Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3594326 A
Publication typeGrant
Publication dateJul 20, 1971
Filing dateFeb 14, 1969
Priority dateDec 3, 1964
Publication numberUS 3594326 A, US 3594326A, US-A-3594326, US3594326 A, US3594326A
InventorsRene Karl Himmel
Original AssigneeNcr Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Method of making microscopic capsules
US 3594326 A
Images(4)
Previous page
Next page
Description  (OCR text may contain errors)

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

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4115315 *Feb 16, 1977Sep 19, 1978Ncr CorporationMica coated with titanium dioxide
US4540602 *Sep 20, 1982Sep 10, 1985Freund Industry Company, LimitedProcess for the preparation of activated pharmaceutical compositions
US4777089 *May 5, 1986Oct 11, 1988Lion CorporationMicrocapsule containing hydrous composition
US4908233 *Apr 13, 1988Mar 13, 1990Lion CorporationDispersing capsule core material in solution containing first water soluble polymer, adding inorganic or organic salt, adding second water soluble polymer which undergoes no phase separation with the salt
US4940588 *Mar 17, 1988Jul 10, 1990Elan CorporationControlled release powder and process for its preparation
US4952402 *Mar 17, 1988Aug 28, 1990Elan Corporation, P.L.C.Edible taste-masked drugs; micromatrix active material coated with nontoxic polymer; liquids; tablets
US4954412 *Oct 31, 1988Sep 4, 1990Xerox CorporationProcesses for the preparation of encapsulated toner compositions
US5089272 *Mar 29, 1989Feb 18, 1992Snow Brand Milk Products Co., Ltd.Process for producing capsules having a permeability-controllable membrane
US5205290 *Apr 5, 1991Apr 27, 1993Unger Evan CKits for imaging gastrointestinal disorders; anti-gas; biocompatible polymers, thickeners
US5281408 *Jan 19, 1993Jan 25, 1994Unger Evan CAdministering a contrast agent and scanning using tomography to form images
US5346730 *Jul 26, 1991Sep 13, 1994Kali-Chemie AgProcess for depositing a copper containing layer I
US5456900 *Sep 7, 1993Oct 10, 1995Unger; Evan C.Low density microspheres and their use as contrast agents for computed tomography
US5527521 *Jun 1, 1995Jun 18, 1996Imarx Pharmaceutical Corp.Low density microspheres and suspensions and their use as contrast agents for computed tomography and in other applications
US5547656 *May 24, 1995Aug 20, 1996Imarx Pharmaceutical Corp.Low density microspheres and their use as contrast agents for computed tomography, and in other applications
US5733572 *Nov 29, 1994Mar 31, 1998Imarx Pharmaceutical Corp.Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles
US5736121 *May 19, 1995Apr 7, 1998Imarx Pharmaceutical Corp.Administering stabilized aqueous suspension of gaseous precursor to patient, allowing phase transition form liquid to gas, scanning
US5769080 *Feb 22, 1994Jun 23, 1998Dupont Merck Pharmaceutical CompanyGas filled liposomes and stabilized gas bubbles and their use as ultrasonic contrast agents
US5770222 *Jun 7, 1995Jun 23, 1998Imarx Pharmaceutical Corp.Therapeutic drug delivery systems
US5776429 *Apr 30, 1996Jul 7, 1998Imarx Pharmaceutical Corp.Method of preparing gas-filled microspheres using a lyophilized lipids
US5830430 *Feb 21, 1995Nov 3, 1998Imarx Pharmaceutical Corp.Cationic lipids and the use thereof
US5846517 *Jan 30, 1997Dec 8, 1998Imarx Pharmaceutical Corp.Methods for diagnostic imaging using a renal contrast agent and a vasodilator
US5853752 *Jun 6, 1995Dec 29, 1998Imarx Pharmaceutical Corp.Methods of preparing gas and gaseous precursor-filled microspheres
US5874062 *May 19, 1995Feb 23, 1999Imarx Pharmaceutical Corp.Medical diagnosis with fluorocarbons in microspheres
US5922304 *Mar 9, 1995Jul 13, 1999Imarx Pharmaceutical Corp.Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents
US5985246 *Jul 8, 1997Nov 16, 1999Imarx Pharmaceutical Corp.Contrast agents for ultrasonic imaging and methods for preparing the same
US5997898 *Jun 6, 1995Dec 7, 1999Imarx Pharmaceutical Corp.Stabilized compositions of a sf6 gas and a phosphorylated fluorinated amphiphilic compound, contrast agents for ultrasound.
US6001335 *Jun 18, 1996Dec 14, 1999Imarx Pharmaceutical Corp.Synthesizing a lipid vesicle having a gas encapsulated therein for ultrasonic imaging, by subjecting a solvent-free composition of a gaseous precursor and lipid in aqueous medium to a first pressure, then a second lower pressure
US6028066 *Jul 2, 1997Feb 22, 2000Imarx Pharmaceutical Corp.For delivering higher concentrations of bioactive agents to improve efficacy of the bioactive agents
US6033645 *Jun 19, 1996Mar 7, 2000Unger; Evan C.Methods for diagnostic imaging by regulating the administration rate of a contrast agent
US6033646 *Feb 19, 1998Mar 7, 2000Imarx Pharmaceutical Corp.Method of preparing fluorinated gas microspheres
US6039557 *Apr 7, 1997Mar 21, 2000Imarx Pharmaceutical Corp.Apparatus for making gas-filled vesicles of optimal size
US6056938 *May 5, 1998May 2, 2000Imarx Pharaceutical Corp.Cationic lipids and the use thereof
US6071494 *Aug 28, 1998Jun 6, 2000Imarx Pharmaceutical Corp.Lipid, protein or polymer and a gas or gaseous precursor, in combination with a renal vasodilator.
US6071495 *Oct 2, 1997Jun 6, 2000Imarx Pharmaceutical Corp.Targeted gas and gaseous precursor-filled liposomes
US6088613 *Jun 7, 1995Jul 11, 2000Imarx Pharmaceutical Corp.Method of magnetic resonance focused surgical and therapeutic ultrasound
US6090800 *May 6, 1997Jul 18, 2000Imarx Pharmaceutical Corp.Reaction product containing dexamethasone
US6117414 *Nov 10, 1997Sep 12, 2000Imarx Pharmaceutical Corp.Administering hydrophilic polymer covalently bonded to biocompatible lipid filled with perfluorocarbon of sulfur hexafluoride gas
US6120751 *Sep 8, 1997Sep 19, 2000Imarx Pharmaceutical Corp.Charged lipids and uses for the same
US6123923 *Dec 18, 1997Sep 26, 2000Imarx Pharmaceutical Corp.Optoacoustic contrast agents and methods for their use
US6139819 *Sep 17, 1997Oct 31, 2000Imarx Pharmaceutical Corp.Comprising lipid, protein, polymer and/or surfactant, and a gas, in combination with a targeting ligand; targeting ligand targets coagula, including emboli and/or thrombi, particularly in patients suffering from arrhythmic disorder
US6143276 *Mar 21, 1997Nov 7, 2000Imarx Pharmaceutical Corp.Methods for delivering bioactive agents to regions of elevated temperatures
US6146657 *Nov 1, 1996Nov 14, 2000Imarx Pharmaceutical Corp.Liposome filled with an insoluble gas and a soluble gas, wherein said liposome comprises phosphatidylcholine(s), phosphatidylethanolamine(s), and phosphatidic acid(s); use in ultrasonic or magnetic resonance imaging
US6231834Dec 2, 1997May 15, 2001Imarx Pharmaceutical Corp.Methods for ultrasound imaging involving the use of a contrast agent and multiple images and processing of same
US6315981Mar 19, 1999Nov 13, 2001Imarx Therapeutics, Inc.Used for obtaining image of an internal region of humans
US6403056Mar 31, 2000Jun 11, 2002Imarx Therapeutics, Inc.Administering agent; applying ultrasonic frequency
US6414139Sep 3, 1996Jul 2, 2002Imarx Therapeutics, Inc.Silicon amphiphilic compounds and the use thereof
US6416740May 11, 1998Jul 9, 2002Bristol-Myers Squibb Medical Imaging, Inc.Acoustically active drug delivery systems
US6443898Jun 7, 1995Sep 3, 2002Imarx Pharmaceutical Corp.Therapeutic delivery systems
US6444660Feb 3, 2000Sep 3, 2002Imarx Therapeutics, Inc.Dexamethasone covalently bonded to a lipid moiety via a linking group
US6461586Jul 10, 2000Oct 8, 2002Imarx Therapeutics, Inc.Method of magnetic resonance focused surgical and therapeutic ultrasound
US6479034Jul 17, 1998Nov 12, 2002Bristol-Myers Squibb Medical Imaging, Inc.Method of preparing gas and gaseous precursor-filled microspheres
US6521211Feb 3, 1999Feb 18, 2003Bristol-Myers Squibb Medical Imaging, Inc.Methods of imaging and treatment with targeted compositions
US6528039Jun 18, 1997Mar 4, 2003Bristol-Myers Squibb Medical Imaging, Inc.Low density microspheres and their use as contrast agents for computed tomography and in other applications
US6537246Jun 18, 1997Mar 25, 2003Imarx Therapeutics, Inc.Oxygen delivery agents and uses for the same
US6548047Sep 15, 1997Apr 15, 2003Bristol-Myers Squibb Medical Imaging, Inc.Thermal preactivation of gaseous precursor filled compositions
US6551576Mar 31, 1998Apr 22, 2003Bristol-Myers Squibb Medical Imaging, Inc.Container with multi-phase composition for use in diagnostic and therapeutic applications
US6576220May 10, 2001Jun 10, 2003Imarx Therapeutics, Inc.Non-invasive methods for surgery in the vasculature
US6638767Dec 21, 2000Oct 28, 2003Imarx Pharmaceutical CorporationMethods for delivering compounds into a cell
US6716412Mar 21, 2001Apr 6, 2004Imarx Therapeutics, Inc.Methods of ultrasound treatment using gas or gaseous precursor-filled compositions
US6743779Apr 29, 1997Jun 1, 2004Imarx Pharmaceutical Corp.Methods for delivering compounds into a cell
US6773696Oct 25, 2002Aug 10, 2004Bristol-Myers Squibb Medical Imaging, Inc.Wherein void comprises vapor of volatile liquid (aliphatic hydrocarbons, chlorofluorocarbons, tetraalkyl silanes, and perfluorocarbons); for computed tomography imaging of the gastrointestinal region
US6808720Jan 15, 2002Oct 26, 2004Imarx Therapeutics, Inc.Charged lipids and uses for the same
US6884407May 18, 2000Apr 26, 2005Bristol-Myers Squibb Pharma CompanyMethods for diagnostic imaging involving the use of a contrast agent and a coronary vasodilator
US6998107Jun 10, 2004Feb 14, 2006Bristol-Myers Squibb Pharma Comapanycomprises void containing vapor of volatile liquid perfluorocarbon, combined with aqueous solution to form contrast agent, for oral/rectal administration or injection; for gastrointestinal imaging/tomography
US7078015Nov 8, 2004Jul 18, 2006Imarx Therapeutics, Inc.Temperature activated gaseous liposomes; therapy drug delivery; accumulating in cancer and disease tissue
US7083572Mar 26, 2002Aug 1, 2006Bristol-Myers Squibb Medical Imaging, Inc.Therapeutic delivery systems
US7105151Jan 6, 2003Sep 12, 2006Imarx Therapeutics, Inc.Oxygen delivery agents and uses for the same
US7329402Jan 13, 2003Feb 12, 2008Imarx Pharmaceutical Corp.Methods of imaging and treatment
US7344705Oct 18, 2005Mar 18, 2008Bristol-Myers Squibb Medical Imaging, Inc.Composition comprising low density microspheres
US7452551Oct 30, 2000Nov 18, 2008Imarx Therapeutics, Inc.Administering to the patient a contrast agent comprising, in an aqueous carrier, targeted vesicles formulated from a lipid or polymer, a perfluorocarbon gas, a targeting ligand, scanning the patient using ultrasound to obtain an image
US7612033Mar 18, 2004Nov 3, 2009Imarx Pharmaceutical Corp.administering to the cell a composition which comprises the compound to be delivered and an organic halide such as a perfluorocarbon; ultrasound
US7780875Jan 13, 2006Aug 24, 2010Cinvention AgComposite materials containing carbon nanoparticles
US8084056Sep 22, 2003Dec 27, 2011Lantheus Medical Imaging, Inc.Useful as an ultrasonic contrast agent; making by dissolving a nonaqueous solvent in a lipid blend, then contacting the solution with an aqueous solution to form a lipid suspension
US8658205Aug 1, 2011Feb 25, 2014Lantheus Medical Imaging, Inc.Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
US8685441Jul 23, 2013Apr 1, 2014Lantheus Medical Imaging, Inc.Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
WO1992020441A1 *May 14, 1992Nov 15, 1992Allied Colloids LtdParticulate polymeric compositions and their production_________
Classifications
U.S. Classification427/213.32, 264/4.3, 424/494, 424/497, 514/963, 264/4, 514/731, 428/402.22, 428/402.24, 428/402.2
International ClassificationB41M5/165, A61K9/50, B01J13/10
Cooperative ClassificationB41M5/165, B01J13/10, Y10S514/963, A61K9/50
European ClassificationA61K9/50, B41M5/165, B01J13/10
Legal Events
DateCodeEventDescription
Jan 16, 1982AS02Assignment of assignor's interest
Owner name: APPLETON PAPERS INC.
Effective date: 19811130
Owner name: EURAND AMERICA, INCORPORATED, 1464-A, MIAMISBURG-C
Jan 16, 1982ASAssignment
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