Formulation for parenteral administration
The instant invention provides pharmaceutical formulations for a long acting injectable drug product comprising a suspension of doravirine for parenteral administration via intramuscular or subcutaneous routes. The drug product can be used for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset of AIDS (acquired immunodeficiency syndrome) or ARC (AIDS related complex).
1. A parenteral pharmaceutical composition for intramuscular or subcutaneous administration comprising a suspension of particles of crystalline Form II of doravirine (D-AHII) wherein the particles have a specific surface area within a range from 22.2 m 2 /g to 1.8 m 2 /g.
2. The composition of claim 1 wherein the D-AHII has a particle size from about 100 nm (D 10 ) to about 20 μm (D 90 ).
3. The composition of claim 1 wherein the D-AHII has a median particle size from about 200 nm to about 8 μm.
4. The composition of claim 2 comprised of D-AHII at a concentration range from 1% to 30%.
5. The composition of claim 2 comprised of D-AHII at a concentration range from 10% to 30%.
6. The composition of claim 2 comprised of D-AHII at a concentration range from 20% to 30%.
7. The composition of claim 4 further comprised of a surfactant which is one or more of polysorbate 80, polysorbate 20, poloxyamer 188, Vitamin E TPGS, docusate sodium or sodium deoxycholate.
8. The composition of claim 7 wherein the surfactant is polysorbate 80 or Vitamin E TPGS or a combination of both.
9. The composition of claim 4 wherein the D-AHII:surfactant weight ratio is from 150:1 to 1:1.
10. The composition of claim 9 which is a microsuspension of D-AHII wherein the D-AHII:surfactant weight ratio is from 150:1 to 20:1.
11. The composition of claim 9 which is a nanosuspension of D-AHII wherein the D-AHII:surfactant weight ratio is from 7.5:1 to 5:1.
12. The composition of claim 1 further comprising a viscosity modifying agent which is PEG 3350 or sodium carboxymethylcellulose or a combination of both, wherein the concentration of the viscosity modifying agent is from 0.1 wt % to 3.0 wt % and the viscosity of the suspending vehicle is from 1.4 cP to 1220 cP.
13. The composition of claim 1 wherein the pH of the composition is 7.
14. The composition of claim 13 comprising a phosphate buffering agent.
15. The composition of claim 1 further comprising a tonicity modifier which is one or more of dextrose, mannitol, sucrose, trehalose or sodium chloride.
16. The composition of claim 15 wherein the tonicity modifier is:
(a) for a microsuspension, mannitol or sodium chloride or a combination of both; or
(b) for a nanosuspension, one or more of sucrose, trehalose or sodium chloride.
17. The composition of claim 16 wherein the tonicity modifier is:
(a) for a microsuspension, sodium chloride; or
(b) for a nanosuspension, trehalose.
18. The composition of claim 1 comprising:
Components
Quantity
D-AHII
30.0%
(w/v)
Polyethylene glycol 3350
3%
(w/v)
Polysorbate 80
0.2%
(w/v)
Phosphate buffer
10
mM
Water
QS to 100%
pH
7.0
Particle size distribution, micron
2.58/7.61/15.33
(D 10 /D 50 /D 90 )
Specific surface area (m 2 /g)
1.82.