Liquid oral formulations for tadalafil
The present disclosure is directed to pharmaceutical compositions comprising a PDE V inhibitor and one or more pharmaceutical excipients or additives wherein the pharmaceutical compositions are in the form of liquid pharmaceutical compositions. The pharmaceutical compositions of the present disclosure are useful for the treatment of diseases or conditions which are treatable by administration of PDE V inhibitor drug such as pulmonary arterial hypertension, erectile dysfunction, etc.
1. A liquid oral pharmaceutical composition comprising
about 4 mg/mL tadalafil or a pharmaceutically acceptable salt thereof;
a pharmaceutically acceptable excipient comprising a wetting agent comprising ethanol, glycerin, propylene glycol, or a combination thereof in an amount of from about 100 mg/mL to about 1000 mg/mL; and
a vehicle comprising water;
wherein the pharmaceutical composition has a pH of about 5.
2. The liquid oral pharmaceutical composition of claim 1 , wherein the tadalafil comprises particulate tadalafil having a d90 particulate size of from about 1 micron to about 200 microns.
3. The liquid oral pharmaceutical composition of claim 1 , wherein the tadalafil comprises particulate tadalafil having a d90 particulate size of from about 1 micron to about 100 microns.
4. The liquid oral pharmaceutical composition of claim 1 , wherein the tadalafil comprises particulate tadalafil having a d90 particulate size of from about 5 microns to about 10 microns.
5. The liquid oral pharmaceutical composition of claim 1 , wherein the liquid oral pharmaceutical composition has a pH of 5.
6. The liquid oral pharmaceutical composition of claim 1 , wherein the wetting agent is present in an amount of from about 100 mg/mL to about 800 mg/mL.
7. The liquid oral pharmaceutical composition of claim 1 , wherein the wetting agent is present in an amount of from about 100 mg/mL to about 600 mg/mL.
8. The liquid oral pharmaceutical composition of claim 1 , wherein the wetting agent is present in an amount of from about 100 mg/mL to about 500 mg/mL.
9. The liquid oral pharmaceutical composition of claim 1 , wherein the wetting agent is present in an amount of about 400 mg/mL.
10. The liquid oral pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient further comprises a viscosity modifying agent comprising an acacia, an agar, alginic acid, a carbomer, a dextrin, a gelatin, a veegum, a gellan gum, a sodium alginate, a methylcellulose, a hydroxyethyl cellulose, a hydroxypropyl cellulose, a hydroxypropylmethyl cellulose, a hydroxypropyl starch, a maltodextrin, a methylcellulose, a modified starch, a pectin, a poloxamer, a polycarbophil, a polyethylene glycol, a polyvinyl acetate, a poly (vinyl alcohol), a potassium alginate, a polyvinyl pyrrolidone, a pregelatinized starch, a propylene glycol alginate, a sodium alginate, a carboxymethyl cellulose, an alkali metal salt of a carboxymethyl cellulose, a microcrystalline cellulose, a gum arabic, a karaya gum, a sterculia gum, a tragacanth, a xanthan gum, a bentonite, a carageenan, a guar gum, a colloidal silicon dioxide, or a combination thereof, in an amount of from about 0.1 mg/mL to about 100 mg/mL.
11. The liquid oral pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient further comprises a viscosity modifying agent comprising an acacia, an agar, alginic acid, a carbomer, a dextrin, a gelatin, a veegum, a gellan gum, a sodium alginate, a methylcellulose, a hydroxyethyl cellulose, a hydroxypropyl cellulose, a hydroxypropylmethyl cellulose, a hydroxypropyl starch, a maltodextrin, a methylcellulose, a modified starch, a pectin, a poloxamer, a polycarbophil, a polyethylene glycol, a polyvinyl acetate, a poly (vinyl alcohol), a potassium alginate, a polyvinyl pyrrolidone, a pregelatinized starch, a propylene glycol alginate, a sodium alginate, a carboxymethyl cellulose, an alkali metal salt of a carboxymethyl cellulose, a microcrystalline cellulose, a gum arabic, a karaya gum, a sterculia gum, a tragacanth, a xanthan gum, a bentonite, a carageenan, a guar gum, a colloidal silicon dioxide, or a combination thereof, in an amount of from about 1 mg/mL to about 20 mg/mL.
12. The liquid oral pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient further comprises an anti-foaming agent comprising a simethicone, a simethicone emulsion, an organic phosphate, a paraffin oil, a stearate, a glycol, or a combination thereof, in an amount of from about 0.1 mg/mL to about 100 mg/mL.
13. The liquid oral pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient further comprises a pH adjusting agent, a pH modifying agent, or a combination thereof comprising acetic acid, adipic acid, ammonium carbonate, ammonium hydroxide, ammonium phosphate, boric acid, citric acid, diethanolamine, fumaric acid, hydrochloric acid, malic acid, nitric acid, propionic acid, potassium acetate, potassium bicarbonate, potassium citrate, potassium metaphosphate, potassium phosphate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium glycolate, sodium hydroxide, sodium lactate, sodium phosphate, sodium propionate, succinic acid, sulfuric acid, tartaric acid, triethylamine, triethanolamine, tromethamine, trolamine, or a combination thereof.
14. The liquid oral pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient further comprises a pH adjusting agent, a pH modifying agent, or a combination thereof, wherein the pH modifying agent comprises acetic acid, adipic acid, ammonium carbonate, ammonium hydroxide, ammonium phosphate, boric acid, citric acid, diethanolamine, fumaric acid, hydrochloric acid, malic acid, nitric acid, propionic acid, potassium acetate, potassium bicarbonate, potassium citrate, potassium metaphosphate, potassium phosphate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium glycolate, sodium hydroxide, sodium lactate, sodium phosphate, sodium propionate, succinic acid, sulfuric acid, tartaric acid, triethylamine, triethanolamine, tromethamine, trolamine, or a combination thereof, in an amount of from about 0.01 M to about 0.1 M.
15. The liquid oral pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient further comprises a surfactant comprising a sodium lauryl sulfate, a docusate sodium, a cocamidopropyl amino betaine, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene 15 hydroxystearate, a polyoxyethylene castor oil derivative, a polyoxyethylene stearate, a sorbitan fatty acid ester, a polyoxyethylene alkyl ether, a polyoxyethylene nonylphenol ether, or a combination thereof, in an amount of: (i) from 0.1 mg/mL to about 100 mg/mL.
16. The liquid oral pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient further comprises a surfactant comprising a sodium lauryl sulfate, a docusate sodium, a cocamidopropyl amino betaine, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene 15 hydroxystearate, a polyoxyethylene castor oil derivative, a polyoxyethylene stearate, a sorbitan fatty acid ester, a polyoxyethylene alkyl ether, a polyoxyethylene nonylphenol ether, or a combination thereof, in an amount of from about 0.1 mg/mL to about 1 mg/mL.
17. The liquid oral pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient further comprises:
a preservative in an amount of: (i) from about 0.1 mg/mL to about 2.4 mg/mL or (ii) about 2.4 mg/mL;
a sweetener in an amount of: (i) from about 0.1 mg/mL to about 6 mg/mL, (ii) from about 0.1 mg/mL to about 1 mg/mL, or (iii) about 1 mg/mL;
a flavorant in an amount of about 0.1 mg/mL;
or a combination thereof.
18. The liquid oral pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient further comprises a viscosity modifying agent, an anti-foaming agent, a pH modifying agent, a pH adjusting agent, a surfactant, or a combination thereof.
19. The liquid oral pharmaceutical composition of claim 1 , wherein the wetting agent is present in an amount of from about 100 mg/mL to about 800 mg/mL; and
wherein the pharmaceutically acceptable excipient further comprises:
a viscosity modifying agent in an amount of from about 0.1 mg/mL to about 100 mg/mL;
an anti-foaming agent in an amount of from about 0.1 mg/mL to about 100 mg/mL;
a pH modifying agent in an amount of from about 0.01 M to about 0.5 M;
a surfactant in an amount of from about 0.1 mg/mL to about 100 mg/mL;
or a combination thereof.
20. The liquid oral pharmaceutical composition of claim 1 , wherein the wetting agent is present in an amount of from about 100 mg/mL to about 700 mg/mL; and
wherein the pharmaceutically acceptable excipient further comprises:
a preservative in an amount of from about 0.1 mg/mL to about 2.4 mg/mL;
a sweetener in an amount of from about 0.1 mg/mL to about 6 mg/mL;
a flavorant in an amount of from about 0.1 mg/mL to about 50 mg/mL;
a viscosity modifying agent in an amount of from about 1 mg/mL to about 20 mg/mL;
an anti-foaming agent in an amount of from about 0.1 mg/mL to about 0.5 mg/mL;
a pH modifying agent in an amount of from about 0.01 M to about 0.1 M;
a surfactant in an amount of from about 0.1 mg/mL to about 1 mg/mL;
or a combination thereof.
21. The liquid oral pharmaceutical composition of claim 1 , wherein the wetting agent is present in an amount of from about 200 mg/mL to about 600 mg/mL; and
wherein the pharmaceutically acceptable excipient further comprises:
a preservative in an amount of from about 0.1 mg/mL to about 2.4 mg/mL;
a sweetener in an amount of from about 0.1 mg/mL to about 6 mg/mL;
a flavorant in an amount of from about 0.1 mg/mL to about 50 mg/mL;
a viscosity modifying agent in an amount of from about 1 mg/mL to about 6 mg/mL;
an anti-foaming agent in an amount of from about 0.1 mg/mL to about 0.5 mg/mL;
a pH modifying agent in an amount of from about 0.01 M to about 0.1 M;
a surfactant in an amount of from about 0.1 mg/mL to about 1 mg/mL;
or a combination thereof.
22. The liquid oral pharmaceutical composition of claim 1 ,
wherein the pharmaceutically acceptable excipient further comprises:
a preservative in an amount of from about 0.1 mg/mL to about 2.4 mg/mL;
a sweetener in an amount of from about 0.1 mg/mL to about 6 mg/mL;
a flavorant in an amount of from about 0.1 mg/mL to about 50 mg/mL;
a viscosity modifying agent in an amount of from about 1 mg/mL to about 6 mg/mL;
an anti-foaming agent in an amount of from about 0.1 mg/mL to about 0.5 mg/mL;
a pH modifying agent in an amount of from about 0.01 M to about 0.1 M;
a surfactant in an amount of from about 0.1 mg/mL to about 1 mg/mL;
or a combination thereof.
23. The liquid oral pharmaceutical composition of claim 1 , wherein the wetting agent comprises glycerin in an amount of from about 100 mg/mL to about 1000 mg/mL; and
wherein the pharmaceutically acceptable excipient further comprises:
a preservative comprising benzoic acid or a salt thereof in an amount of from about 0.1 mg/mL to about 2.4 mg/mL;
a sweetener comprising sucralose in an amount of from about 0.1 mg/mL to about 6 mg/mL;
a flavorant in an amount of from about 0.1 mg/mL to about 50 mg/mL;
a viscosity modifying agent comprising xanthan gum in an amount of from about 1 mg/mL to about 3 mg/mL;
an anti-foaming agent comprising a 30% simethicone emulsion in an amount of from about 0.1 mg/mL to about 0.5 mg/mL;
a pH modifying agent comprising a citrate buffer, a phosphate buffer, or a combination thereof in an amount of from about 0.01 M to about 0.1 M;
a surfactant comprising a polyoxyethylene sorbitan fatty acid ester in an amount of from about 0.1 mg/mL to about 1 mg/mL;
or a combination thereof.
24. The liquid oral pharmaceutical composition of claim 1 ,
wherein the wetting agent comprises glycerin in an amount of about 400 mg/mL; and
wherein the pharmaceutically acceptable excipient further comprises:
a preservative comprising benzoic acid or a salt thereof in an amount of from about 0.1 mg/mL to about 2.4 mg/mL;
a sweetener comprising sucralose in an amount of from about 0.1 mg/mL to about 1 mg/mL,
a flavorant present in an amount of about 0.1 mg/mL;
a viscosity modifying agent comprising xanthan gum in an amount of from about 2 mg/mL to about 3 mg/mL;
an anti-foaming agent comprising a 30% simethicone emulsion in an amount of about 0.5 mg/mL;
a pH modifying agent comprising a citrate buffer, a phosphate buffer, or a combination thereof in an amount of from about 0.03 M;
a surfactant comprising a polyoxyethylene sorbitan fatty acid ester in an amount of from about 0.1 mg/mL to about 1 mg/mL;
or a combination thereof.
25. A method for the treatment of a condition, which comprises administering to a human patient in need thereof a therapeutically effective amount of the liquid oral pharmaceutical composition of claim 1 , wherein said condition is selected from the group consisting of pulmonary arterial hypertension, erectile dysfunction, benign prostatic hyperplasia, and a combination thereof.
26. A method for the treatment of a condition, which comprises administering to a human patient in need thereof a therapeutically effective amount of the liquid oral pharmaceutical composition of claim 1 , wherein said condition is pulmonary arterial hypertension.
27. A method for the treatment of a condition, which comprises administering to a human patient in need thereof a therapeutically effective amount of the liquid oral pharmaceutical composition of claim 1 , wherein said condition is erectile dysfunction.
28. A method for the treatment of a condition, which comprises administering to a human patient in need thereof a therapeutically effective amount of the liquid oral pharmaceutical composition of claim 1 , wherein said condition is benign prostatic hyperplasia.