Nanoparticulate prodrugs
The present invention relates to anti-inflammatory drug formulation. Especially, this invention relates to corticosteroid prodrug nanoparticle. In a first aspect, this invention relates to a nanoparticle comprising a therapeutic agent and a surface coating material. The invention also relates to a process of manufacturing at least one nanoparticle of invention. The invention also relates to pharmaceutical composition and pharmaceutical kits.
1. A nanoparticle comprising a glucocorticoid prodrug and a surface coating material wherein the nanoparticle size is ranging from 20 to 400 nm; wherein the surface coating material is selected from (PEG)-modified phospholipids, wherein the glucocorticoid prodrug is a lipophilic long-chain ester of a glucocorticoid; wherein the glucocorticoid prodrug is in an amorphous state; wherein the glucocorticoid prodrug loading rate is higher than 25% in weight to the weight of nanoparticle;
wherein the nanoparticle is not porous; and
wherein the nanoparticle has a polyoxyethylene surface density Surface PEG smaller than 0.30 nm 2 per polyoxyethylene chain
wherein
Surface
PEG
=
S
available
N
(
cot
.
mater
.
)
N(cot.mater.) being the number of surface coating material molecules in the nanoparticle
N
(
c
o
t
.
m
ater
.
)
=
m
(
c
o
t
.
mater
.
)
M
(
c
o
t
.
mater
.
)
×
N
a
Savailable being the surface available within the nanoparticle,
S available =Ssp ×( m (prodrug)+ m (cot.mater.))
Ssp being the specific surface of the nanoparticle
S
s
p
=
6
ρ
d
m(cot.mater.) being the mass of the surface coating material in the nanoparticle, M(cot.mater.) being the molar mass of the surface coating material, Na being the Avogadro constant, m(prodrug) being the mass of the prodrug in the nanoparticle, p being the density of the prodrug, and d being the average diameter of the nanoparticle.
2. The nanoparticle according to claim 1 , wherein the glucocorticoid prodrug is a lipophilic long-chain ester of dexamethasone.
3. The nanoparticle according claim 1 , wherein the glucocorticoid prodrug is dexamethasone palmitate.
4. The nanoparticle according to claim 1 , wherein the surface coating material is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (ammonium salt).
5. A medicament comprising at least one nanoparticle according to claim 1 .
6. A pharmaceutical composition comprising at least one nanoparticle according to claim 1 and at least one pharmaceutically acceptable excipient.
7. The pharmaceutical composition according to claim 6 , wherein the pharmaceutical composition is formulated for intravenous administration.
8. A kit comprising a container containing a pharmaceutical composition according to claim 6 .
9. A process for manufacturing at least one nanoparticle according to claim 1 , including the following steps:
performing a nanoprecipitation process or an emulsion-evaporation process starting from a solution of glucocorticoid prodrug and surface coating material in a volatile solvent and aqueous solution, or from a solution of glucocorticoid prodrug in a volatile solvent and an aqueous solution of surface coating material, and
obtaining at least one nanoparticle comprising the glucocorticoid prodrug and the surface coating material.
10. The process of claim 9 , wherein the process starts from a solution of glucocorticoid prodrug and surface coating material in volatile solvent and water.
11. The process of claim 9 , wherein the process starts from a solution of glucocorticoid prodrug in volatile solvent and a water solution of surface coating material.
12. The nanoparticle according claim 2 , wherein the glucocorticoid prodrug is dexamethasone palmitate.
13. The nanoparticle according to claim 2 , wherein the surface coating material is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (ammonium salt).
14. The nanoparticle according to claim 3 , wherein the surface coating material is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (ammonium salt).