Methotrexate Composition

Abstract

A Methotrexate composition for oral administration is provided comprising a pharmaceutically acceptable salt of Methotrexate and an aqueous carrier agent. The Methotrexate salt is substantially or completely soluble in the aqueous carrier agent, forming an aqueous solution. There is also provided a method of manufacturing a Methotrexate composition for oral administration, comprising mixing a pharmaceutically acceptable salt of Methotrexate with an aqueous carrier agent until the Methotrexate salt is substantially or completely soluble in the carrier agent to form an aqueous solution.

Claims

1. A methotrexate composition for oral administration, said composition comprising: methotrexate or a salt thereof; one or more buffer agents to adjust the pH of the composition, wherein the pH of the composition is 6 to 7, and wherein the one or more buffer agents have a buffer strength of 43 mM to 87 mM; one or more preserving agents; one or more agents selected from flavouring compounds and sweetening agents; and purified water.

2. The methotrexate composition of claim 1, wherein the methotrexate solution comprises a salt of methotrexate.

3. The methotrexate composition of claim 2, wherein the salt of methotrexate is methotrexate disodium.

4. The methotrexate composition of claim 2, wherein the salt of methotrexate is present in the composition at 10 mg/5 ml.

5. The methotrexate composition of claim 2, wherein the salt of methotrexate is present in the composition in the range of 0.05 mg/1 ml to 20 mg/1 ml.

6. The methotrexate composition of claim 1, wherein the pH of the composition is in the range of pH 6.6-6.9.

7. The methotrexate composition of claim 1, wherein the one or more buffer agents comprise citric acid, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trometamol (tris), hydrochloric acid, ascorbic acid, sodium ascorbate, any of the abovementioned sodium salts replaced with potassium salts, or any combination thereof.

8. The methotrexate composition of claim 1, wherein the one or more buffer agents comprise citric acid-sodium citrate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, trometamol (tris)-hydrochloric acid buffer, trometamol (tris)-citric acid buffer, ascorbic acid-sodium ascorbate buffer, or any of the abovementioned sodium salts replaced with potassium salts.

9. The methotrexate composition of claim 1, wherein the one or more buffer agents comprise citric acid and sodium citrate.

10. The methotrexate composition of claim 1, wherein the one or more buffer agents have a strength of 43 mM.

11. The methotrexate composition of claim 1, wherein the one or more preserving agents comprise sodium methyl hydroxybenzoate, sodium ethyl hydroxybenzoate, sodium propyl hydroxybenzoate, sodium benzoate, potassium sorbate, or a combination thereof.

12. The methotrexate composition of claim 1, wherein the one or more preserving agents comprise sodium methyl hydroxybenzoate and sodium propyl hydroxybenzoate.

13. The methotrexate composition of claim 1, comprising a sweetening agent.

14. The methotrexate composition of claim 13, wherein the sweetening agent comprises sucralose, acesulfame K, or any other water soluble sweetener.

15. The methotrexate composition of claim 1, comprising a flavouring compound.

16. The methotrexate composition of claim 1, wherein the composition is an aqueous solution and is free of methotrexate precipitation after stored at 25° C. for 6 months.

Description

BRIEF DESCRIPTION OF THE DRAWING

[0034] FIG. 1 is a graph showing results of analysis of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0035] Detailed embodiments of the present invention will now be described.

Test 1

[0036] The Applicants initially undertook a study to calculate the pH at which a Methotrexate composition containing 10 mg/5 ml Methotrexate Disodium remained stable (i.e. showed little or no pH drift over time) and the buffering conditions that provided this stability. The samples in test 1 included Batch A which had the pH adjusted to pH 6 and included buffering agents; Batch B which had been adjusted to pH 6 but contained no buffering agents; and Batch C which had the pH adjusted to 7 and included buffering agents.

[0037] More particularly, Batch A included 250 ml of purified water, 5.72 g of Disodium Hydrogen Phosphate Dihydrate, 1.88 g of Citric Acid Monohydrate, 1.096 g* of Methotrexate Disodium and the formulation was made up to 500 ml in purified water. (*Methotrexate Disodium amount includes a QS calculation to account for the sodium salt and raw material water content to produce 10 mg/5 ml of Methotrexate base in the product). The pH was adjusted to pH 6.0 using 10% Citric Acid solution.

[0038] Batch B included 250 ml of purified water, 1.096 g* of Methotrexate Disodium and the formulation was made up to 500 ml in purified water. (*Methotrexate Disodium amount includes a QS calculation to account for the sodium salt and raw material water content to produce 10 mg/5 ml of Methotrexate base in the product). The pH was adjusted to pH 6.0 using 10% Citric Acid solution.

[0039] Batch C included 250 ml of purified water, 7.76 g of Disodium Hydrogen Phosphate Dihydrate, 0.68 g of Citric Acid Monohydrate, 1.096 g* of Methotrexate Disodium and the formulation was made up to 500 ml in purified water. (*Methotrexate Disodium amount includes a QS calculation to account for the sodium salt and raw material water content to produce 10 mg/5 ml of Methotrexate base in the product). The pH was adjusted to pH 7.0 using 10% Citric Acid solution.

[0040] Initially the temperature of the compositions was maintained at 25° C. and the pH was measured at the starting point (t=0), at week 2, week 4 and week 8. The results are shown in Table 1 below.

TABLE-US-00001 TABLE 1 Time - weeks Batch Variables Condition 0 2 4 8 A pH 6 Buffered 25° C. pH 5.98 pH 6.09 pH 6.15 pH 6.18 B pH 6 25° C. pH 6.36 pH 6.51 pH 6.59 pH 7.22 Unbuffered C pH 7.0 25° C. pH 6.93 pH 7.02 pH 7.10 pH 7.17 Buffered NB: At the time of manufacture the pH of both the pH 6 buffered and pH 6 unbuffered formulations were adjusted to pH 6.00.

[0041] Firstly, the results show the instability of the pH of the composition when no buffering agents are used, based on the fact that at T=0 the unbuffered solution of Batch B had already increased to pH 6.36. This suggests that the pH of the Methotrexate solution drifted upwards in the short time between the end of manufacture of the composition and the testing of the samples.

[0042] The results from test 1 show that the buffered pH 6.0 and pH 7.0 formulations had minimal pH drift during the study. The unbuffered pH 6.0 formulation showed a marked increase in pH during the study. This test demonstrated that the Methotrexate formulation required a buffer system to control pH drift and to stabilise the resulting composition.

Test 2

[0043] The next test was undertaken to determine what effect a buffering system had on the levels of degradants present in a 10 mg/5 ml Methotrexate solution over time. The % of a known degradant (Impurity E) was measured using an HLPC assay. The same batch samples were made up as for test 1 and the conditions were maintained at 25° C. The % of degradation was measured at the start point (T=0), week 2, week 4 and week 8. The results are shown in Table 2 below.

TABLE-US-00002 TABLE 2 Time- weeks Batch Variables Condition 0 2 4 8 A pH 6 Buffered 25° C. 0.00% 0.00% 0.00% 0.13% B pH 6 25° C. 0.02% 0.10% 0.16% 0.68% Unbuffered C pH 7.0 25° C. 0.00% 0.12% 0.19% 1.80% Buffered

[0044] The results show that even after 8 weeks, the levels of degradation in the Buffered pH 6 formulation remain low throughout the trial with only 0.13% for the 25° C. sample with a corresponding pH of 6.18.

[0045] The unbuffered pH 6 formulation showed a much higher level of degradation of 0.68% at a corresponding pH of 7.22.

[0046] This data also showed that without a buffer the Methotrexate 10 mg/5 ml formulation showed a tendency for the pH to drift upwards. However, if the pH drifts up to pH 7 or above, the level of the degradation increases rapidly which will limit the shelf-life of the product.

[0047] Therefore, it was concluded that it was preferable to use a buffer system in the formulation to obtain a level of stability sufficient for obtaining a prolonged shelf life of the product. In order to choose a suitable buffer system and to calculate the desired buffer strength, a buffer was chosen and comprised an 87 millimolar Citric Acid/Disodium Hydrogen phosphate buffer system. The initial formulation tried was as follows:

Example 1

[0048]

TABLE-US-00003 Ingredient Weight/5 ml Purified Water (A) 3 ml Methotrexate Disodium QS to 10.97 mg Sodium Methyl QS to 4.80 mg Hydroxybenzoate Sodium Ethyl QS to 2.40 mg Hydroxybenzoate Citric Acid Monohydrate 25.0 mg Disodium Hydrogen 57.2 mg Phosphate Dihydrate Sucralose 2.5 mg Raspberry Flavour 545742E 10.0 mg Purified Water (C) To 5 ml QS—Quantum Satis (as much as is required to make up the required volume/weight).

[0049] However, on storage a yellow precipitate was seen which was identified as Methotrexate. Therefore further investigation work was carried out to try to identify the causative factors of the precipitate and resolve them.

[0050] Batches were prepared at various pHs in the range 5.6-6.0 and were prepared at ½, 1/10.sup.th and 1/20.sup.th the original buffer strength of example 1 (i.e. the citric acid monohydrate and disodium hydrogen phosphate dihydrate buffer system). The original buffer strength was taken from a citrate-phosphate buffer table (http://microscopy.berkeley.edu/Resources/instruction/buffers.html).

[0051] Visual observations showed that both the pH and ionic strength of the buffer affected the rate of precipitation of the Methotrexate (i.e. the point in time at which precipitation is seen) and the amount of Methotrexate precipitate produced.

[0052] The graph in FIG. 1 shows the results of the analysis of the filtered supernatant solution for the above Methotrexate formulation at ½ and 1/10th original buffer strength at four different pH values; 5.6, 5.7, 5.8 and 5.9. The analysis is based on the fact that the lower the % of Methotrexate found in the supernatant (i.e. Assay % SA), the lower the amount of Methotrexate remains in solution i.e. fully dissolved. Samples of the supernatant above the precipitate were filtered through a Whatman No. 4 Filter Paper and was assayed using HPLC for the Methotrexate active component.

[0053] The results show that by increasing the pH of the formulation towards pH 6.0, this increases the amount of Methotrexate dissolved in the formulation.

[0054] The results also show that there is less Methotrexate dissolved when a ½ strength buffer system is used compared to the formulation using a 1/10.sup.th strength buffer system. This in turn suggests that the Methotrexate composition of the present invention is more physically stable at a lower ionic buffer strength i.e. does not precipitate out of solution.

[0055] This analytical work is backed up by stability studies which are shown in Table 3 below. The stability studies were undertaken using the example 1 formulation but using either a citrate-phosphate buffer system at half the strength (i.e. 43 mmol) or 1/10.sup.th of the strength (i.e. 8.7 mmol) compared to that of example 1. The formulations were adjusted to 5 different pH values; 5.6, 5.7, 5.8, 5.9 and 6.0. One set of formulations were stored at 5° C. and one set of formulations were stored at 25° C. for each buffer strength and each pH value for the duration of the study. The study took place over a 6 month time period.

TABLE-US-00004 TABLE 3 ½ Buffer strength 1/10.sup.th Buffer Strength (43 mmol) (8.7 mmol) pH 5° C. 25° C. 5° C. 25° C. 5.6. PPT @ 1 M PPT @ 1 M PPT @ 1 M PPT @ 1 M 5.7 PPT @ 1 M PPT @ 1 M PPT @ 1 M PPT @ 1 M 5.8 PPT @ 1 M PPT @ 1 M PPT @ 1 M PPT @ 1 M 5.9 PPT @ 1 M PPT @ 1 M PPT @ 1 M PPT @ 5 M 6.0 CS @ 6 M CS @ 6 M CS @ 6 M CS @ 6 M PPT—precipitate observed CS—Clear Solution. No precipitate 1 M represents 1 month time period 5 M represents 5 month time period 6 M represents 6 month time period

[0056] The results show that visually there was a increase in the amount of Methotrexate in solution as the pH in the formulations increased from 5.6 to 5.9.

[0057] Table 4 shows the results of a similar test undertaken using a standard formulation with different ionic strengths of a citrate-phosphate buffer used and all the formulations adjusted to pH 6.0. One set of formulations were kept at 5° C. and one set of formulations were kept at 25° C. for the duration of the study.

[0058] Each formulation included 300 g Purified Water, 0.571 g of Sodium Methyl Hydroxybenzoate (equivalent of 0.96 g/L free acid), 0.281 g of Sodium Ethyl Hydroxybenzoate (equivalent to 0.48 g/L free acid), 0.25 g Sucralose, 1 g of Raspberry flavour, 1.293 g Methotrexate Disodium (QS to 2.194 g/L) and made up to 500 ml using Purified Water.

[0059] The Citrate-Phosphate control had 5.72 g Disodium Hydrogen Phosphate Dihydrate and 2.50 g of Citric Acid Monohydrate. The Citrate-Phosphate ½ strength buffer had 2.86 g Disodium Hydrogen Phosphate Dihydrate and 1.25 g of Citric Acid Monohydrate. The Citrate-Phosphate 1/10th strength buffer had 0.572 g Disodium Hydrogen Phosphate Dihydrate and 0.250 g of Citric Acid Monohydrate. The Citrate-Phosphate 1/20.sup.th strength buffer had 0.286 g Disodium Hydrogen Phosphate Dihydrate and 0.125 g of Citric Acid Monohydrate.

TABLE-US-00005 TABLE 4 Buffet Strength Test 5° C. 25° c. Citrate- 87 mmol Appearance PPT @ 2 M PPT @ 6 M Phosphate Degradant NT 0.97% @ 5 M (Control) (Impurity C) Citrate- 43 mmol Appearance PPT @ 3 M CS @ 6 M Phosphate Degradant NT 0.85% @ 5 M (½ strength) (Impurity C) Citrate- 8.7 mmol Appearance CS @ 6 M CS @ 6 M Phosphate Degradant NT 0.76% @ 5 M ( 1/10 strength) (Impurity C) Citrate- 4.3 mmol Appearance CS @ 6 M CS @ 6 M Phosphate Degradant NT 0.70% @ 5 M ( 1/20 strength) (Impurity C) NT—Not Tested PPT—precipitate observed CS—Clear Solution. No precipitate 2 M represents 2 month time period 3 M represents 3 month time period 6 M represents 6 month time period

[0060] The results in Table 4 show that the lower the ionic strength of the citrate phosphate buffer, the more stable the formulation is at pH 6.0. No precipitate is observed at a buffer strength of mmol on storage at 5° C. There is also a decrease in the amount of degradation observed (impurity C) as the buffer strength is decreased.

[0061] Table 5 shows a similar test to that undertaken for Table 4 but a separate phosphate and citrate buffers were used.

[0062] The formulation of the phosphate buffer used in each sample included 180 g Purified Water, 0.3426 g of Sodium Methyl Hydroxybenzoate *1 (equivalent of 0.96 g/L free acid), 0.1686 g of Sodium Ethyl Hydroxybenzoate *1 (equivalent to 0.48 g/L free acid), 0.15 g Sucralose, 0.6 g of Raspberry flavour, 0.7758 g of Methotrexate Disodium (QS to 2.194 g/L) and made up to 300 ml using Purified Water.

[0063] In the 66 mmol phosphate buffer the formulation included 0.357 g of Disodium Hydrogen Phosphate Dihydrate and 2.82 g of Sodium Dihydrogen Phosphate Dihydrate. In the 33 mmol phosphate buffer the formulation included 0.1785 g of Disodium Hydrogen Phosphate Dihydrate and 1.41 g of Sodium Dihydrogen Phosphate Dihydrate. In the 6.6 mmol phosphate buffer the formulation included 0.0357 g of Disodium Hydrogen Phosphate Dihydrate and 0.282 g of Sodium Dihydrogen Phosphate Dihydrate. In the 3.3 mmol phosphate buffer the formulation included 0.0182 g of Disodium Hydrogen Phosphate Dihydrate and 0.141 g of Sodium Dihydrogen Phosphate Dihydrate.

[0064] The formulation of the citrate buffer used in each sample included 600 g Purified Water, 1.141 g of Sodium Methyl Hydroxybenzoate *1 (equivalent of 0.96 g/L free acid), 0.563 g of Sodium Ethyl Hydroxybenzoate *1 (equivalent to 0.48 g/L free acid), 0.50 g Sucralose, 2.0 g of Raspberry Flavour, 2.520 g of Methotrexate Disodium (QS to 2.194 g/L) and made up to 1000 ml using Purified Water.

[0065] In the 100 mmol citrate buffer the formulation included 25.7 g of Sodium Citrate and 2.65 g of Citric Acid Monohydrate. In the 4.3 mmol citrate buffer the formulation included 1.18 g of Sodium Citrate and 0.1155 g of Citric Acid Monohydrate.

TABLE-US-00006 TABLE 5 Buffet Strength 5° C. 25° c. Phosphate 66 mmol PPT @ 2 M PPT @ 2 M Phosphate 33 mmol PPT @ 2 M CS @ 3 M Phosphate 6.6 mmol CS @ 3 M CS @ 3 M Phosphate 3.3 mmol CS @ 3 M CS @ 3 M Citrate 87 mmol PPT @ 1 week PPT @ 1 M Citrate 8.7 mmol PPT @ 3 M CS @ 4 M PPT—precipitate observed CS—Clear Solution. No precipitate 2 M represents 2 month time period 3 M represents 3 month time period 6 M represents 4 month time period

[0066] The results in table 5 support the results in table 4 in that the lower the ionic strength of the buffer system used in the formulation at pH 6.0, the more stable the Methotrexate formulation was over time.

[0067] Example 2 below shows a further Methotrexate formulation according to an embodiment of the present invention.

Example 2

[0068]

TABLE-US-00007 Specifi- Ingredient cation Weight/5 ml Weight/litre Purified Water (A) Ph. Eur 3 ml 600.00 g Sodium Methyl Ph. Eur QS to 4.80 mg QS to 0.96 g Hydroxybenzoate Free acid free acid Sodium Ethyl Ph. Eur QS to 2.40 mg QS to 0.48 g Hydroxybenzoate free acid free acid Disodium Hydrogen Ph. Eur 5.72 mg 1.144 g Phosphate Dihydrate Citric Acid Monohydrate Ph. Eur 6.27 mg 1.254 g Raspberry Flavour 545742E HSE 10.0 mg 2.00 g Sucralose USP 2.5 mg 500.00 mg Purified water (B) Ph. Eur 0.375 ml 75.00 g Methotrexate Disodium Ph. Eur QS to 10.97 mg QS to 2.194 g (equivalent to 10 mg/5 ml Methotrexate base) Disodium Hydrogen HSE QS to pH QS to pH Phosphate Dihydrate (as a 10% .sup.w/.sub.v solution) Citric Acid Monohydrate HSE QS to pH QS to pH (as a 10% .sup.w/.sub.v solution) Purified Water (C) Ph. Eur To 5 ml To 1000 ml (1010.0 g*)g *based on weight per ml of 1.010 g/ml) Ph. Eur—European Pharmacopoeia HSE—In House Standard USP—United States Pharmacopoeia QS—Quantum Satis (Methotrexate Disodium and the Sodium p-Hydroxybenzoate preservatives are hygroscopic, therefore will require QS calculations prior to dispensing and batch manufacture.)

[0069] An example method of manufacture is set out below for the formulation shown in example 2. This method is typically undertaken at room temperature and pressure and could be carried out using a propeller mixer or a high shear mixer for example.

Manufacturing Process

[0070] 1. Add the aqueous carrier agent in the form of Purified Water (A) to the main manufacturing vessel. [0071] 2. Add the preservatives in the form of Sodium Methylhydroxybenzoate and Sodium Ethyl Hydroxybenzoate to the main vessel and mix until substantially dissolved using a suitable mixer. [0072] 3. Add the buffer agent Disodium Hydrogen Phosphate Dihydrate to the main vessel and mix until substantially dissolved using a suitable mixer. [0073] 4. Add the buffer agent Citric Acid Monohydrate to the main vessel and mix until substantially dissolved using a suitable mixer. [0074] 5. Add the flavouring agent in the form of Raspberry Flavour to the main vessel and mix until substantially dispersed using a suitable mixer. [0075] 6. Add the sweetening agent in the form of Sucralose to the main vessel and mix until substantially dissolved using a suitable mixer. [0076] 7. Into a suitable clean separate stage vessel dispense aqueous carrier agent in the form of purified water (B). [0077] 8. Add the Methotrexate Disodium salt into the separate stage vessel and mix until substantially dissolved either by hand or using a suitable mixer. [0078] 9. Add the separate stage Methotrexate solution (from stage 8) into the main vessel and mix until substantially dispersed using a suitable mixer. [0079] 10. Check the pH. If it is outside the range of 6.25+/−0.15 adjust the pH until it is within this range by using either 10% w/v solution of Citric Acid Monohydrate to lower the pH or a 10% w/v solution of Disodium Hydrogen Phosphate Dihydrate to increase the pH. [0080] 11. Add Purified Water (C) to make to final weight and mix until substantially dispersed using a suitable mixer. [0081] 12. The finished product is filled into amber glass bottles.

[0082] While the invention has been described with a certain degree of particularity, it is manifest that many changes may be made in the details of construction and the arrangement of components without departing from the spirit and scope of this disclosure. It is understood that the invention is not limited to the embodiments set forth herein for purposes of exemplification, but is limited only by the scope of the attached claims, including the full range of equivalency to which each element thereof is entitled.