Method of incorporating water-soluble heat-sensitive therapeutic agents in albumin microspheres

• US 4,357,259 A
• Filed: 12/12/1977
• Issued: 11/02/1982
• Est. Priority Date: 08/01/1977
• Status: Expired due to Term

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Senyei, Andrew E., Widder, Kenneth J.
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US05/859,842
• Time in Patent Office: 1,786 Days
• Field of Search: 252/316, 424/22, 424/36, 427/338, 106/135
• US Class Current: 264/4.3
• CPC Class Codes: A61K 41/0052 Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
• CPC Class Codes: A61K 49/1821 coated or functionalised microparticles or nanoparticles
• CPC Class Codes: A61K 49/1869 coated or functionalised with a protein being an albumin, e.g. HSA, BSA, ovalbumin
• CPC Class Codes: A61K 49/1887 Agglomerates, clusters, i.e. more than one (super)(para)magnetic microparticle or nanoparticle are aggregated or entrapped in the same maxtrix
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/5094 Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: G01N 2333/765 Serum albumin, e.g. HSA
• CPC Class Codes: G01N 2446/20 the magnetic material being present in the particle core
• CPC Class Codes: G01N 2446/30 the magnetic material being dispersed in the polymer composition before their conversion into particulate form

Abstract

A method is provided for incorporating water-soluble therapeutic agents in albumin microspheres. This method is particularly advantageous where the therapeutic agent is heat-sensitive. All steps of the method can be carried out at relatively low temperatures, such as ambient room temperature. The method may be applied to the preparation of intravascularly-administrable, magnetically-responsive microspheres.

Claims

1. The method of incorporating a water-soluble heat-sensitive therapeutic agent in albumin microspheres, in which all steps thereof are carried out at a temperature within the range from 1°

to 45°

C., said method including the steps of preparing an aqueous albumin solution of the said therapeutic agent, said albumin solution containing from 5 to 50 parts by weight of albumin per 100 parts of water and from 1 to 20 parts by weight of said therapeutic agent per 100 parts of albumin, emulsifying said albumin solution with a vegetable oil to form a water-in-oil emulsion containing dispersed droplets of the albumin solution, removing the oil by washing the dispersed droplets with an oil-soluble water-immiscible organic solvent, and recovering the resulting microspheres, wherein said method also includes the step of contacting said microspheres with an organic solvent solution of an aldehyde hardening agent to increase the stability of said microspheres and to decrease the release rate of said drug therefrom.

2. The method of claim 1 in which said hardening agent is formaldehyde, and in which said organic solvent solution is formed by transferring formaldehyde from an aqueous solution thereof into said organic solvent, the residual aqueous solution being separated from said organic solvent solution prior to said contacting.

3. The method of claim 1 or claim 2 in which said albumin solution also contains magnetic particles.

4. The method of claim 13 or claim 2 in which said organic solvent solution contains from 0.2 to 20% by weight of said aldehyde hardening agent.