METHOTREXATE FORMULATION

Abstract

A liquid pharmaceutical composition comprises methotrexate free acid and a buffer, wherein the pH of the composition is in the range of 6.5 to 8.2. Processes for preparation of the liquid pharmaceutical composition are also described. The liquid pharmaceutical composition is useful in therapy.

Claims

1. A liquid pharmaceutical composition comprising methotrexate free acid and a buffer, wherein the pH of the composition is in the range of 6.5 to 8.2

2. A composition according to claim 1, wherein the pH of the composition is 6.6, 6.7, 6.8, 6.9 or 7.

3. A composition according to claim 1, wherein the pH is 6.8.

4. A composition according to claim 1, wherein the pH is 7.

5. A composition according to claim 1, wherein the buffer strength is in the range of 0.01 to 1 M.

6. A composition according to claim 1, wherein the buffer strength is in the range of 0.01 to 0.1 M.

7. A composition according to claim 1, wherein the buffer strength is from 0.01 M to 0.06 M.

8. A composition according to claim 1, wherein the buffer strength is from 0.02 M to 0.05 M.

9. A composition according claim 1, wherein the buffer strength is 0.05 M.

10. A composition according to claim 1, wherein the buffer strength is 0.02M.

11. A composition according to claim 1, wherein the buffer is sodium citrate buffer.

12. A composition according to claim 1, wherein the buffer is phosphate buffer.

13. A composition according to claim 1, wherein the liquid composition is a solution or a suspension.

14. A composition according to claim 13, wherein the liquid is a solution.

15. A composition according to claim 1, wherein the composition further comprises one or more preservatives.

16. A composition according to claim 15, wherein the one or more preservatives comprise ethyl parahydroxybenzoate and/or methyl parahydroxybenzoate.

17. A composition according to claim 16, wherein the methyl parahydroxybenzoate is methyl parahydroxybenzoate sodium salt.

18. A composition according to claim 1, wherein the composition further comprises one or more flavouring compounds and/or sweetening agents.

19. A composition according claim 18, wherein the one or more flavouring compounds and/or sweetening agents comprise orange flavour or berry flavour and/or sucralose.

20. A composition according to claim 1, wherein the composition further comprises one or more co-solvents.

21. A composition according to claim 1, wherein the composition comprises glycerol.

22. A composition according to claim 1, wherein the composition comprises polyethylene glycol.

23. A composition according to claim 22, wherein the polyethylene glycol is PEG 400.

24. A composition according to claim 1, comprising: 0.4-20 mg/ml methotrexate free acid; PEG 400; ethyl parahydroxybenzoate; methyl parahydroxybenzoate sodium salt; glycerol; orange flavour; sucralose; and sodium citrate buffer or phosphate buffer.

25. A liquid pharmaceutical composition according to claim 1, for oral administration.

26. A process for preparing a liquid pharmaceutical composition according to claim 1, comprising adding buffer to methotrexate free acid to adjust the pH to 6.5-8.2.

27. A composition according to claim 1, for use in therapy, wherein administration is via the oral route.

28. A method of administering methotrexate to a patient in need of therapy, comprising orally administering to the patient a therapeutically effective amount of a liquid pharmaceutical composition according to claim 1.

29. A method according to claim 28, wherein the therapy is for psoriasis, psoriatic arthritis, systemic dermatomyositis, seronegative arthritis, adult rheumatoid arthritis, resistant juvenile rheumatoid arthritis, polyarthritic forms of active juvenile idiopathic arthritis (JIA), graft versus host disease, mycosis fungoides, spondyloarthropathy, spondyloarthropathies, ankylo sing spondylitis, neoplasms, acute lymphoblastic leukemia, prophylaxis of meningeal leukaemia, breast cancer, bladder cancer, head cancer, neck cancer, non-Hodgkin's lymphoma, osteogenic sarcoma, adult soft tissue sarcoma, choriocarcinoma or lung cancer, haemoblastosis, or any other malignant tumours or conditions for which methotrexate is indicated.

30. A method according to claim 28, wherein the patient is a child.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] As used herein, the term “pharmaceutically acceptable” means any molecular entity or composition that does not produce an adverse, allergic, or other untoward or unwanted reaction when administered to an individual. As used herein, the term “pharmaceutically acceptable composition” is synonymous with “pharmaceutical composition”. A pharmaceutical composition of the invention may be used for human and veterinary applications. In a preferred embodiment of the invention, a composition of the invention is administered to humans, most preferably to children. The pharmaceutical compositions disclosed herein may be administered to an individual alone, or in combination with other active ingredients.

[0023] The term “child” or “paediatric patient” as used herein refers to a patient under the age of 18 years. Preferably, the child is from 0 to 16 years. More preferably, the child is 0 to 12 years.

[0024] The term co-solvent as used herein means any solvent present in the liquid formulation that increases the solubility of a substance. The co-solvent may enhance the solubility of the free acid of methotrexate.

[0025] In the present invention, the pH of the composition is in the range of 6.5 to 8.2

[0026] In a preferred embodiment, the pH of the composition is in the range of 6.5 to 8.2 or 6.5 to 8.0 or 6.5 to 7.0. In another preferred embodiment, the pH of the composition is in the range of 6.6 to 8.2 or 6.6 to 8.0 or 6.6 to 7.0. In a preferred embodiment, the pH is 6.6, 6.7, 6.8 or 6.9. In a more preferred embodiment, the pH is 6.7 or 6.8. In a further preferred embodiment, the pH is 6.8. In another more preferred embodiment, the pH is 7.

[0027] In a particularly preferred embodiment, the pH is 6.8 and the buffer strength is 0.05 M. In another particularly preferred embodiment, the pH is 7.0 and the buffer strength is 0.02 M.

[0028] Various buffers may be used to prepare a pharmaceutical composition of the invention, provided that the resulting preparation is pharmaceutically acceptable. Such buffers include, without limitation, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline and borate buffers. It is understood that acids or bases can be used to adjust the pH of a composition as needed. In a preferred embodiment, the buffer is sodium citrate buffer. In a more preferred embodiment, the sodium citrate buffer comprises tri-sodium citrate, citric acid and purified water. In another preferred embodiment, the buffer is phosphate buffer.

[0029] Preferably, the buffer strength is in the range of 0.01 to 0.1 M or 0.01 to 1 M. More preferably the buffer strength is 0.01 M to 0.06 M. In a further preferred embodiment, the buffer strength is 0.02 M to 0.06 M, more preferably 0.02 M to 0.05 M and most preferably 0.02 M or 0.05 M. It is surprising that stable compositions form with such a low strength of buffer.

[0030] The active ingredients and/or excipients can be soluble or can be delivered as a suspension in the desired carrier or diluent. In a preferred embodiment of the invention, the liquid pharmaceutical composition is a solution.

[0031] In a preferred embodiment, one or more preservatives are used. The preservatives used may be ethyl parahydroxybenzoate or methyl parahydroxybenzoate or the pharmaceutically acceptable salts thereof, or any suitable preservative known in the art. In an even more preferred embodiment, ethyl parahydroxybenzoate and methyl parahydroxybenzoate are used. In an even more preferred embodiment, ethyl parahydroxybenzoate and methyl parahydroxybenzoate sodium salt are used.

[0032] Preferably, a flavouring compound and/or sweetener are used. The flavouring used may be any suitable flavouring known in the art. Preferably, the flavouring is orange or berry flavour. The sweetener used may be any suitable sweetener known in the art. In a preferred embodiment, the sweetener is sucralose. In a more preferred embodiment, a composition of the invention comprises orange flavour and sucralose. This was found to improve palatability. It is believed that the buffer of the present invention acts in synergy with the orange and sucralose to yield an improved flavour.

[0033] In the present invention, one or more co-solvents may be present in the formulation.

[0034] In a preferred embodiment, glycerol is used. This also has a positive impact on taste. Preferably, the glycerol used is Kollisolv ® G 99.

[0035] In another preferred embodiment of the invention, polyethylene glycol is present in the formulation. More preferably, the polyethylene glycol is PEG 400. It is thought that the polyethylene glycol enhances the solubility of the free acid of methotrexate.

[0036] In a particularly preferred embodiment, glycerol and polyethylene glycol are present in the formulation.

[0037] Preferably, a composition of the invention comprises (and preferably consists of) methotrexate free acid, one or more preservatives, one or more co-solvents, a flavouring agent, a sweetener and buffer.

[0038] More preferably, a composition of the invention comprises methotrexate free acid, polyethylene glycol, ethyl parahydroxybenzoate, methyl parahydroxybenzoate sodium salt, glycerol, orange flavour, sucralose and sodium citrate buffer.

[0039] According to the invention, the amount of methotrexate free acid in a composition of the invention ranges from 0.4 mg/ml to 20 mg/ml. Preferably, the methotrexate free acid is present in a concentration of 1 mg/ml to 10 mg/ml. More preferably, the methotrexate free acid is present in a concentration of 1 mg/ml to 5 mg/ml.

[0040] Careful selection of excipients, including the flavourings, co-solvents, buffer components and preservatives has ensured conformance with the European Medicines Agency's guidelines on pharmaceutical development of medicines for paediatric use, since pharmaceutical excipients which are acceptable for adults may not necessarily be metabolised or eliminated in the same way in children.

[0041] In one aspect, there is provided a process for preparing a liquid pharmaceutical composition of the invention comprising adding buffer to methotrexate free acid to adjust the pH to 6.5 to 8.2. In this process, the skilled person will know what additional steps are required in order to prepare the preferred compositions of the invention, for example adding a buffer or adding stabilisers or preservatives. The skilled person will know routine procedures and conditions for preparing such compositions.

[0042] The pharmaceutical compositions according to the present invention may optionally include a pharmaceutically-acceptable carrier that facilitates processing of an active ingredient into pharmaceutically-acceptable compositions. As used herein, the term “pharmacologically-acceptable carrier” means any carrier that has substantially no long term or permanent detrimental effect when administered. Any pharmaceutically acceptable carriers known to the skilled person can be used including, without limitation, aqueous media such as, water, solvents, co-solvents, diluents and the like. Further excipients, adjuvants or flavouring agents etc. may be added. Providing the pharmacologically acceptable carrier, excipient, adjuvant or flavouring agent etc. is compatible with the active ingredient, its use in pharmaceutically acceptable compositions is contemplated.

[0043] A composition of the invention is preferably suitable for oral administration. It is preferably useful in therapy, wherein administration is via the oral route. A composition of the invention may be any type of oral liquid, including solutions, syrups, elixirs, and suspensions.

[0044] A composition of the invention may be useful in the treatment 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, Crohn'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-Hodgkin'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.

[0045] Therapy according to the invention may be conducted in a generally known manner, depending on various factors, such as the sex, age or condition of the patient, and the existence or otherwise of one or more concomitant therapies.

[0046] Preferably, the patient is a human patient. However, a formulation of the present invention may also be used for veterinary use.

[0047] The formulation should be stored under appropriate conditions, known to the skilled person, for example in type III amber glass flasks, vials or bottles.

[0048] The methotrexate liquid oral formulations and processes for preparation described in the present invention are demonstrated in the examples below. These examples are provided as an illustration only and should not be construed as limitation of the present invention.

EXAMPLES

Example 1

[0049] Four oral liquid formulations were prepared in accordance with the table below:

TABLE-US-00001 Quantity Name of Ingredient (mg/ml) Reference to Standards Methotrexate Free Acid 0.4-20  Ph Eur Polyethylene Glycol (PEG 400) 2-6 Ph Eur Ethyl parahydroxybenzoate 0.1-0.5 Ph Eur Methyl parahydroxybenzoate 1-5 Ph Eur sodium salt Glycerol (Kollisolv G 99)  50-200 Ph Eur Orange or Berry flavour 0.01-0.2  — Sucralose 1-5 Ph Eur Sodium citrate buffer Qs to 1 ml Ph Eur components [containing: Tri-sodium Citrate, Citric Acid, Purified Water]

[0050] The formulations had the following differing buffer strength/pH: [0051] Formulation 1: 0.05 M sodium citrate buffer, pH 6.8 [0052] Formulation 2: 0.05 M sodium citrate buffer, pH 6.2 (Comparative) [0053] Formulation 3: 0.1 M sodium citrate buffer, pH 6.8 [0054] Formulation 4: 0.1 M sodium citrate buffer, pH 6.2 (Comparative)

Testing

[0055] The formulations were stored in amber glass bottles and sealed with child resistant closures before storing at ICH stability conditions. The chemical and physical stability of the formulations were periodically observed.

Results

[0056] All formulations according to the present invention, following storage at 25° C. and 40° C. for three months, showed no change in appearance or pH. Such data show that under the conditions evaluated the low buffer concentration is sufficient for maintaining the pH of the formulations.

[0057] Related substance data (impurities testing) showed an increase in total related substances for all samples stored at 40° C. independent of formulation composition. However, the formulations that were adjusted to pH 6.2 showed a greater increase in total related substances of approximately 5% compared to the formulations adjusted to pH 6.8 of approximately 3.5% to 4.5%.

[0058] Following three months' storage, formulation 1 displayed the lowest level of impurities. This system appears to provide greater chemical stability than the 3 alternative systems.

[0059] Following one month storage, formulations 1 and 3 were clear, whereas formulations 2 and 4 (comparative) showed precipitation. This shows that solutions at pH 6.8 are more stable than the formulations at pH 6.2.

[0060] Formulation 1 displayed less degradation than other formulations. The formulations at pH 6.8 had lower degradation than the formulations at pH 6.2.

[0061] In a palatability test, the orange flavouring was found to be more palatable than a berry flavouring, suggesting that there may be synergy between the orange flavouring, the sucralose and the buffer.