Pharmaceutical compositions comprising venglustat
The present disclosure relates to pharmaceutical compositions, including dosage forms, such as tablets or capsules, comprising venglustat, in free base, or pharmaceutically acceptable salt form, a diluent/filler and a lubricant, optionally in combination with one or more additional therapeutic agents, to processes for manufacture thereof, and to methods of use in the treatment or prevention of disease.
1. A process for the manufacture of an oral pharmaceutical composition comprising venglustat, (S)-quinuclidin-3-yl(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate:
in free base or pharmaceutically acceptable salt form, wherein the composition is a finished dosage form which is a tablet, and wherein the process comprises the steps of:
(a) sieving each ingredient;
(b) combining venglustat, in free base or pharmaceutically acceptable salt form, with a diluent/filler, and with sodium stearyl fumarate as a first lubricant, and optionally with a glidant, any colors or flavors, or any other excipients, or a combination thereof;
(c) blending and/or milling and/or granulating the resulting the mixture;
(d) optionally screening the resulting mixture;
(e) adding at least one other diluent or carrier to the mixture;
(f) blending and/or milling and/or granulating the resulting mixture;
(g) optionally screening the resulting mixture;
(h) adding magnesium stearate as a second lubricant and any additional excipients;
(i) blending and/or milling the resulting mixture;
(j) optionally granulating the resulting mixture;
(k) optionally screening the resulting mixture;
(l) compressing the resulting material to form a tablet;
(m) optionally applying one or more coatings to the tablet; and
(n) optionally packaging the resulting finished dosage form.
2. The process according to claim 1 , wherein the venglustat is venglustat malate.
3. The process according to claim 1 , wherein steps (i), (j), and/or (k) are repeated for additional excipients added in step (h) before proceeding to steps (l), (m), or (n).
4. The process according to claim 1 , wherein the magnesium stearate is added as the final excipient added before final mixing and compression to form the tablet.
5. The process according to claim 1 , wherein the diluent/filler is mannitol, and the disintegrant is crospovidone, and the binder is hydroxypropyl cellulose, and the glidant is silica.
6. The process according to claim 1 , wherein the process comprises the following steps:
(a) sieving each of a first portion of mannitol, silica, venglustat malate, flavor, and sodium stearyl fumarate, and optionally sucralose;
(b) combining the venglustat malate with the sieved mannitol, silica, flavor, and sodium stearyl fumarate, and optionally sucralose, optionally wherein each ingredient is sieved sequentially into a common container to combine the ingredients;
(c) blending and/or milling and/or granulating the resulting mixture;
(e) sieving a second portion of mannitol, low-substituted hydroxypropyl cellulose, and crospovidone, and adding these sieved ingredients to the mixture from step (c);
(f) blending and/or milling and/or granulating the resulting mixture;
(h) sieving magnesium stearate and adding it to the mixture from step (f);
(i-j) blending and/or milling and/or granulating the resulting mixture;
(l) compressing the resulting material to form a tablet; and
(n) optionally packaging the resulting finished dosage form.
7. The process according to claim 6 , wherein sodium stearyl fumarate is combined in step (b) in an amount to provide 2-3% by weight of sodium stearyl fumarate in the tablet.
8. The process according to claim 6 , wherein magnesium stearate is added in step (h) in an amount to provide from 0.1-1% by weight of magnesium stearate in the tablet.
9. A process for the manufacture of an oral pharmaceutical composition comprising venglustat, (S)-quinuclidin-3-yl(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate:
in free base or pharmaceutically acceptable salt form, wherein the composition is a finished dosage form which is a capsule, and wherein the process comprises the steps of:
(a) sieving each ingredient;
(b) combining venglustat, in free base or pharmaceutically acceptable salt form, with a diluent/filler, and optionally with a glidant, any colors or flavors, or any other excipients, or a combination thereof;
(c) blending and/or milling and/or granulating the resulting the mixture;
(d) optionally screening the resulting mixture;
(e) adding at least one other diluent or carrier to the mixture and adding a first portion of magnesium stearate as a lubricant to the mixture;
(f) blending and/or milling and/or granulating the resulting mixture;
(g) optionally screening the resulting mixture;
(h) adding the remaining portion of magnesium stearate as a lubricant and any additional excipients;
(i) blending and/or milling the resulting mixture;
optionally granulating the resulting mixture;
(k) optionally screening the resulting mixture;
(l) filling the resulting material into hard capsules; and
(m) optionally applying one or more coatings to the capsule; and
(n) optionally packaging the resulting finished dosage form;
wherein steps (i), (j), and/or (k) are repeated for additional excipients added in step (h) before proceeding to steps (l), (m), or (n).
10. The process according to claim 9 , wherein the venglustat is venglustat malate.
11. A process for the manufacture of an oral pharmaceutical composition comprising venglustat, (S)-quinuclidin-3-yl(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate:
in malate salt form, wherein the composition is a finished dosage form which is a capsule, wherein the process comprises the following steps:
(a) sieving one or more ingredients to be used in step (b);
(b) combining venglustat malate with a first portion of microcrystalline cellulose, and croscarmellose sodium, optionally sucralose and optionally flavor, optionally wherein these ingredients are not previously sieved;
(c) blending and/or milling and/or granulating the resulting mixture;
(d) optionally sieving the resulting mixture;
(e) adding a second portion of microcrystalline cellulose, silica, and a first portion of magnesium stearate to the mixture from step (c), optionally wherein these added ingredients are previously sieved from step (a);
(f) blending and/or milling and/or granulating the resulting mixture;
(h) sieving the remaining portion of magnesium stearate and/or adding it to the mixture from step (f);
(i-j) blending and/or milling and/or granulating the resulting mixture;
(l) filling the resulting material into hard capsules; and
(n) optionally packaging the resulting finished dosage form.
12. The process according to claim 11 , wherein the first portion of magnesium stearate comprises 15-50% by weight, or 20-30% by weight of the total magnesium stearate lubricant added, and wherein the remaining portion of magnesium stearate comprises 50-85% by weight, or 70-80% by weight, of the total magnesium stearate lubricant added.