AU2006202585A1 - An albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease - Google Patents

Description

S&FRef: 593031D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant Actual Inventor(s): Address for Service: Invention Title: Dey, of, Napa, California, United States of America Imtiaz Chaundry Partha Banerjei Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) An albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease.

The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c SAn Albuterol and Ipratropium Inhalation Solution, System, Kit and Method for

O

SRelieving Symptoms of Chronic Obstructive Pulmonary Disease CROSS REFERENCE TO RELATED APPLICATIONS ;This application claims priority under 35 U.S.C. 119 from U.S. Provisional Application Serial Ns No. 60/346,078, filed October 26, 2001, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates to a combination bronchodilator therapy for relieving symptoms associated with chronic obstructive pulmonary disease.

BACKGROUND OF INVENTION (-i 10 Chronic obstructive pulmonary disease (COPD) is a slowly progressive airway disease that (Niq N produces a decline in lung function that is not fully reversible. The airway limitation in COPD is Sassociated with an abnormal inflammatory response of the lungs to noxious particles or gases.

(N In the an estimated 16 million Americans have been diagnosed with some form of COPD, and as many as 16 million others have the condition but have not yet been diagnosed. According to the U.S. Centers for Disease Control and Prevention, COPD is the fourth leading cause of death in the U.S. (behind heart disease, cancer and stroke), claiming the lives of 112,000 Americans annually.

In terms of health care utilization, the number of physician visits for COPD in the U.S. increased from 9.3 million to 16 million between 1985 and 1995. The number of hospitalizations for COPD in 1995 was estimated to be 500,000. Although prevalence, hospitalization and death rates for COPD are higher in men than women, death rates have risen faster in women in recent years. COPD is clearly a major and growing health care threat in the U.S. and throughout the rest of the world.

In the prior art, antimicrobial agents such as benzalkonium chloride (BAC) are often present in inhalation solutions used to treat COPD. The presence of BAC in these solutions generally does not affect the short-term (single dose) bronchodilator response. However, case reports suggest that repeated use of COPD treatments with BAC may result in paradoxic bronchoconstriction. When inhaled by COPD subjects, BAC may also cause dose-dependent bronchoconstriction. Despite these side effects, many commercially available inhalation solutions contain BAC.

Also, treatments for COPD often come in multiple dosage units and must be diluted to specific concentrations suitable for treating patients. This poses several problems. For instance, COPD treatments requiring administration of a single dose unit from multiple dosage units sometimes lack proper mixing or diluting instructions, or the instructions for preparing and using the COPD treatment may be hard to follow or can be easily lost. Of even greater import is haphazard diluting or mixing of COPD medications, which can result in administering the wrong dosage. This could be especially harmful for patients less tolerant to higher dosages of asthma medications. Incorrect mixing can also result in treatment failure such that additional medical attention is required, thereby increasing the time, expense and personnel costs associated with therapy.

There is, therefore, a need for an improved inhalation solution, system, kit and method for relieving symptoms associated with COPD.

LibC/593031 spec SUMMARY OF THE INVENTION SOne object of the present invention is to provide a dual bronchodilator inhalation solution to relieve bronchospasm in patients suffering from COPD.

Another object of the present invention is to provide a prepackaged, sterile, premixed, INO 5 premeasured albuterol and ipratropium inhalation solution for the relief of bronchospasm in patients suffering from COPD.

It is yet another object of the present invention to provide a BAC-free albuterol and ipratropium O0 inhalation solution to treat bronchospasm associated with COPD.

A further object of the present invention is to provide a method of administering an albuterol and ipratropium inhalation formulation for relief of bronchospasm associated with COPD.

An additional object of the present invention is to provide a kit and/or system for administering a Sdual bronchodilator to relieve bronchospasm associated with COPD.

A further object of the present invention is to provide a process for making an albuterol and ipratropium inhalation solution for use in relieving bronchospasm associated with COPD.

Another object of the invention includes a device for use in relieving the symptoms of COPD.

Other objects, features and advantages of the present invention will be apparent to those of ordinary skill in the art in view of the following detailed description of the invention and accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1-4 depict a non-limiting example of administering the inhalation solution of the present invention by a nebulizer.

Figure 5 depicts a non-limiting example of a unified prepackaged kit or system of the present invention.

Figure 6 depicts a non-limiting example of one or more pre-filled containers comprising the inhalation system of the present invention.

Figure 7 depicts a non-limiting example of a label utilized in the present invention.

DETAILED DESCRIPTION OF THE INVENTION Albuterol The present invention relies on the bronchodilation effects of albuterol to provide relief from symptoms associated with COPD. As used herein, the term "albuterol" includes, but is not limited to, any form of albuterol which is capable of producing a desired bronchodilation effect in patients, including, but not limited to, all tautomeric forms, enantomeric forms, stereoisomers, anhydrides, acid addition salts, base salts, solvates, analogues and derivatives of albuterol.

In the present invention, acceptable salts of albuterol may include, but are not limited to, hydrochloride, sulfate, maleate, tartrate, citrate and the like. These salts are described in U.S. Patent No. 3,644,353, which is incorporated herein by reference in its entirety.

In the present invention, the preferred salt of albuterol is sulfate. In an alternative embodiment, the inhalation solution of the present invention comprises the sulfate salt of racemic albuterol.

Albuterol sulfate is a relatively selective beta-2-adrenergic bronchodilator with an empirical formula of UbC/593031sped1 0 C 1 3

H

2 1

NO

3 The chemical name for albuterol sulfate is a'-[(tert-butylamino)methyl]-4-hydroxy-m-

O

0 xylene-a, a'-diol sulfate (2:1)(salt), and its established chemical structure is as follows:

H

3 C H 3 n HO

-CH

3 N N .H 2 S0 4 HO H2SO4

OH

00 2 I, Ipratropium The present invention also relies on the bronchodilation effect of ipratropium to provide relief IND from symptoms associated with COPD. Ipratropium is an anticholinergic bronchodilator. As used herein, the term "ipratropium" includes, but is not limited to, any form of ipratropium which is capable of producing a desired bronchodilation effect in patients suffering from COPD, including, but not limited to, all tautomeric forms, enantomeric forms, stereoisomers, anhadrides, acid addition salts, base salts, salvates, analogues and derivatives of ipratropium.

In the present invention, acceptable salts of ipratropium may include, but are not limited to, halide salts such as bromide, chloride and iodide. These and other acceptable salts are described in U.S. Patent No. 3,505,337, which is incorporated herein by reference in its entirety.

In one embodiment of the present invention, the preferred salt of ipratropium is bromide, which is chemically described as 8-azoniabicyclo -octane, hydroxyl-l-oxo-2-phenylpropoxy)- 8methyl-8-(1-methylethyl)-bromide, monohydrate, (endo, syn)-, Ipratropium bromide has a molecular weight of 430.4 and the empirical formula C2oH 3 oBrNO 3

*H

2 0. It is freely soluble in water and lower alcohol, and is insoluble in lipohilic solvents such as ether, chloroform and flourocarbon.

The established chemical structure of ipratropium bromide is as follows:

CH

3 3CN

HCH

3 Q Br-.H 2 0 O OH 0 In the present invention, the albuterol and ipratropium may be provided in a variety of pharmaceutically acceptable vehicles, including, but not limited to, water or other aqueous solutions comprising a pharmaceutically acceptable amount of an osmotic agent.

In one alternative embodiment, the inhalation solution of the present invention comprises a therapeutically effective amount of albuterol and ipratropium. As used herein, the phrase "therapeutically effective amount of albuterol and/or ipratropium" means a safe and tolerable amount of both compounds, as based on industry and/or regulatory standards. Such amount being sufficient LUbC/593031speo 0 to effectively induce bronchodilation and/or provide relief of bronchospasm in patients suffering form 0 COPD.

In the inhalation solution of the present invention, a therapeutically effective amount of albuterol Smay include from about 0.63mg to about 4.2mg albuterol. Here, the potency of the albuterol is equivalent to from about 0.75mg to about 5mg of albuterol sulfate. In an alternative embodiment, a therapeutically effective amount of albuterol may include about 2.5mg albuterol.

In another alternative embodiment of the present invention, a therapeutically effective amount of albuterol may include from about 0.60mg to about 5.0mg albuterol, including the following intermediate ranges of albuterol: about 0.60mg to about 0.70mg; about 0.71mg to about 0.80mg; o about0.81mgtoabout0.90mg; about 0.91mg to about 1.00mg; about 1.01mg to about 1.10mg; about Sabout 1.11mg to about 1.20mg; about 1.21mg to about 1.30mg; about 1.31mg to about 1.40mg; about 1.41mg to about 1.50mg; about 1.51mg to about 160mg about 1.61mg to about 1.70mg; about 1.71mg to about 1.80mg; about 1.21mg to about 1.90mg; about 1.31mg to about 1.00mg; about 1.71mg to about 1.80mg; about 1.81mg to about 1.90mg; about 1.91mg to about 2.00mg; about 2.01mg to about 2.10mg; about 2.11mg to about 2.20mg; about 2.21mg to about 2.30mg; about 2.31mg to about 2.40mg; about 2.41mg to about 2.50mg; about 2.51mg to about 2.60mg; about 2.61mg to about 2.70mg; about 2.71mg to about 2.80mg; about 2.81mg to about 2.90mg; about 2.91mg to about 3.00; about 3.01 to about 3.10; about 3.11 to about 3.20; about 3.21 to about 3.30mg; about 3.31mg to about 3.40mg; about 3.41mg to about 3.50mg; about 3.51mg to about 3.60mg; about 3.61 to about 3.70mg; about 3.71 to about 3.80mg; about 3.81mg to about 3.90mg; about 3.91mg to about 4.0mg; about 4.01mg to about 4.10mg; about 4.11mg to about 4.20mg; about 4.21mg to about 4.30mg; about 4.31mg to about 4.40mg; about 4.41mg to about 4.50mg; about 4.51mg to about 4.60mg; about 4.61mg to about 4.70mg; about 4.71mg to about 4.80mg; about 4.81mg to about 4.90mg; about 4.91mg to about 5.00mg.

In another alternative embodiment of the present invention, a therapeutically effective amount of albuterol may include from about 0.75mg to about 5.0mg albuterol sulfate, including the following intermediate amounts: about 0.75mg to about 0.80mg; about 0.81 to about 0.90mg; about 0.91mg to about 1.00mg; about 1.01mg to about 1.10mg; about 1.11mg to about 1.20mg; about 1.21mg to about 1.30mg; about 1.31mg to about 1.40mg; about 1.41mg to about 1.50mg; about 1.51mg to about 1.60mg; about 1.61mg to about 1.70mg; about 1.71mg to about 1.80mg; about 1.81mg to about 1.90mg; about 1.91mg to about 2.00mg; about 2.01mg to about 2.10mg; about 2.11mg to about 2.20mg; about 2.21mg to about 2.30mg; about 2.31mg to about 2.40mg; about 2.41mg to about 2.50mg; about 2.51mg to about 2.60mg; about 2.61mg to about 2.70mg; about 2.71mg to about 2.80mg; about 2.81mg to about 2.90mg; about 2.91mg to about 3.00; about 3.01 to about 3.10; about 3.11 to about 3.20; about 3.21 to about 3.30mg; about 3.31mg to about 3.40mg; about 3.41mg to about 3.50mg; about 3.51mg to about 3.60mg; about 3.61 to about 3.70mg; about 3.71 to about 3.80mg; about 3.81mg to about 3.90mg; about 3.91mg to about 4.0mg; about 4.01mg to about 4.10mg; about 4.11mg to about 4.20mg; about 4.21mg to about 4.30mg; about 4.31mg to about 4.40mg; about 4.41mg to about 4.50mg; about 4.51mg to about 4.60mg; about 4.61mg to about 4.70mg; about 4.71mg to about 4.80mg; about 4.81mg to about 4.90mg; about 4.91mg to about 5.00mg.

UbC/593031 Spe ID In another alternative embodiment of the present invention, a therapeutically effective amount 0 0of albuterol may include from about 0.020 to about 0.14 by weight albuterol, including the following intermediate ranges: about 0.020 wt to about 0.029 wt about 0.030 wt to about S0.039 wt about 0.040 wt to about 0.049 wt about 0.050 wt to about 0.059 wt %;about IN 5 0.060 wt to about 0.069 wt about 0.070 wt to about 0.079 wt about 0.080 wt to about 0.089 wt about 0.090 wt to about 0.099 wt about 0.10 wt to about 0.14 wt In yet another alternative embodiment of the present invention a therapeutically effective amount of albuterol may include from about 0.025 to about 0.17 by weight albuterol sulfate, including the following intermediate ranges: about 0.025 wt to about 0.029 wt about 0.030 wt 0 10 to about 0.039 wt about 0.040 wt to about 0.049 wt about 0.050 wt to about 0.059 wt

(N

I0 %;about 0.060 wt to about 0.069 wt about 0.070 wt to about 0.079 wt about 0.080 wt to Sabout 0.089 wt about 0.090 wt to about 0.099 wt about 0.10 wt to about 0.17 wt In another alternative embodiment of the present invention a therapeutically effective amount of ipratropium bromide may include from about 0.01mg to about 1.0mg of ipratropium bromide. Such is therapeutically effective amount may also include the following intermediate ranges of ipratropium bromide: about 0.01mg to about 0.02mg; about 0.02mg to about 0.04mg; about 0.05 to about 0.07mg; about 0.08mg to about 0.10mg; about 0.11mg to about 0.13mg; about 0.14mg to about 0.16mg; about 0.17mg to about 0.19mg; about 0.20mg to about 0.22mg; 0.23mg to about 0.25mg; 0.26mg to about 0.28mg; about 0.29mg to about 0.31mg; about 0.32 to about 0.34mg; about 0.35mg to about 0.37mg; about 0.36mg about 0.38mg; about 0.39mg to about 0.41mg; about 0.42mg to about 0.44mg; about 0.45mg to about 0.47mg; about 0.48mg to about 0.50mg; about 0.51mg to about 0.53mg; about 0.54mg to about 0.56mg; about 0.57mg to about 0.59mg; about 0.60mg to about 0.62mg; about 0.63mg to about 0.65mg; about 0.66mg to about 0.68mg; about 0.69mg to about 0.71mg; about 0.72mg to about 0.74mg; about 0.75mg to about 0.77mg; about 0.79mg to about 0.81mg; about 0.82mg to about 0.84mg; about 0.85mg to about 0.87mg; about 0.88mg to about 0.91mg; about 0.92mg to about 0.94mg; about 0.95mg to about 0.97mg; about 0.98mg to about 1.00mg.

In another alternative embodiment of the present invention, a therapeutically effective amount of ipratropium may include from about 0.001% to about 0.030% by weight ipratropium bromide, including the following intermediate ranges of ipratropium bromide: about 0.001 wt to about 0.005 wt about 0.006 wt to about 0.010 wt about 0.011 wt to about 0.015 wt about 0.016 wt to about 0.020 wt about 0.021 wt to about 0.025 wt 0.026 wt to about 0.030 wt Most pharmaceutical inhalation solutions contain the anti-microbial agent BAC. One problem with these solutions is that the BAC may cause paradoxic bronchoconstriction if the solution is administered repeatedly over short intervals. Another problem is that, when inhaled by patients, the BAC can cause dose-dependent bronchoconstriction. The inhalation solution of the present invention may be provided without BAC, thereby making it suitable, especially in an emergency situation, where the inhalation solution is administered repeatedly over a short period of time. Also, administering a BAC-free inhalation solution to a patient reduces the concomitant liability of adverse effects associated with BAC. It also reduces the toxicity and other side effects associated with BAC.

UbC/593031sped The inhalation solution of the present invention may also be provided in sterile, unit dose treatments, thus eliminating the need to include BAC in the solution. Moreover, as shown in Table 1, in its sterile form the formulation of the present invention (which comprises a therapeutically effective amount of albuterol sulfate and ipratropium bromide) provides a stable inhalation solution such that the formulation can be stored on a shelf) for long periods of time.

Table 1 Stability Data 00

OON

0.083 wt Albuterol Sulfate and 0.017 wt Ipratropium Bromide Assay* Osmolality Albut er ol Ipratropium bromide pH (mOsm/kg) Time zero 98 98 3.3 283 12 months 105 99 3.4 285 24 months 102 101 3.5 282 3 months 100 99 3.5 284 0 C/15%RH02 3.4 283 6 months 103 102 3.4 283 as percent of label claim (0.083 wt albuterol sulfate and 0.017 wt ipratropium bromide) Another benefit of a sterile inhalation solution is that it reduces the possibility of introducing contaminants into the patient when administered, thereby reducing the chance of an opportunistic infection in the patient.

Non-adherence to COPD medication therapy and medication error are considerable problems.

These problems can be significantly reduced by providing COPD patients a prepackaged, premixed, premeasured amount of albuterol and ipratropium. Providing these compounds in this fashion makes COPD therapy simple because it increases convenience and eliminates confusion in preparing appropriate dosages. These advantages are especially significant where treatments often come in multiple dosage units and must be diluted to specific concentrations suitable for treating patients. As discussed previously, this poses several problems.

The present invention overcomes the aforementioned problems by providing therapeutically effective amounts of both albuterol and ipratropium in prepackaged, premixed, premeasured and/or unit dose amounts. In one embodiment, the present invention comprises one or more prefilled containers. The one or more containers each comprising a single unit dose of an aqueous solution comprising a therapeutically effective amount of albuterol and ipratropium for the treatment of COPD.

Providing the inhalation solution in such a manner eliminates the need to dilute or mix COPD medications to obtain proper dosages for treatment. Also, no special pharmacy compounding is required, thereby reducing the chance of medication errors. Further, there is a lower risk of crosscontamination, and less waste of medication when providing an inhalation solution in a premixed, ready to use form.

Other features of the present invention include improved user compliance and quality of life as compared to conventional treatments for COPD. While the level of compliance of any COPD treatment depends in part on the motivation of the user and the skill of the individual dispensing the treatment, compliance nevertheless may be improved by controlling factors such as the ease with which the treatment may be administered, as well as the desirability of receiving the treatment.

UbC/59303lspedc 0 The present invention provides a convenient, fast and reliable treatment for COPD and clearly 0 represents an improvement over traditional COPD treatments. Also, the present invention is designed to facilitate user compliance by providing one or more dispensing containers comprising a premixed, Spremeasured inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium for the treatment of COPD. Such containers may be utilized in a method of treating COPD or the containers may be incorporated in a system and/or kit for treating the same.

In one alternative embodiment, the present invention is a sterile, premixed, premeasured, BACo free inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium in a single container. Each unit dose container comprises 3.0mg/3 ml of albuterol sulfate (equivalent to 2.5mg of albuterol) and 0.5mg ipratropium bromide in a sterile, aqueous Dsolution. Sodium chloride may be added to make the solution isotonic and hydrochloric acid may be 0added to adjust pH of the solution to about 4.0. The inhalation solution of the present invention may or may not include a chelating agent, such as EDTA.

In another alternative embodiment, the inhalation solution of the present invention may be supplied as a 3 ml, sterile, BAC-free, nebulizer solution comprising from about 0.20 to about ipratropium bromide and from about 0.75mg/3 ml to about 3.0mg/3 ml of albuterol sulfate. The nebulizer solution is contained in a unit-dose, low-density polyethylene (LDPE) container. Each unitdose container may be disposed in a foil pouch, and each foil pouch may contain 5 or more unit-dose containers. Each foil pouch containing the unit dose container may be disposed in a shelf carton.

The present invention provides an albuterol and ipratropium inhalation solution for treating different stages of COPD, including but not limited to, stages 0 to III. Some characteristics associated with the different stages of COPD are shown in Table 2. The information in this table is presented for illustrative purposes only. It is not intended to limit the scope of the invention.

Table 2 Stage Severity Description 0 At risk Normal spirometry Chronic symptoms (cough, sputum production) I Mild FEVi/FVC FEV, 80% predicted With or without chronic symptoms II Moderate FEVi/FVC 30% FEVi 80% predicted (IIA: 50% FEV, (lIB: 30%> FEV 1 With or without chronic symptoms III Severe FEVi/FVC FEVi 30% predicted or less than 50% predicted with respiratory failure or clinical signs of right heart failure.

In the present invention, a therapeutically effective amount of albuterol and ipratropium is administered to induce bronchodilation and/or provide relief of bronchospasm associated with COPD.

Such amount of albuterol and ipratropium may be administered to a patient after the onset of LibC/593031spec 0bronchospasm to reduce breathing difficulties resulting from COPD. In another embodiment, the Salbuterol and ipratropium may be administered prophylactically, that is, to prevent COPD progression.

The quantity of albuterol and ipratropium to be administered will be determined on an individual Sbasis, and will be based at least in part on consideration of the patient's size, the severity of the IND 5 symptoms to be treated, and the results sought. The actual dosage (quantity of albuterol and ipratropium administered at a time) and the number of administrations per day will depend on the mode of administration, such as inhaler, nebulizer or oral administration. For example, about of albuterol and about 0.5mg of ipratropium bromide administered by nebulization 4 times per day with up to 2 additional 3 ml doses allowed per day, if needed, would be adequate to produce the desired bronchodilation effect in most patients.

0 Further, the albuterol and ipratropium inhalation solution of the present invention may be 0administered together with one or more other drugs. For example, an antiasthmatic drug such as theophylline or terbutaline, or an antihistamine or analgesic such as aspirin, acetaminophen or ibuprofen, may be administered with or in dose temporal proximity to administration of a therapeutically effective amount of albuterol. The present invention and the one or more drugs may be administered in one formulation or as two separate entities. According to the present invention, a therapeutically effective amount of albuterol and ipratropium, alone or in combination with another drug(s), may be administered to a individual periodically as necessary to reduce symptoms of COPD.

In another alternative embodiment, the inhalation solution of the present invention may be administered by nebulizer. Such nebulizer including, but not limited to, a jet nebulizer, ultrasonic nebulizer and breath actuated nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate air flow. The nebulizer being equipped with a mouthpiece or suitable face mask. Specifically, a Pari-LC-PlusM nebulizer (with face mask or mouthpiece) connected to a PRONEBTM compressor may be used to deliver the inhalation solution of the present invention to a patient.

In an alternative embodiment, the system and/or kit of the present invention comprises an inhalation solution comprising a therapeutically effective amount of albuterol and ipratropium in a prepackaged, premeasured, premixed and/or single unit dose form for the treatment of COPD. The inhalation solution may be sterile and/or BAC-free.

In another embodiment, the present invention provides a system and/or kit for organizing and storing one or more prefilled dispensing containers, each container comprising a premixed, premeasured inhalation solution. The inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium. Such system and/or kit may provide such containers in prepackaged form. The one or more containers may be comprised of plastic including, but not limited to, a semi-permeable plastic such as LDPE. The container may also comprise a Twist-FlexTM top, such top comprising an easy-to-grip tab-like handle such that the container may be opened, for example, by twisting off the tab by hand. The Twist-Flex M top is advantageous in that it allows for easy dispensing of the solution, prevents spillage and eliminates the need to open the container by cutting off the top, or the like, thereby reducing cross-contamination.

One or more of the semi-permeable single unit dose containers may be prepackaged in an aluminum UbC/593031sped IND foil pouch, such that the foil provides a protective barrier against environmental contaminants and

O

O light. Such a barrier improves the shelf-life and stability of the inhalation solution.

In another alternative embodiment, the present invention comprises a prepackaged inhalation ;system and/or kit suitable for patients suffering from COPD. Such prepackaged system and/or kit comprising: one or more single unit dosages of a therapeutically effective amount of albuterol and ipratropium; administration instructions for the use of said unit dose as a treatment for COPD; and a dispensing container prefilled with the one or more unit doses of albuterol and ipratropium.

In another alternative embodiment, the prepackaged inhalation system and/or kit of the present invention provides one or more premixed, premeasured single unit dose vials comprising a io therapeutically effective amount of albuterol and ipratropium for the treatment of bronchospasm IND associated with COPD, and instructions for using the same.

SThe prepackaged inhalation system and/or kit may be provided in one of any number of forms, including, but not limited to, a box containing one or more prepackaged, unit dose vials or a box containing individual packages or pouches comprising one or more unit dose vials. For example, an embodiment of a unified prepackaged system and/or kit for treating COPD in patients is depicted in Figure 5. Specifically, Figure 5 depicts support package Support package (10) may include, but is not limited to, a box, carton or any other enclosed container. The support package comprising one or more prepackaged, pre-filled dispensing containers (21-25). Each container comprising a premixed, premeasured inhalation solution. The inhalation solution comprising a unit dose of a therapeutically effective amount of albuterol and ipratropium for treating COPD. The inhalation solution may be provided in sterile and/or BAC-free form.

Support package (10) may also incorporate one or more labels (13) therein. One or more labels (13) may comprise indicia (14) indicating that the inhalation solution can be used to relieve symptoms associated with COPD, such as bronchospasm. The label may also comprise indicia which provides instructions for using the inhalation solution to relieve such symptoms. As used herein "indicia" includes, but is not limited to, wording, pictures, drawings, symbols and/or shapes. A nonlimiting example of the indicia that may appear on the one or more labels (13) is shown in Figure 7.

The one or more labels may be positioned on one or more surfaces of support package (10) or a separate sheet, or any combination thereof. Support package (10) may also incorporate lid (16) to 3o enclose the packaging material therein.

The system and/or kit of the present invention may also include a label and/or instructions designed to facilitate user compliance. For example, in an embodiment, a system and/or kit of the present invention comprises packaging material containing one or more prepackaged vials comprising a sterile, premixed, premeasured unit dose of an inhalation solution comprising a therapeutic effective amount of albuterol and ipratropium. The packaging material may further comprise a label indicating that each vial can be used with a nebulizer for the relief of symptoms associated with COPD, such as bronchospasm. Such instructions may also include instructions on dosage for each nebulizer treatment, as well as instructions for administration, such as by nebulizer. The instructions may be positioned on one or more surfaces of the packaging material therein, or the instructions may be provided on a separate sheet, or any combination thereof.

UbC/593031sp80 I0 The present invention is also directed to a method of treating symptoms associated with COPD,

O

0 including bronchospasm, wherein a therapeutically effective amount of albuterol and ipratropium may be administered as a unit dose. Such unit dose may be in the form of a nebulizer solution.

SIn an alternative embodiment, the method of the present invention comprises the step of administering to a patient a therapeutically effective amount of albuterol and ipratropium. Such solution may also be prepackaged, premixed, premeasured, BAC-free and/or sterile. Such solution may also be in a single unit dose vial.

In another alternative embodiment, the method of the present invention comprises the step of administering to a patient in need an inhalation solution comprising a therapeutically effective amount 0 10 of albuterol and ipratropium. The inhalation solution being administered by nebulizer, more preferably ND a jet nebulizer connected to an air compressor with adequate air flow.

0In yet another alternative embodiment, in reference to Figures 1-4, the method of the present invention comprises the steps: placing an inhalation solution comprising a therapeutically effective amount of albuterol and ipratropium into a nebulizer cup The nebulizer may be powered by attachment to compressed gas cylinders or an electrically driven compressor; (ii) using a adapter to fit the nebulizer cup lid to a mouthpiece or facemask (iii) drawing the inhalation solution up by the velocity of a gas jet and fragmenting it into an aerosol; (iv) passing the aerosol through the mouthpiece or facemask to the patient afflicted with bronchospasm; and the patient continues breathing until no more mist is formed in the nebulizer chamber This may occur in about 5-15 minutes.

In one alternative embodiment, the usual starting dosage for patients may be about 2.50mg albuterol and 0.5mg ipratropium administered 3 or 4 times daily, as needed by nebulization. To administer these amounts of albuterol and ipratropium, the entire contents of one unit dose vial about 3.0mg/3 ml albuterol sulfate and 0.5mg/3 ml ipratropium bromide) may be used. Preferably, the nebulizer flow rate is adjusted to deliver the albuterol and ipratropium over 5 to 15 minutes.

Further, in an alternative embodiment, the method of the present invention comprises the steps: preparing an inhalation solution comprising a therapeutically effective amount of albuterol and ipratropium by diluting one or more solutions comprising the ipratropium or albuterol; and (ii) administering the inhalation solution to a patient in need thereof.

The present invention also provides a process for making a prepackaged, sterile, premixed, premeasured, and/or BAC-free inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium. In such an embodiment, the method of the present invention comprises one or more of the following steps: adding at least a therapeutically effective amount of albuterol and ipratropium in a carrier, such as water; (ii) sterilizing the solution and sealing the container. An osmotic adjusting agent may be added to adjust the isotonicity of the solution.

Preferably, the solution of the present invention is isotonic, and an osmotic adjusting agent may be added to adjust the isotonicity of the solution to about 280 to about 320 mOsm/kg. Additionally, an acid hydrochloride) may be added to adjust the pH of the solution to a level of about 3.0 to about preferably about UbC/593031 sped IND In another embodiment, a process for making an inhalation solution of the present invention 0 Ocomprises one or more of the following steps: adding at least a therapeutically effective amount of albuterol and ipratropium in a carrier such as water; (ii) placing the mixture in a container, and ;sterilizing the mixture by steam sterilization, or any other sterilizing means known in the art. Each albuterol and ipratropium mixture being filled into a vial, and then packaged, stored and/or used directly. Here, the resulting mixture is stable, and after sterilization, it can be dispersed, if necessary, into multiple mixtures each containing a unit dose of a therapeutically effective amount of albuterol and ipratropium.

Osmotic adjusting agents which may be used include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other osmotic adjusting IND agents may also include, but are not limited to, mannitol, glycerol, and dextrose and mixtures thereof.

In an alternative embodiment, the present invention may comprise about 0.4 to about 1.0 weight percent ionic salt. Preferably, the present invention comprises 0.9 wt of an osmotic adjusting agent.

In an alternative embodiment, the inhalation solution of the present invention may be prepared as follows: fitting a stainless steel formulation tank with a bottom drain and a tri-blender for mixing; (ii) filling the tank with approximately 95% of the required amount of Purified Water USP at a temperature of between 18 0 C to 25 0 C; while mixing, (iii) adding EDTA USP, hydrochloric acid, and at least a therapeutically effective amount of Albuterol Sulfate USP and Ipratropium Bromide to the tank; (iv) continue mixing until all chemical components are dissolved; adding Purified Water USP to adjust the final volume, if necessary, thus producing an albuterol and ipratropium bromide mixture.

From the formulation tank, the albuterol and ipratropium mixture is pumped through sanitary delivery lines directly into a form-fill-seal (FFS) machine. The albuterol and ipratropium mixture passes through a 0.2 micron sterilizing cartridge filter, then into a reservoir tank, through a second 0.2 micron sterilizing cartridge filter to the filling nozzles within the sterile air shower compartment, and subsequently into formed vials of low density polyethylene (LDPE). The albuterol and ipratropium mixture being sterile filled into the vials such that each vial contains a single unit dose of a therapeutically effective amount of albuterol. The filled vials are then sealed. The FFS machine may form, fill and seal the vials in a continuous operation under aseptic conditions, thus producing a sterile product. For example, cards of five filled vials (Figure 6) may be overwrapped into a protective laminated foil pouch using an autowrapper machine. Six to twelve such pouches may then be packaged in a shelf carton, thus forming a prepackaged therapeutic system for treating COPD in patients. An appropriate label and instructions may be added in the shelf carton.

The present invention is also directed to a method of forming a unit-dose nebulizer solution comprising the step of: preparing a mixture containing a therapeutically effective amount of albuterol and ipratropium bromide in a pharmaceutically acceptable carrier. Said mixture being suitable for nebulization in a nebulizer.

In an alternative embodiment, the present invention also comprises a device for use in the relief of symptoms associated with COPD, including bronchospasm. Such device may take the form of a label, written instructions or any other form incorporating indicia thereon. The device may comprise UbC/593031 sped

NO

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(-i (-q indicia which indicates that a patient suffering from symptoms associated with COPD can be treated with at least one prepackaged, sterile, premixed, premeasured and/or BAC-free inhalation solution comprising a unit dose of a therapeutically effective amount of albuterol and ipratropium in a single vial, The inhalation solution being suitable for nebulization in a nebulizer. The device may also 5 comprise indicia which provides instructions for utilizing the inhalation solution to treat said symptoms in patients.

Examples To evaluate the efficacy and safety of the inhalation solution of the present invention, a doubleblind, randomized, positive control trial was performed. The design, results and conclusion of the study are described in detail below.

Patients A total of 863 patients were initially randomized for enrollment in the trial. To be eligible for enrollment, patients had to meet the criteria described in Table 3.

Table 3 Inclusion/Exclusion Criteria Design Element Description Inclusion Criteria Diagnosis with COPD with an FEV 1 between 25% and 65% of the normal predicted value.

Age >40 years.

Regular use of one or more bronchodilators for a minimum of 3 months prior to enrollment.

History of at least 10 pack-years of smoking.

Ability to refrain from the use of theophylline, salmeterol and oral 13 agonists for the duration of the trial (as judged by the investigator).

Ability to safely complete a 6-minute walk.

Willingness to provide informed consent.

Exclusion Criteria Diagnosis of anthracosis, silicosis, any parenchymal disease not attributable to COPD, polycythemia, or pulmonale, hypoxia, or a primary diagnosis attributable to allergic rhinitis, atopy, or COPD.

Clinically significant obstructive urinary disease, narrow-angle glaucoma, unstable angina pectoris or myocardial infarction in the past 6 months, known drug abuse within the last 12 months, or hospitalization for pulmonary exacerbation within the past 2 months.

Known hypersensitivity to any component of the study medications.

Investigational drug use within 30 days of first dose of study medication.

Pregnancy or breastfeeding.

Interventions The doses of each individual agent and the ipratropium and albuterol combination were as shown in Table 4 below. All study medications were administered 4 times per day (ideally every 6 hours) by inhalation using a Pari LC Plus

T

M nebulizer and Pari PronebM compressor. Concomitant use of bronchodilators was restricted during the trial. Oral and inhaled steroic use was permitted throughout the trial, provided that dosing remained constant.

Table 4 Study Medication Albuterol (base) Ipratropium bromide Albuterol alone Ipratropium alone Albuterol and Ipratropium 2.5mg Combination UbC/593031speci SEfficacy Results Of the 863 patients who were randomized and began treatment, 289 withdrew prematurely from the trial, including 28 patients who did not meet the inclusion/exclusion criteria and were inappropriately enrolled. A total of 663 patients received both the inhalation solution of the present s invention and at least one other study medication and completed at least one post-dose measurement of FEV 1 These subjects contributed to the 647 evaluable comparisons in each portion of the primary analysis, as the majority of patients completed treatment on all three study medications.

The primary efficacy variable was the change from pre-dose to peak FEVi measured within 3 00 ihours after dosing during the crossover phase of the trial. As can be seen in Table 5, the mean increase in FEV1 was significantly higher for the albuterol and ipratropium combination than for either agent used alone. The improvement for the combination over albuterol alone was 23.6% and over ipratropium alone was 37.2%. The time course of FEV 1 response is shown in Table 6.

(Table Efficacy Results in Crossover Phase Parameter Combination vs. Albuterol Combination vs. Ipratropium n Combination Albuterol p value n Combination Ipratropium p value mean mean mean mean Peak FEV 1 (liters) 647 0.387 0.313 <0.001 647 0.387 0.282 <0.001 Table 6 Mean change in FEV1 Measured on Day 14 4 a 1 -amB During the parallel phase of the trial, separate groups of patients self-administered only one of the three study medications during the final 6 weeks of the trial, Results for the parallel phase yielded results essentially identical to the crossover phase. The albuterol and ipratropium combination maintained the same magnitude of superiority over each component medication alone that was observed during the crossover phase in peak FEVi response.

UbC/593031 spea Safetyrrolerability Adverse reactions concerning the albuterol and ipratropium combination were evaluated from the clinical trials described above. Treatment-emergent adverse events that were reported by 1% or greater of patients are summarized by medication in Table 6. As can be seen, there were no differences between the albuterol and ipratropium combination and the individual medication in incidence of patients with adverse events across body systems.

Table 6 Adverse Event Reports (ADVERSE EVENTS OCCURRING IN OF TREATMENT GROUP(S) AND WHERE THE COMBINATION TREATMENT SHOWED THE HIGHEST PERCENTAGE) Body System Albuterol Ipratropium Albuterol and COSTART Term n n Ipratropium Combination n NUMBER OF PATIENTS 761 754 765 N Patients with A 327 (43.0) 329 367 (48.0) (43.6) BODY AS A WHOLE Pain 8(1.1) 4(0.5) 10(1.3) Pain chest 11 14(1.9) 20(2.6)

DIGESTIVE

Diarrhea 5 9(1.2) 14(1.8) Dyspepsia 7(0.9) 8(1.1) 10(1.3) Nausea 7(0.9) 6(0.8) 11 (1.4)

MUSCULO-SKELETAL

Cramps leg 8 6(0.8) 11(1.4)

RESPIRATORY

Bronchitis 11(1.4) 13(1.7) 13(1.7) Lung Disease 36 34 49 (6.4) Pharyngitis 27 27 34 (4.4) Pneumonia 7 8(1.1) 10(1.3)

UROGENITAL

Infection urinary tract 3 9(1.2) 12 (1.6) Additional adverse reactions reported in more than 1% of patients treated with the albuterol and ipratropium combination included constipation and voice alterations.

The figures and attachments herein are presented for illustrative proposes only. They are not intended to limit the scope of the invention. Further, it should be understood that various changes and modifications to the presently preferred embodiment described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

Also, the invention may suitably comprise, consist of or consist essentially of the elements described herein further, and the invention described herein suitably may be practiced in the absence of any element which is not specifically disclosed herein.

UbC/593031sped

Claims (41)

1. An inhalation solution comprising: a premixed, premeasured aqueous formulation comprising a single unit dose of a Stherapeutically effective amount of albuterol and ipratropium bromide for inducing bronchodilation or IND 5 providing relief of bronchospasm in patients suffering from chronic obstructive pulmonary disease, wherein the amount of albuterol in the inhalation solution ranges from about 0.60mg to about and the amount of ipratropium bromide ranges from about 0.01mg to about 1.0mg; the solution being provided in a single container.

2. The inhalation solution of claim 1, wherein the inhalation solution is sterile.

3. The inhalation solution of claim 1, wherein the inhalation solution is free of benzalkonium ID chloride.

4. The inhalation solution of claim 1, wherein the pH of the inhalation solution ranges from about 3.0 to about The inhalation solution of claim 1, wherein the pH of the inhalation solution is about is 6. The inhalation solution of claim 1, wherein the albuterol is in the form of an acid addition salt thereof.

7. The inhalation solution of claim 6, wherein the acid addition salt of albuterol is albuterol sulfate.

8. The inhalation solution of claim 1, wherein the albuterol is in the form of a racemic mixture.

9. The inhalation solution of claim 1, wherein the amount of albuterol in the inhalation solution ranges from about 2.00mg to about 3.00mg. The inhalation solution of claim 1, wherein the amount of albuterol in the solution is about

11. The inhalation solution of claim 1, wherein the inhalation solution is suitable for nebulization in a nebulizer.

12. The inhalation solution of claim 11, wherein said nebulizer is selected from the group consisting of a jet nebulizer, ultrasonic nebulizer and breath actuated nebulizer.

13. An inhalation solution comprising: a sterile, premixed, premeasured aqueous formulation free of benzalkonium chloride comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium bromide for inducing bronchodilation or providing relief of bronchospasm in patients suffering from chronic obstructive pulmonary disease, wherein the amount of albuterol in the solution is about 2.50mg and the amount of ipratropium bromide is about 0.5mg, the solution being provided in a single container and wherein the inhalation solution is suitable for nebulization in a nebulizer.

14. A method of inducing bronchodilation or providing relief of bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said method comprising the step: administering to said patient the inhalation solution of claim 1. The method of claim 14, wherein the inhalation solution is sterile when administered to the patient. UbC593031sped 0 16. The method of claim 14, wherein the inhalation solution is free of benzalkonium chloride. O 0 17. The method of claim 14, wherein the albuterol is in the form of an acid addition salt thereof. S18. The method of claim 17, wherein the acid addition salt of albuterol is albuterol sulfate.

19. The method of claim 14, wherein the albuterol is in the form of a racemic mixture. The method of claim 14, wherein the amount of albuterol in the inhalation solution ranges from about 2.0mg to about

21. The method of claim 14, wherein the amount of albuterol in the inhalation solution is about

22. The method of claim 14, wherein the inhalation solution is administered to the patient by I0 nebulization.

23. A method of inducing bronchodilation or providing relief of bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said method comprising the step: administering to the patient the inhalation solution of claim 13 by nebulization.

24. A method of inducing bronchodilation or providing relief of bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said method comprising the steps: a) placing the inhalation solution into a chamber of a nebulizer, said nebulizer having a mouthpiece or facemask associated with the chamber of the nebulizer; b) positioning the mouthpiece or facemask in close proximity to the patient's mouth or face; c) passing the inhalation solution in a mist form from the nebulizer chamber through the mouthpiece or facemask to the patient while the patient breathes into the mouthpiece or facemask; and d) the patient breathing into the mouthpiece or facemask until at least substantially all the mist is removed from the nebulizer chamber.

25. A method of inducing bronchodilation or providing relief of bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said method comprising the steps of: providing instructions for administering to the patient the inhalation solution of claims 1.

26. A kit for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said kit comprising: one or more containers; said one or more containers each comprising a premixed, premeasured aqueous inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium bromide; wherein the amount of albuterol in the solution ranges from about 0.60mg to about 5.00mg and the amount of ipratropium bromide in the solution ranges from about 0.01mg to about 1.00mg; the solution being suitable for nebulization in a nebulizer.

27. The kit according to claim 26, wherein the inhalation solution is sterile.

28. The kit according to claim 26, wherein the inhalation solution is free of benzalkonium chloride.

29. The kit according to claim 26, wherein the amount of albuterol in the inhalation solution ranges from about 2.0mg to about 3.0mg albuterol. UbC/593031 sped ^0 30. The kit according to claim 26, wherein the amount of albuterol in the inhalation solution is Sabout 2.50mg.

31. The kit according to claim 26, further comprising a label which indicates that the Sinhalation solution can be used to relieve bronchospasm in patients suffering from chronic obstructive IND 5 pulmonary disease.

32. The kit according to claim 26, further comprising instructions for using the inhalation solution to relieve bronchospasm associated with chronic obstructive pulmonary disease.

33. The kit according to claim 26, wherein the one or more containers are packaged in the same pouch or box.

34. The kit of claim 33, wherein said one or more containers comprise semi-permeable I0 plastic and are packaged in an aluminum foil pouch. A kit for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said kit comprising: a) one or more containers; said one or more containers each comprising a sterile, benzalkonium-free, premixed, premeasured aqueous inhalation solution for use in a nebulizer; said inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium bromide, wherein said amount of albuterol is about 2.50mg and the amount of ipratropium bromide is about b) a label which indicates that the inhalation solution can be used to relieve bronchospasm in patients suffering from chronic obstructive pulmonary disease; and c) instructions for using the solution to relieve said bronchospasm.

36. A prepackaged therapeutic system for treating bronchospasm in patients suffering from chronic obstructive pulmonary disease, said prepackaged therapeutic system comprising packaging material, wherein said packaging material comprises: a) one or more containers; said one or more containers each comprising a premixed, premeasured aqueous inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium bromide; wherein said amount of albuterol ranges from 0.60mg to about 5.0mg and said amount of ipratropium bromide ranges from about 0.01mg to about 1.0mg; the solution being suitable for nebulization in a nebulizer.

37. The prepackaged therapeutic system of claim 36, wherein said amount of albuterol ranges from about 2.00mg to about 3.00mg.

38. The prepackaged therapeutic system of claim 36, wherein said amount of albuterol is about

39. The prepackaged therapeutic system of claim 36, wherein the inhalation solution in each of the one or more containers is sterile. The prepackaged therapeutic system of claim 36, wherein the inhalation solution in each of the one or more containers is free of benzalkonium chloride.

41. The prepackaged therapeutic system of claim 36, wherein said packaging material further comprises a label which indicates that the inhalation solution can be used to relieve bronchospasm associated with chronic obstructive pulmonary disease. UbC/593031 spec

42. The prepackaged therapeutic system of claim 36, wherein said packaging material 0 comprises instructions for using the solution to relieve said bronchospasm.

43. A prepackaged therapeutic system for treating bronchospasm in patients suffering from chronic obstructive pulmonary disease, said prepackaged therapeutic system comprising packaging s material, wherein said packaging material comprises: a) one or more containers; the one more containers each comprising a sterile, premixed, premeasured aqueous inhalation solution free of benzalkonium chloride for nebulization in a nebulizer; the inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium bromide, wherein the amount of albuterol is about 2.50mg and the amount of ipratropium bromide is about 0 b) a label indicating that the inhalation solution can be used to relieve said bronchospasm; 0and c) instructions for using the inhalation solution to relieve said bronchospasm.

44. A method of making a premixed, premeasured inhalation solution for treating bronchospasm in patients suffering from chronic obstructive pulmonary disease; said method comprising the steps: a) placing a unit dose of a therapeutically effective amount of albuterol and ipratropium bromide in a vehicle, wherein the concentration of albuterol in the vehicle ranges from about 0.60mg to about 5.0mg and the concentration of the ipratropium bromide in the carrier ranges from 0.01mg to 1.00mg; and b) providing the inhalation solution in a single container. The method of claim 44, further comprising the step of adding hydrochloric acid to adjust the pH of the inhalation solution to a level ranging from about 3.0 to about

46. The method of claim 44, further comprising the step of adding an osmotic agent to adjust the isotonicity of the inhalation solution; wherein the osmotic adjusting agent is selected from the group consisting of sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof.

47. The method according to claim 44, further comprising the step: sterilizing the inhalation solution by passing it through a filter or by steam sterilization.

48. The method of claim 44, further comprising the step of adding hydrochloric acid to adjust the pH of the inhalation solution to about

49. A device for use in relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease, the device having indicia; the indicia providing instructions for utilizing a premixed, premeasured inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium bromide to treat said bronchospasm; wherein said amount of albuterol ranges from about 2.00mg to about 3.00mg albuterol and the amount of ipratropium bromide ranges from 0.20mg to 0.60mg; said solution being suitable for nebulization in a nebulizer. An inhalation solution substantially as hereinbefore described with reference to any one of the examples. UbC/593031 spe 19

51. A kit for treating bronchospasm in a patient suffering from chronic obstructive pulmonary 0 disease, said kit being substantially as hereinbefore described with reference to any one of the 1 examples.

52. A prepackaged therapeutic system for treating bronchospasm in patients suffering from chronic obstructive pulmonary disease, said prepackaged therapeutic system being substantially as hereinbefore described with reference to any one of the examples.

53. A method of making a premixed, premeasured inhalation solution for treating Sbronchospasm in patients suffering from chronic obstructive pulmonary disease; said method being 00 io substantially as hereinbefore described with reference to any one of the examples.

54. A device for use in relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease, the device being substantially as hereinbefore described with reference to the 0 accompanying drawings. Dated 16 June, 2006 DEY, L.P. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON UbC/593031speci