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WO2019211708A1 - Stable pharmaceutical compositions of dianhydrogalactitol - Google Patents

Stable pharmaceutical compositions of dianhydrogalactitol Download PDF

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Publication number
WO2019211708A1
WO2019211708A1 PCT/IB2019/053418 IB2019053418W WO2019211708A1 WO 2019211708 A1 WO2019211708 A1 WO 2019211708A1 IB 2019053418 W IB2019053418 W IB 2019053418W WO 2019211708 A1 WO2019211708 A1 WO 2019211708A1
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Prior art keywords
acid
dianhydrogalactitol
ready
composition
present
Prior art date
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Ceased
Application number
PCT/IB2019/053418
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French (fr)
Inventor
Parva Yogeshchandra Purohit
Paras Rasiklal VASANANI
Ashokkumar Hajabhai BARIA
Kalyani Mahendrakumar VYAS
Deep Pravinbhai JAVIA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kashiv Biosciences LLC
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Kashiv Biosciences LLC
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Publication date
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Publication of WO2019211708A1 publication Critical patent/WO2019211708A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a stable pharmaceutical preparation containing Dianhydrogalactitol or its pharmaceutically acceptable salts for the treatment of cancer.
  • the pharmaceutical composition of the present invention is in the form of ready to use or ready to dilute solutions providing a better patient compliance.
  • Dianhydrogalactitol is a small-molecule chemotherapeutic. It is a first-in-class alkylating agent with a unique bi-functional DNA cross-linking mechanism targeting the N7 position of guanine. This mechanism is distinct from other alkylating agents and Dianhydrogalactitol is used in the treatment of various types of cancer which includes but not limited to chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), lung cancer, Non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, cervical cancer, medulloblastoma, glioma and Glioblastoma multiforme (GBM).
  • CML chronic myelogenous leukemia
  • AML acute myeloid leukemia
  • NSCLC Non-small cell lung cancer
  • GBM Glioblastoma multiforme
  • GBM also includes recurrent Glioblastoma, unmethylated Glioblastoma, refractory Glioblastoma and Gliosarcoma.
  • Dianhydrogalactitol is a new treatment option for patients whose tumors are resistant to currently available chemotherapies.
  • GBM The treatment of GBM is extremely difficult because of following facts: (1) the tumor cells develop resistance against conventional therapies; (2) the brain is susceptible to damage using conventional therapy; (3) the brain has a very limited capability to get repaired by itself; and (4) many conventional therapeutic drugs cannot cross the blood-brain barrier.
  • Symptomatic treament by the use of corticosteroids and anticonvulsant agents focuses on relieving symptoms and improving the patient's neurologic function.
  • symptomatic therapy cannot reduce the progression of the tumor.
  • concurrent administration of phenytoin with radiation therapy can result in substantial side effects including erythema multiforme and Steven-Johnson syndrome.
  • Dianhydrogalactitol refers to 1, 2-bis (oxiran-2-yl) ethane-1,2-diol or pharmaceutically acceptable salts thereof or hydrates thereof. It has molecular weight of 146.142 g/mol. Water solubility of dianhydrogalactitol is found to be 1000 mg/ml. Dianhydrogalactitol has log P value of -1.4.
  • Dianhydrogalactitol is efficacious in inhibiting the growth of cancer stem cells. It is active against tumors that are refractory to temozolomide; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol is a new treatment option for patients whose tumors are resistant to currently available chemotherapies.
  • Dianhydrogalactitol is a bi-functional alkylating agent, with potential antineoplastic activity. Upon administration, Dianhydrogalactitol crosses the blood brain barrier (BBB) and appears to be selective for tumor cells. This agent alkylates and crosslinks DNA which ultimately leads to a reduction in cancer cell proliferation. In addition, Dianhydrogalactitol does not show cross-resistance to other conventional chemotherapeutic agents and has a long half-life in the brain.
  • BBB blood brain barrier
  • US8563758 discloses improved method of synthesis of dianhydrohexitols such as dianhydrogalactitol comprising conversion of the hexitol to a dibromohexitol by reaction with concentrated hydrobromic acid, followed by conversion of the dibromohexitol to the dianhydrohexitol by reaction with potassium carbonate.
  • CN106692071 discloses freeze dried dianhydrogalactitol powder with a melting point of 101.5 ⁇ 2 °C and method of its preparation by non-aqueous freeze drying method using organic solvents like t-butanol, glacial acetic acid, anhydrous ethanol or isopropanol.
  • CN106389352 discloses stable Dianhydrogalactitol lyophilized powder for injection and method of its preparation by freeze drying.
  • CN105663072 discloses a Dianhydrogalactitol thin membrane coated tablet and a preparation method thereof.
  • Common pharmaceutical excipients such as lactose, pregelatinized starch, microcrystalline cellulose, micro powder silica gel and magnesium stearate are used in certain proportions, and a compressed tablet is prepared by direct compression and coated with a thin membrane coating.
  • Advantages disclosed in the invention are improved stability, improved absorption, improved bioavailability and cost reduction in manufacturing.
  • CN105663028 discloses a double-layer sustained-release suppository intended for rectal administration containing dianhydrogalactitol (dose 40 mg) and a preparation method thereof. Sustained-release medicine participates in systemic circulation through middle and lower rectal veins, and the liver first-pass effect and decomposition in the digestive tract are avoided.
  • Microcapsule of this invention comprises dianhydrogalactitol as an active pharmaceutical ingredient and other pharmaceutically acceptable carriers such as polyacrylic resin III, diethyl phthalate, castor oil and mannitol.
  • Microcapsule of this invention has a grain size of 45-100 micrometre with relatively high stability and encapsulation efficiency of more than or equal to 80 per cent with drug loading capacity of 30.2-35.8 per cent.
  • Dianhydrogalactitol is available as a lyophilized powder for the treatment of CML and lung cancer in china by Guangxi Wuzhou Pharmaceutical Company. It is further reconstituted for administration as intravenous injection.
  • Dianhydrogalactitol in the prior art , there still exists a need for providing a stable Dianhydrogalactitol pharmaceutical composition which can be administered parentally as a ready to use or ready to dilute option to a person in need thereof.
  • inventive liquid compositions have substantially improved long term stability when compared to currently available formulations. Further, the inventive formulations are advantageously ready to use or ready to dilute and reconstitution of lyophilized powders is not required.
  • the present invention relates to a stable pharmaceutical composition of dianhydrogalactitol wherein the said composition is ready to use or ready to dilute injection formulation.
  • the formulation is preferably a ready-to-use liquid injection and/or ready-to-dilute liquid concentrate formulation for parenteral administration.
  • composition refers to the composition of a dianhydrogalactitol compound in a form suitable to administer to a mammalian subject, preferably a human.
  • composition of the dianhydrogalactitol compound may comprise addition of pharmaceutically acceptable excipients, diluents, carriers or mixtures thereof.
  • the formulation is preferably a ready to use or ready to dilute liquid injection formulation for parenteral administration.
  • stable used here in the context of formulating pharmaceutical composition in which total impurities level of both specified and unspecified impurities complies as per ICH standards.
  • stable formulation refers to any preparation of Dianhydrogalactitol or pharmaceutically acceptable salts thereof having sufficient physical and chemical stability to allow storage at a convenient temperature, such as between about 0° C. and about 50° C., for a commercially reasonable period of time.
  • chemical stability refers to formation of drug-related impurities in terms of total impurity, maximum individual unknown impurity and single maximum individual impurity.
  • chemical stability also includes stabilizing agent content and maintenance of pH of the finished formulation.
  • stability is required for commercially relevant times after manufacturing, such as for about 6, 12, 18, 24 or 36 months, during which a product is kept in its original packaging under specified storage condition.
  • the terms “about” and “approximately” should be understood to mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value.
  • the terms “Pharmaceutically acceptable salts” should be understood to mean salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid
  • the terms “Pharmaceutically acceptable” should be understood to mean that it is useful in preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • ready to use means that the drug solution is sterile and does not require any further dilution or reconstitution for administration to a person in need thereof.
  • ready to use is synonymous with “ready to infuse” or “ready to inject” and “ready to administer” solution.
  • ready to dilute means that the drug solution is sterile and further diluted with diluent before administration to a person in need thereof.
  • the present invention relates to a stable pharmaceutical composition of dianhydrogalactitol wherein the said composition is ready to use or ready to dilute injection formulation.
  • ready-to-use formulation of dianhydrogalactitol includes ready-to-dilute liquid concentrate of dianhydrogalactitol and/or ready-to-use liquid solution of dianhydrogalactitol.
  • Dianhydrogalactitol formulation may be used for the treatment of various types of cancer which includes but not limited to chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), lung cancer, Non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, cervical cancer, medulloblastoma, glioma and Glioblastoma multiforme (GBM).
  • GBM also includes recurrent Glioblastoma, unmethylated Glioblastoma, refractory Glioblastoma and Gliosarcoma.
  • stable ready to use or ready to dilute Dianhydrogalactitol formulation provides following advantages over lyophilized, spray dried or freeze dried dosage forms.
  • ready to use or ready to dilute dianhydrogalactitol composition comprises therapeutically effective amount of dianhydrogalactitol in the range of 1-1000 mg.
  • compositions of the present invention have a pH of from about 3 to 9.
  • the composition is maintained at a pH of from about 4 to about 8.
  • the sterile pharmaceutical preparation is filled in suitable container/closure system, e.g., ampoules, vials, prefilled syringe system, auto-injectors, etc. It can also be directly filled preferably in a prefilled syringe system.
  • suitable container/closure system e.g., ampoules, vials, prefilled syringe system, auto-injectors, etc. It can also be directly filled preferably in a prefilled syringe system.
  • composition of the present invention can be supplied in unit container of volume from 0.5 ml to 100 ml, preferably 1 ml to 80 ml.
  • composition of the present invention can be supplied in concentration of about 1 mg/mL to about 300 mg/mL.
  • concentration is about 100 mg/mL to about 200 mg/mL. More preferably the concentration is about 40 mg/mL to about 80 mg/mL. Further, more preferably the concentration is about 1 mg/mL to about 5 mg/mL.
  • the pharmaceutically acceptable excipients that can be used in the present invention includes but not limited to solvents, tonicity modifier, solubilizing agent, buffer, preservatives like anti-oxidants, anti-microbial or chelating agents.
  • the sealable vessel for prevention of oxidation of the sensitive material, it is desirable to remove headspace oxygen and moisture or both from the sealable vessel as quickly as possible. This may be aided by, for example, purging the sealable container with a gas which is substantially oxygen-free, or substantially moisture free, or substantially oxygen and moisture free before, during or after step, or any combination thereof. Purging can be expected to reduce the oxygen level in the sealable container to a level of from about 0.5% to about 10%, typically about 5% or lower, depending on the efficiency of flushing and how quickly the container is sealed after flushing.
  • the gas used for purging the sealable container may be any appropriate inert gas known to those in the art, the most commonly used gases being argon, helium, nitrogen or mixtures thereof. However the most preferred inert gas is nitrogen.
  • suitable solvents comprise aqueous solvent, non-aqueous solvent, co-solvents or suitable mixture thereof.
  • Solvents are used in amounts sufficient to dissolve all the solid components of the present invention.
  • Suitable non-aqueous solvents and co-solvents comprises, but not limited to, ethanol, propylene glycol, polyethylene glycols, glycerin, benzyl alcohol, glycofurol, solketal, ethyl lactate, tetrahydrofurfuryl alcohol, glycerol formal, ethylene glycol, butylene glycol, polypropylene glycol, polybutylene glycol, polysorbates, niacinamide, formic acid, n-butanol, isopropanol (IPA), acetic acid, methanol, polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG) or suitable mixtures thereof.
  • Suitable aqueous solvent includes water.
  • the tonicity modifiers may optionally be present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
  • tonicity modifier may include but not limited to physiologically acceptable inorganic alkali or alkaline earth salts such as sodium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium carbonate and calcium hydrogen carbonate; physiologically acceptable organic salts such as sodium lactate; physiologically acceptable carbohydrates, such as glucose, fructose, sorbitol, mannitol, galactose, inositol, maltitol, lactose, trehalose, maltose, sucrose, dextran 1, dextran 10, dextran 40, dextran 70, starch and hydroxyethyl starch; physiologically acceptable amino acids, peptides or proteins such as glycine, albumin and gelatines; as well as mixtures thereof may, for example, be used.
  • physiologically acceptable inorganic alkali or alkaline earth salts such as sodium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium carbonate and calcium hydrogen carbonate
  • the solubilizing agent may optionally be present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
  • Solubilising agent is meant to be any compound that may assist in solubilising the active by accommodating the active in a cavity formed in the solubilising aid to form inclusion complexes.
  • solubilizing agent may include but not limited to cyclodextrins such as ⁇ cyclodextrin, ⁇ cyclodextrin, ⁇ cyclodextrin; calixarenes and the like as well as their pharmaceutically useful derivatives. Combinations of more than one of these solubilising agents in different ratios or proportions as required are covered within the scope of the invention without limitation.
  • the buffer or acidifying or alkalizing agent may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.1% to about 15% by weight of composition; more preferably of about 0.1% to about 10% by weight of the composition.
  • buffer or acidifying or alkalizing agent may include but not limited inorganic acids and bases, such as hydrochloric acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, phosphorous acid, carbonic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide; alkali salts and alkaline earth salts, as well as alkali hydrogen salts and alkaline earth hydrogen salts of inorganic oxo acids of phosphorus, sulfur, carbon and nitrogen, such as sodium phosphate and its hydrate, sodium hydrogen phosphate and its hydrate, disodium hydrogen phosphate and its hydrate, disodium sulfate, sodium hydrogen sulfate, sodium sulfite, calcium sulfite, magnesium sulfite, calcium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, sodium nitrate, sodium nitrite, calcium nitrite, magnesium nitrate and magnesium
  • the preservatives can be optionally used in the present invention which includes but not limited to like anti-oxidants, anti-microbials or chelating agents.
  • the antioxidant may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
  • antioxidants examples include but not limited to ascorbic acid, sodium metabisulphite, sodium bisulfite, thiourea, butylhydroxytoluene (BHT), butylated hydroxytoluene (BHA), sodium formaldehyde sulfoxide, tocopherols, sodium ethylenediaminetetraacetate and/or any combinations thereof.
  • the antimicrobial agent may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
  • antimicrobial agents examples include but not limited to benzalkonium chloride, benzyl alcohol, phenol, chlorocresol, metacresol, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, sorbic acid, potassium sorbate, phenylmercuric salts, benzoic acid and/or its derivatives such as sodium benzoate, methylhydroxybenzoate, propylhydroxybenzoate as well as mixtures thereof.
  • the chelating agent may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
  • chelating agents examples include but not limited to diethylenetriaminepentaacetic acid (DTPA), ethylene-diaminetetraacetic acid (EDTA), macrocyclics, humic acid, citric acid, gluconic acid, malic acid, tartaric acid and/or any combinations thereof.
  • DTPA diethylenetriaminepentaacetic acid
  • EDTA ethylene-diaminetetraacetic acid
  • macrocyclics macrocyclics
  • humic acid citric acid, gluconic acid, malic acid, tartaric acid and/or any combinations thereof.
  • Further embodiment of the present invention includes method of treatment of cancer in a subject such as a human.
  • such method of treatment includes administration of ready to use or ready to dilute liquid pharmaceutical dianhydrogalactitol compositions of the present invention.

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Abstract

The present invention relates to a stable pharmaceutical preparation containing dianhydrogalactitol or its pharmaceutically acceptable salts for the treatment of various types of cancer. For purpose of the present invention, the formulation is preferably a ready to use or ready to dilute injection formulation for parenteral administration. The formulation of the present invention provides a better patient compliance as compared to the currently available lyophilized formulation.

Description

STABLE PHARMACEUTICAL COMPOSITIONS OF DIANHYDROGALACTITOL
The present invention relates to a stable pharmaceutical preparation containing Dianhydrogalactitol or its pharmaceutically acceptable salts for the treatment of cancer. The pharmaceutical composition of the present invention is in the form of ready to use or ready to dilute solutions providing a better patient compliance.
Dianhydrogalactitol is a small-molecule chemotherapeutic. It is a first-in-class alkylating agent with a unique bi-functional DNA cross-linking mechanism targeting the N7 position of guanine. This mechanism is distinct from other alkylating agents and Dianhydrogalactitol is used in the treatment of various types of cancer which includes but not limited to chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), lung cancer, Non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, cervical cancer, medulloblastoma, glioma and Glioblastoma multiforme (GBM). GBM also includes recurrent Glioblastoma, unmethylated Glioblastoma, refractory Glioblastoma and Gliosarcoma. Dianhydrogalactitol is a new treatment option for patients whose tumors are resistant to currently available chemotherapies.
The treatment of GBM is extremely difficult because of following facts: (1) the tumor cells develop resistance against conventional therapies; (2) the brain is susceptible to damage using conventional therapy; (3) the brain has a very limited capability to get repaired by itself; and (4) many conventional therapeutic drugs cannot cross the blood-brain barrier. Symptomatic treament by the use of corticosteroids and anticonvulsant agents focuses on relieving symptoms and improving the patient's neurologic function. However, such symptomatic therapy cannot reduce the progression of the tumor. On the other hand, concurrent administration of phenytoin with radiation therapy, can result in substantial side effects including erythema multiforme and Steven-Johnson syndrome.
Dianhydrogalactitol refers to 1, 2-bis (oxiran-2-yl) ethane-1,2-diol or pharmaceutically acceptable salts thereof or hydrates thereof. It has molecular weight of 146.142 g/mol. Water solubility of dianhydrogalactitol is found to be 1000 mg/ml. Dianhydrogalactitol has log P value of -1.4.
Figure pctxmlib-appb-I000001
Dianhydrogalactitol is efficacious in inhibiting the growth of cancer stem cells. It is active against tumors that are refractory to temozolomide; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol is a new treatment option for patients whose tumors are resistant to currently available chemotherapies.
Dianhydrogalactitol is a bi-functional alkylating agent, with potential antineoplastic activity. Upon administration, Dianhydrogalactitol crosses the blood brain barrier (BBB) and appears to be selective for tumor cells. This agent alkylates and crosslinks DNA which ultimately leads to a reduction in cancer cell proliferation. In addition, Dianhydrogalactitol does not show cross-resistance to other conventional chemotherapeutic agents and has a long half-life in the brain.
The prior art discloses various formulations of Dianhydrogalactitol as mentioned below.
US8563758 discloses improved method of synthesis of dianhydrohexitols such as dianhydrogalactitol comprising conversion of the hexitol to a dibromohexitol by reaction with concentrated hydrobromic acid, followed by conversion of the dibromohexitol to the dianhydrohexitol by reaction with potassium carbonate.
CN106692071 discloses freeze dried dianhydrogalactitol powder with a melting point of 101.5±2 °C and method of its preparation by non-aqueous freeze drying method using organic solvents like t-butanol, glacial acetic acid, anhydrous ethanol or isopropanol.
CN106389352 discloses stable Dianhydrogalactitol lyophilized powder for injection and method of its preparation by freeze drying.
CN105663072 discloses a Dianhydrogalactitol thin membrane coated tablet and a preparation method thereof. Common pharmaceutical excipients such as lactose, pregelatinized starch, microcrystalline cellulose, micro powder silica gel and magnesium stearate are used in certain proportions, and a compressed tablet is prepared by direct compression and coated with a thin membrane coating. Advantages disclosed in the invention are improved stability, improved absorption, improved bioavailability and cost reduction in manufacturing.
CN105663028 discloses a double-layer sustained-release suppository intended for rectal administration containing dianhydrogalactitol (dose 40 mg) and a preparation method thereof. Sustained-release medicine participates in systemic circulation through middle and lower rectal veins, and the liver first-pass effect and decomposition in the digestive tract are avoided.
CN105581996 discloses Dianhydrogalactitol microcapsule and a preparation method thereof. Microcapsule of this invention comprises dianhydrogalactitol as an active pharmaceutical ingredient and other pharmaceutically acceptable carriers such as polyacrylic resin III, diethyl phthalate, castor oil and mannitol. Microcapsule of this invention has a grain size of 45-100 micrometre with relatively high stability and encapsulation efficiency of more than or equal to 80 per cent with drug loading capacity of 30.2-35.8 per cent.
Currently Dianhydrogalactitol is available as a lyophilized powder for the treatment of CML and lung cancer in china by Guangxi Wuzhou Pharmaceutical Company. It is further reconstituted for administration as intravenous injection.
However, following are the disadvantages which may be associated with lyophilized, spray dried or freeze dried dosage forms:
  • Handling and processing time increases
  • Equipment becomes costly and complex
Considering the drawbacks associated with the marketed formulation of Dianhydrogalactitol in the prior art , there still exists a need for providing a stable Dianhydrogalactitol pharmaceutical composition which can be administered parentally as a ready to use or ready to dilute option to a person in need thereof.
With the efforts of the inventors of the current invention, a stable ready to use or ready to dilute Dianhydrogalactitol solution for parenteral administration has been developed, which would overcome the formulation issues as disclosed in the back-ground art.
One of the advantages of the inventive liquid compositions is that they have substantially improved long term stability when compared to currently available formulations. Further, the inventive formulations are advantageously ready to use or ready to dilute and reconstitution of lyophilized powders is not required.
The present invention relates to a stable pharmaceutical composition of dianhydrogalactitol wherein the said composition is ready to use or ready to dilute injection formulation. For purpose of the present invention, the formulation is preferably a ready-to-use liquid injection and/or ready-to-dilute liquid concentrate formulation for parenteral administration.
For purposes of the present invention, the following definitions will be used:
As used herein, the terms “composition” refer to the composition of a dianhydrogalactitol compound in a form suitable to administer to a mammalian subject, preferably a human. Often, composition of the dianhydrogalactitol compound may comprise addition of pharmaceutically acceptable excipients, diluents, carriers or mixtures thereof. For purpose of the present invention, the formulation is preferably a ready to use or ready to dilute liquid injection formulation for parenteral administration.
The inventors have defined term "stable" used here in the context of formulating pharmaceutical composition in which total impurities level of both specified and unspecified impurities complies as per ICH standards.
The term “stable formulation” refers to any preparation of Dianhydrogalactitol or pharmaceutically acceptable salts thereof having sufficient physical and chemical stability to allow storage at a convenient temperature, such as between about 0° C. and about 50° C., for a commercially reasonable period of time.
The term “physical stability” refers to maintenance of color, dissolved oxygen level, head space oxygen level, and particulate matter; and the term “chemical stability” relates to formation of drug-related impurities in terms of total impurity, maximum individual unknown impurity and single maximum individual impurity. For the purpose of the present invention, chemical stability also includes stabilizing agent content and maintenance of pH of the finished formulation. For pharmaceutical products, stability is required for commercially relevant times after manufacturing, such as for about 6, 12, 18, 24 or 36 months, during which a product is kept in its original packaging under specified storage condition.
As used herein, the terms “about” and “approximately” should be understood to mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value.
As used herein, the terms “Pharmaceutically acceptable salts” should be understood to mean salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
As used herein, the terms “Pharmaceutically acceptable” should be understood to mean that it is useful in preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
The term “ready to use” as used herein means that the drug solution is sterile and does not require any further dilution or reconstitution for administration to a person in need thereof. The term “ready to use” is synonymous with “ready to infuse” or “ready to inject” and “ready to administer” solution.
The term “ready to dilute” as used herein means that the drug solution is sterile and further diluted with diluent before administration to a person in need thereof.
The present invention relates to a stable pharmaceutical composition of dianhydrogalactitol wherein the said composition is ready to use or ready to dilute injection formulation.
According to another embodiment of the present invention, ready-to-use formulation of dianhydrogalactitol includes ready-to-dilute liquid concentrate of dianhydrogalactitol and/or ready-to-use liquid solution of dianhydrogalactitol.
According to another embodiment of the present invention, ready to use or ready to dilute Dianhydrogalactitol formulation may be used for the treatment of various types of cancer which includes but not limited to chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), lung cancer, Non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, cervical cancer, medulloblastoma, glioma and Glioblastoma multiforme (GBM). GBM also includes recurrent Glioblastoma, unmethylated Glioblastoma, refractory Glioblastoma and Gliosarcoma.
According to another embodiment of the present invention, stable ready to use or ready to dilute Dianhydrogalactitol formulation provides following advantages over lyophilized, spray dried or freeze dried dosage forms.
  • Does not require lyophilisation step during manufacturing of the formulation.
  • Reduced handling as well as processing time
  • Reduced overall cost
  • Improved stability as compared to lyophilized and spray dried products
  • Compared to spray drying, process of the present invention provides more stable formulation as process of the present invention avoids high processing temperature by use of hot air and resulting degradation due to the same.
In another embodiment of the present invention, ready to use or ready to dilute dianhydrogalactitol composition comprises therapeutically effective amount of dianhydrogalactitol in the range of 1-1000 mg.
The compositions of the present invention have a pH of from about 3 to 9. Preferably, the composition is maintained at a pH of from about 4 to about 8.
According to another embodiment, the sterile pharmaceutical preparation is filled in suitable container/closure system, e.g., ampoules, vials, prefilled syringe system, auto-injectors, etc. It can also be directly filled preferably in a prefilled syringe system.
Pharmaceutical formulation of the present invention can be supplied in unit container of volume from 0.5 ml to 100 ml, preferably 1 ml to 80 ml.
Pharmaceutical formulation of the present invention can be supplied in concentration of about 1 mg/mL to about 300 mg/mL. Preferably the concentration is about 100 mg/mL to about 200 mg/mL. More preferably the concentration is about 40 mg/mL to about 80 mg/mL. Further, more preferably the concentration is about 1 mg/mL to about 5 mg/mL.
The pharmaceutically acceptable excipients that can be used in the present invention includes but not limited to solvents, tonicity modifier, solubilizing agent, buffer, preservatives like anti-oxidants, anti-microbial or chelating agents.
According to another embodiment of the present invention, for prevention of oxidation of the sensitive material, it is desirable to remove headspace oxygen and moisture or both from the sealable vessel as quickly as possible. This may be aided by, for example, purging the sealable container with a gas which is substantially oxygen-free, or substantially moisture free, or substantially oxygen and moisture free before, during or after step, or any combination thereof. Purging can be expected to reduce the oxygen level in the sealable container to a level of from about 0.5% to about 10%, typically about 5% or lower, depending on the efficiency of flushing and how quickly the container is sealed after flushing.
The gas used for purging the sealable container may be any appropriate inert gas known to those in the art, the most commonly used gases being argon, helium, nitrogen or mixtures thereof. However the most preferred inert gas is nitrogen.
In one embodiment suitable solvents comprise aqueous solvent, non-aqueous solvent, co-solvents or suitable mixture thereof. Solvents are used in amounts sufficient to dissolve all the solid components of the present invention. Suitable non-aqueous solvents and co-solvents comprises, but not limited to, ethanol, propylene glycol, polyethylene glycols, glycerin, benzyl alcohol, glycofurol, solketal, ethyl lactate, tetrahydrofurfuryl alcohol, glycerol formal, ethylene glycol, butylene glycol, polypropylene glycol, polybutylene glycol, polysorbates, niacinamide, formic acid, n-butanol, isopropanol (IPA), acetic acid, methanol, polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG) or suitable mixtures thereof. Suitable aqueous solvent includes water.
The tonicity modifiers may optionally be present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
Examples of tonicity modifier that may be suitable for use in the present invention may include but not limited to physiologically acceptable inorganic alkali or alkaline earth salts such as sodium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium carbonate and calcium hydrogen carbonate; physiologically acceptable organic salts such as sodium lactate; physiologically acceptable carbohydrates, such as glucose, fructose, sorbitol, mannitol, galactose, inositol, maltitol, lactose, trehalose, maltose, sucrose, dextran 1, dextran 10, dextran 40, dextran 70, starch and hydroxyethyl starch; physiologically acceptable amino acids, peptides or proteins such as glycine, albumin and gelatines; as well as mixtures thereof may, for example, be used.
The solubilizing agent may optionally be present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
Solubilising agent is meant to be any compound that may assist in solubilising the active by accommodating the active in a cavity formed in the solubilising aid to form inclusion complexes. Examples of solubilizing agent that may be suitable for use in the present invention may include but not limited to cyclodextrins such as α cyclodextrin, β cyclodextrin, γ cyclodextrin; calixarenes and the like as well as their pharmaceutically useful derivatives. Combinations of more than one of these solubilising agents in different ratios or proportions as required are covered within the scope of the invention without limitation.
The buffer or acidifying or alkalizing agent may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.1% to about 15% by weight of composition; more preferably of about 0.1% to about 10% by weight of the composition.
Examples of buffer or acidifying or alkalizing agent that may be suitable for use in the present invention may include but not limited inorganic acids and bases, such as hydrochloric acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, phosphorous acid, carbonic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide; alkali salts and alkaline earth salts, as well as alkali hydrogen salts and alkaline earth hydrogen salts of inorganic oxo acids of phosphorus, sulfur, carbon and nitrogen, such as sodium phosphate and its hydrate, sodium hydrogen phosphate and its hydrate, disodium hydrogen phosphate and its hydrate, disodium sulfate, sodium hydrogen sulfate, sodium sulfite, calcium sulfite, magnesium sulfite, calcium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, sodium nitrate, sodium nitrite, calcium nitrite, magnesium nitrate and magnesium nitrite; salts of chlorine, such as sodium chloride, calcium chloride and magnesium chloride, organic bases and acids such as formic acid, acetic acid, propionic acid, lactic acid, oxalic acid, malonic acid, maleic acid, tartaric acid, citric acid, pyruvic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, ascorbic acid, tris(hydroxymethyl-)aminomethane (2-amino-2-(hydroxymethyl)-1,3-propane diol (Trometamol; TRIS), 1-desoxy-(methylamino)-D-glucitol (N-methylglucamine; Meglumin); alkali salts and alkaline earth salts of organic bases and acids such as sodium acetate; as well as mixtures thereof.
The preservatives can be optionally used in the present invention which includes but not limited to like anti-oxidants, anti-microbials or chelating agents.
The antioxidant may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
Examples of antioxidants that may be suitable for use in the present invention may include but not limited to ascorbic acid, sodium metabisulphite, sodium bisulfite, thiourea, butylhydroxytoluene (BHT), butylated hydroxytoluene (BHA), sodium formaldehyde sulfoxide, tocopherols, sodium ethylenediaminetetraacetate and/or any combinations thereof.
The antimicrobial agent may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
Examples of antimicrobial agents that may be suitable for use in the present invention may include but not limited to benzalkonium chloride, benzyl alcohol, phenol, chlorocresol, metacresol, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, sorbic acid, potassium sorbate, phenylmercuric salts, benzoic acid and/or its derivatives such as sodium benzoate, methylhydroxybenzoate, propylhydroxybenzoate as well as mixtures thereof.
The chelating agent may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
Examples of chelating agents that may be suitable for use in the present invention may include but not limited to diethylenetriaminepentaacetic acid (DTPA), ethylene-diaminetetraacetic acid (EDTA), macrocyclics, humic acid, citric acid, gluconic acid, malic acid, tartaric acid and/or any combinations thereof.
Further embodiment of the present invention includes method of treatment of cancer in a subject such as a human. In another embodiment of the present invention, such method of treatment includes administration of ready to use or ready to dilute liquid pharmaceutical dianhydrogalactitol compositions of the present invention.
The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLE 1
Ingredients Amount/Concentration range
Dianhydrogalactitol 800 mg
Sodium hydroxide or Hydrochloric acid 10%
BHT 5%
Water q.s. to 10mL
Preparation of liquid pharmaceutical formulation having concentration of 80mg/mL according to the present invention and analysis of the formulation by HPLC:
Mixing Dianhydrogalactitol and water for injection.
Adding suitable amount of Sodium hydroxide or Hydrochloric acid to above solution.
Optionally adding solubilizing agent and Tonicity modifier.
Adding suitable amount of BHT to above solution.
Sterilizing the above solution by physical or chemical sterilization methods.
Packaging of the final solution in suitable container system.

Claims (6)

  1. A stable ready to use or ready to dilute pharmaceutical composition comprising dianhydrogalactitol or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients.
  2. The stable composition as claimed in claim 1, wherein the formulation is ready-to-use liquid injection and/or ready-to-dilute liquid concentrate formulation for parenteral administration.
  3. The stable composition as claimed in claim 1, wherein the pH of the final composition is from about 3 to 9.
  4. The stable composition as claimed in claim 1, wherein the excipients are selected from the group consisting of solvents, tonicity modifier, solubilizing agent, buffer, preservatives or mixtures thereof.
  5. The stable composition as claimed in claim 4, wherein the preservatives are selected from the group consisting of anti-oxidants, anti-microbial or chelating agents.
  6. The stable composition as claimed in claim 1, wherein the composition is sterilized by physical or chemical sterilization methods.
PCT/IB2019/053418 2018-05-04 2019-04-25 Stable pharmaceutical compositions of dianhydrogalactitol Ceased WO2019211708A1 (en)

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IN201821016975 2018-05-04

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020037328A1 (en) * 2000-06-01 2002-03-28 Brown Dennis M. Hexitol compositions and uses thereof
US20160158186A1 (en) * 2013-05-31 2016-06-09 Del Mar Pharmaceuticals Use of dianhydrogalactitol and analogs and derivatives thereof to treat recurrent malignant glioma or progressive secondary brain tumor
US9827330B2 (en) * 2014-03-21 2017-11-28 Abbvie Inc. Anti-EGFR antibodies and antibody drug conjugates

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US20020037328A1 (en) * 2000-06-01 2002-03-28 Brown Dennis M. Hexitol compositions and uses thereof
US20160158186A1 (en) * 2013-05-31 2016-06-09 Del Mar Pharmaceuticals Use of dianhydrogalactitol and analogs and derivatives thereof to treat recurrent malignant glioma or progressive secondary brain tumor
US9827330B2 (en) * 2014-03-21 2017-11-28 Abbvie Inc. Anti-EGFR antibodies and antibody drug conjugates

Non-Patent Citations (2)

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Title
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