WO2014118696A2 - Pharmacuetical compositions of rapamycin esters and its derivatives - Google Patents

Pharmacuetical compositions of rapamycin esters and its derivatives Download PDF

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Publication number
WO2014118696A2
WO2014118696A2 PCT/IB2014/058602 IB2014058602W WO2014118696A2 WO 2014118696 A2 WO2014118696 A2 WO 2014118696A2 IB 2014058602 W IB2014058602 W IB 2014058602W WO 2014118696 A2 WO2014118696 A2 WO 2014118696A2
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WO
WIPO (PCT)
Prior art keywords
acid
temsirolimus
pharmaceutical composition
solvent
propylene glycol
Prior art date
Application number
PCT/IB2014/058602
Other languages
French (fr)
Other versions
WO2014118696A3 (en
Inventor
Prasanna SAGAR
Sachin ZILESINGH REWARIA
Venkata Ramana Rao PATHIPATI
Simhachalam PYDI
Sunil Kumar SIKHAKOLLI
Sampath Kumar NAMASHIVAYAGAARI
Original Assignee
Gland Pharma Limited
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Publication date
Application filed by Gland Pharma Limited filed Critical Gland Pharma Limited
Publication of WO2014118696A2 publication Critical patent/WO2014118696A2/en
Publication of WO2014118696A3 publication Critical patent/WO2014118696A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

Definitions

  • the present invention relates to pharmaceutical compositions of rapamycin esters and its derivatives.
  • Rapamycin is a fermentation product of Streptomyces hygroscopicus and was first reported in 1975 (J. Antibiot 28:727 (1975). Rapamycin 42-[3hydroxy-2- (hydroxymethyl)-2-methylpropanoate] generically known as CCI-779 or Temsirolimus.
  • Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked.
  • FKBP-12 intracellular protein
  • temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.
  • US Patent No. 8,026,276 of Rubino et al discloses parenteral formulations containing CCI-779, an alcoholic co-solvent, and an antioxidant, another parenteral formulation containing CCI-779, an alcoholic solvent, an antioxidant, a diluent solvent, and a surfactant. Further processes for preparing parenteral CCI-779 formulations using a co-solvent concentrate are also provided.
  • Rapamycin Esters in particular Rapamycin 42- ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid that is free of antioxidants and a process of preparing the same.
  • Ashraf et al discloses a stable pharmaceutical composition of CCI-779 for oral administration comprising Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, a water soluble polymer, a surfactant, an antioxidant, and a pH modifying agent
  • Ashraf et al discloses pharmaceutical compositions containing a stable and bioavailable form of micronized Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) along with an antioxidant or a chelating agent, or mixtures thereof.
  • US Patent No. 7,074,804 Zhu et al discloses an oral formulation of Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid using wet granulation method, utilizing isomer C of the drug, a water soluble polymer, a pH modifying agent, a surfactant, and an antioxidant. Further the patent also provides an injectable formulation containing Rapamycin 42-ester with 3- hydroxy-2-(hydroxymethyl)-2-methylpropionic acid isomer C, a parenterally acceptable cosolvent, an antioxidant, a diluent solvent, and a surfactant.
  • Rapamycin and its related compounds are susceptible to chemical instability during synthesis of the compounds or during their compositions as a dosage form.
  • the chemical instability of Rapamycin esters is mainly attributed to their oxidative degradation or to cleavage of a lactone bond in the molecule, resulting in the opening of the ring and formation of a degradation product.
  • aspects of the present invention relate to liquid pharmaceutical compositions of rapamycin esters and its derivatives.
  • Another aspect of the invention relates to lyophilized pharmaceutical compositions of rapamycin esters and its derivatives. Another aspect of the invention relates to stable lyophilized pharmaceutical compositions of rapamycin esters and its derivatives with or without antioxidant.
  • the present invention provides innovative liquid composition of temsirolimus.
  • temsirolimus is solvated in non-aqueous solvent such as alcohol such as ethanol or dehydrated alcohol, propylene glycol or combinations thereof.
  • non-aqueous solvent such as alcohol such as ethanol or dehydrated alcohol, propylene glycol or combinations thereof.
  • the inventive approach circumvents problems associated with prior art compositions of rapamycin esters and its derivatives, such as chemical instability, inconvenient storage and transportation, and discomfort of patients due to cold infusions.
  • the compositions can be used to treat a wide variety of indications that are sensitive to temsirolimus treatment.
  • the acid may be an organic acid, inorganic acid, amino acid.
  • organic acid include, but are not limited to, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, formic acid, benzene sulphonic acid, benzoic acid, maleic acid, malonic acid, glutamic acid, succinic acid, aspartic acid, diatrizoic acid, acetic acid and mixtures thereof.
  • inorganic acid include, but are not limited to hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid and mixtures thereof.
  • amino acid include, but are not limited to, cysteine, glycine, alanine, lysine, arginine, glutathione, methionine, leucine, aspartic acid and mixtures thereof.
  • the acid is lactic acid at a concentration of 0.01 -0.2 mg/ml of the solvent, between 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
  • the acid is benzoic acid at a concentration of 0.01 - 0.2 mg/ml of the solvent, between 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
  • the acid is cysteine HCI at a concentration of 0.01 - 0.2 mg/ml of the solvent, between 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
  • the acid is citric acid at a concentration of 0.01 -0.2 mg/ml of the solvent, between 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
  • a liquid pharmaceutical composition is provided for administering temsirolimus to a patient.
  • the composition comprises temsirolimus solvated in a solvent that comprises nonaqueous solvent such as alcohol such as ethanol or dehydrated alcohol, propylene glycol or combinations thereof.
  • the amount of temsirolimus in the pharmaceutical composition is between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent, for example 25 mg per ml.
  • the amount of temsirolimus in the pharmaceutical composition is between 0.1 and 200 mg per vial, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per vial, for example 30 mg per vial.
  • the composition further comprises one or more pharmaceutically acceptable excipients.
  • the excipients comprises of one or more solvent selected from the group consisting of alcohol like dehydrated alcohol; one or more co-solvent selected from the group consisting of glycols, like ethylene glycol, and propylene glycol.
  • the solvent is alcohol, wherein the concentration of alcohol is between 0.1 -99.9%, optionally between 1 -90%, between 10-60%, or between 20-40%.
  • the solvent is a combination of propylene glycol and alcohol, wherein the concentration of propylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -90%, between 10-60%, or between 20- 40%.
  • the pharmaceutical composition may also optionally comprise one or more antioxidants.
  • the antioxidants as disclosed in US publication no. 2004/0167152 ranging from citric acid, d,l-.alpha.-tocopherol, BHA, BHT, monothioglycerol, ascorbic acid, propyl gallate, and mixtures thereof can be used to providing stable Temsirolimus compositions for parenteral administration.
  • the pH of the pharmaceutical composition may be adjusted to be between pH 4 and pH 8, for example between pH 4.2 and pH 7, and further between pH 4.5 and pH 6.8.
  • the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising the active ingredient, organic acid, solvent and co-solvent.
  • the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising temsirolimus, amino acid, propylene glycol, dehydrated alcohol.
  • the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising temsirolimus, lactic acid, propylene glycol, dehydrated alcohol.
  • the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising temsirolimus, benzoic acid, propylene glycol, dehydrated alcohol.
  • the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising temsirolimus, cysteine HCI, propylene glycol, dehydrated alcohol.
  • the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising temsirolimus, citric acid, propylene glycol, dehydrated alcohol.
  • the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising temsirolimus, citric acid, propylene glycol, dehydrated alcohol and optionally it may include antioxidants such as BHA and / or BHT.
  • the present invention relates to process of preparing the liquid pharmaceutical composition comprising:
  • step (b) adding acid to step (a) mixture to get a clear solution
  • step (c) optionally, adding anti-oxidant to step (b) mixture and stirring to obtain a clear solution; and d) finally adding propylene glycol to the above step (c) mixture to obtain a clear liquid solution.
  • the act further comprise: adding propylene glycol to the solution containing temsirolimus such that pH of the resulting solution is between pH 4 and pH 8, for example between pH 4.5 and pH 7, and further between pH 5 and pH 6.8.
  • the present invention provides lyophilized pharmaceutical composition
  • lyophilized pharmaceutical composition comprising an active ingredient one or more bulking agent(s) and optionally an anti-oxidant.
  • the present invention provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising temsirolimus, acid, one or more bulking agent(s) and optionally an anti-oxidant.
  • the present invention provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising temsirolimus, acid, mannitol and optionally an anti-oxidant.
  • the present invention provides a lyophilized pharmaceutical composition comprising temsirolimus, acid, sugar and optionally an anti-oxidant.
  • the present invention provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising temsirolimus, acid, sorbitol and optionally an anti-oxidant.
  • the present invention provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising temsirolimus, acid, cyclodextrin and optionally an antioxidant.
  • the present invention relates to process of preparing the lyophilized pharmaceutical composition comprising:
  • step (b) adding acid to step (a) mixture to get a clear solution
  • step (b) adding bulking agent and optionally an anti-oxidant to step (b) mixture and stirring to obtain a clear solution;
  • active ingredient or drug refers to a substance that has a physiological effect when ingested or otherwise introduced into the body, in particular or a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being.
  • excipient or "pharmaceutically acceptable excipient” means a component of a pharmaceutical product that is not a pharmacologically active ingredient, such as filler, diluent, carrier, preservative, etc.
  • excipients that are useful in preparing pharmaceutical compositions are generally safe, non- toxic, and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use.
  • the term includes both one and more than one such excipients.
  • composition is intended to encompass a combination including active ingredients and pharmaceutically acceptable excipients, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions involving one or more of the ingredients.
  • formulation or “dosage form” or “composition” refers to finished pharmaceutical products that are suitable for administration, including, but not limited to, injections, etc.
  • the term “stability” as used herein includes both physical and chemical stability.
  • the term “physical stability” refers to maintenance of the form of active agents, such as crystalline or amorphous, and the term “chemical stability” relates to a limited formation of impurities.
  • Carrier or “vehicle” as used herein refers to pharmacologically inert materials that provide a more or less fluid matrix, suitable for topical drug administration. Carriers and vehicles useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of a pharmaceutical formulation or drug delivery system in a deleterious manner.
  • the topical formulations of the present invention are particularly suitable for parenteral administration. Formulations suitable for parenteral dosage forms such as injectables such as intravenous, intramuscular or subcutaneous, implants and the like. Other parenteral ingredients used in the formulation are generally those commonly used and recognized by persons skilled in the art of parenteral formulations.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically-acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids.
  • Pharmaceutically- acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • Pharmaceutically acceptable salts are those forms of compounds, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • salt forms of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in at page 1418 of Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985.
  • terapéuticaally effective amount of a compound of this invention means an amount effective to modulate the formation or progression of a infection in a host.
  • temsirolimus includes the compound temsirolimus, pharmaceutically acceptable salts and esters thereof, and any of polymorphs, solvates and hydrates thereof.
  • aspects of the present invention relate to innovative liquid pharmaceutical compositions of temsirolimus and a suitable solvent system.
  • the pharmaceutical compositions of the present invention can be used to treat patient suffering from a disease sensitive to the treatment with temsirolimus, such as hematological disorders, benign tumors, malignant tumors, restenosis, and inflammatory diseases via various routes of administration such as intravenous, intramuscular, or subcutaneous injection.
  • the present invention provides stable liquid injectable pharmaceutical composition comprising temsirolimus and one or more acid.
  • the acids include, but not limited to organic acid, inorganic acid and amino acid.
  • organic acid include, but are not limited to, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, formic acid, benzene sulphonic acid, benzoic acid, maleic acid, malonic acid, glutamic acid, succinic acid, aspartic acid, diatrizoic acid, acetic acid and mixtures thereof.
  • inorganic acid include but not limited to hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid and mixtures thereof.
  • amino acid include, but are not limited to, cysteine, glycine, alanine, lysine, arginine, glutathione, methionine, leucine, aspartic acid and mixtures thereof.
  • the concentration of acid is between 0.01 -0.2 mg/ml of the solvent, further 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
  • the acid is lactic acid at a concentration of 0.01 - 0.2 mg/ml of the solvent, further 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
  • the acid is benzoic acid at a concentration of 0.01 - 0.2 mg/ml of the solvent, further 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
  • the acid is cysteine HQ at a concentration of 0.01 - 0.2 mg/ml of the solvent, further 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
  • present invention further comprises one or more pharmaceutically acceptable excipients.
  • the excipients comprise of a solvent and a co-solvent.
  • solvents include alcohol, but are not limited to, ethanol, dehydrated ethanol and mixtures thereof.
  • co-solvents include, but are not limited to, ethylene glycol, propylene glycol, polyethylene glycol and mixtures thereof.
  • temsirolimus is dissolved in dehydrated alcohol at different concentrations.
  • the composition may optionally comprise between 1 and 100; between 1 and 50; between 2 and 50; between 2 and 100; between 5 and 100; between 10 and 100 or between 20 and 100 mg temsirolimus per ml of dehydrated alcohol.
  • Specific examples of temsirolimus per dehydrated alcohol concentrations include but are not limited to 2, 5, 10, 20, 22, 25, 30, 40 and 50 mg/ml.
  • temsirolimus is dissolved in solvent at different concentrations.
  • the composition may optionally comprise between 0.1 and 200; between 1 and 100; between 1 and 50; between 2 and 50; between 2 and 100; between 5 and 100; between 10 and 100 or between 20 and 100 mg temsirolimus per ml of alcohol.
  • Specific examples of temsirolimus per alcohol concentrations include but are not limited to 2, 5, 10, 20, 22, 25, 30, 40 and 50 mg/vial.
  • temsirolimus is dissolved in propylene glycol at different concentrations.
  • the composition may optionally comprise between 0.1 and 200; between 0.1 and 100; between 0.1 and 50; between 2 and 50; between 2 and 100; between 5 and 100; between 10 and 100 or between 20 and 100 mg temsirolimus per ml of propylene glycol.
  • Specific examples of temsirolimus per propylene glycol concentrations include but are not limited to 2, 5, 10, 20, 22, 25, 30, 40 and 50 mg/ml.
  • temsirolimus is dissolved in a solvent combining dehydrated alcohol and propylene glycol at different concentrations.
  • concentration of propylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -90%, between 10-80%, or between 50-70%.
  • the solvent system comprises of dehydrated alcohol and propylene glycol or mixtures thereof.
  • the solvent system comprises of an acid, dehydrated alcohol and propylene glycol or mixtures thereof.
  • the solvent system comprises of alcohol and propylene glycol or mixtures thereof. It is believed and experimentally proven that addition of propylene glycol can improve chemical stability, reduce viscosity of the compositions and facilitate dissolution of temsirolimus in the solvent.
  • the pharmaceutical composition may also optionally comprise one or more antioxidants.
  • antioxidants include, but not limited to, Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT), a-tocopherol, monothioglycerol, propyl gallate and mixtures thereof as disclosed in US publication no. 2004/0167152.
  • the pharmaceutical composition may optionally further include other excipients added in an amount sufficient to enhance the stability of the composition, maintain the product in solution, or prevent side effects (e.g., potential ulceration, vascular irritation or extravasation) associated with the administration of the inventive compositions.
  • other excipients added in an amount sufficient to enhance the stability of the composition, maintain the product in solution, or prevent side effects (e.g., potential ulceration, vascular irritation or extravasation) associated with the administration of the inventive compositions.
  • excipients include, but are not limited to, mannitol, sorbitol, lactose, dextrose, cyclodextrin such as, .alpha.-, .beta.-, and .gamma.-cyclodextrin, and modified, amorphous cyclodextrin such as hydroxypropyl-, hydroxyethyl-, glucosyl-, maltosyl-, maltotriosyl-, carboxyamidomethyl-, carboxymethyl-, sulfobutylether-, and diethylamino- substituted .alpha.-, .beta.-, and .gamma.-cyclodextrin.
  • the pharmaceutical composition may optionally further include other bulking agents added in an amount sufficient to enhance the stability of the composition, maintain the product in lyophilized form, or prevent side effects (e.g., potential ulceration, vascular irritation or extravasation) associated with the administration of the inventive compositions.
  • other bulking agents added in an amount sufficient to enhance the stability of the composition, maintain the product in lyophilized form, or prevent side effects (e.g., potential ulceration, vascular irritation or extravasation) associated with the administration of the inventive compositions.
  • excipients include, but are not limited to, mannitol, sorbitol, lactose, dextrose, cyclodextrin such as, .alpha.-, .beta.-, and .gamma.-cyclodextrin, and modified, amorphous cyclodextrin such as hydroxypropyl-, hydroxyethyl-, glucosyl-, maltosyl-, maltotriosyl-, carboxyamidomethyl-, carboxymethyl-, sulfobutylether-, and diethylamino- substituted .alpha.-, .beta.-, and .gamma.-cyclodextrin, sugars.
  • Therapeutically active agents other than temsirolimus may also be used in combination with the composition without departing from the present invention. These agents may optionally be added to the compositions. Preferably the therapeutically active agents synergistically enhance the effect of temsirolimus.
  • therapeutic agents include, but are not limited to alkylating agents, agents that are members of the retinoids superfamily, hormonal agents, plant-derived agents, biologic agents, interleukins, interferons, cytokines, immuno-modulating agents, and monoclonal antibodies.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising, temsirolimus, lactic acid, anhydrous citric acid, propylene glycol, optionally a -tocopherol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising, temsirolimus, lactic acid, propylene glycol, optionally a -tocopherol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, lactic acid, propylene glycol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising, temsirolimus, benzoic acid, propylene glycol, optionally a -tocopherol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, benzoic acid, propylene glycol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, cysteine HCI, propylene glycol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, Butylated hydroxyanisole, propylene glycol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, Butylated hydroxytoluene (BHT), propylene glycol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, citric acid, propylene glycol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising, temsirolimus, citric acid and lactic acid, propylene glycol, dehydrated alcohol.
  • Another embodiment of the present invention provides a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising, temsirolimus, citric acid and lactic acid, propylene glycol, optionally a -tocopherol, dehydrated alcohol.
  • step (a) Preparing a clear solution by adding drug to dehydrated alcohol and stirring; b) adding organic acid to step (a) mixture to get a clear solution;
  • step (b) optionally, adding anti-oxidant to step (b) mixture and stirring to obtain a clear solution;
  • the act further comprise: adding propylene glycol to the solution containing temsirolimus such that pH of the resulting solution is between pH 4 and pH 8, for example between pH 4.2 and pH 7, and further between pH 4.5 and pH 6.8.
  • Another embodiment of the present invention provides a lyophilized pharmaceutical composition comprising, temsirolimus, acid and mannitol.
  • Another embodiment of the present invention provides a lyophilized pharmaceutical composition comprising, temsirolimus, acid and sugar.
  • Another embodiment of the present invention provides a lyophilized pharmaceutical composition comprising, temsirolimus, acid and sorbitol.
  • Another embodiment of the present invention provides a lyophilized pharmaceutical composition comprising, temsirolimus, acid and cyclodextrin
  • the present invention relates to process of preparing the lyophilized pharmaceutical composition
  • process of preparing the lyophilized pharmaceutical composition comprising: a) Preparing a clear solution by adding active ingredient to solvent and stirring;
  • step (b) adding acid to step (a) mixture to get a clear solution
  • step (b) adding bulking agent and optionally an anti-oxidant to step (b) mixture and stirring to obtain a clear solution;
  • a sterilized vessel for administering temsirolimus to a host in need thereof.
  • the sterilized vessel comprises a pharmaceutical composition according to the present invention.
  • the vessel for example, may be a vial, syringe, or ampoule.
  • the vessel may come in different sizes.
  • the vessel may comprise between 1 and 50, 1 and 25, 1 and 20 or 1 and 10 ml of the pharmaceutical composition.
  • compositions of the present inventions are analyzed by suitable analytical method.
  • kits for administering temsirolimus to a host in need thereof.
  • the kit comprises temsirolimus in a solid, preferably powder form, and a non-aqueous diluent that comprises polysorbate 80, polyethylene glycol 400, dehydrated alcohol, or combinations thereof.
  • the kit may comprise a first vessel (vial 1 ) comprising temsirolimus and solvent system; and a second vessel (vial 2) comprising a diluent that comprises polysorbate 80, polyethylene glycol 400, dehydrated alcohol, or combinations thereof; wherein adding the vial 2 diluent to the vial 1 composition results in the formation of a pharmaceutical composition for administering temsirolimus that comprises between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent, for example 25 mg per ml.
  • Mixing the solid temsirolimus and diluent may optionally form a pharmaceutical composition that comprises between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent. For example 25 mg per ml.
  • the kit may comprise a first vessel (vial 1 ) comprising temsirolimus and bulking agent and / or anti-oxidant; and a second vessel (vial 2) comprising a diluent that comprises polysorbate 80, polyethylene glycol 400, dehydrated alcohol, or combinations thereof; wherein adding the vial 2 diluent to the vial 1 composition results in the formation of a pharmaceutical composition for administering temsirolimus that comprises between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent, for example 25 mg per ml.
  • Mixing the solid temsirolimus and diluent may optionally form a pharmaceutical composition that comprises between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent. For example 25 mg per ml.
  • the solvent system is a combination of propylene glycol and dehydrated ethanol, wherein the concentration of propylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -95%, between 10- 85%, or between 40-70%.
  • the solvent system is a combination of polyethylene glycol and dehydrated ethanol, wherein the concentration of polyethylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -95%, between 10-85%, or between 40-70%.
  • the solvent system is a combination of propylene glycol, polyethylene glycol and dehydrated ethanol, wherein the concentration of propylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -90%, between 10-60%, or between 20-40%; and the concentration of polyethylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -90%, between 10-60%, or between 20-40%.
  • Vial 1 includes liquid composition comprising temsirolimus, an acid, a solvent and a co-solvent.
  • Vial 1 includes liquid composition comprising temsirolimus, an acid, optionally antioxidant, solvent and a co-solvent.
  • Vial 1 includes liquid composition comprising temsirolimus, lactic acid, dehydrated alcohol and propylene glycol.
  • Vial 1 includes liquid composition comprising temsirolimus, cysteine HCI, dehydrated alcohol and propylene glycol.
  • Vial 2 includes the non-aqueous diluent that comprises polysorbate 80, polyethylene glycol 400, dehydrated alcohol, or combinations thereof similar as that disclosed in the Innovator label composition.
  • the kit may optionally further include instructions.
  • the instructions may describe how the vial 1 and vial 2 should be mixed to form a clear liquid pharmaceutical composition.
  • the instructions may also describe how to administer the resulting pharmaceutical composition to a patient. It is noted that the instructions may optionally describe the administration methods according to the present invention.
  • the diluent and temsirolimus composition may be contained in separate vessels.
  • the vessels may come in different sizes.
  • the vessel may comprise between 1 and 50, 1 and 25, 1 and 20, or 1 and 10 ml of the diluent.
  • a method for administering temsirolimus to a host in need of, such as a patient suffering from a disease that is sensitive to the treatment with temsirolimus.
  • the temsirolimus-containing pharmaceutical composition of the present invention may be administered orally, parenterally, topically, intraperitoneal ⁇ , intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the pharmaceutical composition is administered intravenously, intramuscularly, or subcutaneously.
  • the method comprises: administering to the patient a therapeutically effective amount of temsirolimus in a pharmaceutical composition according to the present invention.
  • the method may further comprise administering a therapeutic agent other than temsirolimus in combination with the pharmaceutical composition.
  • the pharmaceutical composition may further comprise a therapeutic agent selected from the group consisting of alkylating agents, agents that are members of the retinoids superfamily, hormonal agents, plant-derived agents, biologic agents, interleukins, interferons, cytokines, immuno-modulating agents, and monoclonal antibodies.
  • the method comprises: taking a pharmaceutical comprising between 0.1 and 200 mg temsirolimus solvated in a non-aqueous solvent that comprises dehydrated ethanol, propylene glycol or combinations thereof; diluting the pharmaceutical composition with a diluent; and administering the resulting diluted pharmaceutical composition; wherein the dilution is performed 10 hr, 2 hr, 1 hr, 30 min, 10 min, 5 min or less before administration.
  • a method comprises mixing temsirolimus that is in a liquid pharmaceutical composition with a solvent system to form a pharmaceutical composition, and administering the pharmaceutical composition to a patient.
  • the pharmaceutical composition may be formed by mixing the temsirolimus with the diluent shortly prior to administration to a patient (e.g., within one day, or even 6, 5, 4, 3, 2 or 1 hours or less before administration). This reduces decomposition of the temsirolimus.
  • compositions 1 . Temsirolimus 25 25 25 25 25 25
  • step (a) Citric acid was added to step (a) mixture to obtain a clear solution.
  • step (b) Lactic acid or Butylated Hydroxy Anisole and Butylated Hydroxy Toluene or Butylated Hydroxy Anisole was added to step (b) mixture respectively and stirred vigorously to obtain a clear solution.
  • step (b) Mannitol or Sugar or Sorbitol or Cyclodextrin was added to step (b) mixture respectively and stirred vigorously to obtain a clear solution.
  • compositions were evaluated for stability assessment.

Abstract

The present invention provides liquid and lyophilized pharmaceutical compositions comprising rapamycin esters and its derivatives; further this invention provides innovative liquid and lyophilized compositions of temsirolimus.

Description

PHARMACUETICAL COMPOSITIONS OF RAPAMYCIN ESTERS AND ITS DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions of rapamycin esters and its derivatives.
BACKGROUND OF THE INVENTION
Rapamycin is a fermentation product of Streptomyces hygroscopicus and was first reported in 1975 (J. Antibiot 28:727 (1975). Rapamycin 42-[3hydroxy-2- (hydroxymethyl)-2-methylpropanoate] generically known as CCI-779 or Temsirolimus.
The preparation and use of hydroxyesters of rapamycin, including Temsirolimus (CCI-779), are disclosed in US Patent No 5362718.
Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.
US Patent No. 8,026,276 of Rubino et al discloses parenteral formulations containing CCI-779, an alcoholic co-solvent, and an antioxidant, another parenteral formulation containing CCI-779, an alcoholic solvent, an antioxidant, a diluent solvent, and a surfactant. Further processes for preparing parenteral CCI-779 formulations using a co-solvent concentrate are also provided.
US Publication No. 20120252835 Rajput et al discloses a stable composition of Temsirolimus, BHA or BHT as anti-oxidants and alcoholic solvent for parenteral administration. The pH of the composition is below 5.0 and further can include a chelating agent and/or a surfactant. A method of producing the composition is also described.
US Publication No. 201 10301 189 Khattar et al discloses a stable
pharmaceutical compositions of Rapamycin Esters, in particular Rapamycin 42- ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid that is free of antioxidants and a process of preparing the same.
US Publication No. 20070142422 Rubino et al in another, discloses a method for preparing a rapamycin composition having increased potency by selecting the active ingredient having less than 1.5% oxidative and hydrolytic rapamycin impurities and formulating the selected rapamycin with an antioxidant and optional excipients wherein the antioxidant is .alpha.-tocopherol. The pH of the pharmaceutical composition developed is in the range of about 4 to about 6. Further, it is disclosed that the formulation developed may be administered by parenteral route as well as oral route.
US Publication No. 20050020615 Rubino et al discloses lyophilized CCI-779 formulations composed of CCI-779 and t-butyl alcohol or ethanol. Further solutions useful in preparing said lyophilized CCI-779 formulations, methods of reconstituting same, and uses for same is also disclosed.
US Application Publication No. 2004/0077677 Ashraf et al discloses a stable pharmaceutical composition of CCI-779 for oral administration comprising Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, a water soluble polymer, a surfactant, an antioxidant, and a pH modifying agent
US Publication No. 20050152983 Ashraf et al discloses pharmaceutical compositions containing a stable and bioavailable form of micronized Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) along with an antioxidant or a chelating agent, or mixtures thereof.
US Patent No. 7,074,804 Zhu et al discloses an oral formulation of Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid using wet granulation method, utilizing isomer C of the drug, a water soluble polymer, a pH modifying agent, a surfactant, and an antioxidant. Further the patent also provides an injectable formulation containing Rapamycin 42-ester with 3- hydroxy-2-(hydroxymethyl)-2-methylpropionic acid isomer C, a parenterally acceptable cosolvent, an antioxidant, a diluent solvent, and a surfactant.
Gu et al in US Patent No. 7,202,256 discloses that the stability of Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid or proline- Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid in parenterally acceptable alcoholic cosolvents is enhanced by the addition of an antioxidant to the formulation.
Joseph, TR et al in PCT Publication No. 200501 1688 discloses Lyophilized and or freeze dried CCI-779 formulations and solutions useful for preparing freeze- dried CCI-779 formulations composed of CCI-779 and a solvent selected from dimethylsulfoxide, acetonitrile, ethanol, and isopropanol or t-butyl alcohol. This publiction further discloses methods of preparing the lyophilized CCI-779 formulations, methods of reconstituting same and uses for same.
From the above prior art disclosures it is evident that Rapamycin and its related compounds are susceptible to chemical instability during synthesis of the compounds or during their compositions as a dosage form. The chemical instability of Rapamycin esters is mainly attributed to their oxidative degradation or to cleavage of a lactone bond in the molecule, resulting in the opening of the ring and formation of a degradation product.
It was surprisingly found that temsirolimus in combination with organic acids produced stable liquid composition and lyophilized compositions of temsirolimus with one or more bulking agents also was found to be stable. Hence there remains, therefore an unmet need for improved, stable liquid compositions and lyophilized compositions that are effective for diseases that are sensitive to the treatment with temsirolimus.
SUMMARY OF THE INVENTION
Aspects of the present invention relate to liquid pharmaceutical compositions of rapamycin esters and its derivatives.
Another aspect of the invention relates to lyophilized pharmaceutical compositions of rapamycin esters and its derivatives. Another aspect of the invention relates to stable lyophilized pharmaceutical compositions of rapamycin esters and its derivatives with or without antioxidant.
The present invention provides innovative liquid composition of temsirolimus. According to the invention, temsirolimus is solvated in non-aqueous solvent such as alcohol such as ethanol or dehydrated alcohol, propylene glycol or combinations thereof. The inventive approach circumvents problems associated with prior art compositions of rapamycin esters and its derivatives, such as chemical instability, inconvenient storage and transportation, and discomfort of patients due to cold infusions. The compositions can be used to treat a wide variety of indications that are sensitive to temsirolimus treatment.
Another aspect of the present invention relates to the acid, the acid may be an organic acid, inorganic acid, amino acid. Examples of organic acid include, but are not limited to, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, formic acid, benzene sulphonic acid, benzoic acid, maleic acid, malonic acid, glutamic acid, succinic acid, aspartic acid, diatrizoic acid, acetic acid and mixtures thereof. Examples of inorganic acid include, but are not limited to hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid and mixtures thereof. Examples of amino acid include, but are not limited to, cysteine, glycine, alanine, lysine, arginine, glutathione, methionine, leucine, aspartic acid and mixtures thereof.
In a variation, the acid is lactic acid at a concentration of 0.01 -0.2 mg/ml of the solvent, between 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
In a variation, the acid is benzoic acid at a concentration of 0.01 - 0.2 mg/ml of the solvent, between 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
In a variation, the acid is cysteine HCI at a concentration of 0.01 - 0.2 mg/ml of the solvent, between 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
In a variation, the acid is citric acid at a concentration of 0.01 -0.2 mg/ml of the solvent, between 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent. In one aspect of the invention, a liquid pharmaceutical composition is provided for administering temsirolimus to a patient. In one embodiment, the composition comprises temsirolimus solvated in a solvent that comprises nonaqueous solvent such as alcohol such as ethanol or dehydrated alcohol, propylene glycol or combinations thereof.
According to the embodiment, the amount of temsirolimus in the pharmaceutical composition is between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent, for example 25 mg per ml.
According to the embodiment, the amount of temsirolimus in the pharmaceutical composition is between 0.1 and 200 mg per vial, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per vial, for example 30 mg per vial.
In another aspect, the composition further comprises one or more pharmaceutically acceptable excipients. The excipients comprises of one or more solvent selected from the group consisting of alcohol like dehydrated alcohol; one or more co-solvent selected from the group consisting of glycols, like ethylene glycol, and propylene glycol.
According to the embodiment, the solvent is alcohol, wherein the concentration of alcohol is between 0.1 -99.9%, optionally between 1 -90%, between 10-60%, or between 20-40%.
According to the embodiment, the solvent is a combination of propylene glycol and alcohol, wherein the concentration of propylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -90%, between 10-60%, or between 20- 40%.
The pharmaceutical composition may also optionally comprise one or more antioxidants. The antioxidants as disclosed in US publication no. 2004/0167152 ranging from citric acid, d,l-.alpha.-tocopherol, BHA, BHT, monothioglycerol, ascorbic acid, propyl gallate, and mixtures thereof can be used to providing stable Temsirolimus compositions for parenteral administration. The pH of the pharmaceutical composition may be adjusted to be between pH 4 and pH 8, for example between pH 4.2 and pH 7, and further between pH 4.5 and pH 6.8.
In an aspect the present invention provides a liquid pharmaceutical composition comprising the active ingredient, organic acid, solvent and co-solvent.
In another aspect the present invention provides a liquid pharmaceutical composition comprising temsirolimus, amino acid, propylene glycol, dehydrated alcohol.
In another aspect the present invention provides a liquid pharmaceutical composition comprising temsirolimus, lactic acid, propylene glycol, dehydrated alcohol.
In another aspect the present invention provides a liquid pharmaceutical composition comprising temsirolimus, benzoic acid, propylene glycol, dehydrated alcohol.
In another aspect the present invention provides a liquid pharmaceutical composition comprising temsirolimus, cysteine HCI, propylene glycol, dehydrated alcohol.
In another aspect the present invention provides a liquid pharmaceutical composition comprising temsirolimus, citric acid, propylene glycol, dehydrated alcohol.
In another aspect the present invention provides a liquid pharmaceutical composition comprising temsirolimus, citric acid, propylene glycol, dehydrated alcohol and optionally it may include antioxidants such as BHA and / or BHT.
In another aspect the present invention relates to process of preparing the liquid pharmaceutical composition comprising:
a) Preparing a clear solution by adding active ingredient to dehydrated alcohol and stirring;
b) adding acid to step (a) mixture to get a clear solution;
c) optionally, adding anti-oxidant to step (b) mixture and stirring to obtain a clear solution; and d) finally adding propylene glycol to the above step (c) mixture to obtain a clear liquid solution.
According to the embodiment, the act further comprise: adding propylene glycol to the solution containing temsirolimus such that pH of the resulting solution is between pH 4 and pH 8, for example between pH 4.5 and pH 7, and further between pH 5 and pH 6.8.
In another aspect the present invention provides lyophilized pharmaceutical composition comprising an active ingredient one or more bulking agent(s) and optionally an anti-oxidant.
In an aspect the present invention provides a lyophilized pharmaceutical composition comprising temsirolimus, acid, one or more bulking agent(s) and optionally an anti-oxidant.
In an aspect the present invention provides a lyophilized pharmaceutical composition comprising temsirolimus, acid, mannitol and optionally an anti-oxidant.
In an aspect the present invention provides a lyophilized pharmaceutical composition comprising temsirolimus, acid, sugar and optionally an anti-oxidant.
In an aspect the present invention provides a lyophilized pharmaceutical composition comprising temsirolimus, acid, sorbitol and optionally an anti-oxidant.
In an aspect the present invention provides a lyophilized pharmaceutical composition comprising temsirolimus, acid, cyclodextrin and optionally an antioxidant.
In another aspect the present invention relates to process of preparing the lyophilized pharmaceutical composition comprising:
a) Preparing a clear solution by adding active ingredient to solvent and
stirring;
b) adding acid to step (a) mixture to get a clear solution;
c) adding bulking agent and optionally an anti-oxidant to step (b) mixture and stirring to obtain a clear solution; and
d) finally the above solution is lyophilized. DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
The term "active ingredient or drug" refers to a substance that has a physiological effect when ingested or otherwise introduced into the body, in particular or a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being.
The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not a pharmacologically active ingredient, such as filler, diluent, carrier, preservative, etc. The excipients that are useful in preparing pharmaceutical compositions are generally safe, non- toxic, and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. The term includes both one and more than one such excipients.
The term "composition" is intended to encompass a combination including active ingredients and pharmaceutically acceptable excipients, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions involving one or more of the ingredients.
The terms "formulation" or "dosage form" or "composition" refers to finished pharmaceutical products that are suitable for administration, including, but not limited to, injections, etc.
The term "optional" or "optionally" means that the subsequently described element, component or circumstance may or may not be present, so that the description includes instances where the element, component, or circumstance is included and instances where it is not.
The term "stability" as used herein includes both physical and chemical stability. The term "physical stability" refers to maintenance of the form of active agents, such as crystalline or amorphous, and the term "chemical stability" relates to a limited formation of impurities. "Carrier" or "vehicle" as used herein refers to pharmacologically inert materials that provide a more or less fluid matrix, suitable for topical drug administration. Carriers and vehicles useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of a pharmaceutical formulation or drug delivery system in a deleterious manner. The topical formulations of the present invention are particularly suitable for parenteral administration. Formulations suitable for parenteral dosage forms such as injectables such as intravenous, intramuscular or subcutaneous, implants and the like. Other parenteral ingredients used in the formulation are generally those commonly used and recognized by persons skilled in the art of parenteral formulations.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
"Pharmaceutically-acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically- acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. Pharmaceutically acceptable salts are those forms of compounds, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Pharmaceutically-acceptable salt forms of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in at page 1418 of Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985.
The term "therapeutically effective amount" of a compound of this invention means an amount effective to modulate the formation or progression of a infection in a host.
The term "temsirolimus" includes the compound temsirolimus, pharmaceutically acceptable salts and esters thereof, and any of polymorphs, solvates and hydrates thereof.
Aspects of the present invention relate to innovative liquid pharmaceutical compositions of temsirolimus and a suitable solvent system. The pharmaceutical compositions of the present invention can be used to treat patient suffering from a disease sensitive to the treatment with temsirolimus, such as hematological disorders, benign tumors, malignant tumors, restenosis, and inflammatory diseases via various routes of administration such as intravenous, intramuscular, or subcutaneous injection.
In another embodiment the present invention provides stable liquid injectable pharmaceutical composition comprising temsirolimus and one or more acid.
In another embodiment, the acids include, but not limited to organic acid, inorganic acid and amino acid. Examples of organic acid include, but are not limited to, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, formic acid, benzene sulphonic acid, benzoic acid, maleic acid, malonic acid, glutamic acid, succinic acid, aspartic acid, diatrizoic acid, acetic acid and mixtures thereof. Examples of inorganic acid include but not limited to hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid and mixtures thereof. Examples of amino acid include, but are not limited to, cysteine, glycine, alanine, lysine, arginine, glutathione, methionine, leucine, aspartic acid and mixtures thereof.
In another embodiment, the concentration of acid is between 0.01 -0.2 mg/ml of the solvent, further 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
In another embodiment, the acid is lactic acid at a concentration of 0.01 - 0.2 mg/ml of the solvent, further 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
In another embodiment, the acid is benzoic acid at a concentration of 0.01 - 0.2 mg/ml of the solvent, further 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
In one more embodiment, the acid is cysteine HQ at a concentration of 0.01 - 0.2 mg/ml of the solvent, further 0.04-0.1 mg/ml, for example between 0.03-0.07 mg/ml of the solvent.
In another embodiment present invention further comprises one or more pharmaceutically acceptable excipients. The excipients comprise of a solvent and a co-solvent. Examples of solvents include alcohol, but are not limited to, ethanol, dehydrated ethanol and mixtures thereof. Examples of co-solvents include, but are not limited to, ethylene glycol, propylene glycol, polyethylene glycol and mixtures thereof.
It has now been discovered that the addition of an excipient to lyophilized preparations of temsirolimus, or pharmaceutically acceptable salts thereof, results in preparations that are stable and readily and reproducibly reconstituted to form solutions suitable for injection into humans. Lyophilization processes suitable for use with temsirolimus or pharmaceutically acceptable salts thereof have also been discovered. In one embodiment, temsirolimus is dissolved in dehydrated alcohol at different concentrations. For example, the composition may optionally comprise between 0.1 and 200; between 1 and 100; between 1 and 50; between 2 and 50; between 2 and 100; between 5 and 100; between 10 and 100 or between 20 and 100 mg temsirolimus per ml of dehydrated alcohol. Specific examples of temsirolimus per dehydrated alcohol concentrations include but are not limited to 2, 5, 10, 20, 22, 25, 30, 40 and 50 mg/ml.
In one embodiment, temsirolimus is dissolved in solvent at different concentrations. For example, the composition may optionally comprise between 0.1 and 200; between 1 and 100; between 1 and 50; between 2 and 50; between 2 and 100; between 5 and 100; between 10 and 100 or between 20 and 100 mg temsirolimus per ml of alcohol. Specific examples of temsirolimus per alcohol concentrations include but are not limited to 2, 5, 10, 20, 22, 25, 30, 40 and 50 mg/vial.
In another embodiment, temsirolimus is dissolved in propylene glycol at different concentrations. For example, the composition may optionally comprise between 0.1 and 200; between 0.1 and 100; between 0.1 and 50; between 2 and 50; between 2 and 100; between 5 and 100; between 10 and 100 or between 20 and 100 mg temsirolimus per ml of propylene glycol. Specific examples of temsirolimus per propylene glycol concentrations include but are not limited to 2, 5, 10, 20, 22, 25, 30, 40 and 50 mg/ml.
In yet another embodiment, temsirolimus is dissolved in a solvent combining dehydrated alcohol and propylene glycol at different concentrations. The concentration of propylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -90%, between 10-80%, or between 50-70%.
In another embodiment of the present invention, the solvent system comprises of dehydrated alcohol and propylene glycol or mixtures thereof.
In another embodiment of the present invention, the solvent system comprises of an acid, dehydrated alcohol and propylene glycol or mixtures thereof.
In an embodiment of the present invention, the solvent system comprises of alcohol and propylene glycol or mixtures thereof. It is believed and experimentally proven that addition of propylene glycol can improve chemical stability, reduce viscosity of the compositions and facilitate dissolution of temsirolimus in the solvent.
The pharmaceutical composition may also optionally comprise one or more antioxidants. Examples of antioxidants include, but not limited to, Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT), a-tocopherol, monothioglycerol, propyl gallate and mixtures thereof as disclosed in US publication no. 2004/0167152.
The pharmaceutical composition may optionally further include other excipients added in an amount sufficient to enhance the stability of the composition, maintain the product in solution, or prevent side effects (e.g., potential ulceration, vascular irritation or extravasation) associated with the administration of the inventive compositions. Examples of excipients include, but are not limited to, mannitol, sorbitol, lactose, dextrose, cyclodextrin such as, .alpha.-, .beta.-, and .gamma.-cyclodextrin, and modified, amorphous cyclodextrin such as hydroxypropyl-, hydroxyethyl-, glucosyl-, maltosyl-, maltotriosyl-, carboxyamidomethyl-, carboxymethyl-, sulfobutylether-, and diethylamino- substituted .alpha.-, .beta.-, and .gamma.-cyclodextrin.
The pharmaceutical composition may optionally further include other bulking agents added in an amount sufficient to enhance the stability of the composition, maintain the product in lyophilized form, or prevent side effects (e.g., potential ulceration, vascular irritation or extravasation) associated with the administration of the inventive compositions. Examples of excipients include, but are not limited to, mannitol, sorbitol, lactose, dextrose, cyclodextrin such as, .alpha.-, .beta.-, and .gamma.-cyclodextrin, and modified, amorphous cyclodextrin such as hydroxypropyl-, hydroxyethyl-, glucosyl-, maltosyl-, maltotriosyl-, carboxyamidomethyl-, carboxymethyl-, sulfobutylether-, and diethylamino- substituted .alpha.-, .beta.-, and .gamma.-cyclodextrin, sugars.
Therapeutically active agents other than temsirolimus may also be used in combination with the composition without departing from the present invention. These agents may optionally be added to the compositions. Preferably the therapeutically active agents synergistically enhance the effect of temsirolimus. Examples of therapeutic agents that may be used in conjunction with the pharmaceutical compositions of the present invention include, but are not limited to alkylating agents, agents that are members of the retinoids superfamily, hormonal agents, plant-derived agents, biologic agents, interleukins, interferons, cytokines, immuno-modulating agents, and monoclonal antibodies.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, lactic acid, anhydrous citric acid, propylene glycol, optionally a -tocopherol, dehydrated alcohol.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, lactic acid, propylene glycol, optionally a -tocopherol, dehydrated alcohol.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, lactic acid, propylene glycol, dehydrated alcohol.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, benzoic acid, propylene glycol, optionally a -tocopherol, dehydrated alcohol.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, benzoic acid, propylene glycol, dehydrated alcohol.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, cysteine HCI, propylene glycol, dehydrated alcohol.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, Butylated hydroxyanisole, propylene glycol, dehydrated alcohol.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, Butylated hydroxytoluene (BHT), propylene glycol, dehydrated alcohol. Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, citric acid, propylene glycol, dehydrated alcohol.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, citric acid and lactic acid, propylene glycol, dehydrated alcohol.
Another embodiment of the present invention provides a liquid pharmaceutical composition comprising, temsirolimus, citric acid and lactic acid, propylene glycol, optionally a -tocopherol, dehydrated alcohol.
In another embodiment the present invention relates to process of preparing the liquid pharmaceutical composition comprising:
a) Preparing a clear solution by adding drug to dehydrated alcohol and stirring; b) adding organic acid to step (a) mixture to get a clear solution;
c) optionally, adding anti-oxidant to step (b) mixture and stirring to obtain a clear solution; and
d) finally adding propylene glycol to the above step (c) mixture to obtain a clear liquid solution.
According to the embodiment, the act further comprise: adding propylene glycol to the solution containing temsirolimus such that pH of the resulting solution is between pH 4 and pH 8, for example between pH 4.2 and pH 7, and further between pH 4.5 and pH 6.8.
Another embodiment of the present invention provides a lyophilized pharmaceutical composition comprising, temsirolimus, acid and mannitol.
Another embodiment of the present invention provides a lyophilized pharmaceutical composition comprising, temsirolimus, acid and sugar.
Another embodiment of the present invention provides a lyophilized pharmaceutical composition comprising, temsirolimus, acid and sorbitol.
Another embodiment of the present invention provides a lyophilized pharmaceutical composition comprising, temsirolimus, acid and cyclodextrin
In another embodiment the present invention relates to process of preparing the lyophilized pharmaceutical composition comprising: a) Preparing a clear solution by adding active ingredient to solvent and stirring;
b) adding acid to step (a) mixture to get a clear solution;
c) adding bulking agent and optionally an anti-oxidant to step (b) mixture and stirring to obtain a clear solution; and
d) finally the above solution is lyophilized.
In another aspect of the present invention, a sterilized vessel is provided for administering temsirolimus to a host in need thereof. In one embodiment, the sterilized vessel comprises a pharmaceutical composition according to the present invention. The vessel, for example, may be a vial, syringe, or ampoule. The vessel may come in different sizes. For example, the vessel may comprise between 1 and 50, 1 and 25, 1 and 20 or 1 and 10 ml of the pharmaceutical composition.
In an embodiment, the compositions of the present inventions are analyzed by suitable analytical method.
In yet another aspect of the present invention, a kit is provided for administering temsirolimus to a host in need thereof. In one embodiment, the kit comprises temsirolimus in a solid, preferably powder form, and a non-aqueous diluent that comprises polysorbate 80, polyethylene glycol 400, dehydrated alcohol, or combinations thereof.
In another aspect of the present invention, mix up of the solid temsirolimus and the solvent system results in a liquid pharmaceutical composition. For example, the kit may comprise a first vessel (vial 1 ) comprising temsirolimus and solvent system; and a second vessel (vial 2) comprising a diluent that comprises polysorbate 80, polyethylene glycol 400, dehydrated alcohol, or combinations thereof; wherein adding the vial 2 diluent to the vial 1 composition results in the formation of a pharmaceutical composition for administering temsirolimus that comprises between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent, for example 25 mg per ml. Mixing the solid temsirolimus and diluent may optionally form a pharmaceutical composition that comprises between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent. For example 25 mg per ml.
In another aspect of the present invention, mix up of the lyophilized composition and the solvent system results in a liquid pharmaceutical composition. For example, the kit may comprise a first vessel (vial 1 ) comprising temsirolimus and bulking agent and / or anti-oxidant; and a second vessel (vial 2) comprising a diluent that comprises polysorbate 80, polyethylene glycol 400, dehydrated alcohol, or combinations thereof; wherein adding the vial 2 diluent to the vial 1 composition results in the formation of a pharmaceutical composition for administering temsirolimus that comprises between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent, for example 25 mg per ml. Mixing the solid temsirolimus and diluent may optionally form a pharmaceutical composition that comprises between 0.1 and 200 mg per ml of solvent, optionally between 1 and 100, between 2 mg and 80 mg, 5 mg and 60 mg, between 10 mg and 40 mg per ml of the solvent. For example 25 mg per ml.
According to the embodiment, the solvent system is a combination of propylene glycol and dehydrated ethanol, wherein the concentration of propylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -95%, between 10- 85%, or between 40-70%.
Also according to the embodiment, the solvent system is a combination of polyethylene glycol and dehydrated ethanol, wherein the concentration of polyethylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -95%, between 10-85%, or between 40-70%.
Also according to the embodiment, the solvent system is a combination of propylene glycol, polyethylene glycol and dehydrated ethanol, wherein the concentration of propylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -90%, between 10-60%, or between 20-40%; and the concentration of polyethylene glycol in the solvent is between 0.1 -99.9%, optionally between 1 -90%, between 10-60%, or between 20-40%. In one embodiment Vial 1 includes liquid composition comprising temsirolimus, an acid, a solvent and a co-solvent.
In one embodiment Vial 1 includes liquid composition comprising temsirolimus, an acid, optionally antioxidant, solvent and a co-solvent.
In another embodiment Vial 1 includes liquid composition comprising temsirolimus, lactic acid, dehydrated alcohol and propylene glycol.
In another embodiment Vial 1 includes liquid composition comprising temsirolimus, cysteine HCI, dehydrated alcohol and propylene glycol.
In another embodiment Vial 2 includes the non-aqueous diluent that comprises polysorbate 80, polyethylene glycol 400, dehydrated alcohol, or combinations thereof similar as that disclosed in the Innovator label composition.
The kit may optionally further include instructions. The instructions may describe how the vial 1 and vial 2 should be mixed to form a clear liquid pharmaceutical composition. The instructions may also describe how to administer the resulting pharmaceutical composition to a patient. It is noted that the instructions may optionally describe the administration methods according to the present invention.
The diluent and temsirolimus composition may be contained in separate vessels. The vessels may come in different sizes. For example, the vessel may comprise between 1 and 50, 1 and 25, 1 and 20, or 1 and 10 ml of the diluent.
In yet another aspect of the invention, a method is provided for administering temsirolimus to a host in need of, such as a patient suffering from a disease that is sensitive to the treatment with temsirolimus. The temsirolimus-containing pharmaceutical composition of the present invention may be administered orally, parenterally, topically, intraperitoneal^, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. Preferably, the pharmaceutical composition is administered intravenously, intramuscularly, or subcutaneously.
In one embodiment, the method comprises: administering to the patient a therapeutically effective amount of temsirolimus in a pharmaceutical composition according to the present invention.
The method may further comprise administering a therapeutic agent other than temsirolimus in combination with the pharmaceutical composition. For example, the pharmaceutical composition may further comprise a therapeutic agent selected from the group consisting of alkylating agents, agents that are members of the retinoids superfamily, hormonal agents, plant-derived agents, biologic agents, interleukins, interferons, cytokines, immuno-modulating agents, and monoclonal antibodies.
In another embodiment, the method comprises: taking a pharmaceutical comprising between 0.1 and 200 mg temsirolimus solvated in a non-aqueous solvent that comprises dehydrated ethanol, propylene glycol or combinations thereof; diluting the pharmaceutical composition with a diluent; and administering the resulting diluted pharmaceutical composition; wherein the dilution is performed 10 hr, 2 hr, 1 hr, 30 min, 10 min, 5 min or less before administration.
Related to the kit, a method is also provided that comprises mixing temsirolimus that is in a liquid pharmaceutical composition with a solvent system to form a pharmaceutical composition, and administering the pharmaceutical composition to a patient. Advantageously, the pharmaceutical composition may be formed by mixing the temsirolimus with the diluent shortly prior to administration to a patient (e.g., within one day, or even 6, 5, 4, 3, 2 or 1 hours or less before administration). This reduces decomposition of the temsirolimus.
Certain specific aspects and embodiments of the invention will be explained in more detail with reference to the following examples, being provided only for purposes of illustration, and it is to be understood that the present invention is not deemed to be limited thereto.
EXAMPLES:
A) Pharmaceutical Liquid compositions:
Figure imgf000020_0001
1 . Temsirolimus 25 25 25 25
2. Propylene glycol 503 503 503 503
3. Lactic acid - q.s - -
4. Anhydrous citric acid q.s q.s q.s q.s
Butylated Hydroxy Anisole
5. - - q.s q.s
(BHA)
Butylated Hydroxy
6. - - q.s - Toluene (BHT)
7. Dehydrated alcohol 395 395 395 395
Manufacturing process:
a) A clear solution was prepared by adding drug to dehydrated alcohol and stirred continuously.
b) Citric acid was added to step (a) mixture to obtain a clear solution.
c) Lactic acid or Butylated Hydroxy Anisole and Butylated Hydroxy Toluene or Butylated Hydroxy Anisole was added to step (b) mixture respectively and stirred vigorously to obtain a clear solution.
d) Finally propylene glycol was added to the above step (c) mixture to obtain a clear liquid solution.
B) Pharmaceutical Lyophilized compositions:
Figure imgf000021_0001
*-Solvent would be removed after lyophilization
Manufacturing process:
a) A clear solution was prepared by adding drug to alcohol and stirred continuously. b) Citric acid was added to step (a) mixture to obtain a clear solution.
c) Mannitol or Sugar or Sorbitol or Cyclodextrin was added to step (b) mixture respectively and stirred vigorously to obtain a clear solution.
d) Finally the above solution was lyophilized.
Stability study compilation data:
Figure imgf000022_0001
CCS- Clear Colorless Solution; RLD- Reference Listed Drug
The compositions were evaluated for stability assessment.

Claims

1 . A liquid pharmaceutical composition comprising temsirolimus and an acid.
2. The pharmaceutical composition according to claim 1 , wherein the acid is an organic acid, comprises one or more of lactic acid, maleic acid, tartaric acid, oxalic acid, malonic acid, citric acid and mixtures thereof.
3. The pharmaceutical composition according to claim 1 , further comprises one or more pharmaceutically acceptable excipients such as one or more solvent and one or more co-solvents.
4. The pharmaceutical composition according to claim 3, the carrier comprises of one or more solvent selected from the group consisting of alcohol like dehydrated alcohol; one or more co-solvent selected from the group consisting of glycols, like ethylene glycol, and propylene glycol.
5. A liquid pharmaceutical composition comprising:
a) temsirolimus;
b) anhydrous citric acid;
c) propylene glycol; and
d) dehydrated alcohol.
6. A liquid pharmaceutical composition comprising:
a) temsirolimus;
b) lactic acid;
c) anhydrous citric acid;
d) propylene glycol; and
e) dehydrated alcohol.
7. A lyophilized pharmaceutical composition comprising temsirolimus, acid and one or more bulking agents.
8. The lyophilized pharmaceutical composition according to claim 7, bulking agents comprise of mannitol, sugar, sorbitol, cyclodextrin and mixtures thereof.
9. A lyophilized pharmaceutical composition comprising:
a) temsirolimus;
b) sugar; and
c) anhydrous citric acid.
10. The liquid and lyophilized pharmaceutical compositions comprising temsirolimus, acid and one or more bulking agents substantially as herein described and exemplified.
PCT/IB2014/058602 2013-01-29 2014-01-28 Pharmacuetical compositions of rapamycin esters and its derivatives WO2014118696A2 (en)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2017129772A1 (en) 2016-01-29 2017-08-03 Xellia Phamaceuticals Aps Stable pharmaceutical compositions of temsirolimus
WO2018057788A1 (en) * 2016-09-22 2018-03-29 Mercator Medsystems, Inc. Treatment of restenosis using temsirolimus
US10441747B2 (en) 2002-01-22 2019-10-15 Mercator Medsystems, Inc. Methods and systems for inhibiting vascular inflammation
US10576063B2 (en) 2017-05-26 2020-03-03 Mercator Medsystems, Inc. Combination therapy for treatment of restenosis
US11654267B2 (en) 2018-03-14 2023-05-23 Mercator Medsystems, Inc. Medical instrument and medical method for localized drug delivery

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1553940E (en) * 2002-07-30 2008-05-09 Wyeth Corp Parenteral formulations containing a rapamycin hydroxyester
KR20060052880A (en) * 2003-07-25 2006-05-19 와이어쓰 Cci-779 lyophilized formulations

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10441747B2 (en) 2002-01-22 2019-10-15 Mercator Medsystems, Inc. Methods and systems for inhibiting vascular inflammation
WO2017129772A1 (en) 2016-01-29 2017-08-03 Xellia Phamaceuticals Aps Stable pharmaceutical compositions of temsirolimus
WO2018057788A1 (en) * 2016-09-22 2018-03-29 Mercator Medsystems, Inc. Treatment of restenosis using temsirolimus
CN109996549A (en) * 2016-09-22 2019-07-09 墨卡托医疗系统公司 Restenosis is treated using tamiros
US10617678B2 (en) 2016-09-22 2020-04-14 Mercator Medsystems, Inc. Treatment of restenosis using temsirolimus
US10576063B2 (en) 2017-05-26 2020-03-03 Mercator Medsystems, Inc. Combination therapy for treatment of restenosis
US10925863B2 (en) 2017-05-26 2021-02-23 Mercator Medystems, Inc. Combination therapy for treatment of restenosis
US11813249B2 (en) 2017-05-26 2023-11-14 Mercator Medsystems, Inc. Combination therapy for treatment of restenosis
US11654267B2 (en) 2018-03-14 2023-05-23 Mercator Medsystems, Inc. Medical instrument and medical method for localized drug delivery

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