WO2024079565A1 - Concentrés stables de mitomycine - Google Patents

Concentrés stables de mitomycine Download PDF

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Publication number
WO2024079565A1
WO2024079565A1 PCT/IB2023/059902 IB2023059902W WO2024079565A1 WO 2024079565 A1 WO2024079565 A1 WO 2024079565A1 IB 2023059902 W IB2023059902 W IB 2023059902W WO 2024079565 A1 WO2024079565 A1 WO 2024079565A1
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WO
WIPO (PCT)
Prior art keywords
composition
mmc
solvents
water
mitomycin
Prior art date
Application number
PCT/IB2023/059902
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English (en)
Inventor
Harshal Prabhakar Bhagwatwar
Manoj Nerurkar
Haripriya POTTI
Suhas S LAVHEKAR
Original Assignee
Harshal Prabhakar Bhagwatwar
Manoj Nerurkar
Potti Haripriya
Lavhekar Suhas S
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Application filed by Harshal Prabhakar Bhagwatwar, Manoj Nerurkar, Potti Haripriya, Lavhekar Suhas S filed Critical Harshal Prabhakar Bhagwatwar
Publication of WO2024079565A1 publication Critical patent/WO2024079565A1/fr

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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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 disclosure relates generally to highly concentrated, stable, non-aqueous formulations of Mitomycin C (MMC) for the treatment of cancer and other disease conditions.
  • MMC Mitomycin C
  • the formulations of the present invention have exceptional stability and may be injected directly or diluted with sterile water for injection or other suitable media acceptable for parenteral administration. Also provided are methods of manufacture and use of the formulations in clinical therapy.
  • MMC is an antineoplastic antibiotic isolated from Streptomyces Caespitosus. It is used in the treatment of various types of cancer including gastric, pancreatic, breast, head and neck, biliary, lung, bladder and cervical cancers. It is available as a lyophilized powder comprising MMC and mannitol (5, 20 and 40 mg vials; Accord) which is to be reconstituted with water for injection to achieve a concentration of 0.5 mg/mL. This solution is approved to be administered intravenously (IV) via an in-dwelling catheter directly or for slow continuous IV infusion after suitable dilution. This solution is stable for 14 days under refrigeration or 7 days at room temperature and must be discarded if unused.
  • IV intravenously
  • MMC modified release product for local pyelocalyceal administration
  • the product commercially available under the brand name JELMYTOTM (UroGen Pharma, Inc.) is based on the formation of a slow-release gel inside the bladder from a liquid thermo-reversible hydrogel composition.
  • the product is provided as two vials of 40 mg lyophilized MMC each along with 80 mg of mannitol and a third vial containing 20 mL of the liquid hydrogel composition.
  • the MMC vials are combined with the hydrogel through a series of extremely complex mixing steps conducted at a low temperature of 2-8°C resulting in unsatisfactory mixing and administration of the product.
  • the product should be used immediately after reconstitution and should be discarded if unused due to rapid degradation of the MMC in solution.
  • flexibility in the speed and timing of reconstitution would greatly help in this treatment modality.
  • a concentrated composition of MMC allowing mixing of 80 mg of MMC rapidly with the hydrogel composition would be a tremendous value addition to this therapy.
  • EP 0415430A1 describes non-aqueous compositions comprising MMC.
  • the ‘430 application describes the need for a stable solution formulation of MMC. Solubilities in a variety of nonaqueous solvents are provided as well as stability in different solvents such as polyethylene glycol (PEG), propylene glycol (PG), dimethylacetamide (DMA) and other solvents. MMC was very unstable in water and also in PEG. Solutions at 5 mg/mL were studied and were found to be most stable in a composition comprising PG with a finite percentage of water (5%).
  • PEG polyethylene glycol
  • PG propylene glycol
  • DMA dimethylacetamide
  • a liquid composition for the delivery of MMC is described. More specifically the present disclosure describes non-aqueous solutions of MMC which are highly concentrated and resistant to physical or chemical instability. Processes to manufacture such compositions and their use in clinical practice are also described.
  • compositions are highly concentrated, with MMC concentrations in excess of 5 mg/mL reported in the literature; 5-10 mg/mL or higher and could be as high as the saturation solubility of the MMC in the respective solvent or solvent mixtures. Concentrations of close to 300 mg/mL are achievable with solvents such as DMA which are approved for human use in parenteral formulations. In more specific embodiments of the invention MMC concentrations of 40-80 mg/mL are envisaged.
  • compositions of high MMC concentration can be achieved through novel combinations of non-aqueous solvents, with or without the presence of water.
  • the non-aqueous solvents are water-miscible.
  • the non-aqueous solvents are water immiscible.
  • the compositions use mixtures of water-miscible and immiscible organic solvents. Presence of low amounts of water is well within the scope of the invention though the presence of water is known to be detrimental to the stability of MMC.
  • compositions with highly reduced levels of water such as for example less than 5 %w/w; preferably less than 1 % w/w; more preferably less than 0.5 %w/w water in the composition.
  • Compositions free from water are covered within the scope of this invention.
  • MMC concentrates of exceptional physical and chemical stability are produced. Such compositions allow for reduced reconstitution times in infusion clinics and also allow for reduced wastage of the composition.
  • MMC concentrates as described above with added preservatives to allow for multiple doses of MMC to be dispensed from the same container; thereby improving manufacturing, transportation, storage efficiencies, and clinical efficiencies.
  • the MMC is chemically stable for extended periods of time upon storage. Further such compositions are also physically stable with no incidence of crystallization and other signs of physical instability.
  • compositions which are readily miscible with delivery fluids such as water for injection, normal saline among others. This allows for the compositions to be injected directly into infusion bottles/bags just before administration allowing for reduced reconstitution time.
  • multiple dose containers are provided which allow for the tailoring of the amount of the composition which is required to be diluted, suited to the patient being treated. This allows for reduced wastage of the composition.
  • the MMC concentrates of the invention are readily miscible with the hydrogel component of JEMLYTOTM described above in all proportions.
  • the reconstitution process as described in the JELMYTOTM label can thus be simplified using the concentrates of the invention. Processes to manufacture such compositions and their use in clinical practice are also described.
  • compositions comprising highly concentrated solutions of MMC in non-aqueous organic solvents can be prepared by using judicious selection of organic solvents. Such formulations demonstrate exceptional stability.
  • Another key aspect of the invention is that compositions with exceptional stability can be achieved through reduction in the water content of the composition.
  • highly concentrated as defined in the invention is intended to encompass solutions of MMC with concentrations significantly in excess of the 5 mg/mL described in the prior art. Such solutions would thus have MMC concentrations in excess of for example 5 mg/mL or 10 mg/mL or 20 mg/mL or 40 mg/mL up to 250 mg/mL up to the saturation solubility of MMC in the solvent depending on the non-aqueous solvents used or combination of non-aqueous solvents used.
  • Non-aqueous organic solvents of the present invention are of two types: Water-miscible and water-immiscible organic solvents.
  • Water-miscible organic solvents could be any solvents which are readily miscible with water in all proportions.
  • Such solvents could include for example DMA, dimethyl formamide, DMSO, NMP, 2-pyrrolidone, glycerol, PEG, PG, ethanol and the like without any limitations.
  • Other organic solvents which are miscible with water in all proportions are all included within the scope of the invention without limitation.
  • Water-immiscible organic solvents could be organic solvents which are partially miscible to completely immiscible with water. Such solvents could include for example triacetin, benzyl benzoate, triethyl citrate, propylene carbonate, benzyl alcohol and the like without limitations.
  • the non-aqueous organic solvents of the invention are proven to be safe for human parenteral administration. Any organic solvent acceptable for human parenteral administration and mixtures of such solvents are within the scope of this invention.
  • the composition could comprise for example a solution of MMC in a solvent such as PEG, PG which have a lower solubility for MMC to achieve compositions with lower concentrations of MMC; up to for example 10-20 mg/mL.
  • compositions with high concentrations such as for example 30-300 mg/mL of MMC other solvents such as DMA, NMP, DMSO and the like can be used.
  • intermediate concentrations of MMC a judicious combination of solvents can be used to achieve the desired concentrations.
  • the MMC may be partially solubilized and partially in suspension. The proportion of the MMC in solution or in suspension can be decided based on the combination of solvents used and the defined final use of the composition. Use of fine suspensions would allow for a highly concentrated composition of MMC whereby very low amounts of the organic solvents would be used in clinical practice. This is one of the advantages of the invention. Overall reduction in the amounts of organic solvents used.
  • mixtures of non-aqueous miscible and immiscible organic solvents are envisaged.
  • MMC solutions in a water-miscible solvent could be mixed with a water- immiscible solvent to enhance stability.
  • a MMC concentrate in a water-miscible organic solvent could be mixed with a water-immiscible organic solvent in different ratios as long as the MMC stays in solution.
  • the ratio of the solvents could range from 0 to 100 r ⁇ : / ⁇ : to 100 t
  • the MMC concentrates of the invention could also contain other additives such as preservatives, antioxidants, pH adjusting or buffering agents, and the like.
  • the compositions could be filled into suitable packaging materials such as ampoules, single or multiple dose vials, prefilled syringes and the like without limitation provided the basic requirements of the invention are met.
  • MMC concentrates filled into prefilled syringes are a special embodiment of the invention.
  • An important embodiment of the invention is the preparation of MMC concentrates of exceptional stability. Such concentrates are prepared through the reduction of the moisture content of the compositions. Compositions with less than l%w/w moisture provide exceptional chemical stability. In further aspects of this embodiment, moisture contents as low as 0.8% or 0.6% or 0.4% or 0.2% or lower are beneficial for the chemical stability of MMC. Lower the moisture content the better the stability.
  • a preferred composition of the invention is a MMC concentrate in neat DMA with less than 0.1 %w/w moisture. This concentrate is exceptionally stable at refrigeration temperatures and room temperature.
  • the reduction in the moisture content could be achieved through a combination of methods.
  • the MMC could be dried by for example recrystaillizing the MMC in the last stage of the synthetic process from a dry organic solvent in an atmosphere with low relative humidity.
  • Another method could include for example subjecting the API to an environment of low humidity in a drying chamber containing a suitable dessicant.
  • Processes to reduce the moisture content of drug substances are well known in the art of manufacturing and packaging of active ingredients and are included herein in their entirety without limitation.
  • MMC with low moisture content are available from commercial MMC manufacturers.
  • Such as dry API is then stored in suitable containers in a dry environment.
  • Secondary packaging such as aluminum double laminated bags with desiccant pouches could be used to store the canisters containing the dry mitomycin. Suitable precautions should be taken while opening the container for formulation processing such as the control of the relative humidity in the area to levels below about 40 % or lower and the like.
  • Procedures to handle moisture sensitive materials are well known in the art and are all incorporated herein by reference without limitation.
  • the MMC can be further dried by incorporating the MMC in the solvents of the invention and then further passing the solution through a bed of moisture adsorbents such as for example molecular sieves to obtain a solution with low moisture contents.
  • adsorbents such as for example molecular sieves
  • compositions using low moisture DMA and other solvents and MMC with a low moisture content allows for the preparation of the concentrate without passing through the molecular sieves.
  • the solvent or solvent mixtures are passed through the molecular sieves to reduce the moisture content and then the MMC is dissolved therein.
  • molecular sieves as used in this description is intended to include multiple forms of desiccants which upon coming in contact with the liquids of the invention have the capability to extract moisture. More generally, molecular sieves are crystalline metal silicates. These uniformly sized materials have very small holes of uniform size distributed throughout their matrix. Sieves of various pore sizes are available in the market commercially. The molecular sieves are themselves available in different particle sizes (4-12 mesh and the like) and shapes. Attention is directed to the Sigma-Aldrich catalog section of molecular sieves for example for a more detailed description of the different types and categories of molecular sieves available commercially for different applications.
  • the molecular sieves can be added directly to the MMC concentrate followed by mixing till the moisture content is reduced. Samples of the concentrate can be removed periodically to test for moisture content. The beads are subsequently removed and the concentrate is then subjected to normal pharmaceutical processing.
  • the molecular sieves can be packed into cylinders or tubes to create columns or beds packed with the sieves and the solvents or the MMC concentrates can be passed through the beds till the moisture content is reduced as described above.
  • the type and amount of beads required for the reduction of moisture will depend on the level of moisture in the solvent or concentrate, the type of sieve selected and its moisture adsorbing capacity and are all within the scope of routine experimentation.
  • the liquid could be recirculated through the bed multiple times using for example a pumping means till the moisture content is reduced to the desired level.
  • a pumping means whatever the means used the final moisture content should be as described above. It is preferable to use a molecular sieve which is acceptable for pharmaceutical use.
  • Solvents of the invention are also available commercially with a low moisture content. Use of such solvents directly with or without the use of further drying is also within the scope of the invention.
  • the MMC concentrates could be aseptically filtered through 0.22-micron filters of suitable grade material such as PTFE and the like which are compatible with the solvents of the invention. Any suitable method of sterilization of the composition is within the scope of the invention. Any process of reducing the moisture content to less than about 1 % is within the scope of the invention as long as the final composition has a moisture content of less than 1 %w/w.
  • the MMC concentrates of the invention can be administered by a slow intravenous push.
  • a higher concentration of MMC may be preferred to reduce the amount of solvent used and to minimize pain and irritation at the injection site.
  • the required volume of the MMC concentrate can be added to the relevant infusion fluid to get instantaneous mixing of the solutions and formation of the infusion.
  • the reversible thermal hydrogel can be mixed with the desired amount of the MMC concentrate.
  • the MMC concentrate mixes rapidly with the hydrogel. Less than about 5 minutes are required to get a clear solution when compared with the tedious procedure referenced in the JELMYTOTM label.
  • MMC saturation solubility at 25°C was evaluated in different solvents.
  • the solubility was determined by adding weighed aliquots of MMC to 1 g of individual solvents with vortex mixing and sonication until MMC un-dissolved particles were observed.
  • the resulting solutions were subjected to filtration through 0.22-micron PTFE filters and subsequently analyzed by a specific, stability-indicating HPLC method.
  • Table 1 below describes the saturation solubility of MMC in neat individual water-miscible and water-immiscible organic solvents.
  • MMC is very poorly soluble in water but demonstrates exceptionally high solubility in DMA, DMSO and NMP.
  • PEG and PG demonstrate lower MMC solubility, while benzyl alcohol, a poorly miscible to water-immiscible organic solvent also demonstrates low MMC solubility.
  • Example 2 Preparation of MMC concentrates in mixtures of water- miscible organic solvents Solutions of MMC in mixtures of organic solvents were prepared as per Example 1. Table 2 below describes the results of MMC solubility in mixtures of water-miscible organic solvents. Table 2: Solubility of MMC in mixtures of water-miscible solvents
  • Example 3 Stability of MMC concentrates in mixtures of water-miscible organic solvents
  • a MMC concentrate was prepared at a concentration of 80 mg/mL in a combination of 70:30%w/w of PEG 400: DMA.
  • the concentrate was filled into vials and sealed with rubber plugs and placed on stability.
  • Table 3 depicts the performance on stability Table 3: From the data, it is observed that due to high moisture content and also due to high pH, the rate of degradation is faster on stability. In further experiments, the moisture level and pH were controlled to get a stable product.
  • Example 4 MMC concentrates with reduced moisture content
  • a MMC concentrate was prepared as per Example 4 at a concentration of 80 mg/mL in a mixture of PEG 400 and DMA at a ratio of 70:30.
  • the concentrate thus prepared had a moisture content of 0.76%w/w before treatment.
  • the concentrate was then exposed to molecular sieves (3 A° beads, 4 to 8 mesh; Sigma Aldrich) at a ratio of 0.5:1 (molecular sieves: concentrate) in a sealed container under nitrogen. The mixture was allowed to equilibrate for 7 hours.
  • the concentrate thus obtained was subsequently filtered and filled into vials and loaded on stability. Table 4 It is obvious from the above example that a composition with reduced moisture has enhanced stability when compared with a formulation with moisture present at higher level.
  • Example 5 MMC concentrates with pH stabilizers From the examples above, it is apparent that a reduced moisture content has a surprising effect on MMC stability in non-aqueous organic solution concentrates. It is also observed that the pH of the concentrates rises on stability with associated degradation of the MMC.
  • MMC concentrates were thus prepared in different ratios of PEG 400 to DMA as per the procedures outlined above with added buffering for pH control.
  • the placebo compositions with or without alkaline stabilizers were prepared by blending in different predefined ratios of the solvents and passed through molecular sieves to achieve a moisture content below about 0.1%w/w. MMC was then added to the different compositions to achieve a final MMC concentration of 80 mg/mL. The formulations were then filtered and filled into vials and loaded on stability.
  • MMC concentrate is prepared at a concentration of 80 mg/mL as per the procedures outlined in the examples above.
  • the solvent mixture used comprises PEG 400, DMA and benzyl alcohol in a ratio of 70:28:2 %.
  • Benzyl alcohol is the poorly water miscible solvent used.
  • a clear dark violet to black colored solution is produced which is then filled in 10 mL vials.
  • the solution thus prepared serves as a preserved formulation of MMC for multiple dose administration in a hospital setting.
  • Example 7 Mixing of the MMC concentrates with a reversible thermal hydrogel
  • Hydrogel was prepared as per the JELMYTOTM label composition. The below is the composition and manufacturing process.
  • the required quantity of HPMC was dissolved in 50% batch volume of the cooled WFI.
  • the required quantities of poloxamer 407 and PEG 400 were added and mixed till completely solubilized.
  • the final volume was made up with WFI.
  • the hydrogel bulk solution is filled in 20 mL clear glass vials at a fill volume of 20 mL, flushed with nitrogen, stoppered and sealed.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une composition liquide non aqueuse stable de mitomycine C. Dans certains modes de réalisation, la composition liquide se présente sous la forme de concentrés liquides non aqueux avec des concentrations élevées de mitomycine C. L'invention concerne également des procédés de préparation des compositions liquides et des procédés d'utilisation des concentrés en thérapie clinique.
PCT/IB2023/059902 2022-10-12 2023-10-03 Concentrés stables de mitomycine WO2024079565A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202241058449 2022-10-12
IN202241058449 2022-10-12

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0415430A1 (fr) * 1989-09-01 1991-03-06 Bristol-Myers Squibb Company Solutions stables à base de mitomycine C
US20200276128A1 (en) * 2013-10-22 2020-09-03 Medac Gesellschaft Fur Klinische Spezialpraparate Mbh Process for the preparation of a freeze-dried pharmaceutical composition containing mitomycin c
IN202121042020A (fr) * 2021-09-17 2023-03-24

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0415430A1 (fr) * 1989-09-01 1991-03-06 Bristol-Myers Squibb Company Solutions stables à base de mitomycine C
US20200276128A1 (en) * 2013-10-22 2020-09-03 Medac Gesellschaft Fur Klinische Spezialpraparate Mbh Process for the preparation of a freeze-dried pharmaceutical composition containing mitomycin c
IN202121042020A (fr) * 2021-09-17 2023-03-24

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