Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-04
2004-02-03
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06686365
ABSTRACT:
The present invention relates to a liquid composition comprising the known compound pemetrexed, in particular, the present invention relates to a liquid composition comprising pemetrexed 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 U.S. Pat. No. 5,344,932, 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. Pemetrexed Disodium is the active ingredient in the anticancer drug ALIMTA now in clinical development by Eli Lilly and Company.
The formulation teachings of the U.S. Pat. No. 5,344,932 provide that the compounds claimed therein can be administered parenterally.
A ready to use, stable, ready to reconstitute 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. It is particularly desirable if the stable formulation can be prepared without the use of freeze drying techniques. The desired liquid formulation can offer enhanced safety for caregiver handling of the cytotoxic materials. Further, a stable, ready to use formulation is more acceptable to the customer.
It was discovered that a simple, isotonic saline solution of pemetrexed 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 pemetrexed 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.
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 pemetrexed 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) pemetrexed;
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 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. The 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 thioglycolic acid 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.
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 1 (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 pemetrexed is preferably from about 20 to about 100 mg/ml. It is especially preferred that the pemetrexed concentration is from about 30 mg/ml to about 70 mg/ml. A further preferred embodiment is when the pemetrexed concentration is from about 35 mg/ml to about 50 mg/ml. A further preferred embodiment is a pemetrexed 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, th
Kemken Jens
Riebesehl Bernd Ulrich
Eli Lilly and Company
McGraw Elizabeth A.
Reamer James H.
Vorndran-Jones MaCharri R.
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