COMPOSITIONS AND METHODS FOR INJECTING PARTICLE SUSPENSIONS
The present disclosure provides high concentration injectable particle suspensions of therapeutic biologics that permit administration without the need for resuspension. In particular, the compositions disclosed herein are highly concentrated low volume injectable particle suspensions that do not require manual premixing or resuspension prior to administration.
1 . A pharmaceutically effective composition, comprising a suspension of a plurality of particles comprising a therapeutic biologic or salt thereof in a suspension medium, wherein:
the suspension medium comprises a pharmaceutically acceptable liquid carrier and a flocculation agent;
the concentration of the therapeutic biologic or salt thereof in the composition is greater than about 250 mg/mL.
2 . The composition of claim 1 , wherein the concentration of the flocculation agent in the composition is from 0.1 mg/mL to 10 mg/mL.
3 . The composition of claim 1 , wherein the flocculation agent is ionic.
4 . The composition of claim 3 , wherein the ionic flocculation agent is magnesium stearate, sodium dodecyl sulfate, sodium stearate, cetyltrimethylammonium bromide, lecithin, or a combination thereof.
5 . The composition of claim 1 , wherein the flocculation agent is non-ionic.
6 . The composition of claim 5 , wherein the non-ionic flocculation agent is a polysorbate, an alkylphenol ethoxylate, glycerol, polyoxyethylated castor oil, docusate, decyl glucoside, nonoxynol-9, a sorbitan ester, sorbitan monooleate, ethanolamine, polyoxyl 35 castor oil, poloxyl 40 hydrogenated castor oil, carbomer 1342, a corn oil-mono-di-triglyceride, a polyoxyethylated oleic glyceride, a poloxamer, or a combination thereof.
7 . The composition of claim 1 , wherein the composition after 30 days of storage at about 40° C. has less than about 1° C. thermal shift in its differential scanning fluorimetry (DSF) profile compared to its DSF profile prior to storage.
8 . The composition of claim 1 , wherein the composition increases in flocculation volume after initial mixing.
9 . The composition of claim 8 , wherein the composition has a flocculation volume greater than about 60% after the initial mixing.
10 . The composition of claim 8 , wherein the flocculation volume is reduced by less than about 10% after at least one month under container closure storage conditions at less than about 40° C.
11 . The composition of claim 1 , wherein the composition has substantially the same flocculation volume for at least one month under container closure storage conditions at less than about 40° C.
12 . The composition of claim 1 , wherein the plurality of particles and flocculation agent remain substantially suspended in the liquid carrier for at least one month under container closure storage conditions at less than about 40° C.
13 . The composition of claim 1 , wherein substantially all of the particles have less than about 10% aggregation of the therapeutic biologic.
14 . The composition of claim 1 , wherein substantially all of the particles have less than about 10% fragmentation of the therapeutic biologic.
15 . The composition of claim 1 , wherein substantially all of the particles have less than about 5% change in charge variants of the therapeutic biologic.
16 . The composition of claim 1 , wherein substantially all of the particles have a circularity of about 0.80 to about 1.00.
17 . The composition of claim 1 , wherein substantially all of the particles have less than about 7% moisture by weight.
18 . The composition of claim 1 , wherein substantially all of the particles have less than about 10% internal void spaces.
19 . The composition of claim 1 , wherein substantially all of the particles have greater than about 60% therapeutic biologic by weight.
20 . The composition of claim 1 , wherein substantially all of the particles further comprise a carbohydrate, a pH adjusting agent, a salt, a chelator, a surfactant, a protein stabilizer, an emulsifier, an antiseptic, an amino acid, an antioxidant, a paraben, a bactericide, a fungicide, a preservative, or a combination thereof.
21 . The composition of claim 20 , wherein the pH adjusting agent is acetate, citrate, glutamate, glycinate, histidine, lactate, maleate, phosphate, succinate, tartrate, bicarbonate, aluminum hydroxide, phosphoric acid, hydrochloric acid, DL-lactic/glycolic acids, phosphorylethanolamine, tromethamine, imidazole, glyclyglycine, monosodium glutamate, sodium hydroxide, potassium hydroxide, or a combination thereof.
22 . The composition of claim 20 , wherein the chelator is disodium edetate, ethylenediaminetetraacetic acid pentetic acid, or a combination thereof.
23 . The composition of claim 1 , wherein the liquid carrier comprises ethyl oleate, ethyl caprylate, propylene glycol dicaprylate, diglycerides, trigylcerides, sesame oil, propylene glycol diesters of saturated plant fatty acids C8 and C10 (PGD), triacetin, or a combination thereof.
24 . The composition of claim 1 , wherein the therapeutic biologic is an antibody or fragment thereof.
25 . The composition of claim 1 , wherein the concentration of the therapeutic biologic or salt thereof in the composition is greater than about 400 mg/mL.
26 . The composition of claim 1 , wherein the concentration of the flocculation agent in the composition is from 0.01% to 0.1% by weight.