Pemetrexed formulations
The present invention is directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable after dilution for at least about 48 hours when stored at 2° C. to 8° C. The present invention is also directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable for at least about 24 months when stored at 2° C. to 8° C.
1. A method of treating pleural mesothelioma or non-squamous, non-small cell lung cancer in a patient in need thereof comprising
providing a liquid pharmaceutical composition consisting of:
20 mg/mL to 30 mg/mL of pemetrexed diacid;
200 mg/mL to 300 mg/mL of propylene glycol;
12 mg/mL to 24 mg/mL of tromethamine;
optionally HCl; and
water,
wherein the pH of the composition is from about 7.4 to 7.6, wherein the composition is suitable for multi-dose administration, and wherein the composition remains stable when stored for about 14 months at a temperature of 2° ° C. to 8° C. in a container having a head-space oxygen content of about 20% v/v, such that the composition comprises no more than 3% w/w of total impurities after said storage;
diluting the liquid composition with normal saline, water for injection, 5% dextrose in water, Ringer's Injection, or Lactated Ringer's Injection to form a diluted liquid composition; and
intravenously administering the diluted liquid composition to the patient.
2. The method of claim 1 , wherein the liquid pharmaceutical composition consists of:
25 mg/mL of the pemetrexed diacid;
250 mg/mL to 300 mg/mL of the propylene glycol;
17 mg/mL to 21 mg/mL of the tromethamine;
optionally HCl; and
water,
wherein the pH of the composition is from about 7.4 to 7.6.
3. The method of claim 1 , wherein the liquid pharmaceutical composition consists of:
25 mg/mL of the pemetrexed diacid;
250 mg/mL to 300 mg/mL of the propylene glycol;
18 mg/mL to 20 mg/mL of the tromethamine;
optionally HCl; and
water,
wherein the pH of the composition is from about 7.4 to 7.6.
4. The method of claim 1 , wherein the liquid composition is in a vial.
5. The method of claim 4 , wherein the vial is a multi-dose vial.
6. A method of treating pleural mesothelioma in a patient in need thereof comprising
providing a liquid pharmaceutical composition consisting of:
20 mg/mL to 30 mg/mL of pemetrexed diacid;
200 mg/mL to 300 mg/mL of propylene glycol;
12 mg/mL to 24 mg/mL of tromethamine;
optionally HCl; and
water,
wherein the pH of the composition is from about 7.4 to 7.6, wherein the composition is suitable for multi-dose administration, and wherein the composition remains stable when stored for about 14 months at a temperature of 2° C. to 8° C. in a container having a head-space oxygen content of about 20% v/v, such that the composition comprises no more than 3% w/w of total impurities after said storage;
diluting the liquid composition with normal saline, water for injection, 5% dextrose in water, Ringer's Injection, or Lactated Ringer's Injection to form a diluted liquid composition; and
intravenously administering the diluted liquid composition to the patient.
7. The method of claim 6 , wherein the liquid pharmaceutical composition consists of:
25 mg/mL of the pemetrexed diacid;
250 mg/mL to 300 mg/mL of the propylene glycol;
17 mg/mL to 21 mg/mL of the tromethamine;
optionally HCl; and
water,
wherein the pH of the composition is from about 7.4 to 7.6.
8. The method of claim 6 , wherein the liquid pharmaceutical composition consists of:
25 mg/mL of the pemetrexed diacid;
250 mg/mL to 300 mg/mL of the propylene glycol;
18 mg/mL to 20 mg/mL of the tromethamine;
optionally HCl; and
water,
wherein the pH of the composition is from about 7.4 to 7.6.
9. The method of claim 6 , wherein the liquid composition is in a vial.
10. The method of claim 9 , wherein the vial is a multi-dose vial.
11. A method of treating non-squamous, non-small cell lung cancer in a patient in need thereof comprising
providing a liquid pharmaceutical composition consisting of:
20 mg/mL to 30 mg/mL of pemetrexed diacid;
200 mg/mL to 300 mg/mL of propylene glycol;
12 mg/mL to 24 mg/mL of tromethamine;
optionally HCl; and
water,
wherein the pH of the composition is from about 7.4 to 7.6, wherein the composition is suitable for multi-dose administration, and wherein the composition remains stable when stored for about 14 months at a temperature of 2° ° C. to 8° C. in a container having a head-space oxygen content of about 20% v/v, such that the composition comprises no more than 3% w/w of total impurities after said storage;
diluting the liquid composition with normal saline, water for injection, 5% dextrose in water, Ringer's Injection, or Lactated Ringer's Injection to form a diluted liquid composition; and
intravenously administering the diluted liquid composition to the patient.
12. The method of claim 11 , wherein the liquid pharmaceutical composition consists of:
25 mg/mL of the pemetrexed diacid;
250 mg/mL to 300 mg/mL of the propylene glycol;
17 mg/mL to 21 mg/mL of the tromethamine;
optionally HCl; and
water,
wherein the pH of the composition is from about 7.4 to 7.6.
13. The method of claim 11 , wherein the liquid pharmaceutical composition consists of:
25 mg/mL of the pemetrexed diacid;
250 mg/mL to 300 mg/mL of the propylene glycol;
18 mg/mL to 20 mg/mL of the tromethamine;
optionally HCl; and
water,
wherein the pH of the composition is from about 7.4 to 7.6.
14. The method of claim 11 , wherein the liquid composition is in a vial.
15. The method of claim 14 , wherein the vial is a multi-dose vial.