Pharmaceutical oral dosage form of q203

Abstract

To provide pharmaceutical oral dosage forms of Q203.SOLUTION: The invention relates to a novel pharmaceutical oral dosage form of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, in particular, a ditosylate form thereof. In another aspect, the invention relates to a pharmaceutical oral dosage form according to the invention for use in the treatment of a bacterial infection, preferably tuberculosis or Buruli ulcer. In yet a further aspect, the invention relates to a method for treating a bacterial infection, preferably tuberculosis or Buruli ulcer, where the pharmaceutical dosage form is administered to a patient in need thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to new pharmaceutical dosage forms of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, particularly in its ditosylate form. [Background technology]

[0002] Tuberculosis as a disease continues to cause millions of deaths every year. Inappropriate use of chemotherapy has led to an increasing number of drug-resistant cases. This situation seems to be worsening with the emergence of strains that are highly resistant to all currently known drugs. Current chemotherapy consists of compounds that directly target Mycobacterium tuberculosis, either by neutralizing common signaling pathways and key processes (e.g. RNA polymerization and protein synthesis inhibition) or by interfering with mycobacteria-specific cell envelope synthesis. The most widely used dedicated antituberculosis drugs, isoniazid, ethionamide, and pyriazin amide, are prodrugs that require activation first. They are administered to patients in courses of several months. Patients infected with multidrug-resistant strains of M. tuberculosis may have to undergo combination therapy for extended periods of time. WO 2011 / 113606 describes various antituberculous compounds and their use in treating bacterial infections, including the compound "Q203," which is chemically 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide. In a publication by Pethe et al. (Nature Medicine, 19, 1157-1160 (2013), this compound is reported to be active against tuberculosis by interfering with bacterial energy metabolism (by inhibiting cytochrome bc1 activity, an essential component of the electron transport chain required for the synthesis of ATP). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2011 / 113606 [Non-patent literature]

[0004] [Non-Patent Document 1] Pethe et al., Nature Medicine (2013) 19, 1157-1160 Summary of the Invention [Means for solving the problem]

[0005] Although the compound shows promise for the future treatment of tuberculosis and related infections, its administration is hindered by its rather low solubility in aqueous solutions. This also makes it difficult to prepare suitable pharmaceutical dosage forms of the compound. Various attempts to formulate it into a suitable oral dosage form have been unsuccessful. Thus, there is a need in the art to devise and provide pharmaceutical dosage forms that are suitable for oral consumption and that allow the drug to be administered by ingestion.

[0006] The present invention addresses these and related needs.

[0007] In a first aspect, the present invention relates to a pharmaceutical oral dosage form of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, said dosage form comprising: a) a granule comprising 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, at least one pharma- ceutically acceptable intragranular excipient, and a solubilizing agent; b) a blend surrounding the granules and comprising at least one binder, at least one lubricant and at least one disintegrant, and optionally a filler; Contains a mixture of. In one embodiment, the at least one pharma- ceutically acceptable intragranular excipient is selected from a binder, a filler, and a combination of the two.

[0008] In one embodiment, the granule (a) consists of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, a binder, a filler, and a solubilizer.

[0009] In one embodiment, the granules a) do not contain a lubricant and do not contain a disintegrant or a superdisintegrant.

[0010] In one embodiment, the binder in the granules a) is not crosslinked starch, microcrystalline cellulose, crosslinked cellulose, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked alginic acid, soy polysaccharide or calcium silicate.

[0011] In one embodiment, the binder in the granules a) is selected from gum acacia, gum tragacanth, gelatin, sucrose, starch, and non-crosslinked polyvinylpyrrolidone (PVP), preferably non-crosslinked polyvinylpyrrolidone (PVP).

[0012] In one embodiment, the binder in the granules a) is present in the pharmaceutical dosage form in an amount of about 0.1% to 5% by weight, preferably about 0.2% to 3.5% by weight, more preferably about 0.3% to 3% by weight. In one embodiment, the filler in the granules a) is selected from mannitol, dextrose, dextrin, lactose, sorbitol, sucrose, inositol, preferably mannitol.

[0013] In one embodiment, the filler in the granules a) is present in the pharmaceutical dosage form in an amount of about 1.5% to 25% by weight, preferably about 1.75% to 22.5% by weight, more preferably about 1.9% to 20% by weight.

[0014] In one embodiment, the solubilizer in the granules a) is selected from D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS), sodium lauryl sulfate (SLS), polyoxyethylene sorbitan monooleate (Tween®), cetyl triamethyl ammonium bromide (CTAB), amino acids (e.g. glycine), polyethylene glycol, preferably D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS).

[0015] In one embodiment, the solubilizer in the granules a) is present in the pharmaceutical dosage form in an amount of about 0.5% to 8% by weight, preferably about 0.6% to 7.5% by weight, more preferably about 0.68% to 6.8% by weight.

[0016] A pharmaceutical oral dosage form according to any of the preceding claims, wherein the granules comprise or preferably consist of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, a binder which is non-crosslinked polyvinylpyrrolidone (PVP), a filler which is mannitol, and a solubilizer which is D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS).

[0017] In one embodiment, the at least one binder in the blend (b) surrounding the granules is selected from starch, microcrystalline cellulose, povidone, hydroxylpropylcellulose, hydroxylpropylmethylcellulose and combinations thereof, preferably a binder also having disintegrant qualities, more preferably microcrystalline cellulose.

[0018] In one embodiment, the at least one binder in the blend (b) surrounding the granules is present in the pharmaceutical dosage form in an amount of about 25% to 50% by weight, preferably about 28% to 45% by weight, more preferably about 30% to 43% by weight.

[0019] In one embodiment, the at least one lubricant in the blend (b) surrounding the granules is selected from magnesium stearate, calcium stearate, PEG6000, sodium stearyl stearate, sodium lauryl sulfate, colloidal silicon dioxide, and combinations thereof, wherein preferably, the at least one lubricant in the blend (b) surrounding the granules is a combination of colloidal silicon dioxide and magnesium stearate.

[0020] In one embodiment, the at least one lubricant in the blend (b) surrounding the granules is present in the pharmaceutical dosage form in an amount of about 1% to 5% by weight, preferably about 0.5% to 4% by weight, more preferably about 0.75% to 3.5% by weight, where when the at least one lubricant in the blend (b) surrounding the granules is a combination of colloidal silicon dioxide and magnesium stearate, the colloidal silicon dioxide is present in the pharmaceutical dosage form in an amount of about 0.5% to 3.5% by weight, preferably about 1% to 2.5% by weight, more preferably about 2% by weight, and in such combination, the magnesium stearate is present in the pharmaceutical dosage form in an amount of about 0.1% to 2% by weight, preferably about 0.5% to 1.5% by weight, more preferably about 0.8% by weight.

[0021] In one embodiment, the at least one disintegrant in the blend (b) surrounding the granules is selected from crosslinked starch, starch glycolate (e.g., sodium starch glycolate), microcrystalline cellulose, crosslinked cellulose, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked alginic acid, croscarmellose (e.g., croscarmellose sodium or croscarmellose calcium), soy polysaccharides, and calcium silicate.

[0022] In one embodiment, the at least one disintegrant in the blend (b) surrounding the granules is present in the pharmaceutical dosage form in an amount of about 5% to 12% by weight, preferably about 7.5% to 10% by weight, more preferably about 8% to 8.5% by weight.

[0023] In one embodiment, the blend surrounding the granules includes a filler that is preferably the same filler as the filler contained in the granules.

[0024] In one embodiment, the filler in the blend surrounding the granules is present in the pharmaceutical dosage form in an amount of about 25% to 50% by weight, preferably about 27.5% to 45% by weight, and more preferably about 31% to 43% by weight.

[0025] In one embodiment, the 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate is present in the pharmaceutical dosage form in an amount of about 1% to 35% by weight, preferably about 2% to 30% by weight, and more preferably about 2.7% to 27.5% by weight.

[0026] In one embodiment, the pharmaceutical oral dosage form comprises: a) granules comprising 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate in an amount of about 23-30% by weight of said dosage form, mannitol in an amount of about 15-25% by weight of said dosage form, polyvinylpyrrolidone in an amount of about 1-5% by weight of said dosage form, D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS) in an amount of about 5-8% by weight of said dosage form; and b) a blend surrounding said granules and comprising microcrystalline cellulose in an amount of about 30-34% by weight of said dosage form, colloidal silicon dioxide in an amount of about 1-3% by weight of said dosage form, magnesium stearate in an amount of about 0.5-1.5% by weight of said dosage form, and croscarmellose sodium in an amount of about 7-10% by weight of said dosage form; or c) granules comprising 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate in an amount of about 12-15% by weight of said dosage form, mannitol in an amount of about 8-12% by weight of said dosage form, polyvinylpyrrolidone in an amount of about 1-2% by weight of said dosage form, D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS) in an amount of about 2-5% by weight of said dosage form; and d) a blend surrounding said granules and comprising microcrystalline cellulose in an amount of about 30-33% by weight of said dosage form, mannitol in an amount of about 30-33% by weight of said dosage form, magnesium stearate in an amount of about 0.5-1.5% by weight of said dosage form, and croscarmellose sodium in an amount of about 7-10% by weight of said dosage form; or e) granules comprising 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate in an amount of about 1-5% by weight of said dosage form, mannitol in an amount of about 1-3% by weight of said dosage form, polyvinylpyrrolidone in an amount of about 0.1-0.5% by weight of said dosage form, D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS) in an amount of about 0.5-0.8% by weight of said dosage form; and f) a blend surrounding said granules and comprising microcrystalline cellulose in an amount of about 40-45% by weight of said dosage form, mannitol in an amount of about 40-45% by weight of said dosage form, magnesium stearate in an amount of about 0.5-1.5% by weight of said dosage form, and croscarmellose sodium in an amount of about 7-10% by weight of said dosage form; Contains a mixture of.

[0027] In a further aspect, the present invention relates to a method for preparing a pharmaceutical oral dosage form as defined above, said method comprising the steps of: i) granulating 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate and the components of granule a) (as defined above) by a suitable granulation process; the suitable granulation process is preferably selected from fluidized bed granulation, high shear granulation, fluidized bed drying, fluidized spray drying, single pot granulation, steam granulation, thermal adhesion granulation, pneumatic dry granulation, moisture activated dry granulation, melt granulation, freeze granulation, and foam granulation; ii) blending the granules obtained in step i with the blend components (as defined above); iii) compressing the mixture obtained in step ii into a pharmaceutical dosage form, preferably a tablet; and optionally iv) coating the dosage form obtained in step iii), The present invention relates to a method comprising the steps of:

[0028] In a still further aspect, the present invention relates to a pharmaceutical oral dosage form obtainable by the process as defined above.

[0029] In yet another aspect the present invention relates to a pharmaceutical oral dosage form according to the invention for use in the treatment of a bacterial infection, preferably tuberculosis or Buruli ulcer.

[0030] In yet a further aspect, the present invention also relates to a method for the treatment of a bacterial infection, preferably tuberculosis or Buruli ulcer, wherein said pharmaceutical dosage form is administered to a patient in need thereof.

[0031] The inventors have surprisingly found that it is possible to formulate 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate (Q203) into a pharmaceutical oral dosage form. The dosage form can be produced by a robust manufacturing process that provides high dosage uniformity. Furthermore, pharmaceutical dosage forms according to embodiments of the present invention can be designed to achieve highly reproducible disintegration and / or dissolution in aqueous solutions.

[0032] The invention will now be further described by reference to the following drawings, which are presented for purposes of illustration and not for purposes of limiting the invention, and more particularly: [Brief description of the drawings]

[0033] [Figure 1] FIG. 1 shows a comparison of the Q203 dissolution profiles of various tablet formulations presented below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The invention will now be further described by reference to the following examples, which are offered to illustrate, but not to limit, the invention. EXAMPLES

[0035] Working Example Exemplary formulations containing Q203 as the active ingredient were produced. To confirm the manufacturability of samples of various strengths, low, medium and high concentration Q203 tablets were produced and prepared according to the following general procedures: granulation, blending, compression and coating. Example 1 Composition of the formulation [Table 1]

[0036] Formulation preparation process 1. Sift the Q203, Minntol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and PVP K29 / 32. 2. Add #1 powder to granulator and mix. 3. Add Vitamin E-TPGS to the water. 4. Mix and dry. 5. Discharge and sieve the granules. 6. Charge the blender with the granules, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. 7. Blend for 15 minutes longer. 8. Discharge and compress tablets. Example 2 Composition of the formulation [Table 2]

[0037] Formulation preparation process 1. Sift the Q203, Minntol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and PVP K29 / 32. 2. Add #1 powder to granulator and mix. 3. Add Vitamin E-TPGS to the water. 4. Mix and dry. 5. Discharge and sieve the granules. 6. Charge the blender with the granules, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. 7. Blend for 15 minutes longer. 8. Discharge and compress tablets. Example 3 Composition of the formulation [Table 3]

[0038] Formulation preparation process 1. Sift the Q203, Minntol and PVP K29 / 32. 2. Add #1 powder to granulator and mix. 3. Add Vitamin E-TPGS to the water. 4. Mix and dry. 5. Discharge and sieve the granules. 6. Charge the blender with the granules, microcrystalline cellulose, mannitol, croscarmellose sodium and magnesium stearate. 7. Blend for 15 minutes longer. 8. Discharge and compress tablets. Example 4 Composition of the formulation [Table 4]

[0039] Formulation preparation process 1. Sift the Q203, Minntol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and PVP K29 / 32. 2. Add #1 powder to granulator and mix. 3. Add Vitamin E-TPGS to the water. 4. Mix and dry. 5. Discharge and sieve the granules. 6. Charge the blender with the granules, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. 7. Blend for 15 minutes longer. 8. Discharge and compress tablets. Example 5 Comparison of Q203 dissolution profiles

[0040] Drug release testing utilizing USP Apparatus 2 with 900 mL of 0.1 N HCl at 75 rpm was used to study the in vitro release at 37° C.±0.5° C. In the guidelines for dissolution testing of immediate release solid oral dosage forms, it was recommended that for BCS Class 2 products, which are drugs that dissolve slowly or are poorly water soluble, the product quality be characterized to ensure 85% dissolution. The Q203 tablets prepared according to Examples 2, 3 and 4 show rapid dissolution; complete dissolution (>90%) in 15 minutes is observed for all three batches. Thus, the formulations are suitable formulations and achieve highly reproducible disintegration and / or dissolution. The results are shown in the following table and in FIG. 1 (it should be noted that dissolution>100% means that such dissolution is higher than the dissolution of the respective control formulation used in the dissolution test). [Table 5] In certain embodiments, for example, the following items are provided: (Item 1) 1. A pharmaceutical oral dosage form of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, said dosage form comprising: a) a granule comprising 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, at least one pharma- ceutically acceptable intragranular excipient, and a solubilizing agent; b) a blend surrounding the granules and comprising at least one binder, at least one lubricant and at least one disintegrant, and optionally a filler; A pharmaceutical oral dosage form comprising a mixture of (Item 2) 2. The pharmaceutical oral dosage form according to item 1, wherein the at least one pharma- ceutically acceptable intragranular excipient is selected from a binder, a filler, and a combination of the two. (Item 3) 3. The pharmaceutical oral dosage form according to any of items 1 and 2, wherein the granules a) consist of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, a binder, a filler, and a solubilizer. (Item 4) 2. The pharmaceutical oral dosage form according to any of the preceding items, wherein the granules a) do not contain a lubricant and do not contain a disintegrant or a superdisintegrant. (Item 5) 5. The pharmaceutical oral dosage form according to any of items 2 to 4, wherein the binder in the granules a) is not cross-linked starch, microcrystalline cellulose, cross-linked cellulose, cross-linked polyvinylpyrrolidone (crospovidone), cross-linked alginic acid, soy polysaccharides or calcium silicate. (Item 6) 6. The pharmaceutical oral dosage form according to any of items 2 to 5, wherein the binder in the granules a) is selected from gum acacia, gum tragacanth, gelatin, sucrose, starch, and non-crosslinked polyvinylpyrrolidone (PVP), preferably non-crosslinked polyvinylpyrrolidone (PVP). (Item 7) 7. The pharmaceutical oral dosage form according to item 6, wherein the binder in the granules a) is present in the pharmaceutical dosage form in an amount of about 0.1% to 5% by weight, preferably about 0.2% to 3.5% by weight, more preferably about 0.3% to 3% by weight. (Item 8) 8. The pharmaceutical oral dosage form according to any of items 2 to 7, wherein the filler in the granules a) is selected from mannitol, dextrose, dextrin, lactose, sorbitol, sucrose, inositol, preferably mannitol. (Item 9) 9. The pharmaceutical oral dosage form according to item 8, wherein the filler in the granules a) is present in the pharmaceutical dosage form in an amount of about 1.5% to 25% by weight, preferably about 1.75% to 22.5% by weight, more preferably about 1.9% to 20% by weight. (Item 10) The solubilizer in the granules a) is D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS), sodium lauryl sulfate (SLS), polyoxyethylene sorbitan monooleate (Tween (登録商標) ), cetyltrimethylammonium bromide (CTAB), amino acids such as glycine, polyethylene glycol, preferably D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS). (Item 11) 11. The pharmaceutical oral dosage form according to item 10, wherein said solubilizer in said granules a) is present in said pharmaceutical dosage form in an amount of about 0.5% to 8% by weight, preferably about 0.6% to 7.5% by weight, more preferably about 0.68% to 6.8% by weight. (Item 12) The pharmaceutical oral dosage form according to any of the preceding items, wherein the granules comprise, preferably consist of, 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, a binder which is non-crosslinked polyvinylpyrrolidone (PVP), a filler which is mannitol, and a solubilizer which is D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS). (Item 13) The pharmaceutical oral dosage form according to any of the preceding items, wherein the at least one binder in the blend (b) surrounding the granules is selected from starch, microcrystalline cellulose, povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose and combinations thereof, preferably a binder also having disintegrant qualities, and more preferably microcrystalline cellulose. (Item 14) 14. The pharmaceutical oral dosage form according to item 13, wherein the at least one binder in the blend (b) surrounding the granules is present in the pharmaceutical dosage form in an amount of about 25% to 50% by weight, preferably about 28% to 45% by weight, more preferably about 30% to 43% by weight. (Item 15) The pharmaceutical oral dosage form according to any of the preceding items, wherein the at least one lubricant in the blend (b) surrounding the granules is selected from magnesium stearate, calcium stearate, PEG 6000, sodium stearyl stearate, sodium lauryl sulfate, colloidal silicon dioxide and combinations thereof, preferably the at least one lubricant in the blend (b) surrounding the granules is a combination of colloidal silicon dioxide and magnesium stearate. (Item 16) 16. The pharmaceutical oral dosage form according to item 15, wherein the at least one lubricant in the blend (b) surrounding the granules is present in the pharmaceutical dosage form in an amount of about 1% to 5% by weight, preferably about 0.5% to 4% by weight, more preferably about 0.75% to 3.5% by weight, and wherein if the at least one lubricant in the blend (b) surrounding the granules is a combination of colloidal silicon dioxide and magnesium stearate, the colloidal silicon dioxide is present in the pharmaceutical dosage form in an amount of about 0.5% to 3.5% by weight, preferably about 1% to 2.5% by weight, more preferably about 2% by weight, and wherein in such combination the magnesium stearate is present in the pharmaceutical dosage form in an amount of about 0.1% to 2% by weight, preferably about 0.5% to 1.5% by weight, more preferably about 0.8% by weight. (Item 17) The pharmaceutical oral dosage form according to any of the preceding items, wherein the at least one disintegrant in the blend (b) surrounding the granules is selected from crosslinked starch, starch glycolate, e.g., sodium starch glycolate, microcrystalline cellulose, crosslinked cellulose, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked alginic acid, croscarmellose, e.g., croscarmellose sodium or croscarmellose calcium, soy polysaccharides, and calcium silicate. (Item 18) 18. The pharmaceutical oral dosage form according to item 17, wherein the at least one disintegrant in the blend (b) surrounding the granules is present in the pharmaceutical dosage form in an amount of about 5% to 12% by weight, preferably about 7.5% to 10% by weight, more preferably about 8% to 8.5% by weight. (Item 19) 19. The pharmaceutical oral dosage form according to any of items 2 to 18, wherein the blend surrounding the granules comprises a filler, the filler being preferably the same filler as that contained in the granules. (Item 20) 20. The pharmaceutical oral dosage form according to item 19, wherein the filler in the blend surrounding the granules is present in the pharmaceutical dosage form in an amount of about 25% to 50% by weight, preferably about 27.5% to 45% by weight, more preferably about 31% to 43% by weight. (Item 21) The pharmaceutical oral dosage form according to any of the preceding items, wherein the 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate is present in the pharmaceutical dosage form in an amount of about 1% to 35% by weight, preferably about 2% to 30% by weight, and more preferably about 2.7% to 27.5% by weight. (Item 22) a) a granule comprising 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate in an amount of about 23-30% by weight of said dosage form, mannitol in an amount of about 15-25% by weight of said dosage form, polyvinylpyrrolidone in an amount of about 1-5% by weight of said dosage form, D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS) in an amount of about 5-8% by weight of said dosage form; and b) a blend surrounding said granules and comprising microcrystalline cellulose in an amount of about 30-34% by weight of said dosage form, colloidal silicon dioxide in an amount of about 1-3% by weight of said dosage form, magnesium stearate in an amount of about 0.5-1.5% by weight of said dosage form, and croscarmellose sodium in an amount of about 7-10% by weight of said dosage form; or c) granules comprising 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate in an amount of about 12-15% by weight of said dosage form, mannitol in an amount of about 8-12% by weight of said dosage form, polyvinylpyrrolidone in an amount of about 1-2% by weight of said dosage form, D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS) in an amount of about 2-5% by weight of said dosage form; and d) a blend surrounding said granules and comprising microcrystalline cellulose in an amount of about 30-33% by weight of said dosage form, mannitol in an amount of about 30-33% by weight of said dosage form, magnesium stearate in an amount of about 0.5-1.5% by weight of said dosage form, and croscarmellose sodium in an amount of about 7-10% by weight of said dosage form; or e) granules comprising 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate in an amount of about 1-5% by weight of said dosage form, mannitol in an amount of about 1-3% by weight of said dosage form, polyvinylpyrrolidone in an amount of about 0.1-0.5% by weight of said dosage form, D-α-tocopherol polyethylene glycol succinate (vitamin E-TPGS) in an amount of about 0.5-0.8% by weight of said dosage form; and f) a blend surrounding said granules and comprising microcrystalline cellulose in an amount of about 40-45% by weight of said dosage form, mannitol in an amount of about 40-45% by weight of said dosage form, magnesium stearate in an amount of about 0.5-1.5% by weight of said dosage form, and croscarmellose sodium in an amount of about 7-10% by weight of said dosage form; 2. The pharmaceutical oral dosage form according to any of the preceding items, comprising a mixture of: (Item 23) 23. A method for preparing a pharmaceutical oral dosage form according to any one of items 1 to 22, wherein the method comprises the steps of: i) granulating 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate and the components of granule a) as described in any of items 1 to 22 by a suitable granulation process; The suitable granulation process is preferably selected from fluidized bed granulation, high shear granulation, fluidized bed drying, fluidized spray drying, single pot granulation, steam granulation, thermoplastic granulation, pneumatic dry granulation, moisture activated dry granulation, melt granulation, freeze granulation, and foam granulation; ii) blending the granules obtained in step i with a blend component as defined in any of items 1 to 22; iii) compressing the mixture obtained in step ii) into a pharmaceutical dosage form, preferably a tablet; and optionally iv) coating the dosage form obtained in step iii), The method includes: (Item 24) 24. A pharmaceutical oral dosage form obtainable by the method according to item 23. (Item 25) 25. The pharmaceutical oral dosage form according to any of items 1 to 22 or 24 for use in the treatment of a bacterial infection, preferably tuberculosis or Buruli ulcer.

Claims

[Claim 1] The invention described in the specification.

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