WO1994008592A1 - Lyophilized cyclophosphamide compositions - Google Patents

Lyophilized cyclophosphamide compositions Download PDF

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Publication number
WO1994008592A1
WO1994008592A1 PCT/FI1993/000390 FI9300390W WO9408592A1 WO 1994008592 A1 WO1994008592 A1 WO 1994008592A1 FI 9300390 W FI9300390 W FI 9300390W WO 9408592 A1 WO9408592 A1 WO 9408592A1
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Prior art keywords
cyclophosphamide
dextran
weight
compositions
composition according
Prior art date
Application number
PCT/FI1993/000390
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French (fr)
Inventor
Hannu Uolevi Jalonen
Pertti Tapani Rantala
Original Assignee
Orion-Yhtymä Oy
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Application filed by Orion-Yhtymä Oy filed Critical Orion-Yhtymä Oy
Priority to AU48216/93A priority Critical patent/AU4821693A/en
Publication of WO1994008592A1 publication Critical patent/WO1994008592A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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

Definitions

  • This invention relates to cyclophosphamide compositions.
  • lyophilized cyclophosphamide a drug widely used in the treatment of neoplastic disease
  • European specification 0251657 proposes the use of galactitol as an ingredient in lyophilized cyclophosphamide compositions stated to have enhanced chemical and physical stability and uniform appearance and consistency.
  • European Specification 0394045 proposes the use of alanine as an excipient in lyophilized cyclophosphamide compositions.
  • Kovalcik et al Journal of Parenteral Science & Technology 42(1) pp 29-37 and 42(5) pp 165-173 have examined the stability of cyclophosphamide in lyophilized cakes containing mannitol, lactose and sodium bicarbonate (first paper) and urea, polyvinylpyrrolidone and dextran (second paper).
  • the first paper recommends the use of mannitol or sodium bicarbonate and the rehydration of the compositions so that the cyclophosphamide is present as the crystalline monohydrate.
  • the second paper recommends the use of urea, again with the cyclophosphamide in the monohydrate form.
  • the cyclophosphamide/dextran composition lost about 25 % of its cyclophosphamide content after storage for about ten weeks and 40 % of its cyclophosphamide content after sixteen weeks.
  • dextran is an excellent excipient for cyclophosphamide compositions having good storage stability provided that the proportion of dextran, in relation to the cyclophosphamide is carefully controlled.
  • the present invention accordingly provides a storage-stable cyclophosphamide composition suitable for reconstitution in water or other suitable diluent before administration comprising, for each part by weight of cyclophosphamide (calculated as anhydrous cyclophosphamide), from 0.3 to 1.2 part, preferably 0.4 to 1.0 part, more preferably 0.5 to 0.6 part by weight of dextran.
  • the cyclophosphamide may be present e.g. as the crystalline monohydrate or in anhydrous crystalline form.
  • the cyclophosphamide is in essentially anhydrous crystalline form.
  • compositions may be rapidly reconstituted in water or other suitable diluent to provide solutions for oral or parenteral administration.
  • the new compositions When packed in the usual containers for lyophilized compositions, the new compositions show excellent chemical and physical stability and have a superior appearance.
  • the dextran used in the new compositions is commercially available.
  • the molecular weight is appropriately in the range of 1000 to 150,000, preferably about 40,000 to 120,000, more preferably about 40,000 to 70,000.
  • the dextran used in the new compositions may be a combination of two or more dextrans of different molecular weight.
  • Typical dosage units contain 100, 200 or 500 milligrams or 1 or 2 grams of cyclophosphamide, calculated as the anhydrous form.
  • the amount of water required for reconstitution may be varied over a wide range, but is preferably about 4 to 5 ml for each 100 mg of cyclophosphamide.
  • the new compositions may be made by dissolving the dextran in water, suitably in the proportion of 30 to 100 parts by weight of water for each part by weight of dextran.
  • the cyclophosphamide is then added to the solution and dissolved.
  • the dissolution may be aided by an ultrasonicator.
  • the solution obtained is then sterilised, e.g. by filtration, and dispensed into suitable vessels for lyophilization.
  • suitable vessels for lyophilization may be carried out in conventional manner.
  • the lyophilization vessels are filled with nitrogen or other suitable inert gas and sealed. Average moisture content of the lyophilized product is not more than about 1.0 %, typically less than 0.5 %, e.g. about 0.2 %.
  • the cyclophosphamide is obtained in essentially anhydrous crystalline form. This may be re-hydrated to obtain the monohydrate e.g. a form containing around 0.07 parts water to every part of cyclophosphamide. However, since this does not provide any notable improvement in storage stability compared with the anhydrous crystalline form, formation of the monohydrate is generally considered unnecessary.
  • the dextran was dissolved in the water.
  • the cyclophosphamide was then added and dissolution was enhanced using an ultrasonicator.
  • the solution obtained was filtered through a Millipore Sterivex-GS 0.22 ⁇ m filter unit, and a clear colourless solution was obtained.
  • the solution was dispensed into 24 ml vials provided with stoppers.
  • the vials were placed in a freeze-dryer and cooled to -50 °C for 11 hours.
  • the freeze-drying chamber was then evacuated to a pressure of 0.1 mbar and condenser cooled to about -80 °C.
  • the shelves were then allowed to warm up to about +10 °C and the drying process was continued for about 54 hours. Nitrogen was then admitted to the chamber and the vials were closed.
  • the average moisture content of three vials was found to be 0.2 % by weight of the cyclophosphamide determined by Karl Fischer titration. It was demonstrated that the cyclophosphamide was in anhydrous crystalline form by differential scanning calorimetry (DSC) carried out on ten vials. The endothermal peak temperature was between 52.2 and 53.0 °C in each case. This shows that the cyclophosphamide is in anhydrous crystalline form, since the melting point of the monohydrate is about 49.5 °C. The contents of the vials could easily be reconstituted in water within about ten seconds.
  • Example 2 The preparation of the solution was similar to Example 1.
  • the solution was dispensed into 10 ml vials provided with stoppers.
  • the freeze-drying procedure was similar to Example 1 except that the chamber pressure was 0.05 mbar and drying time was 30 hours.
  • the average moisture content of 8 vials was 0.1 %.
  • the endothermal peak temperatures of ten vials (DSC) were between 51.8-52.9 °C demonstrating that the cyclophosphamide was in anhydrous crystalline form.
  • the contents of the vials could be reconstituted in water within a few seconds.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Lyophilized cyclophosphamide compositions of good storage stability comprise cyclophosphamide, and a controlled amount of dextran.

Description

LYOPHILIZED CYCLOPHOSPHAMIDE COMPOSITIONS
This invention relates to cyclophosphamide compositions.
The storage stability of lyophilized cyclophosphamide, a drug widely used in the treatment of neoplastic disease, is known to be unsatisfactory, and there have been several proposals for improving it. Reference may be made for example to Unites States Patent 4537883 which proposes the use of mannitol as an ingredient in lyophilized cyclophosphamide compositions stated to have improved thermal stability. European specification 0251657 proposes the use of galactitol as an ingredient in lyophilized cyclophosphamide compositions stated to have enhanced chemical and physical stability and uniform appearance and consistency. European Specification 0394045 proposes the use of alanine as an excipient in lyophilized cyclophosphamide compositions.
Kovalcik et al (Journal of Parenteral Science & Technology 42(1) pp 29-37 and 42(5) pp 165-173) have examined the stability of cyclophosphamide in lyophilized cakes containing mannitol, lactose and sodium bicarbonate (first paper) and urea, polyvinylpyrrolidone and dextran (second paper). The first paper recommends the use of mannitol or sodium bicarbonate and the rehydration of the compositions so that the cyclophosphamide is present as the crystalline monohydrate. The second paper recommends the use of urea, again with the cyclophosphamide in the monohydrate form. This paper states that in the dextran-containing composition the cyclophosphamide is present in amorphous form, and that this form does not change if an attempt is made to rehydrate the formulation. The formulation made by Kovalcik et al contained 25 mg of cyclophosphamide and 100 mg of dextran in a solution volume of 1 ml. It appears that after lyophilization the formulation still contained 4.19 % by weight of water, this being the loss of weight on heating. This weight loss was reversed on humidification of the lyophilized cake. According to data presented by these workers, the cyclophosphamide/dextran composition lost about 25 % of its cyclophosphamide content after storage for about ten weeks and 40 % of its cyclophosphamide content after sixteen weeks.
It has now unexpectedly been discovered that dextran is an excellent excipient for cyclophosphamide compositions having good storage stability provided that the proportion of dextran, in relation to the cyclophosphamide is carefully controlled.
The present invention accordingly provides a storage-stable cyclophosphamide composition suitable for reconstitution in water or other suitable diluent before administration comprising, for each part by weight of cyclophosphamide (calculated as anhydrous cyclophosphamide), from 0.3 to 1.2 part, preferably 0.4 to 1.0 part, more preferably 0.5 to 0.6 part by weight of dextran.
The cyclophosphamide may be present e.g. as the crystalline monohydrate or in anhydrous crystalline form. Preferably the cyclophosphamide is in essentially anhydrous crystalline form.
These compositions may be rapidly reconstituted in water or other suitable diluent to provide solutions for oral or parenteral administration. When packed in the usual containers for lyophilized compositions, the new compositions show excellent chemical and physical stability and have a superior appearance.
The dextran used in the new compositions is commercially available. The molecular weight is appropriately in the range of 1000 to 150,000, preferably about 40,000 to 120,000, more preferably about 40,000 to 70,000. The dextran used in the new compositions may be a combination of two or more dextrans of different molecular weight.
Typical dosage units contain 100, 200 or 500 milligrams or 1 or 2 grams of cyclophosphamide, calculated as the anhydrous form. The amount of water required for reconstitution may be varied over a wide range, but is preferably about 4 to 5 ml for each 100 mg of cyclophosphamide.
The new compositions may be made by dissolving the dextran in water, suitably in the proportion of 30 to 100 parts by weight of water for each part by weight of dextran. The cyclophosphamide is then added to the solution and dissolved. The dissolution may be aided by an ultrasonicator. The solution obtained is then sterilised, e.g. by filtration, and dispensed into suitable vessels for lyophilization. The latter may be carried out in conventional manner. After the water has been removed, the lyophilization vessels are filled with nitrogen or other suitable inert gas and sealed. Average moisture content of the lyophilized product is not more than about 1.0 %, typically less than 0.5 %, e.g. about 0.2 %. The cyclophosphamide is obtained in essentially anhydrous crystalline form. This may be re-hydrated to obtain the monohydrate e.g. a form containing around 0.07 parts water to every part of cyclophosphamide. However, since this does not provide any notable improvement in storage stability compared with the anhydrous crystalline form, formation of the monohydrate is generally considered unnecessary.
The following examples illustrate the invention.
EXAMPLE 1
For a batch of 150 vials containing 500 mg each of cyclophosphamide, a solution was prepared from the following ingredients:
Cyclophosphamide monohydrate 80.25 g
Dextran (mw=70,000) 45.0 g
Water for injection 2.21
The dextran was dissolved in the water. The cyclophosphamide was then added and dissolution was enhanced using an ultrasonicator. The solution obtained was filtered through a Millipore Sterivex-GS 0.22 μm filter unit, and a clear colourless solution was obtained. The solution was dispensed into 24 ml vials provided with stoppers. The vials were placed in a freeze-dryer and cooled to -50 °C for 11 hours. The freeze-drying chamber was then evacuated to a pressure of 0.1 mbar and condenser cooled to about -80 °C. The shelves were then allowed to warm up to about +10 °C and the drying process was continued for about 54 hours. Nitrogen was then admitted to the chamber and the vials were closed.
The average moisture content of three vials was found to be 0.2 % by weight of the cyclophosphamide determined by Karl Fischer titration. It was demonstrated that the cyclophosphamide was in anhydrous crystalline form by differential scanning calorimetry (DSC) carried out on ten vials. The endothermal peak temperature was between 52.2 and 53.0 °C in each case. This shows that the cyclophosphamide is in anhydrous crystalline form, since the melting point of the monohydrate is about 49.5 °C. The contents of the vials could easily be reconstituted in water within about ten seconds.
To compare the stability of the anhydrous and hydrated forms of the cyclophosphamide, about half the vials were rehydrated by placing them in a humidity chamber at 75 % relative humidity. The moisture content was monitored by Karl Fischer titration. The average moisture content in the humidified vials rose to 4.9 %. The crystal structure of the cyclophosphamide was determined by differential scanning colorimetry.
Stability tests were carried out on the samples at temperatures of 35 °C, 25 °C and 15 °C, and the samples were assayed by HPLC after 7, 22 and 56 days. The results shown in the following Table were obtained.
Figure imgf000006_0001
EXAMPLE 2
For a batch of 100 vials containing 100 mg each of cyclophosphamide, a solution was prepared from the following ingredients:
Cyclophosphamide monohydrate 10.70 g
Dextran (mw=40,000) 6.00 g
Water for injection 0.4 ml
The preparation of the solution was similar to Example 1. The solution was dispensed into 10 ml vials provided with stoppers. The freeze-drying procedure was similar to Example 1 except that the chamber pressure was 0.05 mbar and drying time was 30 hours.
The average moisture content of 8 vials was 0.1 %. The endothermal peak temperatures of ten vials (DSC) were between 51.8-52.9 °C demonstrating that the cyclophosphamide was in anhydrous crystalline form. The contents of the vials could be reconstituted in water within a few seconds.
The stability tests were carried out on the samples at the temperature of 35 °C. After 21 days and 28 days 11 vials were tested with TLC (Thin Layer Chromatography) using chloroform-methanol-ammonia -solution (90:8:2) as eluent. No degradation was determined in any vial.

Claims

1. A storage-stable cyclophosphamide composition comprising, for each part by weight of cyclophosphamide (calculated as anhydrous cyclophosphamide), from 0.3 to 1.2 parts by weight of dextran.
2. A composition according to claim 1 comprising, for each part by weight of cyclophosphamide (calculated as anhydrous cyclophosphamide) from 0.4 to 1.0 parts by weight of dextran.
3. A composition according to claim 1 comprising, for each part by weight of cyclophosphamide (calculated as anhydrous cyclophosphamide) 0.5 to 0.6 parts by weight of dextran.
4. A composition according to claims 1 to 3 wherein the molecular weight of dextran is 40,000 to 120,000.
5. A composition according to claim 4 wherein the molecular weight of dextran is 40,000 to 70,000.
6. A composition according to any one of the preceding claims wherein cyclophosphamide is in essentially anhydrous crystalline form.
7. A storage-stable cyclophosphamide composition according to any one of the preceding claims made by lyophilization of an aqueous solution comprising the cyclophosphamide and the dextran.
8. A composition according to any one of the preceding claims in sterile unit dosage form.
PCT/FI1993/000390 1992-10-09 1993-09-30 Lyophilized cyclophosphamide compositions WO1994008592A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU48216/93A AU4821693A (en) 1992-10-09 1993-09-30 Lyophilized cyclophosphamide compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9221303A GB2271281A (en) 1992-10-09 1992-10-09 Stabilised cyclophosphamide compositions
GB9221303.2 1992-10-09

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WO1994008592A1 true WO1994008592A1 (en) 1994-04-28

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1951822A1 (en) * 1969-10-14 1971-04-22 Kowa Co Anti-cancer prepn
US4537883A (en) * 1982-11-12 1985-08-27 Mead Johnson & Company Lyophilized cyclophosphamide
EP0251657A2 (en) * 1986-06-26 1988-01-07 Cetus-Ben Venue Therapeutics Therapeutic compositions with galactitol as carrier
EP0394045A2 (en) * 1989-04-20 1990-10-24 Erbamont, Inc. Cyclophosphamide lyophilizates

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1951822A1 (en) * 1969-10-14 1971-04-22 Kowa Co Anti-cancer prepn
US4537883A (en) * 1982-11-12 1985-08-27 Mead Johnson & Company Lyophilized cyclophosphamide
EP0251657A2 (en) * 1986-06-26 1988-01-07 Cetus-Ben Venue Therapeutics Therapeutic compositions with galactitol as carrier
EP0394045A2 (en) * 1989-04-20 1990-10-24 Erbamont, Inc. Cyclophosphamide lyophilizates

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF PARENTERAL SCIENCE & TECHNOLOGY, Volume 42, No. 5, October 1988, T.R. KOVALCIK et al., "Stability of Cyclophosphamide in Lyophilized Cakes. II. Urea, Polyvinylpyrrolidone, and Dextran as Excipients", page 165 - page 173. *
STN INTERNATIONAL, File Biosis, STN Accession No. 85:334093, BATTISTO J.R. et al.: "Dextran Augments Delayed-Type Hypersensitivity by Interrupting 1 Limb of the Suppressor Cascade"; & J. IMMUNOL., 134 (4), 1985, 2131-2138. *
STN INTERNATIONAL, File CA, CHEMICAL ABSTRACTS, Volume 76, No. 3, 17 January 1972, (Columbus, Ohio, US), GROSFELD, J.L. et al.: "Potentiation of Radio-Mimetic Drugs in Transplanted Lung Carcinoma", Abstract No. 10383k; & CURR. TOP. SURG. RES., 3, 385-90, 1970. *

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GB2271281A (en) 1994-04-13
AU4821693A (en) 1994-05-09
GB9221303D0 (en) 1992-11-25

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