Process for the preparation of dispersible colloidal systems of a substance in the form of nanoparticles

• US 5,118,528 A
• Filed: 10/04/1990
• Issued: 06/02/1992
• Est. Priority Date: 12/31/1986
• Status: Expired due to Term

• Current Assignee: Centre National De La Recherche Scientifique
• Original Assignee: Centre National De La Recherche Scientifique
• Inventors: Thies, Curt, Devissaguet, Jean-Philippe, Fessi, Curt, Puisieux, Francis
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US07/593,522
• Time in Patent Office: 607 Days
• Field of Search: 264/4.6, 427/213.36, 424/469, 424/485, 424/486, 424/487, 514/965
• US Class Current: 427/213.36
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: C08J 3/14 by precipitation from solutions C08J3/122 takes precedence
• CPC Class Codes: Y10S 977/775 Nanosized powder or flake, e.g. nanosized catalyst
• CPC Class Codes: Y10S 977/875 with tip detail
• CPC Class Codes: Y10S 977/895 having step or means utilizing chemical property
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer

Abstract

The process according to the invention comprises: (1) the preparation of a liquid phase consisting essentially of a solution of the substance in a solvent or in a mixture of solvents to which may be added one or more surfactants, (2) the preparation of a second liquid phase consisting essentially of a non-solvent or a mixture of non-solvents for the substance and to which may be added one or more surfactants, the non-solvent or the mixture of non-solvents for the substance being miscible in all proportions with the solvent or the mixture of solvents for the substance, (3) the addition of one of the liquid phases prepared in (1) or (2) to the other with moderate stirring so as to produce a colloidal suspension of nanoparticles of the substance, and (4) is desired, the removal of all or part of the solvent or the mixture of solvents for the substance and of the non-solvent or the mixture of non-solvents for the substance so as to produce a colloidal suspension of nanoparticles of the desired concentration or to produce a powder of nanoparticles.

Claims

1. A process for the preparation of dispersible colloidal systems of a substance in the form of spherical particles of the matrix type and of a size less than 500 nm (nanoparticles), comprising:

combining (1) a first liquid phase consisting essentially of a solution of a film-forming material and a biologically active substance in a solvent or in a mixture of solvents to which may be added one or more surfactants, and (2) a greater volume of a second liquid phase consisting essentially of a non-solvent or a mixture of non-solvents for the film-forming material and biologically active substance and to which may be added one or more surfactants, the non-solvent or the mixture of non-solvents for the film-forming material and biologically active substance being miscible in all proportions with the solvent or mixture of solvents for the film-forming material and biologically active substance;

thereby substantially instantaneously to precipitate from said solvent and said non-solvent composite particles of said film-forming material and biologically active substance to produce a colloidal suspension of composite nanoparticles.

2. The process according to claim 1, further comprising removing at least a portion of the solvent or the mixture of solvents and of the non-solvent or mixture of non-solvents thereby to produce a colloidal suspension of nanoparticles of a desired concentration, or to produce a powder of nanoparticles.

3. The process according to claim 2, wherein said solvents and non-solvents are substantially completely removed by lyophilization.

4. The process according to claim 1, wherein said combining step comprises adding said first liquid phase to said second liquid phase.

5. The process according to claim 1, wherein a lesser amount of non-solvent is used to form said second phase than solvent used to prepare said first liquid phase.

6. The process according to claim 1, wherein said colloidal suspension comprises 0.1 to 10% by weight of at least one surfactant.

7. The process according to claim 6, wherein said at least one surfactant is present in said colloidal suspension in an amount of 0.2 to 2% by weight.

8. The process according to claim 1, wherein said film-forming material is a polymer.

9. The process according to claim 8, wherein said polymer is present in said first liquid phase in an amount of 0.1 to 10% by weight.

10. The process according to claim 9, wherein the concentration of the polymer is between 0.2 and 2% by weight.

11. The process according to claim 8, wherein a second substance is bound to the nanoparticles of said colloidal suspension.

12. The process according to claim 11, wherein said second substance is a biologically active substance.

13. The process according to claim 1, wherein said biologically active substance is a fatty substance.

14. The process according to claim 1, wherein the nanoparticles have a diameter of about 200 nm.

15. A process for the preparation of dispersible colloidal systems of a substance in the form of spherical particles of the matrix type and of a size less than 500 nm (nanoparticles), comprising:

combining (1) a first liquid phase consisting essentially of a solution of a polymer in a solvent or in a mixture of solvents to which may be added one or more surfactants, and (2) a greater volume of a second liquid phase consisting essentially of a non-solvent or a mixture of non-solvents for the polymer and to which may be added one or more surfactants, the non-solvent or the mixture of non-solvents for the polymer being miscible in all proportions with the solvent or mixture of solvents for the polymer;

thereby substantially instantaneously to precipitate from said solvent and said non-solvent particles of said polymer to produce a colloidal suspension of nanoparticles.

16. The process according to claim 15, wherein the polymer is polylactic acid.