Sustained release formulation and tablets prepared therefrom
View Patent ↗Disclosed are formulations and tablets made therefrom comprising the compound of Formula IA or Formula IB which have sustained-release properties, and the dispersion containing the compounds of Formula IA or IB which facilitates such sustained release: Formula IA, Formula IB.
1. A dispersion comprising a compound of Formula IA or a salt thereof:
a plasticizer and a matrix polymer, wherein said matrix polymer is: (a) a polymer made from free-radical polymerization of methacrylic acid and methylmethacrylate in a 1:2 ratio, and having an average molar mass of approximately 125,000 g/mol; or (b) a polymer made from free radical polymerization of a 1:1 mixture of methacrylic acid and ethylacrylate, and having a weight average molecular mass of approximately 320 Kg/mol.
2. The dispersion of claim 1 , wherein said compound of Formula IA and is present in the amount of about 5 wt. %, said plasticizer is triethylcitrate and is present in the amount of about 25 wt.%, and said matrix polymer is methacrylic acid/methacrylate 1:2 ratio and is present in an amount of about 70 wt.%.
3. A formulation comprising: (i) the polymer dispersion of claim 2 ; (ii) one or more controlled-release polymers; and (iii) a precipitation inhibitor.
4. The formulation of claim 3 , further comprising one or more of a glidant; binder; anti-oxidant; compression aid, disintegrant or lubricant.
5. A tablet prepared from the formulation of claim 4 having a target hardness of 15 ±3 kp.
6. The tablet of claim 5 which comprises about 5 mg of the compound of Formula IA.
7. The tablet of claim 5 which comprises about 10 mg of the compound of Formula IA.
8. The tablet of claim 6 which is further combined with an immediate-release formulation comprising about 5 mg of the compound of Formula IA.
9. The tablet of claim 6 which provides the release profile of FIG. 3A .
10. The tablet of claim 7 which provides the release profile of FIG. 3B .
11. The tablet of claim 8 which provides the release profile of FIG. 3C .
12. A tablet having the constituent ratio of either Table X, Y or Z:
TABLE X
Quantity/
Amount for
Tablet
3000 g
Component
(mg)
(g)
Extrudate containing 4% of API (Compound of
125.0
750.0
Formula 1)
Microcrystalline Cellulose
88.90
533.40
Polyethylene oxide (~M.W. of 500,000)
75.0
450.0
PolyOX WSR Coagulant)
Polyethylene oxide (~M.W. of 200,000)
75.0
450.0
PolyOX WSR 60K
Hypromellose Acetate Succinate (HPMCAS-
204.0
1224.0
MG)
Croscarmellose Sodium
30.0
180.0
Magnesium Stearate
1.50
9.0
Butylated Hydroxytoluene (BHT)
0.60
3.6
Tablet weight
600.0.
TABLE Y
Quantity/
Amount for
Tablet
3450 g
Component
(mg)
(g)
Extrudate containing 5% of API (Compound of
100.00
600.00
Formula 1)
Microcrystalline Cellulose
104.94
629.63
Polyethylene oxide (~M.W. of 500,000)
71.90
431.40
PolyOX WSR Coagulant)
Polyethylene oxide (~M.W. of 200,000)
71.90
431.40
PolyOX WSR 60K
Hypromellose Acetate Succinate (HPMCAS-
195.50
1173.00
MG)
Croscarmellose Sodium
28.75
172.50
Magnesium Stearate
1.44
8.63
Butylated Hydroxy toluene (BHT)
0.58
3.45
Tablet weight
575.0.
TABLE Z
Quantity/
Quantity/
tablet
5000 g batch
Component
(mg)
(g)
(Controlled Release Layer)
Extrudate containing 5.0% API (Compound of
100.00
751.90
Formula 1)
Microcrystalline Cellulose
112.10
842.90
Polyethylene oxide (~M.W. of 500,000)
33.25
250.00
Polyethylene oxide (~M.W. of 200,000)
38.00
285.70
Hypromellose Acetate Succinate MG
166.25
1250.00
Croscarmellose Sodium
23.75
178.60
Magnesium Stearate
1.19
8.90
Butylated Hydroxytoulene
0.47
3.50
Weight of 12-hr controlled release layer
475.0
3571.50
(Immediate Release Layer)
Compound of Formula 1
5.0
35.7
Povidone
5.0
35.7
Mannitol
129.6
925.7
Microcrystalline cellulose
50.0
357.1
Croscarmellose Sodium
10.0
71.4
Magnesium Stearate
0.40
2.9
Weight of immediate release layer
200.0
1428.5
Total tablet weight
675.00
5000.0.
13. A tablet of the constituents of Table X of claim 12 which is combined with an immediate release formulation comprising about 5 mg of a compound of Formula IA.