PHARMACEUTICAL COMPOSITION
The present invention relates to a pharmaceutical composition comprising a tablet core comprising a combination of actives selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, bupropion hydrobromide and escitalopram oxalate, and bupropion hydrobromide and quetiapine fu-marate, and at least one pharmaceutically acceptable excipient, and a control-releasing coat surrounding the tablet core, wherein said composition surprisingly provides for a synchronous release of the combination of active agents in-vitro. The once-daily pharmaceutical composition surprisingly also provides for enhanced absorption of bupropion hydrobromide when administered to a subject in need of such administration.
1 . A pharmaceutical composition comprising:
a) a homogenous core comprising a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, at least one stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient, and
b) a control-releasing coating surrounding said core, said coating comprising a water-insoluble water-permeable film-forming polymer, a water-soluble polymer and optionally at least one plasticizer.
2 . The pharmaceutical composition of claim 1 wherein said pharmaceutical composition provides for a synchronous release of the combination of actives independent of pH of dissolution media.
3 . The pharmaceutical composition of claim 1 wherein said combination of actives is bupropion hydrobromide and escitalopram oxalate.
4 . The pharmaceutical composition of claim 1 , wherein said stabilizer is selected from the group consisting at least one suitable pharmaceutically acceptable inorganic acid, at least one suitable pharmaceutically acceptable organic acid, at least one suitable pharmaceutically acceptable salt of an organic base, at least one suitable pharmaceutically acceptable salt of an inorganic acid, at least one suitable pharmaceutically acceptable acid salt of an amino acid, potassium metabisulfite, sodium bisulfite, or at least one suitable pharmaceutically acceptable phenylated antioxidant, or any combination thereof.
5 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable inorganic acid, which at a concentration of about 0.31% w/w/forms an aqueous solution having a pH of from about 0.5 to about 0.4.
6 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable organic acid that has a solubility in water at 20° C. of less than about 10 g/100 g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
7 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable dicarboxylic acid that has a solubility in water at 20° C. of less than about 10 g/100 g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
8 . The pharmaceutical composition of claim 1 wherein said stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.70 to about 3.10 at a concentration of about 10% w/w.
9 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.95 to about 3.05, at a concentration of about 20% w/w.
10 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one salt of an organic base having an aqueous pH of from about 2.70 to about 2.72, at a concentration of about 20% w/w.
11 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an inorganic acid having an aqueous pH of from about 4.20 to about 4.30 at a concentration of about 10 w/w.
12 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable acid salt of an amino acid.
13 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer is selected from the group consisting of potassium metabisulfite, sodium bisulfite, and any combination thereof.
14 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable phenylated antioxidant.
15 . The pharmaceutical composition of claim 14 wherein said at least one stabilizer is selected from the group consisting of butlylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and any combination thereof.
16 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises butlylated hydroxytoluene.
17 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises citric acid.
18 . The pharmaceutical composition of claim 1 wherein said at least one stabilizer comprises a combination of citric acid and butylayed hydroxytoluene.
19 . The pharmaceutical composition of claim 1 , wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of a binder, a lubricant, a filler, a glidant, and any combinations thereof.
20 . The pharmaceutical composition of claim 1 , wherein said water-insoluble water-permeable film-forming polymer is selected from the group consisting of cellulose ethers, cellulose esters, methacrylic acid derivatives, aqueous ethylcellulose dispersions, aqueous acrylic enteric systems, polyvinyl derivatives, and any combination thereof.
21 . The pharmaceutical composition of claim 1 , wherein said water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and any combination thereof.
22 . The pharmaceutical composition of claim 1 , wherein said at least one plasticizer, when said plasticizer is present, is selected from the group consisting of an ester, a polyalkylene glycol and any combination thereof.
23 . The pharmaceutical composition of claim 1 , wherein said at least one plasticizer, when said plasticizer is present, comprises a combination of two plasticizers.
24 . The pharmaceutical composition of claim 1 , wherein said composition is in the form of a tablet.
25 . The pharmaceutical composition of claim 1 , when administered to a subject in need of such administration provides a about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate.
26 . The pharmaceutical composition of claim 3 wherein said bupropion hydrobromide is present at an amount at least about 10% less than a single active agent pharmaceutical composition comprising 348 mg bupropion hydrobromide.
27 . A method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject the pharmaceutical composition of claim 1 .
28 . A pharmaceutical composition comprising a controlled release matrix core, said controlled release matrix core comprising at least one hydrophilic control-releasing polymer present in a control-releasing amount, a therapeutically effective combination of active agents selected from the group consisting of bupropion hydrochloride and escitalopram oxalate, bupropion hydrobromide and citalopram hydrochloride, and bupropion hydrobromide and escitalopram oxalate, at least one stabilizer present in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient.
29 . The pharmaceutical composition of claim 28 wherein said pharmaceutical composition provides for a synchronous release of the combination of actives independent of pH of dissolution media.
30 . The pharmaceutical composition of claim 28 wherein said combination of actives is bupropion hydrobromide and escitalopram oxalate.
31 . The pharmaceutical composition of claim 28 , wherein said stabilizer is selected from the group consisting at least one suitable pharmaceutically acceptable inorganic acid, at least one suitable pharmaceutically acceptable organic acid, at least one suitable pharmaceutically acceptable salt of an organic base, at least one suitable pharmaceutically acceptable salt of an inorganic acid, at least one suitable pharmaceutically acceptable acid salt of an amino acid, potassium metabisulfite, sodium bisulfite, or at least one suitable pharmaceutically acceptable phenylated antioxidant, or any combination thereof.
32 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable inorganic acid, which at a concentration of about 0.31% w/w/forms an aqueous solution having a pH of from about 0.5 to about 0.4.
33 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable organic acid that has a solubility in water at 20° C. of less than about 10 g/100 g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
34 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable dicarboxylic acid that has a solubility in water at 20° C. of less than about 10 g/100 g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
35 . The pharmaceutical composition of claim 28 wherein said stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.70 to about 3.10 at a concentration of about 10% w/w.
36 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.95 to about 3.05, at a concentration of about 20% w/w.
37 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one salt of an organic base having an aqueous pH of from about 2.70 to about 2.72, at a concentration of about 20% w/w.
38 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an inorganic acid having an aqueous pH of from about 4.20 to about 4.30 at a concentration of about 10 w/w.
39 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable acid salt of an amino acid.
40 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer is selected from the group consisting of potassium metabisulfite, sodium bisulfite, and any combination thereof.
41 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable phenylated antioxidant.
42 . The pharmaceutical composition of claim 41 wherein said at least one stabilizer is selected from the group consisting of butlylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and any combination thereof.
43 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises butlylated hydroxytoluene.
44 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises citric acid.
45 . The pharmaceutical composition of claim 28 wherein said at least one stabilizer comprises a combination of citric acid and butylayed hydroxytoluene.
46 . The pharmaceutical composition of claim 28 , wherein said at least one hydrophilic control-releasing polymer is selected from the group consisting of hydrophilic celluloses, ethylcellulose, polysaccharides, polyvinylpyrrolidone, ethylcellulose, polymethacrylates, and mixtures of polyvinyl acetate and polyvinylpyrrolidone, and any combination thereof.
47 . The pharmaceutical composition of claim 28 , wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of a binder, a lubricant, a filler, a glidant, and any combination thereof.
48 . The pharmaceutical composition of claim 28 , wherein said composition is in the form of a tablet.
49 . The pharmaceutical composition of claim 28 further comprising a control-releasing coating surrounding said core, said coating comprising a water-insoluble water-permeable film-forming polymer, a water-soluble polymer and optionally at least one plasticizer.
50 . The pharmaceutical composition of claim 49 , wherein said water-insoluble water-permeable film-forming polymer is selected from the group consisting of cellulose ethers, cellulose esters, methacrylic acid derivatives, aqueous ethylcellulose dispersions, aqueous acrylic enteric systems, polyvinyl derivatives, and any combination thereof.
51 . The pharmaceutical composition of claim 49 , wherein said water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and any combination thereof.
52 . The pharmaceutical composition of claim 49 , wherein said at least one plasticizer, when said plasticizer is present, is selected from the group consisting of an ester, a polyalkylene glycol and any combination thereof.
53 . The pharmaceutical composition of claim 49 , wherein said at least one plasticizer, when said plasticizer is present, comprises a combination of two plasticizers.
54 . The pharmaceutical composition of claim 49 , wherein said composition is in the form of a tablet.
55 . The pharmaceutical composition of claim 49 wherein said combination of actives is bupropion hydrobromide and escitalopram oxalate.
56 . The pharmaceutical composition of claim 30 wherein said bupropion hydrobromide is present at an amount at least about 10% less than a single active agent pharmaceutical composition comprising 348 mg bupropion hydrobromide.
57 . The pharmaceutical composition of claim 55 wherein said bupropion hydrobromide is present at an amount at least about 10% less than a single active agent pharmaceutical composition comprising 348 mg bupropion hydrobromide.
58 . A method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject the pharmaceutical composition of claim 28 .
59 . A method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject the pharmaceutical composition of claim 49 .
60 . A pharmaceutical composition comprising:
a) a core comprising a first immediate release layer comprising a therapeutically effective amount of an active agent selected from the group consisting of bupropion hydrochloride and bupropion hydrobromide, optionally a stabilizer in an effective stabilizing amount, and at least one pharmaceutically acceptable excipient in direct contact with a second immediate release layer comprising an active agent selected from the group consisting of citalopram hydrochloride and escitalopram oxalate, optionally a stabilizer, and at least one pharmaceutically acceptable excipient, and
b) a control-releasing coating surrounding said core, said coating comprising a water-insoluble water-permeable film-forming polymer, a water-soluble polymer and at least one plasticizer.
61 . The pharmaceutical composition of claim 60 wherein said pharmaceutical composition provides for a synchronous release of the combination of actives independent of pH of dissolution media.
62 . The pharmaceutical composition of claim 60 wherein said combination of actives is bupropion hydrobromide and escitalopram oxalate.
63 . The pharmaceutical composition of claim 60 , wherein said stabilizer, when said stabilizer is present, for the first immediate release layer is selected from the group consisting of at least one suitable pharmaceutically acceptable inorganic acid, at least one suitable pharmaceutically acceptable organic acid, at least one suitable pharmaceutically acceptable salt of an organic base, at least one suitable pharmaceutically acceptable salt of an inorganic acid, at least one suitable pharmaceutically acceptable acid salt of an amino acid, potassium metabisulfite, sodium bisulfite, and any combination thereof.
64 . The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable inorganic acid, which at a concentration of about 0.31% w/w/forms an aqueous solution having a pH of from about 0.5 to about 0.4.
65 . The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable organic acid that has a solubility in water at 20° C. of less than about 10 g/100 g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
66 . The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable dicarboxylic acid that has a solubility in water at 20° C. of less than about 10 g/100 g water and that at a concentration of about 60% w/w forms an aqueous suspension having a pH of from about 0.9 to about 4.0.
67 . The pharmaceutical composition of claim 63 wherein said stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.70 to about 3.10 at a concentration of about 10% w/w.
68 . The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an organic base having an aqueous pH of from about 2.95 to about 3.05, at a concentration of about 20% w/w.
69 . The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one salt of an organic base having an aqueous pH of from about 2.70 to about 2.72, at a concentration of about 20% w/w.
70 . The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable salt of an inorganic acid having an aqueous pH of from about 4.20 to about 4.30 at a concentration of about 10 w/w.
71 . The pharmaceutical composition of claim 63 wherein said at least one stabilizer comprises at least one suitable pharmaceutically acceptable acid salt of an amino acid.
72 . The pharmaceutical composition of claim 63 wherein said at least one stabilizer is selected from the group consisting of potassium metabisulfite, sodium bisulfite, and any combination thereof.
73 . The pharmaceutical composition of claim 63 wherein said at least one stabilizer, when said stabilizer is present comprises citric acid.
74 . The pharmaceutical composition of claim 60 , wherein said stabilizer, when said stabilizer is present, for the second immediate release layer comprises at least one suitable pharmaceutically acceptable phenylated antioxidant.
75 . The pharmaceutical composition of claim 74 wherein said at least one stabilizer is selected from the group consisting of butlylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and any combination thereof.
76 . The pharmaceutical composition of claim 60 wherein said at least one stabilizer, when said stabilizer is present, in the first immediate release layer comprises citric acid and said at least one stabilizer, when said stabilizer is present, in the second immediate release layer comprises butylated hydroxytoluene.
77 . The pharmaceutical composition of claim 60 , wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of a binder, a lubricant, a filler, a glidant, and any combination thereof.
78 . The pharmaceutical composition of claim 60 , wherein said water-insoluble water-permeable film-forming polymer is selected from the group consisting of cellulose ethers, cellulose esters, methacrylic acid derivatives, aqueous ethylcellulose dispersions, aqueous acrylic enteric systems, polyvinyl derivatives, and any combination thereof.
79 . The pharmaceutical composition of claim 60 , wherein said water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and any combination thereof.
80 . The pharmaceutical composition of claim 60 , wherein said at least one plasticizer, when said plastizer is present, comprises a combination of two plasticizers.
81 . The pharmaceutical composition of claim 60 , wherein said at least one plasticizer, when said plasticizer is present, is selected from the group consisting of an ester, a polyalkylene glycol and any combination thereof.
82 . The pharmaceutical composition of claim 60 , wherein said composition is in the form of a tablet.
83 . The pharmaceutical composition of claim 60 , when administered to a subject in need of such administration provides a about 15-25% increase in the bioavailability of bupropion when compared to co-administration of single active agent pharmaceutical compositions of bupropion hydrobromide and citalopram hydrochloride or bupropion hydrobromide and escitalopram oxalate.
84 . The pharmaceutical composition of claim 62 wherein said bupropion hydrobromide is present at an amount at least about 10% less than a single active agent pharmaceutical composition comprising 348 mg bupropion hydrobromide.
85 . A method of treating a mood and/or anxiety disorder in a subject in need of such treatment comprising administering once daily to said subject the pharmaceutical composition of claim 60 .