|Publication number||US3594326 A|
|Publication date||Jul 20, 1971|
|Filing date||Feb 14, 1969|
|Priority date||Dec 3, 1964|
|Publication number||US 3594326 A, US 3594326A, US-A-3594326, US3594326 A, US3594326A|
|Inventors||Rene Karl Himmel|
|Original Assignee||Ncr Co|
|Export Citation||BiBTeX, EndNote, RefMan|
|Referenced by (86), Classifications (20), Legal Events (2)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent 3,594,326 METHOD OF MAKING MICROSCOPIC CAPSULES Rene Karl Himmel, Kilchberg, Switzerland, assiguor to The National Cash Register Company, Dayton, Ohio No Drawing. Continuation of application Ser. No. 415,809, Dec. 3, 1964. This application Feb. 14, 1969, Ser. No. 802,731
Int. Cl. B01j 13/02; A61k 9/04; B4411 1/02 U.S. Cl. 252316 2 Claims ABSTRACT OF THE DISCLOSURE The process of forming minute capsules en masse which comprises (a) establishing an agitated system consisting of a liquid polar vehicle constituting a continuous first phase, a second phae dispersed therein consisting of minute mobile entities of core material, and a third phase dispersed therein consisting of minute, mobile liquid entities of a wall-forming soltuion of a non-polar polymeric material, the said core material being wettable by said wall-forming solution, the said three phases being mutually incompatible, the third phase constituting such a part of the total three-phase system, by volume that it can exist as a dispersed phase of minute mobile entities capable of and sufficient in amount to deposit around the core entities, and wherein the wall-forming polymeric material has a decreasing solubility with increasing temperature in the vehicle, and wherein the third phase is maintained as such, at least in part, by the presence of a polyelectrolyte polymer (b) hardening the walls so formed by elevating the temperature of the system to a temperature above the gel point of the Wall-forming polymer, and (c) separating the hardened capsules from the rest of the system at a temperature above that at which resolution of the capsule walls takes place to any substantial degree.
This application is a continuation of copending application Ser. No. 415,809, filed Dec. 3, 1964, and now abandoned.
This invention relates to a process of manufacturing minute capsules en masse in a liquid manufacturing vehicle and to the capsule product, each capsule comprising a core and a seamless protecting wall surrounding the core. By minute capsules are meant capsules, for example, from a few microns to several thousand microns and possibly somewhat larger in average size.
The capsule-forming process of this invention involves the establishment of a system that is characterized as follows (these terms being defined below):
(1) It is in an agitated state;
(2) It comprises the following three phases, characterized first of all by being mutually incompatible (as defined herein) and further characterized, respectively, as follows:
(a) a continuous liquid phase polar vehicle that constitutes at least a substantial portion by volume of the three phases in total,
(b) a discontinuous phase of minute, mobile entities of core material, either solid or liquid, dispersed in the vehicle, and
'(c) a discontinuous phase of minute, mobile entities of wall-forming material dispersed in the vehicle and constituted by a liquid solution of a wall-forming polymeric material, said solution being capable of wetting the core material on contact, having a decreasing solubility in the vehicle with a rise in temperature, and said solution preferably having a viscosity greater than the liquid phase vehicle (a), and wherein the wall-forming polymer is non-ionic and there is present in the system a polyelectrolyte sufiicient in amount to aid in maintaining the wall-forming polymer solution as a sep arate phase.
This agitated system results without more in a deposit of the solution of the wall-forming polymeric material around the entities of core material. By reason of the ability of polymer solution to wet the core material, and of the viscosity and volume relation of the dispersed phase of wall-forming polymer solution, the dispersed wallforming polymer solution is capable of deposit around the dispersed entities of core material and also is capable after deposit of maintaining itself as 'a wall against the shearing forces that exist as an incident of the required agitation of the system. The deposits accumulate to a maximum thickness, which may be varied by varying the amount of the Wall material provided and the degree and type of agitation used, which may vary in accordance with the need for protection of the core material and the protective characteristics of the wall-forming material selected for use.
Following deposition of the liquid solution of the wallforming polymeric material, the temperature of the system is elevated preferably above the gelation temperature of the wall-forming polymer to harden the capsule walls and thereby density and impart to them greater durability and greater impermeability relative to the core material and the environment, among other properties.
After hardening the capsule Walls by elevating the temperature, it is necessary to separate the hardened capsules at a temperature above that at which a substantial amount of the wall-forming polymeric material would be dissolved by the vehicle. If, however, the hardened capsule walls are treated so that they become permanently insolubilized in the vehicle medium, then obviously there is no need for separation of the capsules, and the system may be returned to room temperature without concern that the wall material will be redissolved by the vehicle.
The subject process of making capsules en masse in a liquid polar vehicle by the system defined above utilizes a polyelectrolyte to assist the establishment of the wallforming polymer solution as a separate phase.
In one form, the process involves forming a solution of the wall-forming polymeric material having the decreased solubility with increase in temperature property noted above in the vehicle and dispersing the core material therein. Upon heating and agitation of the mass, a coacervate solution of the wall-forming polymeric material separates out and deposits about the cone material to form embryonic capsules. Continued heating at the same or elevated temperatures effects a hardening of the deposit. Thereafter, separation of the capsules may be carried out at the elevated temperatures, subsequently, the separated capsules are dried.
In another form, the process contemplates adding components to form the system without the necessity of going from a solution of the wall-forming polymeric material to a separated coacervate solution of the polymeric material; i.e. one knowing the relative concentrations of the various components and conditions that will produce a coacervate solution, need only provide such components in the required relative amounts and under conditions that yield a coacervate solution of the polymer. For example, the various components of the system, except the wall-forming polymer, can be brought to a temperature at which it is known that the coacervate solution will form and the wall-forming polymeric material then added to produce a coacervate solution of same and consequent wrapping of the core material with an embryonic shell of wall-forming polymeric material.
In yet another form, a coacervate solution of the wallforming polymeric material is formed and separated from its equilibrium liquid. A system for microencapsulation utilizing the separate polymer solution may be had by forming a three-phase system as described above, wherein a liquid vehicle, other than the equilibrium liquid of the coacervate solution, is employed, said liquid vehicle meeting the other criteria of incompatibility set forth herein.
This new process in one respect is an improvement of US. Pat. No. 2,800,458 to Green and US. Pat. No. 2,800,547 to Green et al., and US. Reissue Pat. No. 24,899 to Green et al. in that it provides, in one form, a process directed to a changing condition for bringing about coacervation. It is particularly directed to a system wherein the polymeric wall material has a substantial solubility in a solvent, for example, water at room or lower temperature, thus providing an encapsulated material which may be released into a liquid medium at low temperature by dissolution of the capsule wall. A further utility is that core materials having the property of decreasing solubility with increasing temperature may be eificiently encapsulated by the system of this invention. Further, the subject process is an improvement of Baken, U.S. application Ser. No. 413,348, filed Nov. 23, 1964, now abandoned.
It has been discovered that if the polymeric material of the capsule wall possesses the above described solubility characteristic and if the associated liquid of the wall-forming polymer solution and the vehicle are selected to satisfy the further criteria set forth herein, not
only is it possible to produce a system in which deposit of the dispersed entities of the solution of the wallforming polymeric material around particular dispersed core entities can be achieved, but also this can be done with combinations of core materials, wall-forming polymers, and vehicles that could not before be used to successfully encapsulated by en masse microencapsulation techniques.
The further criteria which define the useful classes of materials for the vehicle and the coacervate solution of the wall-forming polymers are these: l) the liquid wallforming solution of polymeric materials which form the capsule wall must be capable of wetting the core material in order to deposit around core entities; (2) the solution of polymeric material(s) should have a viscosity, preferably of about 200 to 4000 centipoises, such that it may both deposit and maintain itself deposited around the core entities despite the shearing forces of the agitation needed to maintain the material of the system as a dispersion; (3) the solution of polymeric material(s) preferably constitutes about 5% to 20% by volume of the total three-phase system, so that it can exist as a dispersed phase of mobile entities capable of deposit around the core entities; and (4) the core material, the solution of the polymeric material(s), and the vehicle must be mutually immiscible.
The wetting action of polymeric materials in solution as regards a particular core material may be measured by standard contact-angle measurements, adsorption measurements, and the like, and suitable selections may be made thereby, all in accordance with existing knowledge of this subject per se. The solvent for the polymeric materials(s) may in certain instances be selected to enhance the weting action of a particular polymeric material solution with respect to a chosen core material.
The stated criterion that the core material, the polymeric matrial solution, and the vehicle be mutually incompatible is used in the sense that their separate existence in the system must not be impaired by a reactivity or miscibility between them.
Prefabricated incomplete systems for use in carrying out the novel process may be established and stored for future use. Even unskilled operators may complete such systems by the addition of the missing components, with the required agitation and heat, together with the agents for hardening of the walls, to make capsules at a later time. The missing component(s) may involve any of those three necessary to form an operative system, and the absence may be total or partial.
Whether the liquid solution of wall-forming polymeric material is formed by effecting a phase separation or by adding components in proper amount to create said solu tion without need for phase separation, the agency that causes or maintains the separation of the wall-forming polymer solution may be one or more changing conditions including as an essential condition the presence of a sufiicient amount of polyelectrolyte. In the usual case the insolubility of the wall-forming polymer with increasing temperature Will be employed as a changing condition in conjunction with the polyelectrolyte. Illustrative of changing conditions which may be used alone or in combination with the addition of polyelectrolyte to the mass is the presence of a non-solvent for the wallforming polymer which is compatible with the vehicle, or other known techniques that provide a changing condition to effect or maintain a separation of the wall-forming polymer solution, such as, for example, change in microion concentration (salt, pH), all of which are techniques employed to bring about separation of a coacervate solution.
The preferred system is one in which the liquid associated with the wall-forming non-polar polymer solution also is used as a major component material of the manufacturing vehicle and wherein there is present as a component as polyelectrolyte polymer which may or may not possess the property of decreased solubility with increased temperature and which is complementary to the wallforming polymer in the sense that it assists in creating an incompatibility between the vehicle and the solution of the Wall-forming polymeric materia(s) and induces or maintains the solution as a separate phase in the system. In other words, it completes a liquid system in which the wall-forming solution of polymeric material can exist as a separate phase, which may be dispersed in the vehicle by agitation, because of repulsive forces between the polymeric material of the wall-forming solution and the complementary material. Without the complementary polyelectrolyte polymeric material, if the vehicle included or consisted of the same liquid that is used as the solvent of the wall-forming polymeric solution, the vehicle would be more compatible with and would dilute the polymer solution. Thus, the stated incompatibility between the vehicle and the solution of wall-forming polymeric material connotes the presence of a complementary material as a constituent of the vehicle when the vehicle includes a liquid compatible with or identical to the solvent used in the wall-forming coacervate solution.
The nature of the core material is the primary guide to the selection of the particular non-polar polymeric wall-forming material and of its polar solvent, and also to the selection of the liquid vehicle if that is not to consist of or include as a component the same material that is used as the wall-forming polymer solvent. This is because the process conditions usually are chosen with the object of encapsulating some given core material. Hence the wall-forming polymeric solution must be incompatible with the core material, but capable of wetting and depositing around entities of it. The wall-forming polymeric material may be hydrophobic; again the nature of the core material and the requirement that core material and Wallforming material be incompatible dictating the choice of non-polar polymeric material. In the preferred system from the class of polymers and solvents made eligible by these criteria, the further choice is from among those polymer-solvent pairs which can form a wall-forming polymer solution. When, as preferred, the vehicle is made up chiefly or Wholly of the same material as the polymer solvent, the only further choice is, in the preferred embodiment, with respect to the complementary material (polyelectrolyte polymer), which again, must meet the incompatibility requirement. The complementary material must be incompatible with the core material and must act to make the wall-forming non-polar polymeric material solution more incompatible with the vehicle.
Given these criteria of selection, not known before in total as the determinants of an operative encapsulation system, the classes of materials that are useful in constituting the polar vehicle and the solution of the non-polar wall-forming polymer of the present system are ascertainable from existing knowledge and means of selection of polymeric materials and solvents in respect of four properties; viz:
( 1) solubility of the polymeric material in various solvents:
(2) ability of the non-polar polymeric material solution to wet the given nucleus material, liquid or solid;
(3) the temperature-solubility characteristics of the nonpolar polymeric material; and
(4) ability of a solution of the non-polar polymer to exist in a separate solution phase in the vehicle liquid.
Materials thus selected are useful in the encapsulation of any incompatible and wettable core material, liquid or solid.
POLYMERIC MATERIAL Examples of hydrophilic, non-polar wall-forming polymeric material which possess the property of decreased solubility with increasing temperature include methyl cellulose, polyvinylmethyl ether, and ethylhydroxyethyl cellulose. An example of suitable hydrophobic wall-forming polymeric material is nitrocellulose.
Examples of hydrophilic polyelectrolyte polymeric material which are complementary to the wall-forming polymer and assist in establishing the wall-forming polymer solute and carboxymethylcellulose, sodium carboxymethylcellulose, and gum arabic.
SOLVENTS Water may be used as the solvent of the wall-forming solution in the instances where the wall-forming polymer is hydrophilic, organic polar solvents where the polymeric material is hydrophobic. Obviously, the choice of solvent is dependent upon the solubility of the wall-forming polymer therein. Preferably, where the encapsulation involves a phase separation the solvent should be one wherein the polymer is reasonably soluble at room temperature, so that upon elevation there will be sufficient polymer available for phase separation and deposit about the core material.
In general, the decrease in solubility with increase in temperature of the wall-forming polymeric material can be affected by appropriate selection of the polymer and solvent. The solvent ability varies with both the size and shape of the solvent molecules. As a rule small solvent molecules are better solvents at elevated temperatures than lower temperatures, whereas with large solvent molecules the reverse is true.
CORE MATERIALS Core materials may be any substance that survives separately in the system but those for which the process of the subject invention is particularly suited are, as stated above, those materials which are insoluble in the vehicle phase, for example, such as, chloroform, Aroclor (chlorinated biphenyl), kerosene, mynacet(acetylated monoglyceride), lemon oil, menthol, aspirin, resins, pigments and dyes.
In its broader aspect, the invention is not in the discovery of particular polymeric materials or solvents or vehicles but rests on and applies to the discovery that liquid and solid core materials can be enscapsulated as nuclei in an agitated fluid system by utilizing a polyelectrolyte complementary to and lessening the solubility of wall-forming polymeric material in a polar liquid.
The proper volume relation of the wall-forming phase (of proper viscosity) can be predetermined to a close enough approximation by calculation from readily-ascertained data on the relation of viscosity to concentration for a solution of the intended wall-forming polymeric material in the chosen solvent.
The order of addition can be reversed, or the two polymeric materials and the solvent can be brough together at one time, once the proper quantitative relations are established for the particular materials being used, since the resulting volume and viscosity (concentration) of the two separate phases are independent of the order of assembly.
The core material, always a minor component of the total volume of the system, can be added either before or during or after the formation of the solution into two solution phases. Similarly, the agitation of the system can be begun before, during, or after either of these steps. It is preferred, however, to agitate before, during and after the phase separation, and to introduce the core material after the phase separation has taken place.
The intensity of the agitation is made such as to reduce the core material to the desired entity size, if such is necessary, and, in any event, to assure thorough dispersion of it in the vehicle. The core entity size is preselected to give the desired capsule size after allowance for encapsulating wall thickness. With solid core materials, the entity size can be predetermined and obtained by any suitable grinding or milling.
In the following example, the novel process will be disclosed in detail as applied to the encapsulation of various materials. The example illustrates the sequence of steps in an application of the invention employing a nonionic polymer and a polyelectrolyte.
(1) Into grams of an aqueous 2% methylcellulose solution is thoroughly stirred 10 grams of the water insoluble material or nuclei to be encapsulated either in the form of powder or as a liquid in which case the mixture is stirred until the material is thoroughly emulsified to the requisite drop size.
(2) In this solution, and whilst stirring, is thoroughly mixed 100 grams of a 2% aqueous solution of carboxymethylcellulose.
(3) The mixed solution is now heated to about 60 C.
(4) At any time during the heating 300 cos. of a 20% solution of sodium chloride or sulphate or ammonium chloride or sulphate is added.
(5) The heating is continued for about 1 hour during which the polymers separate out to form homogeneous and continuous coatings separately round the nuclei thus to preform the capsules.
(*6) Whilst still warm the separated phase is segregated by decanting the supernatant or by filtration.
(7) The segregated phase is now dried in an oven or by hot air blast to drive off the remanent water in the capsule walls which results in a dry freely flowing powder like residue composed of individual capsules with the walls consisting of the two polymers in a complex admixture. The walls may be hardened or plasticized.
What is claimed is:
1. The process of forming minute capsules en masse which comprises the steps consisting essentially of (a) establishing an agitated system consisting of first,
second and third liquid phases, said system consisting of a liquid polar vehicle constituting a continuous first phase, said first phase having dispersed therein a polyelectrolyte polymer, a second phase dispersed therein consisting of minute mobile entities of core material, and a third phase dispersed therein consisting of minute, mobile liquid entities of a wallforming solution of methylcellulose; further the said core material being wettable by said wall-forming solution, the said three phases being mutually incompatible, and the third phase constituting such a part of the total three-phase system by volume, that it can exist as a dispersed phase of minute mobile entities capable of and sufiicient in amount to deposit around the core entities; and further wherein the third phase is formed by elevating the temperature of the system to cause the emergence of a coacervate solution of methylcellulose and said third phase is maintained as such, at least in part, by the presence of a polyelectrolyte polymer which is complementary to methylcellulose,
(b) hardening the walls so formed by elevating the temperature of the system to a temperature above the gel point of methylcellulose, and
(c) separating the hardened capsules from the rest of the system at a temperature above that at which resolution of the capsule walls takes place to any substantial degree.
2. The process of claim 1 wherein during the formation of the third phase the system is heated to a temperature References Cited UNITED STATES PATENTS 3/1966 Hiestand et al. 252316X 4/1966 Studt et al. 252316 RICHARD D. LOVERING, Primary Examiner US. Cl. X.R.
99--1l8, 140, 166; ll7-l00; 264-4; 424-33. 34, 35- 343
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US4115315 *||Feb 16, 1977||Sep 19, 1978||Ncr Corporation||Pearlescent capsules and process for their preparation|
|US4540602 *||Sep 20, 1982||Sep 10, 1985||Freund Industry Company, Limited||Process for the preparation of activated pharmaceutical compositions|
|US4777089 *||May 5, 1986||Oct 11, 1988||Lion Corporation||Microcapsule containing hydrous composition|
|US4908233 *||Apr 13, 1988||Mar 13, 1990||Lion Corporation||Production of microcapsules by simple coacervation|
|US4940588 *||Mar 17, 1988||Jul 10, 1990||Elan Corporation||Controlled release powder and process for its preparation|
|US4952402 *||Mar 17, 1988||Aug 28, 1990||Elan Corporation, P.L.C.||Controlled release powder and process for its preparation|
|US4954412 *||Oct 31, 1988||Sep 4, 1990||Xerox Corporation||Processes for the preparation of encapsulated toner compositions|
|US5089272 *||Mar 29, 1989||Feb 18, 1992||Snow Brand Milk Products Co., Ltd.||Process for producing capsules having a permeability-controllable membrane|
|US5205290 *||Apr 5, 1991||Apr 27, 1993||Unger Evan C||Low density microspheres and their use as contrast agents for computed tomography|
|US5281408 *||Jan 19, 1993||Jan 25, 1994||Unger Evan C||Low density microspheres and their use as contrast agents for computed tomography|
|US5346730 *||Jul 26, 1991||Sep 13, 1994||Kali-Chemie Ag||Process for depositing a copper containing layer I|
|US5456900 *||Sep 7, 1993||Oct 10, 1995||Unger; Evan C.||Low density microspheres and their use as contrast agents for computed tomography|
|US5527521 *||Jun 1, 1995||Jun 18, 1996||Imarx Pharmaceutical Corp.||Low density microspheres and suspensions and their use as contrast agents for computed tomography and in other applications|
|US5547656 *||May 24, 1995||Aug 20, 1996||Imarx Pharmaceutical Corp.||Low density microspheres and their use as contrast agents for computed tomography, and in other applications|
|US5733572 *||Nov 29, 1994||Mar 31, 1998||Imarx Pharmaceutical Corp.||Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles|
|US5736121 *||May 19, 1995||Apr 7, 1998||Imarx Pharmaceutical Corp.||Stabilized homogenous suspensions as computed tomography contrast agents|
|US5769080 *||Feb 22, 1994||Jun 23, 1998||Dupont Merck Pharmaceutical Company||Gas filled liposomes and stabilized gas bubbles and their use as ultrasonic contrast agents|
|US5770222 *||Jun 7, 1995||Jun 23, 1998||Imarx Pharmaceutical Corp.||Therapeutic drug delivery systems|
|US5776429 *||Apr 30, 1996||Jul 7, 1998||Imarx Pharmaceutical Corp.||Method of preparing gas-filled microspheres using a lyophilized lipids|
|US5830430 *||Feb 21, 1995||Nov 3, 1998||Imarx Pharmaceutical Corp.||Cationic lipids and the use thereof|
|US5846517 *||Jan 30, 1997||Dec 8, 1998||Imarx Pharmaceutical Corp.||Methods for diagnostic imaging using a renal contrast agent and a vasodilator|
|US5853752 *||Jun 6, 1995||Dec 29, 1998||Imarx Pharmaceutical Corp.||Methods of preparing gas and gaseous precursor-filled microspheres|
|US5874062 *||May 19, 1995||Feb 23, 1999||Imarx Pharmaceutical Corp.||Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents|
|US5922304 *||Mar 9, 1995||Jul 13, 1999||Imarx Pharmaceutical Corp.||Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents|
|US5985246 *||Jul 8, 1997||Nov 16, 1999||Imarx Pharmaceutical Corp.||Contrast agents for ultrasonic imaging and methods for preparing the same|
|US5997898 *||Jun 6, 1995||Dec 7, 1999||Imarx Pharmaceutical Corp.||Stabilized compositions of fluorinated amphiphiles for methods of therapeutic delivery|
|US6001335 *||Jun 18, 1996||Dec 14, 1999||Imarx Pharmaceutical Corp.||Contrasting agents for ultrasonic imaging and methods for preparing the same|
|US6028066 *||Jul 2, 1997||Feb 22, 2000||Imarx Pharmaceutical Corp.||Prodrugs comprising fluorinated amphiphiles|
|US6033645 *||Jun 19, 1996||Mar 7, 2000||Unger; Evan C.||Methods for diagnostic imaging by regulating the administration rate of a contrast agent|
|US6033646 *||Feb 19, 1998||Mar 7, 2000||Imarx Pharmaceutical Corp.||Method of preparing fluorinated gas microspheres|
|US6039557 *||Apr 7, 1997||Mar 21, 2000||Imarx Pharmaceutical Corp.||Apparatus for making gas-filled vesicles of optimal size|
|US6056938 *||May 5, 1998||May 2, 2000||Imarx Pharaceutical Corp.||Cationic lipids and the use thereof|
|US6071494 *||Aug 28, 1998||Jun 6, 2000||Imarx Pharmaceutical Corp.||Methods for diagnostic imaging using a contrast agent and a renal vasodilator|
|US6071495 *||Oct 2, 1997||Jun 6, 2000||Imarx Pharmaceutical Corp.||Targeted gas and gaseous precursor-filled liposomes|
|US6088613 *||Jun 7, 1995||Jul 11, 2000||Imarx Pharmaceutical Corp.||Method of magnetic resonance focused surgical and therapeutic ultrasound|
|US6090800 *||May 6, 1997||Jul 18, 2000||Imarx Pharmaceutical Corp.||Lipid soluble steroid prodrugs|
|US6117414 *||Nov 10, 1997||Sep 12, 2000||Imarx Pharmaceutical Corp.||Method of computed tomography using fluorinated gas-filled lipid microspheres as contract agents|
|US6120751 *||Sep 8, 1997||Sep 19, 2000||Imarx Pharmaceutical Corp.||Charged lipids and uses for the same|
|US6123923 *||Dec 18, 1997||Sep 26, 2000||Imarx Pharmaceutical Corp.||Optoacoustic contrast agents and methods for their use|
|US6139819 *||Sep 17, 1997||Oct 31, 2000||Imarx Pharmaceutical Corp.||Targeted contrast agents for diagnostic and therapeutic use|
|US6143276 *||Mar 21, 1997||Nov 7, 2000||Imarx Pharmaceutical Corp.||Methods for delivering bioactive agents to regions of elevated temperatures|
|US6146657 *||Nov 1, 1996||Nov 14, 2000||Imarx Pharmaceutical Corp.||Gas-filled lipid spheres for use in diagnostic and therapeutic applications|
|US6231834||Dec 2, 1997||May 15, 2001||Imarx Pharmaceutical Corp.||Methods for ultrasound imaging involving the use of a contrast agent and multiple images and processing of same|
|US6315981||Mar 19, 1999||Nov 13, 2001||Imarx Therapeutics, Inc.||Gas filled microspheres as magnetic resonance imaging contrast agents|
|US6403056||Mar 31, 2000||Jun 11, 2002||Imarx Therapeutics, Inc.||Method for delivering bioactive agents using cochleates|
|US6414139||Sep 3, 1996||Jul 2, 2002||Imarx Therapeutics, Inc.||Silicon amphiphilic compounds and the use thereof|
|US6416740||May 11, 1998||Jul 9, 2002||Bristol-Myers Squibb Medical Imaging, Inc.||Acoustically active drug delivery systems|
|US6443898||Jun 7, 1995||Sep 3, 2002||Imarx Pharmaceutical Corp.||Therapeutic delivery systems|
|US6444660||Feb 3, 2000||Sep 3, 2002||Imarx Therapeutics, Inc.||Lipid soluble steroid prodrugs|
|US6461586||Jul 10, 2000||Oct 8, 2002||Imarx Therapeutics, Inc.||Method of magnetic resonance focused surgical and therapeutic ultrasound|
|US6479034||Jul 17, 1998||Nov 12, 2002||Bristol-Myers Squibb Medical Imaging, Inc.||Method of preparing gas and gaseous precursor-filled microspheres|
|US6521211||Feb 3, 1999||Feb 18, 2003||Bristol-Myers Squibb Medical Imaging, Inc.||Methods of imaging and treatment with targeted compositions|
|US6528039||Jun 18, 1997||Mar 4, 2003||Bristol-Myers Squibb Medical Imaging, Inc.||Low density microspheres and their use as contrast agents for computed tomography and in other applications|
|US6537246||Jun 18, 1997||Mar 25, 2003||Imarx Therapeutics, Inc.||Oxygen delivery agents and uses for the same|
|US6548047||Sep 15, 1997||Apr 15, 2003||Bristol-Myers Squibb Medical Imaging, Inc.||Thermal preactivation of gaseous precursor filled compositions|
|US6551576||Mar 31, 1998||Apr 22, 2003||Bristol-Myers Squibb Medical Imaging, Inc.||Container with multi-phase composition for use in diagnostic and therapeutic applications|
|US6576220||May 10, 2001||Jun 10, 2003||Imarx Therapeutics, Inc.||Non-invasive methods for surgery in the vasculature|
|US6638767||Dec 21, 2000||Oct 28, 2003||Imarx Pharmaceutical Corporation||Methods for delivering compounds into a cell|
|US6716412||Mar 21, 2001||Apr 6, 2004||Imarx Therapeutics, Inc.||Methods of ultrasound treatment using gas or gaseous precursor-filled compositions|
|US6743779||Apr 29, 1997||Jun 1, 2004||Imarx Pharmaceutical Corp.||Methods for delivering compounds into a cell|
|US6773696||Oct 25, 2002||Aug 10, 2004||Bristol-Myers Squibb Medical Imaging, Inc.||Contrast agent comprising low density microspheres|
|US6808720||Jan 15, 2002||Oct 26, 2004||Imarx Therapeutics, Inc.||Charged lipids and uses for the same|
|US6884407||May 18, 2000||Apr 26, 2005||Bristol-Myers Squibb Pharma Company||Methods for diagnostic imaging involving the use of a contrast agent and a coronary vasodilator|
|US6998107||Jun 10, 2004||Feb 14, 2006||Bristol-Myers Squibb Pharma Comapany||Composition comprising low density microspheres|
|US7078015||Nov 8, 2004||Jul 18, 2006||Imarx Therapeutics, Inc.||Ultrasound imaging and treatment|
|US7083572||Mar 26, 2002||Aug 1, 2006||Bristol-Myers Squibb Medical Imaging, Inc.||Therapeutic delivery systems|
|US7105151||Jan 6, 2003||Sep 12, 2006||Imarx Therapeutics, Inc.||Oxygen delivery agents and uses for the same|
|US7329402||Jan 13, 2003||Feb 12, 2008||Imarx Pharmaceutical Corp.||Methods of imaging and treatment|
|US7344705||Oct 18, 2005||Mar 18, 2008||Bristol-Myers Squibb Medical Imaging, Inc.||Composition comprising low density microspheres|
|US7452551||Oct 30, 2000||Nov 18, 2008||Imarx Therapeutics, Inc.||Targeted compositions for diagnostic and therapeutic use|
|US7612033||Mar 18, 2004||Nov 3, 2009||Imarx Pharmaceutical Corp.||Methods for delivering compounds into a cell|
|US7780875||Jan 13, 2006||Aug 24, 2010||Cinvention Ag||Composite materials containing carbon nanoparticles|
|US8084056||Sep 22, 2003||Dec 27, 2011||Lantheus Medical Imaging, Inc.||Preparation of a lipid blend and a phospholipid suspension containing the lipid blend|
|US8658205||Aug 1, 2011||Feb 25, 2014||Lantheus Medical Imaging, Inc.||Preparation of a lipid blend and a phospholipid suspension containing the lipid blend|
|US8685441||Jul 23, 2013||Apr 1, 2014||Lantheus Medical Imaging, Inc.||Preparation of a lipid blend and a phospholipid suspension containing the lipid blend|
|US8747892||Jul 25, 2013||Jun 10, 2014||Lantheus Medical Imaging, Inc.||Preparation of a lipid blend and a phospholipid suspension containing the lipid blend|
|US9545457||Feb 24, 2014||Jan 17, 2017||Lantheus Medical Imaging, Inc.||Preparation of a lipid blend and a phospholipid suspension containing the lipid blend|
|US20030159836 *||Apr 20, 2001||Aug 28, 2003||Keizou Kashiki||Fire-extingushing agent, water for fire extinguishing and method of fire extinguishing|
|US20060155376 *||Jan 13, 2006||Jul 13, 2006||Blue Membranes Gmbh||Composite materials containing carbon nanoparticles|
|US20060177379 *||Dec 30, 2005||Aug 10, 2006||Soheil Asgari||Composition comprising an agent providing a signal, an implant material and a drug|
|US20060211802 *||Mar 20, 2006||Sep 21, 2006||Soheil Asgari||Porous sintered metal-containing materials|
|US20070003749 *||Jun 30, 2006||Jan 4, 2007||Soheil Asgari||Process for production of porous reticulated composite materials|
|US20070003753 *||Jun 30, 2006||Jan 4, 2007||Soheil Asgari||Medical devices comprising a reticulated composite material|
|US20070088114 *||Oct 18, 2006||Apr 19, 2007||Blue Membranes Gmbh||Thermoset particles and methods for production thereof|
|US20080213611 *||Jan 18, 2008||Sep 4, 2008||Cinvention Ag||Porous, non-degradable implant made by powder molding|
|WO1992020441A1 *||May 14, 1992||Nov 26, 1992||Allied Colloids Limited||Particulate polymeric compositions and their production_________|
|U.S. Classification||427/213.32, 264/4.3, 424/494, 424/497, 514/963, 264/4, 514/731, 428/402.22, 428/402.24, 428/402.2|
|International Classification||B41M5/165, A61K9/50, B01J13/10|
|Cooperative Classification||B41M5/165, B01J13/10, Y10S514/963, A61K9/50|
|European Classification||A61K9/50, B41M5/165, B01J13/10|
|Jan 16, 1982||AS02||Assignment of assignor's interest|
Owner name: APPLETON PAPERS INC.
Effective date: 19811130
Owner name: EURAND AMERICA, INCORPORATED, 1464-A, MIAMISBURG-C
|Jan 16, 1982||AS||Assignment|
Owner name: EURAND AMERICA, INCORPORATED, 1464-A, MIAMISBURG-C
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:APPLETON PAPERS INC.;REEL/FRAME:003961/0292
Effective date: 19811130