U.S. patent application number 11/354740 was filed with the patent office on 2006-06-29 for compounds and methods for the treatment of airway diseases and for the delivery of airway drugs.
This patent application is currently assigned to The University of North Carolina at Chapel Hill. Invention is credited to Richard C. JR. Boucher.
Application Number | 20060142208 11/354740 |
Document ID | / |
Family ID | 27381385 |
Filed Date | 2006-06-29 |
United States Patent
Application |
20060142208 |
Kind Code |
A1 |
Boucher; Richard C. JR. |
June 29, 2006 |
Compounds and methods for the treatment of airway diseases and for
the delivery of airway drugs
Abstract
Chronic obstructive airway diseases are treated by administering
an osmotically active compound such as a salt, sugar, sugar
alcohol, or organic osmolyte to the afflicted airway surface. The
compound may be administered as a liquid or dry powder aerosol
formulation. Diseases that can be treated by the method include
cystic fibrosis, chronic bronchitis, and ciliary dyskinesia. The
formulations of the invention can also be used in conjunction with
other active agents such as bronchodilators, sodium channel
blockers, antibiotics, enzymes, or purinoceptor agonists on airway
surfaces.
Inventors: |
Boucher; Richard C. JR.;
(Chapel Hill, NC) |
Correspondence
Address: |
MYERS BIGEL SIBLEY & SAJOVEC
PO BOX 37428
RALEIGH
NC
27627
US
|
Assignee: |
The University of North Carolina at
Chapel Hill
|
Family ID: |
27381385 |
Appl. No.: |
11/354740 |
Filed: |
February 15, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10087355 |
Mar 1, 2002 |
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11354740 |
Feb 15, 2006 |
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09465429 |
Dec 21, 1999 |
6926911 |
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10087355 |
Mar 1, 2002 |
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60137991 |
Jun 7, 1999 |
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60113785 |
Dec 22, 1998 |
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Current U.S.
Class: |
514/23 ; 514/492;
514/504; 514/554; 514/561; 514/564; 514/565 |
Current CPC
Class: |
A61K 9/0078 20130101;
A61K 31/70 20130101; Y10S 514/826 20130101; A61K 31/4965 20130101;
Y10S 514/851 20130101; A61K 9/008 20130101 |
Class at
Publication: |
514/023 ;
514/492; 514/554; 514/561; 514/564; 514/565; 514/504 |
International
Class: |
A61K 31/70 20060101
A61K031/70; A61K 31/28 20060101 A61K031/28; A61K 31/285 20060101
A61K031/285; A61K 31/205 20060101 A61K031/205; A61K 31/198 20060101
A61K031/198 |
Goverment Interests
STATEMENT OF FEDERAL SUPPORT
[0002] This invention was made with Government support under Grant
No. HL51818 from the National Institutes of Health. The United
States government has certain rights in this invention.
Claims
1-29. (canceled)
30. A method of treating chronic obstructive pulmonary disease in a
subject in need of such treatment, comprising administering at
least one osmotically active compound to an airway surface of the
subject in an amount effective to increase the volume of liquid on
the airway surface, wherein the at least one osmotically active
compound comprises at least one salt comprising: (a) a
pharmaceutically acceptable anion selected from the group
consisting of acetate, benzenesulfonate, benzoate, bitartrate,
bromide, calcium edetate, camsylate, carbonate, chloride, citrate,
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isethionate, lactate, lactobionate,
malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate,
phosphate or diphosphate, polygalacturonate, salicylate, stearate,
subacetate, succinate, sulfate, tannate, tannate, teoclate and
triethiodide; and (b) a pharmaceutically acceptable cation selected
from the group consisting of benzathine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine, procaine, D-Lysine,
L-lysine, D-arginine, L-arginine, uiethylammonium, N-methyl Do
glycerol, aluminum, calcium, lithium, magnesium, potassium, sodium,
zinc, iron, and ammonium.
31. The method according to claim 30, wherein the subject is
afflicted with one or more chronic obstructive pulmonary diseases
selected from the group consisting of cystic fibrosis, chronic
bronchitis and ciliary dyskinesia.
32. The method according to claim 30, wherein the airway surface is
a pulmonary airway surface.
33. The method according to claim 30, wherein the airway surface is
a nasal airway surface or sinus airway surface.
34. The method according to claim 30, wherein said administering
step of the at least one osmotically active compound is an aerosol
inhalation administering step.
35. The method according to claim 30, wherein said at least one
salt comprises: an anion selected from the group consisting of
sulfate, nitrate, gluconate, iodide, chloride, bromide, and
phosphate; and a cation selected from the group consisting of
choline, lithium, meglumine, D-lysine, ammonium, sodium, magnesium
calcium, and potassium.
36. The method according to claim 30, wherein said at least one
salt is sodium chloride.
37. The method according to claim 30, wherein said at least one
salt is sodium nitrate.
38. The method according to claim 30, wherein the method further
comprises administering a bronchodilator to said subject prior to
or concurrently with said at least one osmotically active compound
in an amount sufficient to inhibit bronchoconstriction.
39. The method of claim 38, wherein the bronchodilator is selected
from the group consisting of 1-adrenergic agonists, anticholinergic
agonists and xanthine derivatives.
40. The method according to claim 39, wherein the .beta.-adrenergic
agonist is epinephrine, isoproterenol, albuterol, terbutaline,
pirbuterol, metaproteronol or salmeterol.
41. The method according to claim 30, wherein the method further
comprises administering agents selected from the group consisting
of an enzyme drug, an anti-inflammatory agent, an antibiotic, an
antiviral agent, an anti-neoplastic agent, an antihistamine, an
anti-pneumocystis carinii pneumonia agent, an anti-tuberculosis
agent, an expectorant and a chelator of divalent cations.
42. The method according to claim 41, wherein the enzyme drug is
DNase or .alpha..sub.1-antitrypsin.
43. The method according to claim 41, wherein the antibiotic is
tetracycline, choramphenicol, an aminoglycosides, a beta-lactam, a
cephalosporin, erythromycin or clindamycin.
Description
STATEMENT OF PRIORITY
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/087,355, which is a divisional of U.S.
patent application Ser. No. 09/465,429, filed Dec. 21, 1999, now
U.S. Pat. No. 6,926,911, which claims priority from U.S.
Provisional Patent Application Ser. No. 60/137,991 filed Jun. 7,
1999 and from U.S. Provisional Patent Application Ser. No.
60/113,785 filed Dec. 22, 1998, the disclosures of all of which are
to be incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
[0003] This invention relates to methods and compositions useful
for hydrating airway surfaces.
BACKGROUND OF THE INVENTION
[0004] Chronic obstructive pulmonary diseases are characterized by
the retention of mucous secretions in the lungs. Examples of such
diseases include cystic fibrosis, chronic bronchitis, and primary
or secondary ciliary dyskinesia. Such diseases affect approximately
15 million patients in the United States, and are the sixth leading
cause of death. Other airway or pulmonary diseases characterized by
the accumulation of retained mucous secretions include sinusitis
(an inflammation of the paranasal sinuses associated with upper
respiratory infection) and pneumonia.
[0005] U.S. Pat. No. 5,817,028 to Anderson describes a method for
the provocation of air passage narrowing (for evaluating
susceptibility to asthma) and/or the induction of sputum in
subjects. It is suggested that the same technique can be used to
induce sputum and promote mucociliary clearance. Substances
suggested include sodium chloride, potassium chloride, mannitol and
dextrose.
SUMMARY OF THE INVENTION
[0006] Certain objects, advantages and novel features of the
invention will be set forth in the description that follows, and
will become apparent to those skilled in the art upon examination
of the following, or may be learned with the practice of the
invention.
[0007] A first aspect of the present invention is a method for
treating chronic obstructive pulmonary disease in a subject in need
of such treatment. The method comprises administering a
non-absorbable, osmotically active compound (hereinafter referred
to as an "active compound") such as a salt, sugar, sugar alcohol,
organic osmolyte, or other osmotically active compound to an airway
surface of the subject in an amount effective to increase the
volume of fluid on the airway surface.
[0008] In one embodiment of the foregoing, a bronchodilator is
administered to the patient prior to or concurrently with the
active compound to inhibit bronchoconstriction that may be induced
by the active compound.
[0009] The active compound may be administered as a delayed or
controlled release formulation, such as by encapsulating the active
compound in liposomes, encapsulating the compound in a
biodegradable polymer, etc.
[0010] A second aspect of the present invention is a therapeutic
method of administering an active agent to an airway surface of a
subject in need thereof. The method comprises administering the
active agent in an effective therapeutic amount in a vehicle, the
vehicle comprising an osmotically active compound of the present
invention in an amount effective to increase the volume of liquid
on the airway surface.
[0011] A third aspect of the present invention is a method for the
lavage of the lung of a patient in need thereof. The method
comprises administering a liquid comprising an active compound of
the present invention to an afflicted portion of the lung of the
patient (e.g., a lobe) in an amount effective to wash the afflicted
lung portion, the active compound in the solution being present in
an amount effective to increase the volume of liquid on the airway
surface of the portion of the lung to which the liquid is
administered.
[0012] Active compounds of the present invention, used either as
active compounds alone, or as active compounds used in conjunction
with other kinds of active agents (e.g., bronchodilators,
purinergic receptors, antibiotics, enzymes, anti-inflammatory
agents, etc.), may be administered to airway surfaces (including
nasal surfaces) by any suitable means, such as by droplets, sprays,
aerosols of respirable or non-respirable particles, or
transbronchoscopic lavage. The active compounds of the present
invention may be administered in aqueous or non-aqueous (e.g.,
solid particulate) form.
[0013] Formulations of the active compounds of the present
invention, either with or without other active ingredients for
administration to airway surfaces, are also an aspect of this
invention.
[0014] The use of an active compound of the present invention for
the preparation of a medicament for carrying out the methods
described above are also an aspect of this invention.
[0015] One object of the methods and formulations described herein
is to expand or increase the volume of fluid on airway surfaces,
particularly the volume of the periciliary liquid layer, and to
thereby increase or facilitate cough clearance, mucociliary
clearance, and/or gas-liquid dependent clearance of mucous.
[0016] The foregoing and other aspects of the present invention are
explained in detail in the specification set forth below.
DETAILED DESCRIPTION
[0017] The present invention now will be described more fully
hereinafter, in which preferred embodiments of the invention are
illustrated. This invention may, however, be embodied in many
different forms and should not be construed as limited to the
embodiments set forth herein. Rather, these embodiments are
provided so that this disclosure will fully convey the scope of the
invention to those skilled in the art. Unless otherwise defined,
all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art
to which this invention belongs. All publications, patent
applications, patents, and other references mentioned herein are
incorporated by reference in their entirety.
[0018] Active compounds of the present invention are molecules or
compounds that are osmotically active (i.e., are "osmolytes").
"Osmotically active" compounds of the present invention are
membrane-impermeable (i.e., essentially non-absorbable) on the
airway or pulmonary epithelial surface. The terms "airway surface"
and "pulmonary surface," as used herein, include pulmonary airway
surfaces such as the bronchi and bronchioles, alveolar surfaces,
and nasal and sinus surfaces. Active compounds of the present
invention may be ionic osmolytes (i.e., salts), or may be non-ionic
osmolytes (i.e., sugars, sugar alcohols, and organic osmolytes). It
is specifically intended that both racemic forms of the active
compounds that are racemic in nature are included in the group of
active compounds that are useful in the present invention.
[0019] Active compounds useful in the present invention that are
ionic osmolytes include any salt consisting of a pharmaceutically
acceptable anion and a pharmaceutically acceptable cation.
Preferably, either (or both) of the anion and cation are
non-absorbable (i.e., osmotically active and not subject to rapid
active transport) in relation to the airway surfaces to which they
are administered. Such compounds include but are not limited to
anions and cations that are contained in FDA approved commercially
marketed salts, see, e.g., Remington: The Science and Practice of
Pharmacy, Vol. II, pg. 1457 (19th Ed. 1995), and can be used in any
combination including their conventional combinations.
[0020] Pharmaceutically acceptable anions that can be used to carry
out the present invention include, but are not limited to, acetate,
benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide,
calcium edetate, camsylate (camphorsulfonate), carbonate, chloride,
citrate, dihydrochloride, edetate, edisylate
(1,2-ethanedisulfonate), estolate (lauryl sulfate), esylate
(1,2-ethanedisulfonate), fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate (p-glycollamidophenylarsonate),
hexylresorcinate, hydrabamine
(N,N'-Di(dehydroabietyl)ethylenediamine), hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate
(embonate), pantothenate, phosphate or diphosphate,
polygalacturonate, salicylate, stearate, subacetate, succinate,
sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate),
triethiodide, bicarbonate, etc. Particularly preferred anions
include sulfate, nitrate, gluconate, iodide, bicarbonate, bromide,
and phosphate. In that chloride is absorbed by airway surfaces, it
is a less preferred anion.
[0021] Pharmaceutically acceptable cations that can be used to
carry out the present invention include, but are not limited to,
organic cations such as benzathine (N,N'-dibenzylethylenediamine),
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methyl D-glucamine), procaine, D-Lysine, L-lysine, D-arginine,
L-arginine, triethylammonium, N-methyl D-glycerol, and the like.
Particularly preferred organic cations are 3-carbon, 4-carbon,
5-carbon and 6-carbon organic cations. Metallic cations useful in
the practice of the present invention include but are not limited
to aluminum, calcium, lithium, magnesium, potassium, sodium, zinc,
iron, ammonium, and the like. Particularly preferred cations
include potassium, choline, lithium, meglumine, D-lysine, ammonium,
magnesium, and calcium. In that sodium is absorbed by airway
surfaces, it is a less preferred cation for the purposes of the
present invention. As between the dextrorotatory (D) form and the
levorotatory (L) form of an active compound of the present
invention, the D-form is preferred.
[0022] Specific examples of salts that may be used as active
compounds to carry out the present invention include, but are not
limited to, potassium chloride, choline chloride, choline iodide,
lithium chloride, meglumine chloride, L-lysine chloride, D-lysine
chloride, ammonium chloride, potassium sulfate, potassium nitrate,
potassium gluconate, potassium iodide, ferric chloride, ferrous
chloride, potassium bromide, etc. Either a single salt or a
combination of different salts may be used to carry out the present
invention. Combinations of different salts are preferred. When
different salts are used, one of the anion or cation may be the
same among the differing salts.
[0023] Active compounds of the present invention also include
non-ionic osmolytes such as sugars, sugar-alcohols, and organic
osmolytes. Sugars and sugar-alcohols useful in the practice of the
present invention include but are not limited to 3-carbon sugars
(e.g., glycerol, dihydroxyacetone); 4-carbon sugars (e.g., both the
D and L forms of erythrose, threose, and erythrulose); 5-carbon
sugars (e.g., both the D and L forms of ribose, arabinose, xylose,
lyxose, psicose, fructose, sorbose, and tagatose); and 6-carbon
sugars (e.g., both the D and L forms of altose, allose, glucose,
mannose, gulose, idose, galactose, and talose, and the D and L
forms of allo-heptulose, allo-hepulose, gluco-heptulose,
manno-heptulose, gulo-heptulose, ido-heptulose, galacto-heptulose,
talo-heptulose). Additional sugars useful in the practice of the
present invention include raffinose, raffinose series
oligosaccharides, and stachyose. Both the D and L forms of the
reduced form of each sugar/sugar alcohol useful in the present
invention are also active compounds within the scope of the
invention. For example, glucose, when reduced, becomes sorbitol;
within the scope of the invention, sorbitol and other reduced forms
of sugar/sugar alcohols (e.g., dulcitol, arabitol) are accordingly
active compounds of the present invention. As with the ionic
osmolytes of the present invention, as between the dextrorotatory
(D) form and the levorotatory (L) form of an active compound of the
present invention, the D-form is preferred.
[0024] Active compounds of the present invention additionally
include the family of non-ionic osmolytes termed "organic
osmolytes." The term "organic osmolytes" is generally used to refer
to molecules used to control intracellular osmolality in the
kidney. See e.g., J. S. Handler et al., Comp. Biochem. Physiol,
117, 301-306 (1997); M. Burg, Am. J. Physiol. 268, F983-F996
(1995). Although the inventor does not wish to be bound to any
particular theory of the invention, it appears that these organic
osmolytes are useful in controlling extracellular volume on the
airway/pulmonary surface. Organic osmolytes useful as active
compounds in the present invention include but are not limited to
three major classes of compounds: polyols (polyhydric alcohols),
methylamines, and amino acids. The polyol organic osmolytes
considered useful in the practice of this invention include, but
are not limited to, inositol, myo-inositol, and sorbitol. The
methylamine organic osmolytes useful in the practice of the
invention include, but are not limited to, choline, betaine,
carnitine (L-, D- and DL forms), phosphorylcholine,
lyso-phosphorylcholine, glycerophosphorylcholine, creatine, and
creatine phosphate. The amino acid organic osmolytes of the
invention include, but are not limited to, the D- and L forms of
glycine, alanine, glutamine, glutamate, aspartate, proline and
taurine. Additional osmolytes useful in the practice of the
invention include tihulose and sarcosine. Mammalian organic
osmolytes are preferred, with human organic osmolytes being most
preferred. However, certain organic osmolytes are of bacterial,
yeast, and marine animal origin, and these compounds are also
useful active compounds within the scope of the present
invention.
[0025] Under certain circumstances, an osmolyte precursor may be
administered to the subject; accordingly, these compounds are also
useful in the practice of the invention. The term "osmolyte
precursor" as used herein refers to a compound which is converted
into an osmolyte by a metabolic step, either catabolic or anabolic.
The osmolyte precursors of this invention include, but are not
limited to, glucose, glucose polymers, glycerol, choline,
phosphatidylcholine, lyso-phosphatidylcholine and inorganic
phosphates, which are precursors of polyols and methylamines.
Precursors of amino acid osmolytes within the scope of this
invention include proteins, peptides, and polyamino acids, which
are hydrolyzed to yield osmolyte amino acids, and metabolic
precursors which can be converted into osmolyte amino acids by a
metabolic step such as transamination. For example, a precursor of
the amino acid glutamine is poly-L-glutamine, and a precursor of
glutamate is poly-L-glutamic acid.
[0026] Also intended within the scope of this invention are
chemically modified osmolytes or osmolyte precursors. Such chemical
modifications involve linking to the osmolyte (or precursor) an
additional chemical group which alters or enhances the effect of
the osmolyte or osmolyte precursor (e.g., inhibits degradation of
the osmolyte molecule). Such chemical modifications have been
utilized with drugs or prodrugs and are known in the art. (See, for
example, U.S. Pat. Nos. 4,479,932 and 4,540,564; Shek, E. et al.,
J. Med. Chem. 19:113-117 (1976); Bodor, N. et al., J. Pharm. Sci.
67:1045-1050 (1978); Bodor, N. et al., J. Med Chem. 26:313-318
(1983); Bodor, N. et al., J. Pharm. Sci. 75:29-35 (1986);
[0027] In general, osmotically active compounds of the present
invention (both ionic and non-ionic) that do not promote, or in
fact deter or retard bacterial growth are preferred.
[0028] The active compounds, methods and compositions of the
present invention are useful as therapeutics for the treatment of
chronic obstructive airway or pulmonary disease in subjects in need
of such treatment. The active compounds, compositions and methods
described herein may also be used to induce the production of a
sputum or mucous sample in a patient. Additionally, the active
compounds, compositions and methods described herein can be used
for the lavage of the lungs and/or airways of a patient. The active
compounds and compositions described herein may also be
administered with other active agents that are to be introduced
into airways of a subject, and in fact may function as vehicles or
carriers for the other active agents.
[0029] Suitable subjects to treated according to the present
invention include both avian and mammalian subjects, preferably
mammalian. Any mammalian subject in need of being treated according
to the present invention is suitable, including dogs, cats and
other animals for veterinary purposes. Human subjects are
preferred. Human subjects of both genders and at any stage of
development (i.e., neonate, infant, juvenile, adolescent, adult)
can be treated according to the present invention. Preferred
subjects include those humans afflicted with a chronic obstructive
airway or pulmonary disease, including but not limited to cystic
fibrosis, chronic bronchitis, emphysema, primary and secondary
ciliary dyskinesia, sinusitis, and pneumonia. Human subjects
afflicted with cystic fibrosis are particularly preferred.
[0030] Active compounds disclosed herein may be administered to
airway surfaces including the nasal passages, sinuses and lungs of
a subject by any suitable means known in the art, such as by nose
drops, mists, etc. In one embodiment of the invention, the active
compounds of the present invention are administered by
transbronchoscopic lavage. In a preferred embodiment of the
invention, the active compounds of the present invention are
deposited on lung airway surfaces by administering an aerosol
suspension of respirable particles comprised of the active
compound, which the subject inhales. The respirable particles may
be liquid or solid. Numerous inhalers for administering aerosol
particles to the lungs of a subject are known.
[0031] Inhalers such as those developed by Inhale Therapeutic
Systems, Palo Alto, Calif., USA, may be employed, including but not
limited to those disclosed in U.S. Pat. Nos. 5,740,794; 5,654,007;
5,458,135; 5,775,320; and 5,785,049. The Applicant specifically
intends that the disclosures of all patent references cited herein
be incorporated by reference herein in their entirety. Inhalers
such as those developed by Dura Pharmaceuticals Inc, San Diego,
Calif., USA, may also be employed, including but not limited to
those disclosed in U.S. Pat. Nos. 5,622,166; 5,577,497; 5,645,051;
and 5,492,112. Additionally, inhalers such as those developed by
Aradigin Corp., Hayward, Calif., USA, may be employed, including
but not limited to those disclosed in U.S. Pat. Nos. 5,826,570;
5,813,397; 5,819,726; and 5,655,516. These apparatuses are
particularly suitable as dry particle inhalers.
[0032] Aerosols of liquid particles comprising the active compound
may be produced by any suitable means, such as with a
pressure-driven aerosol nebulizer or an ultrasonic nebulizer. See,
e.g., U.S. Pat. No. 4,501,729. Nebulizers are commercially
available devices which transform solutions or suspensions of the
active ingredient into a therapeutic aerosol mist either by means
of acceleration of compressed gas, typically air or oxygen, through
a narrow venturi orifice or by means of ultrasonic agitation.
Suitable formulations for use in nebulizers consist of the active
ingredient in a liquid carrier, the active ingredient comprising up
to 40% w/w of the formulation, but preferably less than 20% w/w.
The carrier is typically water (and most preferably sterile,
pyrogen-free water) or a dilute aqueous alcoholic solution.
Perfluorocarbon carriers may also be used. Optional additives
include preservatives if the formulation is not made sterile, for
example, methyl hydroxybenzoate, antioxidants, flavoring agents,
volatile oils, buffering agents and surfactants.
[0033] Aerosols of solid particles comprising the active compound
may likewise be produced with any solid particulate medicament
aerosol generator. Aerosol generators for administering solid
particulate medicaments to a subject produce particles which are
respirable, as explained above, and generate a volume of aerosol
containing a predetermined metered dose of a medicament at a rate
suitable for human administration. One illustrative type of solid
particulate aerosol generator is an insufflator. Suitable
formulations for administration by insufflation include finely
comminuted powders which may be delivered by means of an
insufflator or taken into the nasal cavity in the manner of a
snuff. In the insufflator, the powder (e.g., a metered dose thereof
effective to carry out the treatments described herein) is
contained in capsules or cartridges, typically made of gelatin or
plastic, which are either pierced or opened in situ and the powder
delivered by air drawn through the device upon inhalation or by
means of a manually-operated pump. The powder employed in the
insufflator consists either solely of the active ingredient or of a
powder blend comprising the active ingredient, a suitable powder
diluent, such as lactose, and an optional surfactant. The active
ingredient typically comprises from 0.1 to 100% w/w of the
formulation. A second type of illustrative aerosol generator
comprises a metered dose inhaler. Metered dose inhalers are
pressurized aerosol dispensers, typically containing a suspension
or solution formulation of the active ingredient in a liquified
propellant. During use these devices discharge the formulation
through a valve adapted to deliver a metered volume, typically from
10 to 150 .mu.l, to produce a fine particle spray containing the
active ingredient. Suitable propellants include certain
chlorofluorocarbon compounds, for example, dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane and mixtures
thereof. The formulation may additionally contain one or more
co-solvents, for example, ethanol, surfactants, such as oleic acid
or sorbitan trioleate, antioxidants and suitable flavoring
agents.
[0034] The aerosol, whether formed from solid or liquid particles,
may be produced by the aerosol generator at a rate of from about 10
to 150 liters per minute, more preferably from about 30 to 150
liters per minute, and most preferably about 60 liters per minute.
Aerosols containing greater amounts of medicament may be
administered more rapidly.
[0035] The dosage of the active compounds disclosed herein will
vary depending on the condition being treated and the state of the
subject, but generally may be from about 0.1 or 1 to about 30, 50
or 100 milliosmoles of the salt, deposited on the airway surfaces.
The daily dose may be divided among one or several unit dose
administrations.
[0036] Other active agents may be administered concurrently to the
subject in need thereof with the osmotically active compounds of
the present invention. As used herein, the term "concurrently"
means sufficiently close in time to produce a combined effect (that
is, concurrently may be simultaneously, or it may be two or more
events occurring within a short time period before or after each
other). When administered with other active agents, the active
compounds of the present invention may function as a vehicle or
carrier for the other active agent, or may simply be administered
concurrently with the other active agent. The active compound of
the present invention may be used as a dry or liquid vehicle for
administering other active ingredients to airway surfaces. Such
other active agents may be administered for treating the disease or
disorder for which they are intended, in their conventional manner
and dosages, in combination with the active compounds of the
present invention, which may be thought of as serving as a vehicle
or carrier for the other active agent. Any such other active
ingredient may be employed, particularly where hydration of the
airway surfaces (i.e., the activity of the osmotically active
compounds of the present invention) facilitates the activity of the
other active ingredient (e.g., by facilitating or enhancing uptake
of the active ingredient, by contributing to the mechanism of
action of the other active ingredient, or by any other mechanisms).
In a preferred embodiment of the invention, when the active
compound of the present invention is administered concurrently with
another active agent, the active compound of the present invention
has an additive effect in relation to the other active agent; that
is, the desired effect of the other active agent is enhanced by the
concurrent administration of the active compounds of the present
invention.
[0037] In particular, bronchodilators may be administered
concurrently with the active compounds of the present invention.
Bronchodilators that can be used in the practice of the present
invention include, but are not limited to, .beta.-adrenergic
agonists including but not limited to epinephrine, isoproterenol,
fenoterol, albutereol, terbutaline, pirbuterol, bitolterol,
metaproterenol, isoetharine, salmeterol, xinafoate, as well as
anticholinergic agents including but not limited to ipratropium
bromide, as well as compounds such as theophylline and
aminophylline. These compounds may be administered in accordance
with known techniques, either prior to or concurrently with the
active compounds described herein.
[0038] Other active ingredients that may be administered with the
active compounds of the present invention include ion transport
modulators and other active agents known to be useful in the
treatment of the subject afflicted with a chronic obstructive
pulmonary disease (e.g., DNase, antibiotics, etc.).
[0039] Ion transport modulators that can be administered as active
agents along with the active compounds of the present invention
herein include, sodium channel blockers such as amiloride, benzamil
or phenamil, purinoceptor (particularly P2Y.sub.2) receptor
agonists such as UTP, UTP-.gamma.-S, dinucleotide P2Y.sub.2
receptor agonists, and .beta.-agonists. Thus the method of the
present invention may be used as a vehicle system to administer the
active compounds described in U.S. Pat. No. 5,837,861 to Pendergast
et al., U.S. Pat. No. 5,635,160 to Stutts et al., U.S. Pat. No.
5,656,256 to Boucher et al., U.S. Pat. No. 5,292,498 to Boucher et
al., and U.S. Pat. No. 4,501,729 to Boucher et al., the disclosures
of all of which are to hereby incorporated by reference herein in
their entirety.
[0040] Other active ingredients that can be administered in
combination with the formulations described herein include nucleic
acids or oligonucleotides; viral gene transfer vectors (including
adenovirus, adeno-associated virus, and retrovirus gene transfer
vectors); enzymes; and hormone drugs or physiologically active
proteins or peptides such as insulin, somatostatin, oxytocin,
desmopressin, leutinizing hormone releasing hormone, nafarelin,
leuprolide, adrenocorticotrophic hormone, secretin, glucagon,
calcitonin, growth hormone releasing hormone, growth hormone, etc.
Enzyme drugs that may be used to carry out the present invention,
include but are not limited to DNAse (for the treatment of, e.g.,
cystic fibrosis), .alpha..sub.1-antitrypsin (e.g., to inhibit
elastase in the treatment of emphysema), etc. Suitable
anti-inflammatory agents, including steroids, for use in the
methods of the present invention include, but are not limited to,
beclomethasone dipropionate, prednisone, flunisolone,
dexamethasone, prednisolone, cortisone, theophylline, albuterol,
cromolyn sodium, epinephrine, flunisolide, terbutaline sulfate,
alpha-tocopherol (Vitamin E), dipalmitoylphosphatidylcholine,
salmeterol and fluticasone dipropionate. Examples of antibiotics
that may be employed include, but are not limited to tetracycline,
choramphenicol, aminoglycosides, for example, tobramycin,
beta-lactams, for example ampicillin, cephalosporins, erythromycin
and derivatives thereof, clindamycin, and the like. Suitable
anti-viral agents include acyclovir, ribavirin, ganciclovir and
foscarnet. Suitable anti-neoplastic agents include, but are not
limited to, etoposid, taxol, and cisplatin. Antihistamines include,
but are not limited to, diphenhydramine and ranitadine.
Anti-Pneumocystis carinii pneumonia drugs such as pentamidine and
analogs thereof may also be used. Anti-tuberculosis drugs such as
rifampin, erythromycin, chlorerythromycin, etc. Chelators of
divalent cations (e.g., EGTA, EDTA), expectorants, and other agents
useful in the loosening of mucous secretions (e.g.,
n-acetyl-L-cysteine) may also be administered as desired in the
practice of the present invention.
[0041] The present invention is particularly useful for chronic
treatments: that is, treatments wherein the administration is
repeated two or more times in close proximity to one another, so
that the multiple treatments achieve a combined therapeutic effect.
For example, the administration may be carried out two, three,
four, five, six or seven times a week, on separate days throughout
the week. The treatment may be carried out for a period of two,
four, or six days or more; daily for two or four weeks or more;
daily for two or four months or more. etc. For example, the
administering step may be carried out three, four, five or six
times a day for the duration of the condition being treated, with
chronic conditions receiving chronic treatments.
[0042] The compounds, compositions and methods described herein can
be used for the lavage of a lung, or lung lobe, in a patient in
need thereof by administering an effective therapeutic amount of
the compositions to the lung of a subject. Lavage may be carried
out with a bronchoscope by instilling a volume of fluid into a
desired lobe of the lung (e.g., 30 milliliters to 3 liters,
typically 300 milliliters) in accordance with known techniques.
Lavage may be single administration or repetitive (e.g., three
washings). A portion of the instilled fluid is removed or
aspirated, after instillation, in accordance with known techniques.
The lavage solution may be an aqueous solution, or may be a
perfluorocarbon liquid such as used for blood substitutes.
[0043] Solid or liquid particulate pharmaceutical formulations
containing active compounds of the present invention should include
particles of respirable size: that is, particles of a size
sufficiently small to pass through the mouth and larynx upon
inhalation and into the bronchi, bronchioles, and (if necessary)
the alveoli of the lungs. The bronchioles are a particularly
preferred target for delivery to the airway surfaces. In general,
particles ranging from about 1 to 5 or 6 microns in size (more
particularly, less than about 4.7 microns in size) are respirable.
Particles of non-respirable size which are included in the aerosol
tend to be deposited in the throat and swallowed, and the quantity
of non-respirable particles in the aerosol is preferably minimized.
For nasal administration, a particle size in the range of 10-500
.mu.m is preferred to ensure retention in the nasal cavity.
[0044] In the manufacture of a formulation according to the
invention, active compounds of the present invention may be admixed
with, inter alia, an acceptable carrier. The carrier must, of
course, be acceptable in the sense of being compatible with any
other ingredients in the formulation and must not be deleterious to
the patient. The carrier may be a solid or a liquid, or both, and
is preferably formulated with the compound as a unit-dose
formulation, for example, a capsule, which may contain from 0.5% to
99% by weight of the active compound. One or more active compounds
may be incorporated in the formulations of the invention, which
formulations may be prepared by any of the well-known techniques of
pharmacy consisting essentially of admixing the components.
[0045] Compositions containing respirable dry particles of active
compound may be prepared by grinding the active compound with a
mortar and pestle, and then passing the micronized composition
through a 400 mesh screen to break up or separate out large
agglomerates.
[0046] The pharmaceutical composition may optionally contain a
dispersant which serves to facilitate the formation of an aerosol.
A suitable dispersant is lactose, which may be blended with the
active agents in any suitable ratio (e.g., a 1 to 1 ratio by
weight).
[0047] The foregoing is illustrative of the present invention, and
is not to be construed as limiting thereof. The invention is
defined by the following claims, with equivalents of the claims to
be included therein.
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