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
  • A61K9/0012—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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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

• Solution comprising treosulfan The invention relates to a solution comprising treosulfan, which is in particular useful for lyophilisation, and the use of such a solution for preparing a corresponding lyophilisate, which lyophilisate has very favourable characteristics for use as a pharmaceutical composition and in particular can be quickly reconstituted to form ready-to-use solutions and shows a high stability and purity.
• Treosulfan chemical name (2S, 3S) - (-) 1, 4-di (mesyloxy) -2, 3- butanediol or L-Threitol-1, 4-di (methanesulfonate) , has the following chemical formula:
• Treosulfan is a dihydroxy derivative of busulfan and acts as an antineoplastic agent in view of its ability to alkylate the DNA. It is in use for the treatment of ovarian cancer either as such or in combination with further chemotherapeutics for example melphalan and dacarbazine (Baynes et al . , Blood 96(11): 170a, Abstr. No. 731, 2000).
• the monotherapy with treosulfan involves administering to the patient an amount of 8 g/m 2 body surface area
• the combination therapy with treosulfan and cisplatin involves administering treosulfan in an amount of 5 g/m 2 .
• Treosulfan has also been used in the treatment of advanced, non resectable non-small cell lung carcinomas (Pawel et al . , Onkologie 21:316-319; 1998).
• EP 1 227 808 Al discloses the use of treosulfan in conditioning therapy before bone marrow or blood stem cell transplantation to a patient.
• the administration of treosulfan can effectively be combined with either administration of further agents, e.g. cyclophosphamid, carboplatin, thiotepa, melphalan, fludarabin, immune suppressive antibodies, or irradiation of the body.
• further agents e.g. cyclophosphamid, carboplatin, thiotepa, melphalan, fludarabin, immune suppressive antibodies, or irradiation of the body.
• busulfan serious side effects can predominantly or entirely be avoided.
• High dosages of treosulfan can even be used without causing serious liver, lung, kidney or CNS toxicities.
• the conditioning phase comprises a period of 2 to 7 days with a total dose of treosulfan of at least 20 g/m 2 body surface area before allogenic transplantation
• Treosulfan is commercially available as capsules for oral use and a sterile powder consisting of crystalline treosulfan for preparing a solution for infusion.
• the solution is administered intravenously within about 15 to 30 minutes.
• the commercial sterile powder is dissolved in e.g. in water to a concentration of 50 mg/ml and the obtained solution is diluted with e.g. isotonic NaCl solution.
• the water used as solvent has to be warmed to 30°C for the reconstitution step.
• the powder has to be completely removed from the walls of the vial. This step is important to avoid formation of powder particles which are sticking to the wall.
• WO 2015/107534 refers to two allegedly novel and distinct polymorphic forms of treosulfan, designated as form I and form II as well as lyophilized formulations which are said to typically include treosulfan of form I.
• These lyophilized formulations are prepared by freeze-drying a solution of treosulfan in water.
• the obtained lyophilisates suffer from a couple of disadvantages. In particular, they require long times for their reconstitution and their content of methanesulfonic acid and water, in particular after storage, is undesirably high and hence their purity and stability is not satisfactory.
• an object of the present invention to avoid the disadvantages of the known solutions of treosulfan and to provide solutions which can comprise treosulfan in a higher concentration and allow to prepare in an economic manner lyophilisates which have favorable characteristics and in particular can be quickly reconstituted to form ready-to-use solutions and show a high stability and purity.
• the invention also relates to the use of the solution according to claim 4 and the process for preparing a lyophilisate of treosulfan according to claims 5 to 16.
• the solution according to the invention is characterized in that it comprises treosulfan and a mixture of water and acetic acid.
• the mixture comprises 2 to 50 % by weight, in particular 2 to 25 % by weight and preferably 2 to 10 % by weight of acetic acid.
• solubility of treosulfan in such a mixture is higher than in either water or acetic acid.
• the solubility at 18°C of treosulfan in water is about 50 mg/ml and in acetic acid is about 18 mg/ml.
• the solution according to the invention comprises treosulfan in an amount of in particular 70 to 250 mg/g, preferably 70 to 155 mg/g and more preferably 70 to 125 mg/g solution.
• the solution may also include additives such as solubilizers, e.g. polysorbate, cyclodextrins , sodium dodecyl sulfate, and poloxamer; chelating agents, e.g. sodium EDTA, DTPA, and calteridol; antioxidants, e.g. butylated hydroxy toluene, butylated hydroxy anisole, methionine, glutathione, metabisulfite sodium, alpha-tocopherol , thioglycolate sodium, cysteine, and ascorbic acid; pH adjusting agents and buffering agents, e.g.
• solubilizers e.g. polysorbate, cyclodextrins , sodium dodecyl sulfate, and poloxamer
• chelating agents e.g. sodium EDTA, DTPA, and calteridol
• antioxidants e.g. butylated hydroxy
• bulking agents e.g. amino acids such as alanine and arginine
• sugar derivatives e.g. sucrose, dextrose, mannitol, trehalose, and mannose
• polymers e.g. polyethylene glycol, gelatin, and dextran
• the solution according to the invention surprisingly allows the economic preparation of a lyophilisate of treosulfan which shows a combination of very advantageous properties.
• the invention is therefore also directed to the use of the solution according to the invention for preparing a lyophilisate of treosulfan.
• the invention is also directed to a process for preparing a lyophilisate of treosulfan which process is characterized in that the solution according to the invention is freeze-dried.
• the freeze-drying of the solution is typically effected by using freeze-drying machines normally employed for pharmaceutical purposes.
• the solution is filled into suitable containers, such as vials, and the containers are placed in a conventional freeze-dryer with coolable and heatable surfaces on which the solution can be exposed to the various temperatures of the freeze-drying process.
• the solution is usually frozen and exposed to a decreased atmospheric pressure.
• sublimation of the solvent from the frozen solution takes place to a great extent, which precipitates for example on cooler regions of the freeze-dryer provided for this. This is then usually followed by a secondary drying at higher temperatures.
• the lyophilisate obtained is normally allowed to come to room temperature and the containers including the lyophilisate are sealed under sterile conditions.
• the process according to the invention comprises
• step (b) freezing the solution, wherein the solution is cooled from the first temperature to a freezing temperature at a cooling rate of not more than 3 K/min, and (c) drying the frozen solution obtained in step (b) to give the lyophilisate .
• the cooling rate in step (b) is not more than 2 K/min, preferably not more than 1.5 K/min and more preferably not more than 1.3 K/min.
• the cooling rate in step (b) is in particular from 0.05 to 1.5 and preferably from 0.1 to 1.3 K/min.
• the first temperature in the process of the invention is in particular from 15°C to 95°C, preferably from 20°C to 50°C and more preferably from 25°C to 35°C.
• the freezing temperature employed in the process is in particular -40°C or less, preferably from -60°C to -40°C and more preferably from -50°C to -40°C.
• the frozen solution is kept at the freezing temperature for in particular at least 1 hour, preferably 1 to 10 hours and more preferably 2 to 8 hours.
• the drying in step (c) includes a primary drying which is carried out by subjecting the frozen solution to a temperature of -25°C or higher, preferably a temperature of -15°C to 0°C, and subjecting the frozen solution to a pressure of 0.03 to 1.0 mbar, preferably 0.1 to 0.6 mbar and more preferably 0.3 to 0.5 mbar.
• the drying in step (c) includes a primary drying which is carried out by subjecting the frozen solution to a temperature of 0°C or higher, preferably a temperature of 0°C to 60°C, more preferably a temperature of 20°C to 60°C, even more preferably a temperature of 30°C to 50°C, and subjecting the frozen solution to a pressure of 0.03 to 1.0 mbar, preferably 0.1 to 0.6 mbar and more preferably 0.3 to 0.5 mbar.
• the primary drying is preferably carried out for at least 5 hours and in particular for at least 10 hours.
• a secondary drying is carried out by subjecting the product of the primary drying to a temperature of at least 30°C, preferably 30 to 50°C, and subjecting the product of the primary drying to a pressure of 0.03 to 1.0 mbar, preferably 0.1 to 0.6 mbar and more preferably 0.3 to 0.5 mbar.
• the secondary drying is preferably carried out for at least 2 hours and in particular for at least 4 hours.
• the lyophilisate obtained by the process according to the invention requires only a very short time for complete dissolution in media usually employed for reconstitution to give ready-to-use injection or infusion solutions.
• Isotonic saline solution and water for injection are typically employed as such media.
• Other pharmaceutically acceptable solutions are also possible for the reconstitution, e.g. Ringer's lactate solutions or phosphate buffers.
• the very short period of time for reconstitution is very favourable since it enables clinic staff to prepare ready-to-use solutions freshly directly before the intended administration to patients, without having to allow for long waiting times for complete dissolution.
• the risk of undesired degradation reactions of the treosulfan decreases.
• the lyophilisate also has a high purity and stability as reflected by its very high content of the active ingredient treosulfan .
• the lyophilisate comprises at least 95 % by weight, in particular at least 96 % by weight, preferably at least 98 % by weight and more preferably at least 99 % by weight of treosulfan.
• the lyophilisate has only a small water content and comprises water in an amount of in particular less than 1 %, preferably less than 0.5 % and more preferably less than 0.1 % by weight, as determined by Karl Fischer titration.
• the lyophilisate obtained by the process according to the invention surprisingly comprises only a very small amount of acetic acid of in particular less than 1.0 % by weight, preferably less than 0.5 % by weight and more preferably less than 0.2 % by weight.
• This is also a substantial and surprising advantage as it shows that the presence of acetic acid in the solution for lyophilisation is associated with favorable properties in the lyophilisate and at the same time its amount in the lyophilisate is desirably low.
• the process according to the invention also allows to prepare the lyophilisate with favorable properties in a highly reproducible manner which is a substantial advantage in comparison to the conventional processes which give products with substantially varying properties.
• Freeze drying was carried out in a freeze dryer GT 2 (Manufacturer: Hof Sonderanlagenbau (Lohra, Germany)) with 0.4 m 2 shelf area and 8 kg ice condenser capacity including means for differential pressure measurement. Determination of amount of treosulfan and impurities by RP- HPLC
• RP- HPLC reversed-phase high pressure liquid chromatography
• the amount of residual acetic acid was determined by HS-GC after esterification to ethyl acetate.
• the lyophilisate of one vial was reconstituted with water using 20 ml of water per 1 g of lyophilisate. 500 m ⁇ of the reconstituted sample were mixed with 100 m ⁇ saturated NaHSCy-solution and 50 m ⁇ of ethanol in a GC-vial. The GC vial was tightly crimped. All samples were prepared in duplicates.
• a stock solution of acetic acid of 1 mg/ml was prepared and diluted to 5 individual standards containing 25 yg/ml to 0.5 yg/ml in water. Each stock solution (500 m ⁇ ) was mixed with 100 m ⁇ saturated NaHSCg solution and 50 m ⁇ of ethanol in a GC-vial.
• the GC method for quantification of residual solvents was used to determine the amount of acetic acid in form of its ethyl ester (see Ph.Eur. 2.4.24 Identification and control of residual solvents: System A).
• the chromatographic conditions used to quantify the amount of ethyl acetate correspond to the USP 467 method for the determination of residual solvents.
• the following gas chromatograph was used:
• the dissolution behavior of the lyophilisates was determined by adding water for injection or 0.45 % by weight of aqueous NaCl solution at room temperature to give a final concentration of about 50 mg/ml.
• the reconstitution process was monitored with regard to dissolution time and behavior. Determination of amount of water by "Karl Fischer titration" About 100 mg of the respective sample was weighed into a glass vial which was sealed with a crimp cap. The sample was transferred into the furnace of a Karl Fischer coulometer type 756, furnace sample processor 774, of Metrohm (Filderstadt , Germany) which was heated to 90 °C. The septum of the cap was penetrated by an injection needle, and the generated water vapour was directly transferred into the titration chamber of the Karl Fischer coulometer via dry nitrogen. The measurement was repeated once. Empty glass vials were used for blank correction .
• the solutions as given in the table below were prepared by dissolving treosulfan in the respective solvent mixture (30 min, 25°C, ultra-sonic bath) .
• the obtained solutions were filtered and the filtered solutions were filled in cleaned and depyrogenized glass vials (10 vials per formulation) which were stoppered in lyophili zation position and sealed in lyophilization bags.
• composition of solution for lyophilisation target dose 500 mg treosulfan per vial
• the samples were loaded into the freeze dryer and lyophilized according to the following lyophilization cycle.
• the vials were vented and opened and 10 ml of 0.45 % by weight aqueous NaCl solution (room temperature) were added using a 10 ml volumetric pipette.
• the lyophilisate cakes of both examples 1 and 2 reconstituted within 1 min only. No pre-heating of the solvent was necessary. The removal of sticky particles adhering to the wall of the vial was also not necessary.
• For all lyophilisates only a very low amount of residual water was determined. Moreover, all samples were free of impurities and showed a similar and high treosulfan content .
• the acetic acid content was below the detection limit (LOD) of the RP-HPLC analysis of 0.003 % by weight.
• Example 3 Solution with 10 % by weight of acetic acid and lyophilisate
• the solution as given in the table below was prepared by weighing 10 g of treosulfan in a 150 ml polypropylene (PP) beaker. The solvent was added and the treosulfan was dissolved under stirring at an ambient temperature of 22 °C. The obtained solution was filled into cleaned and depyrogenized glass vials of a nominal volume of 20 ml.
• PP polypropylene
• composition of solution for lyophilisation target dose about 1000 mg treosulfan per vial
• the vials were stoppered in lyophilization position and sealed in lyophilisation bags.
• the samples were loaded into the freeze dryer and lyophilized according to the following lyophilization cycle.
• the vials were stoppered in lyophilization position and sealed in lyophilization bags.
• the samples were loaded into the freeze dryer and lyophilized according to the following lyophilization cycle.
• lyophilisate cakes were acceptable.
• the vials were vented, opened and 20 ml of 0.45 % by weight aqueous NaCl solution (room temperature) were added using a multistep pipette.
• the lyophilisate cakes reconstituted within 1.5 minutes under shaking. No pre-heating of the solvent was necessary. The removal of sticky particles adhering to the wall of the vials was also not necessary.

Landscapes

• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Medicinal Preparation (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Emergency Medicine (AREA)
• Dermatology (AREA)
• Bioinformatics & Cheminformatics (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=63685771

Family Applications (1)

Country Status (2)

Family Cites Families (6)

• 2019
  • 2019-09-25 EP EP19773090.6A patent/EP3856252A1/de active Pending
  • 2019-09-25 WO PCT/EP2019/075829 patent/WO2020064816A1/en unknown

Also Published As

Similar Documents

Legal Events