Electrospraying formation of particles including agents
The invention provides methods for the preparation of particles including one or more agents, e.g., therapeutic or diagnostic agents. The particles can be formed by creating droplets of a first liquid, e.g., including an agent, and removing the first liquid, e.g., through its dispersal in a second liquid and/or evaporation, to solidify the droplets. Advantageously, the process of forming the particles does not significantly alter the structure or activity of the agents and may enhance the stability of the agents. For example, the particles may be stored for long periods of time without significant loss of activity, and in some embodiments, without the need for refrigeration. These particles may be used to generate stabilized pharmaceutical compositions for storage or other logistical purposes, pharmaceutical suspensions, pharmaceutical powder formulations (e.g., inhalable powders, injectable powders), creams or other topical pastes, nutraceuticals, or cosmetics.
1. A method of forming particles, the method comprising:
providing droplets comprising an aqueous first liquid and an antibody or fragment thereof, wherein the droplets are formed by electrospray;
contacting the droplets with an organic solvent, wherein the droplets float or do not float on the organic solvent; and
allowing the droplets to dry, thereby forming the particles.
2. The method of claim 1 , wherein the organic solvent has a density lower than or matching that of the droplets, wherein the droplets do not float on the organic solvent, and the aqueous first liquid disperses into the organic solvent to dry the droplets.
3. The method of claim 1 , wherein the concentration of the antibody or fragment thereof in the aqueous first liquid is from 200 to 600 mg/mL.
4. The method of claim 1 , wherein the particles have a mass loading of the antibody or fragment thereof from 50% to 70%.
5. The method of claim 1 , wherein the aqueous first liquid is selected from the group consisting of water, 0.9% saline, lactated Ringer's solution, dextrose 5%, and a buffer.
6. 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 surfactant, 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, or a nutrient media.
7. The method of claim 6 , wherein the carbohydrate is dextran, trehalose, sucrose, agarose, mannitol, lactose, sorbitol, or maltose.
8. The method of claim 6 , 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, or monosodium glutamate.
9. The method of claim 6 , wherein the salt is sodium chloride, calcium chloride, potassium chloride, sodium hydroxide, stannous chloride, magnesium sulfate, sodium glucoheptonate, sodium pertechnetate, or guanidine hydrochloride.
10. The method of claim 6 , wherein the surfactant is polysorbate, magnesium stearate, sodium dodecyl sulfate, glycerin, or polyoxyethylated castor oil.
11. The method of claim 6 , wherein the emulsifier is polysorbate 80, polysorbate 20, sorbitan monooleate, ethanolamine, polyoxyl 35 castor oil, poloxyl 40 hydrogenated castor oil, carbomer 1342, a corn oil-mono-di-triglyceride, a polyoxyethylated oleic glyceride, or a poloxamer.
12. The method of claim 6 , wherein the amino acid is alanine, aspartic acid, cysteine, isoleucine, glutamic acid, leucine, methionine, phenylalanine, pyrrolysine, serine, selenocysteine, threonine, tryptophan, tyrosine, valine, asparagine, L-arginine, histidine, glycine, glutamine, or a combination thereof.
13. The method of claim 6 , wherein the protein stabilizer is selected from the group consisting of trehalose, PEG 200, PEG 300, PEG 3350, PEG 8000, PEG 10000, PEG 20000, polyoxamers, polyvinylpyrrolidone, polyacrylic acids, poly(vinyl) polymers, polyesters, polyaldehydes, tert-polymers, polyamino acids, hydroxyethyl starch, N-methyl-2-pyrrolidone, sorbitol, sucrose, and mannitol.
14. The method of claim 1 , wherein the organic solvent is selected from the group consisting of benzyl benzoate, acetone, ethyl lactate, dimethyl isosorbide, dimethyl sulfoxide, glycofurol, diglyme, methyl tert-butyl ether, polyethylene glycol, 2-pyrrolidone, tetrahydrofurfuryl alcohol, trigylcerides, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, amyl acetate, chloroform, dichloromethane, ethanol, methanol, propanol, butanol, acetonitrile, diethyl ether, diglyme, 1,2-dimethoxyethane, dimethylformamide, pentane, toluene, and any combination thereof.
15. The method of claim 1 , further comprising removing the particles from the organic solvent through centrifugation, sieving, filtration, magnetic collection, solvent exchange, or decanting.
16. The method of claim 1 , wherein the antibody or fragment thereof in the particles has 0.5 to 1.0 activity per unit.
17. The method of claim 15 , wherein the particles are subjected to one or more secondary desiccation steps after separation from the organic solvent.