Morphine sulphate microgranules, method for preparing same and compositions containing same
View Patent ↗The present invention concerns a novel sustained-release oral formulation of morphine sulphate in the form of microgranules. Each microgranule comprises a neutral support grain coated with an active layer and with a sustained-release layer, characterized in that the sustained-release layer contains a copolymer of methacrylic acid and of methyl methacrylate ester, the relative proportion of the free carboxyl groups and of the ester groups of which is equal to 0.5 approximately, and a silica exhibiting a hydrophobic character. The present invention also concerns a process for preparing these microgranules which is carried out entirely in aqueous medium by emplacing on neutral support grains.
1. Sustained-release morphine sulphate microgranules each comprising a neutral support grain coated with an active layer and with a sustained-release layer, said sustained-release layer containing:
a copolymer of poly(ethylacrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1;
a plasticizer; and
a lubricant;
wherein said sustained-release layer further comprises a hydrophobic silica which represents 0.2 to 1% by weight of the microgranules and wherein said microgranules are devoid of any outer protective film.
2. Microgranules according to claim 1 , characterized in that the relative mass proportion of the morphine sulphate and of the neutral support grain is between 40/60 and 60/40.
3. Microgranules according to claim 1 , characterized in that the morphine sulphate represents 30 to 40% by mass of the microgranules.
4. Process for preparing the microgranules according to claim 1 , characterized in that the active layer and the sustained-release layer are applied onto the neutral grains by emplacing in aqueous solution.
5. Pharmaceutical composition containing the microgranules according to claim 1 , optionally obtained according to the process for preparing the microgranules, characterized in that the active layer and the sustained-release layer are applied onto the neutral grains by emplacing in aqueous solution.
6. Microgranules according to claim 1 , wherein the plasticizer is triethylcitrate.
7. Microgranules according to claim 1 , further comprising 30–40% wt neutral support grain.
8. Microgranules according to claim 1 , further comprising 10–20% wt binder.
9. Microgranules according to claim 1 , further comprising 1–2.5% wt plasticizer.
10. Microgranules according to claim 1 , further comprising 2–4% wt lubricant.
11. Microgranules according to claim 1 , further comprising 5–15% wt methacrylic acid copolymer.
12. Microgranules according to claim 1 , further comprising 30–40% wt morphine sulphate, 30–40% wt neutral support grain, 10–20% wt binder, 1–2.5% wt plasticizer, 2–4% wt lubricant, and 0.2–1% wt hydrophobic silica.
13. Microgranules according to claim 1 , characterized in that they have the following composition (% by mass):
morphine sulphate
37.3
neutral grains
37.3
hydroxypropylmethylcellulose
13.0
poly(ethylacrylate, methyl methacrylate,
8.2
trimethylammonioethyl methacrylate chloride) 1:2:0.1
triethylcitrate
1.6
talc and
2.1
hydrophobic silica
0.4.
14. Microgranules according to claim 1 , characterized in that they have the following composition (% by mass):
morphine sulphate
35.1
neutral grains
39.7
Hydroxypropylmethylcellulose
12.3
poly(ethylacrylate, methyl methacrylate,
8.2
trimethylammonioethyl methacrylate chloride) 1:2:0.1
Triethylcitrate
1.6
talc and
2.6
hydrophobic silica
0.4.
15. Microgranules according to claim 1 , characterized in that they have the following composition (% by mass):
morphine sulphate
40.9
neutral grains
34.3
hydroxypropylmethylcellulose
14.3
poly(ethylacrylate, methyl methacrylate,
6.7
trimethylammonioethyl methacrylate chloride) 1:2:0.1
triethylcitrate
1.3
talc and
2.2
hydrophobic silica
0.3.
16. Microgranules according to claim 1 , characterized in that they have the following composition (% by mass):
morphine sulphate
41.9
neutral grains
33.0
Hydroxypropylmethylcellulose
11.7
PEG 4000
2.9
poly(ethylacrylate, methyl methacrylate,
7.3
trimethylammonioethyl methacrylate chloride) 1:2:0.1
Triethylcitrate
1.4
Talc
1.4
hydrophobic silica
0.4.