Tablet dosage formulations of oleyl phosphocholine

Abstract

The present invention relates to tablet dosage formulations of oleyl phosphocholine for oral administration and the processes for their preparation. Specifically, the present invention provides a process for preparing an oleyl phosphocholine containing granulate, said process comprising a blending step, a hot melt agglomeration step and a milling step. The present invention further provides a process for preparing a tablet comprising the oleyl phosphocholine containing granulate, said process comprising the step of preparing an OIPC containing granulate according to the invention, a blending step, a compression step, and optionally a coating step. The invention further provides any intermediate and/or en product resulting from these steps and processes.

Claims

1. A process for making an olelyl phosphocholine (OIPC) containing granulate, said process comprising a blending step, a melt-agglomeration step and a milling step, wherein the blending step comprises preparing a mixture of olelyl phosphocholine and one or more granulation excipients; wherein the melt-agglomeration step comprises preparing a granulate by heating said mixture and subjecting said heated mixture to mechanical shear force; wherein the milling step comprises preparing a milled granulate by cooling said granulate and milling said cooled granulate; and wherein no solvent is added during the process for granulation.

2. A process according to claim 1, wherein the blending step comprises preparing a mixture of oleyl phsophocholine, a spacer, an antioxidant, a filler and optionally one or more further granulation excipients.

3. The process according to claim 1, wherein the mixture comprises a spacer selected from the group consisting of polyethylene glycol, polyethylene glycol esters, polypropylene glycol, polypropylene glycol esters, polyvinyl pyrrolidone (PVP), poly-(2-oxazoline)s (POX), polyacrylic acid (PAA), hydroxypropylmethylcellulose and mixtures thereof.

4. The process according to claim 1, wherein the mixture comprises an antioxidant selected from the group consisting of alpha tocopherolacetate, Vitamin E, Vitamin E TPGS, diethylhexyl syringylidene malonate, diisopropyl vanillidene malonate, tetrahydrocurcumenoids, tocopherol, carotenoids, anthocyanidins, hydroquinone monomethyl ether, ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), propyl gallate and ethoxyquin (EMQ) and mixtures thereof.

5. The process according to claim 1, wherein the mixture comprises a filler selected from the group consisting of calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulphate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar spheres, talc, xylitol, silicium dioxide, and mixtures thereof.

6. The process according to claim 1, wherein the melt-agglomeration process comprises a hot-melt extrusion step.

7. The process according to claim 1, comprising a granulation blending step, a hot melt extrusion step and a milling step, wherein the granulation blending step comprises preparing a granulation mixture of olelyl phosphocholine and granulation excipients, wherein said granulation excipients comprise at least a spacer, an antioxidant and a disintegrant, and optionally a binder and/or a lubricant; wherein the hot melt extrusion step comprises preparing an extrudate by heating said granulation mixture and extrudating said heated granulation mixture; wherein the milling step comprises preparing a milled extrudate by cooling said extrudate and granulating said cooled extrudate; wherein no solvent is added during the process for granulation.

8. The process for granulation according to claim 7, wherein the concentration of oleyl phosphocholine in the milled extrudate is between 10 and 50 weight percent, preferably between 25 and 35 weight percent; wherein, if a binder is added as a granulation excipient, the concentration of the binder in the milled extrudate is between 10 and 50 weight percent, preferably between 25 and 35 weight percent; wherein, if a lubricant is added as a granulation excipient, the concentration of the lubricant in the milled extrudate is between 1 and 20 weight percent, preferably between 1 and 10 weight percent; wherein the concentration of the antioxidant in the milled extrudate is between 0.05 and 5 weight percent, preferably between 0.1 and 1 weight percent; wherein the concentration of the disintegrant in the milled extrudate is between 1 and 20 weight percent, preferably between 1 and 10 weight percent; wherein the concentration of the spacer in the milled extrudate is between 10 and 50 weight percent, preferably between 25 and 35 weight percent; wherein the concentrations are relative to the milled extrudate.

9. An olelyl phosphocholine (OIPC) containing granulate obtainable by a process as defined in claim 1.

10. A process for preparing a tablet dosage formulation comprising a process for making an OIPC containing granulate according to claim 1, a blending step, a compression step, and optionally a coating step, wherein the blending step comprises preparing a compression mixture by mixing the OIPC containing granulate with compression excipients, wherein said compression excipients comprise at least a filler and a lubricant, and optionally a binder and/or a disintegrant.

11. The process for preparing a tablet dosage formulation according to claim 10, wherein between 30 and 60 weight percent of the OIPC containing granulate is added during the blending step; wherein the concentration of the filler in the compression mixture is between 10 and 40 weight percent, preferably between 25 and 35 weight percent; wherein the concentration of the lubricant in the compression mixture is between 10 and 30 weight percent, preferably between 15 and 25 weight percent; wherein the concentrations are relative to the compression mixture.

12. The process for preparing a tablet dosage formulation according to claim 10, wherein the tablet dosage formulation comprises oleyl phosphocholine, lactose, colloidal silica, microcrystalline cellulose, hydroxypropylmethyl cellulose, croscarmellose sodium, magnesium stearate and vitamin E: wherein the concentration of oleyl phosphocholine in the tablet dosage formulation is between 5 and 40 weight percent, preferably between 15 and 30 weight percent; wherein the concentration of the lactose in the tablet dosage formulation is between 5 and 25%, preferably between 10 and 20%; wherein the concentration of the colloidal silica in the table dosage formulation is between 15 and 45%, preferably between 20 and 40%; wherein the concentration of the microcrystalline cellulose in the tablet dosage formulation is between 5 and 25 weight percent, preferably between 10 and 20 weight percent; wherein the concentration of the hydroxypropylmethyl cellulose in the tablet dosage formulation is between 5 and 15 weight percent, preferably between 5 and 10 weight percent; wherein the concentration of the croscarmellose sodium in the tablet dosage formulation is between 1 and 5 weight percent, preferably between 2 and 4 weight percent; wherein the concentration of the magnesium stearate in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent; wherein the concentration of the vitamin E in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent; wherein the concentrations are relative to the compression mixture.

13. A tablet dosage formulation obtainable by the process according to claim 10.

14. The tablet dosage formulation according to claim 13, wherein the concentration of oleyl phosphocholine in the tablet dosage formulation is between 5 and 20 weight percent, preferably between 5 and 15 weight percent; wherein the concentration of the filler in the tablet dosage formulation is between 10 and 30 weight percent, preferably between 15 and 25 weight percent; wherein the concentration of the binder in the tablet dosage formulation is between 10 and 30 weight percent, preferably between 15 and 25 weight percent; wherein the concentration of the disintegrant in the tablet dosage formulation is between 1 and 10 weight percent, preferably between 1 and 5 weight percent; wherein the concentration of the lubricant in the tablet dosage formulation is between 5 and 20 weight percent, preferably between 5 and 15 weight percent; wherein the concentration of the antioxidant in the tablet dosage formulation is between 0.05 and 5 weight percent, preferably between 0.1 and 1 weight percent; wherein the concentration of the spacer in the tablet dosage formulation is between 5 and 20 weight percent, preferably between 5 and 15 weight percent; wherein the concentrations are relative to the tablet dosage formulation.

15. The tablet dosage formulation according to claim 13, wherein the tablet dosage formulation comprises oleyl phosphocholine, lactose, colloidal silica, microcrystalline cellulose, hydroxypropylmethyl cellulose, croscarmellose sodium, magnesium stearate and vitamin E: wherein the concentration of oleyl phosphocholine in the tablet dosage formulation is between 5 and 40 weight percent, preferably between 15 and 30 weight percent; wherein the concentration of the lactose in the tablet dosage formulation is between 5 and 25%, preferably between 10 and 20%; wherein the concentration of the colloidal silica in the table dosage formulation is between 15 and 45%, preferably between 20 and 40%; wherein the concentration of the microcrystalline cellulose in the tablet dosage formulation is between 5 and 25 weight percent, preferably between 10 and 20 weight percent; wherein the concentration of the hydroxypropylmethyl cellulose in the tablet dosage formulation is between 5 and 15 weight percent, preferably between 5 and 10 weight percent; wherein the concentration of the croscarmellose sodium in the tablet dosage formulation is between 1 and 5 weight percent, preferably between 2 and 4 weight percent; wherein the concentration of the magnesium stearate in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent; wherein the concentration of the vitamin E in the tablet dosage formulation is between 0.1 and 2 weight percent, preferably between 0.5 and 1 weight percent; wherein the concentrations are relative to the compression mixture.

16. The tablet dosage formulation according to claim 13 comprising a tablet coating, wherein the tablet coating comprises a seal coating, a subcoating, and a colour coating; wherein the seal coating is selected from the group consisting of shellac, zinc oxide, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxylpropylcellulose, hydroxypropylmethylcellulose and mixtures thereof and wherein the concentration of the seal coating is between 1 and 3 weight percent; wherein the subcoating comprises a sugar coating and a powder, wherein the sugar coating is a sucrose based solution or syrup, wherein the powder is talc, talc-calcium mixture, calcium carbonate or mixtures thereof and wherein the concentration of the subcoating is between 70 and 80 weight percent; wherein the colour coating is a dye or a pigment and wherein the concentration of the colour coating is between 20 and 30 weight percent; wherein the wax is Montanglycolwax, beeswax or carnauba wax and wherein the concentration of the wax is less than 0.01 weight percent; wherein the concentrations in this embodiment are relative to the tablet coating.

17. The tablet dosage formulation according to claim 13, wherein, if said tablet dosage formulation is stored for at least 24 months at a temperature of 30° C. and at a relative humidity of 75%, the concentration of each active pharmaceutical ingredient in said tablet dosage formulation does not change by more than 2.5 weight percent, preferably by no more than 1 weight percent; and each active pharmaceutical ingredient in said tablet dosage formulation has a stable dissolution release profile.

18.-19 (canceled)

20. A method for treating a parasitic disease, the method comprising administering the tablet dosage formulation according to claim 13 to a subject in need thereof.

21. The method of claim 20, wherein the method is for the treatment of a parasitic disease selected from the group consisting of leishmaniasis, chagas, malaria and cancer.

Description

LEGEND TO THE FIGURES

[0178] FIG. 1: Process for preparing the tablet core of the tablet dosage formulation in Example 1.

EXAMPLES

[0179] The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.

Example 1: Milled Extrudate

[0180] In this example is provided a milled extrudate, as described in this application. The composition of this milled extrudate is given in Table 1.

TABLE-US-00001 TABLE 1 Composition of milled extrudate % in the milled extrudate mass (mg (157.730 mg milled per tablet) extrudate per tablet) API oleyl 50.000 31.700 phosphocholine Granulation alpha 1.000 0.634 excipient tocopherol- acetate microcrystalline 49.000 31.066 cellulose macrogol 6000 50.000 31.700 sodium 7.730 4.901 croscarmellose Sum 157.730 100.000

Example 2: Tablet Dosage Formulation

[0181] In this example is provided a tablet dosage formulation prepared via a process for preparing a tablet dosage formulation according to the invention. In this process, the milled extrudate as described in Example 1 was an intermediate.

[0182] The composition of the compression mixture in this example, prepared as an intermediate during the process for preparing a tablet dosage formulation according to the invention, is given in Table 2.

[0183] The composition of the tablet dosage formulation in this example is given in Table 3. The composition of the tablet coating of the tablet dosage formulation in this example is given in Table 4.

[0184] The tablet core of the tablet dosage formulation in this example was prepared via the process steps as described in FIG. 1.

TABLE-US-00002 TABLE 2 Composition of the compression mixture mass (mg per tablet) Compression lactose 97.920 excipient monohydrate microcrystalline 47.250 cellulose sodium 9.350 croscarmellose magnesium 3.150 stearate Sum 157.670 Milled 157.730 extrudate Compression 315.400 mixture

TABLE-US-00003 TABLE 3 Composition of tablet dosage formulation % in the tablet dosage mass (mg formulation (557.700 mg per tablet) per tablet) API oleyl 50.000 8.965 phosphocholine Excipient alpha tocopherol- 1.000 0.180 acetate microcrystalline 96.250 17.258 cellulose macrogol 6000 50.000 8.965 sodium 17.080 3.062 croscarmellose lactose 97.920 17.558 monohydrate magnesium 3.150 0.565 stearate Coating 242.300 43.446 Sum 557.700 100.00

TABLE-US-00004 TABLE 4 Composition of the tablet coating mass (mg per tablet) Seal coating 3.976 Talc 0.904 Sugar coating 19.605 Talc-calcium 31.679 mixture Sugar coating 129.870 Colour coating 56.112 Motanylglycolwax 0.160 Sum 234.600

Example 3: Stability of a Tablet Dosage Formulation

[0185] The change of the concentration of oleyl phosphocholine in the tablet dosage formulation described in Example 2 upon storage under different conditions can be found in Table 5.

TABLE-US-00005 TABLE 5 Change of oleyl phosphocholine concentration OIPC concentration in the tablet dosage formulation (mg/tablet) Conditions after X months of storage T RH X = 0 X = 3 X = 6 X = 18 X = 24 X = 36 25° C. 60% 50.2 48.1 48.1 49.15 47.10 50.14 30° C. 75% 50.2 47.5 49.7 50.17 47.46 49.30 40° C. 75% 50.2 48.9 49.9

Example 4: Dissolution of Oleyl Phosphocholine

[0186] The dissolution of oleyl phosphocholine comprised in the tablet dosage formulation described in Example 2, which has been stored for different time periods (18 months, 24 months, 36 months) under different conditions, has been determined by the European Pharmacopoeia 2.9.3 standard dissolution test after 60 minutes. The results can be found in Table 6.

TABLE-US-00006 TABLE 6 Dissolution of oleyl phosphocholine concentration Dissolved weight percentage of oleyl phosphocholine after 60 minutes, relative to the tablet dosage formulation Conditions storage of storage of storage of T RH 18 months 24 months 36 months 25° C. 60% 78.4 83.2 96.4 30° C. 75% 89.9 80.9 83.3