Multiparticulate L-menthol formulations and related methods
Enteric coated multiparticulate formulations that use L-menthol as an active ingredient are disclosed. In one embodiment, the multiparticulate formulation comprises a plurality of particulates having a reduced release under gastric conditions and an elevated release at neutral pH. The particulates comprise a core comprising L-menthol as an active ingredient. The L-menthol is supplied to the core as an at least 80% pure L-menthol material. An enteric coating is over the core. The enteric coating is effective to release at least about 80% of the L-menthol within about two hours of being placed in a substantially neutral pH environment. Other aspects of the invention include methods of making and methods of using the multiparticulate formulations.
1. An L-menthol multiparticulate formulation comprising a plurality of particulates having a reduced release under gastric conditions and an elevated release at neutral pH, wherein the particulates comprise:
a core comprising L-menthol as an active ingredient, the L-menthol being supplied to the core as an at least 80% pure L-menthol material;
an enteric coating over the core, the enteric coating being effective to release at least about 80% of the L-menthol within about two hours of being placed in a substantially neutral pH environment.
2. The multiparticulate formulation of claim 1 , wherein the L-menthol is crystalline.
3. The multiparticulate formulation of claim 2 , wherein the crystalline L-menthol is present as micronized particles.
4. The multiparticulate formulation of claim 1 , wherein the core further comprises a solubilizing agent effective for solubilizing L-menthol.
5. The multiparticulate formulation of claim 1 , wherein the core further comprises an antioxidant effective for preventing the L-menthol from oxidizing.
6. The multiparticulate formulation of claim 5 , wherein the antioxidant is ascorbic acid.
7. The multiparticulate formulation of claim 1 , wherein the core comprises about 30% to about 70% w/w L-menthol.
8. The multiparticulate formulation of claim 1 , wherein the enteric coating comprises a polymeric material having a glass transition temperature T g of at most about 30° C.
9. The multiparticulate formulation of claim 1 , wherein the enteric coating comprises a methacrylic acid based copolymer.
10. The multiparticulate formulation of claim 1 , wherein the enteric coating is effective to release no more than about 10% of the L-menthol within about 2 hours of being placed in a 0.1 N HCl solution and, subsequently, no less than about 85% of the L-menthol within about 45 minutes of being placed in a substantially neutral pH environment.
11. The multiparticulate formulation of claim 1 , wherein the multiparticulate formulation is present in a pharmaceutical dosage form that can be orally administered to a patient.
12. A multiparticulate composition comprising a plurality of spheroidal particulates, the particulates comprising:
a core comprising about 30% to about 70% w/w L-menthol, the L-menthol being supplied to the core as an at least 80% pure L-menthol containing material, the core further comprising about 25% to about 60% w/w microcrystalline cellulose, about 0.5% to about 4% w/w hypromellose, about 1% to about 3% w/w polysorbate 80, about 2% to about 15% w/w colloidal silica, about 4% to about 6% w/w croscarmellose sodium, and about 0.5% to about 4% w/w ascorbic acid;
a sub-coating comprising hypromellose on the core;
an enteric coating on the sub-coating; and wherein
the particulates have an average diameter of not more than 3 mm.
13. The multiparticulate composition of claim 12 , wherein the L-menthol is crystalline.
14. The multiparticulate composition of claim 13 , wherein the L-menthol is micronized.
15. The multiparticulate composition of claim 12 , wherein the L-menthol is present in the amount of about 50% w/w.
16. The multiparticulate composition of claim 12 , wherein the sub-coating is present in the amount of about 1% to about 5% w/w.
17. The multiparticulate composition of claim 12 , wherein the enteric coating is present in the amount of about 10% to about 35% w/w.
18. The multiparticulate composition of claim 12 , wherein the enteric coating comprises a methacrylic acid based copolymer.
19. The multiparticulate composition of claim 12 , wherein the enteric coating is effective to release at least about 80% of the L-menthol within about two hours of being placed in a substantially neutral pH environment.
20. A method of making an L-menthol multiparticulate formulation comprising a plurality of particulates having a reduced release under gastric conditions and an elevated release at neutral pH, the method comprising:
preparing a plurality of cores comprising crystalline L-menthol as an active ingredient;
drying the cores;
coating the cores with an enteric coating effective to release at least about 80% of the L-menthol within about two hours of being placed in a substantially neutral pH environment; and
drying the enteric coated cores.
21. The method of claim 20 , further comprising maintaining a temperature of the cores and enteric coated cores at or below 30° C.
22. The method of claim 21 , wherein the temperature is between about 19° C. and about 22° C.
23. The method of claim 20 , further comprising placing the particulates into a dosage form that can be administered orally to a patient.
24. A method of treating a gastrointestinal disorder, the method comprising administering the multiparticulate formulation of claim 1 to a patient.