Dosage forms comprising a plasma kallikrein inhibitor
The present invention relates to oral solid dosage forms comprising a plasma kallikrein inhibitor, in particular a solid form (Form 1) of the compound of Formula A. Also provided are methods of preparing oral solid dosage forms comprising the compound of Formula A using Form 1 of the compound of Formula A.
1. An oral solid dosage form comprising a solid form of the compound of Formula A
wherein the solid form of the compound of Formula A exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 11.2, 12.5, 13.2, 14.5 and 16.3.
2. The oral solid dosage form of claim 1 , wherein the amount of the solid form of the compound of Formula A in the dosage form is between 0.1 mg and 1,000 mg.
3. The oral solid dosage form of claim 1 , wherein the solid form of the compound of Formula A is present in an amount of between 1 wt % and 70 wt % based on the total weight of the oral solid dosage form.
4. The oral solid dosage form of claim 1 , further comprising a binder.
5. The oral solid dosage form of claim 1 , further comprising a diluent.
6. The oral solid dosage form of claim 5 , wherein the weight ratio of the compound of Formula A to the diluent is between 1:0.1 and 1:500.
7. The oral dosage form of claim 5 , wherein the diluent comprises one or more of calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, powdered cellulose, a dextrate, a dextrin, a dextrose excipient, fructose, kaolin, lactitol, lactose, lactose monohydrate, mannitol, sorbitol, maltitol, starch, pregelatinized starch or sucrose.
8. The oral dosage form of claim 5 , wherein the diluent is present in an amount of between 1 wt % and 99 wt % based on the total weight of the oral solid dosage form.
9. The oral solid dosage form of claim 1 , further comprising a disintegrant, lubricant, and/or glidant.
10. The oral solid dosage form of claim 1 , further comprising an acid.
11. The oral dosage form of claim 10 , wherein the acid is present in an amount of between 1 wt % and 40 wt % based on the total weight of the oral solid dosage form.
12. The oral dosage form of claim 10 , wherein the weight ratio of the compound of Formula A to the acid is between 1:0.1 and 1:2.
13. The oral dosage form of claim 10 , wherein the acid is one or more of maleic acid, tartaric acid, succinic acid and citric acid.
14. The oral solid dosage form of claim 1 , further comprising a surfactant.
15. The oral dosage form of claim 14 , wherein the surfactant is present in an amount of between 1 wt % and 20 wt % based on the total weight of the oral solid dosage form.
16. The oral dosage form of claim 14 , wherein the surfactant is present in an amount of between 1 wt % and 20 wt % based on the total weight of the oral solid dosage form, and/or wherein the weight ratio of the compound of Formula A to the surfactant is between 1:0.01 and 1:1.
17. The oral dosage form of claim 14 , wherein the surfactant comprises sodium lauryl sulfate and/or Tween 80.
18. The oral solid dosage form of claim 1 , further comprising a lipid excipient.
19. The oral dosage form of claim 18 , wherein the excipient is present in an amount of between 10 wt % and 99% based on the total weight of the oral solid dosage form.
20. The oral dosage form of claim 18 , wherein the weight ratio of the compound of Formula A to the lipid excipient is between 1:0.1 and 1:100.
21. The oral dosage form of claim 18 , wherein the lipid excipient comprises one or more of a sucrose fatty acid ester, phospholipid derivative, phosphatidyl derivative, glycosylceramide derivative, fatty acid derivative, nonionic surfactant, vitamin E tocopheryl succinate polyethylene glycol (TPGS), D-α-tocopherol polyethylene glycol succinate (TPGS), glyceryl monooleate, a glyceride derivative, or mixtures thereof.
22. The oral dosage form of claim 21 , wherein the sucrose fatty acid ester is sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, or sucrose erucate.
23. The oral solid dosage form of claim 1 , wherein the oral solid dosage form is in the form of a capsule or a tablet.
24. The oral dosage form of claim 23 , wherein the capsule shell is made from gelatin, hydroxypropyl methylcellulose or starch.
25. The oral dosage form of claim 23 , further comprising a coating.
26. The oral solid dosage form of claim 25 , wherein the coating is an enteric coating.
27. The oral solid dosage form of claim 1 , comprising one or more further active ingredients.
28. The oral solid dosage form of claim 1 , wherein the solid form of the compound of Formula A, wherein the solid form of the compound of Formula A exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 11.2, 12.5, 13.2, 14.5, 16.3, 17.4 and 17.9.
29. The oral solid dosage form of claim 1 , wherein the solid form of the compound of Formula A exhibits an endothermic peak in its DSC thermograph at 151±3° C.
30. A method of treating a disease or condition mediated by plasma kallikrein, said method comprising administering to a mammal in need of such treatment an oral solid dosage form as claimed in claim 1 .
31. The method of claim 30 , wherein the disease or condition mediated by plasma kallikrein is selected from impaired visual acuity, diabetic retinopathy, retinal vascular permeability associated with diabetic retinopathy, diabetic macular edema, hereditary angioedema, retinal vein occlusion, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery and bleeding from post-operative surgery.
32. The method of claim 30 , wherein the disease or condition mediated by plasma kallikrein is selected from retinal vascular permeability associated with diabetic retinopathy, diabetic macular edema and hereditary angioedema.
33. The method of claim 30 , wherein the disease or condition mediated by plasma kallikrein is selected from retinal vascular permeability associated with diabetic retinopathy, and diabetic macular edema.
34. The method of claim 30 , wherein the disease or condition mediated by plasma kallikrein is hereditary angioedema.
35. The method of claim 30 , wherein the disease or condition mediated by plasma kallikrein is diabetic macular edema.
36. The oral solid dosage form of claim 1 , wherein the binder is present in an amount of between 0.1 wt % and 30 wt % based on the total weight of the oral solid dosage form, and/or the weight ratio of the compound of Formula A to the binder is between 1:0.01 and 1:1.
37. The oral solid dosage form of claim 1 , wherein the binder comprises one or more of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, or sodium alginate.
38. A method of preparing an oral solid dosage form comprising a compound of Formula A
wherein the method comprises method (i), method (ii), or method (iii), method (i) comprising the steps of:
(a) mixing a solid form of the compound of Formula A which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 11.2, 12.5, 13.2, 14.5 and 16.3 with a granulation fluid comprising a binder;
(b) granulating the dispersion of step (a) to form granules;
(c) drying the granules;
(d) optionally blending the granules of step (b) or (c) with a diluent, an acid, a surfactant, and/or a lubricant to form blended granules; and
(e) compressing or filling the granules or blended granules into a solid oral dosage form; or
method (ii) comprising the steps of:
(a) dispersing a solid form of the compound of Formula A which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 11.2, 12.5, 13.2, 14.5 and 16.3 in molten lipid excipient;
(b) loading the molten dispersion into a capsule; or
method (iii) comprising loading a capsule with a solid form of the compound of Formula A which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 11.2, 12.5, 13.2, 14.5 and 16.3.
39. The method of claim 38 that is method (i) and wherein the drying in step (c) is performed at a temperature greater than 45° C. and/or in step (e), the granules or blended granules are compressed into a solid oral dosage form in the form of a tablet.
40. The method of claim 39 , wherein step (c) is performed at greater than 55° C.
41. The method of claim 38 that is method (ii) and wherein the lipid excipient is D-α-tocopherol polyethylene glycol succinate (TPGS) or a glyceride derivative and/or the capsule shell is made from gelatin, hydroxypropyl methylcellulose or starch.
42. The method of claim 38 , wherein the solid form of the compound of Formula A, wherein the solid form of the compound of Formula A exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 11.2, 12.5, 13.2, 14.5, 16.3, 17.4 and 17.9.
43. The method of claim 38 , wherein the solid form of the compound of Formula A exhibits an endothermic peak in its DSC thermograph at 151±3° C.
44. The method of claim 38 , wherein the granulation fluid further comprises water, a diluent, a disintegrant, and/or a surfactant.
45. The method of claim 38 , further comprising:
blending the granules of step (b) or (c) with a diluent, an acid, a surfactant, and/or a lubricant to form blended granules; and
compressing or filling the blended granules into the solid oral dosage form.
46. The method of claim 38 , wherein the lipid excipient is D-α-tocopherol polyethylene glycol succinate (TPGS).
47. A solid form of the compound of Formula A
wherein the solid form of the compound of Formula A exhibits an X-ray powder diffraction peak (Cu Kα radiation, expressed in degrees 2θ) at approximately 8.5.
48. The solid form of claim 47 , wherein the solid form of the compound of Formula A further exhibits an X-ray powder diffraction peak (Cu Kα radiation, expressed in degrees 2θ) at approximately 12.8.
49. The solid form of claim 48 , wherein the solid form of the compound of Formula A further exhibits an X-ray powder diffraction peak (Cu Kα radiation, expressed in degrees 2θ) at approximately 14.1.
50. The solid form of claim 49 , wherein the solid form of the compound of Formula A further exhibits an X-ray powder diffraction peak (Cu Kα radiation, expressed in degrees 2θ) at approximately 9.4.
51. The solid form of claim 50 , wherein the solid form of the compound of Formula A further exhibits an X-ray powder diffraction peak (Cu Kα radiation, expressed in degrees 2θ) at approximately 12.2.
52. The solid form of claim 47 , wherein the solid form of the compound of Formula A has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 6 b.
53. A solid form of the compound of Formula A
wherein the solid form of the compound of Formula A exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at approximately 12.8 and 14.1.