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WO2016059590A1 - Composition injectable stable de médicaments à petites molécules et procédé de préparation associé - Google Patents

Composition injectable stable de médicaments à petites molécules et procédé de préparation associé Download PDF

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Publication number
WO2016059590A1
WO2016059590A1 PCT/IB2015/057924 IB2015057924W WO2016059590A1 WO 2016059590 A1 WO2016059590 A1 WO 2016059590A1 IB 2015057924 W IB2015057924 W IB 2015057924W WO 2016059590 A1 WO2016059590 A1 WO 2016059590A1
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WIPO (PCT)
Prior art keywords
injectable composition
small molecule
solution
aqueous solvent
molecule drug
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
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PCT/IB2015/057924
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English (en)
Inventor
Vandana SONAVARIA
Kamal Kumar Upadhyay
Pratikkumar PATEL
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Piramal Enterprises Ltd
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Piramal Enterprises Ltd
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Publication of WO2016059590A1 publication Critical patent/WO2016059590A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to a stable, non-aqueous and ready-to-use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co- crystal thereof; and processes for its preparation.
  • Small molecule drugs are beneficial agents having relatively low molecular weight.
  • parenteral route of administration remains the preferred mode of administration for such drugs.
  • parenteral route of administration is preferred when there is a requirement of rapid onset of drug action or the patient is unable to accept the drug orally.
  • typical practice involves preparing formulations containing such small molecule drugs in aqueous solutions for injections.
  • certain small molecule drugs have poor stability in such aqueous environments.
  • small molecule drugs that are marketed as lyophilized powder for injection include: (i) Bortezomib, commercially available as Velcade®, is available for intravenous injection (IV) use only, and each single dose vial contains 3.S mg of bortezomib as a sterile lyophilized powder, indicated for the treatment of multiple myeloma patients who have received at least one prior therapy; (ii) Caspofungin acetate, commercially available as Cancidas® for injection as lyophilized powder, indicated for the treatment of fungal infections and (iii) Fosaprepitant dimeglumine, commercially available as Emend ® for intravenous injection as lyophilized powder, indicated for the treatment of nausea and vomiting that may be caused by surgery or cancer chemotherapy.
  • the solubility and stability behavior include: (i) Bortezomib, commercially available as Velcade®, is available for intravenous injection (IV) use only, and each single dose vial contains 3.S mg of bortez
  • compositions including lyophilized compositions for small molecule drugs are known in the art.
  • US5952300 discloses a pharmaceutical composition comprising caspofungin as an active ingredient, a pharmaceutically acceptable amount of an excipient such as a sucrose/mannitol mixture to form a lyophilized cake and a pharmaceutically acceptable amount of an acetate buffer effective to provide a pH of between about 4 and 7.
  • EP2170362 discloses a lyophilized anti-fungal composition
  • a lyophilized anti-fungal composition comprising; (a) caspofungin, or a pharmaceutically acceptable salt thereof, in an effective amount; (b) one or more non-reducing sugars having a glass transition temperature T g (s) of at least about 90°C; and (c) an acetate buffer in an amount effective to provide a pH in a range of about 5 to about 7; wherein the weight ratio of one or more non-reducing sugars to caspofungin is in a range of from about 1.1:1 to about 10:1; the composition has a moisture content of about 0.8 weight% or less; and the composition has a glass transition temperature T g (c) of at least about 55°C.
  • the composition needs reconstitution with water prior to use in preventing or treating fungal infections.
  • EP2049142 discloses pharmaceutical composition comprising the compound, caspofungin as an active ingredient, specific bulking agents and without an additional pH modifier which compositions are liquid or solid, e.g. lyophilized compositions.
  • EP2644189 discloses bortezomib formulation with improved stability, and particularly storage-stable multi-dose liquid bortezomib compositions.
  • the examples disclosed in this patent document illustrate that water is an essential ingredient of the composition.
  • the inventors have also provided a simple and cost-effective process for the preparation of the stable, non-aqueous and ready-to-use injectable composition of small molecule drug(s).
  • the present invention provides a stable, non-aqueous and ready-to- use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
  • the present invention provides a stable, non-aqueous and ready-to use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
  • a small molecule drug or a pharmaceutically acceptable salt or a co- crystal thereof (i) a small molecule drug or a pharmaceutically acceptable salt or a co- crystal thereof; (ii) a non-aqueous solvent system consisting of a primary non-aqueous solvent and optionally one or more secondary non-aqueous co-solvent(s);
  • the present invention provides a process for the preparation of a stable,non-aqueous and ready-to-use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof.
  • the present invention provides a method for treating or preventing one or more diseases, disorders or conditions, comprising administering to a subject in need thereof; a stable, non-aqueous and ready-to-use injectable composition of the present invention in an amount effective to treat or prevent the conditions, diseases or disorders.
  • the present invention provides a stable, non-aqueous and ready- to-use injectable composition of a small molecule drug for the manufacture of a medicament for use in the treatment or prevention of one or more diseases, conditions or disorders.
  • the present invention provides a stable, non-aqueous and ready- to-use injectable composition of a small molecule drug for use in the treatment of a subject having one or more diseases, conditions or disorders.
  • the present invention provides a pharmaceutical kit comprising: (a) an injectable composition comprising a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; a non-aqueous solvent system consisting of a primary non-aqueous solvent and optionally one or more secondary nonaqueous co-solvent(s); optionally a polyol; optionally a pH adjusting agent and optionally an antioxidant; and (b) optionally a package insert comprising instructions for using the said injectable composition.
  • the term “about” means approximately and in the context of numerical values the term “about” can be construed to estimate a value that is ⁇ 10% of the value or range recited.
  • the term “stable” as used herein in reference to the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; means that the said composition does not exhibit degradation upon storage over a set time limit, at a set temperature, and at an identified pH; or within the context of the present invention the term “stable” as used herein in reference to the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; means that the said composition exhibit a chromatographic purity, where in the impurities identified are within the acceptable limit.
  • the term "sterile composition” means one in which essentially all forms of microbial life have been destroyed by an appreciable amount to meet the sterilization criteria outlined in the US Pharmacopeia.
  • the term “ready-to-use” or “RTU” as used herein in reference to the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; is a non-aqueous, injectable composition that is stable and is not reconstituted from a lyophilizate.
  • RTU also encompasses within its scope, non-aqueous, injectable composition that is stable and has been diluted from a concentrated, liquid solution just prior to use.
  • non-aqueous composition means a composition with not more than 2 % water content.
  • non-aqueous solvent means a non-polar solvent which contain bonds between atoms of similar electronegativity like carbon and hydrogen by which they lack partial charges and do not contain hydrogen attached to oxygen or nitrogen so that they are unable to form hydrogen bonds with themselves.
  • solvents are selected from the group but not limited to polyethylene glycols (PEGs), ethylene glycol, propylene glycol (PG), dipropylene glycol, tripropylene glycol, polyvinylpyrrolidone (PVP), methoxy propylene glycol (MPEG), glycerol and glycofurol or a mixture thereof.
  • non-aqueous RTU composition means the composition is devoid of any water content in the final finished product or during process for preparation of the same. However, a negligible amount i.e. not more than 2% of water or moisture may be present due to external environmental factors which does not have any impact on the physiochemical property, specifically on the stability of the composition.
  • the term “has not been reconstituted from a lyophilizate” means that a solid has not been dissolved or suspended.
  • pharmaceutically acceptable excipient means a diluent, carrier, or composition auxiliary, which is non-toxic, and inert, which does not have undesirable effects on a subject to whom it is administered and is suitable for delivering a therapeutically active agent (e.g. a small molecule drug) to the target site without affecting the therapeutic activity of the said agent.
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt(s)” means salt(s) of small molecule drug(s), which can be prepared by treating the small molecule drug(s) with an appropriate acid or a base.
  • pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium salts or inorganic base salt.
  • pharmaceutically acceptable organic base addition salts include, but are not limited to, those derived from organic bases such as lysine, arginine, guanidine, and the like.
  • Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like, as well as the salts derived from organic acids such as acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like
  • organic acids such as acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid,
  • co-crystal refers to a crystalline structure made up of two or more components in a definite stoichiometric ratio, where each component is defined as either an atom, ion, or molecule.
  • co-crystal encompasses within its scope many types of compounds, including hydrates, solvates and clathrates.
  • composition refers to a unit dose or multi dose of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which can be prepared by the processes described in one or more embodiments of the present invention.
  • composition refers to a unit dose or multi dose of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which can be prepared by the processes described in one or more embodiments of the present invention.
  • composition refers to a unit dose or multi dose of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which can be prepared by the processes described in one or more embodiments of the present invention.
  • the terms “composition”, “injectable compositions” and “stable, non-aqueous and ready-to-use injectable composition” are used interchangeably.
  • the active pharmaceutical ingredient is a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof.
  • polyol refers to an alcohol containing multilple hydroxyl groups. Polyols may comprise, but are not limited to, glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, or a combination thereof.
  • the term “stirring” encompasses within its scope, sonication or turbulence or agitation by other means. Therefore the term “stirring” can be interchangeably used with the terms “sonication", “turbulence” or "agitation”.
  • the term "pH" is a measure of hydrogen ion concentration, as commonly used in the art. Customarily the pH provides a measure on a scale from 0 to 14 of the acidity or alkalinity of a solution.
  • the pH of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof, of the present invention is between about 2.0 and about 9.0.
  • pH adjusting agent or “pH adjusting agents” as used herein, includes a substance that adjusts the pH of pharmaceutical compositions to intended pH.
  • the pH-adjusting agents may include pharmaceutically acceptable acids, bases, or buffering agents.
  • the acids may include, but are not limited to, one or more inorganic mineral acids such as citric, fumaric, gluconic, lactic, malic, metatartaric, tartaric, ascorbic and benzene sulphonic acid and the like.
  • the pH adjusting agent may be a base or a buffering agent.
  • the bases may be one or more inorganic bases or organic bases, including, but not limited to, alkaline carbonate, alkaline bicarbonate, alkaline earth metal carbonate, alkaline hydroxide, alkaline earth metal hydroxide or amine.
  • the inorganic or organic base may be an alkaline hydroxide such as lithium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydroxide or the like; an alkaline carbonate such as calcium carbonate, sodium carbonate or the like; or an alkaline bicarbonate such as sodium bicarbonate or the like; the organic base may also be sodium acetate.
  • the buffering agent can be, but is not limited to an alkali metal salt of an amino acid, aluminum hydroxide, aluminum magnesium hydroxide, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartarate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium taitarate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphat
  • a relative pH has been measured because it is difficult to measure the absolute pH of a non-aqueous solution due to lack of hydrogen ion activity or concentration. Further, the pH of the composition may vary depending upon the type of instrument and dilution media.
  • solvent system refers to a primary solvent and optionally one or more secondary co-solvent(s) selected from a group of solvents.
  • antioxidants means a substance which is particularly used because certain compounds suitable for use in compositions of the invention are prone to degradation by autoxidation.
  • Antioxidants may comprise, but are not limited to, acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), monothioglycerol, potassium nitrate, ascorbic acid or sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, edetate (“EDTA”) (e.g., disodium edetate), diethylenetriaminepentaacetic acid (“DTPA”), triglycollamate (“NT”), DL- or D- ⁇ -tocopherol, DL- or D- ⁇ -tocopheryl acetate or a combination thereof.
  • BHA butylated hydroxyani
  • Antioxidants may also comprise amino acids such as methionine, histidine, cysteine and those carrying a charged side chain, such as arginine, lysine, aspartic acid, and glutamic acid. Any stereoisomer (e.g., L-, D-, or a combination thereof) of any particular amino acid (e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and combinations thereof) or combinations of these stereoisomers, is also encompassed within the scope of the term "antioxidant” so long as the amino acid is present either in its free base form or its salt form.
  • the antioxidant if present, may be added to compositions in accordance with the invention in an amount of upto, for example, 0.05% (w/v), preferably from 0.001 to 1%.
  • small molecule drug refers to therapeutically active compounds (and/or salts thereof) that can bring about a desired and/or beneficial therapeutic effect on a subject in need thereof.
  • small molecule drug(s) refers to therapeutically active compound(s) having molecular weight of less than about 3000 Daltons.
  • the small molecule drug can be a therapeutically active compound having molecular weight ranging from about 100 Daltons to about 1500 Daltons or from about 150 Daltons to about 1250 Daltons or from about 300 Daltons to about 1100 Daltons or from about 400 Daltons to about 1000 Daltons.
  • a therapeutic agent for example, a peptide such as bortezomib having molecular weight of less than 1500 Daltons shall be regarded as a small molecule drug.
  • the small molecule drugs can be selected from the group of agents consisting of anti-cancer agents, antibacterial agents, immunomodulating agents, anti-obesity drugs, antidiabetic drugs, antifungal agents, anti-viral agents, contraceptives, analgesics, anti-inflammatory agents (e.g. steroids or non-steroidal anti-inflammatory drugs (NSAIDs)), antiemetic drugs, vasodilating agents, vasoconstricting agents, and cardiovascular agents.
  • anti-cancer agents e.g. steroids or non-steroidal anti-inflammatory drugs (NSAIDs)
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the small molecule drug can include, but not limited to, an anti-cancer agent such as azacitidine, bendamustine, bortezomib, carmustine, cisplatin, carboplatin, cyclophosphide, carmustine, daunorubicine, doxorubicin, etoposide, fludarabine, gemcitabine, melphalan, mitomycin, oxaliplatin, pemetrexed, pentostatin, streptozocin, thiotepa, topotecan or vinblastine; a cytoprotective agent such as amifostine; an anti- bacterial agent such as tigecycline, doxycycline, chloramphenicol, azhithromycin or cefazolin; an anti-fungal agent such as caspofungin, micafungin, anidulafungin or voriconazole; an anti-viral agent such as acyclovir or ganciclovir; an anti-cancer
  • protein drug or “protein drug(s)” refers to hormones, enzymes and/or antibodies that are naturally occurring, recombinant or chemically synthesized large biological molecules or macromolecules comprising a plurality of natural or modified amino acids residues bound together by amide (CONH) linkages.
  • peptide drug refers to synthetic or biological compounds (and salts thereof) containing short chains of amino acids bound together by amide (CONH) linkages that have demonstrated or potential use in treating, preventing, or ameliorating one or more diseases, disorders, or conditions in a subject in need thereof.
  • the peptide drugs are short chains of amino acid monomers containing up to 50 amino acids bound together by amide (CONH) linkages and have a molecular weight of less than approximately 5000 Daltons.
  • absolute alcohol refers to ethanol containing from about 98.0 - 99.8 v/v/ % of ethanol and from about 0.2 - 2.0 v/v % of water.
  • the term "subject” refers to an animal, preferably a mammal, and most preferably a human.
  • the term “mammal” is used interchangeably with the term “patient” or “subject”.
  • the phrase "a subject in need thereof means a subject (patient) in need of the treatment of a disease or disorder for which the small molecule drug can be suitably used.
  • the inventors of the present invention have done extensive research and conducted several experiments to develop a stable injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co- crystal thereof which can be prepared in a solubilized and stable form suitable for ready- to-use injection. Further, being a RTU composition, it has enhanced patient compliance and also provides a more stable, safe and effective composition when compared to currently marketed lyophilized compositions.
  • the injectable composition of the present invention can be used for a wide variety of small molecule drugs.
  • the present invention relates to a stable, non-aqueous and ready-to-use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
  • a non-aqueous solvent system consisting of a primary non-aqueous solvent and optionally one or more secondary non-aqueous co-solvent(s);
  • the small molecule drug is a therapeutically active compound having molecular weight of less than about 1500 Daltons.
  • the small molecule drug can be selected from the group of agents consisting of anti-cancer agents, anti-bacterial agents, immunomodulating agents, anti-obesity drugs, antidiabetic drugs, anti-fungal agents, anti-viral agents, contraceptives, analgesics, anti-inflammatory agents (e.g. steroids or non-steroidal antiinflammatory drugs (NSAIDs)), antiemetic drugs, vasodilating agents, vasoconstricting agents, and cardiovascular agents.
  • anti-cancer agents e.g. steroids or non-steroidal antiinflammatory drugs (NSAIDs)
  • NSAIDs non-steroidal antiinflammatory drugs
  • the small molecule drug is an anticancer agent selected from: azacitidine, bendamustine hydrochloride, bortezomib, carmustine, cisplatin, carboplatin, cyclophosphide, carmustine, daunorubicine hydrochloride, doxorubicin hydrochloride, etoposide, fludarabine, gemcitabine, melphalan, mitomycin, oxaliplatin, pemetrexed disodium, pentostatin, streptozocin, thiotepa, topotecan or vinblastine.
  • an anticancer agent selected from: azacitidine, bendamustine hydrochloride, bortezomib, carmustine, cisplatin, carboplatin, cyclophosphide, carmustine, daunorubicine hydrochloride, doxorubicin hydrochloride, etoposide, fludarabine, gemcitabine, melphal
  • the small molecule drug is a cytoprotective agent such as amifostine.
  • the small molecule drug is an anti-bacterial agent selected from: tigecycline, doxycycline hyclate, chloramphenicol, azithromycin or cefazolin sodium.
  • the small molecule drug is an anti-fungal agent selected from: caspofungin, micafungin, anidulafungin or voriconazole.
  • the small molecule drug is an anti-viral agent selected from acyclovir sodium or ganciclovir sodium.
  • the small molecule drug is an anti-psychotic drug selected from thiothixene hydrochloride or midazolam hydrochloride.
  • the small molecule drug is an anti-ulcer agent selected from esomeprazole sodium, lansoprazole or pantoprazole sodium.
  • the small molecule drug is an analgesic selected from metamizole sodium, hydromorphone hydrochloride or remifentanil hydrochloride.
  • the small molecule drug is an anti-inflammatory agent selected from hydrocortisone sodium succinate, methylprednisolone sodium succinate, indomethacin, ketoprofen or parecoxib sodium.
  • the small molecule drug is an antiemetic drug selected from aprepitant, dolasetron mesylate, fosaprepitant, granisetron, ondansetron, metoclopromide hydrochloride, hycosine hydrobromide or promethazine.
  • the small molecule drug is an immunomodulating agent such as methotrexate.
  • the small molecule drug is a cardiovascular agent selected from atenolol, dobutamine hydrochloride or epoprostenol sodium.
  • the small molecule drug is an anesthetic such as methohexital sodium.
  • the small molecule drug is selected from caspofungin, pemetrexed, bortezomib, tigecycline or fosaprepitant.
  • the injectable composition contains the small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration in the range of about 0.1 mg/mL to about 250 mg/mL.
  • the injectable composition contains the small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration in the range of about 0.1 mg/mL to about 100 mg/mL.
  • the injectable composition contains the small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration in the range of about 0.1 mg/mL to about 50 mg/mL.
  • the injectable composition contains the small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration in the range of about 0.1 mg/mL to about 20 mg/mL
  • the injectable composition contains the small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration in the range of about 0.1 mg/mL to about 10 mg/mL.
  • the non-aqueous solvent system comprises 100% primary nonaqueous solvent; or in the non-aqueous solvent system, the primary non-aqueous solvent and the secondary non-aqueous co-solvent can be used in a ratio ranging from about 99:1 to about 50:50.
  • the non-aqueous solvent system comprises 100% primary nonaqueous solvent.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) can be used in the ratio ranging from about 99:1 to about 50:50.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) can be used in the ratio of 99:1,
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent can be used in the ratio of 90: 10.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent can be used in the ratio of 85:15.
  • the non- aqueous solvent system comprises one or more solvent selected from the group consisting of ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol, polyethylene glycol, methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
  • the primary non-aqueous solvent contained in the non-aqueous solvent system is selected from the group consisting of but not limited to ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol and polyethylene glycol or a mixture thereof.
  • the primary non-aqueous solvent is propylene glycol.
  • the optional secondary non-aqueous co-solvent(s) contained in the non-aqueous solvent system is a (C 1 -C 3 )alkyl alcohol selected from the group consisting of but not limited to methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
  • the optional secondary non-aqueous co-solvent(s) contained in the non-aqueous solvent system is isopropyl alcohol, ethanol or an absolute alcohol; or a combination thereof.
  • the optional secondary non-aqueous co-solvent(s) contained in the non-aqueous solvent system is ethanol or an absolute alcohol.
  • the optional secondary non-aqueous co-solvent contained in the non-aqueous solvent system is ethanol.
  • the optional secondary non-aqueous co-solvent contained in the non-aqueous solvent system is absolute alcohol.
  • the optional secondary non-aqueous co-solvent(s) contained in the non-aqueous solvent system is isopropyl alcohol.
  • the optional secondary non-aqueous co-solvent(s) contained in the non-aqueous solvent system is a combination of ethanol/absolute alcohol and isopropyl alcohol.
  • the polyol is selected from a group consisting of but not limited to glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, trehalose or a combination thereof.
  • the polyol is in the range of about 0.01% to about 10% of the total injectable composition of the small molecule drug.
  • the polyol is sorbitol or racemic salts or isomers thereof.
  • the polyol is D-sorbitol.
  • the primary non-aqueous solvent, the secondary co-solvent(s) and the polyol are present in an amount such that the small molecule drug at the concentration of at least 7 mg/ml small molecule drug is completely soluble and stable in the injectable composition.
  • the non-aqueous solvent system contains propylene glycol and ethanol.
  • the non-aqueous solvent system contains propylene glycol and absolute alcohol.
  • the non-aqueous solvent system contains propylene glycol and isopropyl alcohol.
  • the non-aqueous solvent system comprises 100% propylene glycol; or in the non-aqueous solvent system, the propylene glycol and the ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in a ratio ranging from about 99:1 to about 50:50.
  • the non-aqueous solvent system comprises 100% propylene glycol.
  • the propylene glycol and the ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio ranging from about 99:1 to about 50:50.
  • the propylene glycol and the ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 99:1, 95:5,
  • non-aqueous solvent system consisting propylene glycol and ethanol/ absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 90:10.
  • non-aqueous solvent system consisting propylene glycol and ethanol/ absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 85:15.
  • the pH adjusting agent is selected from pharmaceutically acceptable acids, bases, or buffering agents.
  • the pH of the ready-to-use small molecule drug injectable composition of the present invention is between about 2.0 and about 9.0.
  • the pH of the ready-to-use small molecule drug injectable composition of the present invention is between about 3.0 and about 8.0.
  • the antioxidants may be selected from butylated hydroxytoluene, sodium metabisulphite acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole, monothioglycerol, potassium nitrate, ascorbic acid or sodium ascorbate, sodium formaldehyde sulfoxylate, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, edetate, diethylenetriaminepentaacetic acid, triglycollamate, DL- or D- ⁇ - tocopherol, DL- or D- ⁇ -tocopheryl acetate, amino acids, stereoisomers of amino acids; or a combination thereof
  • the antioxidant may be selected from butylated hydroxytoluene or sodium metabisulphite.
  • the present invention relates to a process for the preparation of a stable, non-aqueous and ready-to-use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
  • step (b) adding the second solution of step (b) to the first solution of step (a) under constant stirring to obtain a third solution;
  • step (c) dispersing the small molecule drug in the third solution of step (c) to obtain a clear solution
  • step (e) optionally filtering the solution of step (d); and f) filling the clear solution of step (e) into a container to obtain a preparation in a ready-to-use form.
  • the present invention relates to a process for the preparation of a stable, non-aqueous and ready-to-use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
  • step (b) adding primary non-aqueous solvent to the first solution of step (a) to obtain a second solution;
  • step (c) adding small molecule drug to the second solution of step (b) and allowing to disperse to produce a solution;
  • step (c) optionally filtering the solution of step (c) one or more times to obtain a clear solution
  • step (d) filling the clear solution of step (d) into a container to obtain a composition in a ready-to-use form.
  • the present invention relates to a process for the preparation of the stable, non-aqueous and ready-to-use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
  • step (a) allowing the resulting first solution of step (a) to attain a temperature of 2°C to room temperature;
  • step (c) optionally adding polyol and antioxidant to the first solution of step (b) under constant stirring until the polyol dissolves, to obtain a second solution; d) optionally adding a secondary non-aqueous solvent to the second solution of step (c) under constant stirring for S minutes to 10 minutes to obtain a third solution;
  • step (e) adding small molecule drug to the third solution of step (d) and allowing to disperse to obtain a solution;
  • step (e) optionally filtering the solution as obtained in step (e) one or more times to obtain a clear solution
  • step (f) filling the clear solution of step (f) in suitable containers to obtain a composition in a ready-to-use form.
  • the present invention relates to a process for the preparation of the stable, non-aqueous and ready-to-use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
  • step (a) allowing the resulting first solution of step (a) to attain a temperature of 2°C to room temperature;
  • step (c) optionally adding a secondary non-aqueous solvent to the first solution of step (b) under constant stirring for S minutes to 10 minutes to obtain a second solution; d) adding small molecule drug to the second solution of step (c) and allowing to disperse to obtain a solution;
  • step (d) optionally filtering the solution of step (d) one or more times to obtain a clear solution
  • step (e) filling the clear solution of step (e) in suitable containers to obtain a composition in a ready-to-use form.
  • the said small molecule drug in the process for the preparation of the injectable composition of the small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; is as described above in one or more embodiments of the invention.
  • the non-aqueous solvent system comprises 100% primary non-aqueous solvent; or in the non-aqueous solvent system, the primary non-aqueous solvent and the secondary non- aqueous co-solvent can be used in a ratio ranging from about 99: 1 to about 50:50.
  • the non-aqueous solvent system comprises 100% primary non-aqueous solvent.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent in the process for the preparation of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non-aqueous solvent system, can be used in a ratio ranging from about 99:1 to about 50:50.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent in the process for the preparation of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non-aqueous solvent system, can be used in the ratio of 99:1, 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) in the process for the preparation of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non-aqueous solvent system, the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) can be used in the ratio of 90:10.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) in the process for the preparation of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non-aqueous solvent system, the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) can be used in the ratio of 85: 15.
  • the primary non-aqueous solvent contained in the non-aqueous solvent system is selected from the group consisting of but not limited to ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol and polyethylene glycol or a mixture thereof.
  • the primary non-aqueous solvent is propylene glycol.
  • the secondary non-aqueous co-solvent(s) is a (C 1 -C 3 )alkyl alcohol selected from the group consisting of but not limited to methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
  • the secondary non-aqueous co-solvent(s) is isopropyl alcohol; ethanol or absolute alcohol; or a combination thereof.
  • the secondary non-aqueous co-solvent(s) is ethanol.
  • the secondary non-aqueous co-solvent(s) is absolute alcohol.
  • the secondary non-aqueous co-solvent is isopropyl alcohol.
  • the secondary non-aqueous co-solvent is a combination of ethanol/absolute alcohol and isopropyl alcohol.
  • the polyol is selected from a group consisting of but not limited to glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, trehalose or a combination thereof.
  • the polyol in the process for the preparation of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; is in the range of about 0.01% to about 10% of the total injectable composition of the small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof.
  • the polyol in the process for the preparation of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; the polyol is sorbitol or racemic salts or isomers thereof.
  • the polyol in the process for the preparation of the injectable composition of a small molecule drug; the polyol is D-sorbitol.
  • the non-aqueous solvent system comprises 100% propylene glycol.
  • the non-aqueous solvent system comprises propylene glycol and ethanol.
  • the non-aqueous solvent system comprises propylene glycol and absolute alcohol.
  • the non-aqueous solvent system comprises propylene glycol and isopropyl alcohol.
  • the non-aqueous solvent system comprises 100% propylene glycol; or in the non-aqueous solvent system, the propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in a ratio ranging from about 99:1 to about 50:50.
  • the non-aqueous solvent system comprises 100% propylene glycol.
  • propylene glycol and ethanol/absolute alcohol can be used in the ratio ranging from about 99:1 to about 50:50.
  • propylene glycol and ethanol/absolute alcohol in the process for the preparation of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non-aqueous solvent system, propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 99:1, 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
  • propylene glycol and ethanol/absolute alcohol in the process for the preparation of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non-aqueous solvent system, propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 90:10.
  • propylene glycol and ethanol/absolute alcohol in the process for the preparation of the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non-aqueous solvent system, propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 85:15.
  • the pH adjusting agent is selected from pharmaceutically acceptable acids, bases, or buffering agents.
  • the pH of the ready-to-use injectable composition of small molecule drug obtained by the process as described above is between about 2.0 and about 9.0.
  • the pH of the ready-to-use small molecule drug injectable composition obtained by the process as described above is between about 3.0 and about 8.0.
  • the antioxidant is selected from but not limited to butylated hydroxytoluene, sodium metabisulphite acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole, monothioglycerol, potassium nitrate, ascorbic acid or sodium ascorbate, sodium formaldehyde sulfoxylate, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, edetate, diemylenetriaminepentaacetic acid, triglycollamate, DL- or D- ⁇ - tocopherol, DL- or D- ⁇ -tocopheryl acetate, amino acids, stereoisomers of amino acids; or a combination thereof.
  • the antioxidant is selected from butylated hydroxytoluene or sodium metabisulphite.
  • the present invention relates to use of a stable, non-aqueous and ready-to-use composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; for the manufacture of a medicament for treating or preventing one or more diseases, conditions or disorders.
  • the present invention relates to a method of treating or preventing one or more diseases, conditions or disorders comprising administering to a subject in need thereof; a therapeutically effective amount of a stable, non-aqueous and ready-to- use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition is as described in one or more embodiments of the present invention as described herein above.
  • the diseases, disorders or conditions for the treatment or prevention of which the injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; of the present invention can be used, include, but are not limited to, metabolic disorders(e.g. diabetes or obesity), autoimmune disorders, cardiovascular diseases, respiratory diseases, thyroid diseases, hormonal diseases, neurodegenerative diseases, bacterial infections, viral infections, fungal infections, renal diseases, hepatobiliary diseases, venereal diseases, platelet aggregation, inflammatory diseases, gastrointestinal diseases, cancers, transplantation complications due to rejection reactions, graft rejection and hepatic diseases.
  • metabolic disorders e.g. diabetes or obesity
  • autoimmune disorders e.g. diabetes or obesity
  • cardiovascular diseases e.g., respiratory diseases, thyroid diseases, hormonal diseases, neurodegenerative diseases, bacterial infections, viral infections, fungal infections, renal diseases, hepatobiliary diseases, venereal diseases, platelet aggregation, inflammatory diseases, gastrointestinal diseases, cancers, transplantation complications due to rejection reactions
  • the small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; contained in the stable, non-aqueous and ready-to-use injectable composition which is provided for use in the treatment or prevention of one or more diseases, conditions or disorders (as described herein); is as described above in one or more embodiments of the invention.
  • the stable, non-aqueous and ready-to-use injectable composition of a small molecule drug may be packaged in a suitable container depending upon the composition and the method of administration of the composition.
  • suitable containers known to a person skilled in the art include vials, ampoules and infusion bag.
  • the present invention provides a pharmaceutical kit comprising the stable, non-aqueous and ready-to-use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said composition comprises of the small molecule drug or a pharmaceutically acceptable salt or a co-crystal thereof; a non-aqueous solvent system consisting of a primary nonaqueous solvent and optionally one or more secondary non-aqueous co-solvent(s); optionally a polyol; optionally a pH adjusting agent and optionally an antioxidant.
  • the kit may further comprise a package insert, including information about the indication, usage, doses, direction for administration, contraindications, precautions and warnings.
  • the kit may further contain optional materials for storing and/or administering the small molecule drug, for example, infusion bag as well as instructions for storage and use.
  • the stable, non-aqueous and ready-to-use injectable composition of a small molecule drug of the present invention can be delivered to the subject intravenously.
  • Methods of delivering the RTU injectable composition intravenously are well known in the art.
  • the stable, non-aqueous and ready-to-use injectable composition of a small molecule drug or a pharmaceutically acceptable salt or a co- crystal thereof can be delivered to the subject by infusion.
  • the injectable dosage form may be delivered intravenously through infusion.
  • step (b) The second solution of step (b) was added to the first solution of step (a) to obtain a third solution.
  • step (d) The solution obtained in step (d) was subjected to turbulence for 30-120 minutes to obtain a clear solution.
  • step (e) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
  • Example 2
  • step (b) The solution thus obtained in step (b) was added to propylene glycol of step (a) with continuous stirring until complete miscibility was observed.
  • step (d) Caspofungin was then added to the solution obtained in step (c) to obtain a solution.
  • step (d) The solution obtained in step (d) was subjected to turbulence for 30- 120 minutes to obtain a clear solution.
  • step (e) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
  • step (b) Sorbitol and butylated hydroxytoluene were dissolved in ethanol to obtain a solution.
  • step (c) The solution thus obtained in step (b) was added to propylene glycol of step (a) with continuous stirring until complete miscibility was observed.
  • step (d) Caspofungin was then added to the solution obtained in step (c) to obtain a solution.
  • step (d) The solution obtained in step (d) was subjected to turbulence for 30- 120 minutes to obtain a clear solution..
  • step (e) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
  • step (b) Sorbitol and sodium metabisulphite were dissolved in ethanol to obtain a solution.
  • step (b) The solution thus obtained in step (b) was added to propylene glycol of step (a) with continuous stirring until complete miscibility was observed.
  • step (d) Caspofungin was then added to the solution obtained in step (c) to obtain a solution.
  • step (d) The solution obtained in step (d) was subjected to turbulence for 30- 120 minutes to obtain a clear solution..
  • step (e) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
  • step (b) The solution thus obtained in step (b) was added to propylene glycol of step (a) with continuous stirring until complete miscibility was observed.
  • step (c) Fosaprepitant was then added to the solution obtained in step (c) to obtain a solution.
  • step (d) The solution obtained in step (d) was subjected to turbulence for 30- 120 minutes to obtain a clear solution.
  • step (e) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
  • Example 6 The composition described in Example 6 is prepared by following the same procedure described in the above Example 5. Stability Studies (Example 6):
  • Fosaprepitant was then added to the solution to obtain a solution.
  • step (e) The solution obtained in step (e) was subjected to turbulence for 30- 120 minutes to obtain a clear solution.
  • step (f) The clear liquid concentrate obtained in step (f) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a formulation in a ready-to-use form.
  • Stability Studies (Example 7):
  • Example 8 The composition described in Example 8 is prepared by following the same procedure described in the above Example 7.

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Abstract

La présente invention concerne une composition injectable non-aqueuse, stable et prête à l'emploi d'un médicament à petite molécule ou d'un sel pharmaceutiquement acceptable ou d'un co-cristal de celui-ci ; et des procédés pour sa préparation. Il n'est pas nécessaire de reconstituer la composition injectable du médicament à petites molécules avec de l'eau avant l'administration, ladite composition est ainsi une composition injectable facile à utiliser.
PCT/IB2015/057924 2014-10-16 2015-10-15 Composition injectable stable de médicaments à petites molécules et procédé de préparation associé Ceased WO2016059590A1 (fr)

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EP3485873A1 (fr) * 2017-11-17 2019-05-22 Cadila Healthcare Limited Compositions injectables pharmaceutiques stables de micafungine
US10307432B2 (en) 2015-11-03 2019-06-04 Cipla Limited Stabilized liquid fosaprepitant formulations
WO2020035806A1 (fr) 2018-08-17 2020-02-20 Hospira Australia Pty Ltd Compositions pharmaceutiques liquides de bendamustine
US11065265B2 (en) 2018-05-18 2021-07-20 Spes Pharmaceuticals Inc. Compositions of fosaprepitant and methods of preparation
CN113694018A (zh) * 2021-09-08 2021-11-26 海南制药厂有限公司制药二厂 一种氯霉素注射液及其制备方法
US20220040092A1 (en) * 2020-06-27 2022-02-10 RK Pharma Solutions LLC Ready to use injectable formulations of Micafungin Sodium
WO2023049346A1 (fr) * 2021-09-24 2023-03-30 MAIA Pharmaceuticals, Inc. Compositions de bortézomib
US11986486B2 (en) 2020-11-02 2024-05-21 Spes Pharmaceuticals Inc. Aqueous compositions of bortezomib
WO2025181379A1 (fr) * 2024-03-01 2025-09-04 Etico Lifesciences Private Limited Formulations de pantoprazole liquides, stables au stockage, directement injectables, leurs utilisations et leur fabrication

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WO2014004376A2 (fr) * 2012-06-26 2014-01-03 Del Mar Pharmaceuticals Méthodes de traitement de malignités résistantes à un inhibiteur de tyrosine kinase chez des patients ayant des polymorphismes génétiques ou des dérégulations ou des mutations d'ahi1 à l'aide de dianhydrogalactitol, diacétyldianhydrogalactitol, dibromodulcitol ou des analogues ou dérivés correspondants
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US20120172808A1 (en) * 2010-03-18 2012-07-05 Innopharma, Llc Stable Bortezomib Formulations
US20120277249A1 (en) * 2011-04-28 2012-11-01 Andersson Borje S Parenteral formulations of lipophilic pharmaceutical agents and methods for preparing and using the same
WO2014004376A2 (fr) * 2012-06-26 2014-01-03 Del Mar Pharmaceuticals Méthodes de traitement de malignités résistantes à un inhibiteur de tyrosine kinase chez des patients ayant des polymorphismes génétiques ou des dérégulations ou des mutations d'ahi1 à l'aide de dianhydrogalactitol, diacétyldianhydrogalactitol, dibromodulcitol ou des analogues ou dérivés correspondants
WO2014165136A1 (fr) * 2013-03-12 2014-10-09 Antares Pharma, Inc. Seringues pré-remplies à volume constant et leurs trousses

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US10307432B2 (en) 2015-11-03 2019-06-04 Cipla Limited Stabilized liquid fosaprepitant formulations
EP3485873A1 (fr) * 2017-11-17 2019-05-22 Cadila Healthcare Limited Compositions injectables pharmaceutiques stables de micafungine
US11065265B2 (en) 2018-05-18 2021-07-20 Spes Pharmaceuticals Inc. Compositions of fosaprepitant and methods of preparation
EP3836921A4 (fr) * 2018-08-17 2022-04-20 Hospira Australia Pty Ltd Compositions pharmaceutiques liquides de bendamustine
WO2020035806A1 (fr) 2018-08-17 2020-02-20 Hospira Australia Pty Ltd Compositions pharmaceutiques liquides de bendamustine
US12246007B2 (en) 2018-08-17 2025-03-11 Hospira Australia Pty Ltd Liquid bendamustine pharmaceutical compositions
US20220040092A1 (en) * 2020-06-27 2022-02-10 RK Pharma Solutions LLC Ready to use injectable formulations of Micafungin Sodium
US11986486B2 (en) 2020-11-02 2024-05-21 Spes Pharmaceuticals Inc. Aqueous compositions of bortezomib
CN113694018A (zh) * 2021-09-08 2021-11-26 海南制药厂有限公司制药二厂 一种氯霉素注射液及其制备方法
WO2023049346A1 (fr) * 2021-09-24 2023-03-30 MAIA Pharmaceuticals, Inc. Compositions de bortézomib
US11672813B2 (en) 2021-09-24 2023-06-13 MAIA Pharmaceuticals, Inc. Bortezomib compositions
US11679119B2 (en) 2021-09-24 2023-06-20 MAIA Pharmaceuticals, Inc. Bortezomib compositions
US11752164B2 (en) 2021-09-24 2023-09-12 MAIA Pharmaceuticals, Inc. Bortezomib compositions
US12005069B2 (en) 2021-09-24 2024-06-11 MAIA Pharmaceuticals, Inc. Bortezomib compositions
WO2025181379A1 (fr) * 2024-03-01 2025-09-04 Etico Lifesciences Private Limited Formulations de pantoprazole liquides, stables au stockage, directement injectables, leurs utilisations et leur fabrication

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