PHARMACEUTICAL COMPOSITIONS
The present invention provides for a method of treatment of IgA nephropathy, which method comprises: (i) identifying a pharmaceutically acceptable composition intended to treat IgA nephropathy comprising budesonide and one or more pharmaceutically-acceptable excipients that provide for a modified release of said budesonide after administration to the gastrointestinal tract, which composition fulfils the following requirements in a standard in vitro USP<711>/Ph.Eur. 2.9.3 dissolution test using a dissolution apparatus according to Apparatus 2 (Paddle Apparatus) of said test; (a) the composition fulfils the requirement that no more than about 10% of the budesonide is released into the dissolution medium within about 120 minutes, when the dissolution medium is aqueous and has a pH of about 1.2; (b) the composition fulfils the requirement that no more than about 10% of the budesonide is released into a pharmaceutically-relevant dissolution medium within about 30 minutes; and (c) the composition fulfils the requirement that at least about 70% of the budesonide is released into the pharmaceutically-relevant dissolution medium within about 120 minutes; (ii) wherein the method comprises the step of administering said composition to a patient with IgA nephropathy in need of said treatment.
1 . A method of treating IgA nephropathy in a subject in need thereof, comprising:
administering to the subject a pharmaceutical composition comprising budesonide and one or more extended release excipients;
wherein the one or more extended release excipients comprise a pharmaceutically-acceptable water-insoluble polymer;
wherein the pharmaceutical composition further comprises an enteric coating;
wherein the pharmaceutical composition meets the following release profile in a standard in vitro USP<711> dissolution test using a dissolution apparatus according to Apparatus 2 (Paddle Apparatus) at a paddle rotation speed of 100 rpm:
a) no more than about 10% of the budesonide is released into an aqueous dissolution medium with a pH of about 1.2 within about 120 minutes;
b) no more than about 10% of the budesonide is released into a pharmaceutically-relevant dissolution medium within about 30 minutes; and
c) at least about 70% of the budesonide is released into the pharmaceutically-relevant dissolution medium within about 120 minutes;
wherein the pharmaceutically-relevant dissolution medium is selected from the group consisting of a phosphate buffer medium at a pH of about 6.5, a phosphate buffer medium at a pH of about 6.8, or a Level 1 Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH of about 6.5; and
wherein the pharmaceutical composition is orally administered as a solid dosage form.
2 . The method of claim 1 wherein the pharmaceutically-relevant dissolution medium is a phosphate buffer medium at a pH of about 6.5.
3 . The method of claim 1 wherein the pharmaceutically-relevant dissolution medium is a phosphate buffer medium at a pH of about 6.8.
4 . The method of claim 1 wherein the pharmaceutically-relevant dissolution medium is a Level 1 Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH of about 6.5.
5 . The method of claim 1 , wherein the one or more extended release excipients further comprise a pharmaceutically-acceptable pore-forming polymer.
6 . The method of claim 5 , wherein the water-insoluble polymer comprises one or more coalescable polymers.
7 . The method of claim 5 , wherein the water-insoluble polymer comprises ethylcellulose.
8 . The method of claim 5 , wherein the pore-forming polymer comprises hydroxypropylmethyl cellulose (HPMC).
9 . The method of claim 1 , wherein the budesonide is substantially released to the ileum region of the small intestine in the subject.
10 . The method of claim 9 , wherein at least about 60% of the initial content of budesonide is released to the ileum region of the small intestine in the subject.
11 . The method of claim 9 , wherein at least about 75% of the initial content of budesonide is released to the ileum region of the small intestine in the subject.
12 . The method of claim 9 , wherein at least about 90% of the initial content of budesonide is released to the ileum region of the small intestine in the subject.
13 . The method of claim 1 , wherein the subject is administered a daily dose of about 16 mg of budesonide.
14 . The method of claim 1 , wherein the solid dosage form is a capsule.
15 . The method of claim 14 , wherein the enteric coating is present in an amount of from about 34 mg to about 46 mg per capsule.
16 . The method of claim 1 , wherein the subject experiences a statistically significant reduction in its urine protein-to-creatinine ratio (UPCR) relative to the UPCR baseline in the subject prior to treatment.
17 . The method of claim 16 , wherein the subject has a baseline urine protein-to-creatinine ratio (UPCR) 1.5 g/g.
18 . The method of claim 16 , wherein the subject has a baseline urine protein-to-creatinine ratio (UPCR) 0.8 g/g.
19 . The method of claim 16 , wherein the statistically significant reduction is at least 20% relative to the UPCR baseline in the subject prior to treatment.
20 . The method of claim 16 , wherein the statistically significant reduction is at least 25% relative to the UPCR baseline in the subject prior to treatment.
21 . A method of treating IgA nephropathy in a subject in need thereof, comprising:
administering to the subject a pharmaceutical composition comprising one or more cores comprising budesonide;
wherein the one or more cores are coated with an extended release coating comprising a pharmaceutically acceptable water-insoluble polymer and pharmaceutically-acceptable pore-forming polymer;
wherein the pharmaceutical composition further comprises an enteric coating;
wherein the pharmaceutical composition meets the following release profile in a standard in vitro USP<711> dissolution test using a dissolution apparatus according to Apparatus 2 (Paddle Apparatus) at a paddle rotation speed of 100 rpm:
a) no more than about 10% of the budesonide is released into an aqueous dissolution medium with a pH of about 1.2 within about 120 minutes;
b) no more than about 10% of the budesonide is released into a pharmaceutically-relevant dissolution medium within about 30 minutes; and
c) at least about 70% of the budesonide is released into the pharmaceutically-relevant dissolution medium within about 120 minutes;
wherein the pharmaceutically-relevant dissolution medium is selected from the group consisting of a phosphate buffer medium at a pH of about 6.5, a phosphate buffer medium at a pH of about 6.8, or a Level 1 Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH of about 6.5; and
wherein the pharmaceutical composition is orally administered as a solid dosage form.
22 . The method of claim 21 wherein the pharmaceutically-relevant dissolution medium is a phosphate buffer medium at a pH of about 6.5.
23 . The method of claim 21 wherein the pharmaceutically-relevant dissolution medium is a phosphate buffer medium at a pH of about 6.8.
24 . The method of claim 21 wherein the pharmaceutically-relevant dissolution medium is a Level 1 Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH of about 6.5.
25 . The method of claim 21 , wherein the water-insoluble polymer is present in an amount of from about 45 wt. % to about 90 wt. % of the total extended release coating and the pore-forming polymer is present in an amount of from about 35 wt. % to about 5 wt. % of the total extended release coating.
26 . The method of claim 21 , wherein the water-insoluble polymer is present in an amount of from about 47 wt. % to about 56 wt. % of the total extended release coating and the pore-forming polymer is present in an amount of from about 32 wt. % to about 22 wt. % of the total extended release coating.
27 . The method of claim 21 , wherein the extended release coating is present in an amount of from about 5 wt. % to about 18 wt. % of the total coated core weight.
28 . The method of claim 21 , wherein the extended release coating is present in an amount of from about 6 wt. % to about 13 wt. % of the total coated core weight.
29 . The method of claim 21 , wherein the water-insoluble polymer comprises one or more coalescable polymers.
30 . The method of claim 21 , wherein the water-insoluble polymer comprises ethylcellulose.
31 . The method of claim 21 , wherein the pore-forming polymer comprises hydroxypropylmethyl cellulose (HPMC).
32 . The method of claim 21 , wherein the budesonide is substantially released to the ileum region of the small intestine in the subject.
33 . The method of claim 32 , wherein at least about 60% of the initial content of budesonide is released to the ileum region of the small intestine in the subject.
34 . The method of claim 32 , wherein at least about 75% of the initial content of budesonide is released to the ileum region of the small intestine in the subject.
35 . The method of claim 32 , wherein at least about 90% of the initial content of budesonide is released to the ileum region of the small intestine in the subject.
36 . The method of claim 21 , wherein the subject is administered a daily dose of about 16 mg of budesonide.
37 . The method of claim 21 , wherein the solid dosage form is a capsule.
38 . The method of claim 37 , wherein the enteric coating is present in an amount of from about 34 mg to about 46 mg per capsule.
39 . The method of claim 21 , wherein the subject experiences a statistically significant reduction in its urine protein-to-creatinine ratio (UPCR) relative to the UPCR baseline in the subject prior to treatment.
40 . The method of claim 39 , wherein the subject has a baseline urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g.
41 . The method of claim 39 , wherein the subject has a baseline urine protein-to-creatinine ratio (UPCR)≥0.8 g/g.
42 . The method of claim 39 , wherein the statistically significant reduction is at least 20% relative to the UPCR baseline in the subject prior to treatment.
43 . The method of claim 39 , wherein the statistically significant reduction is at least 25% relative to the UPCR baseline in the subject prior to treatment.