METHODS OF MANUFACTURING CORTISCOSTEROID SOLUTIONS

Abstract

The present invention relates to methods of manufacturing compositions comprising a corticosteriod and at least one solubility enhancer, as well as compositions made by these methods.

Description

DESCRIPTION OF THE FIGURES

FIG. 1 shows the dissolution rate of the corticosteroid, budesonide, with varying amounts of Captisol® (SBE7-β-CD) with and without PS80. The procedures for the studies are described in Examples 1A-1D.

FIG. 2 shows the dissolution rate of the corticosteroid, budesonide, with varying amounts of Captisol® (SBE7-β-CD). The procedures for the studies are described in Examples 1A-1C.

FIG. 3 shows the dissolution rate of the corticosteroid, budesonide, with varying amounts of Captisol® (SBE7-β-CD) with and without PS80. The procedures for the studies are described in Examples 1A-1D.

FIG. 4 is a process flow diagram including process steps according to the present invention.

FIG. 5 is a process flow diagram depicting an alternative embodiment of the dissolution process according to the present invention.

FIG. 6 is a graph demonstrating the effect of temperature on the dissolution profiles of two concentrations of budesonide solution.

Claims

1. A process of making a corticosteroid solution, comprising the steps of: (a) combining ingredients of the corticosteroid solution comprising as starting materials a corticosteroid, at least one solubility enhancer and water in a high sheer mixer having a capacity greater than or equal to about 50 L; and(b) homogenizing the ingredients for a homogenizing period of about 5 hours or less;whereby at least about 98% of the corticosteroid starting material is dissolved within the homogenizing period.

2. The process of claim 1, wherein the corticosteroid is budesonide.

3. The process of claim 1, wherein the solubility enhancer comprises a sulfoalkyl ether cyclodextrin (SAE-CD).

4. The process of claim 3, wherein the SAE-CD is SBE7-β-CD.

5. The process of claim 1, wherein the corticosteroid solution further comprises albuterol.

6. The process of claim 1, wherein at least about 98.5% of the corticosteroid is dissolved within the homogenizing period.

7. The process of claim 1, wherein the homogenizing period is about 2 hours or less.

8. The process of claim 1, wherein at least about 99% of the corticosteroid is dissolved within the homogenizing period.

9. The process of claim 8, wherein the homogenizing period is about 2 hours or less.

10. The process of claim 1, wherein at least about 99.5% of the corticosteroid is dissolved within the homogenizing period.

11. The process of claim 10, wherein the homogenizing period is about 2 hours or less.

12. The process of claim 1, wherein at least about 95% of the corticosteroid is dissolved within the first hour of the homogenizing period.

13. The process of claim 12, wherein at least about 97% of the corticosteroid is dissolved within the first hour of the homogenizing period.

14. The process of claim 1, wherein the high sheer mixer has a capacity of about 100 L to about 10000 L, about 250 L to about 4000 L or about 500 L.

15. The process of claim 1, wherein the budesonide solution substantially excludes polysorbate 80.

16. The process of claim 1, wherein the budesonide solution contains less than about 0.01 wt-% polysorbate 80 or less than about 0.005 wt-% polysorbate 80.

17. The process of claim 1, wherein the budesonide solution comprises two or more solubility enhancers.

18. The process of claim 17, wherein the solubility enhancer is a combination of polyoxyethylene sorbitan monooleate and a cyclodextrin.

19. The process of claim 18, wherein the polyoxyethylene sorbitan monooleate is polysorbate 80.

20. The process of claim 19, wherein the polysorbate is present in an amount of between about 0.005 wt-% to about 0.1 wt-%.

21. The process of claim 1, wherein the high sheer mixer is a FrymaKoruma Dinex model 700, 1300, 2400, 3500, 4200 or 5200.

22. The process of claim 21, wherein the high sheer mixer is a FrymaKoruma Dinex model 700.

23. The process of claim 1, wherein the homogenization speed is between about 1000 to about 3000 rpm.

24. The process of claim 23, comprising homogenizing the mixture at a homogenization speed of about 1500 to about 3000 rpm.

25. The process of claim 24, wherein the homogenization speed is about 1700 rpm to about 2500 rpm.