US3155590A - Encapsulation process and its product - Google Patents

Encapsulation process and its product Download PDF

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US3155590A
US3155590A US21418362A US3155590A US 3155590 A US3155590 A US 3155590A US 21418362 A US21418362 A US 21418362A US 3155590 A US3155590 A US 3155590A
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material
system
liquid
wall
temperature
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Miller Robert Erwin
Jerrold L Anderson
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NCR Corp
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089Processes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02Making microcapsules or microballoons
    • B01J13/06Making microcapsules or microballoons by phase separation
    • B01J13/08Simple coacervation, i.e. addition of highly hydrophilic material
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2984Microcapsule with fluid core [includes liposome]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2989Microcapsule with solid core [includes liposome]

Description

United States Patent 5,155,590 EI JEAPSULATIQN PRGtTESS AND ITS PRODUCT Rehert Erwin Miller and Jerrold L. Anderson, Dayton,

Ohio, assignors to The National Cash Register Company, Dayton, @hio, a corporation of Maryland No Drawing. Filed Aug. 2, 1962, Ser. No. 214,183 25 Claims. (Cl. 167-33).

This invention relates to a cyclic process of manufacturing minute capsules in liquid manufacturing vehicle systems, to such systems, and to the capsule prod uct obtained by use of such process and systems, each capsule comprising a core and a protecting seamless rigid Wall of polymeric material surrounding the core. By minute capsules" are meant capsules from a few microns to several thousand microns and possibly somewhat larger in average size. The wall thickness may vary from fractions of microns to several microns, and more.

In known processes for the manufacture of minute capsules en masse, each capsule consisting of a core entity and a rigid seamless wall formed around it, an agitated liquid vehicle is used in which the core entitles and the liquid wall-forming materials are dispersed, so that the wall material in liquid form may be deposited on each core entity, to form individual capsules with liq uid walls. These liquid walls finally are converted into rigid dense walls. In-these known processes, the wall material is converted to a rigid state by a chemical or physical means, or both, such as temperature gelation, desolvation, use of a washing liquid, cross-linking, chelation, and other means, used singly or in combination.

In this novel process, neither temperature gelation nor hardening agents are used, thereby avoiding a reticulated gel wall structure and the contamination of the residual manufacturing vehicle, such residual vehicle being ready for re-use after being refurnished with the used-up capsule-forming ingredients.

Any one of the systems is used with warming and cooling, with agitation, within a specified temperature range. Any one of the systems, before warming, in the first instance, consists of three immiscible phases; viz.:

(a) A major part by volume of a low-viscosity liquid vehicle, a part of which vehicle at warm temperature is a solvent for the wall material,

(b) The polymeric Wall material to be dispersed in the system and dissolved by part of (a) when the system is warm, and

(c) Particles of core material immiscible with (a) or (b) but wettable by (b) in solution.

After being warmed, phase (1)) is a solution. These systems may be established in any order of addition, warm or cold, agitated or not, and the process may be interrupted and resumed by the re-establishment of the heating and agitation.

The insolubilizing effect of a drop in temperature on the deposited liquid walls, from the warm condition, results in the departure of the solvent into the vehicle phase, where it remains for recycling.

Of particular interest as capsule Wall materials are polymeric materials that have substantial zero solubility in a qualified solvent at room temperature (20 degrees centigrade to 25 degrees centigrade) and increasing solubility therein as the temperature is increased, so that a system may be prepared wherein a dissolved polymeric material deposits on the core entities as liquid walls which shrink into a rigid state as the temperature is lowered. The forcing out of the polymeric material from solution and its solidification should occur somewhat above room room temperature is the norm. However, without de- Patented Nov. 3, 1964 parting from the novel principles of the invention, systems may be created to fit processing temperature ranges having lower limits above or below room temperature, if such be appropriate for the situation, as in the encapsulation of cold-sensitive or heat-sensitive core materials.

The solvent for the polymeric wall material in this process is part of the vehicle in the cold state of a system, and thus, stated reversely, the vehicle in part is the wall material solvent in the warm state of the system. Therefore, an undivided part of the solvent is sometimes part of the vehicle and sometimes part of the liquid wall material. The vehicle is of generally low viscosity and contains, in addition to the solvent, a minor part of a solute, giving up a part of the solvent to the polymer in the warm state. The solute may be an organic low-viscosity liquid or a polymeric material. By furnishing such vehicle solvent with a solute incompatible with the wallforming polymeric material, to establish a major phase of low viscosity, the wall-forming material as a more viscous solution can exist as a separate phase in the vehicle and may be broken up in the vehicle, by agitation, and dispersed as minute liquid entities in the Warm system, ready to coat core material particles that may be present in said system. The separate dispersed entities of viscous Warm liquid solution of wall material coat the particles of core material to a thickness limited by the shearing eifect of the agitation, the later cooling thereof causing the walls to give up the solvent. The walls thereupon shrink on the core particles into a dense, rigid, protective coating. By judicious choice of amounts of ingredients for a complete cycle of the process, a batch of capsules will utilize substantially all of the wall-forming material and the core material, leaving for the next cycle the residual vehicle to be refurnished with amounts of capsule ingredients lost. Any of the vehicle materials lost by entrainment with the recovered capsules, by evaporation or otherwise, also may be replaced between cycles.

The process is economical and newly useful in various respects; viz.:

(1) No hardening agent need be used to make the polymeric material rigid, dense, and solid after it has been deposited on the core particles as a liquid solution.

(2) The vehicle can be used repeatedly, as it contains no hardening agents or irreversible reaction products.

(3) The time for processing each batch is determined only by dispersing requirements, heating time, and cooling time.

(4) The wall material remains unchanged in chemical structure, and, in the event the process is interrupted, the process can be resumed merely by being heated and agitated.

(5) Refurnishing of materials for a new batch of capsules can be accurately controlled from empirical data obtained by trial runs, and, therefore, the process is subject to automation.

By the use of polymeric material that rigidizes by phasing out of solution in a condensed rigid form on being cooled, without retention of the solvent, capsules are formed having Walls which are stable when removed from the system, even when later exposed to warm environments.

The core material of the finished capsules may be ex posed for use by mechanical rupture of the capsule walls, by causing their disintegration by electrical or chemical means, or by leaching action carried out in an appropriate liquid environment, as the rigid wall is of membraneous character.

The novel process has been used to provide capsules that are ingestible and harmless, as far as the wall mate rial is concerned, and vulnerable to core material extraction in the alimentary tracts of living creatures.

An unsuspected virtue of a preferred embodiment of the process is its use in the encapsulation of aspirin (acetylsalicylic acid), which heretofore has resisted wetting by solutions of hydrophobic film-forming polymeric wall materials dispersed in a liquid manufacturing vehicle, because of preferential wetting problems. Especially it was found that ethyl ce ulose t 8.5% to 49%, by weight, ethoxyl content is soluble lI'l eycronexane at near the boiling point of cyclohexane (80 degrees centigrade) and in such solution will deposit on aspirin particles dispersed in a continuous phase vehicle consisting of a cyclohexane solution of an incompatible polymeric material or solvent material. On being cooled, the deposited solution walls of ethyl cellulose lose their solvent, shrinking to a rigid seamless protective wall about each aspirin particle.

Regardless of its special adaptation for the encapsulation of aspirin in ethyl cellulose by use of cyclohexane, the process has a wide range of use with regard to the encapsulation of other core materials, and to the use of other capsule wall materials, solvents, and phase-separation-inducing solutes, and with regard to the temperature ranges which such other materials require.

While attention has been directed to a room-temperature norm for capsule recovery, it will be obvious that such is just a convenient temperature recovery environment. The insolubility-temperature point of the dissolved wall material in a given system is the controlling factor as to the temperature range over which the process takes place. If rigid walls are obtained by cooling the liquid deposit on capsules from an elevated temperature to a temperature lower than room temperature, the capsules are recovered from the system at that lower temperature. Rigid capsules completed at below room temperature, and removed, will not disintegrate, by melting of the walls, at room temperature or higher in the absence of a solvent, unless the polymeric material alone naturally has a liquid state at such higher temperature. Likewise, capsules with rigid walls recovered above room temperature may be used at room temperature and below.

The change of state of the deposited polymeric material solution to a rigid state, by loss of solvent on cooling, is not a gelation in a technical sense, such as occurs in an aqueous gelation solution on being cooled. In this novel process, the polymeric wall material in desolvated condition is a dense, rigid material and not a reticulated network structure entrapping the solvent.

In the recycling of a residual system, the most efficient method of refurnishing the system with capsule ingredients is to furnish what has disappeared in the making of the previous batch of capsules, but such may be varied if thinner or thicker capsule Walls are required for the next batch, or if the particle size of the core materials and the degree of agitation, or both, are varied, that require correspondingly different ratios of capsule-forming material.

The chosen polymeric material must be used in such concentration that, in its existence in solution in the system as a separate liquid phase, it will have a viscosity of between 100 and 10,000 centipoises, but preferably between 1,000 and 4,000 centipoises, in order to cling to small core material particles and to wrap around them to form a complete liquid shell. Therefore, if polymeric materials are used that have characteristics different from the characteristics of the materials disclosed in the examples to follow, concentrations different from those which appear from the proportions of materials given in the examples may be required to give a dispersed liquid solution of polymeric wall-forming material having the necessary viscosity to wrap around the core particles.

The core material may be liquid if it can exist as a separate phase in the system under agitation, is stable to the necessary heating and cooling of the system, and is compatible with the liquid solution of wall-forming material from a non-reaction and wetting behavior standpoint.

To maintain the necessary mobility of the capsuleforming materials in the vehicle, the vehicle must form the major part of the system by volume, the capsuleforming dispersed phases preferably constituting 20% to 30% of the whole system.

Example I s mentioned, the minute encapsulation of acetylsalicync acid particl s. to e recovered as finished capsules at room temperature, will be given herein as the preferred example, as such encapsulation in a controlled manner, with ingestible non-toxic capsule walls, and with sustained release characteristics in the human alimentary canal,

in an economical cyclic manner subject to automation, has not heretofore been accomplished.

Although the proportions of materials are given in exact weights, these proportions may be scaled up or down, for larger or smaller batches, and the amounts and particle sizes of the capsule-forming ingredients may be varied to give the desired ratio of wall material to core material in an average capsule, and to adjust the final average capsule size.

This example utilizes 1) cyclohexane as the solvent vehicle, (2) butyl rubber having a viscosity of -75 Mooney 8-minute reading at 212 degrees Fahrenheit, to maintain the wall material solution as a separate phase, (3) aspirin of a particle size passing a sieve with openings of 0.5 millimeter and retained on one with openings of 0.149 millimeter, as core material, and (4) ethyl cellulose having an ethoxyl content of substantially 48.5% by weight, and a viscosity of 90-94 centipoises as a 5%, by weight, solution in a 20% alcohol/ toluene solvent, as wall material.

Into a 600-milliliter vessel, there are introduced, with agitation sutficient to produce liquid entities of ethyl cellulose-cyclohexane solution of several microns average drop size at 80 degrees centigrade,

200 grams of a 3%, by weight, solution of the specified butyl rubber in cyclohexane,

4 grams of the specified ethyl cellulose, and

48 grams of the specified panticulate size acetylsalicylic acid,

to form a system which is heated to 80 degrees centigrade.

The system is cooled, with continued agitation, when the desired degree of dispersion has been reached. The liquid entities of wall-forming material will commence to deposit on the aspirin particles at about degrees centigrade. The point of wall formation may be determined microscopically, and, after a few trials, automation data for a given batch size may be set down empirically in terms of time and degree of agitation. The cooling is carried on to room temperature, the capsules then being recovered by deeantation, filtering, centrifuging, or the like, and thereafter dried. For recycling, the recovered liquid and residual contents are reconstituted to the original ratios of materials, as determined by testing, the heating and cooling steps thereafter being repeated, with the required agitation.

The SO-degree-centigrade manufacturing starting temperature, for this Example I, insures that the ethyl cellulose is in solution in the cyclohexane, sharing some of it to the exclusion of the butyl rubber. The butyl rubber maintains the more viscous ethyl-cellulose-cyclohexane solution as a separate phase of such concentration that it is broken up as minute liquid entities by the agitation, which is maintained at a level sufiicient to keep the entities of ethyl cellulose solution dispersed among the particles of aspirin, which, thereby, are individually coated with a continuous liquid Wall. The suggested amounts given in this example give a coating in the rigid state of about one micron in thickness if all the wall material is deposited.

For purification, the capsules may be washed with cyclohexane and re-filtered as many times as desired to remove any entrained butyl rubber. If the capsules are washed with pure cyclohexane to eliminate entrained butyl rubher, the Wash liquid may be used over for the same purpose until its contamination with butyl rubber renders it useless, and then the contaminated cyclohexane/butyl rubber wash liquid may be used by being refurnished with capsule ingredients and extra butyl rubber to form a potential capsule-making system.

The capsules of this example are substantially 92% aspirin and may be used for preparing dosage forms.

Example l is applicable to the encapsulation of any solid or liquid particulate material that is wettable by a hot cyclohexane solution of ethyl cellulose of the specified type and not otherwise reactant with the rest of the system.

Example Ia An optional step in this example, which is a modified form of Example I, is provided to bring about the clearing away of potentially toxic materials brought about by decomposition of minute amounts of the aspirin. These decomposition products are salicyclic acid and acetic acid and are found in commercially-produced acetylsalicylic acid. The hot system specified in Example I is supplied with one milliliter of acetic anhydride, any remaining unused portion thereof being removed from the capsules by the washing process after the capsules are completed. This treatment effectively removes any such decomposition products.

Different particle sizes of aspirin, different ratios of aspirin to cyclohexane solution of ethyl cellulose, and different ratios of butyl rubber to cyclohexane used in the system, departing from the exact proportions specified in Example I, may be used, such variations being adopted, as desired, to control the density and the thickness of the capsule walls, such necessary variations being ascertainable by empirical testing, to suit the intended use of the capsules.

With regard to the viscosity of the ethyl-cellulose-cyclohexane solution containing the butyl rubber, the 2% concentration specified was preferred, but departures therefrom one way or another may be made so long as the viscosity of the separated phase is in the range specified. If another phase-separation-inducing material than the specified butyl rubber is used, tests must be made to determine how much to use to get the proper viscosity.

Example 11 This example makes use of a system similar to that disclosed in Example I, except that the material is a liquid solvent of a slowly-evaporating aromatic type, such as TS28R Solvent, now supplied by Shell Oil Company as an aromatic solvent which contains approximately 75% aromatics, has an A.P.I. gravity of 34.4, has a per-gallon Weight of 7.102 pounds, and has a boiling point range of 318 degrees Fahrenheit to 392 degrees Fahrenheit. This is used in the same amount as the cylohexane of Example I. While not necessarily the preferred solvent for use with aspirin as the core material, it may be used successfully with other core materials that are not pre-wet to any extent therewith.

Two examples of systems utilizing ethyl cellulose as the wall material for the encapsulation of aspirin having been given, a number of core materials, other than aspirin, are given that have beenencapsulated with ethyl cellulose:

Ammonium dichromate Acetyl para-amino phenol Amphetamine sulfate Aluminum aspirin Sodium bicarbonate Gelatin Cellulose acetate hydrogen phthalate Polyvinyl pyrrolidone Mannitol Glyceryl guiacolate Dextro-methorphan hydrobromide Calcium gluconate Carboxy methyl cellulose The following solvent materials have been used in these two systems instead of cyclohexane or TS-28R solvent:

n-Hexane plasticized with mono-acetylated glyceride Methylcyclohexane VM & P naphtha So far, the invention has been described in terms of ethyl cellulose as the capsule wall material because, besides being a generally useful film-former, it is eminently useful in cyclohexane solution for encapsulating the perversely-acting aspirin. Other wall-material-vehicle systems with different required temperature ranges may be used, land such will be given as sepanate examples without limitation as to amounts of materials and the core materials to be encapsulated, as these may be determined with the limits heretofore specified as to mobility and viscosity.

Example III Ethyl hydroxy ethyl cellulose of high viscosity is used as the wall material; polybutadiene of 8,000 to 10,000 molecular weight, determined by the osmotic pressure method, is used as the phase-seporation-inducing material; and non-aromatic mineral spirits having an A.P.I. gravity of 52.3, weight per gallon of 6.414 pounds, a flash point of 104 degrees Fahrenheit, and a boiling point range of 310 degrees Fahrenheit to 355 degrees Fahrenheit is used as the solvent. This system is established Within the range of materials needed to give the separated phase the necessary wrapping viscosity. The ethyl hydroxy ethyl cellulose has a content of 2.52.2 of the ethyl ether or" ethyl cellulose and a complementary content of 0.3- 0.5 of the hydroxy ethyl ether of ethyl cellulose, out of a total of three parts available for substitution. The temperature range for this system is 60 degrees centigrade to 40 degrees centigrade, for the higher-viscosity Wall material, and 50 degrees Centigrade to 30 degrees centigrade for the lower-viscosity wall material.

Example IV In this example, the system is established with polyvinyl pyrrolidone/vinyl acetate copolymer as the wall material; polybutadiene of 8,000 to 10,000 molecular weight, as ascertained by the osmotic pressure method, as the phase-separatiominducing agent; and a 5050 mixture of toluene and cyclohexane as the solvent medium, used together to bring about the designated conditions for making capsules, the high temperature of the process for this example being degrees centigrade, and the completion temperature being room temperature (25 degrees centigrade to 20 degrees centigrade).

Example V Example VI This example is like Example I, except that polybutadiene of 8,000 to 10,000 molecular weight is used instead of butyl rubber, enough being used to give a separate ethyl cellulose solution of between 4,000 and 10,000

centipoises, the temperature range being from 80 degrees centigrade to 60 degrees centignade.

Example VII In this example, the wall material is ethyl cellulose with an ethoxyl content of 44.5% to 45%, the phaseseparation-inducing agent is polybutadiene of 8,000 to 10,000 molecular weight, and the solvent is toluene. The processing of the system of this example is carried on between 75 degrees centigrade and 60 degrees centigrade.

Example VIII In this example, polyvinyl pyrrolidone is used with the specified polybutadiene (as the phase-separation-inducing agent, and toluene as the solvent, the system being established within the critical ranges given, and the process being carried on between 110 degrees centigrade and 80 degrees Centigrade.

In all of these examples, the system is so established that a hot viscous separate phase of 'a film-forming polymeric material dissolved in a volatile solvent is formed, the system being agitated, while hot, to initiate the wrapping of entities or" the separated solution of polymeric material around intended core particles; continued agitation completing the deposition of walls around the core particles while the cooling of the system is provided, the capsule walls setting by solvent loss only to a rigid condition.

The systems provided, in completed or uncompleted condition, may be stored before being used in the final process steps of making the capsules by agitation, heating, and cooling. if the process begins with the mixing of the materials, they may be introduced in any order, and the addition of missing ingredients may be made at any time to establish the hot system.

The systems in process may be reversed at any time by being reheated, with subsequent cooling, all with agitation.

The recycling of the process, as described, is made possible by the absence of chemical hardening agents or the establishment of irreversible conditions.

What is claimed is:

1. A system provided for the en masse encapsulation of minute particles by use of agitation and heat followed by cooling with continued agitation, consisting of (a) a major part by volume of a low-viscosity liquid vehicle consisting in part of a solvent for polymeric film-forming wall material, the other part of the vehicle being a non-wall-forming polymeric material ([1) polymeric film-forming wall material of rigid solid characteristics, said polymeric material being soluble in the polymer solvent part of (a) when the system is warm to form a separate phase, said filmforming polymeric material being used to the extent that the warm solution of it has a viscosity of 4,000 to 10,000 centipoises and may be broken up as tiny liquid entities in the vehicle by agitation, and

(c) particulate core material immiscible with (a) or (b) but wettable by the warm solution of (b), (b) plus forming less than 30% of the system, so that the particles and the liquid entities may be freely interspersed in the warm vehicle during capsule formation.

2. The system of claim 1 in which the vehicle includes cyclohexane as the solvent and includes, as the other part of the vehicle, butyl rubber to force the polymeric wall material dissolved in the cyelohexane to exist in the vehicle as a separate dispersible phase of between 4,000 and 10,000 centipoises.

3. The system of claim 2 in which the polymeric wall material is ethyl cellulose of about 48.5% ethoxyl content.

4. The system of claim 3 in which (0) is particulate acetylsalicylic acid.

,5. The system of claim 1 in which (a) constitutes more than 70% of the whole volume and includes a solute holding the solution of (b) as a separate phase.

6. The system of claim 5 in which the vehicle (a) includes cyclohexane as the solvent and (b) is ethyl cellulose.

7. The system of claim 6 in which (c) is acetylsalicylic acid.

8. A continuous process for manufacturing minute capsules en masse, by batches, including the steps of (a) establishing asystem consisting of (l) a major portion, by volume, of a liquid including a solvent for a polymeric fihn-forming material when warm, and a phase-separating solute of non-wall-formingpolymeric material dissolved in the solvent,

(2) a solid polymeric film-forming material soluble as a separate phase in a portion of the solvent of (1) when warm but becoming insoluble therein when cold, said solution of (2) in (l) forming a separate dismrsible liquid phase in the system due to the presence of the phaseseparating solute with which it shares the solvent, and

(3) particles of core material insoluble in (l) or the solution of (2) in the solvent of (1);

(b) warming and agitating the system to a temperature at which the solution of (2) in the solvent of (1) forms a dispersed liquid phase and the particle (3) are interspersed With and coated by the liquid phase dispersion of film-forming polymeric material to form individual liquid-walled capsules;

(0) with continued agitation cooling the system to a temperature at which the liquid walls give up the solvent, leaving each particle coated with a seamless rigid film of (2);

(d) recovering the capsules from the system, leaving the depleted residue;

(e) refurnishing said residue with materials removed with the capsules or otherwise lost;

(f) and repeating steps (b), (c), (d), and (e).

9. Capsules made according to the process of claim 8.

10. The process of claim 8 in which the solvent of the vehicle is cyclohexane, the polymeric wall-forming material is ethyl cellulose with an ethoxyl content of about 48.5 and the dispersed polymeric material solution has a viscosity of 4,000 to 10,000 centipoises.

11. The process of claim 8 in which the warm temperature is above room temperature and the insolubilization of the deposited wall polymer solution is achieved by cooling the solution to room temperature.

12. The process of claim 11 in which the particulate core material is acetylsalicylic acid.

12l3. Capsules made according to the process of claim 14. The process of claim 12 in which the phase-separating solute of the vehicle is butyl rubber.

15. A continuous process for manufacturing minute capsules en masse, by batches, including the steps of (a) providing a mutually-immiscible three-phase system at a given temperature, said three phases being (1) a liquid vehicle of low viscosity provided in an amount constituting a major portion of the system, said vehicle being a solution of a polymeric material solvent and a phase-separating solute consisting of a non-wallorming liquid polymeric material,

(2) a polymeric wall-forming material dissolved in part of the solvent of vehicle (1) but held as a separate liquid dispersible phase by the phaseseparating solute, the solvent returning to become part of the vehicle upon the cooling of the system, leaving the polymeric material as a solid, and

(3) particles of core material insoluble in (l) or (b) agitating the system to disperse (2) as particles among particles (3), whereby said particles (3) each are coated individually by (2);

(c) cooling the system with continued agitation to cause the coatings on the particles to give up the solvent to the vehicle, leaving finished capsules;

(d) after recovering the capsules from the system, reconstituting the system as provided in (a) and repeating steps (b) and (c) to form a new batch of capsules.

16. The process of claim in which the core material is acetylsalicylic acid.

17. The process or" claim 16 in which one milliliter of acetic anhydride is added to the hot system.

18. The process of claim 17 and, in addition thereto, the step in which the capsules are recovered from the residual liquid, which residual liquid is saved and replenished with materials which bring the system to its starting condition (a), whereupon the process may be continued again.

19. The process of claim 16 in which the vehicle is butyl rubber dissolved in cyclohexane, and the polymeric material is ethyl cellulose with an ethoxyl content of about 48.5%.

20. The process of claim 19 and, in addition thereto, the step in which any decomposition products of acetylsalicylic acid are neutralized by the addition of the necessary amount of acetic anhydride to the system, followed by a washing of the capsules with cyclohexane until any excess acetic anhydride and any entrained butyl rubber are washed away.

21. A process for encapsulating minute acetylsalicylic acid particles individually in ethyl cellulose, including the steps of (a) forming an agitated system of:

Parts by weight cyclohexane 194 butyl mbber-viscosity of 60 75 Mooney,

as specified 6 ethyl cellulose-ethoxyl content of about 48.5% 4 Acetylsalicylic acidpowdered to the specified size 48 heated to 80 degrees Centigrade until the dissolved ethyl cellulose has a drop size of several microns; and

(b) cooling the agitated system to room temperature,

to form capsules dispersed in a residual liquid vehicle.

22. The process of claim 21 and, in addition thereto, the step in which the capsules are recovered from the residual liquid, which residual liquid is saved and replenished with materials which bring the system to its starting condition (a), whereupon the process may be continued again.

23. A process of manufacturing minute capsules, en masse in a liquid vehicle, including the steps of (a) establishing an agitated system at a predetermined temperature above room temperature degrees centigrade to 25 degrees centigrade) of (l) a common solvent liquid,

(2) a phase-separation polymeric material soluble in (1) at room temperature and at the predetermined elevated temperature,

(3) a wall-forming polymeric material soluble to an extent in the solution of (2) in (l) at the predetermined elevated temperature, by sharing part of solvent (1) exclusively, to form a separate solution of (3) in (1) phase which separate solution phase has, by reason of determined ratios of (l), (2), and (3), a viscosity of between 1,000 and 4,000 centipoises, said separate solution being dispersed as minute liquid entities of the desired drop size by the degree of agitation, and

(4) intended capsule core material insoluble in the remainder of the system, wettable by the separate dispersed solution of (3) in (1) and dispersed as particles interspersed with and wet by said dispersed solution liquid entities, to form liquid-walled capsules; and

(b) with continued agitation cooling the system to room temperature to cause the polymeric material of the solution deposited on particles (4) to phase out as a solid seamless wall around each particle to form capsules which are self-sustaining in and out of the remainder of the said system.

24. A process of manufacturing minute capsules, en

masse in a liquid vehicle, including the steps of (a) forming an agitated system heated at a predetermined temperature above room temperature, said system consisting of (1) a major portion of a liquid solvent,

(2) a lesser portion of hydrophobic film-forming rigid polymeric material soluble in (1) to the extent of said lesser portion at the predetermined temperature above room temperature,

(3) a polymeric material incompatible with the solution of (2) in 1) and soluble in (1) both at the predetermined temperature and at room temperature, (3) being supplied in empiricallydetermined sufiicient amount to keep the solution of (2) in (l) as a separate liquid phase having at the predetermined temperature a viscosity of from 1,000 to 4,000 centipoises by an appropriation of a share of solvent (1), the agitation keeping the separated phase solution of (2) in (l) dispersed in the rest of the system at the predetermined temperature as minute liquid entities, and

(4) intended capsule core material wettable by the solution of (2) in (1), insoluble in the rest of the system, and dispersable by the agitation as minute particles among the dispersed liquid entities of wall material solution of (2) in (1), whereby the said liquid entities deposit on the core material particles to form a liquid wall about each particle; and

(b) still with agitation, to keep the liquid-walled particles of core material dispersed in the system, bringing the temperature of the system toward room temperature to cause the polymeric wall material in the liquid walls to concentrate as a rigid seamless wall around each particle.

25, The process of claim 24 in which the capsules are recovered from the system and replaced by materials to bring the depleted system to its original state.

References Cited in the file of this patent UNITED STATES PATENTS UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3,155 590 November 3 1964 Robert Erwin Miller et a1 It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below Column 1, line 22, for "entitles" read entities column 9, line 38, for 60 -75" read 60-75 Signed and sealed this 16th day of March 1965.

( SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,155 590 November 3 1964 Robert Erwin Miller et a1 error appears in the above numbered pat- It is hereby certified that t the said Letters Patent should read as ent requiring correction and the, corrected below.

Column l, line 22, for "entitles" read entities column 9, line 38, for "60 75" read 60-75 Signed and sealed this 16th day of March 1965,

(SEAL) Attest:

EDWARD J. BRENNER ERNEST W. SWIDER Commissioner of Patents Attesting Officer

Claims (1)

1. A SYSTEM PROVIDED FOR THE EN MASSE ENCAPSULATION OF MINUTE PARTICLES BY USE OF AGITATION AND HEAT FOLLOWED BY COOLING WITH CONTINUED AGITATION, CONSISTING OF (A) A MAJOR PART BY VOLUME OF A LOW-VISCOSITY LIQUID VEHICLE CONSISTING IN PART OF A SOLVENT FOR POLYMERIC FILM-FORMING WALL MATERIAL, THE OTHER PART OF THE VEHICLE BEING A NON-WALL FORMING POLYMERIC MATERIAL (B) POLYMERIC FILM-FORMING WALL MATERIAL OF RIGID SOLID CHARACTERISTICS, SAID POLYMERIC MATERIAL BEING SOLUBLE IN THE POLYMER SOLVENT PART OF (A) WHEN THE SYSTEM IS WARM TO FORM A SEPARTE PHASE, SAID FILMFORMING POLYMERIC MATERIAL BEING USED TO THE EXTENT THAT THE WARM SOLUTION OF IT HAS A VISCOSITY OF 4,000 TO 10,000 CENTIPOISES AND MAY BE BROKEN UP AS TINY LIQUID ENTITIES IN THE VEHICLE BY AGITATION, AND (C) PARTICULATE CORE MATERIAL IMMISCIBLE WITH (A) OR (B) BUT WETTABLE BY THE WARM SOLUTION OF (B), (B) PLUS (C) FORMING LESS THAN 30% OF THE SYSTEM, SO THAT THE PARTICLES AND THE LIQUID ENTITIES MAY BE FREELY INTERSPERSED IN THE WARM VEHICLE DURING CAPSULE FORMATION.
US3155590A 1962-08-02 1962-08-02 Encapsulation process and its product Expired - Lifetime US3155590A (en)

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US3155590A US3155590A (en) 1962-08-02 1962-08-02 Encapsulation process and its product
GB2118563A GB965070A (en) 1962-08-02 1963-05-28 Process for the manufacture of minute capsules and capsules obtained by such process
NL295964A NL295964A (en) 1962-08-02 1963-07-30
NL295964A NL139668B (en) 1962-08-02 1963-07-30 A process for making small capsules containing acetylsalicylic acid.
DK365563A DK116935B (en) 1962-08-02 1963-07-31 A process for the production of small capsules.
DE1963N0023543 DE1212497B (en) 1962-08-02 1963-07-31 A process for the production of very small capsules
BE635698A BE635698A (en) 1962-08-02 1963-08-01
FR943408A FR1383778A (en) 1962-08-02 1963-08-01 Process for obtaining tiny capsules and capsules produced by this method

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US3341416A (en) * 1963-12-11 1967-09-12 Ncr Co Encapsulation of aspirin in ethylcellulose and its product
US3350270A (en) * 1964-09-18 1967-10-31 Leeds Dixon Lab Inc Aluminum aspirin film-enveloped therapeutic agents in sustained release dosage form
US3400185A (en) * 1965-04-08 1968-09-03 Bristol Myers Co Agglomeration of smaller pharmaceutical particles into larger microspherules and enteic-coating thereof
US3415758A (en) * 1960-03-09 1968-12-10 Ncr Co Process of forming minute capsules en masse
US3488418A (en) * 1965-11-18 1970-01-06 Sterling Drug Inc Sustained relief analgesic composition
US3524910A (en) * 1965-11-18 1970-08-18 Sterling Drug Inc Sustained relief analgesic compositions
US3531418A (en) * 1965-08-18 1970-09-29 Ncr Co En masse encapsulation process
US3623997A (en) * 1966-06-06 1971-11-30 Ncr Co Wall-sealing treatment for minute capsules and minute capsules having walls of sealed polymeric material
DE2333756A1 (en) * 1972-07-05 1974-01-24 Ncr Co A method for continuously producing polymer capsules smaller
US4107072A (en) * 1973-05-25 1978-08-15 Merck & Co., Inc. Process of isolating cyclohexane-free ethylcellulose microcapsules
DE2834373A1 (en) * 1977-08-11 1979-02-22 Tanabe Seiyaku Co microcapsules containing process for the preparation of a pharmaceutical compound
FR2447192A1 (en) * 1979-01-25 1980-08-22 Adria Lab Inc DOSAGE FORM a sustained release of indoprofen
US4316884A (en) * 1979-01-25 1982-02-23 Adria Laboratories, Inc. Sustained release pharmaceutical formulation
US4389331A (en) * 1979-10-31 1983-06-21 Tanabe Seiyaku Co., Ltd. Process for preparing pharmaceutically active compound-containing microcapsules
US4411933A (en) * 1980-04-25 1983-10-25 Tanabe Seiyaku Co., Ltd. Process for preparing ethylcellulose microcapsules
US4507276A (en) * 1982-08-20 1985-03-26 Bristol-Myers Company Analgesic capsule
US4551288A (en) * 1982-08-16 1985-11-05 Sandoz, Inc. Processes for the preparation of liposome drug delivery systems
US4590063A (en) * 1983-06-24 1986-05-20 Adria Laboratories, Inc. Anticonvulsants
US4590170A (en) * 1980-07-09 1986-05-20 Fuji Photo Film Co., Ltd. Process for preparing microcapsule reagents for immunological response
US4693896A (en) * 1985-10-07 1987-09-15 Fmc Corporation Ethylcellulose-coated, gastric-disintegrable aspirin tablet
US4748023A (en) * 1983-01-26 1988-05-31 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of sustained release pharmaceutical compositions having a high active ingredient content
US4822535A (en) * 1985-07-12 1989-04-18 Norsk Hydro A.S. Method for producing small, spherical polymer particles
US4824616A (en) * 1987-06-05 1989-04-25 Toray Silicone Company, Ltd. Method for the production of spherical silicone gel particles
US4867984A (en) * 1984-11-06 1989-09-19 Nagin K. Patel Drug in bead form and process for preparing same
US4937076A (en) * 1984-08-10 1990-06-26 Combe Incorporated Chewable aspirin and buffering material tablet and method for producing same
US4954412A (en) * 1988-10-31 1990-09-04 Xerox Corporation Processes for the preparation of encapsulated toner compositions
US4983401A (en) * 1989-05-22 1991-01-08 Kinaform Technology, Inc. Sustained release pharmaceutical preparations having pH controlled membrane coatings
US4996047A (en) * 1988-11-02 1991-02-26 Richardson-Vicks, Inc. Sustained release drug-resin complexes
US5026559A (en) * 1989-04-03 1991-06-25 Kinaform Technology, Inc. Sustained-release pharmaceutical preparation
US5051305A (en) * 1988-12-30 1991-09-24 Arcade, Inc. Stabilized perfume-containing microcapsules and method of preparing the same
WO1992004031A1 (en) * 1990-09-04 1992-03-19 Edward Shanbrom Preservation of blood, tissues and biological fluids
US5192552A (en) * 1988-12-30 1993-03-09 Egis Gyogyszergyar Process for preparing microcapsules providing the rapid release of a drug as active ingredient
US5252337A (en) * 1991-06-25 1993-10-12 Eurand America, Inc. Controlled release calcium channel blocker microcapsules
US5278194A (en) * 1993-03-25 1994-01-11 Microsome Environmentall dispersible syntactic foam
US5376384A (en) * 1992-12-23 1994-12-27 Kinaform Technology, Inc. Delayed, sustained-release pharmaceutical preparation
US5651984A (en) * 1992-08-04 1997-07-29 Eurand America, Incorporated Controlled release potassium tablet
US6544646B2 (en) 2000-04-27 2003-04-08 Verion Inc. Zero order release and temperature-controlled microcapsules and process for the preparation thereof
US6562460B1 (en) 2001-11-20 2003-05-13 Encap Technologies, Llc Microencapsulated particles and process for manufacturing same
US20040130045A1 (en) * 2001-11-20 2004-07-08 Bayless Robert G. Microencapsulated particles and process for manufacturing same
US20050013860A1 (en) * 2003-07-15 2005-01-20 Gopi Venkatesh Controlled release potassium chloride tablets
US6899958B2 (en) 2002-06-21 2005-05-31 Encap Technologies, Llc. Moisture barrier resins
US20050136096A1 (en) * 2003-08-22 2005-06-23 Davidson R. S. Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
US20050202085A1 (en) * 2000-07-08 2005-09-15 Lovercheck Dale R. Unit dose of material in system and method
US20060210610A1 (en) * 2002-11-14 2006-09-21 Davidson Robert S Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use
US20080124398A1 (en) * 2003-11-14 2008-05-29 Gopi Venkatesh Modified release dosage forms of skeletal muscle relaxants
US20100160428A1 (en) * 2005-11-09 2010-06-24 Protemix Corporation Limited Treatment of mitochondria-related diseases and improvement of age-related metabolic deficits
US9155698B2 (en) 2003-03-28 2015-10-13 Cure Pharmaceutical Corporation Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films
US9783574B2 (en) 2011-08-18 2017-10-10 Otago Innovation Limited Cardiovascular therapeutics

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DE3635141C1 (en) * 1986-10-15 1988-03-03 Pelikan Ag Thermal carbon ribbon with a plastics-bonded fusible dye and a process for producing this strip

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US2980941A (en) * 1958-12-08 1961-04-25 Ncr Co Cleaning sheet
US3069370A (en) * 1958-12-22 1962-12-18 Upjohn Co Coacervation process for encapsulation of lipophilic materials
US3041289A (en) * 1959-01-02 1962-06-26 Ncr Co Method of making walled clusters of capsules

Cited By (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3415758A (en) * 1960-03-09 1968-12-10 Ncr Co Process of forming minute capsules en masse
US3341416A (en) * 1963-12-11 1967-09-12 Ncr Co Encapsulation of aspirin in ethylcellulose and its product
US3350270A (en) * 1964-09-18 1967-10-31 Leeds Dixon Lab Inc Aluminum aspirin film-enveloped therapeutic agents in sustained release dosage form
US3400185A (en) * 1965-04-08 1968-09-03 Bristol Myers Co Agglomeration of smaller pharmaceutical particles into larger microspherules and enteic-coating thereof
US3531418A (en) * 1965-08-18 1970-09-29 Ncr Co En masse encapsulation process
US3488418A (en) * 1965-11-18 1970-01-06 Sterling Drug Inc Sustained relief analgesic composition
US3524910A (en) * 1965-11-18 1970-08-18 Sterling Drug Inc Sustained relief analgesic compositions
DE1617374A1 (en) * 1965-11-18 1971-04-01 Sterling Drug Inc A method for producing a pharmaceutical preparation with delayed action
US3623997A (en) * 1966-06-06 1971-11-30 Ncr Co Wall-sealing treatment for minute capsules and minute capsules having walls of sealed polymeric material
DE2333756A1 (en) * 1972-07-05 1974-01-24 Ncr Co A method for continuously producing polymer capsules smaller
US4107072A (en) * 1973-05-25 1978-08-15 Merck & Co., Inc. Process of isolating cyclohexane-free ethylcellulose microcapsules
DE2834373A1 (en) * 1977-08-11 1979-02-22 Tanabe Seiyaku Co microcapsules containing process for the preparation of a pharmaceutical compound
US4218333A (en) * 1977-08-11 1980-08-19 Tanabe Seiyaku Co., Ltd. Process for the preparation of pharmaceutical substance-containing microcapsules
FR2447192A1 (en) * 1979-01-25 1980-08-22 Adria Lab Inc DOSAGE FORM a sustained release of indoprofen
US4316884A (en) * 1979-01-25 1982-02-23 Adria Laboratories, Inc. Sustained release pharmaceutical formulation
US4389331A (en) * 1979-10-31 1983-06-21 Tanabe Seiyaku Co., Ltd. Process for preparing pharmaceutically active compound-containing microcapsules
US4411933A (en) * 1980-04-25 1983-10-25 Tanabe Seiyaku Co., Ltd. Process for preparing ethylcellulose microcapsules
US4590170A (en) * 1980-07-09 1986-05-20 Fuji Photo Film Co., Ltd. Process for preparing microcapsule reagents for immunological response
US4551288A (en) * 1982-08-16 1985-11-05 Sandoz, Inc. Processes for the preparation of liposome drug delivery systems
US4507276A (en) * 1982-08-20 1985-03-26 Bristol-Myers Company Analgesic capsule
US4748023A (en) * 1983-01-26 1988-05-31 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of sustained release pharmaceutical compositions having a high active ingredient content
US4590063A (en) * 1983-06-24 1986-05-20 Adria Laboratories, Inc. Anticonvulsants
US4937076A (en) * 1984-08-10 1990-06-26 Combe Incorporated Chewable aspirin and buffering material tablet and method for producing same
US4867984A (en) * 1984-11-06 1989-09-19 Nagin K. Patel Drug in bead form and process for preparing same
US4822535A (en) * 1985-07-12 1989-04-18 Norsk Hydro A.S. Method for producing small, spherical polymer particles
US4693896A (en) * 1985-10-07 1987-09-15 Fmc Corporation Ethylcellulose-coated, gastric-disintegrable aspirin tablet
US4824616A (en) * 1987-06-05 1989-04-25 Toray Silicone Company, Ltd. Method for the production of spherical silicone gel particles
US4954412A (en) * 1988-10-31 1990-09-04 Xerox Corporation Processes for the preparation of encapsulated toner compositions
US4996047A (en) * 1988-11-02 1991-02-26 Richardson-Vicks, Inc. Sustained release drug-resin complexes
US5051305A (en) * 1988-12-30 1991-09-24 Arcade, Inc. Stabilized perfume-containing microcapsules and method of preparing the same
US5192552A (en) * 1988-12-30 1993-03-09 Egis Gyogyszergyar Process for preparing microcapsules providing the rapid release of a drug as active ingredient
US5026559A (en) * 1989-04-03 1991-06-25 Kinaform Technology, Inc. Sustained-release pharmaceutical preparation
US4983401A (en) * 1989-05-22 1991-01-08 Kinaform Technology, Inc. Sustained release pharmaceutical preparations having pH controlled membrane coatings
WO1992004031A1 (en) * 1990-09-04 1992-03-19 Edward Shanbrom Preservation of blood, tissues and biological fluids
US5252337A (en) * 1991-06-25 1993-10-12 Eurand America, Inc. Controlled release calcium channel blocker microcapsules
US5651984A (en) * 1992-08-04 1997-07-29 Eurand America, Incorporated Controlled release potassium tablet
US5376384A (en) * 1992-12-23 1994-12-27 Kinaform Technology, Inc. Delayed, sustained-release pharmaceutical preparation
US5478573A (en) * 1992-12-23 1995-12-26 Kinaform Technology, Inc. Delayed, sustained-release propranolol pharmaceutical preparation
US5529790A (en) * 1992-12-23 1996-06-25 Kinaform Technology, Inc. Delayed, sustained-release diltiazem pharmaceutical preparation
US5278194A (en) * 1993-03-25 1994-01-11 Microsome Environmentall dispersible syntactic foam
US6544646B2 (en) 2000-04-27 2003-04-08 Verion Inc. Zero order release and temperature-controlled microcapsules and process for the preparation thereof
US20050202085A1 (en) * 2000-07-08 2005-09-15 Lovercheck Dale R. Unit dose of material in system and method
US20090140207A1 (en) * 2001-11-20 2009-06-04 Encap Technologies, Inc. Microencapsulated particles and process for manufacturing same
US6833191B2 (en) 2001-11-20 2004-12-21 Encap Technologies, Llc Microencapsulated particles and process for manufacturing same
US20040130045A1 (en) * 2001-11-20 2004-07-08 Bayless Robert G. Microencapsulated particles and process for manufacturing same
US20050042452A1 (en) * 2001-11-20 2005-02-24 Encap Technologies, Inc. Microencapsulated particles and process for manufacturing same
US7297404B2 (en) 2001-11-20 2007-11-20 Encap Technologies, Llc Microencapsulated particles and process for manufacturing same
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US6899958B2 (en) 2002-06-21 2005-05-31 Encap Technologies, Llc. Moisture barrier resins
US20060210610A1 (en) * 2002-11-14 2006-09-21 Davidson Robert S Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use
US8999372B2 (en) 2002-11-14 2015-04-07 Cure Pharmaceutical Corporation Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use
US9155698B2 (en) 2003-03-28 2015-10-13 Cure Pharmaceutical Corporation Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films
US20080279937A2 (en) * 2003-07-15 2008-11-13 Eurand, Inc. Controlled release potassium chloride tablets
US7632521B2 (en) 2003-07-15 2009-12-15 Eurand, Inc. Controlled release potassium chloride tablets
US20050013860A1 (en) * 2003-07-15 2005-01-20 Gopi Venkatesh Controlled release potassium chloride tablets
US20050136096A1 (en) * 2003-08-22 2005-06-23 Davidson R. S. Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
US9561182B2 (en) 2003-08-22 2017-02-07 Cure Pharmaceutical Corporation Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
US7829121B2 (en) 2003-11-14 2010-11-09 Eurand Inc. Modified release dosage forms of skeletal muscle relaxants
US7820203B2 (en) 2003-11-14 2010-10-26 Eurand, Inc. Modified release dosage forms of skeletal muscle relaxants
US7790199B2 (en) 2003-11-14 2010-09-07 Eurand, Inc. Modified release dosage forms of skeletal muscle relaxants
US20090017126A1 (en) * 2003-11-14 2009-01-15 Gopi Venkatesh Modified Release Dosage Forms of Skeletal Muscle Relaxants
US8877245B2 (en) 2003-11-14 2014-11-04 Aptalis Pharmatech, Inc. Modified release dosage forms of skeletal muscle relaxants
US20090017127A1 (en) * 2003-11-14 2009-01-15 Gopi Venkatesh Modified Release Dosage Forms of Skeletal Muscle Relaxants
US20080124398A1 (en) * 2003-11-14 2008-05-29 Gopi Venkatesh Modified release dosage forms of skeletal muscle relaxants
US9375410B2 (en) 2003-11-14 2016-06-28 Adare Pharmaceuticals, Inc. Modified release dosage forms of skeletal muscle relaxants
US9399025B2 (en) 2003-11-14 2016-07-26 Adare Pharmaceuticals, Inc. Modified release dosage forms of skeletal muscle relaxants
US20100160428A1 (en) * 2005-11-09 2010-06-24 Protemix Corporation Limited Treatment of mitochondria-related diseases and improvement of age-related metabolic deficits
US9783574B2 (en) 2011-08-18 2017-10-10 Otago Innovation Limited Cardiovascular therapeutics

Also Published As

Publication number Publication date Type
DE1212497B (en) 1966-03-17 application
BE635698A (en) 1963-12-02 grant
GB965070A (en) 1964-07-29 application
NL295964A (en) 1965-05-10 application
FR1383778A (en) 1965-01-04 grant
DK116935B (en) 1970-03-02 grant
NL139668B (en) 1973-09-17 application

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