Polymer microspheres/nanospheres and encapsulating therapeutic proteins therein
Inventors
Assignees
Publication Number
US-7708915-B2
Publication Date
2010-05-04
Expiration Date
2024-05-06
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Abstract
This invention is an improved process to formulate polymeric microspheres/nanospheres and encapsulate therapeutic proteins or other useful substances, and a polymer sphere apparatus. The invention is also methods of purifying protein-containing-polymeric-microspheres from unused polymer, and an apparatus therefore.
Core Innovation
The invention provides improved methods for formulating polymeric microspheres and nanospheres, particularly for encapsulating therapeutic proteins or other useful substances. It introduces the use of supercritical, near-critical, or critical fluid solvents—referred to as SuperFluids™—with or without polar cosolvents, to efficiently solubilize and process the polymers. The method preserves the integrity of both the proteins and the microspheres during the formation and purification processes, and includes the design and use of a specialized apparatus for these purposes.
The problem addressed is that conventional methods of drug delivery and polymer microsphere production are limited by several factors, including the need for large amounts of toxic organic solvents, a wide dispersion of particle sizes, lack of product sterility, time-consuming and inefficient processes, and the risk of loss of protein bioactivity. In particular, exposure to organic solvents can damage protein therapeutics, and residual solvents in the product may be toxic and environmentally problematic.
This invention presents methods that minimize or eliminate the use of toxic organic solvents by utilizing supercritical or near-critical fluids to form uniform polymer spheres and encapsulate bioactive materials. It provides a method and apparatus for purifying protein-containing-polymer-microspheres by removing unused polymers such as polyethylene glycol with high retention of protein activity and sphere integrity. The process is efficient, reduces processing time and costs, and can be automated, making it suitable for producing sterile, uniform microspheres ideal for controlled-release drug delivery applications.
Claims Coverage
This patent contains one independent claim detailing the main inventive feature.
Method of purifying protein-containing-polymer-microspheres using supercritical or near-critical fluid and cosolvent
A method for purifying protein-containing-polymer-microspheres that comprises: 1. Loading a PEG protein-containing-polymer-microspheres product into a column extractor. 2. Pressurizing the extractor with a supercritical or near-critical fluid. 3. Charging a first pump with a supercritical or near-critical fluid, and a second pump with a cosolvent. 4. Pressurizing the pumps and mixing the fluids under pressure. 5. Flowing the fluid-cosolvent mixture through the extractor to solubilize and collect PEG in the cosolvent. 6. Decompressing the extractor and recovering the purified protein-containing-polymer-microspheres. The process can utilize specific supercritical or near-critical fluids such as carbon dioxide, propane, fluorinated propane, Freon-23, or Freon 22, and cosolvents such as ethanol or methanol. Example conditions include a fluid-cosolvent mixture of carbon dioxide:ethanol::70:30, at a pressure of about 2500 psig–5000 psig and temperature of about 10°C–40°C.
The inventive feature centers on a purification method for protein-containing-polymer-microspheres using a supercritical or near-critical fluid/cosolvent system, optimizing recovery and integrity of both proteins and microspheres while efficiently removing unused polymer.
Stated Advantages
The methods require reduced processing time and preparation costs.
The process conserves the integrity of encapsulated proteins and the microspheres during purification.
The use of supercritical or near-critical fluids eliminates or greatly reduces the use of toxic organic solvents.
The methods and apparatus provide for production of uniform polymer spheres with narrow size ranges.
The process and apparatus can be readily automated, minimizing labor and increasing efficiency.
Use of supercritical or near-critical fluids allows for product sterility.
Minimizes risk of contamination, loss of yield, and potential for exposure to toxic residual solvents.
Allows process conditions to be adjusted by changing temperature, pressure, or solvent components.
Documented Applications
Controlled release of therapeutic agents such as biological molecules and pharmaceuticals using polymer microspheres/nanospheres.
Encapsulation of proteins (e.g., insulin, cytochrome-C, tetanus and diphtheria toxoids) for drug delivery.
Purification of protein-containing-polymer-microspheres by removal of unreacted polymers such as polyethylene glycol.
In vitro and in vivo delivery and sustained release of insulin using encapsulated polymer nanospheres.
Production of sterile, uniform biodegradable polymer spheres for medical and pharmaceutical use.
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