US5230884A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Aerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations
Assignee: WALES COLLEGE OF CARDIFF
•
Filing: 1992-02-11
•
Granted: 1993-07-27
•
Expires: 2012-02-11
Abstract
Abstract Highly purified and recombinantly produced polypeptides and proteins can be provided to a patient to treat systemic disorders using a metered dose inhaler (MDI). The polypeptides and proteins are solubilized in reverse micelles formed from the surfactant in the MDI propellant. By controlling the molar ratio of water to surfactant, the amount of polypeptide or protein solubilized in the reverse micelles can be controlled, thereby providing an accurate dosing mechanism. In addition, controlling the molar ratio of water to surfactant also can adjust the size and shape of the reverse micelles which will affect the degree and rate of penetration of the lung mucosa for delivery of the drugs to the patient's blood stream. Proteins which may particularly benefit from the solubilization and systemic delivery process include calcitonin, oxytocin, and insulin.
Inventors
- 👤 Richard M. Evans
- 👤 Stephen J. Farr
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-31 15:41
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/0012; A61K9/007; A61K9/0073; A61K9/008; A61K38/00; A61K38/16; A61K38/17; A61K38/22; A61K38/28; A61K9/10; A61K9/107; A61K9/1075
Claims Analysis
Total Claims: 41
Claim 1
Independent Claim
96 words
An aerosol formulation for delivery of insulin to a patient's lungs, comprising: at least ninety percent by weight of a propellant; less than ten percent by weight of insulin; up to 5% weight in volume of a surfactant; and an amount of water associated with said surfactant which results in a molar ratio of aqueous fluid to surfactant ranging from approximately 1:1 to 20:1, said surfactant being present as reverse micelles dispersed in said propellant, said aqueous fluid associated with said surfactant having a pH less than 5.5, said insulin being solubilized in said reverse micelles.
Claim 2
Dependent Claim
96 words
An aerosol formulation for delivery of insulin to a patient's lungs, comprising: at least ninety percent by weight of a propellant; less than ten percent by weight of insulin; up to 5% weight in volume of a surfactant; and an amount of water associated with said surfactant which results in a molar ratio of aqueous fluid to surfactant ranging from approximately 1:1 to 20:1, said surfactant being present as reverse micelles dispersed in said propellant, said aqueous fluid associated with said surfactant having a pH less than 5.5, said insulin being solubilized in said reverse micelles.
Claim 3
Dependent Claim
21 words
An aerosol formulation as recited in claim 1 wherein said water associated with said surfactant has a pH of approximately 4.
Claim 4
Dependent Claim
16 words
An aerosol formulation as recited in claim 1 wherein said reverse micelles have an oblate shape.
Claim 5
Dependent Claim
16 words
An aerosol formulation as recited in claim 1 wherein said reverse micelles have a prolate shape.
Claim 6
Dependent Claim
16 words
An aerosol formulation as recited in claim 1 wherein said reverse micelles have a spherical shape.
Claim 7
Dependent Claim
38 words
An aerosol formulation as recited in claim 1 wherein said surfactant is selected rom the group consisting of phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine, diphosphatidyl glycerol, sorbitan mono- and tri-oleats, diolein, oleic acid, and phosphatidic acid.
Claim 8
Dependent Claim
18 words
An aerosol formulation as recited in claim 1 wherein surfactant is a combination of two or more compounds.
Claim 9
Dependent Claim
34 words
An aerosol formulation as recited in claim 1 wherein said propellant includes a gas selected from the group consisting of n-butane, isobutane, perfluoropentane, trichlorofluoroethane, dichlorotetrafluoroethane, dichlorofluoroethane, dichlorodifluoromethane, 1,1,1,2-tetrafluoroethane, propane, dimethyl ether, perfluoropropane, and heptafluoropropane.
Claim 10
Independent Claim
126 words
A method of preparing an aerosol formulation for delivery of peptides and proteins to a patient's lungs, comprising the steps of: drying a surfactant from which reverse micelles can be formed; and mixing said surfactant with a peptide or protein, an amount of water, and a propellant to form reverse micelles of said surfactant in said propellant which incorporate said peptide or protein, said surfactant being present in an amount less than five percent weight in volume, said peptide or protein being present in an amount less than ten percent by weight, said propellant being present in an amount of at least ninety percent by weight, and said amount of water resulting in a molar ratio of water to surfactant ranging from approximately 1:1 to 20:1.
Claim 11
Independent Claim
126 words
A method of preparing an aerosol formulation for delivery of peptides and proteins to a patient's lungs, comprising the steps of: drying a surfactant from which reverse micelles can be formed; and mixing said surfactant with a peptide or protein, an amount of water, and a propellant to form reverse micelles of said surfactant in said propellant which incorporate said peptide or protein, said surfactant being present in an amount less than five percent weight in volume, said peptide or protein being present in an amount less than ten percent by weight, said propellant being present in an amount of at least ninety percent by weight, and said amount of water resulting in a molar ratio of water to surfactant ranging from approximately 1:1 to 20:1.
Claim 12
Dependent Claim
31 words
A method as recited in claim 9 wherein said amount of water used in said mixing step results in a molar ratio of water to surfactant ranging from 0.9:1 to 5.6:1.
Claim 13
Dependent Claim
24 words
A method as recited in claim 9 wherein said surfactant is present in an amount ranging between 0.5 and 2.5 percent weight in volume.
Claim 14
Dependent Claim
33 words
A method as recited in claim 9 wherein said drying step reduces an amount of associated water from said surfactant to yield a molar ratio of water to surfactant of 0.5:1 to 1:1.
Claim 15
Dependent Claim
24 words
A method as recited in claim 9 wherein said amount of water in said mixing step results in reverse micelles of an oblate shape.
Claim 16
Dependent Claim
24 words
A method as recited in claim 9 wherein said amount of water in said mixing step results in reverse micelles of a spherical shape.
Claim 17
Dependent Claim
24 words
A method as recited in claim 9 wherein said amount of water in said mixing step results in reverse micelles of a prolate shape.
Claim 18
Dependent Claim
20 words
A method as recited in claim 9 further comprising the step of adjusting the pH of said amount of water.
Claim 19
Independent Claim
114 words
A method of preparing an aerosol formulation for delivery of peptides and proteins to a patient's lungs, comprising the steps of: drying a surfactant from which reverse micelles can be formed; and mixing said surfactant with a peptide or protein, an amount of water, and a propellant to form reverse micelles of said surfactant in said propellant which incorporate said peptide or protein, said surfactant being present in an amount less than five percent weight in volume, said peptide or protein having a concentration in said propellant ranging from 0.025 mg/ml to 4.0 mg/ml, and said amount of water resulting in a molar ratio of water to surfactant ranging from approximately 1:1 to 20:1.
Claim 20
Independent Claim
114 words
A method of preparing an aerosol formulation for delivery of peptides and proteins to a patient's lungs, comprising the steps of: drying a surfactant from which reverse micelles can be formed; and mixing said surfactant with a peptide or protein, an amount of water, and a propellant to form reverse micelles of said surfactant in said propellant which incorporate said peptide or protein, said surfactant being present in an amount less than five percent weight in volume, said peptide or protein having a concentration in said propellant ranging from 0.025 mg/ml to 4.0 mg/ml, and said amount of water resulting in a molar ratio of water to surfactant ranging from approximately 1:1 to 20:1.
Claim 21
Dependent Claim
31 words
A method as recited in claim 17 wherein said amount of water used in said mixing step results in a molar ratio of water to surfactant ranging from 0.9:1 to 5.6:1.
Claim 22
Dependent Claim
24 words
A method as recited in claim 17 wherein said surfactant is present in an amount ranging between 0.5 and 2.5 percent weight in volume.
Claim 23
Dependent Claim
33 words
A method as recited in claim 17 wherein said drying step reduces an amount of associated water from said surfactant to yield a molar ratio of water to surfactant of 0.5:1 to 1:1.
Claim 24
Dependent Claim
24 words
A method as recited in claim 17 wherein said amount of water in said mixing step results in reverse micelles of an oblate shape.
Claim 25
Dependent Claim
24 words
A method as recited in claim 17 wherein said amount of water in said mixing step results in reverse micelles of a spherical shape.
Claim 26
Dependent Claim
24 words
A method as recited in claim 17 wherein said amount of water in said mixing step results in reverse micelles of a prolate shape.
Claim 27
Dependent Claim
32 words
A method as recited in claim 17 wherein said propellant includes a gas selected from the group consisting of n-butane, iosbutane, perfluoropentane, trichlorofluoromethane, dichlorotetrafluoroethane, dichlorofluoroethane, dichlorofluoromethane, 1,1,1,2-tetrafluoroethane, propane, dimethylether, pefluoropropane, and heptafluoropropane.
Claim 28
Dependent Claim
37 words
A method as recited in claim 17 wherein said surfactant is selected from the group consisting of phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine, diphosphatidyl glycerol, sorbitan mono- and tri-oleates, diolein, oleic acid, and phosphatidic acid.
Claim 29
Dependent Claim
20 words
A method as recited in claim 17 further comprising the step of adjusting the pH of said amount of water.
Claim 30
Independent Claim
109 words
A method of preparing an aerosol formulation for delivery of peptides and proteins to a patient's lungs, comprising the steps of: combining a surfactant with a peptide or protein and a propellant, said surfactant being present in an amount less than 5 percent weight in volume, said peptide or protein having a concentration in said propellant ranging from 0.025 mg/ml to 4.0 mg/ml; and adjusting an amount of water associated with said surfactant to solubilize said peptide or protein in reverse micelles formed from said surfactant and dispersed within said propellant, said amount of water being adjusted to a molar ratio of water to surfactant of up to 20:1.
Claim 31
Independent Claim
109 words
A method of preparing an aerosol formulation for delivery of peptides and proteins to a patient's lungs, comprising the steps of: combining a surfactant with a peptide or protein and a propellant, said surfactant being present in an amount less than 5 percent weight in volume, said peptide or protein having a concentration in said propellant ranging from 0.025 mg/ml to 4.0 mg/ml; and adjusting an amount of water associated with said surfactant to solubilize said peptide or protein in reverse micelles formed from said surfactant and dispersed within said propellant, said amount of water being adjusted to a molar ratio of water to surfactant of up to 20:1.
Claim 32
Dependent Claim
20 words
A method as recited in claim 27 wherein said step of adjusting yields reverse micelles that have a prolate shape.
Claim 33
Dependent Claim
20 words
A method as recited in claim 27 wherein said step of adjusting yields reverse micelles that have an oblate shape.
Claim 34
Dependent Claim
20 words
A method as recited in claim 27 wherein said step of adjusting yields reverse micelles that have a spherical shape.
Claim 35
Dependent Claim
20 words
A method as recited in claim 27 further comprising the step of adjusting the pH of said amount of water.
Claim 36
Independent Claim
120 words
A method of preparing an aerosol formulation for delivery of peptides and proteins to a patient's lungs, comprising the steps of: combining a surfactant with a peptide or protein and a propellant, said surfactant being present in an amount less than 5 percent weight in volume, said peptide or protein being present in an amount less than ten percent by weight, said propellant being present in amount of at least ninety percent by weight; and adjusting an amount of water associated with said surfactant to solubilize said peptide or protein in reverse micelles formed from said surfactant and dispersed within said propellant, said amount of water being adjusted to a molar ratio of water to surfactant of up to 20:1.
Claim 37
Independent Claim
120 words
A method of preparing an aerosol formulation for delivery of peptides and proteins to a patient's lungs, comprising the steps of: combining a surfactant with a peptide or protein and a propellant, said surfactant being present in an amount less than 5 percent weight in volume, said peptide or protein being present in an amount less than ten percent by weight, said propellant being present in amount of at least ninety percent by weight; and adjusting an amount of water associated with said surfactant to solubilize said peptide or protein in reverse micelles formed from said surfactant and dispersed within said propellant, said amount of water being adjusted to a molar ratio of water to surfactant of up to 20:1.
Claim 38
Dependent Claim
20 words
A method as recited in claim 32 wherein said step of adjusting yields reverse micelles that have a prolate shape.
Claim 39
Dependent Claim
20 words
A method as recited in claim 32 wherein said step of adjusting yields reverse micelles that have an oblate shape.
Claim 40
Dependent Claim
20 words
A method as recited in claim 32 wherein said step of adjusting yields reverse micelles that have a spherical shape.
Claim 41
Dependent Claim
20 words
A method as recited in claim 32 further comprising the step of adjusting the pH of said amount of water.
References Cited (Backward Citations)
GB372777A
Cited
US4814161A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1996-07-26 | 1997-01-25 | 1997-07-27 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2000-07-26 | 2001-01-25 | 2001-07-27 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2004-07-26 | 2005-01-25 | 2005-07-27 | $7700.00 | Window Closed / Lapsed |