A method for forming particles by continuous droplet formation and dehydration.

Abstract

This invention provides a method for forming pharmaceutically appropriate particles that can be used for therapeutic purposes. [Solution] The method comprises: a) providing a first aqueous liquid containing a therapeutic biological agent; b) contacting the first aqueous liquid containing the therapeutic biological agent with a second organic liquid by a continuous process to form a mixture containing droplets of the aqueous liquid, wherein the droplets of the aqueous liquid contain the therapeutic biological agent; c) dehydrating the droplets of the aqueous liquid in the mixture; and d) removing the first aqueous liquid and the second organic liquid from the mixture to form particles containing the therapeutic biological agent, wherein the particles contain less than about 10% internal void space, and the circularity of the particles is about 0.80 to about 1.00 after removing the first aqueous liquid and the second organic liquid from the mixture.

Claims

1. A method for forming particles by a continuous process, a) To provide a first aqueous liquid containing a therapeutic biological agent; b) To provide a second organic liquid; c) Dispersing the first aqueous liquid in the second organic liquid, thereby forming droplets of the aqueous liquid in the second organic liquid, wherein the droplets of the aqueous liquid contain the therapeutic biological agent; d) Dehydrating the aqueous liquid droplets by maintaining them in the second organic liquid to form particles containing the therapeutic biological agent, wherein the process of dispersing and dehydrating the aqueous liquid droplets proceeds without interruption for a period of approximately 1 second to 60 seconds, approximately 1 minute to 60 minutes, approximately 1 hour to 24 hours, approximately 1 day to 7 days, or approximately 1 week to 4 weeks; e) Separating the particles from the second organic liquid; and f) Further dewatering the particles to achieve an average residual moisture level of less than 10% by weight. A method that includes this.

2. The method according to claim 1, wherein the therapeutic biological agent is an antibody, an antibody fragment, bovine serum albumin (BSA), or human serum albumin (HSA).

3. The method according to claim 1 or 2, wherein the first aqueous liquid is water, 0.9% saline solution, lactated Ringer's solution, buffer solution, 5% dextrose, or a combination thereof.

4. The method according to any one of claims 1 to 3, wherein the first aqueous liquid further comprises carbohydrates, pH adjusters, salts, chelating agents, minerals, polymers, protein stabilizers, emulsifiers, preservatives, amino acids, antioxidants, proteins, organic solvents, parabens, bactericides, fungicides, vitamins, preservatives, nutrient media, oligopeptides, biological additives, chemical additives, surfactants, or combinations thereof.

5. The method according to any one of claims 1 to 4, wherein the concentration of the therapeutic biological agent in the aqueous first liquid is about 10 mg / mL to about 500 mg / mL.

6. The method according to any one of claims 1 to 5, wherein the first aqueous liquid has a viscosity of less than about 20 mPa·s.

7. The method according to any one of claims 1 to 6, wherein the second organic liquid is an organic solvent.

8. 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, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, xylene, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl The method according to claim 7, wherein the material is ether, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, triethylamine, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, decanol, 2-ethylhexyl acetate, amyl acetate, or a combination thereof.

9. The method according to any one of claims 1 to 8, wherein the continuous process comprises continuous membrane emulsification, continuous homogenization, continuous mechanical stirring, continuous mechanical shaking, continuous impingement jet mixing, continuous ultrasonic treatment, continuous microchannel emulsification, continuous microsieve emulsification, continuous capillary extrusion, continuous static mixing, or a combination thereof.

10. The method according to any one of claims 1 to 9, wherein the continuous process includes continuous membrane emulsification, continuous homogenization, continuous impingement jet mixing, continuous static mixing, or a combination thereof.

11. The method according to claim 9 or 10, wherein the continuous membrane emulsification is carried out by rotary membrane emulsification, cross-flow membrane emulsification, or a combination thereof.

12. The method according to claim 9 or 10, wherein the continuous homogenization is carried out by shear homogenization, pressure homogenization, rotor-stator homogenization, microfluidization, or a combination thereof.

13. The method according to claim 9 or 10, wherein the continuous mechanical stirring is performed by a turbulent stirring tank, a magnetic stirring device, a mechanical stirring device, or a combination thereof.

14. The method according to claim 9 or 10, wherein the continuous static mixing includes laminar flow, turbulent flow, transition flow, or a combination thereof.

15. The method according to any one of claims 1 to 14, wherein the dehydration of the aqueous liquid droplets is initiated after contact with the second organic liquid and is carried out at least partially in a continuous drying tube, a continuous drying container, or a combination thereof.

16. The method according to claim 15, wherein the continuous drying vessel includes continuous mechanical stirring.

17. The method according to claim 16, wherein the continuous mechanical stirring is performed by a turbulent stirring tank, a magnetic stirring device, or a mechanical stirring device.

18. The method according to any one of claims 1 to 17, wherein the separation of the particles from the second organic liquid comprises removing the second organic liquid by centrifugation, sieving, filtration, solvent exchange, decanting, liquid cyclone separation, or a combination thereof.

19. The method according to any one of claims 1 to 18, wherein the particles are further dehydrated by freeze-drying, vacuum drying, or by bringing the particles into contact with a flow of gas.

20. The method according to any one of claims 1 to 19, further comprising washing the particles with a washing fluid after step e).

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