CA2519523C - Formulation for a metered dose inhaler using hydro-fluoro-alkanes as propellants - Google Patents
Formulation for a metered dose inhaler using hydro-fluoro-alkanes as propellants Download PDFInfo
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- CA2519523C CA2519523C CA2519523A CA2519523A CA2519523C CA 2519523 C CA2519523 C CA 2519523C CA 2519523 A CA2519523 A CA 2519523A CA 2519523 A CA2519523 A CA 2519523A CA 2519523 C CA2519523 C CA 2519523C
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- 239000000203 mixture Substances 0.000 title claims abstract description 69
- 238000009472 formulation Methods 0.000 title claims abstract description 59
- 239000003380 propellant Substances 0.000 title claims abstract description 19
- 229940071648 metered dose inhaler Drugs 0.000 title claims abstract description 12
- 150000005828 hydrofluoroalkanes Chemical class 0.000 title abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 claims description 14
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 claims description 14
- 229940057282 albuterol sulfate Drugs 0.000 claims description 11
- 229960001361 ipratropium bromide Drugs 0.000 claims description 11
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 11
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical group FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 229960002630 ipratropium bromide monohydrate Drugs 0.000 claims description 3
- 239000000725 suspension Substances 0.000 abstract description 6
- 239000004480 active ingredient Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 239000002245 particle Substances 0.000 description 5
- 239000000969 carrier Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- KVNRKLOLUZSPOE-UHFFFAOYSA-M 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;(8-methyl-8-propan-2-yl-8-azoniabicyclo[3.2.1]octan-3-yl) 3-hydroxy-2-phenylpropanoate;sulfuric acid;bromide Chemical compound [Br-].OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)[N+]1(C)C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 KVNRKLOLUZSPOE-UHFFFAOYSA-M 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
- 230000016615 flocculation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000003381 stabilizer Substances 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
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- 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
- A61K9/10—Dispersions; Emulsions
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
An improved suspension formulation for use in a metered-dose inhaler having a hydro-fluoro-alkane propellant is described, the improvement being the controlled addition of a small quantity of water.
Description
Formulation for a Metered Dose Inhaler Using Hvdro-Fluoro-Alkanes as Propellants Background of the Invention The physical stability (particle size growth, flocculation rate, sedimentation/creaming behaviors) of a non-aqueous based suspension metered dose inhaler (MDI) formulation is a critical factor that affects the pharmaceutical performance characteristics of the drug product. For a suspension MDI, the key pharmaceutical performance characteristics of the formulation include reproducible dosing, ready dispersibility of the suspended medicament, and minimal particle size change over time.
Water has long been considered to have a negative impact on the physical stability of non-aqueous suspensions. In the literature, the following two aspects are well established:
a) too much water results in altered sedimentation characteristics leading to fast sedimentation and therefore to variability in dose of the suspended = active ingredient, and b) too much water can alter the particle size distribution by contributing to the formation of flocculates and aggregates of the individual drug particles or can cause solubilizing and re-crystallizing of drug particles.
Summary of the invention It is therefore an object to provide a formulation wherein the amount of water is about 0.13 to about 0.18 percent (w/w) of the product formulation.
It is another object of the invention to provide a meter dose inhaler containing the formulation according to the invention.
It is yet another object of the invention to provide a process of making a formulation according to the invention.
Detailed Description of the Preferred Embodiments The inventors have determined that a minimum amount of water is needed to ensure adequate re-dispersion of the suspended active ingredient. The term "product formulation" shall be understood to mean all components as described herein contained in the metered dose inhaler. It shall be appreciated by the skilled artisan that this amount of water (w/w) of the product formulation is the final volume, and that one or more of the components may already possess water. The amount of water to add to achieve the desired amount in the product formulation can be determined without undue experimentation by to those of ordinary skill in the art from the teachings in this application and from methods known in the art. Preferably, the amount of water is 0.16 %w/w of the product formulation.
In this case, it has been found by the inventors of this application that adding about 0.13%
or 0.14% of water to the other components as shown in the tables below achieves the preferred amount.
If the active ingredient is not readily re-dispersible, then, after a period of non-use by the patient, the amount of active ingredient per actuation will not be on target (either super-potent or sub-potent). The addition of specific amounts of water can aid in the ready re-dispersibility of the active ingredient in the metering chamber. This fmding has been established for a suspension/solution formulation for use in a metered dose inhaler using an hydro-fluoro-alkane (HFA) as propellant. Specifically, a formulation comprising albuterol sulfate and ipratropium bromide, together with various other excipients and carriers, is described, using the HFA known in the industry as 134a.
Suitable excipients will be apparent to those of ordinary skill in the art.
These include, but are not limited to: organic acids such as citric acid, lubricants such as oleic acid, ethanol and carriers.
Suitable carriers will be apparent to those of ordinary skill in the art.
These include, but are not limited to: soy lecithin, polyvinylpyrollidones, organic polymers, phospholipids.
There are various MDl publications in the literature including US Publications 2003/0066525, 2003/0089368, US2001031244, US2003089369, US2003190287, US2003206870, US Patent nos. 5,225,183, 5,919,435, 6,306,368, 5,836,299, 6,092,696, 6,234,362, 6,036,942, 5,682,875, 6,305,371, and PCT publications WO 95/02651, WO 97/01611, WO 03/002169, WO 00/30607, WO 00/30608 and WO 98/56349 and EP 1 241 113, many deal with all aspects of HFA formulations. The inventors are not aware of any formulation patent publications for suspension MDIs that requires or recommends water to be added to the formulation to enhance performance.
Therefore, in one embodiment there is provided:
a formulation comprising water in an amount of about 0.13 to about 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more active ingredients, and one or more excipients.
In another embodiment there is provided:
a formulation comprising water in an amount of about 0.13 to about 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more excipients, albuterol sulfate and ipratropium bromide, wherein the albuterol sulfate and ipratropium bromide of the formulation are suspended.
Below are three tables showing formulations incorporating the invention, that is, the deliberate addition of water to a formulation to be used in an MDI using at least one HFA as a propellant. The first two tables provide specific details for such formulation having albuterol sulfate and ipratropium bromide as active ingredients. The first table provides the formulation with no canister overfill.
Water has long been considered to have a negative impact on the physical stability of non-aqueous suspensions. In the literature, the following two aspects are well established:
a) too much water results in altered sedimentation characteristics leading to fast sedimentation and therefore to variability in dose of the suspended = active ingredient, and b) too much water can alter the particle size distribution by contributing to the formation of flocculates and aggregates of the individual drug particles or can cause solubilizing and re-crystallizing of drug particles.
Summary of the invention It is therefore an object to provide a formulation wherein the amount of water is about 0.13 to about 0.18 percent (w/w) of the product formulation.
It is another object of the invention to provide a meter dose inhaler containing the formulation according to the invention.
It is yet another object of the invention to provide a process of making a formulation according to the invention.
Detailed Description of the Preferred Embodiments The inventors have determined that a minimum amount of water is needed to ensure adequate re-dispersion of the suspended active ingredient. The term "product formulation" shall be understood to mean all components as described herein contained in the metered dose inhaler. It shall be appreciated by the skilled artisan that this amount of water (w/w) of the product formulation is the final volume, and that one or more of the components may already possess water. The amount of water to add to achieve the desired amount in the product formulation can be determined without undue experimentation by to those of ordinary skill in the art from the teachings in this application and from methods known in the art. Preferably, the amount of water is 0.16 %w/w of the product formulation.
In this case, it has been found by the inventors of this application that adding about 0.13%
or 0.14% of water to the other components as shown in the tables below achieves the preferred amount.
If the active ingredient is not readily re-dispersible, then, after a period of non-use by the patient, the amount of active ingredient per actuation will not be on target (either super-potent or sub-potent). The addition of specific amounts of water can aid in the ready re-dispersibility of the active ingredient in the metering chamber. This fmding has been established for a suspension/solution formulation for use in a metered dose inhaler using an hydro-fluoro-alkane (HFA) as propellant. Specifically, a formulation comprising albuterol sulfate and ipratropium bromide, together with various other excipients and carriers, is described, using the HFA known in the industry as 134a.
Suitable excipients will be apparent to those of ordinary skill in the art.
These include, but are not limited to: organic acids such as citric acid, lubricants such as oleic acid, ethanol and carriers.
Suitable carriers will be apparent to those of ordinary skill in the art.
These include, but are not limited to: soy lecithin, polyvinylpyrollidones, organic polymers, phospholipids.
There are various MDl publications in the literature including US Publications 2003/0066525, 2003/0089368, US2001031244, US2003089369, US2003190287, US2003206870, US Patent nos. 5,225,183, 5,919,435, 6,306,368, 5,836,299, 6,092,696, 6,234,362, 6,036,942, 5,682,875, 6,305,371, and PCT publications WO 95/02651, WO 97/01611, WO 03/002169, WO 00/30607, WO 00/30608 and WO 98/56349 and EP 1 241 113, many deal with all aspects of HFA formulations. The inventors are not aware of any formulation patent publications for suspension MDIs that requires or recommends water to be added to the formulation to enhance performance.
Therefore, in one embodiment there is provided:
a formulation comprising water in an amount of about 0.13 to about 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more active ingredients, and one or more excipients.
In another embodiment there is provided:
a formulation comprising water in an amount of about 0.13 to about 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more excipients, albuterol sulfate and ipratropium bromide, wherein the albuterol sulfate and ipratropium bromide of the formulation are suspended.
Below are three tables showing formulations incorporating the invention, that is, the deliberate addition of water to a formulation to be used in an MDI using at least one HFA as a propellant. The first two tables provide specific details for such formulation having albuterol sulfate and ipratropium bromide as active ingredients. The first table provides the formulation with no canister overfill.
Table 1 COMPONENT MASS PER CAN PERCENT
Albuterol Sulphate 0.0240g 0.208 (micronized) Ipratropium Bromide 0.0042g 0.036 (monohydrate) Ethanol 1.153g 10 (dehydrated, USP) Water 0.0150g 0.13 Polyvinylpyrrolidone 0.0058g 0.050 (PVP, K-25) Citric Acid 0.0005g 0.004 (anhydrous) HFA 134a 10.3285g 89.542 (1,1,1,2-tetrafluoroethane) TOTAL 11.5310g 100 The second table provides the same albuterol sulfate and ipratropium bromide formulation with a projected canister overfill included.
Table 2 COMPONENT MASS PER CAN PERCENT
Albuterol Sulphate 0.0309g 0.208 (micronized) Ipratropium Bromide 0.0054g 0.036 monoh drate Ethanol 1.482g 10 (dehydrated, USP) Water 0.0193g 0.13 Polyvinylpyrrolidone 0.0074g 0.050 (PVP, K-25) Citric Acid 0.0006g 0.004 (anhydrous) HFA 134a 13.2744g 89.542 1, 1, 1,2-tetrafluoroethane) TOTAL 14.82g 100 The third table provides expected ranges for an albuterol sulfate/ipratropium bromide formulation according to the present invention.
Table 3 COMPONENT MASS PER CAN PERCENT
Albuterol Sulphate 0.0240g 0.208 (micronized) 0.0216 - 0.0264 +/-10%
Ipratropium Bromide 0.0042g 0.036 (monohydrate) 0.0038 - 0.0046 Ethanol 1.153g 10 (dehydrated, USP) Polyvinylpyrrolidone 0.0058g 0.050 (PVP, K-25) 0.0049g - 0.0067g +/-15%
Citric Acid 0.0005g 0.004 (anhydrous) HFA 134a 10.325g 89.542 (1, 1, 1,2-tetrafluoroethane) and/or TOTAL 11.5125g 100 This invention will provide a solution to the problem of actuation variability in formulations used in MDIs having at least one HFA as propellant where:
a) the formulation has a suspended, solid medicament and b) the valve is designed to include a metering chamber, that is an area for the formulation to be dosed or dispensed to reside between actuations or dosings.
Provided these two conditions are met, there is the potential that the addition of a small, controlled amount of water can improve the redispersibility of the formulation in the metering chamber. This possibility exists regardless of whether the formulation is a "pure"
suspension, that is, no drug or active ingredient is dissolved in the formulation. This possibility is also independent of the solid medicament, the stabilizing agent (if one is used), the propellants used or the type of co-solvent, if any, used.
Therefore, in another embodiment of the invention, there is provided a metered dose inhaler comprising a formulation as described herein above wherein the albuterol sulfate, and the ipratropium bromide of the formulation is suspended;
a valve containing a metering chamber that is an area for the formulation to be dosed or dispensed to reside between actuations or dosings.
In yet another embodiment of the invention, there is provided a process of making a formulation as desribed herein above, comprising:
preparing a concentrate by adding :
ethanol, citric acid, ipratropium bromide monohydrate, polyvinylpyrrolidone and albuterol sulfate;
preparing a propellant, ethanol and water mixture, said mixture containing:
propellant HFA 134a, a mixture of ethanol and water;
adding the concentrate to the mixture of propellant-ethanol-water to provide the formulation.
Albuterol Sulphate 0.0240g 0.208 (micronized) Ipratropium Bromide 0.0042g 0.036 (monohydrate) Ethanol 1.153g 10 (dehydrated, USP) Water 0.0150g 0.13 Polyvinylpyrrolidone 0.0058g 0.050 (PVP, K-25) Citric Acid 0.0005g 0.004 (anhydrous) HFA 134a 10.3285g 89.542 (1,1,1,2-tetrafluoroethane) TOTAL 11.5310g 100 The second table provides the same albuterol sulfate and ipratropium bromide formulation with a projected canister overfill included.
Table 2 COMPONENT MASS PER CAN PERCENT
Albuterol Sulphate 0.0309g 0.208 (micronized) Ipratropium Bromide 0.0054g 0.036 monoh drate Ethanol 1.482g 10 (dehydrated, USP) Water 0.0193g 0.13 Polyvinylpyrrolidone 0.0074g 0.050 (PVP, K-25) Citric Acid 0.0006g 0.004 (anhydrous) HFA 134a 13.2744g 89.542 1, 1, 1,2-tetrafluoroethane) TOTAL 14.82g 100 The third table provides expected ranges for an albuterol sulfate/ipratropium bromide formulation according to the present invention.
Table 3 COMPONENT MASS PER CAN PERCENT
Albuterol Sulphate 0.0240g 0.208 (micronized) 0.0216 - 0.0264 +/-10%
Ipratropium Bromide 0.0042g 0.036 (monohydrate) 0.0038 - 0.0046 Ethanol 1.153g 10 (dehydrated, USP) Polyvinylpyrrolidone 0.0058g 0.050 (PVP, K-25) 0.0049g - 0.0067g +/-15%
Citric Acid 0.0005g 0.004 (anhydrous) HFA 134a 10.325g 89.542 (1, 1, 1,2-tetrafluoroethane) and/or TOTAL 11.5125g 100 This invention will provide a solution to the problem of actuation variability in formulations used in MDIs having at least one HFA as propellant where:
a) the formulation has a suspended, solid medicament and b) the valve is designed to include a metering chamber, that is an area for the formulation to be dosed or dispensed to reside between actuations or dosings.
Provided these two conditions are met, there is the potential that the addition of a small, controlled amount of water can improve the redispersibility of the formulation in the metering chamber. This possibility exists regardless of whether the formulation is a "pure"
suspension, that is, no drug or active ingredient is dissolved in the formulation. This possibility is also independent of the solid medicament, the stabilizing agent (if one is used), the propellants used or the type of co-solvent, if any, used.
Therefore, in another embodiment of the invention, there is provided a metered dose inhaler comprising a formulation as described herein above wherein the albuterol sulfate, and the ipratropium bromide of the formulation is suspended;
a valve containing a metering chamber that is an area for the formulation to be dosed or dispensed to reside between actuations or dosings.
In yet another embodiment of the invention, there is provided a process of making a formulation as desribed herein above, comprising:
preparing a concentrate by adding :
ethanol, citric acid, ipratropium bromide monohydrate, polyvinylpyrrolidone and albuterol sulfate;
preparing a propellant, ethanol and water mixture, said mixture containing:
propellant HFA 134a, a mixture of ethanol and water;
adding the concentrate to the mixture of propellant-ethanol-water to provide the formulation.
A formulation according to the present invention can be made as follows:
1. Concentrate Preparation Prepare Concentrate with:
Ethanol, Citric acid Ipratropium bromide monohydrate PVP
Albuterol Sulfate Do not add water.
2. Dispensing of Propellant, Ethanol and Water Charge Formulation Vessel with:
Propellant HFA 134a Mixture of ethanol/water Concentration of Formulation at this Process Step:
Propellant 95.45%
Ethanol 4.38%
Water 0.17%
3. Final Product Formulation Add concentrate (from Step 1) to the mixture of propellant-ethanol-water Concentration of Formulation at this Process Step:
Propellant 89.84%
Ethanol 10.00%
Water 0.16%
Actives negligible PVP negligible Citric acid negligible
1. Concentrate Preparation Prepare Concentrate with:
Ethanol, Citric acid Ipratropium bromide monohydrate PVP
Albuterol Sulfate Do not add water.
2. Dispensing of Propellant, Ethanol and Water Charge Formulation Vessel with:
Propellant HFA 134a Mixture of ethanol/water Concentration of Formulation at this Process Step:
Propellant 95.45%
Ethanol 4.38%
Water 0.17%
3. Final Product Formulation Add concentrate (from Step 1) to the mixture of propellant-ethanol-water Concentration of Formulation at this Process Step:
Propellant 89.84%
Ethanol 10.00%
Water 0.16%
Actives negligible PVP negligible Citric acid negligible
Claims (7)
1. A formulation comprising:
water in an amount of about 0.13 to about 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more excipients, and albuterol sulfate and ipratropium bromide, wherein the albuterol sulfate and ipratropium bromide of the formulation are suspended.
water in an amount of about 0.13 to about 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more excipients, and albuterol sulfate and ipratropium bromide, wherein the albuterol sulfate and ipratropium bromide of the formulation are suspended.
2. The formulation according to claim 1, wherein the amount of water is 0.13 to 0.16 % w/w of the product formulation.
3. The formulation according to claim 1 or 2, wherein the HFA
propellant is HFA 134a.
propellant is HFA 134a.
4. The formulation according to claim 1, 2 or 3, wherein the excipients are ethanol, citric acid and polyvinylpyrrolidone.
5. The formulation according to claim 1, 2, 3 or 4, wherein the formulation is in a metered dose inhaler comprising a valve containing a metering chamber that is an area for the formulation to be dosed or dispensed to reside between actuations or dosings.
6. A metered dose inhaler comprising a formulation according to claim 1, 2, 3, 4 or 5;
a valve containing a metering chamber that is an area for the formulation to be dosed or dispensed to reside between actuations or dosings.
a valve containing a metering chamber that is an area for the formulation to be dosed or dispensed to reside between actuations or dosings.
7. A process of making a formulation according to claim 4, comprising:
preparing a concentrate by adding:
ethanol, citric acid, ipratropium bromide monohydrate, polyvinylpyrrolidone and albuterol sulfate;
preparing a propellant, ethanol and water mixture, said mixture containing:
propellant HFA 134a, a mixture of ethanol and water;
adding the concentrate to the mixture of propellant-ethanol-water to provide the formulation.
preparing a concentrate by adding:
ethanol, citric acid, ipratropium bromide monohydrate, polyvinylpyrrolidone and albuterol sulfate;
preparing a propellant, ethanol and water mixture, said mixture containing:
propellant HFA 134a, a mixture of ethanol and water;
adding the concentrate to the mixture of propellant-ethanol-water to provide the formulation.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US45611303P | 2003-03-20 | 2003-03-20 | |
US60/456,113 | 2003-03-20 | ||
PCT/US2004/008375 WO2004084858A2 (en) | 2003-03-20 | 2004-03-19 | Formulation for a metered dose inhaler using hydro-fluoro-alkanes as propellants |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2519523A1 CA2519523A1 (en) | 2004-10-07 |
CA2519523C true CA2519523C (en) | 2012-03-13 |
Family
ID=33098086
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2519523A Expired - Fee Related CA2519523C (en) | 2003-03-20 | 2004-03-19 | Formulation for a metered dose inhaler using hydro-fluoro-alkanes as propellants |
Country Status (28)
Country | Link |
---|---|
US (1) | US7914770B2 (en) |
EP (1) | EP1608336B1 (en) |
JP (1) | JP4708332B2 (en) |
KR (1) | KR101113003B1 (en) |
CN (1) | CN1761455A (en) |
AT (1) | ATE390125T1 (en) |
AU (1) | AU2004224367B2 (en) |
BR (1) | BRPI0408547A (en) |
CA (1) | CA2519523C (en) |
CO (1) | CO5640070A2 (en) |
CY (1) | CY1108137T1 (en) |
DE (1) | DE602004012718T2 (en) |
DK (1) | DK1608336T3 (en) |
EA (1) | EA009087B1 (en) |
EC (1) | ECSP056029A (en) |
ES (1) | ES2304616T3 (en) |
HR (1) | HRP20050822B1 (en) |
ME (1) | ME00420B (en) |
MX (1) | MXPA05009920A (en) |
NO (1) | NO336457B1 (en) |
NZ (1) | NZ542957A (en) |
PL (1) | PL1608336T3 (en) |
PT (1) | PT1608336E (en) |
RS (1) | RS51663B (en) |
SI (1) | SI1608336T1 (en) |
UA (1) | UA89751C2 (en) |
WO (1) | WO2004084858A2 (en) |
ZA (1) | ZA200506463B (en) |
Families Citing this family (31)
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DE102004011381A1 (en) * | 2004-03-05 | 2005-09-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Cartridge with a gas-driven aerosol preparation incorporates a valve or a valve system provided with at least two outer channels oriented to one another at a specified angle |
JP5209963B2 (en) * | 2004-07-02 | 2013-06-12 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Aerosol suspension formulation containing TG227EA or TG134A as propellant |
US20060140873A1 (en) * | 2004-12-27 | 2006-06-29 | Chang Heng W | Aerosol pharmaceutical compositions |
GB0501956D0 (en) * | 2005-01-31 | 2005-03-09 | Arrow Internat | Nebulizer formulation |
GB0518769D0 (en) * | 2005-09-14 | 2005-10-19 | Medpharm Ltd | Topical formulations |
DE102006053374A1 (en) * | 2006-02-09 | 2007-08-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical formulation for aerosols with two or more active substances and at least one surface-active substance |
DE102006014433A1 (en) * | 2006-03-27 | 2007-10-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Metered aerosols for the administration of pharmaceutical preparations |
DE102006017320A1 (en) * | 2006-04-11 | 2007-10-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aerosol suspension formulations with TG 227 ea or TG 134 a as propellant |
WO2008047239A2 (en) * | 2006-09-21 | 2008-04-24 | Medispray Laboratories Pvt. Ltd. | Stable aerosol pharmaceutical formulations |
EP2187969A2 (en) * | 2007-08-17 | 2010-05-26 | Arcion Therapeutics, Inc. | High concentration local anesthetic formulations |
EP2077132A1 (en) | 2008-01-02 | 2009-07-08 | Boehringer Ingelheim Pharma GmbH & Co. KG | Dispensing device, storage device and method for dispensing a formulation |
WO2010019953A1 (en) | 2008-08-15 | 2010-02-18 | Arcion Therapeutics, Inc. | High concentration local anesthetic formulations for treating non-neuropathic pain |
US10011906B2 (en) | 2009-03-31 | 2018-07-03 | Beohringer Ingelheim International Gmbh | Method for coating a surface of a component |
EP3508239B1 (en) | 2009-05-18 | 2020-12-23 | Boehringer Ingelheim International GmbH | Adapter, inhalant apparatus and atomizer |
UA107097C2 (en) | 2009-11-25 | 2014-11-25 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | Dispenser |
US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
WO2011064163A1 (en) | 2009-11-25 | 2011-06-03 | Boehringer Ingelheim International Gmbh | Nebulizer |
EP2585151B1 (en) | 2010-06-24 | 2018-04-04 | Boehringer Ingelheim International GmbH | Nebulizer |
US20120204871A1 (en) * | 2011-02-10 | 2012-08-16 | Julio Cesar Vega | Stable, non-corrosive formulations for pressurized metered dose inhalers |
WO2012130757A1 (en) | 2011-04-01 | 2012-10-04 | Boehringer Ingelheim International Gmbh | Medical device comprising a container |
US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
WO2013152894A1 (en) | 2012-04-13 | 2013-10-17 | Boehringer Ingelheim International Gmbh | Atomiser with coding means |
CN102798044B (en) * | 2012-08-02 | 2014-09-10 | 深圳市华星光电技术有限公司 | Edge-lighting backlight module |
WO2015018904A1 (en) | 2013-08-09 | 2015-02-12 | Boehringer Ingelheim International Gmbh | Nebulizer |
ES2836977T3 (en) | 2013-08-09 | 2021-06-28 | Boehringer Ingelheim Int | Nebulizer |
US10195374B2 (en) | 2014-05-07 | 2019-02-05 | Boehringer Ingelheim International Gmbh | Container, nebulizer and use |
WO2015169430A1 (en) | 2014-05-07 | 2015-11-12 | Boehringer Ingelheim International Gmbh | Nebulizer |
KR102492824B1 (en) | 2014-05-07 | 2023-01-30 | 베링거 인겔하임 인터내셔날 게엠베하 | Nebulizer, indicator device and container |
US20180071231A1 (en) * | 2015-04-10 | 2018-03-15 | 3M Innovative Properties Company | Formulation and aerosol canisters, inhalers, and the like containing the formulation |
GB2573297A (en) * | 2018-04-30 | 2019-11-06 | Mexichem Fluor Sa De Cv | Pharmaceutical composition |
WO2021216779A1 (en) * | 2020-04-21 | 2021-10-28 | Amphastar Pharmaceuticals, Inc. | Anti-viral pharmaceutical formulations administered via devices for lung targeted delivery |
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SE9701750D0 (en) * | 1997-05-12 | 1997-05-12 | Astra Pharma Prod | Inhalation device and method of manufacture thereof |
GB2326334A (en) | 1997-06-13 | 1998-12-23 | Chiesi Farma Spa | Pharmaceutical aerosol compositions |
US20010031244A1 (en) * | 1997-06-13 | 2001-10-18 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
US6423298B2 (en) * | 1998-06-18 | 2002-07-23 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pharmaceutical formulations for aerosols with two or more active substances |
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IT1303788B1 (en) | 1998-11-25 | 2001-02-23 | Chiesi Farma Spa | MEDICINAL AEROSOL FORMULATIONS. |
DZ2947A1 (en) | 1998-11-25 | 2004-03-15 | Chiesi Farma Spa | Pressure metered dose inhaler. |
US6261539B1 (en) | 1998-12-10 | 2001-07-17 | Akwete Adjei | Medicinal aerosol formulation |
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US20030008369A1 (en) * | 1999-03-03 | 2003-01-09 | Board Of Regents, The University Of Texas System | Genetic and epigenetic manipulation of ABC transporters and ecto-phosphatases |
GB0002798D0 (en) * | 2000-02-09 | 2000-03-29 | Glaxo Group Ltd | Actuator nozzle for metered dose inhaler |
EP1241113A1 (en) | 2001-03-12 | 2002-09-18 | CHIESI FARMACEUTICI S.p.A. | Inhaler with means for improving chemical stability of medicinal aerosol solution contained therein |
ATE506093T1 (en) | 2001-06-26 | 2011-05-15 | Norton Healthcare Ltd | IMPROVED AEROSOL REGULATOR |
-
2004
- 2004-03-19 KR KR1020057017414A patent/KR101113003B1/en active IP Right Grant
- 2004-03-19 CN CNA200480007545XA patent/CN1761455A/en active Pending
- 2004-03-19 US US10/804,710 patent/US7914770B2/en active Active
- 2004-03-19 BR BRPI0408547-7A patent/BRPI0408547A/en not_active Application Discontinuation
- 2004-03-19 DK DK04757846T patent/DK1608336T3/en active
- 2004-03-19 UA UAA200509733A patent/UA89751C2/en unknown
- 2004-03-19 MX MXPA05009920A patent/MXPA05009920A/en active IP Right Grant
- 2004-03-19 RS YU20050705A patent/RS51663B/en unknown
- 2004-03-19 ES ES04757846T patent/ES2304616T3/en not_active Expired - Lifetime
- 2004-03-19 CA CA2519523A patent/CA2519523C/en not_active Expired - Fee Related
- 2004-03-19 EP EP04757846A patent/EP1608336B1/en not_active Expired - Lifetime
- 2004-03-19 SI SI200430720T patent/SI1608336T1/en unknown
- 2004-03-19 DE DE602004012718T patent/DE602004012718T2/en not_active Expired - Lifetime
- 2004-03-19 NZ NZ542957A patent/NZ542957A/en not_active IP Right Cessation
- 2004-03-19 JP JP2006507344A patent/JP4708332B2/en not_active Expired - Lifetime
- 2004-03-19 WO PCT/US2004/008375 patent/WO2004084858A2/en active Application Filing
- 2004-03-19 EA EA200501363A patent/EA009087B1/en unknown
- 2004-03-19 PL PL04757846T patent/PL1608336T3/en unknown
- 2004-03-19 AU AU2004224367A patent/AU2004224367B2/en not_active Ceased
- 2004-03-19 PT PT04757846T patent/PT1608336E/en unknown
- 2004-03-19 AT AT04757846T patent/ATE390125T1/en active
- 2004-03-19 ME MEP-2008-626A patent/ME00420B/en unknown
-
2005
- 2005-08-12 ZA ZA200506463A patent/ZA200506463B/en unknown
- 2005-09-19 HR HRP20050822AA patent/HRP20050822B1/en not_active IP Right Cessation
- 2005-09-20 EC EC2005006029A patent/ECSP056029A/en unknown
- 2005-10-19 CO CO05106413A patent/CO5640070A2/en not_active Application Discontinuation
- 2005-10-19 NO NO20054839A patent/NO336457B1/en not_active IP Right Cessation
-
2008
- 2008-06-11 CY CY20081100626T patent/CY1108137T1/en unknown
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