Title of Invention	"A FORMULATION FOR A METERED DOSE INHALER "
Abstract	A formulation for a metered dose inhaler comprising water in an amount of 0.13 to 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more excipients and active ingredients albuterol sulfate and ipratropium bromide wherein the active ingredients of the formulation are suspended, wherein albuterol sulfate is present in an amount of 0.208 (+/-10%), (w/w) of the product formulation and ipratropium bromide is present in an amount of 0.036 (+/-10%), (w/w) of the product formulation.

Title of Invention

"A FORMULATION FOR A METERED DOSE INHALER "

Abstract

A formulation for a metered dose inhaler comprising water in an amount of 0.13 to 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more excipients and active ingredients albuterol sulfate and ipratropium bromide wherein the active ingredients of the formulation are suspended, wherein albuterol sulfate is present in an amount of 0.208 (+/-10%), (w/w) of the product formulation and ipratropium bromide is present in an amount of 0.036 (+/-10%), (w/w) of the product formulation.

Full Text	The present invention relates to a formulation for a metered dose inhaler. Background of the Invention The physical stability (particle size growth, flocculation rate, sedimentation/creatniag 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 sohtbilizing 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. 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 those of ordinary skill in the art from the teachings hi this application and from methods known hi 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 hi the ready re-dispersibility of the active ingredient in the metering chamber. This finding 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 MDI 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 fonnulation 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, albuerol sulfate, ipratropium bromide, and one or more excipients. 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 albuerol sulfate and ipratropium bromide as active ingredients. The first table provides the formulation with no canister overfill. Table 1 (Table Removed) The second table provides the same albuterol sulfate and ipratropium bromide formulation with a projected canister overfill included. Table 2 (Table Removed) The third table provides expected ranges for an albuterol sulfate/ipratropium bromide formulation according to the present invention. Table 3 (Table Removed) 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 HF A 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 Ethanol Water Actives PVP Citric acid 89.84% 10.00% 0.16% negligible negligible negligible All publications cited in this application are incorporated herein by reference in their entirety. We claim: 1. A formulation for a metered dose inhaler comprising water in an amount of 0.13 to 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more excipients and active ingredients albuterol sulfate and ipratropium bromide wherein the active ingredients of the formulation are suspended, wherein albuterol sulfate is present in an amount of 0.208 (+/-10%), (w/w) of the product formulation and ipratropium bromide is present in an amount of 0.036 (+/-10%), (w/w) of the product formulation. 2. The formulation as claimed in claim 1 wherein the amount of water is 0.13 to 0.16%w/w of the product formulation. 3. The formulation as claimed in claim 1 wherein the HFA propellant is HFA 134a. 4. The formulation as claimed in claim 1 wherein the excipients are ethanol, citric acid and polyvinylpyrrolidone. 5. The formulation as claimed in claim 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 as claimed in claims 1 to 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. 7. A process of making a formulation as claimed in the claim 5 comprising: preparing a concentration by adding ethanol, citric acid, ipratropium bromide monohydrate, polyvinylpyrrolidone and albuterol sulfate and preparing a propellant, ethanol and water mixture, wherein said mixture contains propellant HFA 134a, a mixture or ethanol and water; adding the concentrate to the mixture of propellant-ethanol-water to provide the formulation.

Full Text

The present invention relates to a formulation for a metered dose inhaler. Background of the Invention
The physical stability (particle size growth, flocculation rate, sedimentation/creatniag 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 sohtbilizing 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.

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
those of ordinary skill in the art from the teachings hi this application and from methods
known hi 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 hi the ready
re-dispersibility of the active ingredient in the metering chamber. This finding 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 MDI 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
fonnulation 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,
albuerol sulfate,
ipratropium bromide, and
one or more excipients.
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 albuerol sulfate and ipratropium bromide as active ingredients. The first table
provides the formulation with no canister overfill.
Table 1
(Table Removed)
The second table provides the same albuterol sulfate and ipratropium bromide
formulation with a projected canister overfill included.
Table 2
(Table Removed)

The third table provides expected ranges for an albuterol sulfate/ipratropium
bromide formulation according to the present invention.
Table 3
(Table Removed)

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 HF A 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
Ethanol
Water
Actives
PVP
Citric acid
89.84%
10.00%
0.16%
negligible
negligible
negligible
All publications cited in this application are incorporated herein by reference in their entirety.

We claim:

1. A formulation for a metered dose inhaler comprising water in an amount of 0.13 to 0.18 percent (w/w) of the product formulation, at least one HFA as a propellant, one or more excipients and active ingredients albuterol sulfate and ipratropium bromide wherein the active ingredients of the formulation are suspended, wherein albuterol sulfate is present in an amount of 0.208 (+/-10%), (w/w) of the product formulation and ipratropium bromide is present in an amount of 0.036 (+/-10%), (w/w) of the product formulation.
2. The formulation as claimed in claim 1 wherein the amount of water is 0.13 to 0.16%w/w of the product formulation.
3. The formulation as claimed in claim 1 wherein the HFA propellant is HFA 134a.
4. The formulation as claimed in claim 1 wherein the excipients are ethanol, citric acid and polyvinylpyrrolidone.
5. The formulation as claimed in claim 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 as claimed in claims 1 to 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.
7. A process of making a formulation as claimed in the claim 5 comprising: preparing a concentration by adding ethanol, citric acid, ipratropium bromide monohydrate, polyvinylpyrrolidone and albuterol sulfate and preparing a propellant, ethanol and water mixture, wherein said mixture contains propellant HFA 134a, a mixture or ethanol and water; adding the concentrate to the mixture of propellant-ethanol-water to provide the formulation.

Documents:

4127-DELNP-2005-Abstract-(13-10-2008).pdf

4127-DELNP-2005-Abstract-(20-02-2009).pdf

4127-DELNP-2005-Abstract-(21-04-2009).pdf

4127-DELNP-2005-Abstract-(25-03-2009).pdf

4127-delnp-2005-abstract.pdf

4127-DELNP-2005-Claims-(13-10-2008).pdf

4127-DELNP-2005-Claims-(20-02-2009).pdf

4127-DELNP-2005-Claims-(21-04-2009).pdf

4127-DELNP-2005-Claims-(25-03-2009).pdf

4127-delnp-2005-claims.pdf

4127-delnp-2005-complete specification (granted).pdf

4127-DELNP-2005-Correspondence-Others-(03-07-2008).pdf

4127-DELNP-2005-Correspondence-Others-(06-11-2008).pdf

4127-DELNP-2005-Correspondence-Others-(09-02-2009).pdf

4127-DELNP-2005-Correspondence-Others-(13-10-2008).pdf

4127-DELNP-2005-Correspondence-Others-(20-02-2009).pdf

4127-DELNP-2005-Correspondence-Others-(25-03-2009).pdf

4127-delnp-2005-correspondence-others.pdf

4127-DELNP-2005-Description (Complete)-(13-10-2008).pdf

4127-DELNP-2005-Description (Complete)-(20-02-2009).pdf

4127-delnp-2005-description (complete)-(21-04-2009).pdf

4127-delnp-2005-description (complete).pdf

4127-DELNP-2005-Form-1-(13-10-2008).pdf

4127-DELNP-2005-Form-1-(21-04-2009).pdf

4127-delnp-2005-form-1.pdf

4127-delnp-2005-form-18.pdf

4127-DELNP-2005-Form-2-(21-04-2009).pdf

4127-delnp-2005-form-2.pdf

4127-DELNP-2005-Form-3-(06-11-2008).pdf

4127-DELNP-2005-Form-3-(09-02-2009).pdf

4127-DELNP-2005-Form-3-(13-10-2008).pdf

4127-delnp-2005-form-3.pdf

4127-delnp-2005-form-5.pdf

4127-DELNP-2005-GPA-(13-10-2008).pdf

4127-delnp-2005-gpa.pdf

4127-delnp-2005-pct-101.pdf

4127-delnp-2005-pct-105.pdf

4127-delnp-2005-pct-210.pdf

4127-delnp-2005-pct-304.pdf

4127-delnp-2005-pct-308.pdf

4127-DELNP-2005-Petition-137-(20-02-2009).pdf

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Patent Number

233947

Indian Patent Application Number

4127/DELNP/2005

PG Journal Number

20/2009

Publication Date

15-May-2009

Grant Date

22-Apr-2009

Date of Filing

13-Sep-2005

Name of Patentee

BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.

Applicant Address

900 RIDGEBURY ROAD, P.O. BOX 368, RIDGEFIELD, CONNECTICUT 06877-0368, USA.

Inventors:

#	Inventor's Name	Inventor's Address
1	LINDA JEAN KELASH-CANNAVO	BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. 900 RIDGEBURY ROAD, P.O. BOX 368, RIDGEFIELD, CONNECTICUT 06877-0368, USA.
2	GEORGE DESTEFANO	BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. 900 RIDGEBURY ROAD, P.O. BOX 368, RIDGEFIELD, CONNECTICUT 06877-0368, USA.

PCT International Classification Number

A61K 9/10

PCT International Application Number

PCT/US2004/008375

PCT International Filing date

2004-03-19

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/456,113	2003-03-20	U.S.A.