CA1314231C - Ifosphamide lyophilisate and process for its preparation - Google Patents
Ifosphamide lyophilisate and process for its preparationInfo
- Publication number
- CA1314231C CA1314231C CA000550706A CA550706A CA1314231C CA 1314231 C CA1314231 C CA 1314231C CA 000550706 A CA000550706 A CA 000550706A CA 550706 A CA550706 A CA 550706A CA 1314231 C CA1314231 C CA 1314231C
- Authority
- CA
- Canada
- Prior art keywords
- ifosfamide
- weight
- hexitol
- process according
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- 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
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Control Of El Displays (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Indole Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Amplifiers (AREA)
Abstract
Abstract:
Ifosfamide lyophilisate consisting substantially of ifosfamide and 0.1 to 17 parts by weight of a hexitol.
Ifosfamide lyophilisate consisting substantially of ifosfamide and 0.1 to 17 parts by weight of a hexitol.
Description
1 3 ~
The present invention relates to ifosfamide lyophili-sate and process for its preparation.
The chemical name of the active substance ifosfamide is 3-(2-chloroethyl)-2-(chloroethylamino)tetrahydro-2H-1,3,2-oxaza-phosphorin-2-oxide f H2-CH2-C l Cl-CH -CH2-NH N - CH
The present invention relates to ifosfamide lyophili-sate and process for its preparation.
The chemical name of the active substance ifosfamide is 3-(2-chloroethyl)-2-(chloroethylamino)tetrahydro-2H-1,3,2-oxaza-phosphorin-2-oxide f H2-CH2-C l Cl-CH -CH2-NH N - CH
2 \ / ~ CH
0~ 0--CH2 2 In common with cyclophosphamide, ifosfamide belongs to the chemical group of oxazaphosphorins and is used therapeu-tically for the treatment of tumor diseases.
Ifosfamide is a white crystalline powder with a melting point of 48-51C and highly hygroscopic properties. Ifosfamide begins to sinter even below its melting point and must therefore be stored at temperatures that are as low as possible (room tem-perature and below). In addition, contact with moisture in the air should be avoided where possible~
Ifosfamide dissolves in water to the extent of about 10 percent by weight, but is only stable to a limited extent in aqueous solution (maximum 3 to 4 hours at 20 to 22C or 36 hours at 4 to 6C).
131~23~
Ifosfamide is exclusively administered parenterally. The injection vials contain 200 to 5000 mg of ifosfamide in the form of a sterile crystallisate ~hich is dissolved in water for injection purposes before administration so that a 4 concentration is not exceeded. This solution is suitable for intravenous injection. For intravenous short infusion, the ifosfamide solution is dissolved in 500 ml of Ringer's solution or similar infusion liquid. The duration of the infusion is approximately 30 minutes, possibly 1 to 2 hours. In the case of the 24-hour infusion, the ifosfamide solution is for example dissolved in a total of 3 litres of 5~ dextrose sodium chloride solution.
Ifosfamide gives rise to numerous problems during preparation and processing. During preparation of the sterile crystallised ifosfamide there results a product of changing physical characteristics. In particular, dosage accuracy during filling is greatly impaired by the differing free-flowing properties.
The processing of ifosfamide is further impeded hy its hygroscopic properties and low melting point. When stored for a longer period of time the sterile crystallizate sinters and the rate of dissolution decreases. When the ifosfamide begins to sinter, this is accompanied by a drop in clear solubility and in the pH of the solution with .
~3142~
simultaneous yellow colouration; therapeutic use is then gener-ally no longer possible.
The present invention makes available a form of ifosfa-mide with improved properties, such as improved stability, shelf-life, dosability and solubility, which is easier to use, and which is in particular suitable for the preparation of in;ectable solutions.
According to the present invention there is provided a lyophilised preparation comprising of ifosfamide and 0.1 to 17 parts by weight of a hexitol, based on one part by weight of ifosfamide as well as optionally other conventional pharmaceuti-cal auxiliary substances.
The present invention also provides a process for the preparation of an ifosfamide lyophilisate which comprises freez-ing an aqueous or aqueous -ethanolic solution of ifosfamide con-taining 1 to 13 percent by weight of ifosfamide and 0.1 to 17 parts by weight of a hexitol, based on one part by weight of ifosfamide as well as optionally 0 to 16.9 parts by weight (based on 1 part by weight of ifosfamide) of other pharmaceutical auxil-iary substances at between -70 and 0C and removing the water from the so-obtained product in frozen state.
It has now surprisingly been found that the prevlous disadvantages and difficulties associated with the use and stor-age of ifosfamide can be overcome by the handling of a specific ifosfamide lyophilisate. It is in particular surprising that the lfosfamide lyophilisate of the invention has greater thermosta-bility than the hitherto used isofosfamide dry filling.
At 40C, dry fillings with ifosfamide post-darken after only one month's storage. After 2 months the contents of the vial have sintered and turned yellow. At a storage temperature of 55C the dry filed ifosfamide fuses after as little as 4 days.
~31~231 In contrast, the ifosfamide lyophilisate prepared according to the invention displays neither discolouration nor any change in the consistency of the ifosfamide under the above-mentioned storage conditions.
~ - 3a -:
131~23~
The dissolution rate of the ifosfamide lyophilisate is also markedly raised as compared to the ifosfamide dry filling.
Whereas the lyophilisate dissolves immediately on addition of solvent, independent of the storage period, the injection vials containing the dry filling have to be vigorously shaken for 1/2 to 3 minutes after introduction of the solvent. In those cases where dissolution is not immediately completed, as i5 the case with injection vials stored for a longer period of time, it even becomes necessary to let the solution stand for a few minutes. This _ impedes the use of the preparation in the hospital.
In contrast to sterile crystallisate, ifosfamide lyophili-; sate still shows optimum solubility properties after storage over several years.
In addition, the ifosfamide dry filling (i.e. the pure ifosfamide crystallisate) i~ far more sensitive to atmospheric moisture than is the lyophilisate. Thus, the ifosfamide dry filling already liquifies at a relativa humidity of less than 75~, whereas the lyophilisate, although becoming moist, retains its outer form, even at 100% relative humidity.
: ' . .: j : ~-13l423~
Moreover, during filling of the sterile crystallisate, the risk of particular or microbial contamination is far greater than with the lyophilisate.
S In contrast, during preparation of the ifosfamide lyophilisate, sterile filtration of the solution only occurs immediately before filling into the injection vials.
This ensures greater microbiological safety than does the filling of sterile crystallisate. In addition, particular impurities, which have occasionally given rise to complaints in the case of the dry filling, can be more reliably avoided by filtration of the solution.
Not only does the lyophilisation of the ifosfamide improve the product, it is also cheaper than the cost of filling the sterile crystallisate.
It has been found that the process of the invention alone, involving the use of a hexitol such as for example mannitol, produces an improved ifosfamide lyophilisate. For example, admixture of sodium chloride, such as is conventional for the dry filling of other oxazaphosphorins, does not yie]d a lyophilisate For example, in accordance with the invention, an aqueous solution of ifosfamide containing 1 to 13 percent by weight of ifosfamide, as well as 0 1 to 17 par-ts by weight of a 131~231 hexitol, related to one part by weight of ifosfamide is freeze-dried This~aqueous solution advantageously contains 5 to 12 percent by weight, in particular 8 to 10 percent by weight of ifosfamide.
. 5 It is also possible to use corresponding ethanol-water solutions of ifosfamide in place of a purely aqueous solution (ethanol proportion of such a solution up to 45%
weight by weight, for example 1 - 20~ of ethanol). In such 10 cases the ethanol is if possible first of all removed earlier under a vacuum before the remaining ice is sublimed. The conditions for the initial ethanol removal are for example: pressure 5 x 10~1 mbar, temperature rising from -25 to -5c within 10 hours, subsequent]y being raised to +22C. In individual cases these conditions a.]so depend on the different layer heights of the material to be dried in the injection vials and are to be varied accordingly.
The amount of the hexitol in this aqueous or a~ueous-ethanolic solution is generally 1 to 17, preferably 3 to 12, in particular 5 to 9 percent by weight. If the amo~nt of the hexitol is re~ated to one part by weight of ifosfamide, then the amount of the hexitol is 0.1 to 17, preferablyO.1 t.o ~.5, in particular 0.6 to 0.8 parts by weight of the hexitol per one part by weight of ifosfamide.
Hexitols which may be used inc].ude: mannitol, glucitol sorbitol, such as D-sorbitol , dulcitol, allitol, altritol (for example D- and L-altritol), iditol (for example D- and L-iditol), their optically active forms (D- or L-forms) as well as the corresponding racemates. Use is preferably made S of mannitol, such as D-mannitol, L-mannitol, DL-mannitol, sorbitol and/or dulcitol, and in particular preferably D-mannitol. The hexitol may also be mixtures of the hexitols named, for example mixtures of mannitol and sorbitol and/or dulcitol Since dulcitol is less water-soluble than for example mannitol, the dulcitol content in the aqueous solution should for example not exceed 3 percent by weight. In contrast, mannitol and sorbitol may for example be mixed in all ratios.
In addition to a hexitol it i5 also possible to add other conventional pharmaceutical auxiliary substances such as for example glycine, lactose, polyvinylpyrrolidone, glucose, fructose, albumin and equivalent skeleton building substances. The total amount of such substances in the solution which is used for freeze-drying is for example 0 -16 9 parts by weight, for example 0.1 to 7 parts by weight, based on 1 part by weight of ifosfamide. In the finished lyophilisate the total amount of such auxiliary substances may be up to 16.9 parts by weight, related to one part by weight of the hexitol. Individually the amount of such auxiliary substances depends on the amount of the hexitol used in such a way that the total amount of the hexitol and of such other auxiliary substances in the finished lyophilisate is not more than 17 parts by weight, based on 1 part by weight of ifosfamide Sllould only 0.1 p~rt: hy weight of the hexitol ~e present in the lyophilisate, it is therefore possible for up to 1~.9 parts by weight of other auxiliAry suhstances to he present; should for example 8.5 parts by weight of the hexitol be present, the amount of other auxiliary substances may for example be up to 8 5 parts by weight based on 1 part by weight of ifosfamide.
To prepare the solution to be used for freeze-drying a vessel is charged with about 70 to 83~, preferably 80~ of the requisite amount of wnter or aqueous ethanol and the corresponding amount of ifosfamide and mannitol dissolved in succession (i.e. first the ifosfamide and then the mannitol) with continuous stirrirlg or continuous agitation.
After complete dissolution the solution is made up to the final volume and the pH measured The pH of this ~olution should for example bè between 4 and 7 after dilution.
Advantageously a 4~ ifosfamide solution is prepared.
The ifosfamide solution so obtained is then sterilised by filtration using pathogen-proof flters conventionally used for such purposes and then filled into appropriate containers for injection preparations The storage time up to filling into the injection containers should not exceed a period of 3 to 4 hours, including the time taken to prepare the solution, if working is at room temperature (18 to 22C). Should subsequent freeze-drying not be possible immediately, such a solution, optionally also after filling into the injection containers, may for example be stored for up to 36 hours more at lower temperatures, for example between -5 and +10C, preferably +4 to +6C, before freeze-drying begins.
To carry out the process of the invention the so-obtained aqueous ifosfamide solution is filled into containers for injection preparationc, for example ampoules or other glass vessels, and the solution is freeze-dried.
For sterilisation purposes conventional pathogen-proof filters, for example conventional bActerial filters having a pore size of about 0.2~um are used.
When glass vessels or ampoules are used these are first sterilised in the conventional manner.
The hexitols used (preferably mannitol, in particular D-mannitol) should conform to the requirements of the British Pharmacopoeia 1980.
The hexitols used should be as pyrogen-free as possible (pyrogens are fever-inducing endotoxins formed by bactaria).
13~231 The same applies to the ifosfamide us~d. The remova] or destruction of the pyrogen~ is effectRd in conventional manner (for example the solution of active substance is treated with activated charcoal prior to sterile filtration). In addition, the injection water used should be sterile and pyrogen-free and conform to the requirements of the Deutsches Arzneibuch, 9th Edition 1986~ The injection vessels may advantageously be those made from tubular glass or furnace glass of the IIIrd hydrolytic class (for example 10 R, 30 R and 50 H) (see in this connection Deutsches Arzneibuch, 9th Edition, 1986, pages 161 - 164 and DIN standard 58366 part 1 and 5).
Furthermore the injection vessels as well as the additional auxiliary substances such as rubber stoppers and flanged caps must conform to the requirements of DIN standard 58366, Part 2 and Part 3 as well as DIN 58367, Part 1.
The amounts of solution of the ifosfamide solutions to be used for lyophilisation, in the appropriate containers ~ampoules) or other containers for injection preparations are made avAilable per container for example between 1 and ; 500, preferably 1 and 250, in particular 2 and 50 ml. The containers should in each case be so dimensioned that the lyophilisate contained therein may later be dissolved in a larger amount of liquid. They should therefore in general 131~231 have a volume that is sufficiently large for the preparation of a ready-to-use final solution having about 2 to 5 times, preferably 2 to 4 times, in particular 2 to 2.5 times the volume of the originally filled lyophilisate solution.
As already mentioned each ampoule or each glass vessel is advantageously filled with a single dosage of ifosfamide, whereby the amount of ifosfamide per glass vessel is for l0 example between 100 mg to 1G g, preferably 200 mg to 5 g.
Subsequently the solution i5 freeze-dried in the customary manner in this glass vessel or ampoule. It is, however, also possible to lyophilise larger amounts of ifosfamide, i.e. a correspondingly larger solution volume of the t5 ifosfamide solution in a correspondingly larger vessel and subsequently to subdivide or fill the lyophilisate obtained into correspondingly smaller dosages. The lyophilisation itself is carried out in such a way that the ampoules or glass vessels or other vessels which contain the ifosfamide-hexitol solution nre placed directly on a st~nd or on a rack in a freeze-drying chamber. Once the chamber has been closed, the ampoules or vessels are cooled down to temperatures below 0C, for example to temperatures between -70 to 0C, preferably -50 to -30C, in particular -45 to -35C. As soon as the solutions are complete]y frozen the freeze-drying chamber is progressive]y evacuated and drying commences. Firstly the 131~2~1 non-adsorptively bound solvent is removed at temperatures between -30 to +40C, preferably 0 to l30C, in particular ~20 to +30C, whereby a pressure between between 10-3 to 6, preferably 10-2 to 2, in particular 1o-1 to 1 mbar is selec$ed. In the case of the above mentioned temperatures or temperature ranges the temperature always refers to that of the racks.
The process is so controlled that the heat applied via the plate temperature is completely used as heat of sublimation and the temperature of the frozen ifosfamide-containing solution always remains below its eutectic temperature. The desired temperature of the plateæ in each case may for example be programmed via program disks or computers. The time taken to remove this non-adsorptively bound solvent depends on the size of the individual containers and lies for example between about 4 to 40 hours at a plate temperature of +25C and a pressure of 0.8 mbar.
Reference is made by way of example to the times given in the example.
The complete removal of the non-adsorptively bound water is indicated AS follows: Non-adsorptively bound water is present in the form of ice. Using a so-called pres~ure rise measurement it is established whether such water is still present in the lyophilisate. For this purpose a valve is closed between the drying chamber and the condensor to 131~231 which the vacuum pump is also connected~ Any ice present would then quickly sublime and lead to a rise in pressure in the drying chamber.
In the case of pressure rise measurement, the pressure in the chamber after 15 minutes may rise to a maximum of 1 mbar from the starting value, for example 0.8 mbar A rise in excess of this figure would indicate that the main drying was not yet completed Still present, residual adsorptively-bound solvent is then - - removed by post drying This takes for example 3 to 12 hours at a vacuum of 10~1 to 10-4 mbar, in particular 3 - 4 hours at a vacuum of 10-3 to 10-4 mbar.
The lyophilisation process is completed when the residual moisture (determined according to K. Fischer) is below 1~, preferably below 0.5~.
In particular, the post-drying for removal of adsorptively bound water takes place at temperatures between 0 and 40C, prefer~bly 10 to 35C, in particular 20 to 30C
and a pressure between 10-4 to 1 o-1, preferably 10-3 to 10-2, in particular 10-3 to 5 x 10-3 mbar, whereby this post-drying takes for example 2 to 36, preferably 6 to 24, in particular 3 to 12 hours.
13~42331 Following completion of the freeze-drying the vessels are æealed. All stages of the process of the invention are conducted under sterile conditions.
The injection vials are then sealed for example after ventilation of the freeze-drying chamber to normal pressure through addition of dry, sterile air or nitrogen with special freeze-drying rubber stoppers which are treated with silicone to avoid abrasion and to improve lubricity.
Example The following solution is used for freeze-drying:
Ifosfamide 100 mg D-mannitol 70 mg Water of injection ad 1 ml The density of this solution is 1.0563 g/ml at +6C and 1.0527 gJml at +20C.
The amount of solution to be prepared depends on the appropriate filling and freeze-drying capacity.
.
Preparation of the solution:
i~
1 314~31 A vessel is charged with 80% of water of injection and appropriate amounts of ifosfamide and mannitol are added successively to the water with constant stirring. Following complete dissolution the mixture is made up to the final volume and the p~ is measured.
The prepared solution is sterilised by filtration using pathogen proof filters conventionally used for this purpose (for example Sartorius SM 11107 or SM 11307, 0.2 ~m pore size, Pall filter NRP (pore size 0.2 ~m) and stored until filling whilst avoiding particular and bacterial contamination. Storage at room temperature (20 - 22C) should not exceed 3 - 4 hours, including the time required to prepare the solution Should freeze-drying not take place immediately, the solution may be stored for about 36 hours at +4 to ~6C.
For purposes o~ sterile filtration it is also possible to use conventional prefilters (for example Sartorius SM 13400 or Pall LPA) to protect the sterile filter.
Cleaning of the injection vials:
The injection vials are washed with hot and cold demineral-ised water and with air. All cleaning media are freed from suspended matter by filtration.
131~2~
Whilst avoiding recontamination due to particles from the air the vials are dried with hot air and sterilised ldiscontinuously at 180C / 2 hours).
The rubber stoppers used to close the injection vials are cleaned using demineralised water and for example a cleaning agent consisting of nonionogenic surfactants and phosphoric acid esters in aqueous solution.
The cleaned stopper~ are rinsed using demineralised water or filtered demineralised water to free them of fibres and threads. The so-cleaned stoppers are then sterilised using steam.
The so-cleaned and sterilised injection vials are then filled aseptically with the ifosfamide solution and closed using the rubber stoppers.
Fil~ing amounts:
Filling amount Volumes used*
Ifosfamide 200 mg 2 ml 5 ml 500 mg 5 ml 12 5 ml 251 g 10 ml 25 ml 2 g 20 ml 50 ml 5 g 50 ml 125 ml * For the sul)sequent dilbtion of the Iyophilisate 131423~
, ; The filling volumes should not exceed the following limits:
.
Filling volume Limiting value of Average limiting value individual filling of the filling volume volumes : 2 ml 1.9 - 2.1 ml 1.95 - 2 05 ml lO5 ml 4.8 - 5.2 ml 4.9 - 5.1 ml 10 ml 9.7 - 10.3 ml 9.85 - 10 15 ml 20 ml 19.4 - 20 6 ml 19.7 - 20.3 ml 50 ml 48.5 - 51.5 ml 49.25 - 50.75 ml The filling volumes must be statistically monitored, with the filling volume per filling station being measured at ; least once every 30 minutes.
The filled injection v;.als are frozen as quickly as ; possible to -40C.
The condition~ for freeze-drying differ according to the size of the injection vials. The fol~owing vAlu~s may for example app~y:
131~23~
Duration of main drying at a plate temperature of +25C
and 0.6 mbar:
ca. 6 - 8 hours for vessels with 200 mg ifosfamide ca. 10 - 12 hours for vessels with 500 mg ifosfamide ca. 10 - 14 hours for vessels with 1000 mg ifosfamide ca. 20 - 28 hours for vessels with 2000 mg ifosfamide ca. 34 hours for vessels with 5000 mg ifosfamide Duration of post drying ca. 3 - 4 hours under vacuum of 5 x 10-4 mbar, at a plate temperature of +25C.
The residual moisture (determined after K. Fischer) should be less than 0.5~.
Following completion of freeze-drying the injection vials are sealed.
To fix the rubber stoppers flanged caps are superimposed and rolled on. The finished injection vials are checked f~r mechanical defects (cracks, faulty closure, etc.).
0~ 0--CH2 2 In common with cyclophosphamide, ifosfamide belongs to the chemical group of oxazaphosphorins and is used therapeu-tically for the treatment of tumor diseases.
Ifosfamide is a white crystalline powder with a melting point of 48-51C and highly hygroscopic properties. Ifosfamide begins to sinter even below its melting point and must therefore be stored at temperatures that are as low as possible (room tem-perature and below). In addition, contact with moisture in the air should be avoided where possible~
Ifosfamide dissolves in water to the extent of about 10 percent by weight, but is only stable to a limited extent in aqueous solution (maximum 3 to 4 hours at 20 to 22C or 36 hours at 4 to 6C).
131~23~
Ifosfamide is exclusively administered parenterally. The injection vials contain 200 to 5000 mg of ifosfamide in the form of a sterile crystallisate ~hich is dissolved in water for injection purposes before administration so that a 4 concentration is not exceeded. This solution is suitable for intravenous injection. For intravenous short infusion, the ifosfamide solution is dissolved in 500 ml of Ringer's solution or similar infusion liquid. The duration of the infusion is approximately 30 minutes, possibly 1 to 2 hours. In the case of the 24-hour infusion, the ifosfamide solution is for example dissolved in a total of 3 litres of 5~ dextrose sodium chloride solution.
Ifosfamide gives rise to numerous problems during preparation and processing. During preparation of the sterile crystallised ifosfamide there results a product of changing physical characteristics. In particular, dosage accuracy during filling is greatly impaired by the differing free-flowing properties.
The processing of ifosfamide is further impeded hy its hygroscopic properties and low melting point. When stored for a longer period of time the sterile crystallizate sinters and the rate of dissolution decreases. When the ifosfamide begins to sinter, this is accompanied by a drop in clear solubility and in the pH of the solution with .
~3142~
simultaneous yellow colouration; therapeutic use is then gener-ally no longer possible.
The present invention makes available a form of ifosfa-mide with improved properties, such as improved stability, shelf-life, dosability and solubility, which is easier to use, and which is in particular suitable for the preparation of in;ectable solutions.
According to the present invention there is provided a lyophilised preparation comprising of ifosfamide and 0.1 to 17 parts by weight of a hexitol, based on one part by weight of ifosfamide as well as optionally other conventional pharmaceuti-cal auxiliary substances.
The present invention also provides a process for the preparation of an ifosfamide lyophilisate which comprises freez-ing an aqueous or aqueous -ethanolic solution of ifosfamide con-taining 1 to 13 percent by weight of ifosfamide and 0.1 to 17 parts by weight of a hexitol, based on one part by weight of ifosfamide as well as optionally 0 to 16.9 parts by weight (based on 1 part by weight of ifosfamide) of other pharmaceutical auxil-iary substances at between -70 and 0C and removing the water from the so-obtained product in frozen state.
It has now surprisingly been found that the prevlous disadvantages and difficulties associated with the use and stor-age of ifosfamide can be overcome by the handling of a specific ifosfamide lyophilisate. It is in particular surprising that the lfosfamide lyophilisate of the invention has greater thermosta-bility than the hitherto used isofosfamide dry filling.
At 40C, dry fillings with ifosfamide post-darken after only one month's storage. After 2 months the contents of the vial have sintered and turned yellow. At a storage temperature of 55C the dry filed ifosfamide fuses after as little as 4 days.
~31~231 In contrast, the ifosfamide lyophilisate prepared according to the invention displays neither discolouration nor any change in the consistency of the ifosfamide under the above-mentioned storage conditions.
~ - 3a -:
131~23~
The dissolution rate of the ifosfamide lyophilisate is also markedly raised as compared to the ifosfamide dry filling.
Whereas the lyophilisate dissolves immediately on addition of solvent, independent of the storage period, the injection vials containing the dry filling have to be vigorously shaken for 1/2 to 3 minutes after introduction of the solvent. In those cases where dissolution is not immediately completed, as i5 the case with injection vials stored for a longer period of time, it even becomes necessary to let the solution stand for a few minutes. This _ impedes the use of the preparation in the hospital.
In contrast to sterile crystallisate, ifosfamide lyophili-; sate still shows optimum solubility properties after storage over several years.
In addition, the ifosfamide dry filling (i.e. the pure ifosfamide crystallisate) i~ far more sensitive to atmospheric moisture than is the lyophilisate. Thus, the ifosfamide dry filling already liquifies at a relativa humidity of less than 75~, whereas the lyophilisate, although becoming moist, retains its outer form, even at 100% relative humidity.
: ' . .: j : ~-13l423~
Moreover, during filling of the sterile crystallisate, the risk of particular or microbial contamination is far greater than with the lyophilisate.
S In contrast, during preparation of the ifosfamide lyophilisate, sterile filtration of the solution only occurs immediately before filling into the injection vials.
This ensures greater microbiological safety than does the filling of sterile crystallisate. In addition, particular impurities, which have occasionally given rise to complaints in the case of the dry filling, can be more reliably avoided by filtration of the solution.
Not only does the lyophilisation of the ifosfamide improve the product, it is also cheaper than the cost of filling the sterile crystallisate.
It has been found that the process of the invention alone, involving the use of a hexitol such as for example mannitol, produces an improved ifosfamide lyophilisate. For example, admixture of sodium chloride, such as is conventional for the dry filling of other oxazaphosphorins, does not yie]d a lyophilisate For example, in accordance with the invention, an aqueous solution of ifosfamide containing 1 to 13 percent by weight of ifosfamide, as well as 0 1 to 17 par-ts by weight of a 131~231 hexitol, related to one part by weight of ifosfamide is freeze-dried This~aqueous solution advantageously contains 5 to 12 percent by weight, in particular 8 to 10 percent by weight of ifosfamide.
. 5 It is also possible to use corresponding ethanol-water solutions of ifosfamide in place of a purely aqueous solution (ethanol proportion of such a solution up to 45%
weight by weight, for example 1 - 20~ of ethanol). In such 10 cases the ethanol is if possible first of all removed earlier under a vacuum before the remaining ice is sublimed. The conditions for the initial ethanol removal are for example: pressure 5 x 10~1 mbar, temperature rising from -25 to -5c within 10 hours, subsequent]y being raised to +22C. In individual cases these conditions a.]so depend on the different layer heights of the material to be dried in the injection vials and are to be varied accordingly.
The amount of the hexitol in this aqueous or a~ueous-ethanolic solution is generally 1 to 17, preferably 3 to 12, in particular 5 to 9 percent by weight. If the amo~nt of the hexitol is re~ated to one part by weight of ifosfamide, then the amount of the hexitol is 0.1 to 17, preferablyO.1 t.o ~.5, in particular 0.6 to 0.8 parts by weight of the hexitol per one part by weight of ifosfamide.
Hexitols which may be used inc].ude: mannitol, glucitol sorbitol, such as D-sorbitol , dulcitol, allitol, altritol (for example D- and L-altritol), iditol (for example D- and L-iditol), their optically active forms (D- or L-forms) as well as the corresponding racemates. Use is preferably made S of mannitol, such as D-mannitol, L-mannitol, DL-mannitol, sorbitol and/or dulcitol, and in particular preferably D-mannitol. The hexitol may also be mixtures of the hexitols named, for example mixtures of mannitol and sorbitol and/or dulcitol Since dulcitol is less water-soluble than for example mannitol, the dulcitol content in the aqueous solution should for example not exceed 3 percent by weight. In contrast, mannitol and sorbitol may for example be mixed in all ratios.
In addition to a hexitol it i5 also possible to add other conventional pharmaceutical auxiliary substances such as for example glycine, lactose, polyvinylpyrrolidone, glucose, fructose, albumin and equivalent skeleton building substances. The total amount of such substances in the solution which is used for freeze-drying is for example 0 -16 9 parts by weight, for example 0.1 to 7 parts by weight, based on 1 part by weight of ifosfamide. In the finished lyophilisate the total amount of such auxiliary substances may be up to 16.9 parts by weight, related to one part by weight of the hexitol. Individually the amount of such auxiliary substances depends on the amount of the hexitol used in such a way that the total amount of the hexitol and of such other auxiliary substances in the finished lyophilisate is not more than 17 parts by weight, based on 1 part by weight of ifosfamide Sllould only 0.1 p~rt: hy weight of the hexitol ~e present in the lyophilisate, it is therefore possible for up to 1~.9 parts by weight of other auxiliAry suhstances to he present; should for example 8.5 parts by weight of the hexitol be present, the amount of other auxiliary substances may for example be up to 8 5 parts by weight based on 1 part by weight of ifosfamide.
To prepare the solution to be used for freeze-drying a vessel is charged with about 70 to 83~, preferably 80~ of the requisite amount of wnter or aqueous ethanol and the corresponding amount of ifosfamide and mannitol dissolved in succession (i.e. first the ifosfamide and then the mannitol) with continuous stirrirlg or continuous agitation.
After complete dissolution the solution is made up to the final volume and the pH measured The pH of this ~olution should for example bè between 4 and 7 after dilution.
Advantageously a 4~ ifosfamide solution is prepared.
The ifosfamide solution so obtained is then sterilised by filtration using pathogen-proof flters conventionally used for such purposes and then filled into appropriate containers for injection preparations The storage time up to filling into the injection containers should not exceed a period of 3 to 4 hours, including the time taken to prepare the solution, if working is at room temperature (18 to 22C). Should subsequent freeze-drying not be possible immediately, such a solution, optionally also after filling into the injection containers, may for example be stored for up to 36 hours more at lower temperatures, for example between -5 and +10C, preferably +4 to +6C, before freeze-drying begins.
To carry out the process of the invention the so-obtained aqueous ifosfamide solution is filled into containers for injection preparationc, for example ampoules or other glass vessels, and the solution is freeze-dried.
For sterilisation purposes conventional pathogen-proof filters, for example conventional bActerial filters having a pore size of about 0.2~um are used.
When glass vessels or ampoules are used these are first sterilised in the conventional manner.
The hexitols used (preferably mannitol, in particular D-mannitol) should conform to the requirements of the British Pharmacopoeia 1980.
The hexitols used should be as pyrogen-free as possible (pyrogens are fever-inducing endotoxins formed by bactaria).
13~231 The same applies to the ifosfamide us~d. The remova] or destruction of the pyrogen~ is effectRd in conventional manner (for example the solution of active substance is treated with activated charcoal prior to sterile filtration). In addition, the injection water used should be sterile and pyrogen-free and conform to the requirements of the Deutsches Arzneibuch, 9th Edition 1986~ The injection vessels may advantageously be those made from tubular glass or furnace glass of the IIIrd hydrolytic class (for example 10 R, 30 R and 50 H) (see in this connection Deutsches Arzneibuch, 9th Edition, 1986, pages 161 - 164 and DIN standard 58366 part 1 and 5).
Furthermore the injection vessels as well as the additional auxiliary substances such as rubber stoppers and flanged caps must conform to the requirements of DIN standard 58366, Part 2 and Part 3 as well as DIN 58367, Part 1.
The amounts of solution of the ifosfamide solutions to be used for lyophilisation, in the appropriate containers ~ampoules) or other containers for injection preparations are made avAilable per container for example between 1 and ; 500, preferably 1 and 250, in particular 2 and 50 ml. The containers should in each case be so dimensioned that the lyophilisate contained therein may later be dissolved in a larger amount of liquid. They should therefore in general 131~231 have a volume that is sufficiently large for the preparation of a ready-to-use final solution having about 2 to 5 times, preferably 2 to 4 times, in particular 2 to 2.5 times the volume of the originally filled lyophilisate solution.
As already mentioned each ampoule or each glass vessel is advantageously filled with a single dosage of ifosfamide, whereby the amount of ifosfamide per glass vessel is for l0 example between 100 mg to 1G g, preferably 200 mg to 5 g.
Subsequently the solution i5 freeze-dried in the customary manner in this glass vessel or ampoule. It is, however, also possible to lyophilise larger amounts of ifosfamide, i.e. a correspondingly larger solution volume of the t5 ifosfamide solution in a correspondingly larger vessel and subsequently to subdivide or fill the lyophilisate obtained into correspondingly smaller dosages. The lyophilisation itself is carried out in such a way that the ampoules or glass vessels or other vessels which contain the ifosfamide-hexitol solution nre placed directly on a st~nd or on a rack in a freeze-drying chamber. Once the chamber has been closed, the ampoules or vessels are cooled down to temperatures below 0C, for example to temperatures between -70 to 0C, preferably -50 to -30C, in particular -45 to -35C. As soon as the solutions are complete]y frozen the freeze-drying chamber is progressive]y evacuated and drying commences. Firstly the 131~2~1 non-adsorptively bound solvent is removed at temperatures between -30 to +40C, preferably 0 to l30C, in particular ~20 to +30C, whereby a pressure between between 10-3 to 6, preferably 10-2 to 2, in particular 1o-1 to 1 mbar is selec$ed. In the case of the above mentioned temperatures or temperature ranges the temperature always refers to that of the racks.
The process is so controlled that the heat applied via the plate temperature is completely used as heat of sublimation and the temperature of the frozen ifosfamide-containing solution always remains below its eutectic temperature. The desired temperature of the plateæ in each case may for example be programmed via program disks or computers. The time taken to remove this non-adsorptively bound solvent depends on the size of the individual containers and lies for example between about 4 to 40 hours at a plate temperature of +25C and a pressure of 0.8 mbar.
Reference is made by way of example to the times given in the example.
The complete removal of the non-adsorptively bound water is indicated AS follows: Non-adsorptively bound water is present in the form of ice. Using a so-called pres~ure rise measurement it is established whether such water is still present in the lyophilisate. For this purpose a valve is closed between the drying chamber and the condensor to 131~231 which the vacuum pump is also connected~ Any ice present would then quickly sublime and lead to a rise in pressure in the drying chamber.
In the case of pressure rise measurement, the pressure in the chamber after 15 minutes may rise to a maximum of 1 mbar from the starting value, for example 0.8 mbar A rise in excess of this figure would indicate that the main drying was not yet completed Still present, residual adsorptively-bound solvent is then - - removed by post drying This takes for example 3 to 12 hours at a vacuum of 10~1 to 10-4 mbar, in particular 3 - 4 hours at a vacuum of 10-3 to 10-4 mbar.
The lyophilisation process is completed when the residual moisture (determined according to K. Fischer) is below 1~, preferably below 0.5~.
In particular, the post-drying for removal of adsorptively bound water takes place at temperatures between 0 and 40C, prefer~bly 10 to 35C, in particular 20 to 30C
and a pressure between 10-4 to 1 o-1, preferably 10-3 to 10-2, in particular 10-3 to 5 x 10-3 mbar, whereby this post-drying takes for example 2 to 36, preferably 6 to 24, in particular 3 to 12 hours.
13~42331 Following completion of the freeze-drying the vessels are æealed. All stages of the process of the invention are conducted under sterile conditions.
The injection vials are then sealed for example after ventilation of the freeze-drying chamber to normal pressure through addition of dry, sterile air or nitrogen with special freeze-drying rubber stoppers which are treated with silicone to avoid abrasion and to improve lubricity.
Example The following solution is used for freeze-drying:
Ifosfamide 100 mg D-mannitol 70 mg Water of injection ad 1 ml The density of this solution is 1.0563 g/ml at +6C and 1.0527 gJml at +20C.
The amount of solution to be prepared depends on the appropriate filling and freeze-drying capacity.
.
Preparation of the solution:
i~
1 314~31 A vessel is charged with 80% of water of injection and appropriate amounts of ifosfamide and mannitol are added successively to the water with constant stirring. Following complete dissolution the mixture is made up to the final volume and the p~ is measured.
The prepared solution is sterilised by filtration using pathogen proof filters conventionally used for this purpose (for example Sartorius SM 11107 or SM 11307, 0.2 ~m pore size, Pall filter NRP (pore size 0.2 ~m) and stored until filling whilst avoiding particular and bacterial contamination. Storage at room temperature (20 - 22C) should not exceed 3 - 4 hours, including the time required to prepare the solution Should freeze-drying not take place immediately, the solution may be stored for about 36 hours at +4 to ~6C.
For purposes o~ sterile filtration it is also possible to use conventional prefilters (for example Sartorius SM 13400 or Pall LPA) to protect the sterile filter.
Cleaning of the injection vials:
The injection vials are washed with hot and cold demineral-ised water and with air. All cleaning media are freed from suspended matter by filtration.
131~2~
Whilst avoiding recontamination due to particles from the air the vials are dried with hot air and sterilised ldiscontinuously at 180C / 2 hours).
The rubber stoppers used to close the injection vials are cleaned using demineralised water and for example a cleaning agent consisting of nonionogenic surfactants and phosphoric acid esters in aqueous solution.
The cleaned stopper~ are rinsed using demineralised water or filtered demineralised water to free them of fibres and threads. The so-cleaned stoppers are then sterilised using steam.
The so-cleaned and sterilised injection vials are then filled aseptically with the ifosfamide solution and closed using the rubber stoppers.
Fil~ing amounts:
Filling amount Volumes used*
Ifosfamide 200 mg 2 ml 5 ml 500 mg 5 ml 12 5 ml 251 g 10 ml 25 ml 2 g 20 ml 50 ml 5 g 50 ml 125 ml * For the sul)sequent dilbtion of the Iyophilisate 131423~
, ; The filling volumes should not exceed the following limits:
.
Filling volume Limiting value of Average limiting value individual filling of the filling volume volumes : 2 ml 1.9 - 2.1 ml 1.95 - 2 05 ml lO5 ml 4.8 - 5.2 ml 4.9 - 5.1 ml 10 ml 9.7 - 10.3 ml 9.85 - 10 15 ml 20 ml 19.4 - 20 6 ml 19.7 - 20.3 ml 50 ml 48.5 - 51.5 ml 49.25 - 50.75 ml The filling volumes must be statistically monitored, with the filling volume per filling station being measured at ; least once every 30 minutes.
The filled injection v;.als are frozen as quickly as ; possible to -40C.
The condition~ for freeze-drying differ according to the size of the injection vials. The fol~owing vAlu~s may for example app~y:
131~23~
Duration of main drying at a plate temperature of +25C
and 0.6 mbar:
ca. 6 - 8 hours for vessels with 200 mg ifosfamide ca. 10 - 12 hours for vessels with 500 mg ifosfamide ca. 10 - 14 hours for vessels with 1000 mg ifosfamide ca. 20 - 28 hours for vessels with 2000 mg ifosfamide ca. 34 hours for vessels with 5000 mg ifosfamide Duration of post drying ca. 3 - 4 hours under vacuum of 5 x 10-4 mbar, at a plate temperature of +25C.
The residual moisture (determined after K. Fischer) should be less than 0.5~.
Following completion of freeze-drying the injection vials are sealed.
To fix the rubber stoppers flanged caps are superimposed and rolled on. The finished injection vials are checked f~r mechanical defects (cracks, faulty closure, etc.).
Claims (17)
1. A lyophilised preparation comprising of ifosfamide and 0.1 to 17 parts of a hexitol, based on one part by weight of ifosfamide.
2. A lyophilised preparation according to claim 1, in which the hexitol is mannitol.
3. A lyophilised preparation according to claim 1 or 2, which contains conventional pharmaceutical auxiliary sub-stances.
4. A process for the preparation of an ifosfamide lyophilisate which comprises freezing an aqueous or aqueous-ethanolic solution of ifosfamide containing 1 to 13 percent by weight of ifosfamide and 0.1 to 17 parts by weight of a hexitol, based on one part by weight of ifosfamide at between -70 and 0°C
and removing the water from the so-obtained product in frozen state.
and removing the water from the so-obtained product in frozen state.
5. A process according to claim 4, in which the ini-tially non-adsorptively bound water is first removed at a temper-ature between -30 and +40°C and a pressure between 10-3 to 10 mbar and subsequently adsorptively bound water is removed at a temperature between 0 and 40°C and a pressure between 10-4 to 10-1 mbar.
6. A process according to claim 4, in which the hexi-tol is mannitol.
7. A process according to claim 6, in which the solu-tion is an aqueous solution.
8. A process according to claim 7, in which the solu-tion contains 5 to 12 percent by weight ifosfamide
9. A process according to claim 7, in which the solu-tion contains 8 to 10 percent by weight ifosfamide.
10. A process according to claim 6, in which the solu-tion is an aqueous ethanolic solution.
11. A process according to claim 4, 5 or 6, in which the solution contains 1 to 17 percent by weight hexitol.
12. A process according to claim 4, 5 or 6, in which the solution contains 3 to 12 percent by weight hexitol.
13. A process according to claim 4, 5 or 6, in which the solution contains 5 to 9 percent by weight hexitol.
14. A process according to claim 4, 5 or 6, in which the amount of hexitol is 0.1 to 2.5 parts by weight per one part by weight of ifosfamide.
15. A process according to claim 4, 5 or 6, in which the amount of hexitol is 0.16 to 0.8 parts by weight per one part by weight of ifosfamide.
16. A process according to claim 4, 5 or 6, which also contains 0 to 16.9 parts by weight (based on 1 part by weight of ifosfamide) of other pharmaceutical auxiliary substances.
17. Ifosfamide lyophilisate obtained according to claim 4, 5 or 6.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3637089.4 | 1986-10-31 | ||
| DE3637089 | 1986-10-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1314231C true CA1314231C (en) | 1993-03-09 |
Family
ID=6312873
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000550706A Expired - Lifetime CA1314231C (en) | 1986-10-31 | 1987-10-30 | Ifosphamide lyophilisate and process for its preparation |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP0265812B1 (en) |
| JP (1) | JPS63159319A (en) |
| KR (1) | KR900003491B1 (en) |
| AT (1) | ATE55250T1 (en) |
| AU (1) | AU598602B2 (en) |
| CA (1) | CA1314231C (en) |
| DD (1) | DD262582A5 (en) |
| DE (1) | DE3764235D1 (en) |
| DK (1) | DK169308B1 (en) |
| EG (1) | EG18333A (en) |
| ES (1) | ES2017982B3 (en) |
| FI (1) | FI87140C (en) |
| GE (1) | GEP19971025B (en) |
| GR (1) | GR3000708T3 (en) |
| HU (1) | HU197987B (en) |
| IL (1) | IL84312A (en) |
| IN (1) | IN168119B (en) |
| LV (1) | LV10051B (en) |
| MX (1) | MX8958A (en) |
| NO (1) | NO873860L (en) |
| PT (1) | PT86032B (en) |
| RU (1) | RU1836079C (en) |
| UA (1) | UA11075A (en) |
| YU (1) | YU197387A (en) |
| ZA (1) | ZA878183B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2040394T3 (en) * | 1988-03-19 | 1993-10-16 | Asta Medica Aktiengesellschaft | PROCEDURE FOR PREPARING A LYOPHILIZED MATERIAL OF IFOSFAMIDE AND MESNA. |
| US5227373A (en) * | 1991-10-23 | 1993-07-13 | Bristol-Myers Squibb Co. | Lyophilized ifosfamide compositions |
| WO1995007083A1 (en) * | 1993-09-10 | 1995-03-16 | F.H. Faulding & Co. Limited | Ifosfamide lyophilisate composition |
| DE19529057B4 (en) * | 1995-08-08 | 2007-12-13 | Baxter Healthcare S.A. | Ifosfamide lyophilizate preparations |
| KR20010034552A (en) * | 1998-03-03 | 2001-04-25 | 요시히코 시오노 | Pharmaceutical compositions containing the phospholipase inhibitor sodium [[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetate |
| NZ538584A (en) * | 2002-09-05 | 2007-05-31 | Bharat Serums & Vaccines Ltd | Stable liquid composition of oxazaphosphorine, mesna and etherified beta-cyclodextrin |
| EP1569663B1 (en) * | 2002-12-02 | 2010-04-28 | Bharat Serums & Vaccines Ltd. | Ifosfamide compositions for parenteral administration and a process for their preparation |
| US8436190B2 (en) * | 2005-01-14 | 2013-05-07 | Cephalon, Inc. | Bendamustine pharmaceutical compositions |
| EP2412359A1 (en) * | 2006-09-29 | 2012-02-01 | Infa S.A. | Packaging system for pharmaceutical compositions and kit for intravenous administration |
| CN105900385B (en) * | 2014-12-04 | 2019-08-27 | 华为技术有限公司 | Load distribution in data communication network |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3732340A (en) * | 1966-07-11 | 1973-05-08 | Asta Werke Ag Chem Fab | N',o-propylene phosphoric acid ester diamides |
| DE2750207A1 (en) * | 1977-05-09 | 1978-11-16 | Walton J Smith | Anhydrous compsn. prodn. by freeze drying hydrated, hydrolysable prod. - esp. aspirin or aspirin salt solns. |
| DE3279834D1 (en) * | 1981-12-31 | 1989-08-31 | Asta Pharma Ag | 4-sulfido-oxaza phosphorines and their use in the treatment of cancer, and in immunosuppression |
| US4537883A (en) * | 1982-11-12 | 1985-08-27 | Mead Johnson & Company | Lyophilized cyclophosphamide |
-
1987
- 1987-09-15 NO NO873860A patent/NO873860L/en unknown
- 1987-10-20 AT AT87115322T patent/ATE55250T1/en not_active IP Right Cessation
- 1987-10-20 ES ES87115322T patent/ES2017982B3/en not_active Expired - Lifetime
- 1987-10-20 EP EP87115322A patent/EP0265812B1/en not_active Expired - Lifetime
- 1987-10-20 DE DE8787115322T patent/DE3764235D1/en not_active Expired - Lifetime
- 1987-10-23 MX MX895887A patent/MX8958A/en unknown
- 1987-10-26 IN IN837/CAL/87A patent/IN168119B/en unknown
- 1987-10-27 FI FI874727A patent/FI87140C/en not_active IP Right Cessation
- 1987-10-28 EG EG61687A patent/EG18333A/en active
- 1987-10-29 RU SU874203570A patent/RU1836079C/en active
- 1987-10-29 UA UA4203570A patent/UA11075A/en unknown
- 1987-10-29 PT PT86032A patent/PT86032B/en unknown
- 1987-10-29 IL IL84312A patent/IL84312A/en not_active IP Right Cessation
- 1987-10-29 JP JP62272002A patent/JPS63159319A/en active Granted
- 1987-10-30 ZA ZA878183A patent/ZA878183B/en unknown
- 1987-10-30 AU AU80529/87A patent/AU598602B2/en not_active Ceased
- 1987-10-30 CA CA000550706A patent/CA1314231C/en not_active Expired - Lifetime
- 1987-10-30 HU HU874900A patent/HU197987B/en unknown
- 1987-10-30 DD DD87308471A patent/DD262582A5/en not_active IP Right Cessation
- 1987-10-30 YU YU01973/87A patent/YU197387A/en unknown
- 1987-10-30 KR KR1019870012077A patent/KR900003491B1/en not_active IP Right Cessation
- 1987-10-30 DK DK569687A patent/DK169308B1/en not_active IP Right Cessation
-
1990
- 1990-08-09 GR GR90400533T patent/GR3000708T3/en unknown
-
1992
- 1992-10-27 LV LVP-92-174A patent/LV10051B/en unknown
-
1993
- 1993-07-07 GE GEAP1993972A patent/GEP19971025B/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4959215A (en) | Ifosfamide-mesna lyophilizate and process for its preparation | |
| RU2106138C1 (en) | Improved lyophilized and phosphamide compositions | |
| US20090093522A1 (en) | Freeze-dried pantoprazole preparation and pantoprazole injection | |
| US5204335A (en) | Ifosfamide lyophilisate and process for its preparation | |
| FR2853547A1 (en) | INJECTABLE PHARMACEUTICAL COMPOSITIONS CONTAINING PIPERACILLIN AND TAZOBACTAM AND PROCESS FOR THEIR PRODUCTION | |
| CA1314231C (en) | Ifosphamide lyophilisate and process for its preparation | |
| CZ298581B6 (en) | Pharmaceutically stable oxaliplatin preparation for parenteral administration | |
| EP1058547B1 (en) | Pharmaceutical compositions containing the phospholipase inhibitor sodium 3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-phenylmethyl)-1h-indol-4-yl]oxy]acetate | |
| US5972912A (en) | Method for lyophilizing ifosfamide | |
| US11707434B2 (en) | Method for preparing organic solvent-free lyophilized cyclophosphamide | |
| DK175808B1 (en) | Ifosfamide mesna lyophilisate and process for its preparation | |
| CA2952298A1 (en) | A method for preparing lyophilized organic solvent-free cyclophosphamide | |
| RU2666148C1 (en) | Method for preparing water-soluble lyophilized salt form bis(2-thio-4,6-dioxo-1,2,3,4,5,6-hexahydropyrimidin-5-yl)-(4-nitrophenyl)methane | |
| WO2023198704A1 (en) | Acetyl salicylic acid composition for intravenous administration, its storage, production and use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |