U.S. patent application number 15/066360 was filed with the patent office on 2016-06-30 for lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof.
The applicant listed for this patent is Insmed Incorporated. Invention is credited to Jeff WEERS.
Application Number | 20160184302 15/066360 |
Document ID | / |
Family ID | 38123420 |
Filed Date | 2016-06-30 |
United States Patent
Application |
20160184302 |
Kind Code |
A1 |
WEERS; Jeff |
June 30, 2016 |
LIPID-BASED COMPOSITIONS OF ANTIINFECTIVES FOR TREATING PULMONARY
INFECTIONS AND METHODS OF USE THEREOF
Abstract
A system for treating or providing prophylaxus against a
pulmonary infection is disclosed comprising: a) a pharmaceutical
formulation comprising a mixture of free antiinfective and
antiinfective encapsulated in a lipid-based composition, and b) an
inhalation delivery device. A method for providing prophylaxis
against a pulmonary infection in a patient and a method of reducing
the loss of antiinfective encapsulated in a lipid-based composition
upon nebulization comprising administering an aerosolized
pharmaceutical formulation comprising a mixture of free
antiinfective and antiinfective encapsulated in a lipid-based
composition is also disclosed.
Inventors: |
WEERS; Jeff; (Belmont,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Insmed Incorporated |
Bridgewater |
NJ |
US |
|
|
Family ID: |
38123420 |
Appl. No.: |
15/066360 |
Filed: |
March 10, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14080922 |
Nov 15, 2013 |
|
|
|
15066360 |
|
|
|
|
13666420 |
Nov 1, 2012 |
8642075 |
|
|
14080922 |
|
|
|
|
13527213 |
Jun 19, 2012 |
8632804 |
|
|
13666420 |
|
|
|
|
11634343 |
Dec 5, 2006 |
8226975 |
|
|
13527213 |
|
|
|
|
60748468 |
Dec 8, 2005 |
|
|
|
Current U.S.
Class: |
424/450 ;
514/253.08 |
Current CPC
Class: |
A61M 15/0091 20130101;
A61M 11/006 20140204; A61P 31/00 20180101; A61K 45/06 20130101;
A61P 31/04 20180101; A61K 9/0073 20130101; A61P 31/06 20180101;
A61M 11/005 20130101; A61K 31/7034 20130101; A61K 31/7048 20130101;
A61K 47/26 20130101; A61K 9/127 20130101; A61K 31/7036 20130101;
A61P 31/12 20180101; A61P 31/10 20180101; A61M 11/02 20130101; A61M
15/08 20130101; A61M 15/009 20130101; A61P 11/00 20180101; A61M
11/001 20140204; A61K 9/008 20130101; A61K 9/0078 20130101; A61P
31/08 20180101; A61P 11/08 20180101; A61K 9/14 20130101; A61K
31/496 20130101 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 9/00 20060101 A61K009/00; A61K 9/127 20060101
A61K009/127 |
Claims
1. A method of treatment, comprising: aerosolizing a liquid
composition to create aerosolized particles; inhaling the
aerosolized particles into a patient's lungs; wherein the liquid
composition comprises free, unencapsulated ciprofloxacin in an
aqueous solution at an effective concentration with a
pharmaceutically acceptable salt or buffering agent; and a
liposome-encapsulated ciprofloxacin wherein the liposomes of the
liposome-encapsulated ciprofloxacin are comprised of cholesterol
and a phospholipid.
2. The method of claim 1, wherein the phospholipid is a
phosphatidylcholine.
3. The method of claim 2, wherein the phosphatidylcholine is
hydrogenated soy phosphatidyl-choline.
4. The method of claim 1, wherein the aerosolized particles are
sized for positioning the particles within the pulmonary
membrane.
5. The method of claim 1, wherein the ratio by weight of the free
unencapsulated ciprofloxacin to the liposome-encapsulated
ciprofloxacin is between about 1:100 and about 100:1.
6. The method of claim 1, wherein the patient is suffering from a
pulmonary infection.
7. The method of claim 5, wherein the pulmonary infection is due to
P. aeruginosa.
8. The method of claim 1, wherein the liposomes have a mean
diameter of about 0.01 microns to about 3 microns.
9. The method of claim 1, wherein the patient is a cystic fibrosis
patient.
10. The method of claim 7, wherein the patient is a cystic fibrosis
patient.
11. The method of claim 1, wherein the liposomes further comprise
an additional component selected from the group consisting of
synthetic, semi-synthetic or naturally occurring lipids,
phospholipids, tocopherols, sterols, fatty acids and
glycoproteins.
12. The method of claim 1, wherein the patient is a bronchiectasis
patient.
13. The method of claim 3, wherein the patient is a bronchiectasis
patient.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/080,922, filed Nov. 15, 2013, which is a continuation of
U.S. application Ser. No. 13/666,420, filed Nov. 1, 2012, now U.S.
Pat. No. 8,642,075, which is a continuation of U.S. application
Ser. No. 13/527,213, filed Jun. 19, 2012, now U.S. Pat. No.
8,632,804, which is a continuation of U.S. application Ser. No.
11/634,343, filed Dec. 5, 2006, now U.S. Pat. No. 8,226,975, which
claims the benefit of priority from U.S. Provisional Patent
Application Ser. No. 60/748,468, filed Dec. 8, 2005, each of which
is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] According to the World Health Organization, respiratory
diseases are the number one cause of world-wide mortality, with at
least 20% of the world's population afflicted. Over 25 million
Americans have chronic lung disease, making it the number one
disabler of American workers (>$50 B/yr), and the number three
cause of mortality.
[0003] Currently, most infections are treated with oral or
injectable antiinfectives, even when the pathogen enters through
the respiratory tract. Often the antiinfective has poor penetration
into the lung, and may be dose-limited due to systemic
side-effects. Many of these issues can be overcome by local
delivery of the antiinfective to the lungs of patients via
inhalation. For example, inhaled tobramycin (TOBI.RTM., Chiron
Corp, Emeryville, Calif.), is a nebulized form of tobramycin, that
has been shown to have improved efficacy and reduced nephro- and
oto-toxicity relative to injectable aminoglycosides. Unfortunately,
rapid absorption of the drug necessitates that the drug product be
administered twice daily over a period of ca., 20 min per
administration. For pediatrics and young adults with cystic
fibrosis this treatment regimen can be taxing, especially when one
takes into account the fact that these patients are on multiple
time-consuming therapies. Any savings in terms of treatment times
would be welcomed, and would likely lead to improvements in patient
compliance. Achieving improved compliance with other patient
populations (e.g., chronic obstructive pulmonary disease (COPD),
acute bronchial exacerbations of chronic bronchitis) will be
critically dependent on the convenience and efficacy of the
treatment. Hence, it is an object of the present invention to
improve patient compliance by providing formulations with sustained
activity in the lungs. Sustained release formulations of
antiinfectives are achieved by encapsulating the antiinfective in a
liposome. Improving pulmonary targeting with sustained release
formulations would further improve the therapeutic index by
increasing local concentrations of drug and reducing systemic
exposure. Improvements in targeting are also expected to reduce
dose requirements.
[0004] Achieving sustained release of drugs in the lung is a
difficult task, given the multiple clearance mechanisms that act in
concert to rapidly remove inhaled drugs from the lung. These
clearance methods include: (a) rapid clearance from the conducting
airways over a period of hours by the mucociliary escalator; (b)
clearance of particulates from the deep lung by alveolar
macrophages; (c) degradation of the therapeutic by pulmonary
enzymes, and; (d) rapid absorption of small molecule drugs into the
systemic circulation. Absorption of small molecule drugs has been
shown to be nearly quantitative, with an absorption time for
hydrophilic small molecules of about 1 hr, and an absorption time
for lipophilic drugs of about 1 min.
[0005] For TOBI.RTM. the absorption half-life from the lung is on
the order of 1.5 hr. High initial peak concentrations of drug can
lead to adaptive resistance, while a substantial time with levels
below or near the effective minimum inhibitory concentration (MIC),
may lead to selection of resistant phenotypes. It is hypothesized
that keeping the level of antiinfective above the MIC for an
extended period of time (i.e., eliminating sub-therapeutic trough
levels) with a pulmonary sustained release formulation may reduce
the potential for development of resistant phenotypes. Hence, it is
a further object of the present invention to maintain the ratio of
the area under the lung concentration/time curve to the MIC at 24
hr (i.e., the AUIC), not only at an adequate sustained therapeutic
level, but above a critical level, so as to reduce the potential
for selection of resistant strains.
[0006] It is assumed that only the "free" (un-encapsulated) drug
has bactericidal activity. One potential disadvantage of liposomal
sustained release formulations is that the encapsulation of drug in
the liposomal formulation decreases the concentration of free drug
reaching the lung pathogens, drug which is needed to achieve
efficient killing of bacteria immediately following administration.
Hence, it is further an object of the present invention to provide
a formulation that contains sufficient free drug, to be
bactericidal immediately following administration.
[0007] The disclosures of the foregoing are incorporated herein by
reference in their entirety.
SUMMARY OF THE INVENTION
[0008] It is an object of the present invention to use lipid-based
composition encapsulation to improve the therapeutic effects of
antiinfectives administered to an individual via the pulmonary
route.
[0009] The subject invention results from the realization that
administering a pharmaceutical composition comprising both free and
liposome encapsulated antiinfective results in improved treatment
of pulmonary infections.
[0010] In one aspect, the present invention relates to a system for
treating or providing prophylaxis against a pulmonary infection,
wherein the system comprises a pharmaceutical formulation
comprising mixtures of free and lipid-based composition
encapsulated antiinfective, wherein the amount of free
antiinfective is sufficient to provide for immediate bactericidal
activity, and the amount of encapsulated antiinfective is
sufficient to provide sustained bactericidal activity, and reduce
the development of resistant strains of the infectious agent, and
an inhalation delivery device.
[0011] The free form of the antiinfective is available to provide a
bolus of immediate antimicrobial activity. The slow release of
antiinfective from the lipid-based composition following pulmonary
administration is analogous to continuous administration of the
antiinfective, thereby providing for sustained levels of
antiinfective in the lungs. The sustained AUC levels provides
prolonged bactericidal activity between administrations. Further,
the sustained levels provided by the release of antiinfective from
the lipid-based composition is expected to provide improved
protection against the development of resistant microbial
strains.
[0012] Combinations of free and encapsulated drug can be achieved
by: (a) formulation of mixtures of free and encapsulated drug that
are stable to the nebulization; (b) formulation of encapsulated
drug which leads to burst on nebulization.
[0013] The ratio of free to encapsulated drug is contemplated to be
between about 1:100 w:w and about 100:1 w:w, and may be determined
by the minimum inhibitory concentration of the infectious agent and
the sustained release properties of the formulation. The ratio of
free to encapsulated drug can be optimized for a given infectious
agent and drug formulation based on known pharmacodynamic targets
for bacterial killing and prevention of resistance. Schentag, J. J.
J. Chemother. 1999, 11, 426-439.
[0014] In a further embodiment, the present invention relates to
the aforementioned system wherein the antiinfective is selected
from the group consisting of antibiotic agents, antiviral agents,
and antifungal agents. In a further embodiment, the antiinfective
is an antibiotic selected from the group consisting of
cephalosporins, quinolones, fluoroquinolones, penicillins, beta
lactamase inhibitors, carbepenems, monobactams, macrolides,
lincosamines, glycopeptides, rifampin, oxazolidonones,
tetracyclines, aminoglycosides, streptogramins, and sulfonamides.
In a further embodiment, the antiinfective is an aminoglycoside. In
a further embodiment the antiinfective is amikacin, gentamicin, or
tobramycin.
[0015] In a further embodiment, the lipid-based composition is a
liposome. In a further embodiment, the liposome comprises a mixture
of unilamellar vesicles and multilamellar vesicles. In a further
embodiment, the liposome comprises a phospholipid and a sterol. In
a further embodiment, the liposome comprises a phosphatidylcholine
and a sterol. In a further embodiment, the liposome comprises
dipalmitoylphosphatidylcholine (DPPC) and a sterol. In a further
embodiment, the liposome comprises dipalmitoylphosphatidylcholine
(DPPC) and cholesterol.
[0016] In a further embodiment, the present invention relates to
the aforementioned system wherein the antiinfective is an
aminogylcoside and the liposome comprises DPPC and cholesterol. In
a further embodiment, the antiinfective is amikacin, the liposome
comprises DPPC and cholesterol, and the liposome comprises a
mixture of unilamellar vesicles and multilamellar vesicles.
[0017] In a further embodiment, the present invention relates to
the aforementioned system, wherein the ratio by weight of free
antiiinfective to antiinfective encapsulated in a lipid-based
composition is between about 1:100 and about 100:1. In a further
embodiment, the ratio by weight is between about 1:10 and about
10:1. In a further embodiment, the ratio by weight is between about
1:2 and about 2:1.
[0018] In another embodiment, the present invention relates to a
method for treating or providing prophylaxis against a pulmonary
infection in a patient, the method comprising: administering an
aerosolized pharmaceutical formulation comprising the antiinfective
to the lungs of the patient, wherein the pharmaceutical formulation
comprises mixtures of free and lipid-based composition encapsulated
antiinfectives, and the amount of free antiinfective is sufficient
to provide for bactericidal activity, and the amount of
encapsulated antiinfective is sufficient to reduce the development
of resistant strains of the infectious agent.
[0019] In a further embodiment, the aforementioned method comprises
first determining the minimum inhibitory concentration (MIC) of an
antiinfective for inhibiting pulmonary infections, and wherein the
amount of free antiinfective is at least 2 times the MIC,
preferably greater than 4 times the MIC, and preferably greater
than 10 times the MIC of the antiinfective agent, where the MIC is
defined as either the minimum inhibitory concentration in the
epithelial lining of the lung, or alternatively the minimum
inhibitory concentration in the solid tissue of the lung (depending
on the nature of the infection).
[0020] In a further embodiment, the present invention relates to
the aforementioned method, wherein the aerosolized pharmaceutical
formulation is administered at least once per week.
[0021] In a further embodiment, the present invention relates to
the aforementioned method, wherein the antiinfective is selected
from the group consisting of antibiotic agents, antiviral agents,
and antifungal agents. In a further embodiment, the antiinfective
is an antibiotic selected from the group consisting of
cephalosporins, quinolones, fluoroquinolones, penicillins, beta
lactamase inhibitors, carbepenems, monobactams, macrolides,
lincosamines, glycopeptides, rifampin, oxazolidonones,
tetracyclines, aminoglycosides, streptogramins, and sulfonamides.
In a further embodiment, the antiinfective is an aminoglycoside. In
a further embodiment, the antiinfective is amikacin, gentamicin, or
tobramycin.
[0022] In a further embodiment, the lipid-based composition is a
liposome. In a further embodiment, the liposome encapsulated
antiinfective comprises a phosphatidylcholine in admixture with a
sterol. In a further aspect, the sterol is cholesterol. In a
further aspect, the liposome encapsulated antiinfective comprises a
mixture of unilamellar vesicles and multilamellar vesicles. In a
further aspect, the liposome encapsulated antiinfective comprises a
phosphatidylcholine in admixture with cholesterol, and wherein the
liposome encapsulated antiinfective comprises a mixture of
unilamellar vesicles and multilamellar vesicles.
[0023] The ratio of the area under the lung concentration/time
curve to the MIC at 24 hr (i.e., the AUIC) is greater than 25,
preferably greater than 100, and preferably greater than 250.
[0024] The therapeutic ratio of free/encapsulated drug and the
required nominal dose can be determined with standard
pharmacokinetic models, once the efficiency of pulmonary delivery
and clearance of the drug product are established with the aerosol
delivery device of choice.
[0025] In one aspect, the present invention relates to a method of
treating a patient for a pulmonary infection comprising a cycle of
treatment with lipid-based composition encapsulated antiinfective
to enhance bacterial killing and reduce development of phenotypic
resistance, followed by a cycle of no treatment to reduce the
development of adaptive resistance. The treatment regimen may be
determined by clinical research. In one embodiment, the treatment
regime may be an on-cycle treatment for about 7, 14, 21, or 30
days, followed by an off-cycle absence of treatment for about 7,
14, 21, or 30 days.
[0026] In another aspect, the present invention relates to a method
for reducing the loss of antiinfective encapsulated in lipid-based
compositions upon nebulization comprising administering the
antiinfective encapsulated in lipid-based compositions with free
antiinfective.
[0027] The systems and methods of the present invention are useful
for treating, for example, lung infections in cystic fibrosis
patients, chronic obstructive pulmonary disease (COPD),
bronchiectasis, acterial pneumonia, and in acute bronchial
exacerbations of chronic bronchitis (ABECB). In addition, the
technology is useful in the treatment of intracellular infections
including Mycobacterium tuberculosis, and inhaled agents of
bioterror (e.g., anthrax and tularemia). The technology may also be
used as a phophylactic agent to treat opportunistic fungal
infections (e.g., aspergillosis) in immunocompromised patients
(e.g., organ transplant or AIDS patients).
[0028] With bacteria and other infective agents becoming
increasingly resistant to traditional treatments, new and more
effective treatments for infective agent related illnesses are
needed. The present invention addresses these issues by providing a
system comprising a pharmaceutical composition comprising both free
and lipid-based composition encapsulated antiinfective and an
inhalation device. Formulating the antiinfective as a mixture of
free and lipid-based composition encapsulated antiinfective
provides several advantages, some of which include: (a) provides
for a bolus of free antiinfective for immediate bactericidal
activity and a sustained level of antiinfective for prevention of
resistance; (b) simplifies the manufacturing process, as less free
antiinfective need be removed via diafiltration; and (c) allows for
greater antiinfective contents to be achieved in the drug
product.
[0029] These embodiments of the present invention, other
embodiments, and their features and characteristics, will be
apparent from the description, drawings and claims that follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1 depicts the plot of lung concentration (.mu.g/ml) as
a function of time following nebulization of unencapsulated
tobramycin at a nominal dose of 300 mg (TOBI.RTM., Chiron Corp.,
Emeryville, Calif.), and liposomal amikacin at a nominal dose of
100 mg. Lung concentrations for both drug products are calculated
assuming a volume of distribution for aminoglycosides in the lung
of 200 ml. The tobramycin curve was determined by pharmacokinetic
modeling of the temporal tobramycin plasma concentration curve (Le
Brun thesis, 2001).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0031] For convenience, before further description of the present
invention, certain terms employed in the specification, examples
and appended claims are collected here. These definitions should be
read in light of the remainder of the disclosure and understood as
by a person of skill in the art. Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as
commonly understood by a person of ordinary skill in the art.
[0032] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e. to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0033] The term "antibacterial" is art-recognized and refers to the
ability of the compounds of the present invention to prevent,
inhibit or destroy the growth of microbes of bacteria.
[0034] The terms "antiinfective" and "antiinfective agent" are used
interchangeably throughout the specification to describe a
biologically active agent which can kill or inhibit the growth of
certain other harmful pathogenic organisms, including but not
limited to bacteria, yeasts and fungi, viruses, protozoa or
parasites, and which can be administered to living organisms,
especially animals such as mammals, particularly humans.
[0035] The term "antimicrobial" is art-recognized and refers to the
ability of the compounds of the present invention to prevent,
inhibit or destroy the growth of microbes such as bacteria, fungi,
protozoa and viruses.
[0036] The term "bioavailable" is art-recognized and refers to a
form of the subject invention that allows for it, or a portion of
the amount administered, to be absorbed by, incorporated to, or
otherwise physiologically available to a subject or patient to whom
it is administered.
[0037] The terms "comprise" and "comprising" are used in the
inclusive, open sense, meaning that additional elements may be
included.
[0038] The term "illness" as used herein refers to any illness
caused by or related to infection by an organism.
[0039] The term "including" is used herein to mean "including but
not limited to". "Including" and "including but not limited to" are
used interchangeably.
[0040] The term "lipid-based composition" as used herein refers to
compositions that primarily comprise lipids. Non-limiting examples
of lipid-based compositions may take the form of coated lipid
particles, liposomes, emulsions, micelles, and the like.
[0041] The term "mammal" is known in the art, and exemplary mammals
include humans, primates, bovines, porcines, canines, felines, and
rodents (e.g., mice and rats).
[0042] The term "microbe" is art-recognized and refers to a
microscopic organism. In certain embodiments the term microbe is
applied to bacteria. In other embodiments the term refers to
pathogenic forms of a microscopic organism.
[0043] A "patient," "subject" or "host" to be treated by the
subject method may mean either a human or non-human animal.
[0044] The term "pharmaceutically-acceptable salts" is
art-recognized and refers to the relatively non-toxic, inorganic
and organic acid addition salts of compounds, including, for
example, those contained in compositions of the present
invention.
[0045] The term "prodrug" is art-recognized and is intended to
encompass compounds which, under physiological conditions, are
converted into the antibacterial agents of the present invention. A
common method for making a prodrug is to select moieties which are
hydrolyzed under physiological conditions to provide the desired
compound. In other embodiments, the prodrug is converted by an
enzymatic activity of the host animal or the target bacteria.
[0046] The term "treating" is art-recognized and refers to curing
as well as ameliorating at least one symptom of any condition or
disease.
Lipids
[0047] The lipids used in the pharmaceutical formulations of the
present invention can be synthetic, semi-synthetic or
naturally-occurring lipids, including phospholipids, tocopherols,
sterols, fatty acids, glycoproteins such as albumin,
negatively-charged lipids and cationic lipids. In terms of
phosholipids, they could include such lipids as egg
phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg
phosphatidylinositol (EPI), egg phosphatidylserine (EPS),
phosphatidylethanolamine (EPE), and phosphatidic acid (EPA); the
soya counterparts, soy phosphatidylcholine (SPC); SPG, SPS, SPI,
SPE, and SPA; the hydrogenated egg and soya counterparts (e.g.,
HEPC, HSPC), other phospholipids made up of ester linkages of fatty
acids in the 2 and 3 of glycerol positions containing chains of 12
to 26 carbon atoms and different head groups in the I position of
glycerol that include choline, glycerol, inositol, serine,
ethanolamine, as well as the corresponding phosphatidic acids. The
chains on these fatty acids can be saturated or unsaturated, and
the phospholipid may be made up of fatty acids of different chain
lengths and different degrees of unsaturation. In particular, the
compositions of the formulations can include
dipalmitoylphosphatidylcholine (DPPC), a major constituent of
naturally-occurring lung surfactant. Other examples include
dimyristoylphosphatidycholine (DMPC) and
dimyristoylphosphatidylglycerol (DMPG) dipalmitoylphosphatidcholine
(DPPQ and dipalmitoylphosphatidylglycerol (DPPG)
distearoylphosphatidylcholine (DSPQ and
distearoylphosphatidylglycerol (DSPG),
dioleylphosphatidyl-ethanolarnine (DOPE) and mixed phospholipids
like palmitoylstearoylphosphatidyl-choline (PSPC) and
palmitoylstearolphosphatidylglycerol (PSPG), and single acylated
phospholipids like mono-oleoyl-phosphatidylethanolarnine
(MOPE).
[0048] The sterols can include, cholesterol, esters of cholesterol
including cholesterol hemi-succinate, salts of cholesterol
including cholesterol hydrogen sulfate and cholesterol sulfate,
ergosterol, esters of ergosterol including ergosterol
hemi-succinate, salts of ergosterol including ergosterol hydrogen
sulfate and ergosterol sulfate, lanosterol, esters of lanosterol
including lanosterol hemi-succinate, salts of lanosterol including
lanosterol hydrogen sulfate and lanosterol sulfate. The tocopherols
can include tocopherols, esters of tocopherols including tocopherol
hemi-succinates, salts of tocopherols including tocopherol hydrogen
sulfates and tocopherol sulfates. The term "sterol compound"
includes sterols, tocopherols and the like.
[0049] The cationic lipids used can include ammonium salts of fatty
acids, phospholids and glycerides. The fatty acids include fatty
acids of carbon chain lengths of 12 to 26 carbon atoms that are
either saturated or unsaturated. Some specific examples include:
myristylamine, palmitylamine, laurylamine and stearylamine,
dilauroyl ethylphosphocholine (DLEP), dimyristoyl
ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine (DPEP)
and distearoyl ethylphosphocholine (DSEP),
N-(2,3-di-(9-(Z)-octadecenyloxy)-prop-1-yl-N,N,N-trimethylammoniu-
m chloride (DOTMA) and
1,2-bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP).
[0050] The negatively-charged lipids which can be used include
phosphatidyl-glycerols (PGs), phosphatidic acids (PAs),
phosphatidylinositols (PIs) and the phosphatidyl serines (PSs).
Examples include DMPG, DPPG, DSPG, DMPA, DPPA, DSPA, DMPI, DPPI,
DSPI, DMPS, DPPS and DSPS.
[0051] Phosphatidylcholines, such as DPPC, aid in the uptake by the
cells in the lung (e.g., the alveolar macrophages) and helps to
sustain release of the bioactive agent in the lung. The negatively
charged lipids such as the PGs, PAs, PSs and PIs, in addition to
reducing particle aggregation, are believed to play a role in the
sustained release characteristics of the inhalation formulation as
well as in the transport of the formulation across the lung
(transcytosis) for systemic uptake. The sterol compounds are
believed to affect the release characteristics of the
formulation.
Liposomes
[0052] Liposomes are completely closed lipid bilayer membranes
containing an entrapped aqueous volume. Liposomes may be
unilamellar vesicles (possessing a single membrane bilayer) or
multilamellar vesicles (onion-like structures characterized by
multiple membrane bilayers, each separated from the next by an
aqueous layer). The bilayer is composed of two lipid monolayers
having a hydrophobic "tail" region and a hydrophilic "head" region.
The structure of the membrane bilayer is such that the hydrophobic
(nonpolar) "tails" of the lipid monolayers orient toward the center
of the bilayer while the hydrophilic "heads" orient towards the
aqueous phase.
[0053] Liposomes can be produced by a variety of methods (for a
review, see, e.g., Cullis et al. (1987)). Bangham's procedure (J.
Mol. Biol. (1965)) produces ordinary multilamellar vesicles (MLVs).
Lenk et al. (U.S. Pat. Nos. 4,522,803, 5,030,453 and 5,169,637),
Fountain et al. (U.S. Pat. No. 4,588,578) and Cullis et al. (U.S.
Pat. No. 4,975,282) disclose methods for producing multilamellar
liposomes having substantially equal interlamellar solute
distribution in each of their aqueous compartments. Paphadjopoulos
et al., U.S. Pat. No. 4,235,871, discloses preparation of
oligolamellar liposomes by reverse phase evaporation.
[0054] Unilamellar vesicles can be produced from MLVs by a number
of techniques, for example, the extrusion of Cullis et al. (U.S.
Pat. No. 5,008,050) and Loughrey et al. (U.S. Pat. No. 5,059,421)).
Sonication and homogenization cab be so used to produce smaller
unilamellar liposomes from larger liposomes (see, for example,
Paphadjopoulos et al. (1968); Deamer and Uster (1983); and Chapman
et al. (1968)).
[0055] The original liposome preparation of Bangham et al. (J. Mol.
Biol., 1965, 13:238-252) involves suspending phospholipids in an
organic solvent which is then evaporated to dryness leaving a
phospholipid film on the reaction vessel. Next, an appropriate
amount of aqueous phase is added, the 60 mixture is allowed to
"swell", and the resulting liposomes which consist of multilamellar
vesicles (MLVs) are dispersed by mechanical means. This preparation
provides the basis for the development of the small sonicated
unilamellar vesicles described by Papahadjopoulos et al. (Biochim.
Biophys, Acta., 1967, 135:624-638), and large unilamellar
vesicles.
[0056] Techniques for producing large unilamellar vesicles (LUVs),
such as, reverse phase evaporation, infusion procedures, and
detergent dilution, can be used to produce liposomes. A review of
these and other methods for producing liposomes may be found in the
text Liposomes, Marc Ostro, ed., Marcel Dekker, Inc., N.Y., 1983,
Chapter 1, the pertinent portions of which are incorporated herein
by reference. See also Szoka, Jr. et al., (1980, Ann. Rev. Biophys.
Bioeng., 9:467), the pertinent portions of which are also
incorporated herein by reference.
[0057] Other techniques that are used to prepare vesicles include
those that form reverse-phase evaporation vesicles (REV),
Papahadjopoulos et al., U.S. Pat. No. 4,235,871. Another class of
liposomes that may be used are those characterized as having
substantially equal lamellar solute distribution. This class of
liposomes is denominated as stable plurilamellar vesicles (SPLV) as
defined in U.S. Pat. No. 4,522,803 to Lenk, et al. and includes
monophasic vesicles as described in U.S. Pat. No. 4,588,578 to
Fountain, et al. and frozen and thawed multilamellar vesicles
(FATMLV) as described above.
[0058] A variety of sterols and their water soluble derivatives
such as cholesterol hemisuccinate have been used to form liposomes;
see specifically Janoff et al., U.S. Pat. No. 4,721,612, issued
Jan. 26, 1988, entitled "Steroidal Liposomes." Mayhew et al., PCT
Publication No. WO 85/00968, published Mar. 14, 1985, described a
method for reducing the toxicity of drugs by encapsulating them in
liposomes comprising alpha-tocopherol and certain derivatives
thereof. Also, a variety of tocopherols and their water soluble
derivatives have been used to form liposomes, see Janoff et al.,
PCT Publication No. 87/02219, published Apr. 23, 1987, entitled
"Alpha Tocopherol-Based Vesicles".
[0059] The liposomes are comprised of particles with a mean
diameter of approximately 0.01 microns to approximately 3.0
microns, preferably in the range about 0.2 to 1.0 microns. The
sustained release property of the liposomal product can be
regulated by the nature of the lipid membrane and by inclusion of
other excipients (e.g., sterols) in the composition.
Infective Agent
[0060] The infective agent included in the scope of the present
invention may be a bacteria. The bacteria can be selected from:
Pseudomonas aeruginosa, Bacillus anthracis, Listeria monocytogenes,
Staphylococcus aureus, Salmenellosis, Yersina pestis, Mycobacterium
leprae, M. africanum, M. asiaticum, M. avium-intracellulaire, M.
chelonei abscess us, M. fallax, M. fortuitum, M. kansasii, M.
leprae, M. malmoense, M. shimoidei, M. simiae, M. szulgai, M.
xenopi, M. tuberculosis, Brucella melitensis, Brucella suis,
Brucella abortus, Brucella canis, Legionella pneumonophilia,
Francisella tularensis, Pneumocystis carinii, mycoplasma, and
Burkholderia cepacia.
[0061] The infective agent included in the scope of the present
invention can be a virus. The virus can be selected from:
hantavirus, respiratory syncytial virus, influenza, and viral
pneumonia.
[0062] The infective agent included in the scope of the present
invention can be a fungus. Fungal diseases of note include:
aspergillosis, disseminated candidiasis, blastomycosis,
coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis,
and sporotrichosis.
[0063] Antiinfectives
[0064] The term antiinfective agent is used throughout the
specification to describe a biologically active agent which can
kill or inhibit the growth of certain other harmful pathogenic
organisms, including but not limited to bacteria, yeasts and fungi,
viruses, protozoa or parasites, and which can be administered to
living organisms, especially animals such as mammals, particularly
humans.
[0065] Non-limiting examples of antibiotic agents that may be used
in the antiinfective compositions of the present invention include
cephalosporins, quinolones and fluoroquinolones, penicillins, and
beta lactamase inhibitors, carbepenems, monobactams, macrolides and
lincosamines, glycopeptides, rifampin, oxazolidonones,
tetracyclines, aminoglycosides, streptogramins, sulfonamides, and
others. Each family comprises many members.
Cephalosporins
[0066] Cephalosporins are further categorized by generation.
Non-limiting examples of cephalosporins by generation include the
following. Examples of cephalosporins I generation include
Cefadroxil, Cefazolin, Cephalexin, Cephalothin, Cephapirin, and
Cephradine. Examples of cephalosporins II generation include
Cefaclor, Cefamandol, Cefonicid, Cefotetan, Cefoxitin, Cefprozil,
Ceftmetazole, Cefuroxime, Cefuroxime axetil, and Loracarbef.
Examples of cephalosporins III generation include Cefdinir,
Ceftibuten, Cefditoren, Cefetamet, Cefpodoxime, Cefprozil,
Cefuroxime (axetil), Cefuroxime (sodium), Cefoperazone, Cefixime,
Cefotaxime, Cefpodoxime proxetil, Ceftazidime, Ceftizoxime, and
Ceftriaxone. Examples of cephalosporins IV generation include
Cefepime.
Quinolones and Fluoroquinolones
[0067] Non-limiting examples of quinolones and fluoroquinolones
include Cinoxacin, Ciprofloxacin, Enoxacin, Gatifloxacin,
Grepafloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic
acid, Norfloxacin, Ofloxacin, Sparfloxacin, Trovafloxacin, Oxolinic
acid, Gemifloxacin, and Perfloxacin.
Penicillins
[0068] Non-limiting examples of penicillins include Amoxicillin,
Ampicillin, Bacampicillin, Carbenicillin Indanyl, Mezlocillin,
Piperacillin, and Ticarcillin.
Penicillins and Beta Lactamase Inhibitors
[0069] Non-limiting examples of penicillins and beta lactamase
inhibitors include Amoxicillin-Clavulanic Acid,
Ampicillin-Sulbactam, Sulfactam, Tazobactam, Benzylpenicillin,
Cloxacillin, Dicloxacillin, Methicillin, Oxacillin, Penicillin G
(Benzathine, Potassium, Procaine), Penicillin V,
Penicillinase-resistant penicillins, Isoxazoylpenicillins,
Aminopenicillins, Ureidopenicillins, Piperacillin+Tazobactam,
Ticarcillin+Clavulanic Acid, and Nafcillin.
Carbepenems
[0070] Non-limiting examples of carbepenems include
Imipenem-Cilastatin and Meropenem.
Monobactams
[0071] A non-limiting example of a monobactam includes
Aztreonam.
Macrolides and Lincosamines
[0072] Non-limiting examples of macrolides and lincosamines include
Azithromycin, Clarithromycin, Clindamycin, Dirithromycin,
Erythromycin, Lincomycin, and Troleandomycin.
Glycopeptides
[0073] Non-limiting examples of glycopeptides include Teicoplanin
and Vancomycin.
Rifampin
[0074] Non-limiting examples of rifampins include Rifabutin,
Rifampin, and Rifapentine.
Oxazolidonones
[0075] A non-limiting example of oxazolidonones includes
Linezolid.
Tetracyclines
[0076] Non-limiting examples of tetracyclines include
Demeclocycline, Doxycycline, Methacycline, Minocycline,
Oxytetracycline, Tetracycline, and Chlortetracycline.
Aminoglycosides
[0077] Non-limiting examples of aminoglycosides include Amikacin,
Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin,
Tobramycin, and Paromomycin.
Streptogramins
[0078] A non-limiting example of streptogramins includes
Quinopristin+Dalfopristin.
Sulfonamides
[0079] Non-limiting examples of sulfonamides include Mafenide,
Silver Sulfadiazine, Sulfacetamide, Sulfadiazine, Sulfamethoxazole,
Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole, and
Sulfamethizole.
Others
[0080] Non-limiting examples of other antibiotic agents include
Bacitracin, Chloramphenicol, Colistemetate, Fosfomycin, Isoniazid,
Methenamine, Metronidazol, Mupirocin, Nitrofurantoin,
Nitrofurazone, Novobiocin, Polymyxin B, Spectinomycin,
Trimethoprine, Trimethoprine/Sulfamethoxazole, Cationic peptides,
Colistin, Iseganan, Cycloserine, Capreomycin, Pyrazinamide,
Para-aminosalicyclic acid, and Erythromycin
ethylsuccinate+sulfisoxazole.
[0081] Antiviral agents include, but are not limited to:
zidovudine, acyclovir, ganciclovir, vidarabine, idoxuridine,
trifluridine, ribavirin, interferon alpha-2a, interferon alpha-2b,
interferon beta, interferon gamma).
[0082] Anifungal agents include, but are not limited to:
amphotericin B, nystatin, hamycin, natamycin, pimaricin,
ambruticin, itraconazole, terconazole, ketoconazole, voriconazole,
miconazole, nikkomycin Z, griseofulvin, candicidin, cilofungin,
chlotrimazole, clioquinol, caspufungin, tolnaftate.
Dosages
[0083] The dosage of any compositions of the present invention will
vary depending on the symptoms, age and body weight of the patient,
the nature and severity of the disorder to be treated or prevented,
the route of administration, and the form of the subject
composition. Any of the subject formulations may be administered in
a single dose or in divided doses. Dosages for the compositions of
the present invention may be readily determined by techniques known
to those of skill in the art or as taught herein.
[0084] In certain embodiments, the dosage of the subject compounds
will generally be in the range of about 0.01 ng to about 10 g per
kg body weight, specifically in the range of about 1 ng to about
0.1 g per kg, and more specifically in the range of about 100 ng to
about 10 mg per kg.
[0085] An effective dose or amount, and any possible affects on the
timing of administration of the formulation, may need to be
identified for any particular composition of the present invention.
This may be accomplished by routine experiment as described herein,
using one or more groups of animals (preferably at least 5 animals
per group), or in human trials if appropriate. The effectiveness of
any subject composition and method of treatment or prevention may
be assessed by administering the composition and assessing the
effect of the administration by measuring one or more applicable
indices, and comparing the post-treatment values of these indices
to the values of the same indices prior to treatment.
[0086] The precise time of administration and amount of any
particular subject composition that will yield the most effective
treatment in a given patient will depend upon the activity,
pharmacokinetics, and bioavailability of a subject composition,
physiological condition of the patient (including age, sex, disease
type and stage, general physical condition, responsiveness to a
given dosage and type of medication), route of administration, and
the like. The guidelines presented herein may be used to optimize
the treatment, e.g., determining the optimum time and/or amount of
administration, which will require no more than routine
experimentation consisting of monitoring the subject and adjusting
the dosage and/or timing.
[0087] While the subject is being treated, the health of the
patient may be monitored by measuring one or more of the relevant
indices at predetermined times during the treatment period.
Treatment, including composition, amounts, times of administration
and formulation, may be optimized according to the results of such
monitoring. The patient may be periodically reevaluated to
determine the extent of improvement by measuring the same
parameters. Adjustments to the amount(s) of subject composition
administered and possibly to the time of administration may be made
based on these reevaluations.
[0088] Treatment may be initiated with smaller dosages which are
less than the optimum dose of the compound. Thereafter, the dosage
may be increased by small increments until the optimum therapeutic
effect is attained.
[0089] The use of the subject compositions may reduce the required
dosage for any individual agent contained in the compositions
(e.g., the FabI inhibitor) because the onset and duration of effect
of the different agents may be complimentary.
[0090] Toxicity and therapeutic efficacy of subject compositions
may be determined by standard pharmaceutical procedures in cell
cultures or experimental animals, e.g., for determining the
LD.sub.50 and the ED.sub.50.
[0091] The data obtained from the cell culture assays and animal
studies may be used in formulating a range of dosage for use in
humans. The dosage of any subject composition lies preferably
within a range of circulating concentrations that include the
ED.sub.50 with little or no toxicity. The dosage may vary within
this range depending upon the dosage form employed and the route of
administration utilized. For compositions of the present invention,
the therapeutically effective dose may be estimated initially from
cell culture assays.
Pharmaceutical Formulation
[0092] The pharmaceutical formulation of the antiinfective may be
comprised of either an aqueous dispersion of liposomes and free
antiinfective, or a dehydrated powder containing liposomes and free
antiinfective. The formulation may contain lipid excipients to form
the liposomes, and salts/buffers to provide the appropriate
osmolarity and pH. The dry powder formulations may contain
additional excipients to prevent the leakage of encapsulated
antiinfective during the drying and potential milling steps needed
to create a suitable particle size for inhalation (i.e., 1-5
.mu.m). Such excipients are designed to increase the glass
transition temperature of the antiinfective formulation. The
pharmaceutical excipient may be a liquid or solid filler, diluent,
solvent or encapsulating material, involved in carrying or
transporting any subject composition or component thereof from one
organ, or portion of the body, to another organ, or portion of the
body. Each excipient must be "acceptable" in the sense of being
compatible with the subject composition and its components and not
injurious to the patient. Suitable excipients include trehalose,
raffinose, mannitol, sucrose, leucine, trileucine, and calcium
chloride. Examples of other suitable excipients include (1) sugars,
such as lactose, and glucose; (2) starches, such as corn starch and
potato starch; (3) cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)
powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
excipients, such as cocoa butter and suppository waxes; (9) oils,
such as peanut oil, cottonseed oil, safflower oil, sesame oil,
olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol, and
polyethylene glycol; (12) esters, such as ethyl oleate and ethyl
laurate; (13) agar; (14) buffering agents, such as magnesium
hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic compatible substances employed in pharmaceutical
formulations.
Inhalation Device
[0093] The pharmaceutical formulations of the present invention may
be used in any dosage dispensing device adapted for intranasal
administration. The device should be constructed with a view to
ascertaining optimum metering accuracy and compatibility of its
constructive elements, such as container, valve and actuator with
the nasal formulation and could be based on a mechanical pump
system, e.g., that of a metered-dose nebulizer, dry powder inhaler,
soft mist inhaler, or a nebulizer. Due to the large administered
dose, preferred devices include jet nebulizers (e.g., PART LC Star,
AKITA), soft mist inhalers (e.g., PART e-Flow), and capsule-based
dry powder inhalers (e.g., PH&T Turbospin). Suitable
propellants may be selected among such gases as fluorocarbons,
hydrocarbons, nitrogen and dinitrogen oxide or mixtures
thereof.
[0094] The inhalation delivery device can be a nebulizer or a
metered dose inhaler (MDI), or any other suitable inhalation
delivery device known to one of ordinary skill in the art. The
device can contain and be used to deliver a single dose of the
antiinfective compositions or the device can contain and be used to
deliver multi-doses of the compositions of the present
invention.
[0095] A nebulizer type inhalation delivery device can contain the
compositions of the present invention as a solution, usually
aqueous, or a suspension. In generating the nebulized spray of the
compositions for inhalation, the nebulizer type delivery device may
be driven ultrasonically, by compressed air, by other gases,
electronically or mechanically. The ultrasonic nebulizer device
usually works by imposing a rapidly oscillating waveform onto the
liquid film of the formulation via an electrochemical vibrating
surface. At a given amplitude the waveform becomes unstable,
whereby it disintegrates the liquids film, and it produces small
droplets of the formulation. The nebulizer device driven by air or
other gases operates on the basis that a high pressure gas stream
produces a local pressure drop that draws the liquid formulation
into the stream of gases via capillary action. This fine liquid
stream is then disintegrated by shear forces.
[0096] The nebulizer may be portable and hand held in design, and
may be equipped with a self contained electrical unit. The
nebulizer device may comprise a nozzle that has two coincident
outlet channels of defined aperture size through which the liquid
formulation can be accelerated. This results in impaction of the
two streams and atomization of the formulation. The nebulizer may
use a mechanical actuator to force the liquid formulation through a
multiorifice nozzle of defined aperture size(s) to produce an
aerosol of the formulation for inhalation. In the design of single
dose nebulizers, blister packs containing single doses of the
formulation may be employed.
[0097] In the present invention the nebulizer may be employed to
ensure the sizing of particles is optimal for positioning of the
particle within, for example, the pulmonary membrane.
[0098] A metered dose inhalator (MDI) may be employed as the
inhalation delivery device for the compositions of the present
invention. This device is pressurized (pMDI) and its basic
structure comprises a metering valve, an actuator and a container.
A propellant is used to discharge the formulation from the device.
The composition may consist of particles of a defined size
suspended in the pressurized propellant(s) liquid, or the
composition can be in a solution or suspension of pressurized
liquid propellant(s). The propellants used are primarily
atmospheric friendly hydroflourocarbons (HFCs) such as 134a and
227. Traditional chloroflourocarbons like CFC-11, 12 and 114 are
used only when essential. The device of the inhalation system may
deliver a single dose via, e.g., a blister pack, or it may be multi
dose in design. The pressurized metered dose inhalator of the
inhalation system can be breath actuated to deliver an accurate
dose of the lipid-containing formulation. To insure accuracy of
dosing, the delivery of the formulation may be programmed via a
microprocessor to occur at a certain point in the inhalation cycle.
The MDI may be portable and hand held.
EXEMPLIFICATION
Example 1
[0099] Pharmacokinetics of amikacin delivered as both free and
encapsulated amikacin in healthy volunteers. The nebulized
liposomal amikacin contains a mixture of encapsulated (ca., 60%)
and free amikacin (ca., 40%). Following inhalation in healthy
volunteers the corrected nominal dose was 100 mg as determined by
gamma scintigraphy. FIG. 1 depicts the lung concentration of
amikacin and TOBI.RTM. (administered 100% free), based on
pharmacokinetic modeling of serum concentrations over time. Both
curves assume a volume of distribution for aminoglycosides in the
lung of 200 ml. Interestingly, the peak levels of antiinfective in
the lung are approximately equivalent for the 100 mg dose of
liposomal amikacin, and the 300 mg dose of TOBI.RTM.. This is a
consequence of the rapid clearance of the free tobramycin from the
lung by absorption into the systemic circulation with a half-life
of about 1.5 hr. These results serve as a demonstration of the
improved lung targeting afforded by liposomal encapsulation. The
presence of free and encapsulated antiinfective in the amikacin
formulation is demonstrated by the two component pharmacokinetic
profile observed. Free amikacin is rapidly absorbed into the
systemic circulation (with a half-life similar to TOBI), while the
encapsulated drug has a lung half-life of approximately 45 hr. The
free amikacin is available to provide bactericidal activity, while
the encapsulated drug provides sustained levels of drug in the
lung, enabling improved killing of resistant bacterial strains. The
measured lung concentrations for the liposomal compartment are
significantly above the MIC.sub.50 of 1240 clinical isolates of
Pseudomonas aeruginosa, potentially reducing the development of
resistance.
Example 2
[0100] Impact of free amikacin on the percentage of amikacin
encapsulated in liposomes following nebulization. Liposomal
preparations of amikacin may exhibit significant leakage of
encapsulated drug during nebulization. As detailed in Table 1
below, the presence of free amikacin in solution was shown to
surprisingly decrease the leakage of antiinfective by about
four-fold from the liposome. While not wishing to be limited to any
particular theory, it is hypothesized that liposomes break-up and
re-form during nebulization, losing encapsulated antiinfective in
the process. Alternatively, encapsulated antiinfective is lost
during nebulization because the liposome membrane becomes leaky.
When an excess of free antiinfective is present in solution, the
free antiinfective is readily available in close proximity to the
liposome, and is available to be taken back up into the liposome on
re-formation.
TABLE-US-00001 TABLE 1 Effect of free amikacin on the leakage of
amikacin from liposome-encapsulated amikacin. % Free Amikacin %
Free Amikacin % Free Amikacin (Post- (Due to Formulation
(Pre-nebulization) nebulization) nebulization) A 3.3 (n = 1) 42.4
.+-. 3.2 (n = 3) 39.1 .+-. 3.2 (n = 3) B 53.6 .+-. 5.4 (n = 9) 63.3
.+-. 4.7 (n = 9) 9.8 .+-. 5.8 (n = 9)
Wherein n is the number of measurements.
INCORPORATION BY REFERENCE
[0101] All of the patents and publications cited herein are hereby
incorporated by reference.
EQUIVALENTS
[0102] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
* * * * *