Pharmaceutical composition for the treatment of Covid-19 infection

Abstract

A bilayer composition for amelioriation of, or prophylaxis against, SARS-CoV-2 infection comprising a: (i) a first layer consisting of 250 mg to 1600 mg of 5-aminolevulinic acid (ALA), or salt thereof, and pharmaceutically acceptable excipients that allow for immediate release of the 5-aminolevulinic acid; (ii) a second layer consisting of hydroxychloroquine (HCQ), and/or a salt thereof, in a dose of 100 mg-1500 mg, or salt thereof, and at least one pharmaceutically acceptable excipient comprising a release modifier for sustained release of the hydroxychloroquine or chloroquine.

Claims

1. A bilayer tablet comprising: (i) a first layer consisting of 250 mg to 1600 mg of 5-aminolevulinic acid (ALA), or salt thereof, and pharmaceutically acceptable excipients that allow for immediate release of the 5-aminolevulinic acid; (ii) a second layer consisting of hydroxychloroquine (HCQ), and/or a salt thereof, in a dose of 100 mg-1500 mg, or salt thereof, and at least one pharmaceutically acceptable release modifier for sustained release of the hydroxychloroquine.

2. The bilayer tablet of claim 1 wherein the 5-aminolevulinic acid is in a zinc salt form.

3. The bilayer tablet of claim 2 wherein the salt is zinc-aminolevulinic acid.

4. The bilayer tablet of claim 2 wherein the salt is Zn(ALA).sub.2.

5. The bilayer tablet of claim 2 wherein the hydroxychloroquine salt is Zn(HCQ)Cl.sub.2H.sub.2O.

6. The bilayer tablet of claim 5 wherein the 5-aminolevulinic acid salt is Zn(ALA).sub.2.

7. The bilayer tablet of claim 1 in the form of a caplet.

8. The bilayer tablet of claim 1 wherein the first and second layers are coated with a film coating.

9. The bilayer tablet of claim 8 wherein the film coating is an enteric coating.

10. The bilayer tablet of claim 1 wherein the pharmaceutically acceptable excipients that allow for immediate release of the 5-aminolevulinic acid includes microcrystalline cellulose.

11. A bilayer tablet comprising: (i) a first layer consisting of 250 mg to 1600 mg of 5-aminolevulinic acid (ALA), or salt thereof, and pharmaceutically acceptable excipients that allow for immediate release of the 5-aminolevulinic acid; (ii) a second layer consisting of chloroquine (CQ), and/or a salt thereof, in a dose of 100 mg-1500 mg, or salt thereof, and at least one pharmaceutically acceptable release modifier for sustained release of the chloroquine.

12. The bilayer tablet of claim 11 wherein the 5-aminolevulinic acid is in a zinc salt form.

13. The bilayer tablet of claim 12 wherein the salt is zinc-aminolevulinic acid.

14. The bilayer tablet of claim 11 wherein the salt is Zn(ALA).sub.2.

15. The bilayer tablet of claim 11 wherein the hydroxychloroquine salt is Zn(CQ)Cl.sub.2H.sub.2O.

16. The bilayer tablet of claim 15 wherein the 5-aminolevulinic acid salt is Zn(ALA).sub.2.

17. The bilayer tablet of claim 11 in the form of a caplet.

18. The bilayer tablet of claim 11 wherein the first and second layers are coated with a film coating.

19. The bilayer tablet of claim 18 wherein the film coating is an enteric coating.

20. The bilayer tablet of claim 11 wherein the at least one pharmaceutically acceptable release modifier for sustained release of the hydroxychloroquine includes hydroxypropyl methylcellulose.

Description

EXAMPLE 1 (METHOD OF MANUFACTURE)

(1) The bilayer tablet composition is prepared by making two separate granulations containing HCQ in one granulation and 5-ALA in the other granulation.

(2) HCQ is combined with magnesium stearate, and sodium carboxymethyl cellulose and mixed in a high shear granulator. Purified water is added with stirring. The wet granulated material is passed through a mill and then dried until moisture content is 1.0% or less. The milled HCQ formulation is added to milled hyroxypropyl methylcellulose 2208 USP and magnesium stearate added.

(3) The 5-ALA granulation is performed by blending 5-ALA with microcrystalline cellulose, anhydrous lactose, a portion of crospovidone, and a portion of silicon dioxide in a tumble mixer and passed through a suitable conical mill. Magnesium stearate (screened) is blended into the mixture and then compacted using a roller compactor. The granules are blended with the remaining amount of crospovidone and silicon dioxide in a suitable tumble mixer.

(4) A bilayer tablet press is used with the 5-ALA granulation in one hopper and the HCQ granulation in a second hopper. Tablet press is set to obtain the target weight, for the first layer. The second hopper is then opened and the target weight of the tablet press adjusted to obtain the tablet weight desired. Once target weight is obtained, the press is adjusted to obtain the target hardness.

(5) Preferably, the HCQ granulation is manufactured for extend-release, however, the 5-ALA granulation may also, or instead, be manufactured for extend-release.

EXAMPLE 2 (EXEMPLARY FORMULATION)

(6) Bilayer tablet composition comprising 5-ALA and ivermectin, or salts thereof:

(7) TABLE-US-00001 Ingredients % w/w mg/unit First layer: 5-ALA or salt thereof 300.00 Lactose Anhydrous 96.00 Microcrystalline cellulose 302 445.00 Silicon dioxide 9.00 Crospovidour 24.00 Magnesium Stearate 6.00 Purified water Qs Total (immediate 880.00 release layer): Second Layer: CQ or HCQ or salt thereof 200.00 Na Carboxymethyl Cellulose 10.00 Magnesium Stearate 0.71 Hydroxypropyl methylcellulose 78.60 Purified water --- Qs Total (extend layer): 289.31 Core tablet weight (First 1169.31 layer + Second layer) Film coating material weight 40.31 -Opadry II Total weight of coated tablet 1209.62

(8) While the invention has been described by reference to specific embodiments, this was done for purposes of illustration only and should not be construed to, limit the spirit or scope of the invention.