Multiparticulate L-Carnitine And Nootropic Compositions And Related Methods

Abstract

A composition includes a therapeutically effective pharmaceutical dosage form including a plurality of individual particulates. The individual particulates respectively have: a core including an active ingredient combination of an L-carnitine and a nootropic substance and a release controlling polymer over the core that substantially prevents release of the active ingredients in stomach acid and permits release of the active ingredients in an intestinal pH environment. The composition may be used to treat conditions associated with a reduction of the amount of L-carnitine in the body and/or cognitive impairment.

Claims

1. A composition comprising a therapeutically effective pharmaceutical dosage form including a plurality of individual particulates, the individual particulates respectively having: a core including an active ingredient combination of an L-carnitine and a nootropic substance; and a release controlling polymer over the core that substantially prevents release of the active ingredient combination in stomach acid and permits release of the active ingredient combination an intestinal pH environment.

2. The composition of claim 1, wherein the L-carnitine is within an interior solid portion of the core and the nootropic substance is within a coating over the interior solid portion of the core.

3. The composition of claim 1, wherein the core includes a solid interior portion and the L-carnitine and nootropic substance are in the solid interior portion of the core.

4. The composition of claim 1, wherein the L-carnitine is selected from at least one of L-carnitine, acetyl L-carnitine, and propionyl L-carnitine.

5. The composition of claim 1, wherein the nootropic substance is selected from at least one of L-serine and citicoline.

6. The composition of claim 1, wherein an average diameter of the individual particulates is 0.1 to 3 mm.

7. The composition of claim 1, wherein the therapeutically effective pharmaceutical dosage form includes 300 mg to 800 mg of the L-carnitine and 25 mg to 300 mg of the nootropic substance.

8. The composition of claim 1, wherein the therapeutically effective pharmaceutical dosage form includes 400 mg to 600 mg of the L-carnitine and 200 mg to 250 mg of the nootropic substance.

9. The composition of claim 1, wherein the L-carnitine is in an amount that is at least two times greater than the nootropic substance.

10. The composition of claim 1, wherein the individual particulates respectively include by % w/w of the particulate: 35% to 65% w/w of the L-carnitine and 15% to 30% w/w of the nootropic substance.

11. The composition of claim 1, wherein the individual particulates respectively include by % w/w of the particulate: 45% to 55% w/w of the L-carnitine and 20% to 30% w/w of the nootropic substance.

12. The composition of claim 1, wherein: the individual particulates respectively include by %w/w of the particulate: 35% to 65% w/w of the L-carnitine and 15% to 30% w/w of the nootropic substance; the therapeutically effective pharmaceutical dosage form includes 300 mg to 800 mg of the L-carnitine and 25 mg to 300 mg of the nootropic substance; an average diameter of the individual particulates is 0.1 to 3 mm; and the nootropic substance is selected from at least one of L-serine and citicoline.

13. A composition comprising a therapeutically effective pharmaceutical dosage form including a plurality of individual particulates, the individual particulates respectively having by % w/w of the particulate: a solid core including 35% to 65% w/w of an L-carnitine; 1% to 20% w/w of a subcoating over the solid core; 15% to 30% w/w of a nootropic substance that is within the solid core or within the subcoating; and an enteric coating over the subcoating.

14. The composition of claim 13, wherein the core includes a solid interior portion and the L-carnitine and nootropic substance are in the solid interior portion of the core.

15. The composition of claim 13, wherein the L-carnitine is selected from at least one of L-carnitine, acetyl L-carnitine, and propionyl L-carnitine.

16. The composition of claim 13, wherein an average diameter of the individual particulates is 0.1 mm to 3 mm.

17. The composition of claim 13, wherein the nootropic substance is selected from at least one of L-serine and citicoline.

18. The composition of claim 13, wherein the individual particulates respectively include by % w/w of the particulate: 45% to 55% w/w of the L-carnitine and 20% to 30% w/w of the nootropic substance.

19. The composition of claim 13, wherein the L-carnitine is in an amount that is at least two times greater than the nootropic substance.

20. The composition of claim 13, wherein therapeutically effective pharmaceutical dosage form includes 300 mg to 800 mg of the L-carnitine and 25 mg to 300 mg of the nootropic substance.

21. The composition of claim 13, wherein: an average diameter of the individual particulates is 0.1 mm to 3 mm; the nootropic substance is selected from at least one of L-serine and citicoline; the individual particulates respectively include by % w/w of the particulate: 45% to 55% w/w of the L-carnitine and 20% to 30% w/w of the nootropic substance; and therapeutically effective pharmaceutical dosage form includes 300 mg to 800 mg of the L-carnitine and 25 mg to 300 mg of the nootropic substance.

22. A method of treating a physiological condition associated with cognitive impairment, the method comprising: administering to a patient in need thereof a therapeutically effective pharmaceutical dosage form including a plurality of individual particulates, the individual particulates respectively having: a core including an active ingredient combination of an L-carnitine and a nootropic substance; and a release controlling polymer over the core that substantially prevents release of the active ingredient combination in stomach acid and permits release of the active ingredient combination in an intestinal pH environment.

23. The method of claim 22, wherein administering the therapeutically effective pharmaceutical dosage form to the patient comprises administering at least one capsule containing the plurality of individual particulates therein.

24. The method of claim 22, wherein the L-carnitine is within an interior solid portion of the core and the nootropic substance is within a coating over the interior solid portion of the core.

25. The method of claim 22, wherein the core includes a solid interior portion and the L-carnitine and nootropic substance are in the solid interior portion of the core.

26. The method of claim 22, wherein the L-carnitine is selected from at least one of L-carnitine, acetyl L-carnitine, and propionyl L-carnitine.

27. The method of claim 22, wherein the nootropic substance is selected from at least one of L-serine and citicoline.

28. The method of claim 22, wherein an average diameter of the individual particulates is 0.1 to 3 mm.

29. The method of claim 22, wherein the therapeutically effective pharmaceutical dosage form includes 300 mg to 800 mg of the L-carnitine and 25 mg to 300 mg of the nootropic substance.

30. The method of claim 22, wherein the therapeutically effective pharmaceutical dosage form includes 400 mg to 600 mg of the L-carnitine and 200 mg to 250 mg of the nootropic substance.

31. The method of claim 22, wherein the L-carnitine is in an amount that is at least two times greater than the nootropic substance.

32. The method of claim 22, wherein the individual particulates respectively include by % w/w of the particulate: 35% to 65% w/w of the L-carnitine and 15% to 30% w/w of the nootropic substance.

33. The method of claim 22, wherein the individual particulates respectively include by % w/w of the particulate: 45% to 55% w/w of the L-carnitine and 20% to 30% w/w of the nootropic substance.

34. The method of claim 22, wherein: the individual particulates respectively include by % w/w of the particulate: 35% to 65% w/w of the L-carnitine and 15% to 30% w/w of the nootropic substance; the therapeutically effective pharmaceutical dosage form includes 300 mg to 800 mg of the L-carnitine and 25 mg to 300 mg of the nootropic substance; an average diameter of the individual particulates is 0.1 to 3 mm; and the nootropic substance is selected from at least one of L-serine and citicoline.

Description

EXAMPLES

[0085] This section describes a few specific examples of the composition. These examples are presented by way of example only and are not intended to limit the scope of the possible embodiments.

Example 1

[0086] Table 2 lists ingredients in an example of the core. Table 3 lists ingredients in an example of enteric coated particulates.

TABLE-US-00002 TABLE 2 Ingredients of an exemplary embodiment of the core. (grams/ Ingredient Ingredient % w/w) Function L-Carnitine 935.9/78.4 Active ingredient CAB-O-SIL M5P 19.1/1.6 Processing Aid (Colloidal Silicon Dioxide) AVICEL (Micro 227.0/19.0 Filler Crystalline cellulose) Hypromellose 11.9/1.0 Binder (METHOCEL ® A15 Premium) Water (% of (15.0%) dry mass)

TABLE-US-00003 TABLE 3 Ingredients of an exemplary embodiment of enteric-coated particulates. (grams/ Ingredient Ingredient % w/w) Function KOLLICOAT ® 506.6/85.8 Source of MAE 30 DP Solids methacrylic copolymer Triethyl Citrate  75.7/12.8 Plasticizer PLASACRYL ® T20  7.9/1.3 Anti-Adherent Water.sup.1 .sup.1Evaporates

Preparation of Multiparticulate Compositions

[0087] Experimental Details. The equipment that may be utilized to create the compositions herein include the following: top loading balances, hand screens (12, 14, 16, 18, Pan, 70 mesh), Rotap sieve shaker, IKA mixer, KitchenAid food processor (pre-milling), Hobart mixer, LCI Benchtop Granulator, Fitz mill equipped with a 0.065″ screen, Jet Mill, Key International high sheer mixer, Glatt GPCC-3 fluid bed drier, Glatt GPCC-3 fluid bed dried with 7″ Wurster, Karl Fischer moisture analyzer, and a spheronizer.

[0088] Acetyl L-Carnitine pre-conditioning. The Acetyl-L-Carnitine raw material contains large clumps of fine crystals. Also, the material is hygroscopic. It is necessary to de-lump the raw material and reduce the hygroscopicity in order to process the material. 500 g Acetyl-L-Carnitine (Lonza ALC Carnipure) and 10.2 grams CAB-O-SIL M5P (Cabot Corporation) were blended for 1-5 minutes in a KitchenAid Food Processor equipped with blade or similar blender and equipped with intensifier bar or pin bar.

[0089] Preparation of Core. The core was prepared utilizing the following steps and settings. 955 grams ALCAR/SiO.sub.2 (98/2% w/w), 227 grams Microcrystalline Cellulose (Avicel Ph 102; FMC Corporation), and 11.9 grams Methocel A15 LV (Dow) were low shear granulated in a 0.5 Gallon (2 Liter) Hobart or other granulation mixer and mixed at low speed for about 5 minutes. About 162-172 g USP water was sprayed into the mixer to achieve peak granulation moisture of about 12% to about 12.6% w/w, and this was blended for about an additional 10-30 minutes to form a wet mass.

[0090] The wet mass was extruded through a 1.0 mm-hole perforated metal screen using a LCI Benchtop Granulator at speed setting 10.

[0091] The extrudate was spheronized in 25-30 grams sub lots using a Caleva Model 120 spheronizer equipped with a small pyramid plate at high speed for 2-3 minutes.

[0092] The combined spheronization sub lots (˜1373 grams) were dried in a GPCG-3 or similar fluid bed dryer for about 45 minutes with an inlet temperature set point of 50° C. and a process air flow of 60 cfm.

[0093] The finished dried ALCAR multiparticulates were collected between 12-mesh and 18-mesh screens resulting in a loose Bulk Density of about 0.68 g/cc. A Camsizer particle size distribution analysis was performed finding a size distribution of: DV.sub.10 1.002 mm, DV.sub.50 1.177 mm, and DV.sub.90 1.405 mm; a specific surface area (Sv) of 5.132/mm; and a specific surface area (Sm) of 75.923 cm.sup.2/g.

[0094] Application of sub-coating. 1000 grams of ALCAR particulates were separated based on their size. The fraction that fell within the 14-18 mesh size were chosen for sub-coating. The cores were placed into a Glatt GPCC-3 fluid bed drier and the sub-coating was sprayed onto the cores in the form of a 10% hypromellose (hypromellose E5) aqueous solution that was at room temperature.

[0095] The sub-coating solution (306 g USP Water (T>55° C.) and 34 g hypromellose E5) was applied to the cores using the following parameters: the inlet temperature was maintained at about 50° C.; the air flow was maintained at about 50 cfm; the spray rate was maintained between 6.0 and 11.0 g/min; and the filter shake cycle was 45/3 seconds (Time Between Shaking/Shaking Time). The fluid bed drier was setup with a 1.0 mm Schlick 970 nozzle port, and 2X360 air cap setting, a 1.5 cm partition setting, and a multiparticulate bottom plate or equivalent.

[0096] Preparation of enteric coating solutions. The enteric coatings were applied to the cores in a fluidized bed coater (7″ wurster) as a liquid solution. The formula for the enteric coating was 1160 grams USP Water (RT), 506.6 grams BASF KOLLICOAT MAE 30 DP, 75.7 grams PLASACRYL® T20 (Colorcon), and 7.9 grams triethyl citrate USP, which was mixed a minimum of 20 minutes and screen through a 40-mesh screen prior to use.

[0097] The enteric coating solution was applied to 1000 grams of ALCAR particulate cores using the following parameters: the inlet temperature was maintained at about 50° C.; the air flow was maintained at about 50 cfm; the spray rate was maintained between 6.0 and 11.0 g/min; the atomization air pressure was maintained at about 2.0 bar; and the filter shake cycle was 45/3 seconds (Time Between Shaking/Shaking Time). The fluid bed drier was set up with a 1.0 mm Schlick 970 nozzle port, and 2X360 air cap setting, a 1.5 cm partition setting, and a multiparticulate bottom plate or equivalent.

[0098] A finish coat may be applied over the enteric coating, and is applied in a same or similar manner as the enteric coating.

Example 2

[0099] In this prospective example, the L-carnitine and nootropic substance are within the core. The range represents additional examples.

[0100] The dosage form is a multiparticulate and the total mass represents the total mass of the individual particulates in the dosage form.

TABLE-US-00004 TABLE 4 Contents of example dosage form Range Ingredient mg (mg) Core L-carnitine or acetyl L-carnitine 500 300-800 or propionyl L-carnitine microcrystalline cellulose 150 100-500 Hypromellose 100  50-300 (METHOCEL ® K4M) Sub hypromellose 25  15-100 coating (PHARMACOAT ® 615) citicholine or L-serine 225  25-300 Total mass 1000 Enteric KOLLICOAT ® MAE 30, 10-30% Coating triethyl citrate, PLASACRYL ® Weight gain

Example 3

[0101] In this prospective example, the nootropic substance is within the core. The range represents additional examples.

[0102] The dosage form is a multiparticulate and the total mass represents the total mass of the individual particulates in the dosage form.

TABLE-US-00005 TABLE 5 Contents of example dosage form mg/ Range Ingredient gram (mg) Core L-carnitine or acetyl L-carnitine 500 300-800 or propionyl L-carnitine citicholine or L-serine 250  25-300 microcrystalline cellulose 175 100-500 Hypromellose (METHOCEL ® K4M) 50  50-300 Sub hypromellose coating (PHARMACOAT ® 615) 25  15-100 Total mass 1000 Enteric Kollicoat MAE 30, 10-30% Coating triethyl citrate, Plasacryl Weight gain

[0103] This disclosure has described example embodiments, but not all possible embodiments of the composition or associated methods. Where a particular feature is disclosed in the context of a particular embodiment, that feature can also be used, to the extent possible, in combination with and/or in the context of other embodiments. The composition and related methods may be embodied in many different forms and should not be construed as limited to only the embodiments described here. This disclosure describes exemplary embodiments, but not all possible embodiments of the composition and methods. Where a particular feature is disclosed in the context of a particular embodiment, that feature can also be used, to the extent possible, in combination with and/or in the context of other embodiments.