US3155590A - Encapsulation process and its product - Google Patents
Encapsulation process and its product Download PDFInfo
- Publication number
- US3155590A US3155590A US214183A US21418362A US3155590A US 3155590 A US3155590 A US 3155590A US 214183 A US214183 A US 214183A US 21418362 A US21418362 A US 21418362A US 3155590 A US3155590 A US 3155590A
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- United States
- Prior art keywords
- liquid
- vehicle
- solvent
- solution
- capsules
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 238000005538 encapsulation Methods 0.000 title claims description 11
- 238000000034 method Methods 0.000 title description 45
- 239000000463 material Substances 0.000 claims description 100
- 239000002775 capsule Substances 0.000 claims description 66
- 239000007788 liquid Substances 0.000 claims description 55
- 239000002904 solvent Substances 0.000 claims description 51
- 239000011162 core material Substances 0.000 claims description 33
- 239000002245 particle Substances 0.000 claims description 33
- 238000013019 agitation Methods 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 7
- 229920000642 polymer Polymers 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000012071 phase Substances 0.000 description 24
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 22
- 239000001856 Ethyl cellulose Substances 0.000 description 21
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 21
- 229960001138 acetylsalicylic acid Drugs 0.000 description 21
- 229920001249 ethyl cellulose Polymers 0.000 description 21
- 235000019325 ethyl cellulose Nutrition 0.000 description 21
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 18
- 229920005549 butyl rubber Polymers 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- -1 ethoxyl Chemical group 0.000 description 6
- 239000005062 Polybutadiene Substances 0.000 description 5
- 239000007771 core particle Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 238000005191 phase separation Methods 0.000 description 5
- 229920002857 polybutadiene Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000001879 gelation Methods 0.000 description 4
- 239000006193 liquid solution Substances 0.000 description 4
- 238000004064 recycling Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000009736 wetting Methods 0.000 description 3
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229920000896 Ethulose Polymers 0.000 description 2
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 2
- 241001441571 Hiodontidae Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000010924 continuous production Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- MANKSFVECICGLK-UHFFFAOYSA-K aloxiprin Chemical compound [OH-].[Al+3].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O MANKSFVECICGLK-UHFFFAOYSA-K 0.000 description 1
- 229940024544 aluminum aspirin Drugs 0.000 description 1
- JOSWYUNQBRPBDN-UHFFFAOYSA-P ammonium dichromate Chemical compound [NH4+].[NH4+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O JOSWYUNQBRPBDN-UHFFFAOYSA-P 0.000 description 1
- 229940008238 amphetamine sulfate Drugs 0.000 description 1
- PYHRZPFZZDCOPH-UHFFFAOYSA-N amphetamine sulfate Chemical compound OS(O)(=O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-UHFFFAOYSA-N 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 150000001934 cyclohexanes Chemical class 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ILHIHKRJJMKBEE-UHFFFAOYSA-N hydroperoxyethane Chemical compound CCOO ILHIHKRJJMKBEE-UHFFFAOYSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/5089—Processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/08—Simple coacervation, i.e. addition of highly hydrophilic material
-
- Y—GENERAL 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
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2984—Microcapsule with fluid core [includes liposome]
-
- Y—GENERAL 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
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2989—Microcapsule with solid core [includes liposome]
Definitions
- 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.
- 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.
- 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.
- 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.
- 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.:
- 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.
- 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.
- 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.
- 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.
- 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 vehicle can be used repeatedly, as it contains no hardening agents or irreversible reaction products.
- the time for processing each batch is determined only by dispersing requirements, heating time, and cooling time.
- 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.
- aspirin acetylsalicylic acid
- 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.
- the deposited solution walls of ethyl cellulose lose their solvent, shrinking to a rigid seamless protective wall about each aspirin particle.
- 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.
- 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.
- the polymeric wall material in desolvated condition is a dense, rigid material and not a reticulated network structure entrapping the solvent.
- 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.
- the vehicle 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 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,
- 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.
- 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.
- 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.
- 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 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.
- TS28R Solvent now supplied by Shell Oil Company as an aromatic solvent which contains approximately 75% aromatics
- A.P.I. gravity 34.4
- has a per-gallon Weight of 7.102 pounds has a boiling point range of 318 degrees Fahrenheit to 392 degrees Fahrenheit.
- This is used in the same amount
- 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 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 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 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.
- 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.
- 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
- polymeric wall material is ethyl cellulose of about 48.5% ethoxyl content.
- 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,
- a process for encapsulating minute acetylsalicylic acid particles individually in ethyl cellulose including the steps of (a) forming an agitated system of:
- 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;
- 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,
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US214183A US3155590A (en) | 1962-08-02 | 1962-08-02 | Encapsulation process and its product |
BR147244/63A BR6347244D0 (pt) | 1962-08-02 | 1963-02-28 | Processo de encapsulacao e seu produto |
GB21185/63A GB965070A (en) | 1962-08-02 | 1963-05-28 | Process for the manufacture of minute capsules and capsules obtained by such process |
NL295964D NL295964A (tr) | 1962-08-02 | 1963-07-30 | |
NL63295964A NL139668B (nl) | 1962-08-02 | 1963-07-30 | Werkwijze voor het maken van kleine capsules die acetylsalicylzuur bevatten. |
DEN23543A DE1212497B (de) | 1962-08-02 | 1963-07-31 | Verfahren zur Herstellung sehr kleiner Kapseln |
CH957563A CH417538A (fr) | 1962-08-02 | 1963-07-31 | Procédé d'obtention de capsules minuscules |
DK365563AA DK116935B (da) | 1962-08-02 | 1963-07-31 | Fremgangsmåde til fremstilling af små kapsler. |
BE635698D BE635698A (tr) | 1962-08-02 | 1963-08-01 | |
FR943408A FR1383778A (fr) | 1962-08-02 | 1963-08-01 | Procédé d'obtention de capsules minuscules et capsules obtenues par ce procédé |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US214183A US3155590A (en) | 1962-08-02 | 1962-08-02 | Encapsulation process and its product |
Publications (1)
Publication Number | Publication Date |
---|---|
US3155590A true US3155590A (en) | 1964-11-03 |
Family
ID=22798091
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US214183A Expired - Lifetime US3155590A (en) | 1962-08-02 | 1962-08-02 | Encapsulation process and its product |
Country Status (9)
Country | Link |
---|---|
US (1) | US3155590A (tr) |
BE (1) | BE635698A (tr) |
BR (1) | BR6347244D0 (tr) |
CH (1) | CH417538A (tr) |
DE (1) | DE1212497B (tr) |
DK (1) | DK116935B (tr) |
FR (1) | FR1383778A (tr) |
GB (1) | GB965070A (tr) |
NL (2) | NL139668B (tr) |
Cited By (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 (de) * | 1972-07-05 | 1974-01-24 | Ncr Co | Verfahren zum kontinuierlichen herstellen kleiner polymerkapseln |
US4107072A (en) * | 1973-05-25 | 1978-08-15 | Merck & Co., Inc. | Process of isolating cyclohexane-free ethylcellulose microcapsules |
DE2834373A1 (de) * | 1977-08-11 | 1979-02-22 | Tanabe Seiyaku Co | Verfahren zur herstellung von eine pharmazeutische verbindung enthaltenden mikrokapseln |
FR2447192A1 (fr) * | 1979-01-25 | 1980-08-22 | Adria Lab Inc | Forme galenique a liberation prolongee d'indoprofene |
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 |
US4590170A (en) * | 1980-07-09 | 1986-05-20 | Fuji Photo Film Co., Ltd. | Process for preparing microcapsule reagents for immunological response |
US4590063A (en) * | 1983-06-24 | 1986-05-20 | Adria Laboratories, Inc. | Anticonvulsants |
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 |
WO2013024362A2 (en) | 2011-08-18 | 2013-02-21 | Otago Innovation Limited | Cardiovascular therapeutics |
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 |
US10398644B2 (en) | 2002-11-14 | 2019-09-03 | 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 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3635141C1 (de) * | 1986-10-15 | 1988-03-03 | Pelikan Ag | Thermocarbonband mit einer kunststoffgebundenen Aufschmelzfarbe sowie ein Verfahren zur Herstellung dieses Bandes |
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US2843583A (en) * | 1955-03-03 | 1958-07-15 | Hercules Powder Co Ltd | Preparation of finely-divided cellulose derivative compositions |
US2980941A (en) * | 1958-12-08 | 1961-04-25 | Ncr Co | Cleaning sheet |
US3041289A (en) * | 1959-01-02 | 1962-06-26 | Ncr Co | Method of making walled clusters of capsules |
US3069370A (en) * | 1958-12-22 | 1962-12-18 | Upjohn Co | Coacervation process for encapsulation of lipophilic materials |
-
1962
- 1962-08-02 US US214183A patent/US3155590A/en not_active Expired - Lifetime
-
1963
- 1963-02-28 BR BR147244/63A patent/BR6347244D0/pt unknown
- 1963-05-28 GB GB21185/63A patent/GB965070A/en not_active Expired
- 1963-07-30 NL NL63295964A patent/NL139668B/xx not_active IP Right Cessation
- 1963-07-30 NL NL295964D patent/NL295964A/xx unknown
- 1963-07-31 DE DEN23543A patent/DE1212497B/de active Pending
- 1963-07-31 DK DK365563AA patent/DK116935B/da unknown
- 1963-07-31 CH CH957563A patent/CH417538A/fr unknown
- 1963-08-01 BE BE635698D patent/BE635698A/xx unknown
- 1963-08-01 FR FR943408A patent/FR1383778A/fr not_active Expired
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2843583A (en) * | 1955-03-03 | 1958-07-15 | Hercules Powder Co Ltd | Preparation of finely-divided cellulose derivative compositions |
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 (72)
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 (de) * | 1965-11-18 | 1971-04-01 | Sterling Drug Inc | Verfahren zum Herstellen eines pharmazeutischen Praeparates mit verzoegerter Wirkung |
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 (de) * | 1972-07-05 | 1974-01-24 | Ncr Co | Verfahren zum kontinuierlichen herstellen kleiner polymerkapseln |
US4107072A (en) * | 1973-05-25 | 1978-08-15 | Merck & Co., Inc. | Process of isolating cyclohexane-free ethylcellulose microcapsules |
DE2834373A1 (de) * | 1977-08-11 | 1979-02-22 | Tanabe Seiyaku Co | Verfahren zur herstellung von eine pharmazeutische verbindung enthaltenden mikrokapseln |
US4218333A (en) * | 1977-08-11 | 1980-08-19 | Tanabe Seiyaku Co., Ltd. | Process for the preparation of pharmaceutical substance-containing microcapsules |
FR2447192A1 (fr) * | 1979-01-25 | 1980-08-22 | Adria Lab Inc | Forme galenique a liberation prolongee d'indoprofene |
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 |
US5478573A (en) * | 1992-12-23 | 1995-12-26 | Kinaform Technology, Inc. | Delayed, sustained-release propranolol pharmaceutical preparation |
US5376384A (en) * | 1992-12-23 | 1994-12-27 | Kinaform Technology, Inc. | Delayed, sustained-release pharmaceutical preparation |
AU665733B2 (en) * | 1992-12-23 | 1996-01-11 | Kinaform Technology, Inc. | Delayed, sustained-release 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 |
US20040130045A1 (en) * | 2001-11-20 | 2004-07-08 | Bayless Robert G. | 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 |
US20050042452A1 (en) * | 2001-11-20 | 2005-02-24 | Encap Technologies, Inc. | Microencapsulated particles and process for manufacturing same |
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US7297404B2 (en) | 2001-11-20 | 2007-11-20 | Encap Technologies, Llc | Microencapsulated particles and process for manufacturing same |
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US8003211B2 (en) | 2001-11-20 | 2011-08-23 | Encap Technologies, Llc | Microencapsulated particles and process for manufacturing same |
US6899958B2 (en) | 2002-06-21 | 2005-05-31 | Encap Technologies, Llc. | Moisture barrier resins |
US10398644B2 (en) | 2002-11-14 | 2019-09-03 | 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 |
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 |
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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 |
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US20090017127A1 (en) * | 2003-11-14 | 2009-01-15 | Gopi Venkatesh | Modified Release Dosage Forms of Skeletal Muscle Relaxants |
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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 |
US7790199B2 (en) | 2003-11-14 | 2010-09-07 | Eurand, 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 |
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Also Published As
Publication number | Publication date |
---|---|
DE1212497B (de) | 1966-03-17 |
BE635698A (tr) | 1963-12-02 |
NL139668B (nl) | 1973-09-17 |
FR1383778A (fr) | 1965-01-04 |
GB965070A (en) | 1964-07-29 |
NL295964A (tr) | 1965-05-10 |
CH417538A (fr) | 1966-07-31 |
BR6347244D0 (pt) | 1973-05-29 |
DK116935B (da) | 1970-03-02 |
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