GB2365768A - Stable liquid composition containing pemetrexed - Google Patents

Stable liquid composition containing pemetrexed Download PDF

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Publication number
GB2365768A
GB2365768A GB0019599A GB0019599A GB2365768A GB 2365768 A GB2365768 A GB 2365768A GB 0019599 A GB0019599 A GB 0019599A GB 0019599 A GB0019599 A GB 0019599A GB 2365768 A GB2365768 A GB 2365768A
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United Kingdom
Prior art keywords
pharmaceutical composition
concentration
monothioglycerol
cysteine
formulation
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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.)
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GB0019599A
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GB0019599D0 (en
Inventor
Bernd Riebesehl
Jens Kemken
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Lilly Forschung GmbH
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Lilly Forschung GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Lilly Forschung GmbH filed Critical Lilly Forschung GmbH
Priority to GB0019599A priority Critical patent/GB2365768A/en
Publication of GB0019599D0 publication Critical patent/GB0019599D0/en
Priority to CN01804441A priority patent/CN1396828A/en
Priority to DZ013269A priority patent/DZ3269A1/en
Priority to US10/181,379 priority patent/US6686365B2/en
Priority to NZ519727A priority patent/NZ519727A/en
Priority to JP2001556474A priority patent/JP2003521518A/en
Priority to SK1098-2002A priority patent/SK10982002A3/en
Priority to CA002399124A priority patent/CA2399124A1/en
Priority to DK01906523T priority patent/DK1265612T3/en
Priority to IL15047501A priority patent/IL150475A0/en
Priority to PT01906523T priority patent/PT1265612E/en
Priority to MXPA02007191A priority patent/MXPA02007191A/en
Priority to TR2004/01436T priority patent/TR200401436T4/en
Priority to PL01356705A priority patent/PL356705A1/en
Priority to BR0107958-1A priority patent/BR0107958A/en
Priority to ES01906523T priority patent/ES2220716T3/en
Priority to AU34422/01A priority patent/AU3442201A/en
Priority to CZ20022654A priority patent/CZ20022654A3/en
Priority to KR1020027009930A priority patent/KR20020081293A/en
Priority to AT01906523T priority patent/ATE267601T1/en
Priority to DE60103512T priority patent/DE60103512T2/en
Priority to SI200130113T priority patent/SI1265612T1/en
Priority to PCT/US2001/000648 priority patent/WO2001056575A1/en
Priority to EP01906523A priority patent/EP1265612B1/en
Priority to HU0300709A priority patent/HUP0300709A3/en
Priority to EA200200831A priority patent/EA004708B1/en
Priority to MYPI20010433A priority patent/MY129450A/en
Priority to CO01007346A priority patent/CO5280222A1/en
Priority to PE2001000116A priority patent/PE20011223A1/en
Priority to ARP010100507A priority patent/AR027360A1/en
Priority to SV2001000301A priority patent/SV2002000301A/en
Publication of GB2365768A publication Critical patent/GB2365768A/en
Priority to NO20023379A priority patent/NO20023379L/en
Priority to HR20020636A priority patent/HRP20020636A2/en
Priority to HK03103377A priority patent/HK1052461A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A pharmaceutical composition comprising pemetrexed; at least one antioxidant selected from the group consisting of monothioglycerol, L-cysteine, and thioglycolic acid; and a pharmaceutically acceptable excipient. The pharmaceutical formulation is suitable for liquid parenteral administration.

Description

<Desc/Clms Page number 1> PHARMACEUTICAL COMPOSITION The present invention relates to a liquid composition comprising the known compound pernetrexed, in particular, the present invention relates to a liquid composition comprising pernetrexed and an antioxidant; which liquid composition is stable and pharmaceutically elegant.
Certain folic acid antimetabolites are known to be antineoplastic agents. These compounds inhibit enzymatic conversion involving metabolic derivatives of folic acid. One such compound, described by United States Patent 5,473,07 1, is currently being developed for potential use as a pharmaceutical agent. This compound, known as "pemetrexed", is most desirably formulated into a concentrated liquid for administration as an infusion dosage form. Pernetrexed Disodium is the active ingredient in the anticancer drug ALRv1TA now in clinical development by Eli Lilly and Company.
The formulation teachings of the US Patent 5,473,071 provide that the compounds claimed therein can be administered parenterally, and that isotonic saline solutions containing 20-100 mg/ml can be used for parenteral administration.
A ready to use stable solution that could be stored at room temperature is particularly desired for a pharmaceutical such as pemetrexed, wherein such ready to use formulation provides easier, safer handling, storage, and distribution. Further, a stable, ready to use formulation is more acceptable to the customer.
It was discovered that a simple, isotonic saline solution of pernetrexed is not pharmaceutically acceptable for commercial purposes due to degradation of the solution to form unacceptable related substances. It has now been discovered that pharmaceutically acceptable, concentrated, ready to use, liquid solutions of pernetrexed may be prepared when the formulation includes certain antioxidants, including monothioglycerol, L-cysteine, and thioglycolic acid. Other antioxidants were studied; however, surprisingly, of the antioxidants studied, only these provided the desired formulation characteristics described herein.
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The claimed formulation exhibits acceptable stability, retains a pharmaceutically desirable appearance, maintains the desired enatiomeric stability, and fulfils the health care provider's desire for a stable, ready to use liquid formulation. Additionally, the formulation provided herein, is suitable for parenteral dosage, can be delivered to the health care provider in a clear vial and can be stored at temperatures above 4 (four) Celcius in a highly concentrated state.
The present invention addresses the need for a pharmaceutically stable liquid pernetrexed formulation having both color stability and acceptable shelf life stability with regard to retaining the solution dosage form and avoiding unacceptable degradation to undesired related substances. Additionally, the claimed formulations can be diluted to the desired administration concentration by the health care provider. Finally, the formulations provided herein do not require the addition of any preservative, other than the antioxidant, in order to retain the desired concentration and stability.
The present invention particularly provides a pharmaceutical composition comprising: a) pernetrexed; b) at least one antioxidant selected from the group consisting of i) monothioglycerol, ii) L-cysteine, iii) thioglycolic acid; and c) a pharmaceutically acceptable excipient.
The three antioxidants are uniquely effective for the claimed formulation. Surprisingly, common antioxidants, such as sodium metabisulfite, ascorbic acid, sodium EDTA, monoethanolamine gentisate, sodium formaldehyde sulfoxylate, sodium bisulfite, did not provide the desired formulation characteristics.
An especially preferred antioxidant is monothioglycerol.
The concentration of monothioglycerol is most preferably from about I part per million to 8.0 mg/ml, which concentration may be optimized for a given formulation based on the oxygen concentration contacting the formulation. The
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concentration of monothioglycerol may preferably be at least 0.6 mg/ml, more preferably at least 0.8 mg/ml, especially preferably is at least 1.0 mg/ml. The concentration of monothioglycerol is preferably up to 6 mg/ml, more preferably up to 5 mg/ml, and most preferably is up to 3 mg/ml.
It may be preferred that the concentration of monothioglycerol is from about 0.6 mg/ml to about 6 mg/ml. More preferably, the concentration of monothioglycerol is from about 0.8 mg/ml to about 5.0 mg/ml. It is especially preferred that the concentration of monothioglycerol is at least 1.0 mg./ml. An especially desired concentration is from 1.40 mg/ml to about 3.0 mg/ml. A further desired concentration is from about 2 mg/ml to about 3 mg/ml. A further preferred concentration of monothioglycerol is from about 1.2 mg/ml to about 2.4 mg/ml.
In general, the concentration of monothioglycerol, L-cysteine or Thioglycolic acid is most preferably from about 1 part per million to 8.0 mg/ml., which concentration may be optimized for a given formulation based on the oxygen concentration contacting the formulation. L-cysteine or thioglycerol are often most effective at a higher pH. It may be preferred that the concentration of monothioglycerol, L-cysteine or Thioglycolic acid is from about 1.0 mg/ml. to about 6 mg/ml. More preferably, the concentration of monothioglycerol, L-cysteine or Thioglycolic acid is from about 0.8 mg/ml to about 5.0 mg/ml. It is especially preferred that the concentration of monothioglycerol, L-cysteine or Thioglycolic acid is at least 1.0 mg./ml. An especially desired concentration for monothioglycerol, L- cysteine or Thioglycolic acid is from 1.40 mg/ml to about 3.0 mg/ml. A further desired concentration is from about 2 mg/ml to about 3 mg/ml. A further preferred concentration of monothioglycerol, L-cysteine or Thioglycolic acid is from about 1.2 mg/ml to about 2.4 mg/ml. It is preferred to have a concentration of from about 0. 1 (one tenth) mg/ml to 7 mg/ml. When the antioxidant is monothioglycerol. or L- cycsteine, the preferred concentration range is from about 0. 1 (one tenth)mg/ml to about 10.0 mg/ml.
The concentration of L-cysteine is preferably greater than 0. 1 (one tenth) mg/ml, more preferably greater than 0.5 (one half) mg/ml and most preferably greater than 1 (one) mg/ml.
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The concentration of L-cysteine is preferably less than 10 (ten) mg/ml, more preferably less than 8 (eight) mg/ml, and most preferably less than 6 (six) mg/ml.
The concentration of thioglycolic acid is preferably greater than 0.1 (one- tenth) mg/ml, more preferably greater than 0.5 (one-half) mg/ml and most preferably greater than I (one) mg/ml.
The concentration of thioglycolic acid is preferably less than 10 (ten) mg/ml, more preferably less than 8 (eight) mg/ml, and most preferably less than 6 (six) mg/ml.
Additionally, combinations of the three antioxidants, selected from monothioglycerol, L-cysteine and thioglycerol, may also be used in this invention. The concentration of pernetrexed is preferably from about 20 to about 100 mg/ml. It is especially preferred that the pernetrexed concentration is from about 30 mg/ml to about 70 mg/ml. A further preferred embodiment is when the pernetrexed concentration is from about 35 mg/ml to about 50 mg/ml. A further preferred embodiment is a pernetrexed concentration of from 38 mg/ml to about 44 mg/ml. An especially desired concentration of pemetrexed is about 40 mg/ml.
As used herein, the term "pemetrexed" refers to the stable salts, acids and free base forms thereof. The term includes, for example, the free acid, the pharmaceutically acceptable alkali metal, alkaline earth metal, non-toxic metal, ammonium, and substituted ammonium salts, such as for example, the sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, monoethanolammonium, triethanolammonium, pyridinium, substituted pyridinium, and the like. The substituted ammonium salts are one especially preferred group of salts.
As used herein, the term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable formulation carrier, solution or additive to enhance the formulation characteristics. Such additives are well known to the skilled artisan. While any pharmaceutically acceptable diluent is suitable, an especially preferred excipient for parenteral administration is saline solution. For example, sodium chloride, mannitol and the like.
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The disodium salt of pernetrexed is particularly preferred for use in the present formulation.
The pH of the formulation is most preferably from about 5.5 to about 12. The formulation is more preferably from about pH 7 to about 11. It is especially desired that the pH of the forinulation is from 8.0 to 9.0. It is further preferred that the pH is from about 8 to about 9 when the antioxidant is monothioglycerol. When the antioxidant is L-cysteine or thioglycolic acid or any salt form thereof, then the preferred pH is about 8 to about 10. The artisan will appreciate that combinations of these antioxidants can provide new preferred pH ranges. Standard modifications of the composition can provide compositions of various pH within the contemplation of this invention.
It. is generally preferred that the process for preparing the formulation includes the use of a purge of an inert gas. Such inert gases are for example, nitrogen, argon, and the like. The use of an isolator to maintain low oxygen conditions is desirable, but not required for storage of the present formulation.
While any pharmaceutically acceptable stopper may be used to seal the vial containing the formulation, it is preferred to seal the vial with a stopper which is siliconized. A sterlized teflon coated stopper is desired for sealing the storage vial.
Most pharmaceutically acceptable liquid formulation vials or containers can be used to dispense the claimed formulation. It is desired that the containing vessel minimizes the concentration of oxygen that reaches the formulation. Thus, vials or ampules are especially desired vessels for the claimed formulation. A sealed vial is especially desired for commercial purposes in most countries.
The artisan will appreciate that the use of depyrogenated prewashed vials is desired for the storage of a sterile liquid formulation that is intended for parenteral use. The vial may be colored; however, a clear vial is acceptable for storage of the formulation. Any pharmaceutically acceptable material may be used to make the formulation container; however, glass is an especially preferred container material. A glass vial is a preferred container. Other packaging materials for parenterals like plastic vials are preferred options as well. For example, plastic vials may be useful.
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It may be desirable to protect the bulk solution from light during the process of preparing the formulation; however, such protection is not required for the present forinulation.
The resulting formulation can be sterlized using methods known to the artisan. Such sterilisation methods may include, for example, sterile filtration or heating. It is especially beneficial that the presently claimed formulation is stable during heat sterilization. It is preferred that the headspace of the vial contains less than about 8% (eight percent) v/v Oxygen; however, the headspace of the vial may contain more than 8% oxygen if other conditions of the formulation are appropriately adjusted. It is more preferred that the headspace of the vial contains from about 2% to about 5% Oxygen. It is especially preferred that the headspace contains from about 3% to about 5% Oxygen. It is further preferred that the headspace contains less than about one (1) ppm oxygen. Also, preferred is when the headspace oxygen content is less than about 0. 1% (one tenth percent ) v/v oxygen. It is also a prefer-red condition that the headspace of the vial is less than about 1% (one percent) oxygen.
The headspace of the vial can be adjusted to minimize the formulation contact with oxygen. It is generally desired that the headspace is not more than about 1/3 (one third) of the total volume of the container, with the fill taking at least about 2/3 (two thirds) of the total volume of the container. For example, it may be preferred that 5 ml of fill be used for a 7.5 ml vial. If a greater headspace ratio to fill is desired, then the concentration of the antioxidant may be adjusted as necessary.
The pharmaceutical formulation provided herein is suitable for both human clinical use and veterinarian use for animals.
Pernetrexed can be prepared using the processes described in United States Patent 5,473,07 1, hereby incorporated by reference in its entirety. Compositions of pemetrexed are useful to treat cancer, as described in the 5,473,071 patent as well as in Seminars in Oncology, Vol. 26, No. 2, Supplement 6 (April 1999).
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Monothioglycerol is conu-nercially available from suppliers of fine chemicals which are well known to the artisan. To further clarify, Monothioglycerol is Chemical Abstracts number. 96-27-5.
Likewise, L-cysteine (CAS: 52-90-4), L-cysteine hydrochloride monohydrate (CAS: 7048-04-6), L-cycsteine hydrochloride monohydrate anhydrous (CAS: 52-89- 1) and thioglycolic acid (CAS:68-1 1-1) are readily obtained from suppliers of fine chemicals.
Description of Preferred Embodiments.
The Present invention is seen more fully by the examples given below. Example I Pemetrexed, was prepared as a 40 mg/mI solution in water. Monothioglycerol was prepared as a 2.4 mg/mI solution using water for injection. The pH of the monothioglycerol solution was adjusted to 8.5 using sodium hydroxide.
The bulk solution was protected from light. The solution was purged with nitrogen for twenty minutes and then sterile filtered. The formulation was dispensed into prewashed, depyrogenated vials and then stoppered with a prewashed, presterilized teflon coated stopper. Caps were attached using a crimper. The sterile filtration and dispensing steps were conducted using a nitrogen isolator (5% v/v Oxygen).
The solution filled vials were heat sterlized. Example 2 A pharmaceutical composition was prepared substantially as described herein by Example 1, except that the antioxidant was 0.03% L-Cysteine and the pernetrexed concentration was four percent (4%).
Example 3 A pharmaceutical composition was prepared substantially as described herein by Example 1, except that the antioxidant was 0.03% Thioglycolate and the pemetrexed concentration was four percent (4%).
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Claims (20)

  1. We Claim: 1. A phannaceutical composition comprising: a) pemetrexed; b) at least one antioxidant selected from the group consisting of: C) monothioglycerol, ii) L-cysteine, and iii) thioglycolic acid; and c) a pharmaceutically acceptable excipient.
  2. 2. A pharmaceutical composition as claimed by Claim I wherein the composition is a liquid formulation suitable for parenteral administration.
  3. 3. A pharmaceutical composition as claimed by any one of Claims 1 and 2 wherein pemetrexed is the disodium salt.
  4. 4. A pharmaceutical composition as claimed by any one of Claims I to 3 wherein the antioxidant is monothioglycerol.
  5. 5. A pharmaceutical composition as claimed in any one of Claims I to 4 wherein the monothioglycerol concentration is from about I (one) part per million to about 8 (eight) milligrams per milliliter.
  6. 6. A pharmaceutical composition of Claim 5 wherein the monothioglycerol concentration is from about I (one) mg/ml to about 6 (six) mg/ml.
  7. 7. A pharmaceutical composition of Claim 6 wherein the monothioglycerol concentration is from about 1 (one) mg/ml to about 2.5 (two and one half) mg/ml.
  8. 8. A pharmaceutical composition of Claim 4 wherein the monothioglycerol concentration is from about 0.5 (one half) mg/mI to about 3 (three) mg/ml.
    <Desc/Clms Page number 9>
  9. 9. A pharmaceutical composition as claimed by any one of Claims I to 3 wherein the antioxidant is L-cysteine.
  10. 10. A pharmaceutical composition of Claim 9 wherein the L-cysteine concentration is from about 1 (one) part per million to about 8 (eight) mg/ml.
  11. 11. A pharmaceutical composition of Claim 10 wherein the L-cysteine concentration is from about 1 (one) mg/ml to about 6 (six) mg/ml.
  12. 12. A pharmaceutical composition of Claims I to 3 wherein the antioxidant is thioglycolic acid.
  13. 13. A pharmaceutical composition of Claim 12 wherein the thioglycolic acid concentration is from about 1 (one) part per million to about 8 (eight) mg/ml.
  14. 14. A pharmaceutical composition of Claim 13 wherein the thioglycolic acid concentration is. from about 0. 1 (one-tenth) mg/ml to about 6 (six) mg/ml.
  15. 15. A phan-naceutical composition of Claim 4 wherein the monothioglycerol concentration is from about 0. 1 (one tenth) mg/ml to about 10 (ten) mg/ml.
  16. 16. A pharmaceutical composition of Claim 15 wherein the monothioglycerol concentration is from about 0. 1 (one tenth) mg/ml to about 6 (six) mg/ml.
  17. 17. A pharmaceutical composition of Claim 9 wherein the L-cysteine is from about 0. 1 (one tenth) mg/mI to about 10 (ten) mg/ml.
  18. 18. A pharmaceutical composition of Claim 17 wherein the L-cysteine is from about 0. 1 (one tenth) mg/mI to about 6 (six) mg/ml.
    <Desc/Clms Page number 10>
  19. 19. A pharmaceutical composition of Claim 12 wherein the thloglycolic acid is from about 0. 1 (one tenth) mg/ml to about 10 (ten) mg/ml.
  20. 20. A pharmaceutical composition of Claim 19 wherein the thioglycolic acid is from about 0. 1 (one tenth) mg/ml to about 6 (six) mg/ml.
GB0019599A 2000-02-04 2000-08-09 Stable liquid composition containing pemetrexed Withdrawn GB2365768A (en)

Priority Applications (34)

Application Number Priority Date Filing Date Title
GB0019599A GB2365768A (en) 2000-08-09 2000-08-09 Stable liquid composition containing pemetrexed
EA200200831A EA004708B1 (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid
AU34422/01A AU3442201A (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid
KR1020027009930A KR20020081293A (en) 2000-02-04 2001-01-23 Pharmaceutical Composition Comprising Pemetrexed Together With Monothioglycerol L-Cystein or Thioglycolic Acid
US10/181,379 US6686365B2 (en) 2000-02-04 2001-01-23 Pharmaceutical composition
DZ013269A DZ3269A1 (en) 2000-02-04 2001-01-23 PHARMACEUTICAL COMPOSITION COMPRISING PEMETREXED WITH MONOTHIOGLYCEROL, CYSTEIN L OR THIOGLYCOLIC ACID
JP2001556474A JP2003521518A (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrex together with monothioglycerol, L-cysteine or thioglycolic acid
AT01906523T ATE267601T1 (en) 2000-02-04 2001-01-23 PHARMACEUTICAL COMPOSITION CONTAINING PEMETREXED TOGETHER WITH MONOTHIOGLYCEROL, L-CYSTEINE OR THIOGLYCOLIC ACID
CA002399124A CA2399124A1 (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid
DK01906523T DK1265612T3 (en) 2000-02-04 2001-01-23 A pharmaceutical composition comprising pemetrexed and monothioglycerol, l-cysteine or thioglycolic acid
IL15047501A IL150475A0 (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid
PT01906523T PT1265612E (en) 2000-02-04 2001-01-23 PHARMACEUTICAL COMPOSITION UNDERSTANDING PEMETREXED CONVENIENTLY WITH MONOTIOGLICEROL L-CYSTEIN OR THYROGLYCOLIC ACID
MXPA02007191A MXPA02007191A (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol l cystein or thioglycolic acid.
TR2004/01436T TR200401436T4 (en) 2000-02-04 2001-01-23 Pharmaceutical composition containing pemetrexed with monothioglycerol, L-system or thioglycolic acid
PL01356705A PL356705A1 (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid
BR0107958-1A BR0107958A (en) 2000-02-04 2001-01-23 Pharmaceutical composition containing pemetrexate together with l-cysteine monotrioglycerol or thioglycolic acid
ES01906523T ES2220716T3 (en) 2000-02-04 2001-01-23 PHARMACEUTICAL COMPOSITION THAT INCLUDES PEMETREXED WITH MONOTIOGLYCEROL, L-CYSTEINE AND THIOGLYCOLIC ACID.
CN01804441A CN1396828A (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising Pemetrexed together with monothioglycerol L-cystein or thioglycolic acid
CZ20022654A CZ20022654A3 (en) 2000-02-04 2001-01-23 Pharmaceutical composition containing Pemetrexed along with monothioglycerol, L-cysteine or thioglycolic acid
NZ519727A NZ519727A (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol L-cysteine or thioglycolic acid
SK1098-2002A SK10982002A3 (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol L-cystein or thioglycolic acid
DE60103512T DE60103512T2 (en) 2000-02-04 2001-01-23 PHARMACEUTICAL COMPOSITION COMPRISING PEMETREXED WITH MONOTHIOGLYCEROL, L-CYSTEIN OR THIOGLYCOLIC ACID
SI200130113T SI1265612T1 (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol, l-cystein or thioglycolic acid
PCT/US2001/000648 WO2001056575A1 (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid
EP01906523A EP1265612B1 (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothioglycerol, l-cystein or thioglycolic acid
HU0300709A HUP0300709A3 (en) 2000-02-04 2001-01-23 Pharmaceutical composition comprising pemetrexed together with monothiaglycerol l-cystein or thioglycolic acid
MYPI20010433A MY129450A (en) 2000-02-04 2001-01-31 Pharmaceutical composition
CO01007346A CO5280222A1 (en) 2000-02-04 2001-02-01 PHARMACEUTICAL COMPOSITION THAT PEMETREXED INCLUDES
PE2001000116A PE20011223A1 (en) 2000-02-04 2001-02-01 PHARMACEUTICAL COMPOSITION INCLUDING PEMETREXED AND AN ANTIOXIDANT SUCH AS MONOTHIOGLYCEROL, L-CYSTEINE AND THIOGLICOLIC ACID
ARP010100507A AR027360A1 (en) 2000-02-04 2001-02-02 PHARMACEUTICAL COMPOSITION
SV2001000301A SV2002000301A (en) 2000-02-04 2001-02-02 PHARMACEUTICAL COMPOSITION REF. Z-1032
NO20023379A NO20023379L (en) 2000-02-04 2002-07-12 A pharmaceutical composition comprising premetrexed together with monothioglycerol L-cysteine or thioglycolic acid
HR20020636A HRP20020636A2 (en) 2000-02-04 2002-07-26 Pharmaceutical composition comprising pemetrexed with monothioglycerol l-cystein or thioglycolic acid
HK03103377A HK1052461A1 (en) 2000-02-04 2003-05-13 Pharmaceutical composition comprising pemetrexed together with monothioglycerol, l-cystein or thioglycolic acid.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB0019599A GB2365768A (en) 2000-08-09 2000-08-09 Stable liquid composition containing pemetrexed

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GB0019599D0 GB0019599D0 (en) 2000-09-27
GB2365768A true GB2365768A (en) 2002-02-27

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GB (1) GB2365768A (en)

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