US5827531A
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US
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Microcapsules and methods for making
Assignee: National Aeronautics and Space Administration
•
Filing: 1994-12-02
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Granted: 1998-10-27
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Expires: 2014-12-02
Abstract
Abstract Methods of forming multi-lamellar microcapsules having alternating layers of hydrophilic and hydrophobic immiscible liquid phases have been developed using different polymer/solvent systems. The methods use liquid-liquid diffusion and simultaneous lateral phase separation, controlled by proper timed-sequence exposures of immiscible phases and low shear mixing, to form narrow size distributions of spherical, multilamellar microcapsules. The use of special formulations of solubilized drugs, surfactants, and polymeric co-surfactants in aqueous vehicles which are dispersed in hydrocarbon solvents containing small quantities of oil, low molecular weight co-surfactants and glycerides that are aqueous insoluble enables the formation of unique microcapsules which can carry large amounts of pharmaceuticals in both aqueous and non-aqueous solvent compartments. The liquid microcapsules are quickly formed in a single step and can include a polymeric outer "skin" which protects the microcapsules during physical manipulation or exposure to high shear forces. Water-in-oil and oil-in-water microcapsules have been formed both in 1xg and in microgravity, which contain several types of drugs co-encapsulated within different fluid compartments inside the same microcapsule. Large, spherical multi-lamellar microcapsules have been formed including a cytotoxic drug co-encapsulated with a radiocontrast medium which has advantages for chemoembolization of vascular tumors. In certain cases, crystals of the drug form inside the microcapsules providing zero-order and first order, sustained drug release kinetics.
Inventors
- 👤 Dennis R. Morrison
- 👤 Benjamin Mosier
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 22:35
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/48; A61K9/50; A61K9/5089; A61K41/00; A61K41/0028; A61K9/10; A61K9/127; A61K9/1277; A61K9/5073; B; B01; B01J; B01J13/00; B01J13/02; B01J13/06; B01F; B01F33/00; B01F33/30; Y; Y10; Y10T; Y10T428/00; Y10T428/29; Y10T428/2982; Y10T428/2984; Y10T428/2985; Y10T428/2989
Claims Analysis
Total Claims: 88
Claim 1
Independent Claim
146 words
A method of making a multi-layered microcapsule, comprising: formulating a first phase comprising a first solvent, a first microcapsule layer-forming compound soluble in said first phase and immiscible in a second phase, a co-solvent, oil, and water; formulating said second phase immiscible with said first phase, said second phase comprising a second solvent, a second microcapsule layer-forming compound soluble in said second phase and immiscible in said first phase, a surface active agent, and a salt; said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent; creating an interface between said first and second phases in a manner that limits fluid shear equal to or less than about 12 dynes/cm 2 , and maintains adsorptive surface characteristics at said interface.
Claim 2
Independent Claim
146 words
A method of making a multi-layered microcapsule, comprising: formulating a first phase comprising a first solvent, a first microcapsule layer-forming compound soluble in said first phase and immiscible in a second phase, a co-solvent, oil, and water; formulating said second phase immiscible with said first phase, said second phase comprising a second solvent, a second microcapsule layer-forming compound soluble in said second phase and immiscible in said first phase, a surface active agent, and a salt; said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent; creating an interface between said first and second phases in a manner that limits fluid shear equal to or less than about 12 dynes/cm 2 , and maintains adsorptive surface characteristics at said interface.
Claim 3
Dependent Claim
11 words
The method of claim 1 wherein said first solvent is organic.
Claim 4
Dependent Claim
26 words
The method of claim 2 wherein said organic solvent is selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol, and isopropyl alcohol.
Claim 5
Dependent Claim
39 words
The method of claim 1 wherein said first microcapsule layer-forming compound is selected from the group consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, polyvinyl pyrrolidone, polyvinyl alcohols, hydrocolloids, and lecithins.
Claim 6
Dependent Claim
11 words
The method of claim 1 wherein said first solvent is aqueous.
Claim 7
Dependent Claim
35 words
The method of claim 4 wherein said hydrocolloid is selected from the group of hydrocolloids consisting of gelatin, gum tragacanth, carrageenan, Karaya gum, Guar gum, gum arabic, alginates, carboxymethyl cellulose, hydroxypropyl cellulose, and carboxypropyl cellulose.
Claim 8
Dependent Claim
37 words
The method of claim 1, said first phase further comprising a co-solvent, wherein said co-solvent is selected from the group of co-solvents consisting of C 3 -C 8 alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide.
Claim 9
Dependent Claim
51 words
The method of claim 1 wherein said oil is selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, C 20 -C 38 paraffinic oil, and liquid petrolatum.
Claim 10
Dependent Claim
16 words
The method of claim 1 wherein said oil is an unsaturated oil which has been halogenated.
Claim 11
Dependent Claim
24 words
The method of claim 1 wherein said second microcapsule layer-forming compound is selected from the group consisting of polyethyleneglycol, polyvinylpyrrolidone, polyvinyl alcohols, and hydrocolloids.
Claim 12
Dependent Claim
20 words
The method of claim 1 wherein said surface active agent has a hydrophilic/lipophilic balance value of about 10.0 or greater.
Claim 13
Dependent Claim
45 words
The method of claim 11 wherein said surface active agent is selected from the group of surface active agents consisting of sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C 12 -C 20 fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol amphoteric salts, and quaternary ammonium salts.
Claim 14
Dependent Claim
36 words
The method of claim 1 wherein said salt is selected from the group of salts consisting of NaCl, KCl, CaCl 2 , MgCl 2 , quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt.
Claim 15
Dependent Claim
14 words
The method of claim 1 wherein said first phase further comprises a pharmaceutical composition.
Claim 16
Dependent Claim
30 words
The method of claim 14 wherein said pharmaceutical composition is selected from the group of pharmaceutical compositions consisting of cytotoxins, proteases, cytokines, anti-nauseants, steroids, anti-fungal agents, fibrinolytic enzymes, and antibiotics.
Claim 17
Dependent Claim
12 words
The method of claim 14 wherein said pharmaceutical composition is in suspension.
Claim 18
Dependent Claim
14 words
The method of claim 1 wherein said second phase further comprises a pharmaceutical composition.
Claim 19
Dependent Claim
30 words
The method of claim 17 wherein said pharmaceutical composition is selected from the group of pharmaceutical compositions consisting of cytotoxins, proteases, cytokines, anti-nauseants, steroids, anti-fungal agents, fibrinolytic enzymes, and antibiotics.
Claim 20
Dependent Claim
12 words
The method of claim 17 wherein said pharmaceutical composition is in suspension.
Claim 21
Dependent Claim
21 words
The method of claim 14 wherein said pharmaceutical is at a concentration sufficient to allow nascent crystal formation within said microcapsule.
Claim 22
Dependent Claim
35 words
The method of claim 1, wherein after said microcapsule forms, taking additional steps comprising: formulating a third phase comprising an oil or C 20 -C 38 paraffin; and, contacting said microcapsule with said third phase.
Claim 23
Dependent Claim
13 words
The method of claim 21, wherein said third phase further comprises a polymer.
Claim 24
Dependent Claim
14 words
The method of claim 21, wherein said third phase further comprises a pharmaceutical composition.
Claim 25
Dependent Claim
30 words
The method of claim 1, wherein after said microcapsule forms, taking additional steps comprising: formulating a third phase comprising an aqueous solution; and, contacting said microcapsule with said third phase.
Claim 26
Dependent Claim
14 words
The method of claim 24, wherein said third phase further comprises a pharmaceutical composition.
Claim 27
Dependent Claim
13 words
The method of claim 24, wherein said third phase further comprises an adjuvant.
Claim 28
Dependent Claim
14 words
The method of claim 24, wherein said third phase further comprises an activator agent.
Claim 29
Dependent Claim
17 words
The method of claim 26, wherein said adjuvant further comprises an immunoglobulin, peptide, protein, hydrocolloid or polysaccharide.
Claim 30
Dependent Claim
42 words
The method of claim 28, wherein said hydrocolloid is selected from the group of such hydrocolloids consisting of collagen, isoelectric gelatin, agar, gum arabic, gum tragacanth, carboxymethylcellulose (CMS), carboxymethyl/ethyl cellulose (CMEC), hydroxyethylcellulose (HEC), hydroxymethyl/ethyl cellulose (HMEC), hydroxypropyl cellulose (HPC), alginates and carrageenans.
Claim 31
Dependent Claim
28 words
The method of claim 24, wherein said third phase further comprises a surface active agent compatible with the hydrophilic/lipophilic balance value of an outer coating of said microcapsule.
Claim 32
Dependent Claim
32 words
The method of claim 1 wherein one or more of said phases further comprise fluorescent molecules selected from the group of fluorescent molecules consisting of fluoresceins, cyanins, naturally fluorescent molecules, and rhodamines.
Claim 33
Dependent Claim
18 words
The method of claim 1 wherein said adsorptive surface characteristics comprise a Helmholtz charge distribution at said interface.
Claim 34
Dependent Claim
45 words
The method of claim 1 wherein said maintenance of adsorptive surface characteristics is promoted by carrying out the method under microgravity of less than or about equal to 1×10 -2 g and with fluid shear of no more than between about 2-12 dynes/cm 2 .
Claim 35
Dependent Claim
15 words
The method of claim 33 wherein said microgravity is at least 1.0 minute in duration.
Claim 36
Dependent Claim
22 words
The method of claim 1 wherein said maintenance of adsorptive surface characteristics is promoted by carrying out the method below ambient temperature.
Claim 37
Dependent Claim
23 words
The method of claim 1 wherein said maintenance of adsorptive surface characteristics is promoted by substantially balancing the specific gravity between said phases.
Claim 38
Independent Claim
301 words
A method of making a multi-layered microcapsule, comprising: formulating a first phase comprising an organic solvent selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol and isopropyl alcohol, a first microcapsule layer-forming compound soluble in said first phase selected from the group of polymers consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, and lecithins, a co-solvent selected from the group of co-solvents consisting of C 3 -C 8 alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, an oil selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, C 20 -C 28 paraffinic oil, liquid petrolatum, and water; formulating a second phase immiscible with said first phase, said second phase comprising water, a second microcapsule layer-forming compound soluble in said second phase selected from the group consisting of polyethyleneglycol, dextran, polyvinylpyrrolidone, polyvinyl alcohols, hydrocolloids, and lecithins, a surface active agent selected from the group consisting of sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C 12 -C 20 fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol, quaternary ammonium salts, and a salt selected from the group of salts consisting of NaCl, KCl, CaCl 2 , MgCl 2 , quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt; said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent; creating an interface between said first and second phases in a manner that limits fluid shear to less than about 12 dynes/cm 2 , and maintains adsorptive surface characteristics at said interface.
Claim 39
Independent Claim
301 words
A method of making a multi-layered microcapsule, comprising: formulating a first phase comprising an organic solvent selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol and isopropyl alcohol, a first microcapsule layer-forming compound soluble in said first phase selected from the group of polymers consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, and lecithins, a co-solvent selected from the group of co-solvents consisting of C 3 -C 8 alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, an oil selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, C 20 -C 28 paraffinic oil, liquid petrolatum, and water; formulating a second phase immiscible with said first phase, said second phase comprising water, a second microcapsule layer-forming compound soluble in said second phase selected from the group consisting of polyethyleneglycol, dextran, polyvinylpyrrolidone, polyvinyl alcohols, hydrocolloids, and lecithins, a surface active agent selected from the group consisting of sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C 12 -C 20 fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol, quaternary ammonium salts, and a salt selected from the group of salts consisting of NaCl, KCl, CaCl 2 , MgCl 2 , quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt; said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent; creating an interface between said first and second phases in a manner that limits fluid shear to less than about 12 dynes/cm 2 , and maintains adsorptive surface characteristics at said interface.
Claim 40
Dependent Claim
11 words
Microcapsules produced by any of the methods of the preceding claims.
Claim 41
Dependent Claim
15 words
The microcapsules of claim 38 wherein said microcapsules are of a uniform distribution of diameters.
Claim 42
Dependent Claim
19 words
The microcapsules of claim 39 wherein said diameter distribution is in a range of about 1.0 to 350.0 microns.
Claim 43
Dependent Claim
16 words
The microcapsule of claim 38 further comprising at least one nascent crystal of a pharmaceutical composition.
Claim 44
Dependent Claim
20 words
The microcapsules of claim 41 wherein said crystal occupies at least about 10 percent of the volume of said microcapsule.
Claim 45
Dependent Claim
9 words
A microcapsule produced by the method of claim 37.
Claim 46
Dependent Claim
107 words
A multi-layered microcapsule, comprising: a first layer comprising a first solvent, a first microcapsule layer-forming compound soluble in said first layer and immiscible with a second layer, a co-solvent, oil, and water; said second layer immiscible with said first layer, said second layer comprising a second solvent, a second microcapsule layer-forming compound soluble in said second layer and immiscible with said first layer, a surface active agent, and a salt; said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; and, said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent.
Claim 47
Dependent Claim
107 words
A multi-layered microcapsule, comprising: a first layer comprising a first solvent, a first microcapsule layer-forming compound soluble in said first layer and immiscible with a second layer, a co-solvent, oil, and water; said second layer immiscible with said first layer, said second layer comprising a second solvent, a second microcapsule layer-forming compound soluble in said second layer and immiscible with said first layer, a surface active agent, and a salt; said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; and, said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent.
Claim 48
Dependent Claim
11 words
The microcapsule of claim 44 wherein said first solvent is organic.
Claim 49
Dependent Claim
26 words
The microcapsule of claim 45 wherein said organic solvent is selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol and isopropyl alcohol.
Claim 50
Dependent Claim
34 words
The microcapsule of claim 45 wherein said first microcapsule layer-forming compound is selected from the group consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, and lecithins.
Claim 51
Dependent Claim
11 words
The microcapsule of claim 44 wherein said first solvent is aqueous.
Claim 52
Dependent Claim
29 words
The microcapsule of claim 48 wherein said first microcapsule layer-forming compound is selected from the group of microcapsule layerforming compounds consisting of polyvinyl pyrrolidone, polyvinyl alcohols, hydrocolloids, and lecithins.
Claim 53
Dependent Claim
35 words
The microcapsule of claim 49 wherein said hydrocolloid is selected from the group of hydrocolloids consisting of gelatin, gum tragacanth, carrageenan, Karaya gum, Guar gum, gum arabic, alginates, carboxymethyl cellulose, hydroxypropyl cellulose, and carboxypropyl cellulose.
Claim 54
Dependent Claim
37 words
The microcapsule of claim 44, said first layer further comprising a co-solvent, wherein said co-solvent is selected from the group of co-solvents consisting of C 3 -C 8 alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide.
Claim 55
Dependent Claim
51 words
The microcapsule of claim 44 wherein said oil is selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, C 20 -C 38 paraffinic oil, and liquid petrolatum.
Claim 56
Dependent Claim
16 words
The microcapsule of claim 44 wherein said oil is an unsaturated oil which has been halogenated.
Claim 57
Dependent Claim
42 words
The microcapsule of claim 44 wherein said second microcapsule layer-forming compound is selected from the group consisting of polyethyleneglycol, dextran, polyvinylpyrrolidone, polyvinyl alcohols, gelatin, gum tragacanth, carrageenan, Karaya gum, Guar gum, gum arabic, alginates, carboxymethyl cellulose, hydroxypropyl cellulose, carboxypropyl cellulose, and lecithins.
Claim 58
Dependent Claim
20 words
The microcapsule of claim 44 wherein said surface active agent has a hydrophilic/lipophilic balance value of about 10.0 or greater.
Claim 59
Dependent Claim
46 words
The microcapsule of claim 55 wherein said surface active agent is selected from the group of nonionic surface active agents consisting of sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C 12 -C 20 fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol, amphoteric salts, and quaternary ammonium salts.
Claim 60
Dependent Claim
36 words
The microcapsule of claim 44 wherein said salt is selected from the group of salts consisting of NaCl, KCl, CaCl 2 , MgCl 2 , quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt.
Claim 61
Dependent Claim
14 words
The microcapsule of claim 44 wherein said first layer further comprises a pharmaceutical composition.
Claim 62
Dependent Claim
30 words
The microcapsule of claim 58 wherein said pharmaceutical composition is selected from the group of pharmaceutical compositions consisting of cytotoxins, proteases, cytokines, anti-nauseants, steroids, anti-fungal agents, fibrinolytic enzymes, and antibiotics.
Claim 63
Dependent Claim
12 words
The microcapsule of claim 58 wherein said pharmaceutical composition is in suspension.
Claim 64
Dependent Claim
14 words
The microcapsule of claim 44 wherein said second layer further comprises a pharmaceutical composition.
Claim 65
Dependent Claim
30 words
The microcapsule of claim 61 wherein said pharmaceutical composition is selected from the group of pharmaceutical compositions consisting of cytotoxins, proteases, cytokines, anti-nauseants, steroids, anti-fungal agents, fibrinolytic enzymes, and antibiotics.
Claim 66
Dependent Claim
12 words
The microcapsule of claim 61 wherein said pharmaceutical composition is in suspension.
Claim 67
Dependent Claim
23 words
The microcapsule of claim 58 or 61 wherein said pharmaceutical is at a concentration sufficient to allow nascent crystal formation within said microcapsule.
Claim 68
Dependent Claim
17 words
The microcapsule of claim 44 comprising a third layer, said third layer comprising an oil or paraffin.
Claim 69
Dependent Claim
14 words
The microcapsule of claim 65, wherein said third layer further comprises a pharmaceutical composition.
Claim 70
Dependent Claim
15 words
The microcapsule of claim 65, wherein said third layer further comprises a surface active agent.
Claim 71
Dependent Claim
16 words
The microcapsule of claim 44 comprising a third layer, said third layer comprising an aqueous solution.
Claim 72
Dependent Claim
14 words
The microcapsule of claim 68, wherein said third layer further comprises a pharmaceutical composition.
Claim 73
Dependent Claim
13 words
The microcapsule of claim 68, wherein said third layer further comprises an adjuvant.
Claim 74
Dependent Claim
17 words
The microcapsule of claim 70, wherein said adjuvant further comprises an immunoglobulin, peptide, protein, hydrocolloid or polysaccharide.
Claim 75
Dependent Claim
20 words
The microcapsule of claim 71, wherein said peptide or said protein selectively adheres to a target cell, tissue or tumor.
Claim 76
Dependent Claim
41 words
The microcapsule of claim 71, wherein said hydrocolloid is selected from the group of such hydrocolloids consisting of collagen, isoelectric gelatin, agar, gum arabic, gum tragacanth, carboxymethylcellulose (CMS), carboxymethyl/ethyl cellulose (CMEC), hydroxyethylcellulose (HEC), hydroxymethyl/ethyl cellulose (HMEC), hydroxypropyl cellulose (HPC), and carrageenans.
Claim 77
Dependent Claim
15 words
The microcapsule of claim 68, wherein said third layer further comprises a surface active agent.
Claim 78
Dependent Claim
32 words
The microcapsule of claim 44 wherein one or more of said layers further comprise fluorescent molecules selected from the group of fluorescent molecules consisting of fluoresceins, cyanins, naturally fluorescent molecules, and rhodamines.
Claim 79
Dependent Claim
8 words
The microcapsule of claim 44 formed under microgravity.
Claim 80
Dependent Claim
15 words
The microcapsule of claim 76 wherein said microgravity is at least 1.0 minutes in duration.
Claim 81
Dependent Claim
9 words
The microcapsule of claim 44 formed below ambient temperature.
Claim 82
Dependent Claim
19 words
The microcapsule of claim 44 comprising layers at least initially substantially balanced as to specific gravity between said layers.
Claim 83
Dependent Claim
275 words
A multi-layered microcapsule, comprising: a first layer comprising an organic solvent selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol and isopropyl alcohol, a first microcapsule layer-forming compound soluble in said first phase selected from the group consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, and lecithins, a co-solvent selected from the group of co-solvents consisting of C 3 -C 8 alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, oil selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, a C 20 -C 38 paraffinic oil, liquid petrolatum, and water; a second layer immiscible with said first layer, said second layer comprising water, a second microcapsule layer-forming compound soluble in said second phase selected from the group consisting of polyethyleneglycol, dextran polyvinylpyrrolidone, polyvinyl alcohols, gelatin, gum tragacanth, carrageenan, Karaya gum, Guar gum, gum arabic, alginates, carboxymethyl cellulose, hydroxypropyl cellulose, carboxypropyl cellulose, and lecithins, a surface active agent sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C 12 -C 20 fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol, amphoteric salts, and quaternary ammonium salts, and a salt selected from the group of salts consisting of NaCl, KCl, CaCl 2 , MgCl 2 , quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt; said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; and, said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent.
Claim 84
Dependent Claim
275 words
A multi-layered microcapsule, comprising: a first layer comprising an organic solvent selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol and isopropyl alcohol, a first microcapsule layer-forming compound soluble in said first phase selected from the group consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, and lecithins, a co-solvent selected from the group of co-solvents consisting of C 3 -C 8 alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, oil selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, a C 20 -C 38 paraffinic oil, liquid petrolatum, and water; a second layer immiscible with said first layer, said second layer comprising water, a second microcapsule layer-forming compound soluble in said second phase selected from the group consisting of polyethyleneglycol, dextran polyvinylpyrrolidone, polyvinyl alcohols, gelatin, gum tragacanth, carrageenan, Karaya gum, Guar gum, gum arabic, alginates, carboxymethyl cellulose, hydroxypropyl cellulose, carboxypropyl cellulose, and lecithins, a surface active agent sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C 12 -C 20 fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol, amphoteric salts, and quaternary ammonium salts, and a salt selected from the group of salts consisting of NaCl, KCl, CaCl 2 , MgCl 2 , quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt; said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; and, said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent.
Claim 85
Dependent Claim
27 words
The microcapsule of claim 58 further comprising at least two different pharmaceuticals, a first pharmaceutical in said first phase and a second pharmaceutical in said second phase.
Claim 86
Dependent Claim
11 words
The microcapsule of claim 44 further comprising a radiopaque contrast agent.
Claim 87
Dependent Claim
12 words
The microcapsule of claim 44 further comprising a magnetic resonance contrast agent.
Claim 88
Dependent Claim
28 words
The microcapsule of claim 83 wherein said contrast agent is selected from the group of metallo-organic compounds consisting of ferrous gluconate, Gadolinium diethylenetriamine pentaacetic acid, and iron pentacarbonyl.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 2001-10-26 | 2002-04-27 | 2002-10-27 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2005-10-26 | 2006-04-27 | 2006-10-27 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2009-10-26 | 2010-04-27 | 2010-10-27 | $7700.00 | Window Closed / Lapsed |