Solid pharmaceutical dispersions with enhanced bioavailability
View Patent ↗Spray dried solid dispersions comprising a sparingly soluble drug and hydroxypropylmethylcellulose acetate succinate (HPMCAS) provide increased aqueous solubility and/or biavailability in a use environment.
1. A process for making a solid dispersion consisting of a sparingly water-soluble drug and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), said drug being molecularly dispersed and amorphous in said dispersion, said process consisting essentially of the steps of:
(a) providing a solution consisting of a sparingly water-soluble drug, HPMCAS, and a solvent, said solvent being an organic compound in which said drug and HPMCAS are mutually soluble, said solution having a ratio of said drug to HPMCAS of from 1 to 0.4 to 1 to 20;
(b) breaking up said solution into small droplets, wherein said droplets range in size from 1 to 500 μm;
(c) directing said droplets and a drying gas into a drying chamber to cause evaporation of a sufficient amount of said solvent from said droplets to cause solidification of said droplets in less than 5 seconds to form said solid dispersion
wherein said drug has a dose to aqueous solubility ratio greater than 100 mL.
2. A process for making a solid dispersion consisting of a sparingly water-soluble drug and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), said drug being molecularly dispersed and amorphous in said dispersion, said process consisting essentially of the steps of:
(a) providing a solution consisting of a sparingly water-soluble drug, HPMCAS, and a solvent, said solvent being an organic compound in which drug and HPMCAS are mutually soluble, said solution having a ratio of said drug to HPMCAS of from 1 to 0.4 to 1 to 20;
(b) breaking up said solution into small droplets, wherein said droplets range in size from 1 to 500 μm;
(c) directing said droplets and a drying gas into a drying chamber to cause evaporation of a sufficient amount of said solvent from said droplets to cause solidification of said droplets in less than 5 seconds to form particles of said solid dispersion
wherein said drug is crystalline when undispersed.
3. The process of claim 1 or 2 , wherein HPMCAS is present in an amount in said solution that constitutes at least 50 wt % of said solid dispersion.
4. The process of claim 1 or 2 , wherein said solvent has a boiling point of less than 150° C.
5. The process of claim 1 or 2 , wherein the pressure in said drying chamber is at a partial vacuum.
6. The process of claim 1 or 2 , wherein said drying gas is heated.
7. The process of claim 5 , wherein said drying gas is heated.
8. The process of claim 1 or 2 , wherein said solvent is selected from the group consisting of alcohols and ketones.
9. The process of claim 1 or 2 , wherein said solvent is selected from the group consisting of methanol and acetone.
10. The process of claim 1 or 2 , wherein said solidification occurs in less than 2 seconds.
11. The process of claim 1 or 2 , wherein said particles have a diameter of less than 50 μm.
12. The process of claim 1 or 2 , wherein said particles have a diameter of less than 25 μm.
13. The process of claim 1 or 2 , further comprising the step of evaporating solvent from said dispersion following solidification.
14. The process of claim 1 or 2 , wherein said solid dispersion has a residual solvent content of less than 2 wt %.
15. The process of claim 1 or 2 , wherein the concentration of drug in said solvent is less than 20 g/100 g of said solvent.
16. A process for making a solid dispersion consisting of a sparingly water-soluble drug and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), said drug being molecularly dispersed and amorphous in said dispersion, said process consisting essentially of the steps of:
(a) providing a solution consisting of a sparingly water-soluble drug, HPMCAS, and a solvent, said solvent being an organic compound in which the drug and HPMCAS are mutually soluble, said solution having a ratio of said drug to HPMCAS of from 1 to 0.4 to 1 to 20, and the concentration of said drug in said solvent is less than 20 g/100 g of solvent;
(b) breaking up said solution into small droplets, wherein said droplets range in size from 1 to 500 μm;
(c) directing said droplets and a drying gas into a drying chamber to cause evaporation of a sufficient amount of said solvent from said droplets to cause solidification of said droplets in less than 5 seconds to form said solid dispersion.