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 . (canceled)
2 . A method of treatment of IgA nephropathy in a subject in need thereof, comprising orally administering to said subject a dose of about 16 mg of budesonide, which dose is contained in one or more pharmaceutical compositions comprising budesonide,
wherein the composition releases at least 90% of the budesonide to the ileum region of the small intestine to reduce the formation by mucosal B cells in Peyer's patches in the ileum of secretory galactose-deficient IgA antibodies that drive immune complex formation in IgA nephropathy, to treat said IgA nephropathy, and limiting systemic exposure of said budesonide; and
wherein the composition further comprises an enteric coating.
3 . The method of claim 2 , wherein the composition begins releasing budesonide only once the ileum is reached and at least 90% of budesonide is released throughout the entire ileum, wherein the release is predicted by an in vitro/in vivo correlation (IVIVC) physiologically based pharmacokinetic model that considers gut wall metabolism.
4 . The method of claim 3 , wherein the IVIVC physiologically based pharmacokinetic model used to predict the release is carried out using GastroPlus® software version 9.8.3002.
5 . The method of claim 2 , wherein the enteric coating comprises a blend of methacrylic acid and methyl methacrylate copolymers.
6 . The method of claim 5 , wherein the enteric coating is a blend of methacrylic acid and methyl methacrylate copolymers 1:1, and 1:2.
7 . The method of claim 2 , wherein the composition is in the form of one or more capsules or tablets.
8 . The method of claim 2 , wherein the method comprises administering the pharmaceutical composition to the subject at least one hour before the first meal of the day.
9 . The method of claim 2 , wherein the composition further comprises an extended-release component.
10 . The method of claim 9 , wherein the extended-release component comprises a pharmaceutically-acceptable cured polymeric blend of a water-insoluble polymer having a solubility in water (at 25° C.) of less than about 0.1 mg/mL and a water-soluble polymer having a solubility in water (at 25° C.) of at least about 10 mg/mL.
11 . The method according to claim 2 , wherein the enteric coating is located at the exterior of the composition.
12 . The method according to claim 10 , wherein the composition is in the form of one or more capsules.
13 . The method according to claim 12 , wherein the one or more capsules each contain a plurality of cores comprising budesonide, and the plurality of cores are coated with the extended release pharmaceutically-acceptable cured polymeric blend.
14 . The method according to claim 13 , wherein the water-insoluble polymer is present in an amount of from about 45 wt. % to about 90 wt. % of the extended release pharmaceutically-acceptable cured polymeric blend and the water-soluble polymer is present in an amount of from about 35 wt. % to about 5 wt. % of the extended release pharmaceutically-acceptable cured polymeric blend.
15 . The method according to claim 13 , wherein the water-insoluble polymer is present in an amount of from about 45 wt. % to about 65 wt. % of the extended release pharmaceutically-acceptable cured polymeric blend and the water-soluble polymer is present in an amount of from about 35 wt. % to about 15 wt. % of the extended release pharmaceutically-acceptable cured polymeric blend.
16 . The method according to claim 13 , wherein the water-insoluble polymer is present in an amount of from about 47 wt. % to about 56 wt. % of the extended release pharmaceutically-acceptable cured polymeric blend and the water-soluble polymer is present in an amount of from about 32 wt. % to about 22 wt. % of the extended release pharmaceutically-acceptable cured polymeric blend.
17 . The method according to claim 13 , wherein the extended release pharmaceutically-acceptable cured polymeric blend is present in an amount of from 5 wt. % to about 18 wt. % of the total coated core weight.
18 . The method according to claim 13 , wherein the extended release pharmaceutically-acceptable cured polymeric blend is present in an amount of from about 6 wt. % to about 16 wt. % of the total coated core weight.
19 . The method according to claim 13 , wherein the extended release pharmaceutically-acceptable cured polymeric blend is present in an amount of from about 6 wt. % to about 12 wt. % of the total coated core weight.
20 . The method according to claim 10 , wherein the water-insoluble polymer is an alkyl cellulose.
21 . The method according to claim 20 , wherein the alkyl cellulose is an ethyl cellulose.
22 . The method according to claim 10 , wherein the water-soluble polymer is selected from polyethylene glycol (PEG), hydroxypropylmethyl cellulose (HPMC), and hydroxypropyl cellulose (HPC).
23 . The method according to claim 10 , wherein the water-insoluble polymer is an alkyl cellulose and the water-soluble polymer is selected from polyethylene glycol (PEG), hydroxypropylmethyl cellulose (HPMC), and hydroxypropyl cellulose (HPC).
24 . The method according to claim 13 , wherein the enteric coating is on the plurality of cores.
25 . The method according to claim 12 , wherein the enteric coating is on the one or more capsules.
26 . The method according to claim 25 , where the enteric coating is present in an amount of from about 34 mg to about 46 mg per capsule.
27 . The method according to claim 25 , where the enteric coating is present in an amount of from about 34 mg to about 42 mg per capsule.
28 . The method according to claim 25 , where the enteric coating is present in an amount of from about 36 mg to about 40 mg per capsule.
29 . The method according to claim 12 , wherein the one or more capsules are size 1 capsules.
30 . The method according to claim 2 , wherein each pharmaceutical composition comprises about 4 mg of budesonide.
31 . The method according to claim 2 , wherein the one or more pharmaceutical compositions meet 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, wherein the pharmaceutically-relevant dissolution medium is a Level 1 Fasted State Simulated Intestinal Fluid at a pH of about 6.5, or a phosphate buffer medium at a pH of about 6.8; and
c) at least about 70% of the budesonide is released into the pharmaceutically-relevant dissolution medium within about 120 minutes.