METHODS OF FORMING PARTICLES BY CONTINUOUS DROPLET FORMATION AND DEHYDRATION
The present disclosure relates to methods that enable the continuous formation of droplets and dehydration of droplets to provide pharmaceutically relevant particles that can be used for therapy. In particular, the methods disclosed herein allow the controlled continuous droplet formation and dehydration that produce circular particles having low internal void spaces comprising bioactive therapeutic biologics.
1 . A method of forming particles by a continuous process, the method comprising:
a) providing an aqueous first liquid comprising a therapeutic biologic;
b) providing an organic second liquid;
c) dispersing the aqueous first liquid into the organic second liquid, thereby forming aqueous liquid droplets in the organic second liquid, wherein the aqueous liquid droplets comprise the therapeutic biologic;
d) dehydrating the aqueous liquid droplets by maintaining the aqueous liquid droplets in the organic second liquid to form particles comprising the therapeutic biologic, wherein the steps of dispersing and dehydrating the aqueous liquid droplets proceed without interruption for a period of about 1 second to about 60 seconds, about 1 minute to about 60 minutes, about 1 hour to about 24 hours, about 1 day to about 7 days, or about 1 week to about 4 weeks;
e) separating the particles from the organic second liquid; and
f) further dehydrating the particles to achieve an average residual moisture level of less than 10% by weight.
2 . The method of claim 1 , wherein the therapeutic biologic is an antibody, antibody fragment, bovine serum albumin (BSA), or human serum albumin (HSA).
3 . The method of claim 1 , wherein the aqueous first liquid is water, 0.9% saline, lactated Ringer's solution, a buffer, dextrose 5%, or a combination thereof.
4 . The method of claim 1 , wherein the aqueous first liquid further comprises a carbohydrate, a pH adjusting agent, a salt, a chelator, a mineral, a polymer, a protein stabilizer, an emulsifier, an antiseptic, an amino acid, an antioxidant, a protein, an organic solvent, a paraben, a bactericide, a fungicide, a vitamin, a preservative, a nutrient media, an oligopeptide, a biologic excipient, a chemical excipient, a surfactant, or a combination thereof.
5 . The method of claim 1 , wherein the concentration of the therapeutic biologic in the aqueous first liquid is from about 10 mg/mL to about 500 mg/mL.
6 . The method of claim 1 , wherein the aqueous first liquid has a viscosity of less than about 20 mPa·s.
7 . The method of claim 1 , wherein the organic second liquid is an organic solvent.
8 . The method of claim 7 , wherein the organic solvent is acetonitrile, chlorobenzene, chloroform, cyclohexane, cumene, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, methylisobutylketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, xylene, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butylacetate, tert-butylmethyl ether, dimethyl sulfoxide, ethanol, ethylacetate, ethyl ether, ethyl formate, formic acid, heptane, isobutylacetate, isopropylacetate, methylacetate, 3-methyl-1-butanol, methylethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propylacetate, triethylamine, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methylisopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, decanol, 2-ethylhexylacetate, amylacetate, or a combination thereof.
9 . The method of claim 1 , wherein the continuous process comprises continuous membrane emulsification, continuous homogenization, continuous mechanical stirring, continuous mechanical shaking, continuous impinging jet mixing, continuous ultra-sound, continuous sonication, continuous micro-channel emulsification, continuous microsieve emulsification, continuous capillary extrusion, continuous static mixing, or a combination thereof.
10 . The method of claim 9 , wherein the continuous process comprises continuous membrane emulsification, continuous homogenization, continuous impinging jet mixing, continuous static mixing, or a combination thereof.
11 . The method of claim 9 , wherein the continuous membrane emulsification is conducted by rotating membrane emulsification, cross-flow membrane emulsification, or a combination thereof.
12 . The method of claim 9 , wherein the continuous homogenization is conducted by shear homogenization, pressure homogenization, rotor-stator homogenization, microfluidization, or a combination thereof.
13 . The method of claim 9 , wherein the continuous mechanical stirring is conducted by a turbulent stirred vessel, a magnetic stirring device, a mechanical stirring device, or a combination thereof.
14 . The method of claim 9 , wherein the continuous static mixing comprises laminar flow, turbulent flow, transition flow, or a combination thereof.
15 . The method of claim 1 , wherein the dehydration of the aqueous liquid droplets begins after contact with the organic second liquid and occurs at least in part in a continuous drying tube, a continuous drying vessel, or a combination thereof.
16 . The method of claim 15 , wherein the continuous drying vessel comprises continuous mechanical stirring.
17 . The method of claim 16 , wherein the continuous mechanical stirring is conducted by a turbulent stirred vessel, a magnetic stirring device, or a mechanical stirring device.
18 . The method of claim 1 , wherein separating the particles from the organic second liquid comprises removing the organic second liquid through centrifugation, sieving, filtration, solvent exchange, decanting, hydrocyclone separation, or a combination thereof.
19 . The method of claim 1 , wherein the particles are further dehydrated by lyophilization, vacuum desiccation, or by contacting the particles with a stream of gas.
20 . The method of claim 1 , further comprising washing the particles after step e) with a washing fluid.