|Publication number||US3567650 A|
|Publication date||Mar 2, 1971|
|Filing date||Feb 14, 1969|
|Priority date||Feb 14, 1969|
|Publication number||US 3567650 A, US 3567650A, US-A-3567650, US3567650 A, US3567650A|
|Inventors||Joseph Anthony Bakan|
|Original Assignee||Ncr Co|
|Export Citation||BiBTeX, EndNote, RefMan|
|Referenced by (99), Classifications (19), Legal Events (1)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent METHOD OF MAKING MICROSCOPIC CAPSULES Joseph Anthony Bakan, Dayton, Ohio, assignor to The National Cash Register Company, Dayton, Ohio No Drawing. Continuation of application Ser. No. 413,348, Nov. 23, 1964. This application Feb. 14, 1969, Ser. No. 802,730
Int. Cl. A61k 9/04; B01j 13/02; B44d 1/02 US. Cl. 252-316 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 vehicle constituting a continuous first phase, 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 wall-forming solution of a polymeric material, the said core material being wettable by said wallforming 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 sufiicient 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, (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. 413,348, filed Nov. 23, 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 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-formed material dispersed in the vehicle and constituted by a liquid solution of a wallforming polymeric material, said solution being capable of wetting the core material on contact, and 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).
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 wall-forming 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 wallforrning material selected for use.
Following deposition of the liquid solution of the wall forming 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.
Broadly stated, the new process of making capsules en masse in a liquid vehicle by establishing a system as defined above utilizes the property of decreased solubility with increase in temperature of the wall-forming polymeric material in the vehicle to harden the embryonic capsule wall. This property may also be utilized in the formation of the wall-forming polymeric material solution, where the separation, in whole or in part, of the wall-forming polymer solution phase is brought about by elevating the temperature of the mass.
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 core material to form embryonic capsules. Continued heating at the same or elevated temperatures efiects 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 separated 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 U.S. Pat. No. 2,800,458 to Green and U.S. Pat. No. 2,800,457 to Green et al., and U.S. 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 efiiciently encapsulated by the system of this invention.
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 he used to successfully encapsulate 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: (1) the liquid wall-forming 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 dispersion; (3) the solution of polymeric material(s) preferably constitutes about 5% to 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 material(s) may in certain instances be selected to enhance the wetting action of a particular polymeric material solution with respect to a chosen core material.
The stated criterion that the core material, the polymeric material 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 4 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 solution 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. In the usual case the insolubility of the wallforming polymer with increasing temperature will be employed as a changing condition. Illustrative of changing conditions which may be used alone or in combination with elevating the temperature of the mass are the presence of a complementary polymer, the presence of a non-solvent for the wall-forming 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 polymer solution also is used as a major component material of the manufacturing vehicle and wherein there is present as a component a polymer which may or may not possess the property of decreased solubility with increased temperature properties and which is complementary to the wall-forming polymer in the sense that it assists in creating an incompatibility between the vehicle and the solution of the wallforming polymeric material(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 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 polymeric wall-forming material and of its 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 hydrophilic or hydrophobic; again the nature of the core material and the requirement that core material and wall-forming material be incompatible dictating the choice of 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 polymersolvent 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, 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 polymeric material solution more incompatible with the vehicle.
A complementary material equivalent to a polymeric material, can be another liquid which is a non-solvent for the polymeric material of the wall-forming solution and which therefore creates an incompatibility condition in the vehicle whereby the wall-forming polymer solution is caused to exist as a separate phase. Another alternative is to employ as the vehicle a liquid which, in addition to being incompatible because of its being immiscible with the core material, is a non-solvent for the wall-forming polymer and is immiscible with the solvent of the wall-forming solution. Such a liquid vehicle therefore is incompatible with the polymer solution and permits the latter to exist as a separate phase.
Given these criteria of selection, not known before in total as the determinants of an operative encapsula tion system, the classes of materials that are useful in constituting the vehicle and the solution of the 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 polymeric material solution to wet the given nucleus material, liquid or solid;
(3) the temperature-solubility characteristics of the polymeric material; and
(4) ability of a solution of the 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 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 polymeric material combinations for use in the preferred system wherein a complementary polymeric material is employed are as follows: methyl cellulose as the film former together with dextran, hydroxypropyldextran, polyvinyl alcohol, or polyvinylpyrrolidone, or 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 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 sufiicient 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. For a given solvent, or even solvents of the same size, compact molecules become better solvents at elevated temperature, extended molecules better solvents at lower temperatures.
CORE MATERIALS Core materials may be any substance that survives separately in the system but those for which the process 6 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, Myvacet (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 encapsulated as nuclei in an agitated fluid system by utilizing the principle of the lessening of solubility of polymeric material in a liquid with increasing temperature.
In a narrower aspect, the invention includes a particular procedure for establishing the defined system from a homogeneous solution of the wall-forming material in a liquid vehicle. This particular procedure involves the formation of a system comprising wall-forming material(s) and a solvent therefor, and a separation of this system into two separate solution phases, one of which is chiefly a coacervate solution of the wall-forming polymer, by a phenomenon of phase separation known as coacervation, wherein the changing condition that provides, at least in part, the motivating factor for the phase separation or coacervation is the decrease in solubility of the wall-forming polymeric material with an increase in temperature.
The invention will be. described hereafter with reference to a system wherein a complementary polymer is present as the motivating factor, and wherein the temperature of the mass is elevated to bring about, at least in part, the phase separation. However, it should be understood that the invention is not limited to such a system. The wall-forming polymer, the complementary polymer, and the solvent may be added in any order, but it is preferable first to form a dilute solution of the wall-forming polymeric material and then to induce the phase separation by addition of the complementary polymeric material, then elevating the temperature of the system.
The complementary polymeric material in that case is one that has either no alfinity or a lesser afiinity for the nucleus material than the intended wall-forming polymeric material, so that the solution of the intended wall former will be the one that preferentially deposits around the dispersed nucleus entities.
The addition of the complementary polymeric material to an initial dilute solution of the wall-forming polymeric material permits better control of the phase separation to yield a wall-forming solution phase of the proper viscosity, and relative volumes, especially in an initial operation before the procedure is standardized quantitatively for any particular combination of polymeric material and solvent. In such an initial operation, the attainment of the desired viscosity in the wall-forming solution phase may be ascertained by microscopic observation of an agitated sample of the system containing dispersed core material, the criterion being that, when a useful wall-forming solution is present, it is seen that discrete entities within liquid walls are formed. A confirmation and basis for quantitative statement can be had by allowing the two separated solution phases to stratify and then measuring the viscosity and relative volume of the phase containing the intended wall-forming polymeric material. If the viscosity is too low, addition of more of the complementary material will cause additional concentration of the wall-forming phase to occur, with a consequent increase of viscosity of that phase, until the desired viscosity is attained.
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. 7
The order of addition can be, reversed, or the two polymeric materials and the solvent can be brought 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 introdgce 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 pre-selected 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.
Another alternative procedure is to pre-form a liquid solution of the wall-forming polymeric material having the desired viscosity and then to disperse it in a vehicle which is a liquid that is immiscible with this polymeric material solution and with the core material. This avoids any phase separation step such as is necessary when the wall-forming polymeric material is initially present in dilute solution and has to be driven out in a more concentrated solution as a separate phase having the desired viscosity, whether by reason of a complementary other polymeric material or by reason of a complementary nonsolvent for the wall-forming polymer.
In the following examples, the novel process will be disclosed in detail as applied to the encapsulation of various materials.
EXAMPLE I Encapsulation of Aroclor 1242 Magnaflux Oil in methyl cellulose Solutions: 1:1 (weight ratio) chlorinated diphenyl Aroclor 1242 Magnaflux Oil (hydrocarbon fraction) (Internal Phase); 1% solution (aqueous) methyl cellulose HG- 90 (Hercules); 25% dextran in water.
Added 50 milliliters of Internal Phase to 400 grams of the 1% aqueous methylcellulose solution to produce an emulsion of the oil in the 100-500 micron drop size range. With stirring, added 400 cc. of the 25 aqueous dextran solution at 25 C. to cause phase separation of a rich methyl-cellulose solution and consequent embryonic encapsulation of the Internal Phase drops in a liquid wall. Then heat the system to 50 C. with stirring over a -minute time span. At this point, complete encapsulation of the oil in a self-supporting wall will have been obtained.
EXAMPLE II Encapsulation of Myvacet (an acetylated monoglyceride) Make up a cold water solution (room temperature) of dextran and 2% methylcellulose (Methocel 6OHG). Add 50 milliliters of Myvacet to 200 milliliters of the 25 dextran solution. Add 200 milliliters of 2% methylcellulose solution dropwise. After preparation has stirred 3 minutes, allowin for good dispersion of the two polymers around the Myvacet oil drops, raise the temperature of the system slowly to 60 C. At 60 C., remove the capsular layer formed on standing and wash it in an 80 C. solution of 10% Na SO Filter off excess water by means of a sieve and allow the capsules to dry on a fluidized bed dryer.
8 EXAMPLE III Encapsulation of Myvacet To 400 milliliters of 1.5% Methocel 60HG (temperature 30 C.) in water was added 50 milliliters of Myvacet which was dispersed to secure 500-1500 micron-sized oil drops. After oil drops are well dispersed in the Methocel solution, add 200 milliliters of a 25 aqueous solution of dextran dropwise. The preparation was heated slowly with stirring to 60 C. The capsular layer formed on standing then is removed and washed with 700 milliliters of 10% Na SO (temperature C.). The excess water was removed, after washing, by means of a sieve, and the capsules were allowed to dry for 24 hours on a blower.
EXAMPLE IV Encapsulation of menthol With agitation throughout each of the steps: add 50 grams of menthol (I.P.) to 300 grams of a 2.5% aqueous methylcellulose solution. Then heated the dispersion to 55 C. Added grams of a 25 aqueous solution of dextran dropwise and heated to 60 C. Then added the following to harden the capsules: (a) 2 grams of Arlex (an aqueous sorbitol solution) (b) 0.1 gram of Atmos 300 (mono and diglycerides of fat forming fatty acids Atlas Chemical Industries) and (c) 14 grams of a 25 aqueous solution of tannic acid, and stirred the capsules for one hour. The capsules were then isolated as discrete entities usin conventional drying techniques.
EXAMPLE V Encapsulation of lemon oil With agitation throughout each of the steps: added 35 grams of lemon oil to 300 grams of a 2.5% aqueous methylcellulose solution. The agitation was adjusted to obtain a lemon oil dropsize in the region of 500 microns. Then added 5 grams of glycerol and heated the dispersion to 55 C. While maintaining the temperature at 55 C. added 90 grams of a 25% aqueous dextran solution dropwise. Then heated the capsules to 60 C. At 60 C. added the following: (a) 0.02 gram of Atmos 300; (b) 14 grams of a 25% aqueous tannic acid solution, stirring the capsules for one hour. The capsules were then isolated as discrete entities using conventional dryin techniques.
EXAMPLE VI Encapsulation of lemon oil With agitation throughout each of the steps: Added 35 grams of lemon oil to 300 grams of a 2.5% aqueous methylcellulose solution. The agitation is adjusted to obtain a lemon oil dropsize in the region of 500 microns. Added 90 grams of a 25% dextran solution dropwise. Then heated the capsules to 60 C., added 3 grams of Parez Resin 613 (melamine/formaldehyde resin-American Cyanamid Co.). Adjusted the pH to 4.5 with a 10% aqueous acetic acid solution, stirring the system for one hour at 60 C. The capsules were then isolated as discrete entities using conventional drying techniques.
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 com tinuous first phase, said first phase having dissolved therein a polymer material complementary to the polymer material of the third phase, 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 wall-forming solution of methylcellulose; further the said core material being wettable by said wallforming solution, the said three phases being mutually incompatible, and the third phase constituting such a part of the total three-phase system, by voltion of the third phase the system is heated to a temume, that it can exist as a dispersed phase of minperature above room temperature but below the gel point ute mobile entities capable of and sufiicient in of the wall-forming polymer to thereby assist in the amount to deposit around the core entities; and furformation of the third phase by causing the coacervate ther wherein the third phase is formed by adding the 5 solution of the wall-forming polymer solution to emerge. complementary polymeric material at substantially room temperature to cause the emergence of a co- References Cited acervate solution of methylcellulose, UNITED STATES PATENTS (b) hardening the walls so formed by elevating the 3,242,051 3/1966 Hiestand et a1 252 316X temperature of the system to a temperature above 0 3 244,640 4/1966 Studt t a1, 252316 the gel point of methylcellulose, and (c) separating the hardened capsules from the rest of RICHARD D. LOVERING, Primary Examiner the system at a temperature above that at which resolution of the capsule walls takes place to any 15 substantial degree. 99-418, 140, 166; 117-100; 2644; 424-33, 34, 35, 2. The process of claim 1 wherein during the forma- 343
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US4025455 *||Apr 2, 1976||May 24, 1977||The Mead Corporation||Cross-linked hydroxypropylcellulose microcapsules and process for making|
|US4376113 *||Aug 26, 1980||Mar 8, 1983||Roussel Uclaf||Stable suspensions and powders of stable microcapsules and their preparation|
|US4880617 *||Oct 6, 1986||Nov 14, 1989||Dow Corning Corporation||Lattice-entrapped composition|
|US4895725 *||Apr 4, 1988||Jan 23, 1990||Clinical Technologies Associates, Inc.||Microencapsulation of fish oil|
|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|
|US5405614 *||Jan 11, 1993||Apr 11, 1995||International Medical Associates, Inc.||Electronic transdermal drug delivery system|
|US5447728 *||Dec 16, 1993||Sep 5, 1995||Emisphere Technologies, Inc.||Desferrioxamine oral delivery system|
|US5456985 *||Jul 14, 1993||Oct 10, 1995||Zgoulli; Slim||Microcapsules of oily liquid|
|US5472712 *||Jun 23, 1993||Dec 5, 1995||Euroceltique, S.A.||Controlled-release formulations coated with aqueous dispersions of ethylcellulose|
|US5540939 *||Apr 25, 1994||Jul 30, 1996||Emisphere Technologies, Inc.||Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof|
|US5541155 *||Apr 22, 1994||Jul 30, 1996||Emisphere Technologies, Inc.||Acids and acid salts and their use in delivery systems|
|US5578323 *||Jun 14, 1993||Nov 26, 1996||Emisphere Technologies, Inc.||Proteinoid carriers and methods for preparation and use thereof|
|US5601846 *||May 9, 1995||Feb 11, 1997||Emisphere Technologies, Inc.||Proteinoid microspheres and methods for preparation and use thereof|
|US5629020 *||Apr 22, 1994||May 13, 1997||Emisphere Technologies, Inc.||Modified amino acids for drug delivery|
|US5643957 *||Oct 25, 1994||Jul 1, 1997||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US5650386 *||Mar 31, 1995||Jul 22, 1997||Emisphere Technologies, Inc.||Compositions for oral delivery of active agents|
|US5667806 *||Jun 7, 1995||Sep 16, 1997||Emisphere Technologies, Inc.||Spray drying method and apparatus|
|US5681585 *||Jun 20, 1996||Oct 28, 1997||Euro-Celtique, S.A.||Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer|
|US5693338 *||Sep 29, 1994||Dec 2, 1997||Emisphere Technologies, Inc.||Diketopiperazine-based delivery systems|
|US5709861 *||Jan 13, 1995||Jan 20, 1998||Emisphere Technologies, Inc.||Compositions for the delivery of antigens|
|US5714167 *||Oct 25, 1994||Feb 3, 1998||Emisphere Technologies, Inc.||Active agent transport systems|
|US5750147 *||Jun 7, 1995||May 12, 1998||Emisphere Technologies, Inc.||Method of solubilizing and encapsulating itraconazole|
|US5756117 *||Aug 10, 1992||May 26, 1998||International Medical Asscociates, Inc.||Multidose transdermal drug delivery system|
|US5759599 *||Oct 5, 1995||Jun 2, 1998||Givaudan Roure Flavors Corporation||Method of flavoring and mechanically processing foods with polymer encapsulated flavor oils|
|US5766633 *||Apr 22, 1994||Jun 16, 1998||Emisphere Technologies, Inc.||Oral drug delivery compositions and methods|
|US5792451 *||Mar 2, 1994||Aug 11, 1998||Emisphere Technologies, Inc.||Oral drug delivery compositions and methods|
|US5804688 *||Feb 7, 1997||Sep 8, 1998||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US5811127 *||Oct 24, 1994||Sep 22, 1998||Emisphere Technologies, Inc.||Desferrioxamine oral delivery system|
|US5820881 *||Apr 28, 1995||Oct 13, 1998||Emisphere Technologies, Inc.||Microspheres of diamide-dicarboxylic acids|
|US5824345 *||Jun 7, 1995||Oct 20, 1998||Emisphere Technologies, Inc.||Fragrances and flavorants|
|US5840340 *||Aug 30, 1996||Nov 24, 1998||Emisphere Technologies, Inc.||Proteinoid carriers and methods for preparation and use thereof|
|US5863944 *||Apr 30, 1997||Jan 26, 1999||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US5866536 *||Feb 6, 1997||Feb 2, 1999||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US5876710 *||Feb 7, 1997||Mar 2, 1999||Emisphere Technologies Inc.||Compounds and compositions for delivering active agents|
|US5879681 *||Feb 7, 1997||Mar 9, 1999||Emisphere Technolgies Inc.||Compounds and compositions for delivering active agents|
|US5932240 *||Dec 8, 1997||Aug 3, 1999||Americare Technology, Inc.||Multidose transdermal drug delivery system|
|US5935601 *||Apr 21, 1995||Aug 10, 1999||Emisphere Technologies, Inc.||Modified amino acids for drug delivery|
|US5939381 *||Feb 7, 1997||Aug 17, 1999||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US5955503 *||Feb 6, 1997||Sep 21, 1999||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US5958457 *||May 10, 1995||Sep 28, 1999||Emisphere Technologies, Inc.||Compositions for the delivery of antigens|
|US5962710 *||May 9, 1997||Oct 5, 1999||Emisphere Technologies, Inc.||Method of preparing salicyloylamino acids|
|US5965121 *||Feb 6, 1997||Oct 12, 1999||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US5972387 *||Nov 21, 1994||Oct 26, 1999||Emisphere Technologies, Inc.||Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof|
|US5976569 *||Apr 29, 1997||Nov 2, 1999||Emisphere Technologies, Inc.||Diketopiperazine-based delivery systems|
|US5989539 *||Feb 6, 1997||Nov 23, 1999||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US5990166 *||Feb 7, 1997||Nov 23, 1999||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US6001347 *||Feb 6, 1997||Dec 14, 1999||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US6051258 *||Jun 7, 1995||Apr 18, 2000||Emisphere Technologies, Inc.||Proteinoid emulsions and methods for preparation and use thereof|
|US6060513 *||Feb 7, 1997||May 9, 2000||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US6071510 *||Apr 23, 1997||Jun 6, 2000||Emisphere Technologies, Inc.||Modified amino acids and compositions comprising the same for delivering active agents|
|US6071538 *||Sep 30, 1997||Jun 6, 2000||Emisphere Technologies, Inc.||Oral delivery composition comprising supramolecular complex|
|US6084112 *||Sep 10, 1996||Jul 4, 2000||Emisphere Technologies, Inc.||Method for preparing ω-aminoalkanoic acid derivatives from cycloalkanones|
|US6090958 *||Feb 7, 1997||Jul 18, 2000||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US6099856 *||Dec 10, 1996||Aug 8, 2000||Emisphere Technologies, Inc.||Active agent transport systems|
|US6100285 *||Nov 11, 1997||Aug 8, 2000||Emisphere Technologies, Inc.||Method of solubilizing itraconazole|
|US6100298 *||Feb 6, 1997||Aug 8, 2000||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US6129933 *||Jul 24, 1997||Oct 10, 2000||Purdue Pharma Lp||Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer|
|US6180140||Jun 2, 1995||Jan 30, 2001||Emisphere Technologies, Inc.||Modified amino acids for drug delivery|
|US6221367||Sep 29, 1997||Apr 24, 2001||Emisphere Technologies, Inc.||Active agent transport systems|
|US6242495||Jun 16, 2000||Jun 5, 2001||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US6245359||Sep 30, 1997||Jun 12, 2001||Emisphere Technologies, Inc.||Active agent transport systems|
|US6313088||Feb 7, 1997||Nov 6, 2001||Emisphere Technologies, Inc.||8-[(2-hydroxy-4-methoxy benzoyl) amino]-octanoic acid compositions for delivering active agents|
|US6331318||Sep 30, 1994||Dec 18, 2001||Emisphere Technologies Inc.||Carbon-substituted diketopiperazine delivery systems|
|US6346242||Feb 8, 2000||Feb 12, 2002||Emishpere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US6348207||Sep 30, 1997||Feb 19, 2002||Emisiphere Technologies, Inc.||Orally deliverable supramolecular complex|
|US6375983||Jun 12, 1997||Apr 23, 2002||Emisphere Technologies, Inc.||Microencapsulated fragrances and method for preparation|
|US6413550||Nov 23, 1998||Jul 2, 2002||Emisphere Technologies, Inc.||Proteinoid carriers and methods for preparation and use thereof|
|US6428780||May 5, 1999||Aug 6, 2002||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US6461545||Jan 6, 2000||Oct 8, 2002||Emisphere Technologies, Inc.||Method of solubilizing and encapsulating itraconazole|
|US6905709||Nov 12, 2001||Jun 14, 2005||Purdue Pharma, Lp||Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer|
|US7316821||Jun 18, 2004||Jan 8, 2008||Purdue Pharma, L.P.|
|US7417022||Apr 11, 2005||Aug 26, 2008||Mhr Institutional Partners Iia Lp||Compounds and compositions for delivering active agents|
|US7553872||Jun 30, 2009||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US8119175||May 5, 2004||Feb 21, 2012||Givaudan S.A.||Alginate matrix particles|
|US8686154||Jun 10, 2009||Apr 1, 2014||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US20030159836 *||Apr 20, 2001||Aug 28, 2003||Keizou Kashiki||Fire-extingushing agent, water for fire extinguishing and method of fire extinguishing|
|US20040121001 *||Dec 8, 2003||Jun 24, 2004||Benjamin Oshlack||Orally adminstrable opioid formulations having extended duration of effect|
|US20040228917 *||Jun 18, 2004||Nov 18, 2004||Purdue Pharma Lp|
|US20050186176 *||Apr 11, 2005||Aug 25, 2005||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US20060134130 *||Nov 1, 2005||Jun 22, 2006||Emisphere Technologies, Inc.||Oral drug delivery compositions and methods|
|US20060166859 *||Feb 13, 2006||Jul 27, 2006||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|US20060292280 *||May 5, 2004||Dec 28, 2006||Soper Jon C||Alginate matrix particles|
|US20080181941 *||Aug 17, 2007||Jul 31, 2008||Purdue Pharma L.P.||Orally administrable opioid formulations having extended duration of effect|
|US20090068269 *||Sep 10, 2008||Mar 12, 2009||Purdue Pharma L.P.||Orally adminstrable opioid formulations having extended duration of effect|
|US20090324540 *||Dec 31, 2009||Emisphere Technologies, Inc.||Compounds and compositions for delivering active agents|
|USRE33429 *||Feb 3, 1989||Nov 6, 1990||Dow Corning Corporation||Lattice-entrapped emollient-moisturizer composition|
|EP0128700A2 *||May 30, 1984||Dec 19, 1984||Moore Business Forms, Inc.||Improvements in microcapsules|
|EP0246469A1 *||Apr 29, 1987||Nov 25, 1987||Hoechst Aktiengesellschaft||Process for encapsulating biologically active material|
|EP2074989A1||Feb 15, 2005||Jul 1, 2009||Euro-Celtique S.A.||Abuse resistance opioid transdermal delivery device|
|EP2351555A2||Feb 15, 2005||Aug 3, 2011||Euro-Celtique S.A.||Abuse resistance opioid transdermal delivery device|
|WO1992020441A1 *||May 14, 1992||Nov 26, 1992||Allied Colloids Limited||Particulate polymeric compositions and their production_________|
|WO1993019621A2 *||Mar 30, 1993||Oct 14, 1993||Tastemaker||Aqueous liquid flavor oil capsules, method of making and using in foods|
|WO1993019621A3 *||Mar 30, 1993||Nov 25, 1993||Tastemaker||Aqueous liquid flavor oil capsules, method of making and using in foods|
|WO1993019622A2 *||Mar 30, 1993||Oct 14, 1993||Tastemaker||Heat-stable and fracturable spray-dried free-flowing flavor oil capsules, method of making and using in foods|
|WO1993019622A3 *||Mar 30, 1993||Nov 25, 1993||Tastemaker||Heat-stable and fracturable spray-dried free-flowing flavor oil capsules, method of making and using in foods|
|WO2004098318A1 *||May 5, 2004||Nov 18, 2004||Givaudan Sa||Alginate matrix particles|
|U.S. Classification||427/213.32, 514/731, 428/402.22, 424/493, 424/497, 514/963, 424/495, 428/402.2, 264/4, 424/494, 264/4.6, 428/402.24|
|International Classification||A61K9/50, B01J13/08|
|Cooperative Classification||A61K9/50, B01J13/08, Y10S514/963|
|European Classification||A61K9/50, B01J13/08|
|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