Amorphous rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid and its pharmaceutical compositions
The present invention provides an amorphous form of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid. This invention also provides processes for preparing the amorphous form and pharmaceutical compositions including the amorphous form.
1. A micronized amorphous form of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid,
said amorphous form having an X-ray diffraction peak pattern comprising abroad halo at 2θ of about 17° and
a differential scanning calorimetry thermogram lacking the endotherm peak of about 164° for crystalline rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid.
2. The micronized form according to claim 1 , which is prepared by micronizing amorphous rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid in a jet mill.
3. The micronized amorphous form according to claim 2 , wherein said jet mill is a TROST™ mill, an MC JETMILL®, or an ALPINE™ AS spiral jet mill.
4. A solid pharmaceutical composition comprising the micronized amorphous form according to claim 1 .
5. A method of preparing a pharmaceutical composition comprising an amorphous form of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, comprising combining the components:
(i) an amorphous form of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid,
(ii) a metal chelator,
(iii) a pH adjuster,
(iv) a surfactant,
(v) at least one filler,
(vi) a binder,
(vii) a disintegrant, and
(viii) a lubricant.
6. The method according to claim 5 , wherein said metal chelator is edetic acid, malic acid, or fumaric acid.
7. The method according to claim 6 , wherein said metal chelator is edetic acid.
8. The method according to claim 5 , wherein said pH adjuster comprises citric acid, ascorbic acid, fumaric acid, or malic acid.
9. The method according to claim 8 , wherein said pH adjuster is citric acid.
10. The method according to claim 5 , wherein said surfactant comprises a compound comprising a polysorbate, a compound comprising a sorbitan ester, poloxamer, or sodium lauryl sulfate.
11. The method according to claim 5 , wherein said surfactant is sodium lauryl sulfate.
12. The method according to claim 5 , wherein said filler is anhydrous lactose, microcrystalline cellulose, mannitol, calcium phosphate, pregelatinized starch, or sucrose.
13. The method according to claim 12 , wherein said filler comprises anhydrous lactose.
14. The method according to claim 12 , wherein said filler comprises microcrystalline cellulose.
15. The method according to claim 5 , wherein said binder comprises povidone, hydroxypropylmethylcellulose, carboxymethylcellulose, or gelatin.
16. The method according to claim 15 , wherein said binder is povidone.
17. The method according to claim 5 , wherein said disintegrant comprises croscarmellose sodium, a starch, sodium starch glycolate, pregelatinized starch or crospovidone.
18. The method according to claim 17 , wherein said disintegrant is croscarmellose sodium.
19. The method according to claim 5 , wherein said lubricant comprises magnesium stearate, stearic acid, or sodium stearyl furamate.
20. The method according to claim 19 , wherein said lubricant comprises magnesium stearate.
21. The method according to claim 5 , wherein said components are dry blended and compressed into a form suitable for administration to a mammalian subject.
22. The method according to claim 5 , wherein said components are dry granulated and compressed into a form suitable for administration to a mammalian subject.
23. The method according to claim 5 , wherein said components are wet granulated and compressed into a form suitable for administration to a mammalian subject.
24. The method according to claim 23 , wherein the form is a tablet or caplet.
25. The method according to claim 23 , wherein the form is a liquid suspension.
26. A method of preparing a pharmaceutical composition comprising an amorphous form of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, comprising the steps of:
(a) combining an (i) amorphous form of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (ii) edetic acid, and (iii) citric acid;
(b) combining sodium lauryl sulfate, a first portion of anhydrous lactose, povidone, and a first portion of croscarmellose sodium;
(c) combining the product of (b) with the product of (a);
(d) combining a second portion of anhydrous lactose and a second portion of croscarmellose sodium with the product of (c);
(e) blending the product of (d); and
(f) combining the product of (e) with magnesium stearate.
27. The method according to claim 26 , wherein the product of step (b) is passed through a screen.