Bronchodilating beta-agonist compositions and methods

Information

  • Patent Grant
  • 7462645
  • Patent Number
    7,462,645
  • Date Filed
    Tuesday, March 20, 2007
    17 years ago
  • Date Issued
    Tuesday, December 9, 2008
    16 years ago
Abstract
Bronchodilating compositions and methods are provided. The compositions are intended for administration as a nebulized aerosol. In certain embodiments, the compositions contain formoterol, or a derivative thereof. Methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders using the compositions provided herein are also provided.
Description
FIELD

Compositions and methods are provided relating to treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders. In particular, the compositions and methods herein include formatter, and/or derivatives thereof. The compositions are propellant-free, sterile unit dose or multidisc inhalation solutions intended for administration via mobilization.


BACKGROUND

Bronchoconstrictive disorders affect millions worldwide. Such disorders include asthma (including bronchial asthma, allergic asthma and intrinsic asthma, e.g., late asthma and airway hyper-responsiveness), chronic bronchitis and other chronic obstructive pulmonary diseases. Compounds having β2-adrenoreceptor agonist activity have been developed to treat these conditions. Such compounds include, but are not limited to, Ablution (α1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxyl-1,3-benzenedimethanol); Bambuterol (dimethylcarbamic acid 5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenyl ester); Bitolterol (4-methyl benzoic acid 4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenyl ester); Broxaterol (3-bromoα-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol); Isoproterenol (4-(1-hydroxyl-2-((1-methyl ethyl)amino)ethyl)-1,2-benzenediol); Trimetoquinol (1,2,3,4-tetra hydro-1-((3,4,5-trimethoxyphenyl)methyl)-6,7-isoquinolinediol); Clenbuterol (4-amino-3,5-dichloro-α-(((1,1-diemethylethyl)amino)methyl)benzene methanol); Fenoterol (5-(1-hydroxyl-2-((2-(4-hydroxyphenyl)-1-methyl ethyl)amino)ethyl)-1,3-benzenediol); Formatter (2-hydroxyl-5-((1RS)-1-hydroxyl-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethylamino)ethyl)formability); (R,R)-Formatter; Desformoterol ((R,R) or (S,S)-3-amino-4-hydroxy-α-(((2-(4-methoxyphenyl)-1-ethyl ethyl)amino)methyl)benzene-methanol); Hexoprenaline (4,4′-(1,6-hexanediyl)-bis(imino-(1-hydroxyl-2,1-ethane-idyll)))bis-1,2-benzenediol); Isoetharine (4-(1-hydroxyl-2-((1-methyl ethyl)amino)butyl)-1,2-benzenediol); Isoprinosine (4-(1-hydroxyl-2-((1-methyl ethyl)amino)ethyl)-1,2-benzenediol); Metaproterenol (5-(1-hydroxyl-2-((1-methyl ethyl)amino)ethyl)-1,3-benzenediol); Picumeterol (4-amino-3,5-dichloro-α-(((6-(2-(2-pyridine)ethics)hexyls)-amino)methyl)benzene methanol); Pirbuterol (α6-(((1,1-dimethylethyl)amino)methyl)-3-hydroxyl-2,6-pyridine methanol); Procter (((R*,S*)-(±)-8-hydroxyl-5-(1-hydroxyl-2-((1-methyl ethyl)amino)butyl)-2(1H)-quinolinone); Reporter ((7-(3-((2-(3,5-dihydroxy-phenyl)-2-hydroxyethyl)amino)propel)-3,7-dihedron-1,3-diethyl-1H-urine-2,6-done); Rimier (4-(hydroxyl-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol ((±)-α1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxyl-1,3-benzenedimethanol); (R)-Salbutamol; Salmeterol ((±)-4-hydroxy-α1-(((6-(4-phenylbutoxy)hexyls)amino)methyl)-1,3-benzenedimethanol); (R)-Salmeterol; Terbutaline (5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol); Tulobuterol (2-chloro-α-(((1,1-diethyl-ethyl)amino)methyl)benzene methanol); and TA-2005 (8-hydroxyl-5-((1R)-1-hydroxyl-2-(N-((1R)-2-(4-methoxyphenyl)-1-methyl ethyl)amino)ethyl)carbostyril hydrochloride).


These compounds are typically formulated for inhalation therapy. Aqueous or liquid formulations are preferred over solid formulations. Powdered formulations are more difficult to administer, particularly to the young and elderly who are most often the patients in need of such therapy. Compounds, such as formatter are not adequately stable in aqueous solutions to be formulated as liquids. Hence there is a need for formulations of compounds, such as formatter, in a form that can be conveniently administered and that are stable for extended periods of time.


SUMMARY

Compositions and methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders are provided. The compositions provided herein are stable solutions of a bronchodilating agent, or a derivative thereof, in a pharmacologically suitable fluid that contains water, that are stable during long term storage. The compositions are suitable for direct administration to a subject in need thereof. Pharmacologically suitable fluids include, but are not limited to, polar fluids, including portico fluids. In certain embodiments herein, the compositions are aqueous solutions.


The compositions provided herein possess an estimated shelf-life of greater than 1, 2 or 3 months usage time at 25° C. and greater than or equal to 1, 2 or 3 years storage time at 5° C. In certain of these embodiments, using Arrhenius kinetics, >80% or >85% or >90% or >95% estimated bronchodilating agent remains after such storage. These compositions are particularly useful for administration via mobilization. In certain embodiments herein, the subject is a mammal. In other embodiments, the subject is a human.


The compositions provided herein are formulated to remain stable over a relatively long period of time. For example, the compositions provided herein are stored between −15° C. and 25° C., or between 2° C. and 8° C., and remain stable for the desired time. In one embodiment, the compositions are stored at 5° C. In other embodiment, the compositions are stored at 25° C.


Among the bronchodilating agents for use herein are Ablution (α1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxyl-1,3-benzenedimethanol); Bambuterol (dimethylcarbamic acid 5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenyl ester); Bitolterol (4-methyl benzoic acid 4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenyl ester); Broxaterol (3-bromo-α-(((1,1-dimethylethyl)amino)-methyl)-5-isoxazolemethanol); Isoproterenol (4-(1-hydroxyl-2-((1-methyl ethyl)amino)ethyl)-1,2-benzenediol); Trimetoquinol (1,2,3,4-tetra hydro-1-((3,4,5-trimethoxyphenyl)methyl)-6,7-isoquinolinediol); Clenbuterol (4-amino-3,5-dichloro-α-(((1,1-dimethylethyl)amino)methyl)benzene methanol); Fenoterol (5-(1-hydroxyl-2-((2-(4-hydroxyphenyl)-1-methyl ethyl)amino)ethyl)-1,3-benzenediol); Formatter (2-hydroxyl-5-((1RS)-1-hydroxyl-2-(((1RS)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)-formability); (R,R)-Formatter; (S,S)-Formatter; Desformoterol ((R,R) or (S,S)-3-amino-4-hydroxy-α-(((2-(4-methoxyphenyl)-1-methyl ethyl)amino)methyl)benzene-methanol); Hexoprenaline (4,4′-(1,6-hexanediyl)-bis(imino(1-hydroxyl-2,1-ethane-idyll)-))bis-1,2-benzenediol); Isoetharine (4-(1-hydroxyl-2-((1-methyl ethyl)amino)-butyl)-1,2-benzenediol); Isoprinosine (4-(1-hydroxyl-2-((1-methyl ethyl)amino)ethyl)-1,2-benzenediol); Metaproterenol (5-(1-hydroxyl-2-((1-methyl ethyl)amino)ethyl)-1,3-benzenediol); Picumeterol (4-amino-3,5-dichloro-α-(((6-(2-(2-pyridine)ethics)hexyls)-amino)methyl)benzene methanol); Pirbuterol (α6-(((1,1-dimethylethyl)amino)methyl)-3-hydroxyl-2,6-pyridine methanol); Procter (((R*,S*)-(±)-8-hydroxyl-5-(1-hydroxyl-2-((1-methyl ethyl)amino)butyl)-2(1H)-quinolinone); Reporter ((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)propel)-3,7-dihedron-1,3-diethyl-1H-urine-2,6-done); Rimier (4-(hydroxyl-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol ((±)-α1-(((1,1-dimethylethyl)-amino)methyl)-4-hydroxyl-1,3-benzenedimethanol); (R)-Salbutamol; Salmeterol ((±)-4-hydroxy-α1-(((6-(4-phenylbutoxy)hexyls)amino)methyl)-1,3-benzenedimethanol); (R)-Salmeterol; Terbutaline (5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol); Tulobuterol (2-chloro-α-(((1,1-diethyl-ethyl)amino)methyl)benzene methanol); and TA-2005 (8-hydroxyl-5-((1R)-1-hydroxyl-2-N-((1R)-2-(4-metonym-phenyl)-1-methyl ethyl)amino)ethyl)carbostyrilhydrochloride).


Of particular interest herein is formatter, having the formula:




embedded image


Formatter for use in the compositions and methods provided herein includes 2-hydroxyl-5-((1RS)-1-hydroxyl-2-(((1RS)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability; or a stereoisomer thereof, and also includes the single enantiomers 2-hydroxyl-5-((1S)-1-hydroxyl-2-(((1S)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability and 2-hydroxyl-5-((1R)-1-hydroxyl-2-(((1R)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability.


In certain embodiments, the compositions are administered via mobilization. Administration of a nebulizer aerosol is preferred over the use of dry powders for inhalation in certain subject populations, including pediatric and geriatric groups.


In one embodiment, the compositions for use in the methods provided herein contain a pharmaceutically acceptable derivative of formatter. In another embodiment, the compositions for use in the methods provided herein contain a pharmaceutically acceptable salt of formatter. Pharmaceutically acceptable salts include, but are not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, maltase, tart rates, citrates, acerbates, succinctness, butyrate's, vale rates and fumigates. In one embodiment, the compositions for use in the methods provided herein contain formatter fumigate or formatter fumigate dehydrate. In another embodiment, the compositions for use in the methods provided herein contain formatter tart rate.


Also provided herein are combinations containing a composition provided herein and a nebulizer. The combinations can be packaged as kits, which optionally contain other components, including instructions for use of the nebulizer. Any nebulizer is contemplated for use in the kits and methods provided herein. In particular, the nebulizers for use herein nebulizer liquid formulations, including the compositions provided herein, containing no propellant. The nebulizer may produce the nebulizer mist by any method known to those of skill in the art, including, but not limited to, compressed air, ultrasonic waves, or vibration. The nebulizer may further have an internal baffle. The internal baffle, together with the housing of the nebulizer, selectively removes large droplets from the mist by impaction and allows the droplets to return to the reservoir. The fine aerosol droplets thus produced are entrained into the lung by the inhaling air/oxygen.


Methods for the treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders, including, but not limited to, asthma, including, but not limited to, bronchial asthma, allergic asthma and intrinsic asthma, e.g., late asthma and airway hyper-responsiveness; chronic bronchitis; and other chronic obstructive pulmonary diseases are provided. The methods involve administering an effective amount of a pharmaceutical composition provided herein to a subject in need of such treatment.


Articles of manufacture, containing packaging material, a composition provided herein, which is useful for treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction, and a label that indicates that the composition is used for treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction, are also provided.







DETAILED DESCRIPTION

Definitions


Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.


As used herein, formatter refers to 2-hydroxyl-5-((1RS)-1-hydroxyl-2-(((1RS)-2-p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability; or a stereoisomer thereof. The term formatter also refers to the single enantiomers 2-hydroxyl-5-((1S)-1-hydroxyl-2-(((1S)-2-p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability ((S,S)-formatter) and 2-hydroxyl-5-((1R)-1-hydroxyl-2-(((1R)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)-ethyl)formability ((R,R)-formatter).


As used herein, formatter fumigate refers to a salt of formatter having the formula (formatter)·1/2 fumigate.


As used herein, formatter free base refers to the neutral, anhydrous form of formatter. Thus, a recitation that a composition contains, e.g., 20 μg/mL of formatter free base means that the composition contains 20 μg/mL of neutral, anhydrous formatter. Such compositions may be prepared using a derivative of formatter.


As used herein, an aerosol is liquid or particulate matter dispersed in air. Aerosols include dispersions of liquids, including aqueous and other solutions, and solids, including powders, in air.


As used herein, a nebulizer solution refers to a solution that is dispersed in air to form an aerosol. Thus, a nebulizer solution is a particular form of an aerosol.


As used herein, a nebulizer is an instrument that is capable of generating very fine liquid droplets for inhalation into the lung. Within this instrument, the mobilizing liquid or solution is atomized into a mist of droplets with a broad size distribution by methods known to those of skill in the art, including, but not limited to, compressed air, ultrasonic waves, or a vibrating orifice. Nebulizers may further contain, e.g., a baffle which, along with the housing of the instrument, selectively removes large droplets from the mist by impaction. Thus, the mist inhaled into the lung contains fine aerosol droplets.


As used herein, a pharmacologically suitable fluid is a solvent suitable for pharmaceutical use which is not a liquefied propellant gas. Exemplary pharmacologically suitable fluids include polar fluids, including portico fluids such as water.


As used herein, a kit refers to one or more items, including, but not limited to, compounds, compositions, combinations, instruments and devices, suitably packaged for use. Kits provided herein optionally contain instructions for use.


As used herein, a combination refers to any association between two or among more items.


As used herein, fluid refers to any composition that can flow. Fluids thus encompass compositions that are in the form of semi-solids, pastes, solutions, aqueous mixtures, gels, lotions, creams and other such compositions.


As used herein, a mixture is a mutual incorporation of two or more substances, without chemical union, the physical characteristics of each of the components being retained.


As used herein, the stability of a composition provided herein refers to the length of time at a given temperature that is greater than 80%, 85%, 90% or 95% of the initial amount of active ingredient, e.g., formatter, is present in the composition. Thus, for example, a composition that is stable for 30 days at 25° C. would have greater than 80%, 85%, 90% or 95% of the initial amount of active ingredient present in the composition at 30 days following storage at 25° C.


As used herein, pharmaceutically acceptable derivatives of a compound include salts, esters, enroll ethers, enroll esters, acids, bases, solvates, hydrates or prod rugs thereof Such derivatives may be readily prepared by those of skill in this art using known methods for such dramatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prod rugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N′-dibenzylethylenediamine, chlorpromazine, chorine, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyramiding-1′-ylmethylbenzimidazole, diethylamide and other alkyl amines, pauperizing and tries(hydroxymethyl)amino methane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, maltase, tart rates, citrates, acerbates, succinctness, butyrate's, vale rates and fumigates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alchemy, alkynes, aryl, heteroaryl, a alkyl, heteroaralkyl, cyclically and heterocyclic esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphoric acids, sulfuric acids, sulfuric acids and moronic acids. Pharmaceutically acceptable enroll ethers include, but are not limited to, derivatives of formula C═C(OR) where R is hydrogen, alkyl, alchemy, alkynes, aryl, heteroaryl, a alkyl, heteroaralkyl, cyclically and heterocyclic. Pharmaceutically acceptable enroll esters include, but are not limited to, derivatives of formula C═C(OC(O)R) where R is hydrogen, alkyl, alchemy, alkynes, aryl, heteroaryl, a alkyl, heteroaralkyl, cyclically and heterocyclic. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecule, in certain embodiments 1 to about 100, in other embodiments 1 to about 10, in further embodiments one to about 2, 3 or 4, solvent or water molecules. Formatter salts and hydrates are used in certain embodiments herein.


As used herein, treatment means any manner in which one or more of the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating cancer.


As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.


As used herein, a prod rug is a compound that, upon in vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prod rug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes. The prod rug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prod rugs of the compound (see, e.g., Norgay (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).


It is to be understood that the compounds for use in the compositions and methods provided herein may contain choral centers. Such choral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds for use in the compositions provided herein may be enantiomerically pure, or be stereo isomeric or diastereomeric mixtures. It is to be understood that the choral centers of the compounds provided herein may undergo epimerization in vivo. Thus, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.


As used herein, bronchoconstriction refers to a reduction in the caliber of a bronchus or bronchi.


As used herein, undesired and/or uncontrolled bronchoconstriction refers to bronchoconstriction that results in or from a pathological symptom or condition. Pathological conditions include, but are not limited to, asthma and chronic obstructive pulmonary disease (COPD). Pathological symptoms include, but are not limited to, asthma and COPD.


As used herein, the statement that a composition is stable during “long term storage” means that the composition is suitable for administration to a subject in need thereof when it has an estimated shelf-life of greater than 1, 2 or 3 months usage time at 25° C. and greater than or equal to 1, 2 or 3 years storage time at 5° C. In certain embodiments herein, using Arrhenius kinetics, >80% or >85% or >90% or >95% estimated bronchodilating agent remains after such storage.


A. Formoterol


Formoterol (2-hydroxyl-5-((1RS)-1-hydroxyl-2-(((1RS)-2-(p-methoxyphen-yl)-1-methyl ethyl)amino)ethyl)formability) is derived from adrenaline and, as noted above, is used as a β2-stimulator in inhalation therapy of respiratory diseases, particularly for the treatment of bronchial asthma. It has been reported that in patients with reversible obstructive respiratory diseases, formatter has a bronchodilator effect. This effect has a relatively rapid onset (approximately 1-3 minutes) and a relatively long duration (greater than 12 hours). Formatter inhibits the release of leukotrienes and other messenger substances involved with inflammation, such as histamines. In addition, formatter may bring about a hyperglycemic activity.


To date, formatter has been formulated as a dry powder and administered via devices such as the TURBUHALER® and the AEROLIZER®. See, e.g., Siberia et al. (2000) Respire. Med. 94(6):607-61 1; Lotvall et al. (1999) Can. Respir. J. 6(5):412-416; Campbell et al. (1999) Respir. Med. 93(4):236-244; Nightingale et al. (1999) Am. J. Respir. Crit. Care Med. 159(6):1786-1790; Lecaillon et al. (1999) Eur. J. Clin. Pharmacol. 55(2);131-138; Bartow et al. (1998) Drugs 55(2):303-322; Ekstrom et al. (1998) Respir. Med. 92(8):1040-1045; Ringdal et al. (1998) Respir. Med. 92(8):1017-1021; Totterman et al. (1998) Eur. Respir. J. 12(3):573-579; Palmqvist et al. (1997) Eur. Respir. J. 10(11):2484-2489; Nielsen et al. (1997) Eur. Respir. J. 10(9);2105-2109; Ullman et al. (1996) Allergy 51(10):745-748; Selroos et al. (1996) Clin. Immunother. 6:273-299; and Schreurs et al. (1996) Eur. Respir. J. 9(8):1678-1683.


Formoterol is also available as a tablet and a dry syrup in certain areas of the world (e.g., ATOCK®, marketed by Yamanouchi Pharmaceutical Co. Ltd., Japan). Formoterol formulations are also available in other areas (e.g., Europe and U.S.) for propellant-based metered dose inhalers and dry powder inhalers (e.g., TURBUHALER®, AEROLIZER® AN) FORADIL AEROLIZER®). None of these formulations are water based. Sterile, stable, aqueous based inhalation solutions of formatter for mobilization are not available, nor have they been reported.


In the treatment of bronchoconstrictive diseases, sufficient amount of the inhaled drug should reach their local site of action in order to be efficacious. It is known that different delivery methods and delivery devices have different deposition characteristics. Consequently, under optimal inhalation conditions, doses from different delivery methods and delivery devices result in different delivered doses and different amounts deposited at the active site. The actual dose reaching the active site also depends upon the amount of drug particles included in the delivered dose and the inhalation characteristics of the patient. No correlation between the amount of drug administered by dry powder inhalers (DPIs) or metered dose inhalers (MDIs) and the actual amount that gets deposited at the active site has been established so far. Nor has a correlation been established between DPI or MDI dosages and mobilization dosages.


Compositions containing formatter in combination with other active ingredients have been disclosed. See, e.g., U.S. Pat. Nos. 6,004,537, 5,972,919 and 5,674,860 (formatter and budenoside), U.S. Pat. Nos. 5,668,110, 5,683,983, 5,677,280 and 5,654,276 (formatter and IL-5 inhibitors), U.S. Pat. No. 6,136,603 (formatter and antisense modulators of IL-5), U.S. Pat. No. 5,602,110 (formatter and million), U.S. Pat. No. 5,525,623 (formatter and a striptease inhibitor), U.S. Pat. Nos. 5,691,336, 5,877,191, 5,929,094, 5,750,549 and 5,780,467 (formatter and a tachykinin receptor antagonist); and International Patent Application Publication Nos. WO 99/00134 (formatter and rofleponide) and WO 99/36095 (formatter and a dopamine D2 receptor agonist).


Other compositions containing formatter have been disclosed in U.S. Pat. Nos. 5,677,809, 6,126,919, 5,733,526, 6,071,971, 6,068,833, 5,795,564, 6,040,344, 6,041,777, 5,874,481, 5,965,622 and 6,161,536.


U.S. Pat. No. 6,150,418 discloses a “liquid active substance concentrate” containing formatter in the form of its free base or in the form of one of the pharmacologically acceptable salts or addition products (adducts) thereof as active substance. This “liquid active substance concentrate” is reported to be a concentrated (i.e., greater than 10 mg/mL, preferably 75 to 500 mg/mL) solution or suspension that is stable for a period of several months possibly up to several years without any deterioration in the pharmaceutical quality. This patent teaches that it is the high concentration that allows for the stability of the concentrate. The “liquid active substance concentrate” is not suitable for direct administration to a patient.


U.S. Pat. No. 6,040,344 discloses an aqueous aerosol formulation of formatter tart rate for use in a nebulizer. This patent states that the formulation disclosed therein is not attractive for long term storage.


B. Compositions for Use in Treatment, Prevention, or Amelioration of One or More Symptoms of Bronchoconstrictive Disorders


Pharmaceutical compositions containing a β2-adrenoreceptor agonist for administration via mobilization are provided. The compositions are sterile filtered and filled in vials, including unit dose vials providing sterile unit dose formulations which are used in a nebulizer and suitably nebulizer. Each unit dose vial is sterile and is suitably nebulizer without contaminating other vials or the next dose.


The unit dose vials are formed in a form-fill-seal machine or by any other suitable method known to those of skill in the art. The vials may be made of plastic materials that are suitably used in these processes. For example, plastic materials for preparing the unit dose vials include, but are not limited to, low density polyethylene, high density polyethylene, polypropylene and polyesters. In one embodiment, the plastic material is low density polyethylene.


In one embodiment, the β2-adrenoreceptor agonist is formatter, or a pharmaceutically acceptable derivative thereof. In other embodiments, the formatter for use in the compositions provided herein is formatter fumigate. Formoterol refers to 2-hydroxyl-5-((1RS)-1-hydroxyl-2-(((1RS)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability; or a stereoisomer thereof. The term formatter also refers herein to the single enantiomers 2-hydroxyl-5-((1S)-1-hydroxyl-2-(((1S)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability and 2-hydroxyl-5-((1R)-1-hydroxyl-2-(((1R)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability.


In certain embodiments, the compositions contain formatter fumigate at a concentration of about 0.1 μg/mL up to about 150 μg/mL, or 0.1 μg/mL up to 150 μg/mL. In further embodiments, the compositions contain formatter fumigate at a concentration of about 0.1 μg/mL up to about 100 μg/mL, or 0.1 μg/mL up to 100 μg/mL. The formatter fumigate is formulated, in certain compositions provided herein, at a concentration of about 0.1 μg/mL up to 50 μg/mL, or 0.1 μg/mL up to 50 μg/mL. In further embodiments, the compositions contain formatter fumigate at a concentration of about 0.1 μg/mL up to about 40 μg/mL, or 0.1 μg/mL up to 40 μg/mL. In further embodiments, the compositions contain formatter fumigate at a concentration of about 0.1 μg/mL up to about 20 μg/mL, or 0.1 μg/mL up to 20 μg/mL. The formatter fumigate is formulated, in other compositions provided herein, at a concentration of about 40 μg/mL, or 40 μg/mL. In further embodiments, the compositions contain formatter fumigate at a concentration of about 35 μg/mL, or 35 μg/mL. In other embodiments, the compositions contain formatter fumigate at a concentration of about 30 μg/mL, or 30 μg/mL. In other embodiments, the compositions contain formatter fumigate at a concentration of about 25 μg/mL, or 25 μg/mL. In further embodiments, the compositions contain formatter fumigate at a concentration of about 20 μg/mL, or 20 μg/mL. In another embodiment, the compositions contain formatter fumigate at a concentration of about 15 μg/mL, or 15 μg/mL. In another embodiment, the compositions contain formatter fumigate at a concentration of about 12 μg/mL, or 12 μg/mL. In another embodiment, the compositions contain formatter fumigate at a concentration of about 10 μg/mL, or 10 μg/mL. In another embodiment, the compositions contain formatter fumigate at a concentration of about 8 μg/mL, or 8 μg/mL. In another embodiment, the compositions contain formatter fumigate at a concentration of about 5 μg/mL, or 5 μg/mL. In another embodiment, the compositions contain formatter fumigate at a concentration of about 2.5 μg/mL, or 2.5 μg/mL. In another embodiment, the compositions contain formatter fumigate at a concentration of about 1 μg/mL, or 1 μg/mL.


In certain embodiments, the compositions contain formatter free base at a concentration of about 0.08 μg/mL up to about 128 μg/mL, or 0.08 μg/mL up to 128 μg/mL. In further embodiments, the compositions contain formatter free base at a concentration of about 0.08 μg/mL up to about 86 μg/mL, or 0.08 μg/mL up to 86 μg/mL. The formatter free base is formulated, in certain compositions provided herein, at a concentration of about 0.08 μg/mL up to 43 μg/mL, or 0.08 μg/mL up to 43 μg/mL. In further embodiments, the compositions contain formatter free base at a concentration of about 0.08 μg/mL up to about 34 μg/mL, or 0.08 μg/mL up to 34 μg/mL. In further embodiments, the compositions contain formatter free base at a concentration of about 0.08 μg/mL up to about 26 μg/mL, or 0.08 μg/mL up to 26 μg/mL. The formatter free base is formulated, in other compositions provided herein, at a concentration of about 0.08 μg/mL up to about 17 μg/mL, or 0.08 μg/mL up to 17 μg/mL. In further embodiments, the compositions contain formatter free base at a concentration of about 34 μg/mL, or 34 μg/mL. In Her embodiments, the compositions contain formatter free base at a concentration of about 30 μg/mL, or 30 μg/mL. In other embodiments, the compositions contain formatter free base at a concentration of about 25.6 μg/mL, or 25.6 μg/mL. In further embodiments, the compositions contain formatter free base at a concentration of about 21.4 μg/mL, or 21.4 μg/mL. In further embodiments, the compositions contain formatter free base at a concentration of about 17 μg/mL, or 17 μg/mL. In another embodiment, the compositions contain formatter free base at a concentration of about 13 μg/mL, or 13 μg/mL. In another embodiment, the compositions contain formatter free base at a concentration of about. 10 μg/mL, or 10 μg/mL. In another embodiment, the compositions contain formatter free base at a concentration of about 9 μg/mL, or 9 μg/mL. In another embodiment, the compositions contain formatter free base at a concentration of about 7 μg/mL, or 7 μg/mL. In another embodiment, the compositions contain formatter free base at a concentration of about 4 μg/mL, or 4 μg/mL. In another embodiment, the compositions contain formatter free base at a concentration of about 2 μg/mL, or 2 μg/mL. In another embodiment, the compositions contain formatter free base at a concentration of about 0.8 μg/mL, or 0.8 μg/mL.


The volume of formatter inhalation solution nebulizer depends on the nebulizer used. In certain embodiments, the volume is from about 0.1 mL up to about 3 mL, or 0.1 mL up to 3 mL. In other embodiments, the volume is about 2 mL, or 2 mL. In other embodiments, the volume is about 1 mL, or 1 mL. In other embodiments, the volume is about 0.5 mL, or 0.5 mL.


The compositions containing the β2-adrenoreceptor agonist, including formatter, are formulated with a pharmacologically suitable fluid. Pharmacologically suitable fluids include, but are not limited to, polar solvents, including, but not limited to, compounds that contain hydroxyl groups or other polar groups. Such solvents include, but are not limited to, water or alcohols, such as ethanol, isopropanol, and glycols including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol and polyoxyethylene alcohols.


Polar solvents also include portico solvents, including, but not limited to, water, aqueous saline solutions with one or more pharmaceutically acceptable salt(s), alcohols, glycols or a mixture thereof. For a saline solution as the solvent or as a component thereof, particularly suitable salts are those which display no or only negligible pharmacological activity after administration.


In the embodiments herein, the compositions have a pH of about 2.0 to about 8.0, or 2.0 to 8.0. In other embodiments, the compositions have a pH of about 4.0 to about 6.0, or 4.0 to 6.0. In other embodiments, the pH is about 4.5 to about 5.5, or 4.5 to 5.5. In certain of the above embodiments, the compositions are formulated at a pH of about 4, 4.4 or 4.6 up to about 5.5, 5.7 or 6; or 4, 4.4 or 4.6 up to 5.5, 5.7 or 6. In other embodiments, the pH is about 5.0, or 5.0. It has been found that the rate constant for decomposition of an aqueous solution of formatter is dependent on pH. The rate constant (kobs) at 60° C. at a pH of 3, 4, 5 and 7 is approximately 0.62, 0.11, 0.044 and 0.55 day. sup.-1, respectively. Therefore, the decomposition of formatter in aqueous solution at 60° C. at a buffer concentration of 5 mM and an ionic strength of 0.05 is slowest at a pH of about 5.0, or 5.0.


The solubility of formatter in aqueous solution has been found to be dependent on pH. Thus, at a pH of between about 5 and about 7, the aqueous solubility of formatter at ambient temperature is approximately 2.2 mg/mL. At a pH of about 4, the aqueous solubility of formatter at ambient temperature is approximately 3 mg/mL, while at a pH of about 3, the aqueous solubility of formatter at ambient temperature is about 4.8 mg/mL. The solubility of formatter in pure water, for example, high performance liquid chromatography (HPLC) water, at ambient temperature is approximately 2 mg/mL.


In other of the above embodiments, the compositions further contain a buffer, including, but not limited to, citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, acidulate, citrate, colliding, format, male ate, Mulvane, phosphate, Rideau-Ward, succinct, citrate-phosphate-borate (Teorell-Stanhagen), vernal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)imino-tris-(hydroxymethyl)methane), ADA (N-(2-actinide)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BISTRIS PROPANE (1,3-bis(tris(hydroxymethyl)methylamine)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS (3-N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropan-esulfonic acid), MOBS (4-(N-morpholino)-butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamine)-2-hydroxypropanesulfonic acid), TRIZMA(® (tris(hydroxymethylaminomethane), HEPPSO (N-(2-hydroxyethylpiperazine-N-(2-hydroxypropanesulfonic acid), POPSO (piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid), TRICINE (N-tris(hydroxyl-methyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)lysine), HEPBS (N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), AMPD (2-amino-2-methyl-1,3-propanediol), and/or any other buffers known to those of skill in the art. In one embodiment, the buffer is citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer. In another embodiment, the buffer is a citrate buffer (citric acid/sodium citrate). The buffer concentration has been found to affect the stability of the composition. Buffer concentrations for use include from about 0 or 0.01 mM to about 150 mM, or 0 or 0.01 mM to 150 mM. In another embodiment, the buffer concentration is about 1 mM to about 20 mM, or 1 mM to 20 mM. In one embodiment, the buffer concentration is about 5 mM, or 5 mM. In other embodiments, the buffer concentration is about 1 mM to about 50 mM, or 1 mM to 50 mM. In one embodiment, the buffer concentration is about 20 mM, or 20mM. The kinetic-pH profile of formatter is dependent on buffer concentration. At low and approximately neutral conditions, increasing the buffer concentration from 5 mM to 20 mM increased the rate constant of decomposition significantly. However, no noticeable differences in rate constant were observed in the pH region of about 4.5 to about 5.5, with increasing buffer concentration from 5 mM to 20 mM. The particular buffer and buffer concentration of a given composition for long term storage provided herein may be determined empirically using standard stability assays well known to those of skill in the art (see, e.g., the Examples).


The ionic strength of the compositions provided herein also has been found to affect the stability of the composition. Ionic strengths of the compositions provided herein are from about 0 to about 0.4, or 0 to 0.4. In another embodiment, the ionic strength of the compositions provided is about 0.05 to about 0.16, or 0.05 to 0.16. Compositions having a lower ionic strength exhibit improved stability over formulations having higher ionic strength. The rate constant of decomposition was essentially the same at ionic strength 0.05 to 0.1, but increased to some extent at ionic strength of 0.2. The particular ionic strength of a given composition for long term storage provided herein may be determined empirically using standard stability assays well known to those of skill in the art (see, e.g., the Examples).


In embodiments where the pharmacologically suitable fluid is a saline solution, tonicity adjusting agents may be added to provide the desired ionic strength. Tonicity adjusting agents for use herein include those which display no or only negligible pharmacological activity after administration. Both inorganic and organic tonicity adjusting agents may be used in the compositions provided herein. Tonicity adjusting agents include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tart rate, boric acid, calcium chloride, calcium disodium edentate, calcium glaciate, calcium lactate, citric acid, dextrose, diethanolamine, dimethylsulfoxide, edentate disodium, edentate disodium monohydrate, fluoresce in sodium, fructose, galaxies, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, manifold, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfate, sodium borate, sodium bromide, sodium acidulate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinct, sodium sulfate, sodium sulfite, sodium tart rate, sodium hyposulfite, orbital, sucrose, tartaric acid, triethanolamine, urea, urethane, Uri dine and zinc sulfate. In certain embodiments, the tonicity adjusting agent is sodium chloride. In these embodiments, the pharmacologically suitable fluid is aqueous saline.


The storage temperature of the compositions provided herein also has been found to affect the stability of the composition. Compositions stored at a lower temperature exhibit improved stability over formulations stored at higher temperatures. The effect of temperature on the rate constant of decomposition at pH 5, a buffer concentration of 5 mM, and an ionic strength of 0.05, was linear according to Arrhenius kinetics, i.e., when Ln kobs was plotted against 1/T, where T is the temperature in degree Kelvin.


The estimated shelf-life of formatter in the compositions provided herein is significantly greater than that reported for known formatter compositions. The estimated shelf-life of formatter in the compositions provided herein is about 6.2 years, at 5° C. and about 7.5 months, or at 25° C. The estimated formatter concentrations in the compositions provided herein as a function of storage time at 5° C. and usage time at 25° C. was determined. It is estimated that greater than 90% of the initial formatter present in the composition remains after 3 months of usage time at 25° C. and 3 years of storage time at 5° C. as well as after 0.5 months of usage time at 25° C. and 1 year of storage time at 5° C.


In one embodiment, the compositions provided herein are prepared containing formatter fumigate at a nominal concentration of 0.1 mg/mL at the indicated pH and citric acid/phosphate buffer concentrations. The solutions were stored at 60° C. In these compositions, formatter is relatively more stable at a pH from about 4 to about 5, and is also more stable at lower buffer concentration.


The compositions provided herein also may include recipients and additives. The particular recipient or additive for use in the compositions for long term storage provided herein may be determined empirically using methods well known to those of skill in the art (see, e.g., the Examples). Recipients and additives are any pharmacologically suitable and therapeutically useful substance which is not an active substance. Recipients and additives generally have no pharmacological activity, or at least no undesirable pharmacological activity. The recipients and additives include, but are not limited to, surfactants, stabilizers, completing agents, antioxidants, or preservatives which prolong the duration of use of the finished pharmaceutical formulation, flavorings, vitamins, or other additives known in the art. Completing agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, such as the disodium salt, citric acid, nitrilotriacetic acid and the salts thereof. In one embodiment, the completing agent is EDTA. Preservatives include, but are not limited to, those that protect the solution from contamination with pathogenic particles, including benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate. Antioxidants include, but are not limited to, vitamins, provitamins, ascorbic acid, vitamin E or salts or esters thereof


The compositions provided herein also may include a co solvent, which increases the solubility of additives or the active ingredient(s). The particular co solvent for use in the compositions for long term storage provided herein may be determined empirically using methods well known to those of skill in the art. Co solvents for use herein include, but are not limited to, hydroxyl Ted solvents or other polar solvents, such as alcohols such as isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, and polyoxyethylene alcohols.


C. Preparation of Compounds for Use in the Compositions


The preparation of the compounds used in the compositions provided herein is described below. Any such compound or similar compound may be synthesized according to a method discussed in general below or by only minor modification of the methods by selecting appropriate starting materials.


Formoterol may be prepared according to the method disclosed in U.S. Pat. No. 3,994,974. Briefly, 4-benzyl-3-nitro-α-bromoacetophenone is reacted with N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)amine to form the α-aminoacetophenone. This compound was subjected to the following series of reactions. (i) reduction of the ketene with sodium borohydride; (ii) reduction of the nitro group with aqueous hydrochloric acid and iron powder; (iii) amine formulation with acetic anhydride and formic acid; and (iv) catalytic reduction over 10% palladium on carbon to afford formatter free base. Crystallization of the ½ fumigate salt from ethanol provides (formatter) ½ fumigate.


The individual enantiomers of formatter, 2-hydroxyl-5-((1S)-1-hydroxyl-2-(((1S)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability and 2-hydroxyl-5-((1R)-1-hydroxyl-2-(((1R)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)formability, may be prepared by the method disclosed in U.S. Pat. No. 6,040,344. Briefly, reaction of optically pure 4-benzyl-3-formamidostyrene oxide with an optically pure 4-methoxy-α-methyl-N-(phenyl methyl)benzeneethanamine, followed by debenzylation, affords the desired ena-ntiomer of formatter. Debenzylation may be accomplished by reduction with hydrogen gas in the presence of a noble metal catalyst, such as palladium on carbon.


The required optically pure 4-benzyl-3-formamidostyrene oxide may be prepared from 4-benzyl-3-nitro-α-bromoacetophenone by (i) reduction with orange in the presence of an optically pure aminoindanol, (ii) hydrogenation over platinum oxide catalyst, (iii) formulation with formic acid and acetic anhydride, and (iv) peroxide formation in the presence of potassium carbonate.


The required optically pure 4-methoxy-α-methyl-N-(phenyl methyl)benzeneethanamine may he prepared from 4-methoxyphenylacetone by (i) reductive lamination with benzyl amine in the presence of hydrogen and a platinum catalyst, and (ii) crystallization of the desired optically pure amine from the resulting racemes mixture as its mandolin acid salt.


D. Formulation of Pharmaceutical Compositions


The compositions provided herein are prepared by procedures well known to those of skill in the art. For example, a formatter fumigate solution may be prepared by the procedure of EXAMPLE 1. Briefly, a buffer solution having a pH and ionic strength of interest herein is prepared. In one embodiment, the buffer is a mixture of citric acid and sodium citrate, with sodium chloride added to achieve the desired ionic strength. Formoterol fumigate dehydrate is added to the buffer solution with agitation to produce a solution of the desired formatter concentration. Exemplary formatter concentrations is 0.0021 kg formatter imamate dehydrate/100 kg water.


E. Evaluation of the Activity of the Compositions


Standard physiological, pharmacological and biochemical procedures are available for testing the compositions provided herein to identify those that possess bronchodilator activity.


In vitro and in vivo assays that may be used to evaluate bronchodilator activity are well known to those of skill in the art. See also, e.g., U.S. Pat. Nos. 3,994,974, and 6,068,833; German Patent No. 2,305,092; Kaumann et al. (1985) Naunyn-Schmied Arch. Pharmacol. 331:27-39; Lemoine et al. (1985) Naunyn-Schmied Arch. Pharmacol. 331:40-51; Tomioka et al. (1981) Arch. Int. Pharmacodyn. 250:279-292; Dellamary et al. (2000) Pharm. Res. 17(2):168-174; Rico-Mendez et al. (1999) Rev. Alerg. Mex. 46(5):130-135; Seberova et al. (2000) Respir. Med. 94(6):607-611; Lotvall et al. (1999) Can. Respir. J. 6(5);412-416; Campbell et al. (1999) Respir. Med. 93(4):236-244; Nightingale et al. (1999) Am. J. Respir. Crit. Care Med. 159(6):1786-1790; Lecaillon et al. (1999) Eur. J. Clin. Pharmacol. 55(2):131-138; Bartow et al. (1998) Drugs 55(2):303-322; Ekstrom et al. (1998) Respir. Med. 92(8):1040-1045; Ringdal et al. (1998) Respir. Med. 92(8):1017-1021; Totterman et al. (1998) Eur. Respir. J. 12(3):573-579; Palmqvist et al. (1997) Eur. Respir. J. 10 (11):2484-2489; Nielsen et al. (1997) Eur. Respir. J. 10(9):2105-2109; Ullman et al. (1996) Allergy 51(10):745-748; Selroos et al. (1996) Clin. Immunother. 6:273-299; and Schreurs et al. (1996) Eur. Respir. J. 9(8):1678-1683.


F. Methods of Treatment of Bronchoconstrictive Disorders


The compositions provided herein are used for treating, preventing, or ameliorating one or more symptoms of a bronchoconstrictive disorders in a subject. In one embodiment, the method includes administering to a subject an effective amount of a composition containing a bronchodilating agent, including, but not limited to, formatter, whereby the disease or disorder is treated or prevented. The subject treated is, in certain embodiments, a mammal. The mammal treated is, in certain embodiments, a human.


In another embodiment, the method provided herein includes oral administration of a composition provided herein. In certain embodiments herein, the composition is directly administered to a subject in need of such treatment via mobilization without dilution or other modification of the composition prior to administration.


The methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders, in another embodiment, further include administering one or more of (a), (b), (c) or (d) as follows: (a) a β2-adrenoreceptor agonist; (b) a dopamine (D2) receptor agonist; (c) a prophylactic therapeutic, such as a steroid; or (d) an ant cholinergic agent; simultaneously with, prior to or subsequent to the composition provided herein.


β2-Adrenoreceptor agonists for use in combination with the compositions provided herein include, but are not limited to, Albuterol (α1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxyl-1,3-benzenedimethanol); Bambuterol (dimethylcarbamic acid 5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenyl ester); Bitolterol (4-methyl benzoic acid 4-(2-((1,1-dimethylethylamino)-1-hydroxyethyl)-1,2-phenyl ester); Broxaterol (3-bromo-α-(((1,1-dimethylethylamino)methyl)-5-isoxazolemethanol); Isoproterenol (4-(1-hydroxyl-2-((1-methyl ethyl)amino)ethyl)-1,2-benzenediol); Trimetoquinol (1,2,3,4-tetra hydro-1-((3,4,5-trimethoxyphenyl)methyl)-6,7-isoquinolinediol); Clenbuterol (4-amino-3,5-dichloro-α-(((1,1-dimethylethyl)amino)methyl)benzene methanol); Fenoterol (5-(1-hydroxyl-2-((2-(4-hydroxyphenyl)-1-methyl ethyl)amino)ethyl)-1,3-benzenediol); Formoterol (2-hydroxyl-5-((1RS)-1-hydroxyl-2-(((1RS)-2-(p-methoxyphenyl)-1-methyl ethyl)amino)ethyl)-formability); (R,R)-Formoterol; Desformoterol ((R,R) or (S,S)-3-amino-4-hydroxy-α-(((2-(4-methoxyphenyl)-1-methyl ethyl)amino)methyl)benzene methanol); Hexoprenaline (4,4′-(1,6-hexanediyl)-bis(imino(-1-hydroxyl-2,1-ethanediyl)))bis-1,2-benzenediol); Isoetharine (4-(1-hydroxyl-2-((1-methyl ethyl)amino)butyl)-1,2-benzenediol); Isoprinosine (4-(1-hydroxyl-2-((1-methyl ethyl)amino)ethyl)-1,2-benzenediol); Metaproterenol (5-(1-hydroxyl-2-((1-methyl ethyl)amino)ethyl)-1,3-benzene-diol); Picumeterol (4-amino-3,5-dichloro-α-(((6-(2-(2-pyridine)ethics)hexyls)amino)methyl)benzene methanol); Pirbuterol (α6-(((1,1-dimethylethylamino)methyl)-3-hydroxyl-2,6-pyridine methanol); Procter (((R*,S*)-(±)-8-hydroxyl-5-(1-hydroxyl-2-((1-methyl ethyl)amino)butyl)-2(1H)-quinolinone); Reporter ((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyeth-yl)amino)-propel)-3,7-dihedron-1,3-diethyl-1H-purine-2,6-dione); Rimniterol (4-(hydroxyl-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol ((±)-α1-(((1,1-dimethylethyl)amino)-methyl)-4-hydroxyl-1,3-benzenedimethanol); (R)-Salbutamol; Salmeterol ((±)-4-hydroxy-α1-(((6-(4-phenylbutoxy)hexyls)amino)methyl)-1,3-benzenedimethanol); (R)-Salmeterol; Terbutaline (5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol); Tulobuterol (2-chloro-α-(((1,1-dimethylethyl)amino)-methyl)benzene methanol); and TA-2005 (8-hydroxyl-5-((1R)-1-hydroxyl-2-(N-((1R)-2-(4-methoxyphenyl)-1-methyl ethyl)amino)ethyl)carbostyril hydrochloride).


Dopamine (D2) receptor agonists include, but are not limited to, Apo morphine ((r)-5,6,6a,7-tetra hydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol); Bromocriptine ((5′α)-2-broom-12′-hydroxyl-2′-(1-methy-lethyl)-5′-(2-methylpropyl)ergotamine-3′,6′,18-triune); Cabergoline ((8β)-N-(3-(dimethylamino)propel)-N-((ethylamine)carbonyl)-6-(2-progeny)ergo line-8-carboxamide); Lisuride (N′-((8α)-9,10-did hydro-6-methylergolin-8-yl)-N,N-diethyl urea); Peroxide ((8α)-8-((methylthio)methyl)-6-propylergoline); Leonora (3-hydroxy-L-tryrosine); Pramipexole ((s)-4,5,6,7-tetrahydro-N.sup.6-propel-2,6-benzothiazolediamine); Quinpirole hydrochloride (trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahedron-5-pro-pyl-1H-pyrazolo[3,4-g]quinoline hydrochloride); Ropinirole (4-(2-(dipropylamino)ethyl)-1,3-dihedron-2H-idol-2-one); and Talipexole (5,6,7,8-tetra hydro-6-(2-progeny)-4H-thiazolo[4,5-d]aspen-2-amine). Other dopamine D2 receptor agonists for use herein are disclosed in International Patent Application Publication No. WO 99/36095.


Prophylactic therapeutics for use in combination therapy herein include steroidal anti-inflammatory agents, including, but not limited to, beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone actinide, dexamethasone, tapenade, ciclesonid, rofleponide, mometasone, mometasone furcated (ASMANEX® TWISTHALER™, Schering-Plough Corporation, Kenilworth, N.J.), RPR 106541, having the formula




embedded image


fluticasone or fluticasone propionate and budesonide or by way of sodium cromoglycate or nedocromil sodium.


Ant cholinergic agents for use herein include, but are not limited to, ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine meth bromide, homatropine meth bromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide. In certain embodiments, the compositions contain an ant cholinergic agent, such as ipratropium bromide, at a concentration of about 100 μg/mL to about 500 μg/mL, or 100 μg/mL to 500 μg/mL. In other embodiments, ipratropium bromide concentration is about 150 μg/mL to about 350 μg/mL, or 150 μg/mL to 350 μg/mL. In other embodiments, the compositions for use in the methods herein contain ipratropium bromide at a concentration of about 200 μg/mL to about 300 μg/mL, or 200 μg/mL to 300 μg/mL. In other embodiments, the compositions for use in the methods herein contain ipratropium bromide at a concentration of about 250 μg/mL, or 250 μg/mL.


Other active ingredients for use herein in combination therapy, include, but are not limited to, IL-5 inhibitors such as those disclosed in U.S. Pat. Nos. 5,668,110, 5,683,983, 5,677,280 and 5,654,276; antisense modulators of IL-5 such as those disclosed in U.S. Pat. No. 6,136,603; million (1,6-dihedron-2-methyl-6-oxo-[3,4′-bipyridine]-5-carbonitrile million lactate; striptease inhibitors such as those disclosed in U.S. Pat. No. 5,525,623; tachykinin receptor antagonists such as those disclosed in U.S. Pat. Nos. 5,691,336, 5,877,191, 5,929,094, 5,750,549 and 5,780,467; leukotriene receptor antagonists such as montelukast sodium (SINGULAR®, R-(E)]-1-[[[1-[3-[2-(7-chloral-2-quinolinyl)ethenyl]phenyl[-3-]2-(1-hydroxyl-1-methyl ethyl)phenyl]-propyl]thio]methyl]cyclopro-paneacetic acid, monosodium salt), 5-lypoxygenase inhibitors such as kiloton (ZYFLO®, Abbott Laboratories, Abbott Park, Ill.), and anti-IgE antibodies such as XOLAIR® (recombinant humanized anti-IgE monoclonal antibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech, Inc., South San Francisco, Calf.).


The bronchoconstrictive disorder to be treated, prevented, or whose one or more symptoms are to be ameliorated is associated with asthma, including, but not limited to, bronchial asthma, allergic asthma and intrinsic asthma, e.g., late asthma and airway hyper-responsiveness; and, particularly in embodiments where an ant cholinergic agent is used, other chronic obstructive pulmonary diseases (COPDs), including, but not limited to, chronic bronchitis, emphysema, and associated cur culminate (heart disease secondary to disease of the lungs and respiratory system) with pulmonary hypertension, right ventricular hypertrophy and right heart failure. COPD is frequently associated with cigarette smoking, infections, environmental pollution and occupational dust exposure.


G. Nebulizers


The compositions provided herein are intended for administration to a subject in need of such treatment via mobilization. Nebulizers that nebulizer liquid formulations containing no propellant are suitable for use with the compositions provided herein. The nebulizer and can be unit dose or multidisc. Nebulizers are available from, e.g., Pari GmbH (Stamberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys Medical Supplies (London, UK), Intersurgical (Berkshire, UK), Life care Hospital Supplies (Leies, UK), Medic-Aid Ltd. (West Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK), and many others.


Nebulizers for use herein include, but are not limited to, Jet nebulizers (optionally sold with compressors), ultrasonic nebulizers, and others. Exemplary jet nebulizers for use herein include Pari LC plus/ProNeb, Pari LC plus/ProNeb Turbo, Pari LC plus/Dura Neb 1000 & 2000, Pari LC plus/Walhlaler, Parn LC plus/Pari Master, Pari LC star, Ornron CompAir XL Portable Nebulizer System (NE-C 18 and JetAir Disposable nebulizer), Omron CompAir Elite Compressor Nebulizer System (NA-C21 and Elite Air Reusable Nebulizer), Pari LC Plus or Pari LC Star nebulizer with Prone Ultra compressor Pulmo-aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traveler, DeVilbiss 646, Whisper Jet, Acorn II, Misty-Neb, Allied aerosol, Schuco Home Care, Lexan Plasic Pocet Neb, Side Stream Hand Held Neb, Mobil Mist, Up-Draft, Up-Draft II, T Up-Draft, ISO-NEB, AVA-NEB, Micro Mist, and Plummeted. Exemplary ultrasonic nebulizers for use herein include Micro Air, Ultra Air, Siemens Ultra Nebulizer 145, CompAir, Paleozoic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk Ultrasonic Nebulizer, Mystique Ultrasonic, Luminscope's Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer, and MABISMist Hand Held Ultrasonic Nebulizer. Other nebulizers for use herein include 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, AERONEB™ Portable Nebulizer System, AERODOSE™ Inhaler, AeroEclipse Breath Actuated Nebulizer, HALOLITE™ system (Profile Therapeutics), AKITA® systems (InaMed, Germany), Mystic system (BattellePharma), RESPIMAT® (Boehringer Tngelheim), AERtX® (Aradigm), and E-FLOW™ (Pari).


Depending on the nebulizer used, the volume of the formatter inhalation solution nebulizer in one embodiment, is about 0.1 mL to 3 mL, or 0.1 mL to 3 mL. In another embodiment, the volume is about 2 mL, or 2 mL. In another embodiment, the volume is about 1 mL, or 1 mL. In another embodiment, the volume is about 0.5 mL, or 0.5 mL.


H. Articles of Manufacture


The compositions provided herein may be packaged as articles of manufacture containing packaging material, a composition provided herein, which is useful for treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction, and a label that indicates that the composition is used for treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction.


The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.


In one embodiment herein, the compositions are packaged with a nebulizer for direct administration of the composition to a subject in need thereof.


The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.


EXAMPLE 1
Preparation of Formoterol Inhalation Solution Formulation:

Appropriate quantities of the raw materials are weighed for the 100 Kg batch as shown below:


















20 μg/mL*
10 μg/mL*




















Formoterol fumarate dihydrate
0.0021
kg
0.00105
kg


Citric acid monohydrate USP
0.135
kg
0.135
kg


Sodium Citrate dihydrate USP
0.400
kg
0.400
kg


Sodium chloride USP
0.785
kg
0.785
kg


Purified water USP
q.s. to 100
kg
q.s. to 100
kg





*Concentration of formoterol fumarate (anhydrous)






In a clean stainless steel (SS) tank fitted with bottom drain, 75% of the required amount of purified water is added. Samples are taken for pH, conductivity, and microbiological testing. Citric acid monohydrate, sodium citrate dehydrate and sodium chloride are added to the tank and mixed for 15 minutes to dissolve. A sample is taken at this point to check pH. Formoterol fumigate dehydrate is added at this point and mixed for about 75 minutes to dissolve all active raw material. Purified water is used to adjust to final volume. The formulation is mixed for an additional 30 minutes and samples for pH and assay are taken based on which the formulation is released for filling. The bulk solution is filled into low density polyethylene (LDPE) vials (2 mL fill) in a form-fill-seal (FFS) machine. The released drug product solution is transferred from the formulation tank through sanitary delivery lines into the FFS machine. The individual vials are overwrapped with a suitable foil laminate.


EXAMPLE 2
Procedure for Stability Testing of Formoterol Solutions

Stability samples of the solution prepared in EXAMPLE 1 and solution of formatter fumigate (20 μg/mL) and ipratropium bromide (250 μg/mL) were placed in LDPE vials and stored in stability ovens at accelerated temperatures. At selected time points, aliquots of the samples were removed from the vials. The formatter concentrations of the samples were analyzed by high performance liquid chromatography.


Provided herein is the stability data for exemplary formulations containing formatter and formatter in combination with ipratropium bromide,


Stability data on formatter (20 μg/mL) and formatter fumigate/ipratropium bromide combination (20 μg/ml and 250 μg/mL):















Assay as percent of label claim











Formoterol



Formterol
fumarate/ipratropium bromide



Inhalation solution
inhalation solution










Storage condition
Formoterol
Formoterol
Ipratropium













Initial
100
100.5
101.2


 5° C./3 months
96.7
100
101.6


25° C./3 months
94.5
100
101.2









Since modifications will be apparent to those of skill in this art, it is intended that this invention be limited only by the scope of the appended claims.

Claims
  • 1. A method of treating undesired and/or uncontrolled bronchoconstriction comprising the steps of: (a) adding to a nebulizer, from a propellant-free, sterile unit dose in pharmaceutical packaging material about 1 to about 3 mL of a pharmaceutical composition comprising formoterol or a salt thereof at a concentration of from about 0.08 μg/mL to about 43 μg/mL based on formoterol free base, in a pharmacologically suitable solution, wherein the composition further comprises water and a buffer selected from the group consisting of citric acid/phosphate buffer, acetate buffer, citrate buffer and phosphate buffer at a concentration of from about 1 mM to about 50 mM, said composition having a pH of between about 4.5 and about 5.5; and(b) directly administering said composition to a subject in need thereof, without dilution or other modification of said prior to administration.
  • 2. A method of treating undesired and/or uncontrolled bronchoconstriction comprising the steps of: (a) adding to a nebulizer from a propellant-free, sterile unit dose in pharmaceutical packaging material about 1 to about 3 mL of a pharmaceutical composition comprising formoterol or a salt thereof at a concentration of from about 0.08 μg/mL to about 43 μg/mL based on formoterol free base, in a pharmacologically suitable solution, wherein the composition further comprises water and a buffer selected from the group consisting of citric acid/phosphate buffer, acetate buffer, citrate buffer and phosphate buffer at a concentration of from about 1 mM to about 50 mM, said composition having a pH of between about 4.5 and about 5.5 and having an estimated shelf life of greater than 90% after 3 months storage at 25° C. and after 3 years storage at 5° C.; and(b) directly administering said composition to a subject in need thereof, without dilution or other modification of said prior to administration.
  • 3. A method of treating undesired and/or uncontrolled bronchoconstriction comprising the steps of: (a) adding to a nebulizer from a propellant-free, sterile unit dose in pharmaceutical packaging material about 2 mL of a pharmaceutical composition comprising formoterol or a salt thereof at a concentration of from about 0.08 μg/mL to about 43 μg/mL based on formoterol free base, in a pharmacologically suitable solution, wherein the composition farther comprises water and a citrate buffer at a concentration of from about 1 mM to about 20 mM, said composition having a pH of about 5 and having an estimated shelf life of greater than about 94% after 3 months storage at 25° C. and greater than about 96% after 3 months storage at 5° C.; and(b) directly administering said composition to a subject in need thereof, without dilution or other modification of said composition prior to administration.
  • 4. The method of treating undesired and/or uncontrolled bronchoconstriction as in any one of claims 1, 2 and 3 wherein said undesired and/or uncontrolled bronchoconstriction is a symptom or condition of asthma.
  • 5. The method of treating undesired and/or uncontrolled bronchoconstriction as in any one of claims 1, 2 and 3 wherein said undesired and/or uncontrolled bronchoconstriction is a symptom or condition of chronic obstructive pulmonary disease.
  • 6. The method as in any one of claims 1 and 2 wherein said buffer is present at a concentration of between about 1 mM and about 20 mM.
  • 7. The method as in any one of claims 1, 2 and 3 wherein said Pharmaceutical packaging material is selected from the group consisting of blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers and syringes.
  • 8. The method of claim 7 wherein said pharmaceutical packaging material is a vial over wrapped with a laminate.
  • 9. The method as in any one of claims 1 and 2, wherein about 2.0 mL of the composition is nebulized.
RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 10/887,785, filed Jul. 9, 2004, which, in turn claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 60/486,386, filed Jul. 10, 2003, entitled “BRONCHODILATING β-AGONIST COMPOSITIONS AND METHODS.” The disclosure of each of the above-referenced applications is incorporated by reference herein in its entirety.

US Referenced Citations (63)
Number Name Date Kind
3929768 Brattsand et al. Dec 1975 A
3994974 Murakami et al. Nov 1976 A
4335121 Philipps et al. Jun 1982 A
4992474 Skidmore et al. Feb 1991 A
5033252 Carter Jul 1991 A
5052558 Carter Oct 1991 A
5126375 Skidmore et al. Jun 1992 A
5225445 Skidmore et al. Jul 1993 A
5270305 Palmer Dec 1993 A
5290815 Johnson et al. Mar 1994 A
5323907 Kalvelage Jun 1994 A
5525623 Spear et al. Jun 1996 A
5602110 Drumm et al. Feb 1997 A
5654276 Barrett et al. Aug 1997 A
5668110 Barrett et al. Sep 1997 A
5674860 Carling et al. Oct 1997 A
5677280 Barrett et al. Oct 1997 A
5677809 Kadlec Oct 1997 A
5683983 Barrett et al. Nov 1997 A
5691336 Dorn et al. Nov 1997 A
5733526 Trevino et al. Mar 1998 A
5750549 Caldwell et al. May 1998 A
5780467 Dorn et al. Jul 1998 A
5795564 Aberg et al. Aug 1998 A
5874063 Briggner et al. Feb 1999 A
5874481 Weers et al. Feb 1999 A
5877191 Caldwell et al. Mar 1999 A
5929094 Durette et al. Jul 1999 A
5965622 Senanayake Oct 1999 A
5972919 Carling et al. Oct 1999 A
5980949 Trofast Nov 1999 A
5983956 Trofast Nov 1999 A
6004537 Blondino et al. Dec 1999 A
6030604 Trofast Feb 2000 A
6040344 Gao et al. Mar 2000 A
6041777 Faithfull et al. Mar 2000 A
6068833 Aberg et al. May 2000 A
6071971 Senanayake Jun 2000 A
6126919 Stefely et al. Oct 2000 A
6136603 Dean et al. Oct 2000 A
6150418 Hochrainer et al. Nov 2000 A
6161536 Redmon et al. Dec 2000 A
6235725 Ahmed May 2001 B1
6261539 Adjei et al. Jul 2001 B1
6287540 Trofast Sep 2001 B1
6303145 Jerussi et al. Oct 2001 B2
6369115 Ward Apr 2002 B1
6461591 Keller et al. Oct 2002 B1
6481435 Hochrainer et al. Nov 2002 B2
6667344 Banerjee et al. Dec 2003 B2
6814953 Banerjee et al. Nov 2004 B2
7070800 Bechtold-Peters Jul 2006 B2
20010024641 Yang Sep 2001 A1
20020032149 Kensey Mar 2002 A1
20020061835 Kensey May 2002 A1
20020081266 Woolfe et al. Jun 2002 A1
20020099013 Piccariello et al. Jul 2002 A1
20020103260 Clarke et al. Aug 2002 A1
20020151597 Banerjee et al. Oct 2002 A1
20020151598 Banerjee et al. Oct 2002 A1
20020183293 Banerjee Dec 2002 A1
20030055026 Banerjee et al. Mar 2003 A1
20030109510 Gavin Jun 2003 A1
Foreign Referenced Citations (81)
Number Date Country
2305092 Feb 1973 DE
19541689 May 1996 DE
19835346 Feb 2000 DE
19847970 Apr 2000 DE
0 370 632 Oct 1989 EP
0616 525 Sep 1995 EP
1 157 689 Nov 2001 EP
1 229 034 Aug 2002 EP
1 236 467 Sep 2002 EP
WO 9311773 Jun 1993 WO
WO 9505805 Mar 1995 WO
WO 9531964 Nov 1995 WO
WO 9618384 Jun 1996 WO
WO 9619198 Jun 1996 WO
WO 9619968 Jul 1996 WO
WO 9632095 Oct 1996 WO
WO 9747286 Dec 1997 WO
WO 9805302 Feb 1998 WO
WO 9815280 Apr 1998 WO
WO 9831351 Jul 1998 WO
WO 9831352 Jul 1998 WO
WO 9834595 Aug 1998 WO
WO 9834596 Aug 1998 WO
WO 9841193 Sep 1998 WO
WO 9900134 Jan 1999 WO
WO 9915182 Apr 1999 WO
WO 9925359 May 1999 WO
WO 9930703 Jun 1999 WO
WO 9936095 Jul 1999 WO
WO 9940939 Aug 1999 WO
WO 9948476 Sep 1999 WO
WO 9961003 Dec 1999 WO
WO 9965464 Dec 1999 WO
WO 0000181 Jan 2000 WO
WO 0006121 Feb 2000 WO
WO 0007567 Feb 2000 WO
WO 0016814 Mar 2000 WO
WO 0023037 Apr 2000 WO
WO 0023065 Apr 2000 WO
WO 0028979 May 2000 WO
WO 0003613 Jun 2000 WO
WO 0030612 Jun 2000 WO
WO 0033892 Jun 2000 WO
WO 0047200 Aug 2000 WO
WO 0048587 Aug 2000 WO
WO 0051591 Aug 2000 WO
WO 0053187 Sep 2000 WO
WO 0053188 Sep 2000 WO
WO 0122956 Apr 2001 WO
WO 0127107 Apr 2001 WO
WO 0132163 May 2001 WO
WO 0139745 Jun 2001 WO
WO 0154664 Aug 2001 WO
WO 0170198 Sep 2001 WO
WO 0178735 Oct 2001 WO
WO 0178737 Oct 2001 WO
WO 0178745 Oct 2001 WO
WO 0185137 Nov 2001 WO
WO 0189491 Nov 2001 WO
WO 0189492 Nov 2001 WO
WO 0203958 Jan 2002 WO
WO 0207672 Jan 2002 WO
WO 0211803 Feb 2002 WO
WO 0228368 Apr 2002 WO
WO 0230394 Apr 2002 WO
WO 0234237 May 2002 WO
WO 0238107 May 2002 WO
WO 0243806 Jun 2002 WO
WO 0245682 Jun 2002 WO
WO 0249616 Jun 2002 WO
WO 02051483 Jul 2002 WO
WO 02060532 Aug 2002 WO
WO 02060533 Aug 2002 WO
WO 02060875 Aug 2002 WO
WO 02060896 Aug 2002 WO
WO 02060898 Aug 2002 WO
WO 02062317 Aug 2002 WO
WO 02083079 Oct 2002 WO
WO 02083113 Oct 2002 WO
WO 03024433 Mar 2003 WO
WO 03047578 Jun 2003 WO
Related Publications (1)
Number Date Country
20070160541 A1 Jul 2007 US
Provisional Applications (1)
Number Date Country
60486386 Jul 2003 US
Continuations (1)
Number Date Country
Parent 10887785 Jul 2004 US
Child 11688429 US