WO2024100679A1 - Formulations parentérales de flucytosine - Google Patents

Formulations parentérales de flucytosine Download PDF

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Publication number
WO2024100679A1
WO2024100679A1 PCT/IN2023/051027 IN2023051027W WO2024100679A1 WO 2024100679 A1 WO2024100679 A1 WO 2024100679A1 IN 2023051027 W IN2023051027 W IN 2023051027W WO 2024100679 A1 WO2024100679 A1 WO 2024100679A1
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Prior art keywords
formulation
flucytosine
pharmaceutically acceptable
acceptable salts
present
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PCT/IN2023/051027
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English (en)
Inventor
Pradeep Bhadauria
Arunprasath Kaliaperumal
Tushar RAJYAGURU
Harshad Harde
Sandip KHAIRNAR
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Cipla Limited
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Publication of WO2024100679A1 publication Critical patent/WO2024100679A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates to stable, sterile, ready-to-use aqueous pharmaceutical formulation comprising flucytosine or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.
  • the formulation is suitable for parenteral administration and is provided in flexible plastic container.
  • the invention further relates to method of manufacture and sterilization of such formulations and using the formulation for treating systemic yeast and fungal infections.
  • Candida and pathogenic fungi from the genus Cryptococcus remain the main fungal pathogens responsible for most cases of serious fungal diseases in the world. These pathogens can invade human organism and may lead to mucosal and skin infections or to deep-seated mycoses of almost all inner organs and thus lead to severe infections.
  • Candida species rely on skin or mucosal breach to cause bloodstream infection Septicemia, endocarditis and urinary system infections, whereas Cryptococcus species exploit depressed cell-mediated immunity characteristic of immunosuppressed person and cause meningitis and pulmonary infections.
  • Cryptococcal meningitis is the most common cause of meningitis in adults accounting for 20-25% of AIDS-related mortality. The treatment for infections caused by both organisms relies on the administration of rapidly fungicidal agents.
  • Flucytosine is an antifungal medication used in the management and treatment of systemic and severe Candida and cryptococcus infections. Flucytosine is 5 -fluorocytosine chemically, a fluorinated pyrimidine which is related to fluorouracil and floxuridine. Its structural formula is:
  • 5FC is taken up by fungal cells by cytosine permease and converted into 5- fluorouracil (5FU) by fungal cytosine deaminase. Further metabolism of 5- fluorouracil (5FU) leads to the formation of 5 -fluorouridine triphosphate, which is incorporated into fungal RNA, and 5-fluorodeoxyuridine monophosphate, an inhibitor of thymidylate synthetase. This results in inhibition of protein and DNA synthesis in the fungal cell. Side effects of 5FC include nausea, vomiting, diarrhea, bone marrow depression, and hepatotoxicity. The latter two are thought to be due to effects of 5 -fluorouracil (5FU) as it is toxic in nature at higher doses.
  • Human cells lack the enzyme cytosine deaminase and are unable to convert 5FC into 5FU. Also, 5FU is toxic and there is always a need to control the conversion of 5FC into 5FU in vivo as well as during the shelf life of formulation.
  • Flucytosine (5FC) is available in the form of capsules (ANCOBON ) in the strength of 250mg and 500mg to be taken by oral route of administration.
  • the dose of this medicine will be different for different patients and depends on the strength of the medicine, the number of doses to be taken each day, the time allowed between doses, and the length of time the patient takes the medicine depending on the medical problem for which the medicine is prescribed.
  • the dose is based on body weight and must be determined by doctor.
  • the dose is usually 50 to 150 mg/kg of body weight per day, taken as divided doses at 6-hour intervals.
  • the use and dose must be determined by doctor.
  • Daily maintenance doses of antifungal medicine are a serious constraint to the effective treatment of fungal infections.
  • the dosage schedules of capsules of flucytosine may lead to a higher workload for clinical personnel and more importantly, poor patient compliance, thereby increasing the probability of administering suboptimal doses, missing the doses and ultimately contributing to the emergence of resistant fungal strains.
  • conversion of 5FC to 5FU it is known that intestinal bacteria do play a role in conversion of 5FC to 5FU in patients, and oral administration of 5FC might be associated with increased 5FU concentrations and more side effects.
  • a dosage form which will avoid the said problems with the capsule dosage form is desired such that a doctor or nurse may administer the medicine as required and also the dosage form which will avoid the possible decomposition by intestinal bacteria is required.
  • Such formulation of 5FC is available as solution for infusion (ANCOTIL) for intravenous or intraperitoneal administration in some countries like Europe and Australia in packs of 5 glass bottles of 250 ml.
  • the duration of the infusion is of the order of 20 to 40 minutes, balancing with the fluid requirements of the patient.
  • the bottles are closed with Teflon coated butyl rubber stoppers and aluminium crimp. It is administered in hospital by doctor or nurse at a daily dosage in adults as 200 mg/kg body weight divided into four doses over the 24 hours.
  • the cytotoxic and teratogenic degradation product 5 -fluorouracil (5FU) may be present in considerable amounts in the product, due to both impurities in the raw material and the formation of 5FU upon sterilisation and inappropriate storage.
  • the proposed formulation is an injection product, it is desired that it should be free from visible particulate matters, any precipitates, and impurities.
  • the manufacturing process of formulation, sterilisation process of formulation and storage of formulation also plays a critical role.
  • Exemplary sterilisation procedures include terminal moist heat sterilization, ethylene oxide, radiation (i.e., gamma and electron beam), and aseptic processing techniques.
  • the inventors subjected the flucytosine solution for infusion in plastic containers to the typically recommended method of sterilisation by regulatory authorities i.e. terminal sterilisation method for sealed packages of large volume parenterals (LVPs).
  • LVPs large volume parenterals
  • a sterile formulation which will overcome the above described shortcomings of capsules and vials of flucytosine, do not have undesirable amount of impurity as well as can be transported and stored easily and which can be administered to a patient by intravenous or intraperitoneal without any intermediate step (s) of dilution/reconstitution or any other type of manipulation (s), which could otherwise compromise the sterility of the solution in the infusion container or could result in an error in dosing to a patient in need thereof.
  • the present invention relates to stable, sterile, ready-to-use aqueous pharmaceutical formulation comprising flucytosine and pharmaceutically acceptable excipients.
  • the formulation is suitable for parenteral administration and is provided in flexible plastic container, which is easy to administer, easy to store, easy to transport.
  • the invention further relates to method of manufacture and sterilization of such formulations and using the formulation for treating systemic yeast and fungal infections.
  • An object of the present invention is to provide stable, sterile, ready to use, aseptic filled solution for infusion in presterilized infusion bag comprising flucytosine, its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients. It is an object of the present invention to provide a sterile ready to use aqueous pharmaceutical formulation comprising flucytosine or its pharmaceutically acceptable salts thereof stored in a flexible plastic container, wherein the pharmaceutical formulation comprises about 5 mg/ml to about 20 mg/ml flucytosine or its pharmaceutically acceptable salts thereof in an aqueous sodium chloride solution and wherein the pharmaceutical formulation is manufactured by aseptic fill finish process.
  • the object of present invention is to provide a stable, sterile, ready-to-use, aseptic filled solution for infusion comprising (a) flucytosine (b) buffering agent, (c) isotonicity adjuster, (d) pH adjusting agent and (e) aqueous vehicle stored in presterilized flexible plastic container.
  • An object is also to provide a method of manufacture and sterilisation process of formulation of present invention comprising flucytosine, its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.
  • another object of present invention is to provide solution for infusion comprising flucytosine and their pharmaceutically acceptable salts and pharmaceutically acceptable excipients manufactured by aseptic fill finish and filled in suitable presterilized infusion bag .
  • Another object of present invention is to provide formulation of flucytosine which is stable for long shelf life.
  • One of the object of present invention is to aseptic filled solution for infusion comprising flucytosine, its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients in presterilized infusion bag, which is easy to administer, easy to store and easy to transport.
  • the present invention relates to stable, sterile, ready-to-use aqueous pharmaceutical formulation comprising flucytosine or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.
  • the formulation is suitable for parenteral administration and may be provided in flexible plastic container.
  • the invention further relates to method of manufacture and sterilization of such formulations and using the formulation for treating systemic yeast and fungal infections.
  • the formulation of present invention is manufactured by aseptic fill finish and filled in presterilized infusion bag.
  • the formulation of flucytosine of present invention is stable for long shelf life and is easy to administer, easy to store and easy to transport.
  • the present invention also relates to a sterile ready to use aqueous pharmaceutical formulation comprising flucytosine or its pharmaceutically acceptable salts thereof that may be stored in a flexible plastic container, wherein the pharmaceutical formulation comprises about 5 mg/ml to about 20 mg/ml flucytosine or its pharmaceutically acceptable salts thereof in an aqueous sodium chloride solution and wherein the pharmaceutical formulation is manufactured by aseptic fill finish process.
  • the formulation comprises about 10 mg/ml of flucytosine or its pharmaceutically acceptable salts thereof.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof further contains about 8.05 mg/ml sodium chloride.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof further contains a buffering agent.
  • the buffering agent is tromethamine.
  • the formulation comprises about 1.5mg/ml tromethamine.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof further contains a pH adjusting agent.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof has a pH between about 5.0 to about 8.0. In a more preferred embodiment, the formulation has a pH of about 7.5.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof is packaged in a flexible plastic container.
  • the flexible plastic container is a flexible bag.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof, when stored for 24 months at 25°C/ 60% RH contains no more than 0.7% of 5 -fluorouracil impurity.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof, when stored for 24 months at 25°C/ 60% RH contains no more than 0.2% of ethenoflucytosine impurity.
  • a further embodiment relates to a sterile ready to use aqueous pharmaceutical formulation comprising flucytosine or its pharmaceutically acceptable salts thereof stored in a flexible plastic container, wherein the pharmaceutical formulation comprises about 5 mg/ml to about 20 mg/ml flucytosine or its pharmaceutically acceptable salts thereof flucytosine in an aqueous sodium chloride solution containing about 8.05 mg/ml sodium chloride, about 1.5 mg/ml tromethamine and optionally a pH adjusting agent, wherein the pharmaceutical formulation is manufactured by aseptic fill finish process.
  • the present invention provides sterile, stable pharmaceutical formulations comprising flucytosine or its pharmaceutically acceptable salts, isomers, racemates, enantiomers, hydrates, solvates, metabolites, polymorphs, and mixtures thereof in a flexible plastic container.
  • a stable, ready-to-use, aseptically filled aqueous solution formulation of flucytosine ready for direct administration to the patient in need thereof without further dilutions.
  • Flucytosine is chemically designated as 5-fluorocytosine, a fluorinated pyrimidine having a molecular formula C4H4FN3O and a molecular weight of 129.05, and having a chemical structure as given below:
  • composition or “formulation” or “dosage form” have been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical formulation which is suitable for administration to a patient or subject.
  • the subject can be an animal, preferably a mammal, more preferably a human.
  • stable formulations refers to flucytosine formulations of present invention that are physically as well as chemically stable as demonstrated by compliance to acceptable specification when the formulation is stored at ambient temperature, such as between about 18°C and about 25°C, for a commercially reasonable period of time, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, or at least about 2 years.
  • the solution of flucytosine of present invention remains physically stable, with no precipitation or crystallization or color change upon storage and the value of percentage transmittance of the solution remaining greater than 90%, preferably greater than 95% for the shelf life period of 18-24 months when stored at room temperature.
  • the solution of flucytosine remains chemically stable when stored at room temperature (about to 18°C about 25° C ), wherein various parameters such as the drug content (assay of flucytosine ) and content of related substances, i.e. known and unknown impurities remains within specified limits such as those specified according to ICH guidelines, upon storage for prolonged period of time such as for at least 12 months, preferably for 18 months, more preferably 24 months or longer.
  • the formulation of present invention is substantially free of impurities.
  • substantially free of impurities shall be understood to include flucytosine containing formulations in which the amount of total impurities is less than about 5% of the sum of peak areas of all degradants, as calculated on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatograph (“HPLC”) after a period of about 18 months at a temperature of from about 5° C. to about 25° C.
  • the amount of impurities is further calculated as being based upon the original amount of flucytosine (or salt thereof) being present in the composition or formulation.
  • the said stable formulations of flucytosine prevent degradation of flucytosine such that not more than 2 % , not more than 1% , not more than 0.4%, or not more than 0.2% of flucytosine impurity or impurities are formed over the storage period.
  • the value of assay of flucytosine remains within the specified limit of 90-110% by weight of the label claim; the total impurities remain below 2.0%, preferably below 1.0% over shelf life.
  • the time for which long term storage are contemplated include periods of at least about 18 months or longer with such that the formulation is substantially free of impurities when stored at room temperature.
  • ready-to-use refers that formulations of the present invention are premixed formulations that are suitable for administration to a patient without dilution or without any manipulation upon removing the formulations from a sealed packaging container or vessel.
  • sterile formulation means a formulation that has been brought to a state of sterility and has not been subsequently exposed to microbiological contamination, i.e. the container holding the sterile formulation has not been compromised.
  • Sterile formulations are generally prepared by pharmaceutical manufacturers in accordance with current Good Manufacturing Practice (cGMP) regulations of the U.S. Food and Drug Administration.
  • cGMP Good Manufacturing Practice
  • aseptic fill finish means a process of aseptic sterilization followed by filling under aseptic conditions into a pre-sterilized container.
  • Aseptic sterilization preferably includes passing the formulation through a sterile filter for e.g. 0.22 pm to yield a sterile formulation. Filling of the sterile formulation into pre- sterilized containers under aseptic conditions completes the aseptic fill finish process.
  • the inventors of the present invention have rigorously conducted experiments with the sterilization process to maintain and control the levels of the impurities, especially the 5-fluorouracil (5-FU) and the ethenoflucytosine impurity within limits.
  • the impurities especially the 5-fluorouracil (5-FU) and the ethenoflucytosine impurity within limits.
  • 5 -fluorouracil is a cytotoxic compound and is not desired in high amounts.
  • the structure of 5-fluorouracil is as given below:
  • 5-fluorouracil is a pyrimidine analogue that competitively inhibits the enzyme thymidylate synthase (TS), thereby creating a thymine deficiency and resulting in inhibition of deoxyribonucleic acid (DNA) synthesis and cytotoxicity. It also inhibits, to a lesser extent, the formation of ribonucleic acid (RNA). These effects are most marked in rapidly growing cells and may lead to cell death. It has been observed that flucytosine is closely related to 5-fluorouracil, and there is a possibility of 5- fluorouracil getting generated as an impurity over the course of time or during manufacturing of flucytosine formulation.
  • ethenoflucytosine impurity Another impurity of particular importance is the ethenoflucytosine impurity.
  • the chemical name of the ethenoflucytosine impurity is 8-fluoroimidazo[l,2-c] pyrimidin-5 (6H) -one and has the below structure:
  • the inventors of the present invention believe to have identified this ethenoflucytosine impurity and through experimentation have been successful to maintain and control the level of this impurity over time. The inventors believe that this impurity has not been reported previously for any flucytosine formulation, let alone, any means for controlling and maintaining the levels.
  • the inventors of the present invention have evaluated different sterilization methods and conditions and have found that the compositions of the present invention when sterilized by aspetic fill finish method demonstrate lower levels of 5- fluorouracil (5-FU) and the ethenoflucytosine impurity.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof, when stored for 24 months at 25°C/ 60% RH contains no more than 0.7% of 5- fluorouracil impurity.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof, when stored for 24 months at 25° C/ 60% RH contains no more than 0.2% of ethenoflucytosine impurity.
  • the formulation of present invention comprises flucytosine or its pharmaceutically acceptable salt in an amount of 5 mg/ml to 20 mg/ml, preferably 10 mg/ml of the total formulation.
  • the stable injectable pharmaceutical formulations of present invention include one or more pharmaceutically acceptable excipients.
  • the formulation of present invention comprises a buffering agent to maintain the pH.
  • the buffering agent may comprise at least one buffering agent selected from the group consisting of citrate (sodium or potassium), acetate, phosphate, malate, lactate, glutamate, titrate, benzoate , glycine, Tromethamine (Tris) and mixtures thereof.
  • the most preferably used buffering agent is tromethamine.
  • the buffering agent may be present in an amount of about 0.01 mg/ml to about 50 mg/ml, more preferably from about 1 mg/ml to about 30 mg/ml, more preferably from about 1 mg/ml to about 10 mg/ml and most preferably from about 1 mg/ml to about 5 mg/ml.
  • the formulation of the present invention contains about 1.5 mg/ml of tromethamine. The amount of buffering agent used differs based on the buffering agent used in the formulation.
  • the parenteral administration of solutions requires that they be adjusted to isotonicity.
  • the isotonicity of the formulation may be obtained by adding an astutely calculated quantity of tonicity agents.
  • suitable tonicity adjusting agent which may be used in the formulation of present invention include, but not limited to, sodium chloride, potassium chloride, calcium chloride , sodium hydroxide, potassium hydroxide, dextrose , sodium carbonate, meglumine , sodium lactate, Ringer's solution and lactated Ringer's solution.
  • the preferred tonicity adjusting agent present in formulation of present invention is sodium chloride.
  • the tonicity agent is present in the amount from about 1.0 mg/ml to about 20 mg/ml, preferably from about 5.0 mg/ml to 10 mg/ml, most preferably around 8.05 mg/ml.
  • the formulations comprise at least one pH adjusting agent such as sodium hydroxide or hydrochloric acid to adjust the pH to around 6.0 to 8.0.
  • the buffering agent is constituted of acetic acid/sodium acetate, using additional acetic acid as a pH adjuster is advantageous.
  • the pH of the formulation changes according to the amount of buffer used. It is preferred to achieve a pH level of between 5.0 and 8.0, preferable to have a pH of about 6.0 to about 7.5, and most preferable to develop a formulation with a pH of about 7.5.
  • the formulation according to the invention preferably an infusion solution, is aqueous. Since it is intended for parenteral administration, it preferably contains water, saline, dextrose solution or mixture thereof. Preferably, water for injection is the liquid constituent of the formulation according to the invention.
  • the present invention relates to stable, sterile, ready-to-use aqueous pharmaceutical formulation comprising flucytosine or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients.
  • the formulation is suitable for parenteral administration and may be provided in flexible plastic container.
  • the invention further relates to method of manufacture and sterilization of such formulations and using the formulation for treating systemic yeast and fungal infections.
  • the formulation of present invention is manufactured by aseptic fill finish and filled in presterilized infusion bag.
  • the formulation of flucytosine of present invention is stable for long shelf life and is easy to administer, easy to store and easy to transport.
  • the present invention also relates to a sterile ready to use aqueous pharmaceutical formulation comprising flucytosine or its pharmaceutically acceptable salts thereof that may be stored in a flexible plastic container, wherein the pharmaceutical formulation comprises about 5 mg/ml to about 20 mg/ml flucytosine or its pharmaceutically acceptable salts thereof in an aqueous sodium chloride solution and wherein the pharmaceutical formulation is manufactured by aseptic fill finish process.
  • the formulation comprises about 10 mg/ml of flucytosine or its pharmaceutically acceptable salts thereof.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof further contains about 8.05 mg/ml sodium chloride.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof further contains a buffering agent.
  • the buffering agent is tromethamine.
  • the formulation comprises about 1.5mg/ml tromethamine.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof further contains a pH adjusting agent.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof has a pH between about 5.0 to about 8.0. In a more preferred embodiment, the formulation has a pH of about 7.5.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof is packaged in a flexible plastic container.
  • the flexible container is a flexible bag.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof, when stored for 24 months at 25°C/ 60% RH contains no more than 0.7% of 5 -fluorouracil impurity.
  • the formulation comprising flucytosine or its pharmaceutically acceptable salts thereof, when stored for 24 months at 25°C/ 60% RH contains no more than 0.2% of ethenoflucytosine impurity.
  • a further embodiment relates to a sterile ready to use aqueous pharmaceutical formulation comprising flucytosine or its pharmaceutically acceptable salts thereof stored in a flexible plastic container, wherein the pharmaceutical formulation comprises about 5 mg/ml to about 20 mg/ml flucytosine or its pharmaceutically acceptable salts thereof flucytosine in an aqueous sodium chloride solution containing about 8.05 mg/ml sodium chloride, about 1.5 mg/ml tromethamine and optionally a pH adjusting agent, wherein the pharmaceutical formulation is manufactured by aseptic fill finish process.
  • the present invention provides a sterile, stable, ready-to- use , aqueous pharmaceutical formulation comprising:
  • aqueous vehicle wherein the formulation is manufactured by aseptic fill finish and filled in a presterilized plastic container.
  • the formulation according to the present invention preferably an infusion solution, can be prepared by conventional processes known to the person skilled in the art.
  • the formulation according to the present invention can be prepared by a process, comprising
  • step (C) filtering the solution of step (C) through a 0.2 um membrane sterile filter and,
  • the ready-to-use pharmaceutical formulations of present invention are dispensed in a pharmaceutically acceptable container such as plastic intravenous bags, including pre-mix bags and admix bags.
  • a pharmaceutically acceptable container such as plastic intravenous bags, including pre-mix bags and admix bags.
  • the containers are flexible plastic bags, such as are customary for injection-ready solutions.
  • plastic container is made of polyolefins and are optionally surrounded by a second bag.
  • the formulation of present invention is filled and stored in polymeric containers that are preferably flexible and are made up of polyethylene, polyvinyl chloride or polypropylene.
  • the formulation of present invention can be aseptically filled and stored in commercially available intravenous bags such as , but are not limited to: ADDEASE®, ADD-VANTAGE®, BFSTM, DUPLEXTM, EXCEL®, FIRST CHOICETM GALAXY®, INTRAVIA®, PROPYFLEXTM, SOLOMIX®, STEDIM® 71, STEDIM®100, VIAFLEX®, VIAFLOTM, and VISIV®and the like.
  • Polymeric containers can further be provided with a moisture barrier as a secondary packaging system to prevent the loss of water during storage and to further ensure the stability of the formulation.
  • a preferred moisture barrier is an aluminum overpouch.
  • sterile pharmaceutical formulation according to the present invention may be prepared using aseptic processing techniques. All the ingredients used for preparing the formulation of present invention are sterile. Sterility is maintained by using sterile materials and a controlled working environment. All containers and apparatus are sterilized, preferably by heat sterilization, prior to filling. The plastic container is then filled under aseptic conditions. Utmost care is taken to avoid the microbiological contamination.
  • Aseptic sterilization is preferably carried out by passing the formulation through at least one sterile filter, for e.g., 0.22 pm.
  • sterile filter for e.g. 0.22 pm.
  • Several sterilizing grade membrane filters are available for aseptic filtration of water based dosage forms such as cellulose acetate, nylon, polyether sulfone (PES), polypropylene (PP), polyvinyl difluoride (PVDF) and the like.
  • the formulation according to the invention is an infusion solution which is prepared for intravenous infusion over a period of time of 2 minutes to 24 hours, more preferably over a period of time of 3 minutes to 6 hours, even more preferably 5 minutes to 1 hour, most preferably 10 minutes to 45 minutes and in particular 20 minutes to 40 minutes.
  • a further aspect of the invention relates to the formulation comprising flucytosine as described above, preferably an infusion solution, for the treatment of systemic yeast and fungal infections due to sensitive organisms: such infections include cryptococcosis, candidiasis, chromomycosis and infections due to Torulopsis glabrata and Hansenula or the use of flucytosine for the production of a formulation described above for the treatment of systemic yeast and fungal infections due to sensitive organisms: such infections include cryptococcosis, candidiasis, chromomycosis and infections due to Torulopsis glabrata and Hansenula.
  • the infection is cryptococcal meningitis and severe systemic candidiasis.
  • the formulation of present invention is administered in combination with amphotericin-B or fluconazole as determined by doctor considering the patient’s condition.
  • the dose of pharmaceutical formulation of present invention to be administered to the patient in need thereof depends on the age, sex, body weight and condition of patient and can be determined by doctor.
  • the formulation of present invention may be directly into a vein, through a central venous catheter, or by intraperitoneal infusion.
  • the daily dosage in adults may be 200 mg/kg body weight divided into 3-10 doses over the 24 hours, preferably 4-7 doses over the 24 hours.
  • a total daily dose can be adjusted by doctor preferably between 100 to 150 mg/kg bodyweight.
  • the formulation of present invention is a ‘ready- to-use’ parenteral dosage form which do not require dilution before administration
  • the volume of the aqueous solution may be from about 50 ml to 1000 ml preferably 100 ml to 300 ml, most preferably 250 ml.
  • the formulation of present invention exhibits acceptable stability retains a pharmaceutically desirable appearance without any particulate matter, precipitates and crystallization of flucytosine. Further, the formulation provided herein, is suitable for parenteral administration.
  • Example 1 Formulation of flucytosine solution for infusion
  • Procedure Dissolve sodium chloride and tromethamine in water for injection under stirring to get clear solution. Add flucytosine gradually to the said solution under continuous stirring . Stir for some time (about 2-3 hours) to ensure uniform mixing of flucytosine in aqueous solution. Measure the pH of solution and if required adjust the pH between 6.0 to 8.0 using hydrochloric acid/sodium hydroxide solution. Adjust the total volume using water for injection and stir to ensure uniform mixing. Fill the solution in a flexible plastic bag using aseptic fill finish.
  • Example 2 Comparative stability study of formulation of flucytosine subjected to different sterilization procedures
  • flucytosine of present invention was subjected to terminal sterilization process by autoclaving at high temperatures and also subjected to aseptic fill finish technique.
  • the assay and impurity profile was determined and presented in table below:
  • the sterile formulation of present invention is not stable when sterilization process at high temperatures like terminal sterilization or any process other than aseptic fill finish is performed.
  • Example 3 Comparative stability study of formulation of flucytosine in various packaging material
  • the sterile formulation prepared in example 1 was subjected to various temperature and humidity conditions to ascertain the stability of the formulation.
  • the formulation was filled using aseptic fill finish in various packaging materials and analyzed for drug content and impurity profile.
  • the below table represents the stability data:

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Formulation pharmaceutique aqueuse stable, stérile et prête à l'emploi comprenant de la flucytosine ou ses sels pharmaceutiquement acceptables et des excipients pharmaceutiquement acceptables dans un récipient en plastique souple pour administration intraveineuse et intrapéritonéale. La formulation est fabriquée par un procédé aseptique de remplissage et de finition et remplie dans une poche de perfusion pré-stérilisée appropriée. La formulation est appropriée pour traiter des infections fongiques et des infections systémiques à levure.
PCT/IN2023/051027 2022-11-08 2023-11-07 Formulations parentérales de flucytosine WO2024100679A1 (fr)

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IN202221063625 2022-11-08
IN202221063625 2022-11-08

Publications (1)

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WO2024100679A1 true WO2024100679A1 (fr) 2024-05-16

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170290852A1 (en) * 2016-04-08 2017-10-12 Wisconsin Alumni Research Foundation Micelle formulations of amphotericin b
WO2021124301A1 (fr) * 2019-12-20 2021-06-24 Vyome Therapeutics Inc. Formulations et méthode pour le traitement des maladies inflammatoires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170290852A1 (en) * 2016-04-08 2017-10-12 Wisconsin Alumni Research Foundation Micelle formulations of amphotericin b
WO2021124301A1 (fr) * 2019-12-20 2021-06-24 Vyome Therapeutics Inc. Formulations et méthode pour le traitement des maladies inflammatoires

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