GB2591681A

GB2591681A - Methotrexate pharmaceutical composition

Info

Publication number: GB2591681A
Application number: GB2104388.0A
Authority: GB
Inventors: Prajapati Hardik; Mehta Sandip; Umrethia Manish; Kumar Mandal Jayanta
Original assignee: FTF Pharma Pvt Ltd
Current assignee: FTF Pharma Pvt Ltd
Priority date: 2018-08-29
Filing date: 2019-08-29
Publication date: 2021-08-04
Also published as: WO2020044114A2; GB202104388D0; WO2020044114A3

Abstract

Though oral liquid formulations of Methotrexate are advantageous as they can suitably be administered to the patients having swallowing difficulties such as pediatric patients, geriatric patients, stroke patients or patients who are unable to take solid oral therapy, they are not much explored in the prior art. Further, liquid formulations of Methotrexate known in the prior art have not been explored at higher pH and in the absence of additional solubilizing agents. An aim of the present invention is therefore to provide chemically and physically stable liquid pharmaceutical compositions of Methotrexate at higher pH and in the absence of solubilizing agents.

Claims

WE CLAIM:

1. A Methotrexate liquid composition, suitable for oral administration, comprising Methotrexate and one or more preservatives, one or more buffering agents, one or more sweetening agents and an aqueous vehicle, wherein the pH of the composition is between about 7.5 and about 9.0.

2. A Methotrexate liquid composition according to claim 1, wherein one or more buffering agents comprises any or any combination of Acetic acid, Adipic acid, Ammonium carbonate, Ammonium hydroxide, Ammonium phosphate, Boric acid, Citric acid, Citric acid monohydrate Diethanolamine, Fumaric acid, Hydrochloric acid, Malic acid, Nitric acid, Propionic acid, Potassium acetate, Potassium bicarbonate, Potassium chloride, Potassium citrate, Potassium metaphosphate, Potassium phosphate, Sodium acetate, Sodium bicarbonate, Sodium borate, Sodium carbonate, Sodium chloride, Sodium citrate, Sodium glycolate, Sodium hydroxide, Sodium lactate, Sodium phosphate, Sodium proprionate, Succinic acid, Sulfuric acid, Tartaric acid, Triethylamine, Triethanolamine, Tromethamine (Tris/Trometamol), Trolamine.

3. A Methotrexate liquid composition according to claim 1, wherein the composition comprises two or more buffer agents to form a buffer system.

4. A Methotrexate liquid composition according to claim 3, wherein the two or more buffer agents are Tris (Trometamol)-Citric Acid Monohydrate Buffer.

5. A Methotrexate liquid composition according to claim 1, wherein one or more preservatives are selected from the group comprising of Alcohol, Ethanol, Chlorobutanol, Phenoxyethanol, Potassium benzoate, Benzyl alcohol, Benzoic acid, Potassium sorbate, Sorbic acid, Benzalkonium chloride, Benzethonium chloride, Cetrimonium bromide, Cetylpyridinium chloride, Bronopol, Chlorbutol, Chlorocresol, Cresol, Butylparaben (butyl 4-hydroxybenzoate) or salt thereof, Methylparaben (methyl 4-hydroxybenzoate) or salt thereof, Propylparaben (propyl 4-hydroxybenzoate) or salt thereof, Ethylparaben (ethyl 4- hydroxybenzoate) or salt thereof, Phenol, Thymol, Phenyl ethanol, Sodium benzoate, Antimicrobial solvents like Propylene glycol, Glycerin, Chloroform or any combinations thereof.

6. A Methotrexate liquid composition according to claim 1, wherein one or more sweetening agents are selected from the group comprising of Glucose, Sucralose, Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose, Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol, Xylitol, Saccharine or the corresponding sodium, potassium or calcium salt, Cyclamate or the corresponding sodium or calcium salt, Aspartame, or Acesulfame or the potassium salt thereof, Dulcin or Ammonium glycyrrhizinate, Alitame, Inulin, Isomalt, Neohesperidin dihydrochalcone, Thaumatin or any combinations thereof.

7. A Methotrexate liquid composition according to claim 1 optionally comprises flavoring agent selected from the group comprising of cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot or any combinations thereof.

8. A Methotrexate liquid composition according to claim 1, wherein the pharmaceutically acceptable dosage of the Methotrexate used is 2.5 mg/5 ml, 5 mg/5 ml, 10 mg/5 ml or in the range of 0.05 mg/l ml to 20 mg/l ml.

9. A Methotrexate liquid composition according to claim 1 comprising: a. 0.05-20 mg Methotrexate free acid; b. Tris (trometamol)-Citric acid buffer system; c. Sodium methyl 4-hydroxy benzoate; d. Sodium propyl 4-hydroxy benzoate; e. Sucralose; and f. Purified water

10. A Methotrexate liquid composition according to claim 1, wherein the composition is stable for prolonged time when stored under typical storage conditions and/or accelerated conditions characterized in that any individual impurity present in the liquid composition is less than about 3.0% and the total impurities present in the liquid composition are less than about 5.0%.

11. A Methotrexate liquid composition according to claim 1, wherein the composition has: (a) a Cmax for Methotrexate, when assayed in the plasma of a mammalian subject following administration that is at least about 50% to about 150% greater than the Cmax for Methotrexate marketed or known formulation, administered at the same dose; (b) an AUC for Methotrexate, when assayed in the plasma of a mammalian subject following administration that is at least about 25% to about 200% greater than the AUC for Methotrexate marketed or known formulation, administered at the same dose; (c) a Tmax for Methotrexate, when assayed in the plasma of a mammalian subject following administration that is less than about 6 hours to about 8 hours; or (d) any combination of (a), (b), and (c).

12. A process for the preparation of the Methotrexate liquid composition according to claim 1 comprising following steps: dissolve sodium methyl 4-hydroxy benzoate and sodium propyl 4-hydroxy benzoate in the required quantity of purified water; add Tris-citric acid buffer in step (1) under stirring to adjust the pH of the mixture obtained in step (1) between about 7.5 and about 9.0; dissolve Methotrexate in the mixture obtained in step (2); dissolve sucralose in the mixture obtained in step (3); and adjust the volume of the mixture obtained in step (4) to the total batch size with purified water.

13. A Methotrexate liquid composition according to claim 1 for use as a folic acid antagonist, as an anti -neoplastic agent, an immunosuppressant, an anti- metabolite, or for use in the treatment of at least one condition selected from the group comprising of spondyloarthropathies, systemic dermatomyositis, severe, recalcitrant psoriasis, including psoriatic arthritis that is not adequately responsive to other forms of therapy, rheumatoid arthritis, seronegative arthritis, adult rheumatoid arthritis systemic dermatomyositis, Crohnâ s disease, multiple sclerosis, polyarthritic forms of severe, active juvenile idiopathic arthritis, resistant juvenile rheumatoid arthritis, graft versus host disease, lupus, morphea (also known as localized scleroderma), ankylosing spondylitis and other autoimmune diseases, and in the treatment of a wide range of neoplastic conditions, such as mycosis fungoides, haemoblastosis, trophoblastic neoplasms, acute lymphoblastic leukaemia, prophylaxis of meningeal leukaemia, Non-Hodgkinâ s lymphomas, osteogenic sarcoma, breast cancer, head and neck cancer, choriocarcinoma and similar trophoblastic diseases, lung cancer, bladder cancer, adult soft tissue sarcoma, and various other malignant tumours or any other condition wherein the patient requires Methotrexate therapy.

14. A Methotrexate liquid composition according to claim 1 is packaged in the pharmaceutically acceptable packaging material selected from the group comprising of containers, pumps, bottles with spray pump, bottles with dropper assembly, bottles, collapsible tubes, glass ampoules, stoppered vials, pre-filled syringes, wherein the bottles and containers are clear or transparent or opaque or amber colored glass bottles and containers or clear or transparent or opaque or amber colored plastic bottles and containers made from polyethylene, low-density polyethylene, high-density polyethylene, polyamide, polyolefin, polycarbonate, acrylic multipolymers, polypropylene, polyethylene terephthalate, polyvinyl chloride, polystyrene.