (2°-8°C, 36°-46°F). After reconstitution as recommended, BiCNU is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F).
  • the inventors have found although the solubilizer, the cyclic oligosaccharides with at least 6 pyranose units, sulfobutyl ether ⁇ -cyclodextrin sodium, increased the stability of carmustine aqueous solution when stored in the refrigerator (2°-8°C), there were still significant levels of impurities in the carmustine sulfobutyl ether ⁇ -cyclodextrin sodium aqueous solution upon storage. Surprisingly, the inventors discovered that the combination of a cyclic
  • oligosaccharides with at least 6 pyranose units, sulfobutyl ether ⁇ -cyclodextrin sodium and a globular protein, albumin significantly increased the stability of carmustine aqueous solution when stored in the refrigerator (2°-8°C). Only negligible amounts of impurity in the carmustine sulfobutyl ether ⁇ -cyclodextrin sodium/albumin aqueous solution upon storage were observed. Unexpectedly, the inventors also discovered that a polar amino acid, cysteine, significantly increases the aqueous stability of carmustine in the sulfobutyl ether ⁇ -cyclodextrin sodium solution while stored in a refrigerator (2°-8°C). Only negligible amounts of impurity in the carmustine sulfobutyl ether ⁇ -cyclodextrin sodium/cysteine aqueous solution upon storage were observed.
  • Various amounts of the chemotherapy drug e.g., an irritating chemotherapy drug, can be used.
  • the skilled artisan can adjust the dosage amount depending on the drug being
  • the intravenous delivery system is a single use dose.
  • the chemotherapy drug e.g., irritating chemotherapy drug
  • the chemotherapy drug is used in a dosage amount of about 10 mg to about 500 mg, about 20 mg to about 200 mg, about 30 mg to about 150 mg, about 40 mg to about lOOmg.
  • the chemotherapy drug is carmustine in a dosage amount of about 10 mg to about 500 mg, about 20 mg to about 200 mg, about 30 mg to about 150 mg, about 50 mg to about 150mg.
  • the chemotherapy drug e.g., carmustine
  • a polymeric carrier is selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof.
  • phospholipids such as egg lecithin
  • polysorbate n 20 to 80
  • bile acids such as glycocholic acid
  • diluents can be used.
  • the diluent is compatible with
  • the diluent is suitable for intravenous administration.
  • the diluent comprises a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
  • the diluent comprises water.
  • the diluent comprises water and a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
  • a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
  • the diluent comprises an amphiphilic agent selected from
  • phospholipids such as egg lecithin
  • polysorbate n 20 to 80
  • bile acids such as glycocholic acid
  • salts cholesterol
  • polyoxyl n castor oil 30 to 40
  • mono-, di-, and triglycerides of medium chain fatty acids glyceryl
  • the diluent is water. In some embodiments, the diluent is 0.9% sodium chloride aqueous solution, or 5% dextrose aqueous solution.
  • the diluent comprises an oil selected from soybean oil, safflower oil, castor oil, sesame oil, cottonseed oil, sunflower oil, a glyceryl ester of fatty acid having melting point of less than 37°C, and combinations thereof.
  • diluent Various volumes of diluent can be used.
  • the diluent is in a
  • the diluent is in a volume of less than 20 ml. In some embodiments, the diluent is in a volume of less than 10 ml.
  • the infusion fluid is in a volume of less than 500 ml, less than 400 ml, less than 300 ml, less than 200 ml, less than 100 ml, less than 80ml, less than 60ml, less than 50 ml, less than 40 ml, less than 30 ml, less than 20 ml, less than 10 ml, or less than 5 ml. In some embodiments, the infusion fluid is in a volume of less than 20 ml. In some embodiments, the infusion fluid is in a volume of less than 10 ml.
  • such intravenous delivery system includes a lyophilized mass of a lipophilic chemotherapy drug, e.g., irritating chemotherapy drug, and a hydrophilic diluent capable of dispersing or dissolving the drug and compatible with intravenous infusion fluids such as 0.9% Sodium Chloride Injection or 5% Dextrose, USP for intravenous administration.
  • a lipophilic chemotherapy drug e.g., irritating chemotherapy drug
  • a hydrophilic diluent capable of dispersing or dissolving the drug and compatible with intravenous infusion fluids such as 0.9% Sodium Chloride Injection or 5% Dextrose, USP for intravenous administration.
  • the chemotherapy drug is an irritating chemotherapy drug.
  • Irritating chemotherapy drugs are known in the art, and include chemotherapy drugs that cause injection site reactions such as inflammation in and/or damage to the tissue surrounding where a drug is injected, including tenderness, redness, burning, and pain at the site of the injection or along the vein.
  • the term "irritating" when referring to a chemotherapy drug includes drugs which cause more severe injection site reaction, e.g., cause extravasation, a leakage of an irritating chemotherapy drug from the blood vessel at the site of injection.
  • Symptoms of the more severe extravasation reaction may initially be the same as the local flare reaction, and subsequently further include pain, edema, blistering, necrosis and severe skin damage.
  • Chemotherapy drugs can be classified, according to their potential to cause inflammation and/or damage to the tissue surrounding the injection site, into five categories of vesicants, exfoliants, irritants, inflammitants, and neutrals.
  • irritating chemotherapy drugs include, but are not limited to vesicants, exfoliants, irritants, and inflammitants.
  • the term "irritating chemotherapy drug” refers to vesicants. Vesicants are drugs with the highest potential to cause tissue destruction. Varying degrees of pain, edema, erythema, blistering and necrosis may occur.
  • the intravenous delivery system as described herein has increased solubility relative to the chemotherapy drug dissolved in water.
  • a chemotherapy drug in an intravenous delivery system as described herein has a 10%, 25%, 50%, 75%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 500%, 600%, 700% or 800% increase in solubility relative to the same chemotherapy drug dissolved in water.
  • the actual solubility of the chemotherapy drug in an intravenous delivery system as described herein is 5%), 10%), 15%), 20%), or 30%> higher compared to the calculated solubility of the chemotherapy drug in the intravenous delivery system.
  • the intravenous delivery system as described herein provides for increased stability of the chemotherapy drug.
  • the increased stability reduces the impurities, e.g., degradation products, in the intravenous delivery system.
  • the increase stability provided by the intravenous delivery system as described herein provides for a more consistent dosing profile.
  • the increased stability provided by the intravenous delivery system as described herein allows the delivery system to be suitable for use for a longer period of time.
  • the intravenous delivery system as described herein provides for a 30%) reduction in impurities after 2 days when stored at 2-8 °C compared to the same
  • the intravenous delivery system as described herein provides for a 40% reduction, 50%> reduction, 60%> reduction, a 70% reduction, a 80%) reduction or a 90% reduction in impurities after 2 days when stored at 2-8 °C compared to the same chemotherapy drug in water. For example, if an intravenous delivery system comprising on a chemotherapy drug and water produced >3%> impurities, and the intravenous delivery system as described herein produced 0.3% impurities, that would constitute a >90%> reduction in impurities.
  • the intravenous delivery system as described herein provides for a 30% reduction, 40% reduction, 50% reduction, 60% reduction, a 70% reduction, a 80% reduction, 90% reduction, or 95% reduction in impurities after 3 days when stored at 2-8 °C compared to the same chemotherapy drug in water.
  • the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system can include a lyophilized mass of carmustine and a diluent of benzyl alcohol.
  • the intravenous delivery system can include a lyophilized mass of carmustine, water and a diluent of benzyl alcohol.
  • a solution Upon reconstitution with water, the diluent or a combination of water and diluent, a solution is obtained.
  • a solution upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, USP, a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system can include a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising benzyl alcohol and ethanol alcohol.
  • the intravenous delivery system can include a co- lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising water, benzyl alcohol and ethanol alcohol.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a lyophilized mass of carmustine, and a diluent comprising polyoxyl 60 hydrogenated castor oil and ethanol alcohol.
  • a solution is obtained.
  • a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising polyoxyl 60 hydrogenated castor oil and ethanol alcohol.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a lyophilized mass of carmustine, and a diluent comprising gamma-cyclodextrin, benzyl alcohol and ethanol alcohol.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising gamma-cyclodextrin, benzyl alcohol and ethanol alcohol.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a lyophilized mass of carmustine, and a diluent comprising Soluplus, benzyl alcohol and ethanol alcohol.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising Soluplus, benzyl alcohol and ethanol alcohol.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polyoxyl 35 hydrogenated castor oil (Cremophor EL), and a diluent comprising lecithin, polysorbate 80 and purified water.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose
  • a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polyoxyl 35 hydrogenated castor oil (Cremophor EL), and a diluent comprising lecithin, polysorbate 80 and ethanol alcohol.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose
  • a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polyoxyl 35 hydrogenated castor oil (Cremophor EL), and a diluent comprising lecithin, polysorbate 80, ethanol alcohol and purified water.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose
  • a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polysorbate 80, and a diluent comprising lecithin, polysorbate 80 and purified water.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polysorbate 80, and a diluent comprising lecithin, polysorbate 80 and ethanol alcohol.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
  • the irritating chemotherapy drug is carmustine. In some embodiments, the irritating chemotherapy drug is carmustine.
  • the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polysorbate 80, and a diluent comprising lecithin, polysorbate 80, ethanol alcohol and purified water.
  • a solution is obtained.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose
  • a solution is obtained and can be administered intravenously.
  • the disclosure is directed to a method of administering a
  • the method comprising, (a) obtaining a lyophilized mass comprising a chemotherapy drug; (b) dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass; (c) combining the dispersed mass in diluent of (b) with an intravenous infusion fluid to form an intravenous solution comprising the drug; and (d) administering the intravenous solution comprising the drug to a patient in need thereof.
  • the method provides for reduced injection site reaction for a subject administered the intravenous solution.
  • the disclosure is directed to a method of making an intravenous solution comprising a chemotherapy drug, e.g., an irritating chemotherapy drug, the method comprising, (a) obtaining a lyophilized mass comprising a chemotherapy drug; (b) dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass; and (c) combining the dispersed mass in diluent of (b) with the intravenous infusion fluid to form an intravenous solution comprising the chemotherapy drug.
  • a chemotherapy drug e.g., an irritating chemotherapy drug
  • the disclosure is directed to a lyophilized composition for use in an intravenous solution, the composition comprising: (a) a chemotherapy drug, e.g., an irritating chemotherapy drug; (b) a solubilizer; and (c) a diluent capable of dispersing the composition ; wherein the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof; and wherein the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex
  • the solubilizer is a globular protein, and the globular protein is albumin.
  • the solubilizer is sulfobutyl ether ⁇ -cyclodextrin sodium.
  • the solubilizer is the combination of sulfobutyl ether ⁇ -cyclodextrin sodium and albumin.
  • the lyophilized compositions described herein further comprise a stabilizer.
  • the stabilizer in the lyophilized composition is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
  • the stabilizer in the lyophilized composition is cysteine.
  • the stabilizer in the lyophilized composition is albumin.
  • the disclosure is directed to a lyophilized composition for use in an intravenous solution, the composition comprising: (a) carmustine and albumin; (b) carmustine and sulfobutyl ether ⁇ -cyclodextrin sodium; or (c) carmustine, sulfobutyl ether ⁇ -cyclodextrin sodium and ablumin.
  • the ratio of carmustine to albumin is 1 : 1 to 1 :50
  • the ratio of carmustine to sulfobutyl ether ⁇ -cyclodextrin sodium is 1 : 10 to 1 :30
  • the ratio of carmustine : sulfobutyl ether ⁇ -cyclodextrin sodium : albumin is 1 : 10: 1 to 1 :30:5.
  • the composition comprising: (a) carmustine and albumin; (b) carmustine and sulfobutyl ether ⁇ -cyclodextrin sodium; or (c) carmustine, sulfobutyl ether ⁇ - cyclodextrin sodium and a stabilizer cysteine.
  • the ratio of carmustine to albumin is 1 : 1 to 1 : 50
  • the ratio of carmustine to sulfobutyl ether ⁇ -cyclodextrin sodium is 1 : 10 to 1 :30
  • the ratio of carmustine : sulfobutyl ether ⁇ -cyclodextrin sodium : cysteine is 1 : 10: 1 to 1 :30:5.
  • the disclosure is directed to an intravenous solution comprising (a) carmustine, (b) a solubilizer selected from sulfobutyl ether ⁇ -cyclodextrin sodium, albumin, or combinations thereof; (c) a stabilizer selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof; (d) a diluent capable of dispersing the carmustine and solubilizer; wherein a, b and c form an intravenous solution.
  • a solubilizer selected from sulfobutyl ether ⁇ -cyclodextrin sodium, albumin, or combinations thereof
  • a stabilizer selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and
  • the stabilizer is cysteine.
  • the diluent in the intravenous solution is water, saline solution, or dextrose aqueous solution. In some embodiments, the diluent in the intravenous solution is water, saline solution, or 5% dextrose aqueous solution.
  • the invention is directed to a lyophilized composition as follows:
  • Exemplary Lyophilized Compositions [0077] In some embodiments, the invention is directed to a lyophilized composition
  • the invention is directed to a lyophilized composition
  • a lyophilized composition Exemplary Lyophilized Compositions:
  • the invention is directed to a lyophilized composition
  • a lyophilized composition Exemplary Lyophilized Compositions:
  • the invention is directed to a lyophilized composition
  • a lyophilized composition Exemplary Lyophilized Compositions:
  • the invention is directed to a lyophilized composition
  • a lyophilized composition Exemplary Lyophilized Compositions: [0082]
  • an intravenous solution comprising:
  • the invention is directed to an intravenous solution comprising:
  • the invention is directed to an intravenous solution comprising:
  • the invention is directed to an intravenous solution comprising:
  • the invention is directed to an intravenous solution comprising: Exemplary intravenous solutions (total percentage cannot exceed 100%) in diluent:
  • any of the intravenous solutions listed in the tables above further comprise an intravenous an intravenous infusion fluid.
  • the intravenous infusion fluid comprises about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
  • the salt is sodium chloride.
  • the sodium chloride is about 0.8%) to about 1.0% sodium chloride.
  • the sugar is glucose or dextrose.
  • the sugar is dextrose at a concentration of about 2% to about 5% (w/v) dextrose.
  • the intravenous solutions as described herein have less than 50% of alcohol, less than 40% of alcohol, less than 30% of alcohol, less than 20% of alcohol, less than 10%) of alcohol, less than 5% of alcohol, less than 3% of alcohol, less than 2% of alcohol, less than 1%) of alcohol, or less than 0.5% of alcohol. In some embodiments, the intravenous solutions as described herein do no comprise alcohol.
  • the irritating chemotherapy drug is carmustine.
  • Such intravenous delivery system includes a lyophilized mass of carmustine, and a diluent comprising soybean oil, safflower oil, egg phospholipids, glycerin and water.
  • a diluent comprising soybean oil, safflower oil, egg phospholipids, glycerin and water.
  • carmustine Upon reconstitution with the diluent, carmustine is dispersed or dissolved in the diluent.
  • Sterile Water for Injection USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a stable system is obtained and can be administered intravenously.
  • a representative intravenous delivery system according to the present invention is shown in Table 2 below.
  • a representative intravenous delivery system according to the present invention is shown in Table 3 below.
  • a representative intravenous delivery system according to the present invention is shown in Table 4 below.
  • a representative intravenous delivery system according to the present invention is shown in Table 6 below.
  • a representative intravenous delivery system according to the present invention is shown in Table 9 below.
  • a representative intravenous delivery system according to the present invention is shown in Table 10 below.
  • a representative intravenous delivery system according to the present invention is shown in Table 11 below.
  • a representative intravenous delivery system according to the present invention is shown in Table 12 below.
  • a synergistic solubility enhancement effect on the aqueous solubility of carmustine was discovered for the combination of a cyclic oligosaccharides with at least 6 pyranose units and a globular protein.
  • the cyclic oligosaccharides with at least 6 pyranose units was sulfobutyl ether ⁇ -cyclodextrin sodium and the globular protein was albumin.
  • the solubility increment due to the presence of 20% w/v albumin is 1.4 mg/mL, while the enhancement due to the presence of 20%w/v sulfobutyl ether ⁇ -cyclodextrin sodium is 11.1 mg/mL.
  • the calculated arithmetic contribution from the combination of albumin and sulfobutyl ether ⁇ -cyclodextrin sodium is 12.5 mg/mL, which corresponds to a theoretical carmustine solubility of 16.6 mg/mL.
  • the actual solubility of carmustine in the combined aqueous system of 20% w/v and 20%w/v sulfobutyl ether ⁇ -cyclodextrin sodium is 18.7 mg/mL, which is almost 13% higher than the calculated arithmetic contribution.
  • EXAMPLE 15 105 A representative intravenous delivery system of carmustine according to the present invention is shown in Table 15 below, then reconstituted in water.
  • Carmustine was solubilized with a solubilizer selected from cyclic oligosaccharides with at least 6 pyranose units (such as sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex sulfobutyl ether sodium). Lyophilized mass comprising carmustine and the solubilizer was obtained after lyophilization. Upon aqueous reconstitution with less than 10 mL purified water, a clear carmustine intravenous delivery system was achieved.
  • the reconstituted carmustine aqueous intravenous delivery system showed significant levels of impurities upon storage at 2°-8°C (Table 14). However, these impurity levels were less than those generated from the carmustine intravenous delivery system without any solubilizers.
  • a representative intravenous delivery system of carmustine according to the present invention is shown in Table 16 below, then reconstituted in water.
  • Carmustine was solubilized with a solubilizer selected from cyclic oligosaccharides with at least 6 pyranose units (such as sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex sulfobutyl ether sodium), globular proteins (such as albumin), and combinations thereof; and stabilized with a stabilizer selected from polar amino acids (such as cysteine), globular proteins (such as albumin), and combinations thereof. Lyophilized mass comprising carmustine, the solubilizer and the stabilizer was obtained after lyophilization.
  • a representative intravenous delivery system of carmustine according to the present invention is shown in Table 17 below which was then reconstituted in water.
  • Carmustine was solubilized with a solubilizer selected from cyclic oligosaccharides with at least 6 pyranose units (such as sulfobutyl ether ⁇ -cyclodextrin sodium, or betadex sulfobutyl ether sodium), globular proteins (such as albumin), and combinations thereof; and stabilized with a stabilizer selected from polar amino acids (such as cysteine), globular proteins (such as albumin), and combinations thereof. Lyophilized mass comprising carmustine, the solubilizer and the stabilizer was obtained after lyophilization.

Abstract

The present disclosure is related to an intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprising, (a) a lyophilized mass comprising the chemotherapy drug; and (b) a diluent capable of dispersing the mass, wherein the diluent is compatible with intravenous infusion fluids and is suitable for intravenous administration; wherein when the diluent disperses the mass and is placed in intravenous infusion fluids, the intravenous delivery system provides for reduced injection site reaction for a subject administered the intravenous infusion fluids.

Description

INTRAVENOUS DELIVERY SYSTEMS FOR CHEMOTHERAPY DRUGS
FIELD OF THE INVENTION
[0001] The present disclosure relates to intravenous delivery systems for chemotherapy drugs, e.g., irritating chemotherapy drugs. More specifically, the present disclosure is related to an intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprising, (a) a lyophilized mass comprising the irritating chemotherapy drug; and (b) a diluent capable of dispersing the mass; wherein the diluent disperses the mass when combined with the mass, wherein when the mass and diluent are combined with an intravenous infusion fluid to form an intravenous solution comprising the drug, and wherein the intravenous solution comprising the drug provides for reduced injection site reaction when administered to a subject.
BACKGROUND OF THE INVENTION
[0002] Most chemotherapy drugs are cytotoxic, therefore frequently having severe side effects.
Moreover, most chemotherapy drugs are delivered intravenously, consequently often causing injection site reactions, inflammation in and/or damage to the tissue surrounding where a drug is injected. One type of injection site reactions is a local reaction, called a flare reaction. Symptoms of the flare reaction include tenderness, redness, burning, and pain at the site of the injection or along the vein. The other type of injection site reactions is a more severe reaction and is caused by extravasation, a leakage of an irritating chemotherapy drug from the blood vessel at the site of injection. Symptoms of the more severe extravasation reaction may initially be the same as the local flare reaction, and subsequently further include pain, edema, blistering, necrosis and severe skin damage.
[0003] Chemotherapy drugs can be classified, according to their potential to cause inflammation and/or damage to the tissue surrounding the injection site, into five categories of vesicants, exfoliants, irritants, inflammitants, and neutrals. Irritating chemotherapy drugs include, but not limited to vesicants, exfoliants, irritants, and inflammitants. Vesicants are drugs with the highest potential to cause tissue destruction. Varying degrees of pain, edema, erythema, blistering and necrosis may occur.
[0004] Carmustine is cell-cycle phase nonspecific, bifunctional, alkylating agent. It alkylates DNA and RNA, cross-links DNA, and inhibits several enzymes by carbamoylation. Carmustine is currently marketed under the brand name of BiCNU in the United States of America.
BiCNU® (carmustine for injection) is indicated for the treatment of brain tumors and various other malignant neoplasms. Each package of BiCNU® includes a vial containing 100 mg lyophilized carmustine and a vial containing 3 mL sterile diluent of Dehydrated Alcohol Injection, USP. The recommended dose of BiCNU® as a single agent in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. Administer as a single dose or divided into daily injections such as 75 to 100 mg/m2 on two successive days.
[0005] Prescribing information instructs that BiCNU® lyophile be dissolved with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP), then aseptically diluted with 27 mL Sterile Water for Injection, USP. The resulting solution contains 3.3 mg of BiCNU®/lmL in 10% ethanol. Once reconstituted, the solution is further diluted with Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The reconstituted solution can be administered to a subject by slow intravenous infusion over at least two hours. Administration of BiCNU® over a period of less than two hours can lead to pain and burning at the site of injection.
[0006] Carmustine is recognized as a vesicant. Therefore, the injection side reactions of BiCNU® include both the local flare reaction and the more severe extravasation reaction if extravasated. The local flare reaction such as burning at the injection site, or along the course of the vein, is common during carmustine administration, even when the reconstituted drug solution is administered by slow intravenous infusion over more than two hours. In addition, due to the high alcohol content of the diluent, side effects also include cardiovascular effect of hypotension, and dermatology/skin effect of flushing. See, e.g., Carmustine, BC Cancer Agency Cancer Drug Manual, Revised: April 2007, 1 September 2010, 1 August 2011).
SUMMARY OF THE INVENTION
[0007] The present disclosure provides intravenous delivery systems for chemotherapy drugs, e.g., irritating chemotherapy drugs, that may alleviate the injection site local flare reaction during drug administration. The present invention also provides intravenous delivery systems for chemotherapy drugs, e.g., irritating chemotherapy drugs, that may alleviate the injection site more severe extravasation reaction if extravasated.
[0008] In some embodiments, the disclosure is directed to an intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprising, (a) a lyophilized mass comprising the chemotherapy drug; and (b) a diluent capable of dispersing the mass; wherein the diluent disperses the mass when combined with the mass, wherein when the mass and diluent are combined with an intravenous infusion fluid to form an intravenous solution comprising the drug, and wherein the intravenous solution comprising the drug provides for reduced injection site reaction when administered to a subject. In some embodiments, the irritating chemotherapy drug is carmustine.
[0009] In some embodiments, the disclosure is directed to an intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprising, (a) an chemotherapy drug; (b) a solubilizer; and (c) a diluent free of non-aqueous solvent capable of dispersing the composition; wherein the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof; and wherein the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, β- cyclodextrin and γ-cyclodextrin, and globular proteins, and combinations thereof.
[0010] In some embodiments, the intravenous delivery system for the chemotherapy drug, e.g., the irritating chemotherapy drug, further comprises a stabilizer, wherein the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
[0011] In some embodiments, the chemotherapy drug, e.g., carmustine, is lyophilized with a solubilizer. In some embodiments, the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, and globular proteins, such as albumin, and combinations thereof.
[0012] In some embodiments, the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
[0013] In some embodiments, the disclosure is directed to an intravenous delivery system,
comprising: (a) a lyophilized mass comprising (i) carmustine, and (ii) a polymeric carrier selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof; and (b) a diluent capable of dispersing the mass, wherein the diluent comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
[0014] In some embodiments, the disclosure is directed to an intravenous delivery system,
comprising: (a) a lyophilized mass comprising (i) carmustine, (ii) a polymeric carrier selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof, and/or (iii) a biocompatible amphiphilic carrier selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof; and (b) a diluent capable of dispersing the mass, wherein the diluent comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400),
dimethylacetamide, and combinations thereof.
[0015] In some embodiments, the disclosure is directed to an intravenous delivery system,
comprising: (a) a lyophilized mass comprising carmustine; and (b) a diluent capable of dispersing the mass, wherein the diluent comprises water and/or an amphiphilic agent selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof.
[0016] In some embodiments, the disclosure is directed to an intravenous solution, comprising:
(a) carmustine; (b) a polymeric carrier selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof; (c) a diluent capable of dispersing the mass, wherein the diluent comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400),
dimethylacetamide, and combinations thereof, and (d) an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
[0017] In some embodiments, the disclosure is directed to an intravenous solution, comprising:
(a) carmustine; (b) a biocompatible amphiphilic carrier selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di- , and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta- cyclodextrin, hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15
hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof; (c) a diluent capable of dispersing the mass, wherein the diluent comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof, and (d) an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
[0018] In some embodiments, the disclosure is directed to an intravenous solution, comprising:
(a) carmustine; (b) a polymeric carrier selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof; (c) a biocompatible amphiphilic carrier selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta- cyclodextrin, hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15
hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof; (d) a diluent capable of dispersing the mass, wherein the diluent comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof, and (e) an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
[0019] In some embodiments, the disclosure is directed to an intravenous solution, comprising:
(a) carmustine; (b) a diluent capable of dispersing the mass, wherein the diluent comprises water and/or an amphiphilic agent selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin,
hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc- PEG)) and combinations thereof; and (c) an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
[0020] In some embodiments, the disclosure is directed to a method of administering a
chemotherapy drug, e.g., an irritating chemotherapy drug, to a subject in need thereof, the method comprising, (a) obtaining a lyophilized mass comprising a chemotherapy drug; (b) dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass, is compatible with an intravenous infusion fluid and is suitable for intravenous administration; (c) combining the dispersed mass in diluent of (b) with an intravenous infusion fluid to form an intravenous solution comprising the drug; and (d) administering the intravenous solution comprising the drug to a patient in need thereof.
[0021] In some embodiments, the disclosure is directed to a method of making an intravenous solution comprising a chemotherapy drug, e.g., an irritating chemotherapy drug, the method comprising, (a) obtaining a lyophilized mass comprising a chemotherapy drug; (b) dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass, is compatible with an intravenous infusion fluid and is suitable for intravenous administration; (c) combining the dispersed mass in diluent of (b) with the intravenous infusion fluid to form an intravenous solution comprising the chemotherapy drug.
[0022] In some embodiments, the disclosure is directed to a lyophilized composition for use in an intravenous solution, the composition comprising: (a) a chemotherapy drug; and (b) a solubilizer; wherein the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof; and wherein the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, and globular proteins, and combinations thereof. In some embodiments, the solubilizer is a globular protein, and the globular protein is albumin. In some embodiments, the solubilizer is sulfobutyl ether β-cyclodextrin sodium. In some embodiments, the solubilizer is the combination of sulfobutyl ether β-cyclodextrin sodium and albumin. In some embodiments, the lyophilized composition further comprises a stabilizer. In some embodiments, the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof. In some embodiments, the stabilizer is cysteine. In some embodiments, the stabilizer is albumin.
[0023] In some embodiments, the disclosure is directed to a lyophilized composition for use in an intravenous solution, the composition comprising: (a) carmustine and albumin; (b) carmustine and sulfobutyl ether β-cyclodextrin sodium; (c) carmustine, sulfobutyl ether β-cyclodextrin sodium and albumin, or (d) carmustine, sulfobutyl ether β-cyclodextrin sodium and cysteine. In some embodiments, the ratio of carmustine to albumin is 1 : 1 to 1 :50, the ratio of carmustine to sulfobutyl ether β-cyclodextrin sodium is 1 : 10 to 1 :30, the ratio of carmustine : sulfobutyl ether β-cyclodextrin sodium : albumin is 1 : 10: 1 to 1 :30:5, or the ratio of carmustine : sulfobutyl ether β-cyclodextrin sodium : cysteine is 1 : 10: 1 to 1 :30:5. In some embodiments, the lyophilized composition further comprises a stabilizer. In some embodiments, the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof. In some embodiments, the stabilizer is cysteine.
[0024] In some embodiments, the disclosure is directed to an intravenous delivery system
comprising: (a) the lyophilized compositions as described herein, and (b) a diluent capable of dispersing the chemotherapy drug and solubulizer, wherein (a) and (b) form the intravenous delivery system.
[0025] In some embodiments, the intravenous delivery system comprises, (a) carmustine, (b)a solubilizer selected from sulfobutyl ether β-cyclodextrin sodium, albumin, or combinations thereof; and (c) a diluent capable of dispersing the carmustine and solubilizer; wherein (a), (b) and (c) form the intravenous delivery system. In some embodiments, the intravenous delivery system further comprises a stabilizer. In some embodiments, the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and a globular protein, and combinations thereof. In some embodiments, the stabilizer is cysteine. In some embodiments, the stabilizer is a globular protein, and the globular protein is albumin. In some embodiments, diluent is water, saline solution, or dextrose aqueous solution.
[0026] In some embodiments, the disclosure is directed to an intravenous solution comprising (a) the intravenous delivery system as described herein, and (a) intravenous infusion fluid, wherein (a) and (b) form the intravenous solution.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention provides intravenous delivery systems for chemotherapy drugs, e.g., irritating chemotherapy drugs, that may alleviate the injection site local flare reaction, such as tenderness, redness, burning, and pain at the site of the injection or along the vein during drug administration. Injection site reactions during intravenous administration of chemotherapy drugs, e.g., irritating chemotherapy drugs, for cancer patients are particularly vulnerable, as subjects in need of chemotherapy agents already exhibit many physical and psychological problems.
Applicants describe herein systems and formulations for alleviating or reducing the injection site reactions, such as the local flare reaction and/or the more sever extravasation reaction during drug administration, which can benefit the subjects, e.g., cancer patients, receiving the chemotherapy drugs.
[0028] The present invention also provides intravenous delivery systems for a chemotherapy drug, e.g., an irritating chemotherapy drug, that may alleviate the injection site more severe extravasation reaction if extravasated, such as tenderness, redness, burning, and pain at the site of the injection or along the vein, edema, blistering, necrosis and severe skin damage.
[0029] In some embodiments, such intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprises a lyophilized mass of a chemotherapy drug, and a diluent, capable of dispersing the lyophilized drug, and compatible with intravenous infusion fluids such as 0.9% Sodium Chloride Injection or 5% Dextrose, USP for intravenous administration. In some embodiments, such intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprises a lyophilized mass which comprises a chemotherapy drug lyophilized with a polymeric carrier and/or a biocompatible amphiphilic carrier, and a diluent, capable of dispersing the co-lyophilized drug-polymeric/amphiphilic carrier, and compatible with intravenous infusion fluids such as 0.9% Sodium Chloride Injection or 5% Dextrose, USP for intravenous administration.
[0030] In some embodiments, the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof. In some embodiments, the chemotherapy drug is carmustine. In some embodiments, the chemotherapy drug is romidepsin.
[0031] In some embodiments, the intravenous system comprises co-administering a second
active agent. In some embodiments, the intravenous system comprises a chemotherapy drug and an antiemetic drug. In some embodiments, the intravenous system comprises carmustine and an antiemetic drug.
[0032] Various antiemetic drugs are known in the art to be useful when co-administered with a chemotherapy drug. In some embodiments, the antiemetic drug is a 5-HT receptor antagonist or an adopamine blocker. In some embodiments, the antiemetic drug is selected from the group consisting of odansetron (Zofiran), palonosetron (Aloxi), procholoperazine (Compazine), lorazepam (Ativan), aoreoitant (Emend), dolastetron (Anzemet), or granistetron (Kytril).
[0033] In some embodiments, the disclosure is directed to an intravenous delivery system for a chemotherapy drug, e.g., an irritating chemotherapy drug, comprising, (a) an chemotherapy drug; (b) a solubilizer; and (c) a diluent free of non-aqueous solvent capable of dispersing the composition; wherein the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof; and wherein the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, β- cyclodextrin and γ-cyclodextrin, and globular proteins, and combinations thereof. [0034] In some embodiments, the intravenous delivery system for the chemotherapy drug, e.g., irritating chemotherapy drug, further comprises a stabilizer, wherein the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof. In some embodiments, the stabilizer can be in the lyophilized mass with the chemotherapy drug and the solubilizer. In some embodiments, the stabilizer can be in the diluent.
[0035] In some embodiments, the chemotherapy drug, e.g., carmustine, is lyophilized with a solubilizer. In some embodiments, the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, and globular proteins, such as albumin, and combinations thereof.
[0036] In some embodiments, the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
[0037] In some embodiments, the chemotherapy drug, e.g., carmustine, is lyophilized with a solubilizer. In some embodiments, the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, and globular proteins, such as albumin, and combinations thereof.
[0038] In some embodiments, the stabilizer is selected from polar amino acids, such as cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
[0039] In some embodiments, any of the intravenous solutions described herein further comprise an intravenous infusion fluid. In some embodiments, the intravenous infusion fluid comprises about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar. In some embodiments, the salt is sodium chloride. In some embodiments, the sodium chloride is about 0.8% to about 1.0% sodium chloride. In some embodiments, the sugar is glucose or dextrose. In some embodiments, the sugar is dextrose at a concentration of about 2% to about 5% (w/v) dextrose.
[0040] Carmustine is freely soluble in ethanol, and slightly soluble in water (4.1 mg/mL).
Surprisingly, it was found that a globular protein, albumin significantly increased the aqueous solubility of carmustine. In addition, it was revealed that a cyclic oligosaccharides with at least 6 pyranose units, sulfobutyl ether β-cyclodextrin sodium tremendously increased the aqueous solubility of carmustine. Unexpectedly, it was further discovered that the combination of a cyclic oligosaccharides with at least 6 pyranose units and a globular protein provided a synergistic effect on the aqueous solubility of carmustine.
[0041] Moreover, carmustine is not generally stable. Generally, an unopened vial of the
carmustine lyophile must be stored in a refrigerator (2°-8°C, 36°-46°F). After reconstitution as recommended, BiCNU is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F). Vials reconstituted as directed and further diluted to a concentration of 0.2 mg/mL in 5% Dextrose Injection, USP, should be stored at room temperature, protected from light and utilized within 8 hours. The inventors have found although the solubilizer, the cyclic oligosaccharides with at least 6 pyranose units, sulfobutyl ether β-cyclodextrin sodium, increased the stability of carmustine aqueous solution when stored in the refrigerator (2°-8°C), there were still significant levels of impurities in the carmustine sulfobutyl ether β-cyclodextrin sodium aqueous solution upon storage. Surprisingly, the inventors discovered that the combination of a cyclic
oligosaccharides with at least 6 pyranose units, sulfobutyl ether β-cyclodextrin sodium and a globular protein, albumin significantly increased the stability of carmustine aqueous solution when stored in the refrigerator (2°-8°C). Only negligible amounts of impurity in the carmustine sulfobutyl ether β-cyclodextrin sodium/albumin aqueous solution upon storage were observed. Unexpectedly, the inventors also discovered that a polar amino acid, cysteine, significantly increases the aqueous stability of carmustine in the sulfobutyl ether β-cyclodextrin sodium solution while stored in a refrigerator (2°-8°C). Only negligible amounts of impurity in the carmustine sulfobutyl ether β-cyclodextrin sodium/cysteine aqueous solution upon storage were observed.
[0042] Various amounts of the chemotherapy drug, e.g., an irritating chemotherapy drug, can be used. The skilled artisan can adjust the dosage amount depending on the drug being
administered, the patient, and the condition being treated. In some embodiments, the intravenous delivery system is a single use dose. In some embodiments, the chemotherapy drug, e.g., irritating chemotherapy drug, is used in a dosage amount of about 10 mg to about 500 mg, about 20 mg to about 200 mg, about 30 mg to about 150 mg, about 40 mg to about lOOmg. In some embodiments, the chemotherapy drug is carmustine in a dosage amount of about 10 mg to about 500 mg, about 20 mg to about 200 mg, about 30 mg to about 150 mg, about 50 mg to about 150mg.
[0043] In some embodiments, the chemotherapy drug, e.g., carmustine, is lyophilized with a polymeric carrier. In some embodiments, the polymeric carrier is selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof. In some embodiments, the biocompatible amphiphilic carrier is selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof.
[0044] Various diluents can be used. In some embodiments, the diluent is compatible with
intravenous infusion fluids. In some embodiments, the diluent is suitable for intravenous administration. In some embodiments, the diluent comprises a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof. In some embodiments, the diluent comprises water. In some embodiments, the diluent comprises water and a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
[0045] In some embodiments, the diluent comprises an amphiphilic agent selected from
phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl
monostearate, sorbitan esters, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, gamma- cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof. In some embodiments, the diluent is water. In some embodiments, the diluent is 0.9% sodium chloride aqueous solution, or 5% dextrose aqueous solution. [0046] In some embodiments, the diluent comprises an oil selected from soybean oil, safflower oil, castor oil, sesame oil, cottonseed oil, sunflower oil, a glyceryl ester of fatty acid having melting point of less than 37°C, and combinations thereof.
[0047] Various volumes of diluent can be used. In some embodiments, the diluent is in a
volume of less than 500 ml, less than 400 ml, less than 300 ml, less than 200 ml, less than 100 ml, less than 80ml, less than 60ml, less than 50 ml, less than 40 ml, less than 30 ml, less than 20 ml, less than 10 ml, or less than 5 ml. In some embodiments, the diluent is in a volume of less than 20 ml. In some embodiments, the diluent is in a volume of less than 10 ml.
[0048] Various volumes of infusion fluids can be used to formulate the intravenous solutions as described herein. In some embodiments, the infusion fluid is in a volume of less than 500 ml, less than 400 ml, less than 300 ml, less than 200 ml, less than 100 ml, less than 80ml, less than 60ml, less than 50 ml, less than 40 ml, less than 30 ml, less than 20 ml, less than 10 ml, or less than 5 ml. In some embodiments, the infusion fluid is in a volume of less than 20 ml. In some embodiments, the infusion fluid is in a volume of less than 10 ml.
[0049] In some embodiments, such intravenous delivery system includes a lyophilized mass of a lipophilic chemotherapy drug, e.g., irritating chemotherapy drug, and a hydrophilic diluent capable of dispersing or dissolving the drug and compatible with intravenous infusion fluids such as 0.9% Sodium Chloride Injection or 5% Dextrose, USP for intravenous administration.
[0050] In some embodiments, the chemotherapy drug is an irritating chemotherapy drug.
Irritating chemotherapy drugs are known in the art, and include chemotherapy drugs that cause injection site reactions such as inflammation in and/or damage to the tissue surrounding where a drug is injected, including tenderness, redness, burning, and pain at the site of the injection or along the vein. In some embodiments, the term "irritating" when referring to a chemotherapy drug includes drugs which cause more severe injection site reaction, e.g., cause extravasation, a leakage of an irritating chemotherapy drug from the blood vessel at the site of injection.
Symptoms of the more severe extravasation reaction may initially be the same as the local flare reaction, and subsequently further include pain, edema, blistering, necrosis and severe skin damage.
[0051] Chemotherapy drugs can be classified, according to their potential to cause inflammation and/or damage to the tissue surrounding the injection site, into five categories of vesicants, exfoliants, irritants, inflammitants, and neutrals. In some embodiments, irritating chemotherapy drugs include, but are not limited to vesicants, exfoliants, irritants, and inflammitants. In some embodiments, the term "irritating chemotherapy drug" refers to vesicants. Vesicants are drugs with the highest potential to cause tissue destruction. Varying degrees of pain, edema, erythema, blistering and necrosis may occur.
[0052] In some embodiments, the intravenous delivery system as described herein has increased solubility relative to the chemotherapy drug dissolved in water. In some embodiments, a chemotherapy drug in an intravenous delivery system as described herein has a 10%, 25%, 50%, 75%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 500%, 600%, 700% or 800% increase in solubility relative to the same chemotherapy drug dissolved in water. In some embodiments, the actual solubility of the chemotherapy drug in an intravenous delivery system as described herein is 5%), 10%), 15%), 20%), or 30%> higher compared to the calculated solubility of the chemotherapy drug in the intravenous delivery system.
[0053] In some embodiments, the intravenous delivery system as described herein provides for increased stability of the chemotherapy drug. In some embodiments, the increased stability reduces the impurities, e.g., degradation products, in the intravenous delivery system. In some embodiments, the increase stability provided by the intravenous delivery system as described herein provides for a more consistent dosing profile. In some embodiments, the increased stability provided by the intravenous delivery system as described herein allows the delivery system to be suitable for use for a longer period of time.
[0054] In some embodiments, the intravenous delivery system as described herein provides for a 30%) reduction in impurities after 2 days when stored at 2-8 °C compared to the same
chemotherapy drug in water. In some embodiments, the intravenous delivery system as described herein provides for a 40% reduction, 50%> reduction, 60%> reduction, a 70% reduction, a 80%) reduction or a 90% reduction in impurities after 2 days when stored at 2-8 °C compared to the same chemotherapy drug in water. For example, if an intravenous delivery system comprising on a chemotherapy drug and water produced >3%> impurities, and the intravenous delivery system as described herein produced 0.3% impurities, that would constitute a >90%> reduction in impurities. In some embodiments, the intravenous delivery system as described herein provides for a 30% reduction, 40% reduction, 50% reduction, 60% reduction, a 70% reduction, a 80% reduction, 90% reduction, or 95% reduction in impurities after 3 days when stored at 2-8 °C compared to the same chemotherapy drug in water. [0055] In some embodiments, the irritating chemotherapy drug is carmustine. In some embodiments, the intravenous delivery system can include a lyophilized mass of carmustine and a diluent of benzyl alcohol. In some embodiments, the intravenous delivery system can include a lyophilized mass of carmustine, water and a diluent of benzyl alcohol. Upon reconstitution with water, the diluent or a combination of water and diluent, a solution is obtained. In some embodiments, upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, USP, a solution is obtained and can be administered intravenously.
[0056] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system can include a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising benzyl alcohol and ethanol alcohol. In some embodiments, the intravenous delivery system can include a co- lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising water, benzyl alcohol and ethanol alcohol. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0057] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a lyophilized mass of carmustine, and a diluent comprising polyoxyl 60 hydrogenated castor oil and ethanol alcohol. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0058] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising polyoxyl 60 hydrogenated castor oil and ethanol alcohol. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0059] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a lyophilized mass of carmustine, and a diluent comprising gamma-cyclodextrin, benzyl alcohol and ethanol alcohol. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0060] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising gamma-cyclodextrin, benzyl alcohol and ethanol alcohol. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0061] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a lyophilized mass of carmustine, and a diluent comprising Soluplus, benzyl alcohol and ethanol alcohol. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0062] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone, and a diluent comprising Soluplus, benzyl alcohol and ethanol alcohol. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0063] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polyoxyl 35 hydrogenated castor oil (Cremophor EL), and a diluent comprising lecithin, polysorbate 80 and purified water. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0064] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polyoxyl 35 hydrogenated castor oil (Cremophor EL), and a diluent comprising lecithin, polysorbate 80 and ethanol alcohol. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0065] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polyoxyl 35 hydrogenated castor oil (Cremophor EL), and a diluent comprising lecithin, polysorbate 80, ethanol alcohol and purified water. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0066] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polysorbate 80, and a diluent comprising lecithin, polysorbate 80 and purified water. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0067] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polysorbate 80, and a diluent comprising lecithin, polysorbate 80 and ethanol alcohol. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0068] In some embodiments, the irritating chemotherapy drug is carmustine. In some
embodiments, the intravenous delivery system includes a co-lyophilized mass of carmustine dispersed in a polymeric carrier of povidone and a biocompatible amphiphilic carrier of polysorbate 80, and a diluent comprising lecithin, polysorbate 80, ethanol alcohol and purified water. Upon reconstitution with the diluent, a solution is obtained. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a solution is obtained and can be administered intravenously.
[0069] In some embodiments, the disclosure is directed to a method of administering a
chemotherapy drug, e.g., an irritating chemotherapy drug, to a subject in need thereof, the method comprising, (a) obtaining a lyophilized mass comprising a chemotherapy drug; (b) dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass; (c) combining the dispersed mass in diluent of (b) with an intravenous infusion fluid to form an intravenous solution comprising the drug; and (d) administering the intravenous solution comprising the drug to a patient in need thereof. In some embodiments, the method provides for reduced injection site reaction for a subject administered the intravenous solution.
[0070] In some embodiments, the disclosure is directed to a method of making an intravenous solution comprising a chemotherapy drug, e.g., an irritating chemotherapy drug, the method comprising, (a) obtaining a lyophilized mass comprising a chemotherapy drug; (b) dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass; and (c) combining the dispersed mass in diluent of (b) with the intravenous infusion fluid to form an intravenous solution comprising the chemotherapy drug.
[0071] In some embodiments, the disclosure is directed to a lyophilized composition for use in an intravenous solution, the composition comprising: (a) a chemotherapy drug, e.g., an irritating chemotherapy drug; (b) a solubilizer; and (c) a diluent capable of dispersing the composition ; wherein the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof; and wherein the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, β-cyclodextrin and γ- cyclodextrin, and globular proteins, and combinations thereof.
[0072] In some embodiments, the solubilizer is a globular protein, and the globular protein is albumin. In some embodiments, the solubilizer is sulfobutyl ether β-cyclodextrin sodium. In some embodiments, the solubilizer is the combination of sulfobutyl ether β-cyclodextrin sodium and albumin. In some embodiments, the lyophilized compositions described herein further comprise a stabilizer. In some embodiments, the stabilizer in the lyophilized composition is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof. In some embodiments, the stabilizer in the lyophilized composition is cysteine. In some embodiments, the stabilizer in the lyophilized composition is albumin.
[0073] In some embodiments, the disclosure is directed to a lyophilized composition for use in an intravenous solution, the composition comprising: (a) carmustine and albumin; (b) carmustine and sulfobutyl ether β-cyclodextrin sodium; or (c) carmustine, sulfobutyl ether β-cyclodextrin sodium and ablumin. In some embodiments, the ratio of carmustine to albumin is 1 : 1 to 1 :50, the ratio of carmustine to sulfobutyl ether β-cyclodextrin sodium is 1 : 10 to 1 :30, or the ratio of carmustine : sulfobutyl ether β-cyclodextrin sodium : albumin is 1 : 10: 1 to 1 :30:5.
[0074] In some embodiments, the composition comprising: (a) carmustine and albumin; (b) carmustine and sulfobutyl ether β-cyclodextrin sodium; or (c) carmustine, sulfobutyl ether β- cyclodextrin sodium and a stabilizer cysteine. In some embodiments, the ratio of carmustine to albumin is 1 : 1 to 1 : 50, the ratio of carmustine to sulfobutyl ether β-cyclodextrin sodium is 1 : 10 to 1 :30, or the ratio of carmustine : sulfobutyl ether β-cyclodextrin sodium : cysteine is 1 : 10: 1 to 1 :30:5.
[0075] In some embodiments, the disclosure is directed to an intravenous solution comprising (a) carmustine, (b) a solubilizer selected from sulfobutyl ether β-cyclodextrin sodium, albumin, or combinations thereof; (c) a stabilizer selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof; (d) a diluent capable of dispersing the carmustine and solubilizer; wherein a, b and c form an intravenous solution. In some
embodiments, the stabilizer is cysteine. In some embodiments, the diluent in the intravenous solution is water, saline solution, or dextrose aqueous solution. In some embodiments, the diluent in the intravenous solution is water, saline solution, or 5% dextrose aqueous solution.
[0076] In some embodiments, the invention is directed to a lyophilized composition as follows:
Exemplary Lyophilized Compositions:
Figure imgf000020_0001
[0077] In some embodiments, the invention is directed to a lyophilized composition Exemplary Lyophilized Compositions:
Figure imgf000021_0001
[0078] In some embodiments, the invention is directed to a lyophilized composition Exemplary Lyophilized Compositions:
Figure imgf000021_0002
[0079] In some embodiments, the invention is directed to a lyophilized composition Exemplary Lyophilized Compositions:
Figure imgf000021_0003
[0080] In some embodiments, the invention is directed to a lyophilized composition Exemplary Lyophilized Compositions:
Figure imgf000021_0004
[0081] In some embodiments, the invention is directed to a lyophilized composition Exemplary Lyophilized Compositions:
Figure imgf000021_0005
[0082] In some embodiments, the invention is directed to an intravenous solution comprising:
Exemplary intravenous solutions (total percentage cannot exceed 100%) in diluent:
Figure imgf000022_0001
[0083] In some embodiments, the invention is directed to an intravenous solution comprising:
Exemplary intravenous solutions (total percentage cannot exceed 100%) in diluent:
Figure imgf000022_0002
[0084] In some embodiments, the invention is directed to an intravenous solution comprising:
Exemplary intravenous solutions (total percentage cannot exceed 100%) in diluent:
Figure imgf000022_0003
[0085] In some embodiments, the invention is directed to an intravenous solution comprising:
Exemplary intravenous solutions (total percentage cannot exceed 100%) in diluent:
Figure imgf000022_0004
[0086] In some embodiments, the invention is directed to an intravenous solution comprising: Exemplary intravenous solutions (total percentage cannot exceed 100%) in diluent:
Figure imgf000023_0001
[0087] In some embodiments, any of the intravenous solutions listed in the tables above further comprise an intravenous an intravenous infusion fluid. In some embodiments, the intravenous infusion fluid comprises about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar. In some embodiments, the salt is sodium chloride. In some embodiments, the sodium chloride is about 0.8%) to about 1.0% sodium chloride. In some embodiments, the sugar is glucose or dextrose. In some embodiments, the sugar is dextrose at a concentration of about 2% to about 5% (w/v) dextrose.
[0088] In some embodiments, the intravenous solutions as described herein have less than 50% of alcohol, less than 40% of alcohol, less than 30% of alcohol, less than 20% of alcohol, less than 10%) of alcohol, less than 5% of alcohol, less than 3% of alcohol, less than 2% of alcohol, less than 1%) of alcohol, or less than 0.5% of alcohol. In some embodiments, the intravenous solutions as described herein do no comprise alcohol.
[0089] In some embodiments, the irritating chemotherapy drug is carmustine. Such intravenous delivery system includes a lyophilized mass of carmustine, and a diluent comprising soybean oil, safflower oil, egg phospholipids, glycerin and water. Upon reconstitution with the diluent, carmustine is dispersed or dissolved in the diluent. Upon further reconstitution with Sterile Water for Injection, USP, and/or 0.9% Sodium Chloride Injection or 5% Dextrose, a stable system is obtained and can be administered intravenously.
EXAMPLES
EXAMPLE 1
[0090] A representative intravenous delivery system according to the present invention is shown in Table 1 below. Table 1
Figure imgf000024_0001
EXAMPLE 2
[0091] A representative intravenous delivery system according to the present invention is shown in Table 2 below.
Table 2
Figure imgf000024_0002
EXAMPLE 3
[0092] A representative intravenous delivery system according to the present invention is shown in Table 3 below.
Table 3
Figure imgf000025_0001
EXAMPLE 4
[0093] A representative intravenous delivery system according to the present invention is shown in Table 4 below.
Table 4
Figure imgf000025_0002
EXAMPLE 5
[0094] A representative intravenous delivery system according to the present invention is shown in Table 5 below. Table 5
Figure imgf000026_0001
EXAMPLE 6
[0095] A representative intravenous delivery system according to the present invention is shown in Table 6 below.
Table 6
Figure imgf000026_0002
EXAMPLE 7
[0096] A representative intravenous delivery system according to the present invention is shown in Table 7 below. Table 7
Figure imgf000027_0001
EXAMPLE 8
7] A representative intravenous delivery system according to the present invention is shown in Table 8 below.
Table 8
Figure imgf000027_0002
EXAMPLE 9
[0098] A representative intravenous delivery system according to the present invention is shown in Table 9 below.
Table 9
Figure imgf000028_0001
EXAMPLE 10
[0099] A representative intravenous delivery system according to the present invention is shown in Table 10 below.
Table 10
Figure imgf000028_0002
EXAMPLE 11
[00100] A representative intravenous delivery system according to the present invention is shown in Table 11 below.
Table 11
Figure imgf000029_0001
EXAMPLE 12
[00101] A representative intravenous delivery system according to the present invention is shown in Table 12 below.
Table 12
Figure imgf000029_0002
Egg phospholipids 2
Glycerin 5
Water q.s. to 100
EXAMPLE 13
102] Surprisingly, as depicted in Table 13, it was found that a globular protein, albumin at a concentration of about 20% w/v significantly increased the aqueous solubility of carmustine from 4.1 mg/mL to about 5.5 mg/mL. A cyclic oligosaccharides with at least 6 pyranose units, sulfobutyl ether β-cyclodextrin sodium at a concentration of about 20% w/v tremendously increased the aqueous solubility of carmustine to approximately 15.2 mg/mL. Moreover, unexpectedly, a synergistic solubility enhancement effect on the aqueous solubility of carmustine was discovered for the combination of a cyclic oligosaccharides with at least 6 pyranose units and a globular protein. In this Example the cyclic oligosaccharides with at least 6 pyranose units was sulfobutyl ether β-cyclodextrin sodium and the globular protein was albumin. The solubility increment due to the presence of 20% w/v albumin is 1.4 mg/mL, while the enhancement due to the presence of 20%w/v sulfobutyl ether β-cyclodextrin sodium is 11.1 mg/mL. The calculated arithmetic contribution from the combination of albumin and sulfobutyl ether β-cyclodextrin sodium is 12.5 mg/mL, which corresponds to a theoretical carmustine solubility of 16.6 mg/mL. However, the actual solubility of carmustine in the combined aqueous system of 20% w/v and 20%w/v sulfobutyl ether β-cyclodextrin sodium is 18.7 mg/mL, which is almost 13% higher than the calculated arithmetic contribution.
Table 13
Solubility
Composition in deionized water (% w/v) (mg/mL)
Actual Calculated
Carmustine in water 4.1 -
Carmustine in ~ 20% albumin/0.1%) citric acid aqueous
5.5 - solution
Carmustine in ~ 20% sulfobutyl ether β-cyclodextrin
15.2 - sodium/0.1%) citric acid aqueous solution
Carmustine in ~ 20% albumin/20%) sulfobutyl ether β-
18.7 16.6 cyclodextrin sodium/0.1%) citric acid aqueous solution EXAMPLE 14
[00103] As depicted in Table 14, it was found although the solubilizer, the cyclic oligosaccharides with at least 6 pyranose units, sulfobutyl ether β-cyclodextrin sodium, increased the stability of carmustine aqueous solution when stored in the refrigerator (2°-8°C), there were still significant levels of impurities in the carmustine sulfobutyl ether β-cyclodextrin sodium aqueous solution upon storage. The presence of about 20% w/v sulfobutyl ether β-cyclodextrin sodium in the aqueous solution reduced the impurity of carmustine from 3.69% to 1.63% on day 2, and 6.02%> to 2.73%) on day 3 respectively. Surprisingly, it was discovered that the combination of a cyclic oligosaccharides with at least 6 pyranose units, sulfobutyl ether β-cyclodextrin sodium and a globular protein, albumin significantly increased the stability of carmustine aqueous solution when stored in the refrigerator (2°-8°C). There was only negligible amounts of impurity in the carmustine sulfobutyl ether β-cyclodextrin sodium/albumin aqueous solution upon storage. The combination of about 20%> w/v sulfobutyl ether β-cyclodextrin sodium and about 4%> albumin further decreased the impurity of carmustine to 0.31%> on day 2, and 0.32%> on day 4
respectively.
[00104] Unexpectedly, it was also discovered that a polar amino acid, cysteine, also significantly increased the aqueous stability of carmustine in the sulfobutyl ether β-cyclodextrin sodium solution while stored in a refrigerator (2°-8°C). There was also only negligible amounts of impurity in the carmustine sulfobutyl ether β-cyclodextrin sodium/cysteine aqueous solution upon storage. The carmustine aqueous solution containing about 20%> w/v sulfobutyl ether β- cyclodextrin sodium and about 4%> w/v cysteine was stable up to 3 days with a total impurity of about 0.6%.
Table 14
Figure imgf000032_0001
EXAMPLE 15 105] A representative intravenous delivery system of carmustine according to the present invention is shown in Table 15 below, then reconstituted in water. Carmustine was solubilized with a solubilizer selected from cyclic oligosaccharides with at least 6 pyranose units (such as sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium). Lyophilized mass comprising carmustine and the solubilizer was obtained after lyophilization. Upon aqueous reconstitution with less than 10 mL purified water, a clear carmustine intravenous delivery system was achieved. The reconstituted carmustine aqueous intravenous delivery system showed significant levels of impurities upon storage at 2°-8°C (Table 14). However, these impurity levels were less than those generated from the carmustine intravenous delivery system without any solubilizers.
Table 15
Figure imgf000032_0002
: Removed during the manufacturing process. EXAMPLE 16
[00106] A representative intravenous delivery system of carmustine according to the present invention is shown in Table 16 below, then reconstituted in water. Carmustine was solubilized with a solubilizer selected from cyclic oligosaccharides with at least 6 pyranose units (such as sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium), globular proteins (such as albumin), and combinations thereof; and stabilized with a stabilizer selected from polar amino acids (such as cysteine), globular proteins (such as albumin), and combinations thereof. Lyophilized mass comprising carmustine, the solubilizer and the stabilizer was obtained after lyophilization. Upon aqueous reconstitution with less than 10 mL purified water, a clear carmustine intravenous delivery system was achieved. The reconstituted carmustine aqueous intravenous delivery system displayed negligible amounts of impurity upon storage at 2°-8°C (Table 14).
Table 16
Figure imgf000033_0001
: Removed during the manufacturing process.
EXAMPLE 17
[00107] A representative intravenous delivery system of carmustine according to the present invention is shown in Table 17 below which was then reconstituted in water. Carmustine was solubilized with a solubilizer selected from cyclic oligosaccharides with at least 6 pyranose units (such as sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium), globular proteins (such as albumin), and combinations thereof; and stabilized with a stabilizer selected from polar amino acids (such as cysteine), globular proteins (such as albumin), and combinations thereof. Lyophilized mass comprising carmustine, the solubilizer and the stabilizer was obtained after lyophilization. Upon aqueous reconstitution with less than 10 mL purified water, a clear carmustine intravenous delivery system was achieved. The reconstituted carmustine aqueous intravenous delivery system exhibited negligible amounts of impurity upon storage at 2°-8°C (Table 14).
Table 17
Figure imgf000034_0001
: Removed during the manufacturing process.

Claims

What is claimed is:
1. An intravenous delivery system for a chemotherapy drug comprising,
a. a lyophilized mass comprising the chemotherapy drug; and
b. a diluent capable of dispersing the mass;
wherein the diluent disperses the mass when combined with the mass, wherein when the mass and diluent are combined with an intravenous infusion fluid to form an intravenous solution comprising the drug, and wherein the intravenous solution comprising the drug provides for reduced injection site reaction when administered to a subject.
2. The intravenous delivery system of claim 1, wherein the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof.
3. The intravenous delivery system of claim 2, wherein the chemotherapy drug is
carmustine.
4. The intravenous delivery system of claim 2, wherein the chemotherapy drug is
romidepsin.
5. The intravenous delivery system of any one of claims 1 to 4, wherein the lyophilized mass comprises a solubilizer.
6. The intravenous delivery system of claim 5, wherein the solubilizer is selected from
cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium, a- cyclodextrin, hydroxypropyl-P-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, a globular protein, and combinations thereof.
7. The intravenous delivery system of claim 6, wherein the solubilizer is sulfobutyl ether β- cyclodextrin sodium.
8. The intravenous delivery system of claim 6, wherein the globular protein is albumin.
9. The intravenous delivery system of claim 6, wherein the solubilizer is the combination of sulfobutyl ether β-cyclodextrin sodium and albumin.
10. The intravenous delivery system of any one of claims 1 to 9, wherein the lyophilized mass further comprises a stabilizer.
11. The intravenous delivery system of claim 9, wherein the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, a globular protein, and combinations thereof.
12. The intravenous delivery system of claim 11, wherein the stabilizer is cysteine.
13. The intravenous delivery system of claim 11, wherein the globular protein is albumin.
14. The intravenous delivery system of any one of claims 1 to 13, wherein the intravenous infusion fluid comprises about 0.5% to 1.5% (w/v) salt or about 2% to about 15% (w/v) sugar.
15. The intravenous delivery system of claim 14, wherein the salt is sodium chloride.
16. The intravenous delivery system of claim 15, wherein the sodium chloride is about 0.8% to about 1.0% sodium chloride.
17. The intravenous delivery system of claim 14, wherein the sugar is glucose or dextrose.
18. The intravenous delivery system of claim 17, wherein the sugar is dextrose at a
concentration of about 2% to about 5% (w/v) dextrose.
19. The intravenous delivery system of any one of claims 1 to 18, wherein the lyophilized mass further comprises a polymeric carrier.
20. The intravenous delivery system of claim 19, wherein the polymeric carrier is selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof.
21. The intravenous delivery system of claim 19, wherein the polymeric carrier is povidone.
22. The intravenous delivery system of any one of claims 1 to 21, wherein the lyophilized mass further comprises a biocompatible amphiphilic carrier.
23. The intravenous delivery system of claim 22, wherein the biocompatible amphiphilic carrier is selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, polyoxyl 15
hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof.
24. The intravenous delivery system of claim 22, wherein the biocompatible amphiphilic carrier is polysorbate 80.
25. The intravenous delivery system of claim 22, wherein the biocompatible amphiphilic carrier is polyoxyl 35 hydrogenated castor oil.
26. The intravenous delivery system of any one of claims 1 to 25, wherein the diluent
comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
27. The intravenous delivery system of claim 26, wherein the diluent comprises benzyl
alcohol.
28. The intravenous delivery system of claim 26, wherein the diluent comprises ethanol alcohol.
29. The intravenous delivery system of claim 26, wherein the diluent comprises benzyl
alcohol and ethanol alcohol.
30. The intravenous delivery system of any one of claims 1 to 29, wherein the diluent
comprises water.
31. The intravenous delivery system of any one of claims 1 to 30, wherein the diluent comprises an amphiphilic agent phospholipids, polysorbate n, wherein n = 20 to 80, bile acids and salts, cholesterol, polyoxyl n castor oil, wherein n = 30 to 40, polyoxyl n hydrogenated castor oil, wherein n = 40 to 60, mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin,
hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof.
32. The intravenous delivery system of claim 31, wherein the amphiphilic agent
phospholipids is egg lecithin, the bile acid is glyocholic acid.
33. The intravenous delivery system of claim 31, wherein the diluent comprises polyoxyl n hydrogenated castor oil, wherein n = 40 to 60.
34. The intravenous delivery system of claim 31, wherein the diluent comprises polyoxyl 60 hydrogenated castor oil.
35. The intravenous delivery system of claim 31, wherein the diluent comprises polysorbate 80.
36. The intravenous delivery system of any one of claims 1 to 35, wherein the diluent
comprises lecithin.
37. The intravenous delivery system of any one of claims 1 to 36, wherein the diluent
comprises an oil selected from soybean oil, safflower oil, castor oil, sesame oil, cottonseed oil, sunflower oil, a glyceryl ester of fatty acid having melting point of less than 37°C, and combinations thereof.
38. The intravenous delivery system of claim 37, wherein the diluent comprises soybean oil.
39. The intravenous delivery system of claim 37, wherein the diluent comprises safflower oil.
40. The intravenous delivery system of any one of claims 1 to 39, wherein the diluent
comprises less than 50% of alcohol.
41. The intravenous delivery system of any one of claims 1 to 40, wherein the chemotherapy drug is carmustine in an amount of 50 mg to 150 mg.
42. The intravenous delivery system of any one of claims 1 to 41, wherein the diluent is in a volume of less than 20 ml.
43. The intravenous delivery system of any one of claims 1 to 41, wherein the diluent is in a volume of less than 10 ml.
44. An intravenous delivery system, comprising:
a. a lyophilized mass comprising (i) carmustine, and (ii) a polymeric carrier selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof; and
b. a diluent capable of dispersing the mass, wherein the diluent comprises a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
45. An intravenous delivery system, comprising:
a. a lyophilized mass comprising (i) carmustine, (ii) a polymeric carrier selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof; and/or (iii) a biocompatible amphiphilic carrier selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof; and b. a diluent capable of dispersing the mass, wherein the diluent comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
46. An intravenous delivery system, comprising:
a. a lyophilized mass comprising carmustine; and
b. a diluent capable of dispersing the mass, wherein the diluent comprises an
amphiphilic agent selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin, hydroxypropyl beta- cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof.
47. An intravenous solution, comprising:
a. carmustine;
b. a polymeric carrier selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof; and
c. a diluent capable of dispersing the mass, wherein the diluent comprises a
hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
48. An intravenous solution, comprising:
a. carmustine;
b. a biocompatible amphiphilic carrier selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof; and
c. a diluent capable of dispersing the mass, wherein the diluent comprises a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
49. An intravenous solution, comprising:
a. carmustine;
b. a polymeric carrier selected from povidone, high molecular weight polyethylene glycol (such as PEG 4000), sodium carboxymethyl cellulose, and combinations thereof;
c. a biocompatible amphiphilic carrier selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof; and
d. a diluent capable of dispersing the mass, wherein the diluent comprises water and/or a hydrophilic solvent selected from benzyl alcohol, ethanol alcohol, benzyl benzoate, propylene glycol, glycerin, low molecular weight polyethylene glycol (such as PEG 400), dimethylacetamide, and combinations thereof.
50. An intravenous solution, comprising:
a. carmustine;
b. a diluent capable of dispersing the mass, wherein the diluent comprises water and/or an amphiphilic agent selected from phospholipids (such as egg lecithin), polysorbate n (n = 20 to 80), bile acids (such as glycocholic acid) and salts, cholesterol, polyoxyl n castor oil (n = 30 to 40), polyoxyl n hydrogenated castor oil (n = 40 to 60), mono-, di-, and triglycerides of medium chain fatty acids, glyceryl monostearate, sorbitan esters, beta-cyclodextrin, hydroxypropyl beta- cyclodextrin, gamma-cyclodextrin, polyoxyl 15 hydroxystearate, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) and combinations thereof; and
c. an intravenous infusion fluid comprising about 0.5% to 1.5% (w/v) salt or about
2% to about 15%) (w/v) sugar.
A method of administering a chemotherapy drug to a subject in need thereof, the method comprising,
a. obtaining a lyophilized mass comprising a chemotherapy drug;
b. dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass;
c. combining the dispersed mass in diluent of (b) with an intravenous infusion fluid to form an intravenous solution comprising the drug; and
d. administering the intravenous solution comprising the drug to a patient in need thereof.
The method of claim 51 , wherein the method provides for reduced injection site reaction for a subject administered the intravenous solution.
A method of making an intravenous solution comprising a chemotherapy drug, the method comprising,
a. obtaining a lyophilized mass comprising a chemotherapy drug;
b. dispersing the mass in a diluent, wherein the diluent is capable of dispersing the mass; and
c. combining the dispersed mass in diluent of (b) with the intravenous infusion fluid to form an intravenous solution comprising the chemotherapy drug.
A lyophilized composition for use in an intravenous solution, the composition comprising:
a. a chemotherapy drug; and
b. a solubilizer; and wherein the chemotherapy drug is selected from carmustine, romidepsin, amsacrine, busulfan, chlormethine, mustine, dacarbazine, dactinomycin, epirubicin, idarubicin, mitomycin, paclitaxel, streptozocin, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof; and
wherein the solubilizer is selected from cyclic oligosaccharides with at least 6 pyranose units, including, but not limited to sulfobutyl ether β-cyclodextrin sodium, or betadex sulfobutyl ether sodium, a-cyclodextrin, hydroxypropyl-P-cyclodextrin, β- cyclodextrin and γ-cyclodextrin, and globular proteins, and combinations thereof.
55. The composition of claim 54, wherein the solubilizer is a globular protein, and the
globular protein is albumin.
56. The composition of claim 54, wherein the solubilizer is sulfobutyl ether β-cyclodextrin sodium.
57. The composition of claim 54, wherein the solubilizer is the combination of sulfobutyl ether β-cyclodextrin sodium and albumin.
58. The composition of any one of claims 54 to 57, further comprising a stabilizer.
59. The composition of claim 58, wherein the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
60. The composition of claim 59, wherein the stabilizer is cysteine.
61. The composition of claim 59, wherein the stabilizer is albumin.
62. A lyophilized composition for use in an intravenous solution, the composition
comprising:
a. carmustine and albumin;
b. carmustine and sulfobutyl ether β-cyclodextrin sodium;
c. carmustine, sulfobutyl ether β-cyclodextrin sodium and albumin, or d. carmustine, sulfobutyl ether β-cyclodextrin sodium and cysteine.
63. The composition of claim 62, wherein the ratio of carmustine to albumin is 1 : 1 to 1 :50, the ratio of carmustine to sulfobutyl ether β-cyclodextrin sodium is 1 : 10 to 1 :30, the ratio of carmustine : sulfobutyl ether β-cyclodextrin sodium : albumin is 1 : 10: 1 to 1 :30:5, or the ratio of carmustine : sulfobutyl ether β-cyclodextrin sodium : cysteine is 1 : 10: 1 to 1 :30:5.
64. The composition of claim 62 or claim 63, further comprising a stabilizer.
65. The composition of claim 64, wherein the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and globular proteins, such as albumin, and combinations thereof.
66. The composition of claim 65, wherein the stabilizer is cysteine.
67. An intravenous delivery system comprising:
a. the composition of any one of claims 54 to 66, and
b. a diluent capable of dispersing the chemotherapy drug and solubulizer, wherein a and b form the intravenous delivery system.
68. An intravenous delivery system comprising,
a. carmustine,
b. a solubilizer selected from sulfobutyl ether β-cyclodextrin sodium, albumin, or combinations thereof;
c. a diluent capable of dispersing the carmustine and solubilizer;
wherein a, b and c form the intravenous delivery system.
69. The intravenous delivery system of claim 67 or 68, further comprising a stabilizer.
70. The intravenous delivery system of claim 69, wherein the stabilizer is selected from polar amino acids, such as selected from cysteine, glutamine, asparagine, serine, threonine, tyrosine, and tryptophan, and a globular protein, and combinations thereof.
71. The intravenous delivery system of claim 70, wherein the stabilizer is cysteine.
72. The intravenous delivery system of claim 70, wherein the stabilizer is a globular protein, and the globular protein is albumin.
73. The intravenous delivery system of any one of claims 67 to 72, wherein the diluent is water, saline solution, or dextrose aqueous solution.
74. The intravenous delivery system of any one of claims 68 to 73, wherein the impurities in the intravenous delivery system provides a 30% reduction in after 1 day when stored at 2°-8°C compared to the same chemotherapy drug in water.
75. The intravenous delivery system of any one of claims 68 to 73, wherein the impurities in the intravenous delivery system provides a 30% reduction in impurities after 3 days when stored at 2°-8°C compared to the same chemotherapy drug in water.
76. An intravenous solution comprising (a) the intravenous delivery system of claims 67 to 75, and (a) intravenous infusion fluid, wherein (a) and (b) form the intravenous solution when combined.
PCT/US2018/060160 2017-11-09 2018-11-09 Intravenous delivery systems for chemotherapy drugs WO2019094819A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762584031P 2017-11-09 2017-11-09
US62/584,031 2017-11-09

Publications (2)

Publication Number Publication Date
WO2019094819A2 true WO2019094819A2 (en) 2019-05-16
WO2019094819A3 WO2019094819A3 (en) 2020-03-26

Family

ID=66438648

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/060160 WO2019094819A2 (en) 2017-11-09 2018-11-09 Intravenous delivery systems for chemotherapy drugs

Country Status (1)

Country Link
WO (1) WO2019094819A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024074600A1 (en) * 2022-10-05 2024-04-11 Institut Gustave Roussy An oral liquid composition of vinorelbine

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2603480B2 (en) * 1987-08-05 1997-04-23 住友製薬株式会社 Stabilized anthracyclines
GB9921954D0 (en) * 1999-09-16 1999-11-17 Pharmacia & Upjohn Spa Formulations for parenteral use of estramustine phosphate with improved pharmacological properties
US7034013B2 (en) * 2001-03-20 2006-04-25 Cydex, Inc. Formulations containing propofol and a sulfoalkyl ether cyclodextrin
CN100544710C (en) * 2007-04-03 2009-09-30 北京世纪博康医药科技有限公司 A kind of Pharmaceutical composition of carmustine, Preparation method and use
ITTO20070608A1 (en) * 2007-08-21 2009-02-22 Medestea Int Spa COMBINATION OF AN ANTINEOPLASTIC AGENT AND ALBUMIN FOR CANCER TREATMENT
CN100563644C (en) * 2007-12-06 2009-12-02 济南帅华医药科技有限公司 A kind of carmustine sustained-release implantation agent for the treatment of entity tumor
WO2009073224A1 (en) * 2007-12-07 2009-06-11 Ambit Biosciences Corp. Methods of treating certain diseases using pyrimidine derivatives
NZ630311A (en) * 2013-12-27 2016-03-31 Celgene Corp Romidepsin formulations and uses thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024074600A1 (en) * 2022-10-05 2024-04-11 Institut Gustave Roussy An oral liquid composition of vinorelbine

Also Published As

Publication number Publication date
WO2019094819A3 (en) 2020-03-26

Similar Documents

Publication Publication Date Title
CN1859898B (en) Compositions for delivering highly water soluble drugs
Strickley Solubilizing excipients in oral and injectable formulations
RU2429837C2 (en) Pharmaceutical composition of taxan, solid composition of taxan, method of producing solid composition of taxan, composition for solubilisation of said solid composition of taxan and set of elements (kit) for composition of taxan for injections
KR20100023862A (en) Solubilized formulation of docetaxel without tween 80
CN109069651A (en) Stable Nimodipine parenteral administration
JP2015503565A (en) Stabilized glucagon nanoemulsion
CA2867295A1 (en) Formulations of bendamustine
US11541006B2 (en) Aqueous formulation for insoluble drugs
EA034565B1 (en) Compositions of levosimendan for intravenous administration as infusion or injection and of infusion concentrate
WO2019094819A2 (en) Intravenous delivery systems for chemotherapy drugs
WO2019136817A1 (en) Cabazitaxel composition for injection and preparation method therefor
EP3247350B1 (en) Liquid formulation of cabazitaxel
KR20150112975A (en) Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery
CN111465389B (en) Pharmaceutical composition of docetaxel conjugate and preparation method thereof
JP2018512395A (en) Pharmaceutical composition comprising taxane-cyclodextrin complex, method of preparation and method of use
JP5811421B2 (en) Non-aqueous oily injectable preparation showing preservative efficacy
JP7267640B2 (en) Teniposide injection solution with excellent dilution stability and its preparation method
Strickley Solubilizing excipients in pharmaceutical formulations
US11957758B2 (en) Pharmaceutical composition of docetaxel conjugate and preparation method
US20210015783A1 (en) Pharmaceutical Compositions Containing Taxane-Cyclodextrin Complexes, Method of Making and Methods of Use
WO2024011169A1 (en) Stable, liquid pharmaceutical compositions comprising melphalan
EP4055005A1 (en) Liquid melphalan composition
EP3220954A2 (en) Process for preparation of parenteral formulation of anidulafungin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18876113

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18876113

Country of ref document: EP

Kind code of ref document: A2