Enhanced stability phenylephrine liquid compositions

Abstract

An oral, liquid pharmaceutical composition is provided. The composition comprises phenylephrine and substantially aldehyde-free polyethylene glycol. The composition has phenylephrine stability compatible with the stability required for commercial preparations. Optionally, the composition may comprise one or more additional active agents.

Description

EXAMPLE 1

An exemplary composition comprising the single first pharmaceutical active phenylephrine is provided in Table 1. This composition is representative and one of many composition that are within the scope of the invention. The exemplary embodiment is provided for illustrative purposes.

TABLE 1
                                 Amount
Ingredient                       (grams/100 ml × 100)
Phenylephrine HCl                0.1% w/v
Glycerin (96% USP)               25% w/v
Sorbitol (70% Solution USP)      10% w/v
Micronized Sucralose Powder (NF) 0.2% w/v
Substantially aldehyde-free      10.0% w/v
polyethylene glycol
colorant                         0.01% w/v
sodium citrate/citric acid       0.95% w/v
sodium benzoate                  0.1% w/v
purified H20 USP                 sufficient quantity to
                                 make final volume

The composition of Table 1 is prepared by simple mixing. The ingredients are mixed in a vessel equipped with a mechanical stirrer (e.g., a Lightnin mixer), the vessel is calibrated and marked to designate the final volume. An aliquot of water substantially less than the target final volume is placed in the vessel and the SAF-PEG is added and mixed with the water. The phenylephrine is added to the solution in the vessel with mixing. The other ingredients are added sequentially with mixing. Colorants may be added directly or premixed with a small amount of water prior to addition to the main vessel. After all other ingredients are added and mixed sufficiently to dissolve, water is added to bring the total volume of the composition to the predetermined final volume and mixing is continued for approximately 10 minutes.

EXAMPLE 2

An exemplary composition comprising phenylephrine and a second active dextromethorphan hydrobromide is provided in Table 2. This composition is representative and one of the many compositions that are within the scope of the invention. The exemplary embodiment is provided for illustrative purposes.

TABLE 2
                              Amount
Ingredient                    (grams/100 ml + 100)
Phenylephrine HCl             0.1% w/v
Dextromethorphan Hydrobromide 0.02% w/v
Glycerin (96% USP)            25% w/v
Sorbitol (70% Solution USP)   10% w/v
Micronized Sucralose          0.2% w/v
Artificial Fruit Flavor       0.2% w/v
Colorant                      <0.1% w/v
Sodium Citrate/Citric Acid    0.95% w/v
Sodium Benzoate               0.1% w/v
Substantially aldehyde-free   10% w/v
polyethylene glycol
Purified H20                  Sufficient quantity
                              to make final volume

The composition of Table 2 may be prepared using the manner of preparation described in Example 1. The active agents phenylephrine and dextromethorphan are added to the water SAF-PEG solution prior to the addition of the other excipients.

EXAMPLE 3

An exemplary composition comprising phenylephrine and the two second active agents, dextromethorphan and guaifenesin is provided in Table 3. This composition is representative and one of many composition that are within the scope of the invention. The exemplary embodiment is provided for illustrative purposes.

TABLE 3
                                 Amount
Ingredient                       (grams/100 ml × 100)
Phenylephrine HCl                0.1% w/v
Dextromethorphan Hydrobromide    0.2% w/v
Guaifenesin                      4% w/v
Glycerin (96% USP)               25% w/v
Sorbitol (70% Solution USP)      10% w/v
Micronized Sucralose Powder (NF) 0.2% w/v
colorant                         0.01% w/v
sodium citrate/citric acid       0.95% w/v
sodium benzoate                  0.1% w/v
Substantially aldehyde-free      10% w/v
polyethylene glycol
purified H20 USP                 sufficient quantity to
                                 make final volume

The composition of Table 3 may be prepared using the manner of preparation described in Example 2.

EXAMPLE 4

An exemplary composition comprising phenylephrine and the three second active agents acetaminophen, chlorpheniramine maleate and dextromethorphan hydrobromide is provided in Table 4. This composition is representative and one of the many compositions that are within the scope of the invention. The exemplary embodiment is provided for illustrative purposes.

TABLE 4
                              Amount
Ingredient                    (grams/100 ml + 100)
Phenylephrine HCl             0.05% w/v
Acetaminophen                 3.2% w/v
Chlorpheniramine Maleate      0.02% w/v
Dextromethorphen Hydrobromide 0.1% w/v
Sorbitol (70% Solution USP)   10% w/v
Glycerin (96% USP)            25% w/v
Micronized Sucralose          0.2% w/v
Artificial Fruit Flavor       0.2% w/v
Colorant                      <0.1% w/v
Sodium Citrate/Citric Acid    0.6% w/v
Sodium Benzoate               0.1% w/v
Substantially aldehyde-free   20% w/v
polyethylene glycol
Propyl Gallate                0.1% w/v
Purified H20                  Sufficient quantity to
                              make final volume

The composition of Table 4 may be prepared using the manner of preparation described in Example 2. Preferably the acetaminophen is added to the water SAF-PEG solution with mixing prior to the addition of the other actives.

Although the foregoing invention has been described in some detail by way of illustrations and examples for purposes of clarity of understanding. It will be obvious that certain changes and modifications may be practiced within the scope of the appended claims. Modifications of the above-described modes of practicing the invention that are obvious to persons of skill in the art are intended to be included within the scope of the following claims.

Claims

1. An oral liquid pharmaceutical composition comprising: a). phenylephrine; andb). substantially aldehyde-free polyethylene glycol, wherein the substantially aldehyde-free polyethylene glycol has less than 20 ppm total aldehyde content and maintains said level of aldehyde content for at least six months.

2. The composition of claim 1, wherein the substantially aldehyde-free polyethylene glycol has less than 10 ppm total aldehyde content and maintains said level of aldehyde content for at least one year.

3. The composition of claim 1, further comprising at least one second active agent selected from the group consisting of analgesics, decongestants, expectorants, anti-tussives, antipyretics, anti-inflammatory agents, cough suppressants and antihistamines.

4. The composition of claim 3, wherein the second active agent is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDS), propionic acid derivatives, ibuprofen, naproxen, ketoprofen, flurbiprofen, zomepirac, sulindac fenoprofen, suprofen, fluprofen, fenbufen; acetic acid derivatives, tolmetin sodium, indomethacin, fenamic acid derivatives, mefenamic acid meclofenamate sodium, biphenyl carboxylic acid derivatives, diflunisal, flufenisal, oxicams, piroxicam, sudoxicam, isoxicam, chlorpheniramine, brompheniramine; dexchlorpheniramine, dexbrompheniramine, triprolidine, chlorcyclizine, diphenhydramine, doxylamine, tripelenamine, cyproheptatine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, carbinoxamine, desloratadine, loratadine, pheniramine, thonzylamine, mizolastine, terfenadine, chlophendianol, caramiphen, dextromethorphan, diphenhydramine, codeine, hydrocodone, pseudoephedrine, ephedrine, phenylephrine, phenylpropenolamine, terpin hydrate, guaifenesin, potassium, potassium guaicolsulfonate, Cox 2 inhibitors, Celecoxib, Rofecoxib, Valdecoxib, aspirin, acetaminophen, phenacetin, salicylate salts and combination thereof.

5. The composition of claim 4, wherein the at least one second active agent is selected from the group consisting of chlorpheniramine, dextromethorphan, guaifenesin, acetaminophen, chlophendianol, diphenhydramine,? brompheniramine, loratadine, aspirin and doxylamine succinate.

6. The composition of claim 1, further comprising a flavor system.

7. The composition of claim 6, wherein the flavor system includes non-aldehyde flavorants.

8. The composition of claim 1, wherein the composition is an aqueous based solution, aqueous based suspension, or liquid fill for a capsule.

9. The composition of claim 1, further comprising an antioxidant.

10. The composition of claim 9, wherein the antioxidant is propyl gallate.

11. A method of treating an mammal in need of treatment comprising providing an effective amount of oral liquid pharmaceutical composition of claim 1.

12. An aqueous oral pharmaceutical composition comprising: a). phenylephrine;b). substantially aldehyde-free polyethylene glycol, wherein the substantially aldehyde-free polyethylene glycol has less than 20 ppm total aldehyde content and maintains said level of aldehyde content for at least six months;c). artificial sweetener;d). up to about 45% glycerin; ande). up to about 50% sorbitol.

13. The composition of claim 12, wherein the substantially aldehyde-free polyethylene glycol has less than 10 ppm total aldehyde content and maintains said level of aldehyde content for at least one year.

14. The composition of claim 12, wherein the artificial sweetener is selected from the group consisting of sucralose, saccharine salts, cyclamates, acesulfame K, dipeptide based sweeteners, aspartame and mixtures thereof.

15. The composition of claim 14, where in the artificial sweetener comprises sucralose.

16. The composition of claim 12, further comprising a flavor system.

17. The composition of claim 16, wherein the flavor system includes non-aldehyde flavorants.

18. The composition of claim 12, further comprising at least one second active agent selected from the group consisting of analgesics, decongestants, expectorants, anti-tussives, antipyretics, anti-inflammatory agents, cough suppressants and antihistamines.

19. The composition of claim 18, wherein the second active agent is selected propionic acid derivatives, ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDS), suprofen, fluprofen, fenbufen; acetic acid derivatives, tolmetin sodium, zomepirac, sulindac, indomethacin, fenamic acid derivatives, mefenamic acid meclofenamate sodium, biphenyl carboxylic acid derivatives, diflunisal, flufenisal, oxicams, piroxicam, sudoxicam, isoxicam, chlorpheniramine, brompheniramine; dexchlorpheniramine, dexbrompheniramine, triprolidine, chlorcyclizine, diphenhydramine, doxylamine, tripelenamine, cyproheptatine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, carbinoxamine, desloratadine, loratadine, pheniramine, thonzylamine, mizolastine, terfenadine, chlophendianol, caramiphen, dextromethorphan, diphenhydramine, codeine, hydrocodone, pseudoephedrine, ephedrine, phenylephrine, phenylpropenolamine, terpin hydrate, guaifenesin, potassium, potassium guaicolsulfonate, Cox 2 inhibitors, Celecoxib, Rofecoxib, Valdecoxib, aspirin, acetaminophen, phenacetin, salicylate salts and combination thereof.

20. The composition of claim 19, wherein the at least one second active agent is selected from the group consisting of chlorpheniramine, dextromethorphan, guaifenesin, acetaminophen, chlophendianol, diphenhydramine, brompheniramine, loratadine, aspirin and doxylamine succinate.

21. The composition of claim 12, wherein the composition is an aqueous based solution.

22. The composition of claim 12, further comprising an antioxidant.

23. The composition of claim 22, wherein the antioxidant is propyl gallate.

24. The composition of claim 12, further comprising a buffering agent.25.

25. The composition of claim 24, wherein the buffering agent maintains a pH below 5.4 in the composition.

26. The composition of claim 25, wherein the buffering agent maintains a pH between about 2 and about 5 in the composition.

27. The composition of claim 12, further comprising a preservative.

28. The composition of claim 27, wherein the preservative is selected from the group consisting of sodium benzoate, sorbates, parabens, EDTA and combinations thereof.

29. An aqueous oral pharmaceutical composition comprising: a). phenylephrine;b). substantially aldehyde-free polyethylene glycol, wherein the substantially aldehyde-free polyethylene glycol has less than 20 ppm total aldehyde content and maintains said level of aldehyde content for at least six months;c). an artificial sweetener;d a viscosity modifying agent;e). up to about 45% glycerin; andf). up to about 50% sorbitol.

30. The composition of claim 29, wherein the substantially aldehyde-free polyethylene glycol has less than 10 ppm total aldehyde content and maintains said level of aldehyde content for at least one year.

31. The composition of claim 29, wherein the viscosity modifying agent is selected from the group consisting of chitosen, microcrystalline cellulose, xanthan, HPMC, HPC, HEC, galaotomannons and combinations thereof.

32. The composition of claim 29, wherein the artificial sweetener is selected from the group consisting of sucralose, saccharine salts, cyclamates, acesulfame K, dipeptide based sweeteners, aspartame and mixtures thereof.

33. The composition of claim 29, wherein the artificial sweetener comprises sucralose.

34. The composition of claim 29, further comprising an effective amount of at least a second active agent selected from the group consisting of analgesics, decongestants, expectorants, anti-tussives, antipyretics, anti-inflammatory agents, cough suppressants and antihistamines.

35. The composition of claim 34, wherein the second active agent is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDS), propionic acid derivatives, ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, suprofen, fluprofen, fenbufen; acetic acid derivatives, tolmetin sodium, zomepirac, sulindac, indomethacin, fenamic acid derivatives, diflunisal, flufenisal, oxicams, piroxicam, sudoxicam, isoxicam, chlorpheniramine, brompheniramine; dexchlorpheniramine, dexbrompheniramine, triprolidine, chlorcyclizine, diphenhydramine, doxylamine, tripelenamine, cyproheptatine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, carbinoxamine, desloratadine, loratadine, pheniramine, thonzylamine, mizolastine, terfenadine, chlophendianol, caramiphen, dextromethorphan, diphenhydramine, codeine, hydrocodone, pseudoephedrine, ephedrine, phenylephrine, phenylpropenolamine, terpin hydrate, guaifenesin, potassium, potassium guaicolsulfonate, Cox 2 inhibitors, Celecoxib, Rofecoxib, Valdecoxib, aspirin, acetaminophen, phenacetin, salicylate salts and combination thereof.

36. The composition of claim 35, wherein the second active agent is selected from the group consisting of chlorpheniramine, dextromethorphan, guaifenesin, acetaminophen, chlorphendianol, doxylamine succinate and ibuprofen.

37. A method of treating an mammal in need of treatment comprising providing an effective amount of an aqueous oral pharmaceutical composition of claims 12 or 29.

38. The method of claim 37, wherein the pharmaceutical composition further comprises at least one second active agent.

39. The method of claim 38, wherein the second active agent is selected from the group consisting of analgesics, decongestants, expectorants, anti-tussives, antipyretics, anti-inflammatory agents, cough suppressants and antihistamines.