Physically stable aqueous suspensions of active pharmaceuticals

• US 20080260837A1
• Filed: 04/20/2007
• Published: 10/23/2008
• Est. Priority Date: 04/20/2007
• Status: Abandoned Application

• Current Assignee: Triad Group, Inc.
• Original Assignee: Qpharma LLC
• Inventors: Namburi, Ranga R., Palkhiwala, Burgise F., Mulamalla, Ratna Prabha, Vattikuti, Bala Murali K.
• Application Number:
  US11/788,466
• Publication Number:
  US 20080260837A1
• Time in Patent Office: Days
• US Class Current: 424/488
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/09 having two or more such linkages
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/225 Polycarboxylic acids
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00

Abstract

The present invention concerns methods of making physically stable aqueous suspensions of sparingly soluble to insoluble in water, active pharmaceuticals. More particularly, the invention provides an aqueous pharmaceutical suspension composition comprising an active pharmaceutical component which is sparingly soluble to insoluble in water; a water soluble, low viscosity grade cellulose polymer with a viscosity range of 3 mPa·s to 50 mPa·s as a surfactant; a suspending agent; and water.

Claims

1. A physically stable pharmaceutical suspension comprising:

a) an active pharmaceutical component which is sparingly soluble to insoluble in water;

b) a water soluble, low viscosity grade cellulose polymer with a viscosity range of from about 3 to about 50 mPa·

s, measured at 2.0% concentration in water at 20°

C. as a surfactant;

c) a suspending agent; and

d) water.

2. The physically stable pharmaceutical suspension of claim 1 wherein the active pharmaceutical component comprises particles have an average particle size in the range of from about 10 μ

m to about 200 μ

m.

3. The physically stable pharmaceutical suspension of claim 1 wherein the active pharmaceutical component which is sparingly soluble to insoluble in water comprises ibuprofen, acetaminophen, guaifenesin, loratadine, propofol, desloratadine, dipyridamole, furosemide, atorvastatin, lovastatin, simvastatin, paroxetin, sertaline, acyclovir, ganicyclovir, itraconazole, ritonavir, saquinavir, beclomethasone dipropionate, flunisolide, fluticasone propionate, budenoside, mometasone furoate, raloxifene HCl, and combinations thereof.

4. The physically stable pharmaceutical suspension of claim 1 further comprising a water soluble active pharmaceutical component comprising

chlorpheniramine maleate, dextromethorphan HBr, pheniramine maleate, bromphenramine maleate, pseudoephedrine hydrochloride, diphenhydramine hydrochloride, doxylamine succinate, oxycodone and combination thereof.

5. The physically stable pharmaceutical suspension of claim 1 wherein the water soluble, low viscosity grade cellulose polymer is a polymer which forms liquid colloidal solutions having a viscosity of from about 3 mPa·

s to about 15 mPa·

s when measured on a 2% w/v aqueous solution at 20°

C.

6. The physically stable pharmaceutical suspension of claim 1 wherein the water soluble, low viscosity grade cellulose polymer comprises hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and combinations thereof.

7. The physically stable pharmaceutical suspension of claim 1 wherein the water soluble, low viscosity grade cellulose polymer comprises hydroxypropyl methyl cellulose which forms liquid colloidal solutions having a viscosity of about 6 mPa·

s when measured on a 2% w/v aqueous solution at 20°

C.

8. The physically stable pharmaceutical suspension of claim 1 wherein the suspending agent comprises a water soluble, high viscosity grade cellulose, a polysaccharide, a gum, an acrylic acid derivative or combinations thereof which forms a liquid colloidal solution has a viscosity of from in excess of 50 mPa·

s in a 1% w/v aqueous solution.

9. The physically stable pharmaceutical suspension of claim 1 wherein the suspending agent comprises xanthan gum, carrageenan gum, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, carboxymethylcellulose sodium 12, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), microcrystalline cellulose, acacia, agar, alamic acid, alginic acid, aluminum monostearate, attapulgite-activated, attapulgite, colloidal activated bentonite, bentonite-purified, bentonite magma, carbomer polymer, cellulose, dextrin, gelatin, gellan gum, guar gum, magnesium aluminum silicate, maltodextrin, pectin, polyethylene oxide, polyvinyl alcohol, povidone, propylene glycol alginate, silicon dioxide, silicon dioxide-colloidal, sodium alginate, starch, corn starch, potato starch, tapioca, wheat tragacanth, or combinations thereof.

10. The physically stable pharmaceutical suspension of claim 1 which further comprises an additional wetting agent.

11. The physically stable pharmaceutical suspension of claim 1 which further comprises an additional wetting agent comprising at least one of benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, docusate sodium, nonoxynol 9, octoxynol 9, poloxamer, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, and tyloxapol or combinations thereof.

12. The physically stable pharmaceutical suspension of claim 1 which further comprises a sweetening agent.

13. The physically stable pharmaceutical suspension of claim 1 which further comprises a sweetening agent which comprises at least one of acesulfame potassium, aspartame, acesulfame, dextrates, dextrose, dextrose excipient, fructose, galactose, maltitol, maltose, mannitol, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, sucralose, sucrose, sugar, sugar-compressible, high fructose corn syrup, confectioner'"'"'s syrup, and tagatose.

14. The physically stable pharmaceutical suspension of claim 1 which further comprises an antimicrobial preservative.

15. The physically stable pharmaceutical suspension of claim 1 which further comprises an antimicrobial preservative which comprises at least one of benzalkonium chloride, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetrimonium bromide, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, ethylparaben, methylparaben, methylparaben sodium, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, and thymol.

16. The physically stable pharmaceutical suspension of claim 1 which further comprises at least one flavor, at least one perfume, or at least one flavor plus at least one perfume.

17. The physically stable pharmaceutical suspension of claim 1 which further comprises a flavor agent comprising at least one of grape, cherry, bubble gum, berry, or combinations thereof.

18. The physically stable pharmaceutical suspension of claim 1 which further comprises an acidifying agent.

19. The physically stable pharmaceutical suspension of claim 1 which further comprises an acidifying agent comprising at least one of acetic acid, acetic acid-glacial, citric acid-anhydrous, citric acid monohydrate, fumaric acid, hydrochloric acid, hydrochloric acid-diluted, malic acid, nitric acid, phosphoric acid, phosphoric acid-diluted, propionic acid, sulfuric acid and tartaric acid.

20. The physically stable pharmaceutical suspension of claim 1 which further comprises an alkalizing agent comprising at least one of an ammonia solution, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, and trolamine.

21. The physically stable pharmaceutical suspension of claim 1 which further comprises a colorant.

22. The physically stable pharmaceutical suspension of claim 1 which further comprises a colorant comprising at least one of FD&

C Blue No. 1. FD&

C Blue No. 2, FD&

C Green No. 3, FD&

C Red No. 4, FD&

C Yellow No. 5, FD&

C Yellow No. 6, D&

C Blue No. 4, D&

C Green No. 5, D&

C Green No. 6, D&

C Orange No. 4, D&

C Orange No. 5, D&

C Orange No. 10, D&

C Orange No. 11, D&

C Red No. 6, D&

C Red No. 7, D&

C Red No. 17, D&

C Red No. 21, D&

C Red No. 22, D&

C Red No. 27, D&

C Red No. 28, D&

C Red No. 30, D&

C Red No. 31, D&

C Red No. 33, D&

C Red No. 34, D&

C Red No. 36, D&

C Violet No. 2, D&

C Yellow No. 7, D&

C Yellow No. 8, D&

C Yellow No. 10, and D&

C Yellow No. 7.

23. The physically stable pharmaceutical suspension of claim 1 wherein the active pharmaceutical component is present in an amount of from about 0.1 weight percent to 20.0 weight percent based on the volume of the physically stable pharmaceutical suspension.

24. The physically stable pharmaceutical suspension of claim 1 wherein the water soluble, low viscosity grade cellulose polymer is present in an amount of from about 0.1 weight percent to 5.0 weight percent based on the volume of the physically stable pharmaceutical suspension.

25. The stable pharmaceutical suspension of claim 1 wherein the suspending agent is present in an amount of from about 0.05 weight percent to 5.0 weight percent based on the volume of the stable pharmaceutical suspension.

26. The physically stable pharmaceutical suspension of claim 1 which has a viscosity range of 1000 mPa·

s to 2500 mPa·

s when measured at 20°

C.

27. The physically stable pharmaceutical suspension of claim 1 wherein the active pharmaceutical component which is sparingly soluble to insoluble in water comprises acetaminophen, ibuprofen, guaifenesin or combinations thereof;

wherein the water soluble, low viscosity grade cellulose polymer comprises hydroxypropyl methyl cellulose which forms liquid colloidal solutions having a viscosity of about 6 mPa·

s when measured on a 2% w/v aqueous solution at 20°

C.; and

wherein the suspending agent comprises a water soluble, high viscosity grade cellulose, a polysaccharide, a gum, an acrylic acid derivative or combinations thereof which forms a liquid colloidal solution has a viscosity of from in excess of 50 mPa·

s in a 1% w/v aqueous solution.

28. A method of forming a physically stable pharmaceutical suspension comprising:

I) combining

a) an active pharmaceutical component which is sparingly soluble to insoluble in water, wherein the active pharmaceutical component comprises particle have an average particle size in the range of from about 10 μ

m to about 200 μ

m;

b) a water soluble, low viscosity grade cellulose polymer with a viscosity range of from about 3 to about 50 mPa·

s, measured at 2.0% concentration in water at 20°

C.;

c) a suspending agent; and

d) water;

II) dispersing the cellulose polymer and suspending agent in a non-solvent medium followed by hydration with the water, and then incorporating the active pharmaceutical component with high shear mixing.