US Government as Represented by the Secretary of the Army

Washington University

Mainlab

Centre De Microencapsulation

Thies Technology, Inc.

The Nimrod Press, Inc.

Curt Thies

Robert H Reid

John E Van Hamont

William R Brown

Jean A Setterstrom

Edgar C Boedeker

Charles E McQueen

Thomas R Tice

Frederick J Cassels

F Donald Roberts

Elliot Jacob

Phil Friden

Daniel L Jarboe

Ramasubbu Jeyanthi

Jean-Pierre Benoit

Norbert S Mason

John E VanHamont

Herve Rolland

Vincent Vande Velde

Andrew Stanisz

Egar C Boedeker

Francis W Linek

Galen G Lapka

Jo&euml;l Richard

In a solvent extraction process for preparing microspheres of a biodegradable polymer, the improvement comprising: preparing a homogenized antigen-sucrose matrix and adding a solvent to the sucrose-antigen matrix to form a solution; preparing a solution of a biodegradable polymer by adding a solvent to the polymer; adding the biodegradable polymer solution to the antigen-sucrose solution; adding an oil to the polymer-sucrose-antigen solution to form an emulsion having a controlled viscosity that corresponds to a predetermined average particle size of distributions of microspheres of biodegradable polymers; centrifuging the emulsion of controlled viscosity and removing the supernatant to obtain microspheres of a predetermined range of particle size distributions of from about 0.5 to about 7.0 micrometers. In immunostimulating composition comprising an encapsulating-microsphere of the biodegradable polymer has an average particle size distribution such that the majority of the microspheres will be taken up by the villous epithelium section of the intestines of a mammalian subject when administered as a vaccine against diseases caused by entero-pathogenic organisms.A solvent extraction process for preparing microspheres of a biodegradable polymer. The process includes preparing a homogenized antigen-----

Microparticle carriers of maximal uptake capacity by both M cells and non-M cells

Novel burst-free, sustained release biocompatible and biodegrable microcapsules which can be programmed to release their active core for variable durations ranging from 1-100 days in an aqueous physiological environment. The microcapsules are comprised of a core of polypeptide or other biologically active agent encapsulated in a matrix of poly(lactide/glycolide) copolymer, which may contain a pharmaceutically-acceptable adjuvant, as a blend of upcapped free carboxyl end group, and end-capped forms ranging in ratios from 100/0 to 1/99.

Therapeutic treatment and prevention of infections with a bioactive materials encapsulated within a biodegradable-biocompatible polymeric matrix

Novel burst-free, sustained release biocompatible and biodegrable microcapsules which can be programmed to release their active core for variable durations ranging from 1-100 days in an aqueous physiological environment. The microcapsules are comprised of a core of polypeptide or other biologically active agent encapsulated in a matrix of poly(lactide/glycolide) copolymer, which may contain a pharmaceutically-acceptable adjuvant, as a blend of upcapped free carboxyl end group and end-capped forms ranging in ratios from 100/0 to 1/99.

The invention concerns a method for preparing microcapsules containing an active substance coated with a substantially polar polymer film, characterized in that it consists in the following steps: suspending an active substance insoluble in a substantially polar polymer solution in an organic solvent, said substantially polar polymer being insoluble in liquid or supercritical CO,, said organic solvent being soluble in liquid or supercritical CO,; contacting the suspension with liquid or supercritical CO,so as to extract the solvent from the polymer in a controlled manner and ensure the coacervation of the polymer; substantially extracting the solvent by means of supercritical CO,and draining off the CO,/solvent mixture; recuperating the microcapsules in the form of dry powder. The invention also concerns microcapsules containing an active substance coated with a substantially polar polymer selected among the group consisting of polysaccharides, cellulose derivatives, acrylic, methacrylic polymers or derivatives of esters of vinyl, polyesters, polyamides, polyanhydrides, polyorthoesters and polyphosphazenes, characterized in that the polymer film has low surface energy and is free from organic solvent and in that the microcapsules are obtainable by said method.

Method for preparing microcapsules comprising active materials coated with a polymer and novel microcapsules in particular obtained according to the method

Method of coating particles and coated spherical particles

A hybrid evaporation-extraction process for preparing microspheres of a p(DL-lactide-to-glycolide) biodegradable polymer, comprising:

Extraction process for producing PLGA microspheres

In a solvent extraction process for preparing microspheres of a biodegrade polymer, the improvement comprising: preparing a homogenized antigen-sucrose matrix and adding a solvent to the sucrose-antigen matrix to form a solution; preparing a solution of a biodegradable polymer by adding a solvent to the polymer; adding the biodegradable polymer solution to the antigen-sucrose solution; adding an oil to the polymer-sucrose-antigen solution to form an emulsion having a controlled viscosity that corresponds to a predetermined average particle size of distributions of microspheres of biodegradable polymers; centrifuging the emulsion of controlled viscosity and removing the supernatant to obtain microspheres of a predetermined range of particle size distributions of from about 0.5 to about 7.0 micrometers. An immunostimulating composition comprising an encapsulating-microsphere of the biodegradable polymer has an average particle size distribution such that the majority of the microspheres will be taken up by the villous epithelium section of the intestines of a mammalian subject when administered as a vaccine against diseases caused by enteropathogenic organisms.

Microparticle carriers of maximal uptake capacity by both M cells and

An apparatus and method for the formation of droplets of uniform size on a laboratory scale are described. A syringe having a plunger and a needle with an orifice at the tip corresponding to a 12-30 gauge needle is inserted into a block member having a cavity such that the needle of the syringe extends through an opening in the bottom of the block member. The block member has a gas inlet into a side of the cavity for flowing of gas pass the orifice of the needle. The block member is mounted in a support housing such that the syringe is in a vertical position. To form droplets, pressure is applied to the plunger, preferably by a piston under gas pressure, to force liquid from the needle tip orifice to form droplets and flowing gas pass the tip to detach droplets of a desired size. In a preferred embodiment, the liquid is a suspension containing living cells and alginate, and droplets formed are solidified in a solidifying medium such as a calcium chloride solution to obtain microcapsules containing living cells.

Preparation of uniform droplets by using gas pressure to force liquid

Microcapsules particularly those less than 300 microns in size are provided which are adapted for injection by conventional means to afford controlled release of the encapsulated drug material, such as a narcotic antagonist, an antibiotic or the like, over a prolonged period. The microcapsules are characterized by a solid core material of a solid, injectable drug material and a wall material engulfing the core material and composed of a polymer material such as a bioabsorbable polymer material. The microcapsules are made by providing a system containing a mixture of particles of a solid, injectable drug material and a solution of a bioabsorbable polymer material in a solvent in which the drug material is substantially insoluble. The system is treated to induce phase separation of the bioabsorbable polymer material from the solution by the addition to the system of a phase separation agent at a temperature at least as low as -30.degree. C. Phase separation may also be carried out at room temperature, but in either event, isolation of the microcapsules formed during the phase separation should be carried out at a temperature at least as low as -30.degree. C. The system is maintained in an agitated condition until the walls of the microcapsules constituted by the bioabsorbable polymer are substantially solidified in order to avoid aggregation or agglomeration of the microcapsules into larger capsules. The microcapsules are ready for injection, for example by being suspended in an aqueous suspending medium, upon being isolated from the system.

Process for preparation of microcapsules

A spirit duplicating master ink contains more than 50 weight % of methyl violet, a binder of poly(vinyl methyl ether) that is of the order of 5 weight % and a 2-ethoxy-ethanol carrier solution of the order of 30 weight % with corn starch filler of the order of 10 weight %. This ink is printed upon a spirit duplicating master to leave a residue with the methyl violet weight % of the order of 73%, that of the 2-ethoxy-ethanol of the order of 7% and that of the corn starch of the order of 20%.

Spirit duplicating with indicia formed by ink comprising dye means and

A method for forming discrete capsules that contain an active agent, such as a pesticide, involves first forming a suspension of the active agent suspended in a solution of an alkali metal silicate such as sodium silicate or a suspension of the active agent suspended in a liquid coacervate resulting from the addition of a coacervation agent such as acetone to the alkali metal silicate solution. The suspension, preferably in the form of droplets formed by ejecting the suspension through an orifice (e.g. a needle), is then contacted with an aqueous solution of a salt such as calcium chloride which reacts with the alkali metal silicate to form an insoluble silicate (e.g., calcium silicate) coating for the active agent while hardening the dispersed active agent in a silicate core matrix. Thus, capsules of the active agent are produced with an insoluble silicate coating. The capsules are maintained in the aqueous salt solution for a sufficient period of time to permit a high degree of conversion of soluble silicate to insoluble silicate. The capsules are then isolated and dried thereby providing structurally intact capsules which act as a free-flow powder. The capsules provide controlled release of the active agent over a prolonged period of time. Methods for preparing such capsules within a three hour period have been devices thereby improving substantially the economics of encapsulating active agents with inorganic coatings. Such brief preparation times are achieved through the use of soluble silicates rich in SiO.sub.2 and by increasing the temperature of the aqueous solution of the salt such as calcium chloride to effectively expedite the capsule curing process.

Method of encapsulating active agents with inorganic coatings

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Ballwin, MO, United States of America

Curt Thies