U.S. patent application number 16/777594 was filed with the patent office on 2020-06-25 for coenzyme q10 aerosol.
This patent application is currently assigned to STC.UNM. The applicant listed for this patent is STC.UNM RHEINISCHE FRIEDRICH-WILHELMS-UNIVERSITAT BONN BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM. Invention is credited to Thiago Cardoso Carvalho, Jason Thomas McConville, Kristina Schonhoff.
Application Number | 20200197300 16/777594 |
Document ID | / |
Family ID | 57586435 |
Filed Date | 2020-06-25 |
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United States Patent
Application |
20200197300 |
Kind Code |
A1 |
McConville; Jason Thomas ;
et al. |
June 25, 2020 |
Coenzyme Q10 Aerosol
Abstract
The present invention provides a formulation of Coenzyme Q10
that can be re-dispersed from a stable dry powder to formulation to
yield a nanodispersion that can be readily aerosolized for
inhalation.
Inventors: |
McConville; Jason Thomas;
(Albuquerque, NM) ; Carvalho; Thiago Cardoso;
(Brunswick, NJ) ; Schonhoff; Kristina; (Bonn,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
STC.UNM
RHEINISCHE FRIEDRICH-WILHELMS-UNIVERSITAT BONN
BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM |
Albuquerque
Bonn
Austin |
NM
TX |
US
DE
US |
|
|
Assignee: |
STC.UNM
Albuquerque
NM
RHEINISCHE FRIEDRICH-WILHELMS-UNIVERSITAT BONN
Bonn
TX
BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM
Austin
|
Family ID: |
57586435 |
Appl. No.: |
16/777594 |
Filed: |
January 30, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15738512 |
Dec 20, 2017 |
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|
PCT/US2016/039173 |
Jun 24, 2016 |
|
|
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16777594 |
|
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62185312 |
Jun 26, 2015 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/122 20130101;
A61K 47/26 20130101; A61K 9/0078 20130101; A61P 43/00 20180101;
A61P 39/06 20180101; A61K 47/14 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/26 20060101 A61K047/26; A61K 47/14 20060101
A61K047/14; A61K 31/122 20060101 A61K031/122 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. (canceled)
17. (canceled)
18. (canceled)
19. (canceled)
20. (canceled)
21. (canceled)
22. (canceled)
23. (canceled)
24. (canceled)
25. An aerosol formulation comprising coenzyme Q10 having an
effective oil phase dispersion size of 1 micron or less, that has
been re-dispersed from a solid dry matrix.
26. The formulation of claim 25, wherein the aerosol is in the form
of a nanoemulsion.
27. The formulation of claim 26 further comprising one or more
carriers, one or more oils, one or more surfactants or a
combination thereof.
28. A coenzyme Q10 formulation comprising: a first stage comprising
an emulsion containing coenzyme Q10 having an effective oil phase
dispersion size of 1 micron or less; a second stage comprising a
solid dry matrix formed from a dried state of said first stage
emulsion; and a third stage aerosol comprising an emulsion formed
from a re-dispersed said second stage solid.
29. The formulation of claim 27 wherein a drying technique such as
for example, freeze drying, or spray drying.
30. A method of preparing a coenzyme Q10 formulation, comprising
the steps of: preparing a first stage comprising an emulsion
containing coenzyme Q10 having an effective oil phase dispersion
size of 1 micron or less; preparing a second stage comprising a
solid dry matrix formed from a dried state of said first stage
emulsion; and preparing a third stage aerosol comprising an
emulsion formed from a re-dispersed said second stage solid.
31. The method of claim 30 wherein said second stage is prepared by
freeze drying or spray drying.
32. A method for making an aerosol formulation containing a desired
amount of CoQ10 comprising the steps of: dissolving CoQ10 in an oil
to create an oil phase; adding at least one surfactant to said oil
phase; adding water to create an emulsion; adding at least one
tonicity agent to make the emulsion isotonic, said emulsion
containing therein droplets of CoQ10 having a first average size;
freeze drying said emulsion; and rehydrating said freeze dried
emulsion with water to make an isotonic emulsion, upon rehydration
said emulsion containing therein droplets of CoQ10 having a second
average droplet size that is less than said first average droplet
size.
33. The method of claim 32 having a mixture ratio of 0.03 g of
CoQ10 to 0.5 g of oil.
34. The method of claim 32 having a mixture ratio of 60 g oil, 1 g
water, 0.5 g oil, 0.5 g surfactant, and 0.03 g CoQ10.
35. The method of claim 32 wherein said second average droplet size
is 117 nanometers or less.
36. The method of claim 32 wherein said second average droplet size
is 64 nanometers or less.
37. A method of treating a disorder comprising administering to a
subject in need of thereof the aerosol formulation of claim 32.
38. The method of claim 37 wherein disorder is cancer,
cardiovascular disease or obesity.
39. The method of claim 37 wherein said formulation is administered
by aerosolization using a jet, ultrasonic, pressurized or vibrating
porous plate nebulizer or other device capable of delivering the
formulation to the nasal passages and/or pulmonary airway.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
15/738512 filed on Dec. 20, 2017, which is a U.S. National Phase of
PCT/US2016/039173 filed on Jun. 24, 2016, which claims the benefit
of U.S. Provisional Application No. 62/185312 filed Jun. 26, 2015
and herein incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Coenzyme Q10 has a melting point around 50.degree. C. and
this makes it difficult to formulate since it is a waxy material;
for example, it cannot be milled using conventional methods.
Additionally, CoQ10 is degraded by heat and exposure to UV light.
CoQ10 is poorly absorbed via the oral route, additionally CoQ10 has
a short half-life in the body when administered via the intravenous
route, this is because it is ubiquitous to the body and so is
easily eliminated.
BRIEF SUMMARY OF THE INVENTION
[0003] By directly targeting the lung, a high concentration of
CoQ10 can be achieved for local therapy. Additionally, absorption
via the pulmonary route can provide a higher and sustained systemic
concentration with one or more doses. CoQ10 is highly lipophilic
and can therefore have a long residence time in the lung epithelium
to provide an extended local therapeutic time.
[0004] One embodiment provides an aerosol formulation comprising
coenzyme Q10. In one embodiment, the aerosol is in the form of an
emulsion, including a nanoemulsion. In another embodiment, the
formulation further comprises one or more carriers, one or more
oils, one or more surfactants or a combination thereof.
[0005] One embodiment provides a method of treating a respiratory
disease/disorder comprising administering to a subject in need of
thereof an aerosol formulation discussed herein. In one embodiment,
the respiratory disease/disorder is cancer. In one embodiment, the
formulation is administered by aerosolization using a jet,
ultrasonic, pressurized or vibrating porous plate nebulizer or
other device capable of delivering the formulation to the nasal
passages and/or pulmonary airway (including lung epithelium).
[0006] One embodiment provides a method of making a coenzyme Q10
(CoQ10) composition comprising dissolving CoQ10 in an oil phase
together to disperse and then adding one or more surfactants to
said dispersion to form an emulsion. In one embodiment, water is
added to the composition after the one or more surfactants are
added.
[0007] Another embodiment provides that the formulations or
compositions described herein are dried (such as by freeze drying,
spray drying or any other drying method). In one embodiment, the
dried formulation or composition is subsequently redispersed into a
formulation that can be nebulized.
[0008] Additional objects and advantages of the invention will be
set forth in part in the description which follows, and in part
will be obvious from the description, or may be learned by practice
of the invention. The objects and advantages of the invention will
be realized and attained by means of the elements and combinations
particularly pointed out in the appended claims.
[0009] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention, as
claimed.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0010] In the drawings, which are not necessarily drawn to scale,
like numerals may describe substantially similar components
throughout the several views. Like numerals having different letter
suffixes may represent different instances of substantially similar
components. The drawings illustrate generally, by way of example,
but not by way of limitation, a detailed description of certain
embodiments discussed in the present document.
[0011] FIG. 1 provides a phase diagram within one week after making
the emulsions. The shaded areas show nano-emulsion regions.
[0012] FIG. 2A, 2B and 2C depict an example of an DLS result of
0.5% oil +2% surfactant +97.5% water.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Detailed embodiments of the present invention are disclosed
herein; however, it is to be understood that the disclosed
embodiments are merely exemplary of the invention, which may be
embodied in various forms. Therefore, specific structural and
functional details disclosed herein are not to be interpreted as
limiting, but merely as a representative basis for teaching one
skilled in the art to variously employ the present invention in
virtually any appropriately detailed method, structure or system.
Further, the terms and phrases used herein are not intended to be
limiting, but rather to provide an understandable description of
the invention.
[0014] Further, the following definitions are included to provide a
clear and consistent understanding of the specification and claims.
As used herein, the recited terms have the following meanings. All
other terms and phrases used in this specification have their
ordinary meanings as one of skill in the art would understand. Such
ordinary meanings may be obtained by reference to technical
dictionaries, such as Hawley's Condensed Chemical Dictionary 14th
Edition, by R. J. Lewis, John Wiley & Sons, New York, N.Y.,
2001.
[0015] References in the specification to "one embodiment," "an
embodiment," etc., indicate that the embodiment described may
include a particular aspect, feature, structure, moiety, or
characteristic, but not every embodiment necessarily includes that
aspect, feature, structure, moiety, or characteristic. Moreover,
such phrases may, but do not necessarily, refer to the same
embodiment referred to in other portions of the specification.
Further, when a particular aspect, feature, structure, moiety, or
characteristic is described in connection with an embodiment, it is
within the knowledge of one skilled in the art to affect or connect
such aspect, feature, structure, moiety, or characteristic with
other embodiments, whether or not explicitly described.
[0016] The singular forms "a," "an," and "the" include plural
reference unless the context clearly dictates otherwise. Thus, for
example, a reference to "a compound" includes a plurality of such
compounds, so that a compound X includes a plurality of compounds
X. It is further noted that the claims may be drafted to exclude
any optional element. As such, this statement is intended to serve
as antecedent basis for the use of exclusive terminology, such as
"solely," "only," and the like, in connection with any element
described herein, and/or the recitation of claim elements or use of
"negative" limitations.
[0017] The term "and/or" means any one of the items, any
combination of the items, or all of the items with which this term
is associated. The phrase "one or more" is readily understood by
one of skill in the art, particularly when read in context of its
usage. For example, one or more substituents on a phenyl ring
refers to one to five, or one to four, for example if the phenyl
ring is disubstituted.
[0018] As used herein, "or" should be understood to have the same
meaning as "and/or" as defined above. For example, when separating
a listing of items, "and/or" or "or" shall be interpreted as being
inclusive, e.g., the inclusion of at least one, but also including
more than one, of a number of items, and, optionally, additional
unlisted items. Only terms clearly indicated to the contrary, such
as "only one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e., "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of"
[0019] As used herein, the terms "including," "includes," "having,"
"has," "with," or variants thereof, are intended to be inclusive
similar to the term "comprising."
[0020] The term "about" can refer to a variation of .+-.5%,
.+-.10%, .+-.20%, or .+-.25% of the value specified. For example,
"about 50" percent can in some embodiments carry a variation from
45 to 55 percent. For integer ranges, the term "about" can include
one or two integers greater than and/or less than a recited integer
at each end of the range. Unless indicated otherwise herein, the
term "about" is intended to include values, e.g., weight
percentages, proximate to the recited range that are equivalent in
terms of the functionality of the individual ingredient, the
composition, or the embodiment. The term about can also modify the
end-points of a recited range.
[0021] As will be understood by the skilled artisan, all numbers,
including those expressing quantities of ingredients, properties
such as molecular weight, reaction conditions, and so forth, are
approximations and are understood as being optionally modified in
all instances by the term "about." These values can vary depending
upon the desired properties sought to be obtained by those skilled
in the art utilizing the teachings of the descriptions herein. It
is also understood that such values inherently contain variability
necessarily resulting from the standard deviations found in their
respective testing measurements.
[0022] As will be understood by one skilled in the art, for any and
all purposes, particularly in terms of providing a written
description, all ranges recited herein also encompass any and all
possible sub-ranges and combinations of sub-ranges thereof, as well
as the individual values making up the range, particularly integer
values. A recited range (e.g., weight percentages or carbon groups)
includes each specific value, integer, decimal, or identity within
the range. Any listed range can be easily recognized as
sufficiently describing and enabling the same range being broken
down into at least equal halves, thirds, quarters, fifths, or
tenths. As a non-limiting example, each range discussed herein can
be readily broken down into a lower third, middle third and upper
third, etc. As will also be understood by one skilled in the art,
all language such as "up to," "at least," "greater than," "less
than," "more than," "or more," and the like, include the number
recited and such terms refer to ranges that can be subsequently
broken down into sub-ranges as discussed above. In the same manner,
all ratios recited herein also include all sub-ratios falling
within the broader ratio. Accordingly, specific values recited for
radicals, substituents, and ranges, are for illustration only; they
do not exclude other defined values or other values within defined
ranges for radicals and substituents.
[0023] One skilled in the art will also readily recognize that
where members are grouped together in a common manner, such as in a
Markush group, the invention encompasses not only the entire group
listed as a whole, but each member of the group individually and
all possible subgroups of the main group.
[0024] Additionally, for all purposes, the invention encompasses
not only the main group, but also the main group absent one or more
of the group members. The invention therefore envisages the
explicit exclusion of any one or more of members of a recited
group. Accordingly, provisos may apply to any of the disclosed
categories or embodiments whereby any one or more of the recited
elements, species, or embodiments, may be excluded from such
categories or embodiments, for example, for use in an explicit
negative limitation.
[0025] The term "contacting" refers to the act of touching, making
contact, or of bringing to immediate or close proximity, including
at the cellular or molecular level, for example, to bring about a
physiological reaction, a chemical reaction, or a physical change,
e.g., in a solution, in a reaction mixture, in vitro, or in
vivo.
[0026] As used herein, an "effective amount" or "therapeutically
effective amount" means an amount sufficient to produce a selected
effect, such as alleviating symptoms of a disease or disorder. In
the context of administering compounds in the form of a
combination, such as multiple compounds, the amount of each
compound, when administered in combination with another
compound(s), may be different from when that compound is
administered alone. Thus, an effective amount of a combination of
compounds refers collectively to the combination as a whole,
although the actual amounts of each compound may vary. The term
"more effective" means that the selected effect is alleviated to a
greater extent by one treatment relative to the second treatment to
which it is being compared.
[0027] The terms "therapeutic agent" and "medicament" are used
interchangeably herein to refer to a wide variety of substances
that, when administered to an organism (human or animal), induce a
desired pharmacologic or biological effect.
[0028] As use herein, the terms "administration of" and or
"administering" a compound should be understood to mean providing a
compound of the invention or a prodrug of a compound of the
invention to a subject in need of treatment.
[0029] As used herein, "alleviating a disease or disorder symptom,"
means reducing the severity of the symptom or the frequency with
which such a symptom is experienced by a patient, or both.
[0030] A "subject" of analysis, diagnosis, or treatment is an
animal. Such animals include mammals, preferably a human. As used
herein, a "subject in need thereof" is a patient, animal, mammal,
or human, who will benefit from the method of this invention.
[0031] A "therapeutic" treatment is a treatment administered to a
subject who exhibits signs of pathology for the purpose of
diminishing or eliminating those signs.
[0032] A "therapeutically effective amount" of a compound is that
amount of compound which is sufficient to provide a beneficial
effect to the subject to which the compound is administered.
[0033] As used herein, the term "aerosol" refers to suspension in
the air. In particular, aerosol refers to the particlization or
atomization of a formulation of the invention and its suspension in
the air.
[0034] As used herein, the term "inhaler" refers both to devices
for nasal and pulmonary administration of a drug, e.g., in
solution, powder and the like. For example, the term "inhaler" is
intended to encompass a propellant driven inhaler, such as is used
to administer antihistamine for acute asthma attacks, and plastic
spray bottles, such as are used to administer decongestants.
[0035] The term "inhalation" as used herein refers to the intake of
air to the alveoli. In specific examples, intake can occur by
self-administration of a medicament of the invention while inhaling
through a nebulizer or other aerosol-delivery device, or by
administration via a respirator, e.g., to a patient on a
respirator. The term "inhalation" used with respect to a medicament
of the invention is synonymous with "pulmonary administration."
[0036] The term "dispersant" as used herein refers to an agent that
assists aerosolization or absorption of the medicament in lung
tissue, or both. Preferably, the dispersant is pharmaceutically
acceptable. As used herein, the modifier
"pharmaceutically-acceptable" means approved by a regulatory agency
of the federal or a state government or listed in the U.S.
Pharmacopoeia or other generally recognized pharmacopoeia for use
in animals, and more particularly in humans.
[0037] The terms "simultaneously," "separately" and "sequentially"
as used herein refer to the administration regime of the medicament
in combination with the administration of a further one or more
therapeutic agent. "Simultaneously administered" refers to the
medicament and one or more therapeutic agents being administered in
a concomitant administration as well as separate administrations,
e.g., within about one-hour, preferably within 5-10 minutes or
less. "Separately administered" as used herein refers to the
medicament and one or more therapeutic agents being administered
independently of one another at an interval, for example at an
interval of about a day to several weeks or months. The active
agents may be administered in either order. "Sequentially
administered" as used herein refers to administration of the
medicament and one or more therapeutic agents in sequence, for
example at an interval or intervals of minutes, hours, days or
weeks, and if appropriate the medicament and one or more
therapeutic agents may be administered in a regular repeating
cycle. In all cases of "simultaneously," "separately" and
"sequentially" administration, the route of administration may be
the same or different.
[0038] As used herein, an "instructional material" includes a
publication, a recording, a diagram, or any other medium of
expression which can be used to communicate the usefulness of the
invention in the kit for effecting alleviation of the various
diseases or disorders recited herein. Optionally, or alternately,
the instructional material may describe one or more methods of
alleviating the diseases or disorders in a cell or a tissue of a
mammal. The instructional material of the kit of the invention may,
for example, be affixed to a container which contains the
identified invention, or portion thereof, or be shipped together
with a container which contains the invention or portion thereof.
Alternatively, the instructional material may be shipped separately
from the container with the intention that the instructional
material and the compound be used cooperatively by the
recipient.
[0039] The invention illustratively described herein may suitably
be practiced in the absence of any element or elements, limitation
or limitations, not specifically disclosed herein. Thus, for
example, the terms "comprising," "including," "containing," etc.
shall be read expansively and without limitation. Additionally, the
terms and expressions employed herein have been used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described or portions thereof, but it is
recognized that various modifications are possible within the scope
of the invention claimed. Thus, it should be understood that
although the present invention has been specifically disclosed by
preferred embodiments and optional features, modification and
variation of the inventions embodied therein herein disclosed may
be resorted to by those skilled in the art, and that such
modifications and variations are considered to be within the scope
of this invention.
[0040] The invention has been described broadly and generically
herein. Each of the narrower species and subgeneric groupings
falling within the generic disclosure also form part of the
invention. This includes the generic description of the invention
with a proviso or negative limitation removing any subject matter
from the genus, regardless of whether or not the excised material
is specifically recited herein.
[0041] Other embodiments are within the following claims and
non-limiting examples. In addition, where features or aspects of
the invention are described in terms of Markush groups, those
skilled in the art will recognize that the invention is also
thereby described in terms of any individual member or subgroup of
members of the Markush group.
[0042] Coenzyme Q10 (CoQ10) is an antioxidant that is made in the
human body. Coenzyme Q10, also known as ubiquinone, ubidecarenone,
coenzyme Q, and abbreviated at times to CoQ10, CoQ, or Q10 is a
1,4-benzoquinone, where Q refers to the quinone chemical group, and
10 refers to the number of isoprenyl chemical subunits in its tail
(IUPAC name
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-Decame-
thyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]
-5,6-dimethoxy-3 -methylcyclohexa-2,5-diene-1,4-dione).
[0043] This oil-soluble substance is present in eukaryotic cells,
primarily in the mitochondria. It is a component of the electron
transport chain and participates in aerobic cellular respiration,
generating energy in the form of ATP. Ninety-five percent of the
human body's energy is generated this way. Therefore, those organs
with the highest energy requirements--such as the heart, liver and
kidney--have the highest CoQ10 concentrations. There are three
redox states of CoQ10: fully oxidized (ubiquinone), semiquinone
(ubisemiquinone), and fully reduced (ubiquinol). The capacity of
this molecule to exist in a completely oxidized form and a
completely reduced form enables it to perform its functions in the
electron transport chain, and as an antioxidant, respectively.
[0044] In one aspect, the amount of CoQ10 in the compositions and
formulations described herein include about 1% to about 20% w/w,
about 2% to about 15%, about 3% to about 10%, about 4% to about 8%,
including about 5%, and about 6% w/w. For example, in one aspect,
the amount of CoQ10 in the compositions and formulations described
herein include about 0.01 g to about 0.2 g of CoQ10 per about 0.1 g
to about 2.0 g of oil and/or triglyceride, including about 0.02 g
to about 0.1 g CoQ10 per about 0.3 g to about 1.0 g of oil and/or
triglyceride, such as about 0.03 g to about 0.06 g CoQ10 per about
0.5 gram to about 0.8 g of oil and/or triglyceride, including about
0.03 g CoQ10 per about 0.5 g of oil and/or triglyceride. One of
skill will readily recognize that that amount of CoQ10 will vary
depending on the amount and/or type of oil and/or triglyceride
used.
[0045] FIG. 1 provides a phase diagram within one week after making
the emulsions. The shaded areas 10-13 show nano-emulsion regions.
In particular, for this embodiment of the present invention, area
13 identified as a region having nano-emulsions present with the
base formulation components discussed above, with a suitable
aqueous component.
[0046] In a preferred embodiment, maximum solubility of one drug
preparation using coconut oil was found to be 6% Q10 in neobee
(coconut oil).
[0047] In one embodiment, the disease or disorder is a respiratory
disease selected from the group consisting of inflammatory lung
disease (characterized by a high neutrophil count, e.g. asthma,
cystic fibrosis, emphysema, chronic obstructive pulmonary
disease/disorder or acute respiratory distress syndrome),
restrictive lung disease (restrictive lung diseases are a category
of respiratory disease characterized by a loss of lung compliance,
causing incomplete lung expansion and increased lung stiffness,
such as in infants with respiratory distress syndrome), upper
respiratory tract infection (the most common upper respiratory
tract infection is the common cold; however, infections of specific
organs of the upper respiratory tract such as sinusitis,
tonsillitis, otitis media, pharyngitis and laryngitis are also
considered upper respiratory tract infections), lower respiratory
tract infection (the most common lower respiratory tract infection
is pneumonia, an infection of the lungs which is usually caused by
bacteria, particularly Streptococcus pneumoniae in Western
countries; worldwide, tuberculosis is a cause of pneumonia; other
pathogens such as viruses and fungi can cause pneumonia for example
severe acute respiratory syndrome and pneumocystis pneumonia;
pneumonia may develop complications such as a lung abscess, a round
cavity in the lung caused by the infection, or may spread to the
pleural cavity), malignant tumors (malignant tumors of the
respiratory system, such as small cell lung cancer, non-small cell
lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of
the lung, large cell lung carcinoma, other lung cancers (carcinoid,
Kaposi's sarcoma, melanoma), lymphoma, head and neck cancer and
mesothelioma), benign tumors, pleural cavity disease, pulmonary
vascular disease, neonatal diseases, bronchiolitis obliterans,
chronic bronchitis, pulmonary fibrosis and/or cystic fibrosis.
[0048] In one embodiment, the disease or disorder is cancer, such
as malignant tumors including malignant tumors of the respiratory
system, such as small cell lung cancer, non-small cell lung cancer,
adenocarcinoma of the lung, squamous cell carcinoma of the lung,
large cell lung carcinoma, other lung cancers (carcinoid, Kaposi's
sarcoma, melanoma), lymphoma, head and neck cancer and
mesothelioma.
[0049] In addition, the formulations set for herein for the various
embodiments of the present invention have many other applications.
In a non-limiting example, the formulations may be used to treat
cardiovascular disease.
[0050] A compound/composition of the invention can be administered
by aerosol. This is accomplished by preparing an aqueous aerosol
droplets, liposomal preparation, or solid particles containing the
composition. A nonaqueous (e.g., fluorocarbon propellant)
suspension can be used. Generally, an aqueous aerosol is made by
formulating an aqueous solution or suspension of a compound of the
invention together with conventional pharmaceutically acceptable
carriers and stabilizers. The carriers and stabilizers can vary,
but typically include nonionic surfactants (Tweens, Pluronics,
sorbitan esters, Capryol, lecithin, Cremophors), pharmaceutically
acceptable co-solvents such as polyethylene glycol, innocuous
proteins like serum albumin, oleic acid (including fatty
acids/triglycerides or their salts, including coconut oil,
safflower oil, butter, cocoa butter, olive oil, and other
plant/vegetable oils), amino acids such as glycine/glycerin,
buffers, salts, sugars, or sugar alcohols (e.g., ethanol). Aerosols
generally are prepared from isotonic solutions.
[0051] Pharmaceutical compositions of the medicament include
sterile aqueous solutions (where water soluble) or dispersions and
sterile powders for the extemporaneous preparation of sterile
solutions or dispersions. Ideally, the composition is stable under
the conditions of manufacture and storage and may include a
preservative to stabilize the composition against the contaminating
action of microorganisms such as bacteria and fungi. For inhalable
solutions, the composition can be delivered as aerosol particles
(solid or liquid) that are of respirable size: that is, particles
of a size sufficiently small to pass through the mouth and larynx
upon inhalation and into the bronchi and alveoli of the lungs. In
general, particles ranging from about 1 to 10 microns in size (more
particularly, less than about 5 microns in size) are respirable. As
used herein, a particle may be a solid, a liquid droplet, and
combination thereof as well as any other known dispersion unit.
Compositions can be formulated to deliver the desired amount to the
lungs of a subject by inhalation, or to the nasal respiratory
epithelium as a topically applied liquid medicament. Liquid
aerosols of respirable particles may be administered by any
suitable means, such as by nebulizing a liquid composition (e.g.,
with a jet nebulizer or an ultrasonic nebulizer), and causing the
subject to inhale the nebulized composition. Alternatively,
subjects maintained on a ventilating apparatus can be administered
an aerosol of respirable particles by nebulizing the liquid
composition and introducing the aerosol into the inspiratory gas
stream of the ventilating apparatus.
[0052] Single or multiple administrations of the pharmaceutical
compositions according to the invention may be carried out. One
skilled in the art would be able, by routine experimentation, to
determine effective, non-toxic dosage levels of the compound and/or
composition of the invention and an administration pattern which
would be suitable for treating the diseases to which the compounds
and compositions are applicable.
[0053] Further, it will be apparent to one of ordinary skill in the
art that the optimal course of treatment, such as the number of
doses of the compound or composition of the invention given per day
for a defined number of days, can be ascertained using convention
course of treatment determination tests.
[0054] Generally, an effective dosage per 24 hours may be in the
range of about 0.0001 mg to about 1000 mg per kg body weight;
suitably, about 0.001 mg to about 750 mg per kg body weight; about
0.01 mg to about 500 mg per kg body weight; about 0.1 mg to about
500 mg per kg body weight; about 0.1 mg to about 250 mg per kg body
weight; or about 1.0 mg to about 250 mg per kg body weight. More
suitably, an effective dosage per 24 hours may be in the range of
about 1.0 mg to about 200 mg per kg body weight; about 1.0 mg to
about 100 mg per kg body weight; about 1.0 mg to about 50 mg per kg
body weight; about 1.0 mg to about 25 mg per kg body weight; about
5.0 mg to about 50 mg per kg body weight; about 5.0 mg to about 20
mg per kg body weight; or about 5.0 mg to about 15 mg per kg body
weight. In another embodiment, an effective dosage per 24 hours may
be in the range of about 2 to 15 mg per kg body weight.
[0055] Alternatively, an effective dosage may be up to about 800
mg/m.sup.2. For example, generally, an effective dosage is expected
to be in the range of about 25 to about 800 mg/m.sup.2, 25 to about
500 mg/m.sup.2, about 25 to about 350 mg/m.sup.2, about 25 to about
300 mg/m.sup.2, about 25 to about 250 mg/m.sup.2, about 50 to about
250 mg/m.sup.2, and about 75 to about 150 mg/m.sup.2.
[0056] In another embodiment, the composition of the invention is
administered with one or more further therapeutic agents. In
another embodiment, the medicament and the one or more further
therapeutic agents are administered sequentially, simultaneously or
separately.
[0057] The following example is intended to further illustrate
certain particularly preferred embodiments of the invention and is
not intended to limit the scope of the invention in any way.
EXAMPLE
[0058] Method
[0059] A mixture of surfactants (e.g., Tween80 and Capryo190) is
made and vortexed for about 2 minutes.
[0060] The triglyceride of coconut oil was weighed in a glass
vessel. It was then allowed to stand for one hour in a water bath
with 37.degree. C. along with the CoQ10, after which it was cooled
down and the surfactant mixture was added. This composition was
then mixed with the vortexer for about 30 seconds. After which, the
composition was allowed to stand until the next day. Water was then
added and it was mixed for about 1 min.
[0061] In yet another embodiment, the present provides a method for
making and administering an aerosol formulation containing a
desired amount of CoQ10 that is particularly useful for creating
aerosol treatments having respirable compositions. In this
embodiment, the emulsion is isotonic and may be made from an oil in
water mixture as well as other isotonic mixtures. In a preferred
embodiment, an isotonic agent is used such as dextrose, glycerin,
potassium chloride, sucrose, sodium chloride, or mannitol amongst
others. It has been found that isotonicity promotes the protection
of the emulsion and the CoQ10 mixed therein during further
processing and storage.
[0062] To further process the isotonic mixture into pellets for
storage and later use, the mixture may be freeze dried. The use of
an isotonic agent that is not a liquid, promotes the formation of a
solid compound.
[0063] Prior to use, the mixture is re-disbursed by adding water or
some other solvent and becomes isotonic again and also
self-emulsifying before use as an aerosol. In addition, during
re-disbursement, the tonicity of the mixture promotes shrinking of
the particles in the emulsion by as much as 20% percent from their
original size at the freeze drying step described above. This
reduction in particle size improves use for aerosol delivery.
[0064] In another embodiment, the present invention provides a
method to reduce the average particle size of the CoQ10 droplets.
In this embodiment, an average reduction may be achieved wherein
the droplets start at about 130 nm on average and are reduced down
to about 117 nm on average, which is a 13 nm reduction in droplet
size. The method may include the steps of making an aerosol
formulation containing a desired amount of CoQ10 by first
dissolving CoQ10 in an oil to create an oil phase. Heat may be
applied and 0.03 g of CoQ10 may be added to 0.5 g of oil.
[0065] At least one surfactant is added to the oil phase. A
preferred mixture ratio is 0.5 g surfactant, 0.03 g of CoQ10 and
0.5 g of oil. The mixture may also be cooled at this step.
[0066] Next water is added to create an emulsion. Preferably water
is incrementally while vortexing. A preferred mixture ratio is 60 g
oil, 1 g water, 0.5 g oil, 0.5 g surfactant, and 0.03 g CoQ10. At
least one tonicity agent is added to the emulsion to make the
emulsion isotonic. Suitable tonicity agents include, but are not
limited to, dextrose, glycerin, potassium chloride, sucrose, sodium
chloride, or mannitol amongst others. At this stage, the emulsion
contains droplets of CoQ10 having a first average size which may be
about 130 nm.
[0067] The emulsion is then freeze dried for storage and rehydrated
for use. Rehydrating may be accomplished by adding water to make an
isotonic emulsion. Upon rehydration, the emulsion contains droplets
of CoQ10 having a second average droplet size that is less than
said first average droplet size of about 117 nm. Over time,
however, the droplets will increase in size. Accordingly,
administration should be performed shortly after rehydration.
[0068] Methods:
[0069] Three different emulsions were prepared in accordance with
the teachings of the present invention: Emulsion (1) comprised 0.03
g CoQ10 and 0.5 g triglyceride of coconut oil, both were heated
together in a water bath for one hour on 37.degree. C., and
periodically shaken every 15 minutes. Following cooling to room
temperature, 0.5 g polysorbate 80 was added before vortex mixing
for 30 seconds using a Vortex-Genie2 mixer. After 24 hours 60 g
ultrapure deionized water was added. The water was added in
increased volumes and vortex mixed periodically. Finally, a
2-minute period of vortex mixing was performed to yield the final
emulsion product. Emulsions (2 and 3) polysorbate 80 and Capryol 90
2:1 used instead of only polysorbate 80. In both cases 0.03 g of
CoQ10 was used. For Emulsion (2) 0.5 g oil and 0.5 g surfactants
were used and for Emulsion (3) 0.47 g oil and 0.96 g surfactants
were used. Both Emulsions (1 and 2) were added with ultrapure
deionized water to 100 mL. Finally, a 1-minute period of vortex
mixing was performed to yield the final emulsion product.
[0070] For Emulsion (1) 0.08 g Sucrose with 0.17 g NaCl added. To
Emulsions (2 and 3) 0.2 g Sucrose and 0.43 g NaCl added. All
emulsions are freeze-dried with the FreeZone.RTM.Triad.TM.Freeze
Dry System.
[0071] Following lyophilization each emulsion was rehydrated with
ultrapure deionized water by shaking for 15 seconds.
[0072] Each emulsion product was analyzed with dynamic light
scattering and the transmission electron microscopy. Aerosol
particle size analysis was evaluated with using a Westech 7 cascade
impactor (flowrate 15 L/min; Emulsion 1 and 2 for 7 minutes and
Emulsion 3 for 8 minutes). The concentration of the impactor
collection cups was measured using a validated HPLC analysis
method.
[0073] Results:
[0074] For Emulsion (1) was 80.11% CoQ10 in the fine particle
fraction of the USP Apparatus 6 cascade impactor, with a fine
powder dose of 496.40 .mu.g. The total emitted fraction was 72.66%
with a total emitted dose of 619.60 .mu.g.
[0075] For Emulsion (2) was the FPF 69.26%, FPD 313.64 .mu.g, TEF
78.84% and TED 461.33 .mu.g.
[0076] For Emulsion (3) was the FPF 84.16%, FPD 306.87 .mu.g, TEF
78.60% and TED 331.59 .mu.g. NGI results are shown in Table 1.
TABLE-US-00001 TABLE 1 USP Apparatus 6 cascade impactor results FPF
[%] = Fine particle TEF [%] = TED [.mu.g] = FPD [.mu.g] = fraction
Total emmited Total emitted Fine powder Emulsion (Stage 4-7)
fraction dose dose 1 80.11 72.66 619.60 496.40 2 69.26 78.84 461.33
313.64 3 84.16 78.60 331.59 306.87
[0077] The particle size of Emulsion (1) at the point without
Sucrose and NaCl was 135.5.+-.1.3 nm with a polydispersity index of
0.216.+-.0.019 nm. After adding Sucrose and NaCl was the particle
size 134.6.+-.0.8 nm with a PDI of 0.181.+-.0.018 nm. The final
product (after lyophilization and rehydration) had a particle size
of 115.7 .+-.0.9 nm and a PDI of 0.162.+-.0.013 nm.
[0078] The particle size of Emulsion (2) without Sucrose and NaCl
was 160.6.+-.1.3 nm with a PDI of 0.229.+-.0.008 nm. After adding
Sucrose and NaCl was the particle size 161.2.+-.1.0 nm with a PDI
of 0.207.+-.0.010 nm. The final product had a particle size of
170.6.+-.1.1 nm and a PDI of 0.236.+-.0.005 nm.
[0079] Emulsion (3) was the particle size without Sucrose and NaCl
95.08.+-.0.1 nm with a PDI of 0.276.+-.0.005 nm. After adding
Sucrose and NaCl was the particle size 96.71.+-.0.7 nm with a PDI
of 0.273.+-.0.007 nm. The final product had a particle size of
64.16.+-.0.3 nm and a PDI of 0.205.+-.0.007 nm. Table 2 summarizes
particles size results.
TABLE-US-00002 TABLE 2 DLS results particle size [nm]/PDI Emulsion
after Emulsion without Emulsion with lyophilization Emulsion
Sucrose and NaCl Sucrose and NaCl and rehydration 1 135.5 .+-.
134.6 .+-. 115.7 .+-. 1.3/0.216 .+-. 0.8/0.181 .+-. 0.9/0.162 .+-.
0.019 0.018 0.013 2 160.6 .+-. 161.2 .+-. 170.6 .+-. 1.3/0.229 .+-.
1.0/0.207 .+-. 1.1/0.236 .+-. 0.008 0.010 0.005 3 95.08 .+-. 96.71
.+-. 64.16 .+-. 0.1/0.276 .+-. 0.7/0.273 .+-. 0.3/0.205 .+-. 0.005
0.007 0.007
[0080] Based on the above, embodiments of the present invention
include the three different emulsions described above. All may be
used as nebulization formulations. By using both surfactants,
particle size was smaller and the FPD was higher with more
surfactant and less oil. The emulsion with only polysorbate 80
yielded a 115.7 nm emulsion with a high FPF.
[0081] In yet another preferred embodiment, the particle/droplet
may be on average 1 micron or less. In other preferred embodiments,
particle/droplet may be on average 500 nanometers or less or 200
nanometers or less.
[0082] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference. In the event that the definition of a
term incorporated by reference conflicts with a term defined
herein, this specification shall control.
[0083] While the foregoing written description enables one of
ordinary skill to make and use what is considered presently to be
the best mode thereof, those of ordinary skill will understand and
appreciate the existence of variations, combinations, and
equivalents of the specific embodiment, method, and examples
herein. The disclosure should therefore not be limited by the above
described embodiments, methods, and examples, but by all
embodiments and methods within the scope and spirit of the
disclosure.
* * * * *