Oral formulation of anhydrous olanzapine form I
The invention relates to a solid formulation for the oral administration of olanzapine that comprises a core of anhydrous olanzapine Form I or a pharmaceutically acceptable salt thereof and, optionally, pharmaceutically acceptable excipients, said core being coated with a functional polymer that acts as filmogenic agent. The method for obtaining it comprises: i) providing anhydrous olanzapine Form I or a salt thereof and, optionally, pharmaceutically acceptable excipients in solid form; ii) providing a functional polymer that acts as filmogenic agent; iii) preparing a dispersion of said functional polymer in an aqueous medium,—and applying the dispersion obtained in step iii) onto the solid form of step i).
1. Solid oral formulation of olanzapine in the form of a tablet, characterised in that it comprises a core of anhydrous metastable olanzapine Form I as active substance, wherein the anhydrous metastable olanzapine Form I has the following X-ray diffraction pattern:
Position (°20)
d (m − 1°)
8.885
9.944
9.005
9.812
10.395
8.503
10.815
8.174
12.915
6.850
13.915
6.359
17.830
4.971
18.385
4.822
18.785
4.720
19.230
4.612
19.620
4.521
21.050
4.217
21.770
4.079
23.635
3.761
24.095
3.691
24.865
3.578
25.465
3.495
26.690
3.337
27.515
3.239
28.665
3.112
34.580
2.592
36.525
2.458
38.645
2.328
and pharmaceutically acceptable excipients, wherein said tablet core has been obtained by direct compression or by dry granulation, with said tablet core being coated with an aqueous soluble a functional polymer containing PVA, that acts as filmogenic agent.
2. Formulation according to claim 1 , wherein said coating also comprises one or more of the following components: from 10 to 50% of opacifier and colorant, from 5 to 30% of lubricant, from 0.5 to 5% of plasticizer, from 0.1 to 3% of thickening agent and from 0 to 20% of filler agent.
3. Formulation according to claim 2 , in which said opacifier and/or colorant is selected from titanium dioxide, calcium carbonate, iron oxides, aluminic lakes or mixtures thereof.
4. Formulation according to claim 2 , where said lubricant is selected from stearate, sodium benzoate, stearic acid, talc or mixtures thereof.
5. Formulation according to claim 2 , where said plasticizer is selected from glycerol, polyethylene glycol, sorbitol, soya lecithin, esters of citric acid or mixtures thereof.
6. Formulation according to claim 2 , where said thickening agent is selected from gum xanthane, bentonite, carrageenates, colloidal silica, ethyl cellulose, gelatin, maltitol, sucrose or mixtures thereof.
7. Formulation according to claim 1 , wherein said core further comprises one or more of the following components: from 20 to 80% of diluent, from 3 to 15% of disintegrant and/or from 0.25 to 5% of lubricant.
8. Formulation according to claim 7 , where said diluent is selected from saccharides and/or their oxidised and/or reduced forms; lactose in its various forms, anhydrous, monohydrate, agglomerated forms or atomised forms; mannitol; cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose or derivatives of cellulose modified chemically, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose; starch, sucrose, pharmaceutically acceptable inorganic compounds, or mixtures thereof.
9. Formulation according to claim 7 , where said disintegrant is selected from Low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, crospovidone, croscarmellose, starch, sodium starch carboxymethyl, derivatives of casein or mixtures thereof.
10. Formulation according to claim 7 , where said lubricant is selected from magnesium stearate, calcium stearate, glyceril palmitostearate, talc, stearic acid, glyceril behenate, sodium lauril sulphate, sodium stearil fumarate or mixtures thereof.
11. Formulation according to claim 1 , wherein said anhydrous metastable olanzapine Form I is thoroughly mixed with an isolating agent.
12. Formulation according to claim 11 , where said isolating agent is selected from glyceril palmitostearate, stearic acid, esters or ethers of higher fatty acids or mixtures thereof.
13. Formulation according to claim 12 , where said isolating agent is glyceril behenate.
14. Method for obtaining a formulation in the form of a tablet according to any of the preceding claims, which comprises the steps:
i) providing anhydrous metastable olanzapine Form I and pharmaceutically acceptable excipients in solid form of a tablet by direct compression or by dry granulation;
ii) providing an aqueous soluble function polymer contain PVA that acts as filmogenic agent;
iii) preparing a dispersion of said functional polymer in an aqueous medium; and
iv) applying the dispersion obtained in step iii) to the tablet obtained in step i).
15. Method according to claim 14 , where said aqueous medium is water.
16. Method according to claim 14 , wherein step i) is carried out in two stages:
i-1) preparing a mixture of anhydrous metastable olanzapine Form I with an isolating agent;
i-2) then adding the other excipients to the mixture obtained in stage i-1) and providing a tablet; and proceeding with the remaining steps ii); iii); and iv).
17. Method according to claim 16 , wherein said isolating agent is selected from: glyceril palmitostearate, stearic acid, esters or ethers of higher fatty acids or mixtures thereof.