U.S. patent application number 17/379660 was filed with the patent office on 2021-11-11 for s-enantiomerically enriched compositions of beta blockers for treating muscle weakness.
The applicant listed for this patent is ACTIMED THERAPEUTICS LIMITED. Invention is credited to Stefan Anker, Andrew J.S. Coats.
Application Number | 20210346320 17/379660 |
Document ID | / |
Family ID | 1000005725398 |
Filed Date | 2021-11-11 |
United States Patent
Application |
20210346320 |
Kind Code |
A1 |
Anker; Stefan ; et
al. |
November 11, 2021 |
S-ENANTIOMERICALLY ENRICHED COMPOSITIONS OF BETA BLOCKERS FOR
TREATING MUSCLE WEAKNESS
Abstract
The use of S-enantiomerically enriched compositions of beta
blockers for treating muscle weakness. The beta blocker can be
oxprenolol or a pharmaceutically acceptable salt thereof.
Inventors: |
Anker; Stefan; (Berlin,
DE) ; Coats; Andrew J.S.; (Richmond, AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ACTIMED THERAPEUTICS LIMITED |
Ascot |
|
GB |
|
|
Family ID: |
1000005725398 |
Appl. No.: |
17/379660 |
Filed: |
July 19, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16078179 |
Aug 21, 2018 |
11096908 |
|
|
PCT/IB2017/000267 |
Feb 24, 2017 |
|
|
|
17379660 |
|
|
|
|
62300620 |
Feb 26, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 21/00 20180101;
A61K 31/138 20130101 |
International
Class: |
A61K 31/138 20060101
A61K031/138; A61P 21/00 20060101 A61P021/00 |
Claims
1. A method of treating muscle weakness in an individual,
comprising administering to the individual an effective amount of
an S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof.
2. A method of preventing body weight loss in an individual with
muscle weakness, comprising administering to the individual an
effective amount of an S-enantiomerically enriched composition of a
beta blocker or a pharmaceutically acceptable salt thereof.
3. A method of preventing and treating muscle wasting in an
individual with muscle weakness, comprising administering to the
individual an effective amount of an S-enantiomerically enriched
composition of a beta blocker or a pharmaceutically acceptable salt
thereof.
4. A method of improving quality of life in an individual with
muscle weakness, comprising administering to the individual an
effective amount of an S-enantiomerically enriched composition of a
beta blocker or a pharmaceutically acceptable salt thereof.
5. The method of any one of claims 1-4, wherein the beta blocker is
oxprenolol or a pharmaceutically acceptable salt thereof.
6. The method of any one of claims 1-5, wherein the muscle weakness
is in an acute state.
7. The method of any one of claims 1-5, wherein the muscle weakness
is localized.
8. The method of any one of claims 1-7, wherein the individual has
suffered a musculoskeletal injury.
9. The method of any one of claims 1-7, wherein the individual has
undergone surgery.
10. The method of claim 9, wherein the surgery is abdominal,
orthopedic, cardiac, brain, lung, eye, or head and neck.
11. The method of any one of claims 1-10, wherein the individual
has been immobilized.
12. The method of any one of claims 1-11, wherein the individual
has been immobilized for at least 48 hours.
13. The method of any one of claims 1-12, wherein the individual
has suffered a major trauma.
14. The method of claim 13, wherein the trauma affects large bones,
abdominal organs, chest organs, or head.
15. The method of any one of claims 1-14, wherein the individual
has suffered fractures of the long bones of the arm or leg.
16. The method of any one of claims 1-15, wherein the composition
comprises an enantiomeric excess of at least about 50% of
S-oxprenolol or a pharmaceutically acceptable salt thereof.
17. The method of claim 16, wherein the composition comprises an
enantiomeric excess of at least about 80% of S-oxprenolol or a
pharmaceutically acceptable salt thereof.
18. The method of claim 17, wherein the composition comprises an
enantiomeric excess of at least about 99% of S-oxprenolol or a
pharmaceutically acceptable salt thereof.
19. The method of claim 18, wherein the composition comprises an
enantiomeric excess of at least about 99.9% of S-oxprenolol or a
pharmaceutically acceptable salt thereof.
20. The method of any one of claims 1-19, wherein the composition
is administered orally.
21. The method of any one of claims 1-20, wherein the amount of
S-oxprenololor a pharmaceutically acceptable salt thereof in the
composition is about 80 to about 160 mg daily.
22. The method of any one of claims 1-21, wherein the composition
is administered daily or twice daily.
23. A pharmaceutical composition comprising a beta blocker or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier for use in treating muscle weakness.
24. The pharmaceutical composition of claim 23, wherein the beta
blocker is oxprenolol or a pharmaceutically acceptable salt
thereof.
25. The pharmaceutical composition of claim 24, wherein the
composition comprises an enantiomeric excess of at least about 50%
of S-oxprenolol or a pharmaceutically acceptable salt thereof.
26. The pharmaceutical composition of claim 25, wherein the
composition comprises an enantiomeric excess of at least about 80%
of S-oxprenolol or a pharmaceutically acceptable salt thereof.
27. The pharmaceutical composition of claim 26, wherein the
composition comprises an enantiomeric excess of at least about 99%
of S-oxprenolol or a pharmaceutically acceptable salt thereof.
28. The pharmaceutical composition of claim 27, wherein the
composition comprises an enantiomeric excess of at least about
99.9% of S-oxprenolol or a pharmaceutically acceptable salt
thereof.
29. A kit comprising a pharmaceutical composition comprising a beta
blocker or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier and instruction for using the
pharmaceutical composition for treating muscle weakness.
30. The kit of claim 29, wherein the beta blocker is oxprenolol or
a pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application No. 62/300,62) filed Feb. 26, 2016, the disclosure of
which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to use of S-enantiomerically
enriched compositions of beta blockers for treating muscle
weakness. The beta blocker can be oxprenolol or a pharmaceutically
acceptable salt thereof.
BACKGROUND
[0003] Skeletal muscle is a plastic tissue which readily adapts to
changes in either physiological demand for work or metabolic need.
Hypertrophy refers to an increase in skeletal muscle mass while
skeletal muscle atrophy refers to a decrease in skeletal muscle
mass. Acute skeletal muscle atrophy or muscle weakness is traceable
to a variety of causes including, but not limited to:
musculoskeletal injury and disuse due to surgery, immobilization,
bed rest, or broken bones.
[0004] Oxprenolol is a non-selective beta blocker which possesses
some intrinsic sympathomimetic activity. Because of its beta
blocker function, oxprenolol has been used for the treatment of
various diseases such as angina pectoris, abnormal heart rhythms,
and high blood pressure. Oxprenolol is lipophilic and crosses the
blood-brain barrier more easily than other more water soluble beta
blockers. As a result, oxprenolol is associated with a higher
incidence of CNS-related side effects than other beta blockers, but
also has more central CNS modes of action.
[0005] The disclosure of all publications, patents, patent
applications, and published patent applications referred to herein
are hereby incorporated herein by reference in their entirety.
BRIEF SUMMARY OF THE INVENTION
[0006] The present disclosure provides, in some embodiments, a
method of treating muscle weakness in an individual, comprising
administering to the individual an effective amount of an
S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof.
[0007] The present disclosure provides, in some embodiments, a
method of preventing body weight loss in an individual with muscle
weakness, comprising administering to the individual an effective
amount of an S-enantiomerically enriched composition of a beta
blocker or a pharmaceutically acceptable salt thereof.
[0008] The present disclosure provides, in some embodiments, a
method of preventing and treating muscle wasting in an individual
with muscle weakness, comprising administering to the individual an
effective amount of an S-enantiomerically enriched composition of a
beta blocker or a pharmaceutically acceptable salt thereof.
[0009] The present disclosure provides, in some embodiments, a
method of improving quality of life in an individual with muscle
weakness, comprising administering to the individual an effective
amount of an S-enantiomerically enriched composition of a beta
blocker or a pharmaceutically acceptable salt thereof.
[0010] In some embodiments, the beta blocker is oxprenolol r a
pharmaceutically acceptable salt thereof.
[0011] In some embodiments, the muscle weakness is in an acute
state. In some embodiments, the muscle weakness is localized. In
some embodiments, wherein the individual has suffered a
musculoskeletal injury. In some embodiments, the individual has
undergone surgery. In some embodiments, the surgery is abdominal,
orthopedic, cardiac, brain, lung, eye, or head and neck. In some
embodiments, the individual has been immobilized. In some
embodiments, the individual has been immobilized for at least 48
hours. In some embodiments, the individual has suffered a major
trauma. In some embodiments, the trauma affects large bones,
abdominal organs, chest organs, or head.
[0012] In some embodiments, the composition comprises an
enantiomeric excess of at least about 50% of an S-enantiomerically
enriched composition of a beta blocker or a pharmaceutically
acceptable salt thereof. In some embodiments, the composition
comprises an enantiomeric excess of at least about 80% of an
S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition comprises an enantiomeric excess of at least about 99%
of an S-enantiomerically enriched composition of a beta blocker or
a pharmaceutically acceptable salt thereof. In some embodiments,
the composition comprises an enantiomeric excess of at least about
99.9% of an S-enantiomerically enriched composition of a beta
blocker or a pharmaceutically acceptable salt thereof.
[0013] In some embodiments, the composition comprises an
enantiomeric excess of at least about 50% of S-oxprenolol or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition comprises an enantiomeric excess of at least about 80%
of S-oxprenolol or a pharmaceutically acceptable salt thereof. In
sonic embodiments, the composition comprises an enantiomeric excess
of at least about 99% of S-oxprenolol or a pharmaceutically
acceptable salt thereof. In some embodiments, the composition
comprises an enantiomeric excess of at least about 99.9% of
S-oxprenolol or a pharmaceutically acceptable salt thereof. In some
embodiments, the composition is administered orally. In some
embodiments, the amount of S-oxprenolol or a pharmaceutically
acceptable salt thereof in the composition is about 80 to about 160
mg daily. In some embodiments, the composition is administered
daily or twice daily.
[0014] The present disclosure provides, in some embodiments, a
pharmaceutical composition comprising a beta blocker or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier for use in treating muscle weakness. In some
embodiments, the beta blocker is oxprenolol or a pharmaceutically
acceptable salt thereof.
[0015] The present disclosure provides, in some embodiments, a kit
comprising a pharmaceutical composition comprising a beta blocker
or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier and instruction for using the
pharmaceutical composition for treating muscle weakness. In some
embodiments, the beta blocker is oxprenolol or a pharmaceutically
acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention provides use of an S-enantiomerically
enriched composition of a beta blocker for achieving beneficial
results in individuals having muscle weakness. In an
S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof, the beta blocker or a
pharmaceutically acceptable salt thereof has one chiral center and
the composition is enantiomerically enriched for the S-enantiomer.
Thus, as used herein, "S-enantiomerically enriched composition of a
beta blocker" refers to a beta blocker having one chiral center and
the composition is enantiomerically enriched for the S-enantiomer.
In some embodiments, the beta blocker is oxprenolol or a
pharmaceutically acceptable salt thereof.
[0017] Thus, the present invention, in one aspect, provides methods
of treating muscle weakness in an individual, comprising
administering to the individual an effective amount of an
S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof. In some embodiments, the
muscle weakness is an acute state in the individual. In some
embodiments, the muscle weakness is localized in the individual. In
some embodiments, the beta blocker is oxprenolol or a
pharmaceutically acceptable salt thereof.
[0018] Also provided are kits, unit dosages, medicines, and
articles of manufacture that are useful for methods described
herein.
DEFINITIONS
[0019] The following terms have the following meanings unless
otherwise indicated. Any undefined terms have their art recognized
meanings.
[0020] As used herein, "treatment" or "treating" is an approach for
obtaining beneficial or desired results including clinical results.
For purposes of this invention, beneficial or desired clinical
results include, but are not limited to, one or more of the
following: alleviating one or more symptoms resulting from the
condition, diminishing the extent of the condition, stabilizing the
condition (e.g., preventing or delaying the worsening of the
condition), preventing or delaying the spread of the condition,
preventing or delaying the recurrence of the condition, delay or
slowing the progression of the condition, ameliorating the
condition state, providing a remission (partial or total) of the
condition, decreasing the dose of one or more other medications
required to treat the condition, delaying the progression of the
condition, increasing the quality of life, and/or prolonging
survival. Also encompassed by "treatment" is a reduction of
pathological consequence of muscle weakness. The methods of the
invention contemplate any one or more of these aspects of
treatment.
[0021] The term "individual" refers to a mammal and includes, but
is not limited to, human, bovine, horse, feline, canine, rodent, or
primate. In some embodiments, the individual is a human.
[0022] As used herein, an "at risk" individual is an individual who
is at risk of developing muscle weakness. An individual "at risk"
may or may not have detectable condition, and may or may not have
displayed detectable condition prior to the treatment methods
described herein. "At risk" denotes that an individual has one or
more so-called risk factors, which are measurable parameters that
correlate with development of muscle weakness. An individual having
one or more of these risk factors has a higher probability of
developing muscle weakness than an individual without these risk
factor(s).
[0023] As used herein, "delaying" the development of a condition
means to defer, hinder, slow, retard, stabilize, and/or postpone
development of the condition. This delay can be of varying lengths
of time, depending on the history of the condition and/or
individual being treated. As is evident to one skilled in the art,
a sufficient or significant delay can, in effect, encompass
prevention, in that the individual does not develop the condition.
A method that "delays" development of a condition is a method that
reduces probability of condition development in a given time frame
and/or reduces the extent of the condition in a given time frame,
when compared to not using the method. Such comparisons are
typically based on clinical studies, using a statistically
significant number of subjects.
[0024] As used herein, by "combination therapy" is meant that a
first agent be administered in conjunction with another agent. "In
conjunction with" refers to administration of one treatment
modality in addition to another treatment modality, such as
administration of a composition described herein in addition to
administration of the other agent to the same individual. As such,
"in conjunction with" refers to administration of one treatment
modality before, during, or after delivery of the other treatment
modality to the individual. Such combinations are considered to be
part of a single treatment regimen or regime.
[0025] The term "effective amount" used herein refers to an amount
of a compound or composition sufficient to treat a specified
disorder, condition or disease such as ameliorate, palliate,
lessen, and/or delay one or more of its symptoms. In reference to
muscle weakness, an effective amount comprises an amount sufficient
to prevent or delay unwanted symptoms associated with muscle
weakness. In some embodiments, an effective amount is an amount
sufficient to delay development. In some embodiments, an effective
amount is an amount sufficient to prevent or delay recurrence. An
effective amount can be administered in one or more
administrations.
[0026] The term "simultaneous administration," as used herein,
means that a first therapy and second therapy in a combination
therapy are administered with a time separation of no more than
about 15 minutes, such as no more than about any of 10, 5, or 1
minutes, When the first and second therapies are administered
simultaneously, the first and second therapies may be contained in
the same composition (e.g., a composition comprising both a first
and second therapy) or in separate compositions e.g., a first
therapy in one composition and a second therapy is contained in
another composition)
[0027] As used herein, the term "sequential administration" means
that the first therapy and second therapy in a combination therapy
are administered with a time separation of more than about 15
minutes, such as more than about any of 20, 30, 40, 50, 60, or more
minutes. Either the first therapy or the second therapy may be
administered first. The first and second therapies are contained in
separate compositions, which may be contained in the same or
different packages or kits.
[0028] As used herein, the term "concurrent administration" means
that the administration of the first therapy and that of a second
therapy in a combination therapy overlap with each other.
[0029] As used herein, by "pharmaceutically acceptable" or
"pharmacologically compatible" is meant a material that is not
biologically or otherwise undesirable, e.g., the material may be
incorporated into a pharmaceutical composition administered to an
individual without causing any significant undesirable biological
effects or interacting in a deleterious manner with any of the
other components of the composition in which it is contained.
Pharmaceutically acceptable carriers or excipients have preferably
met the required standards of toxicological and manufacturing
testing and/or are included on the Inactive Ingredient Guide
prepared by the U.S. Food and Drug administration.
[0030] An "adverse event" or "AE" as used herein refers to any
untoward medical occurrence in an individual receiving a marketed
pharmaceutical product or in an individual who is participating on
a clinical trial who is receiving an investigational or
non-investigational pharmaceutical agent.
[0031] The term "isomers" or "stereoisomers" refers to compounds
which have identical chemical constitution, but differ with regard
to the arrangement of the atoms or groups in space.
[0032] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0033] The term "diastereomers" refers to stereoisomers with two or
more centers of dissymmetry and whose molecules are not mirror
images of one another.
[0034] The term "enantiomers" refers to two stereoisomers of a
compound which are non-superimposable mirror images of one another.
An equimolar mixture of two enantiomers is called a "racemic
mixture" or a "racemate."
[0035] The term "enantiomerically enriched" means that the racemic
mixture (i.e., 50/50 mixture of the enantiomers) has been purified
such that one enantiomer comprises greater than 50% of the total
amount of the compound present. For example, a composition that is
enantiomerically enriched for S-oxprenolol is a composition wherein
more than 50% of the oxprenolol is the S-enantiomer of oxprenolol
(S-oxprenolol).
[0036] The degree of enantiomeric enrichment of a composition can
be determined by "enantiomeric excess," or ee. "Enantiomeric
excess" represents the percentage of one enantiomer in excess of
the other. For instance, a composition having a 75:25 mixture of
S-oxprenolol and R-oxprenolol has a 75-25=50% ee, while a 50:50
racemic mixture has a 50-50=0% ee. The value of ee will be a number
from 0 to 100, 0 being racemic and 100 being pure, single
enantiomer.
[0037] The term "pharmaceutically acceptable salt" means salt which
is acceptable for administration to a subject, such as a mammal
(salts with counterions having acceptable mammalian safety for a
given dosage regime). Such salts can be derived from
pharmaceutically acceptable inorganic or organic bases and from
pharmaceutically acceptable inorganic or organic acids.
"Pharmaceutically acceptable salt" refers to pharmaceutically
acceptable salts of a compound, which salts are derived from a
variety of organic and inorganic counter ions well known in the art
and include, by way of example only, sodium, potassium, calcium,
magnesium, ammonium, tetraalkylammonium, and the like; and when the
molecule contains a basic functionality, salts of organic or
inorganic acids, such as hydrochloride, hydrobromide, formate,
tartrate, besylate, mesylate, acetate, maleate, oxalate, and the
like.
[0038] The term "salt thereof" means a compound formed when a
proton of an acid is replaced by a cation, such as a metal cation
or an organic cation and the like. Where applicable, the salt is a
pharmaceutically acceptable salt, although this is not required for
salts of intermediate compounds that are not intended for
administration to the subject. By way of example, salts of the
present compounds include those wherein the compound is protonated
by an inorganic or organic acid to form a cation, with the
conjugate base of the inorganic or organic acid as the anionic
component of the salt.
[0039] "Solvate" refers to a complex formed by combination of
solvent molecules with molecules or ions of the solute. The solvent
can be an organic compound, an inorganic compound, or a mixture of
both. Some examples of solvents include, but are not limited to,
methanol, N,N-dimethylformamide, tetrahydrofuran,
dimethylsulfoxide, and water. When the solvent is water, the
solvate formed is a hydrate.
[0040] It will be appreciated that the term "or a salt or solvate
thereof" is intended to include all permutations of salts and
solvates, such as a solvate of a pharmaceutically acceptable salt
of a subject compound.
[0041] As used herein, "in conjunction with" refers to
administration of one treatment modality in addition to another
treatment modality. As such, "in conjunction with" refers to
administration of one treatment modality before, during or after
administration of the other treatment modality to the
individual.
[0042] As used herein and in the appended claims, the singular
forms "a," "an," and "the" include plural reference unless the
context clearly indicates otherwise.
[0043] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. For example, description referring to "about X"
includes description of "X."
[0044] It is understood that aspects and variations of the
invention described herein include "consisting" and/or "consisting
essentially of" aspects and variations.
METHODS OF THE PRESENT INVENTION
[0045] The present invention provides use of an S-enantiomerically
enriched composition of a beta blocker for achieving beneficial
results in individuals having muscle weakness.
[0046] In some embodiments, there is provided a method of treating
muscle weakness in an individual, comprising administering to the
individual an effective amount of an S-enantiomerically enriched
composition of a beta blocker or a pharmaceutically acceptable salt
thereof (such as a composition having at least about any one of
10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%,
99%, or 99.9% ee). In some embodiments, the beta blocker is
selected from the group consisting of acebutolol, atenolol,
betaxolol, bisoprolol, carteolol, celeprolol, labetalol,
metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol,
propanolol, sotalol, esmolol, carvedilol, timolol, bopindolol,
medroxalol, bucindolol, levobunolol, metipranolol, celiprolol and
propafenone. In some embodiments, the beta blocker is oxprenolol or
a pharmaceutically acceptable salt thereof. In some embodiments,
the composition comprises an enantiomeric excess of at least about
10% (such as at least about any one of 20%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9%) of S-oxprenolol.
In some embodiments, there is provided a method of treating muscle
weakness in an individual, comprising administering to the
individual an effective amount of a composition comprising
oxprenolol or a pharmaceutically acceptable salt thereof, wherein
the composition comprises an enantiomeric excess of at least about
99% (for example at least about 99.9%) of S-oxprenolol. In some
embodiments, there is provided a method of treating muscle weakness
in an individual, comprising administering (such as orally
administering) to the individual an effective amount of a
composition comprising oxprenolol or a pharmaceutically acceptable
salt thereof, wherein the composition is enantiomerically enriched
for S-oxprenolol (for example comprises an enantiomeric excess of
at least about 99% of S-oxprenolol). In some embodiments, the
amount of S-oxprenolol in the composition is about 50 mg to about
160 mg (such as about 80 to about 160 mg, for example about 100 mg
to about 160 mg).
[0047] Muscle weakness refers to a reduction in the strength of one
or more muscles. To assess muscle weakness, there are several tests
available. In some embodiments, muscle weakness can be assessed by
short physical performance battery scores and standard clinical
assessment of functional performance, muscle strength, gait speed,
leg strength and hand grip strength, 6-minute corridor walk test,
and stair climbing power. In some embodiments, muscle weakness can
be assessed by simple bedside testing such as asking the patient to
perform a handgrip, arm bend, arm raise, leg raise, foot
dorsiflexion or similar limb or body movements against resistance
and assess whether the strength is perceived by either or both of
the doctor or patient as weaker than would be expected.
[0048] Treatment of muscle weakness can be assessed by improvement
of muscle strength over time based on the available tests. In some
embodiments, an improvement of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10%
or more based on any of the tests disclosed herein over 1, 2, 3, 4,
5, 6, or 7 days indicates treatment of muscle weakness. Any
subjective report by the patient that strength has improved, or any
objective test improvement by at least 1, 2, 3, 4, 5, 6, 7, 8, 9,
10% or more would be proof of effective treatment.
[0049] In some embodiments, the muscle weakness is in an acute
state in an individual. For an acute state, the muscle weakness
would have been occurring for a short duration. In an acute state,
muscle weakness would have been lasting up to 1, 2, 3, or 4 weeks.
In some embodiments, acute muscle weakness would have been lasting
up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. The
muscle weakness would be acute as evidenced by any of the patient,
a relative or friend reporting that the muscle weakness has
occurred or worsened in the last 1, 2, 3, or 4 weeks.
[0050] In some embodiments, the muscle weakness is localized in an
individual. By localized, muscle weakness is confined to one area
of the body in an individual. In some embodiments, localized muscle
weakness can occur at a limb (e.g. arm, hand, leg, or foot), neck,
back, chest, or head.
[0051] In some embodiments, the muscle weakness produces secondary
effects, such as body weight loss, lowering the quality of life,
and muscle wasting.
[0052] In some embodiments, there is provided a method of
preventing body weight loss of an individual with muscle weakness,
comprising administering to the individual an effective amount of
an S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof (such as a composition
having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some
embodiments, the beta blocker is selected from the group consisting
of acebutolol, atenolol, betaxolol, bisoprolol, carteolol,
celeprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol,
penbutolol, pindolol, propanolol, sotalol, esmolol, carvedilol,
timolol, bopindolol, medroxalol, bucindolol, levobunolol,
metipranolol, celiprolol and propafenone. In some embodiments, the
beta blocker is oxprenolol or a pharmaceutically acceptable salt
thereof. In some embodiments, the composition comprises an
enantiomeric excess of at least about 10% (such as at least about
any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%,
98%, 99%, or 99.9%) of S-oxprenolol. In some embodiments, there is
provided a method of preventing body weight loss in an individual
with muscle weakness, comprising administering to the individual an
effective amount of a composition comprising oxprenolol or a
pharmaceutically acceptable salt thereof, wherein the composition
comprises an enantiomeric excess of at least about 99% (for example
at least about 99.9%) of S-oxprenolol. In some embodiments, there
is provided a method of preventing body weight loss of an
individual with muscle weakness, comprising administering (such as
orally administering) to the individual an effective amount of a
composition comprising oxprenolol or a pharmaceutically acceptable
salt thereof, wherein the composition is enantiomerically enriched
for S-oxprenolol (for example comprises an enantiomeric excess of
at least about 99% of S-oxprenolol). In some embodiments, the
amount of S-oxprenolol in the composition is about 50 mg to about
160 mg (such as about 80 to about 160 mg, for example about 100 mg
to about 160 mg). In some embodiments, the body weight loss of the
individual is no more than about 20% (for example no more than
about any of 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%)
of the total body weight. In some embodiments, the body weight loss
is evaluated over a time period of about 1 day to 1 month (for
example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20 , 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30
days). In some embodiments, the body weight loss is evaluated over
a time period of about 1 month to 2 years (for example, about 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, or 24 months).
[0053] In some embodiments, there is provided a method of treating
muscle wasting in an individual with muscle weakness, comprising
administering to the individual an effective amount of an
S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof (such as a composition
having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some
embodiments, the beta blocker is selected from the group consisting
of acebutolol, atenolol, betaxolol, bisoprolol, carteolol,
celeprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol,
penbutolol, pindolol, propanolol, sotalol, esmolol, carvedilol,
timolol, bopindolol, medroxalol, bucindolol, levobunolol,
metipranolol, celiprolol and propafenone. In some embodiments, the
beta blocker is oxprenolol or a pharmaceutically acceptable salt
thereof. In some embodiments, the composition comprises an
enantiomeric excess of at least about 10% (such as at least about
any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%,
98%, 99%, or 99.9%) of S-oxprenolol. In some embodiments, there is
provided a method of treating muscle wasting in an individual with
muscle weakness, comprising administering to the individual an
effective amount of a composition comprising oxprenolol or a
pharmaceutically acceptable salt thereof, wherein the composition
comprises an enantiomeric excess of at least about 99% (for example
at least about 99.9%) of S-oxprenolol. In some embodiments, there
is provided a method of treating muscle wasting in an individual
with muscle weakness, comprising administering (such as orally
administering) to the individual an effective amount of a
composition comprising oxprenolol or a pharmaceutically acceptable
salt thereof, wherein the composition is enantiomerically enriched
for S-oxprenolol (for example comprises an enantiomeric excess of
at least about 99% of S-oxprenolol). In some embodiments, the
amount of S-oxprenolol in the composition is about 50 mg to about
160 mg (such as about 80 to about 160 mg, for example about 100 mg
to about 160 mg). In some embodiments, the muscle wasting of the
individual is no more than about 10% (for example no more than
about any of 10%, 9%, 8%, 7%, 6%, or 5%) of the total body weight.
In some embodiments, the muscle wasting is evaluated over a time
period of about 1 day to 1 month (for example, about 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, or 30 days). In some embodiments, the
muscle wasting is evaluated over a time period of about 1 month to
2 years (for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months). In some
embodiments, the method leads to a reduction of muscle wasting,
i.e., a slow-down of muscle loss in the individual. In some
embodiments, the method leads to a reversal of muscle wasting,
i.e., an increase in muscle weight in the individual.
[0054] In some embodiments, there is provided a method of improving
quality of life of an individual with muscle weakness, comprising
administering to the individual an effective amount of an
S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof (such as a composition
having at least about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% ee). In some
embodiments, the beta blocker is selected from the group consisting
of acebutolol, atenolol, betaxolol, bisoprolol, carteolol,
celeprolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol,
penbutolol, pindolol, propanolol, sotalol, esmolol, carvedilol,
timolol, bopindolol, medroxalol, bucindolol, levobunolol,
metipranolol, celiprolol and propafenone. In some embodiments, the
beta blocker is oxprenolol or a pharmaceutically acceptable salt
thereof. In some embodiments, the composition comprises an
enantiomeric excess of at least about 10% (such as at least about
any one of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%,
98%, 99%, or 99.9%) of S-oxprenolol. In some embodiments, there is
provided a method of improving quality of life of an individual
with muscle weakness, comprising administering to the individual an
effective amount of a composition comprising oxprenolol or a
pharmaceutically acceptable salt thereof, wherein the composition
comprises an enantiomeric excess of at least about 99% (for example
at least about 99.9%) of S-oxprenolol. In some embodiments, there
is provided a method of improving quality of life of an individual
with muscle weakness, comprising administering (such as orally
administering) to the individual an effective amount of a
composition comprising oxprenolol or a pharmaceutically acceptable
salt thereof, wherein the composition is enantiomerically enriched
for S-oxprenolol (for example comprises an enantiomeric excess of
at least about 99% of S-oxprenolol). In some embodiments, the
amount of S-oxprenolol in the composition is about 50 mg to about
160 mg (such as about 80 to about 160 mg, for example about 100 mg
to about 160 mg). Improvement of quality of life can be assessed,
for example, by food intake, locomotive activity, improvement in
fatigue or dyspnea or global patient assessment scores, in short
physical performance battery scores, in standard clinical
assessment of functional performance, muscle strength, gait speed,
leg strength and hand grip strength, 6-minute corridor walk test,
stair climbing power, ability to tolerate courses of chemotherapy
and other tests or instruments or questionnaires assessing patient
quality of life.
[0055] In some embodiments, the individual has suffered a
musculoskeletal injury. In some embodiments, musculoskeletal injury
includes fractures, joint dislocations, ligament sprains, muscle
strains, and tendon injuries. In some embodiments, musculoskeletal
injury includes Carpal Tunnel Syndrome, tendonitis, muscle/tendon
strain, ligament sprain, tension neck syndrome, thoracic outlet
compression, rotator cuff tendonitis, epicondylitis, radial tunnel
syndrome, digital neuritis, trigger finger/thumb, DeQuervain's
Syndrome, mechanical back syndrome, degenerative disc disease, and
ruptured/herniated disc. In some embodiments, the musculoskeletal
injury results in immobilization of the individual.
[0056] In some embodiments, the individual has undergone surgery.
In some embodiments, the surgery is abdominal, orthopedic, cardiac,
brain, lung, eye, or head and neck. In some embodiments, the
surgery results in immobilization of the individual.
[0057] In some embodiments, the individual has been immobilized. In
some embodiments, the individual has been immobilized for at least
12, 24, 48, 60, or 72 hours. In some embodiments, the individual
has been immobilized for at least 1, 2, 3, 4, 5, 6, or 7 days.
[0058] In some embodiments, the immobilization is a result of major
trauma, bone fracture, sprains, dislocations, muscle tears,
disruptions or crush injuries, or an acute disabling illness,
including myocardial infarction, stroke, and neurological disorder,
such as Guillain-Barre syndrome. In some embodiments, the
immobilization is a result of enforced bed rest.
[0059] In some embodiments, the individual has suffered a major
trauma. As used herein, "trauma" is a body wound or shock produced
by sudden physical injury as from violence or accident or a
physical wound or injury, such as a fracture, blow, or surgical
procedure, which results in major muscle tissue damage. In some
embodiments, the major trauma affects large bones, abdominal
organs, chest organs, or head.
[0060] In some embodiments, the individual has suffered fractures
of the long bones of the arm or leg. In some embodiments, the
individual has suffered a ligament sprain or muscle strain. In some
embodiments, the individual has suffered a tendon injury. In some
embodiments, the individual has suffered a joint dislocation.
[0061] In some embodiments, muscle weakness is associated with
denervation/nerve damage due to spinal cord injury, autoimmune
disease, or infectious disease; glucocorticoid use for unrelated
conditions; sepsis due to infection or other causes; nutrient
limitation due to illness or starvation; or space travel.
Beta Blockers
[0062] The methods described herein comprise administration of
compositions comprising beta blockers. Beta blockers, which are
used to treat hypertension, can be used for treating muscle
weakness.
[0063] In some embodiments, where the beta blocker contains one
chiral center, the beta blocker is the enantiomerically enriched
S-enantiomer or a pharmaceutically acceptable salt thereof.
[0064] In some embodiments, the beta blocker is selected from the
group consisting of acebutolol, atenolol, betaxolol, bisoprolol,
carteolol, celeprolol, labetalol, metoprolol, nadolol, nebivolol,
oxprenolol, penbutolol, pindolol, propanolol, sotalol, esmolol,
carvedilol, timolol, bopindolol, medroxalol, bucindolol,
levobunolol, metipranolol, celiprolol and propafenone. In some
embodiments, the beta blocker is oxprenolol. Oxprenolol is a
non-selective beta blocker which possesses some intrinsic
sympathomimetic activity.
[0065] In some embodiments, the beta blocker also has partial
5-HT.sub.1A agonism activity. The 5-HT.sub.1A receptor is a subtype
of 5-HT receptor that binds the endogenous neurotransmitter
serotonin (5-hydroxytryptamine, 5-HT). Oxprenolol is a partial
5-HT1a agonist.
S-Enantiomerically Enriched Compositions Beta Blockers
[0066] The methods described herein comprise administration of an
S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof (for example comprising an
enantiomeric excess of at least about 99% of a beta blocker).
[0067] When a compound has a chiral center, the compound can exist
in optically active forms. Optically active compounds have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes R and S are used to
denote the absolute configuration of the molecule about its chiral
center(s). The prefixes "d" and "1" or (+) and (-) are employed to
designate the sign of rotation of plane-polarized light by the
compound, with (-) or 1 meaning that the compound is "levorotatory"
and with (+) or d meaning that the compound is "dextrorotatory."
There is no correlation between nomenclature for the absolute
stereochemistry and for the rotation of an enantiomer. For a given
chemical structure, these compounds, called "stereoisomers," are
identical except that they are mirror images of one another. A
specific stereoisomer can also be referred to as an "enantiomer,"
and a mixture of such isomers is often called an "enantiomeric" or
"racemic" mixture. When a compound has one chiral center, there are
two enantiomers: the S-enantiomer and the R-enantiomer.
[0068] The compositions useful for treating muscle weakness
described herein are enantiomerically enriched for S-enantiomer.
For example, in some embodiments, the composition useful for
treating muscle weakness comprises an enantiomeric excess of at
least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of S-enantiomer of
the beta blocker. in some embodiments, the composition useful for
treating muscle weakness comprises an enantiomeric excess of at
least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or
99.9% of S-enantiomer of the beta blocker. In some embodiments, the
composition useful for treating muscle weakness comprises an
enantiomeric excess of at least about 90%, 95%, 98%, 99%, or 100%,
up to the detectable limit of purity, of S-enantiomer of the beta
blocker. In some embodiments, the composition useful for treating
muscle weakness comprises an enantiomeric excess of any of about
1-4%, 5-9%, 10-19%, 20-29%, 30-39%, 40-49%, 50-59%, 60-69%, 70-79%,
80-89%, 90-99%, or 100% of S-enantiomer of the beta blocker. In
some embodiments, the composition useful for treating muscle
weakness comprises an enantiomeric excess of at least about 99% or
100% of S-enantiomer of the beta blocker (i.e., pure S-enantiomer
of the beta blocker). In some embodiments, the composition useful
for treating muscle weakness comprises an enantiomeric excess of at
least 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 or 100%
of S-enantiomer of the beta blocker (i.e., pure S-enantiomer of the
beta blocker). Methods of making enantiomerically enriched
compositions of beta blockers are known in the art.
[0069] In some embodiments, the beta blocker is selected from the
group consisting of acebutolol, atenolol, betaxolol, bisoprolol,
carteolol, celeprolol, labetalol, metoprolol, nadolol, nebivolol,
oxprenolol, penbutolol, pindolol, propanolol, sotalol, esmolol,
carvedilol, timolol, bopindolol, medroxalol, bucindolol,
levobunolol, metipranolol, celiprolol and propafenone or a
pharmaceutically acceptable salt thereof.
[0070] In some embodiments, the beta blocker is oxprenolol or a
pharmaceutically acceptable salt thereof. Oxprenolol is
1-12-(allyloxy)phenoxyl-3-(isopropylamino)propan-2-ol. The
structure of oxprenolol is shown below.
##STR00001##
[0071] Oxprenolol is a compound with one chiral center. As a
racemic mixture, there is a mixture of (R)-(+)-oxprenolol and
(S)-(-)-oxprenolol. Analytical methods, such as HPLC, can be used
for separation and quantification of (R)-(+)-oxprenolol and
(S)-(-)-oxprenolol in mixtures. The structures of
(R)-(+)-oxprenolol and (S)-(-)-oxprenolol are shown below.
##STR00002##
[0072] The compositions useful for treating muscle weakness
described herein are enantiomerically enriched for S-oxprenolol.
For example, in some embodiments, the composition useful for
treating muscle weakness comprises an enantiomeric excess of at
least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of S-oxprenolol. In
some embodiments, the composition useful for treating muscle
weakness comprises an enantiomeric excess of at least about 90%,
91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% of
S-oxprenolol. In some embodiments, the composition useful for
treating muscle weakness comprises an enantiomeric excess of at
least about 90%, 95%, 98%, 99%, or 100%, up to the detectable limit
of purity, of S-oxprenolol. In some embodiments, the composition
useful for treating muscle weakness comprises an enantiomeric
excess of any of about 1-4%, 5-9%, 10-19%, 20-29%, 30-39%, 40-49%,
50-59%, 60-69%, 70-79%, 80-89%, 90-99%, or 100% of S-oxprenolol. In
some embodiments, the composition useful for treating muscle
weakness comprises an enantiomeric excess of at least about 99% or
100% of S-oxprenolol (i.e., pure S-oxprenolol). In some
embodiments, the composition useful for treating muscle weakness
comprises an enantiomeric excess of at least 99.1, 99.2, 99.3,
99.4, 99.5, 99.6, 99.7, 99.8, 99.9 or 100% of S-oxprenolol (i.e.,
pure S-oxprenololl. Methods of making enantiomerically enriched
compositions of oxprenolol are known in the art.
[0073] Two main routes are established for obtaining
enantiomerically enriched compounds: (1) asymmetric syntheses and
(2) racemic resolutions. (R. A. Sheldon: The Industrial Synthesis
of Optically Active Compounds, in Miklos Simonyi (editor), Problems
and Wonders if Chiral Molecules, Akademiai Kiado, Budapest, 1990,
S. 349-386), The syntheses give medium-high yields and excellent
enantiomeric excess, but the resolutions are limited by 50% yield.
Both technologies involve techniques such as dynamic kinetic
resolution (DKR) and membrane-based extraction (Augustian J et al.,
Process Biochemistry Volume 45, Issue 10, October 2010, Pages
1587-1604). One method describes enantiomer enrichment of
oxprenolol up to 68% enantiomeric excess was achieved by using a
cellulose tris(3,5-dimethylphenylcarbamate) (CTPC)-coated
rayon-belt. (Yashima E. et al., Tetrahedron: Asymmetry Volume 6,
Issue 8, August 1995, Pages 1889-1890).
[0074] The compositions useful for treating muscle weakness
described herein in some embodiments are present in pharmaceutical
compositions. The pharmaceutical compositions may further comprise
one or more pharmaceutically acceptable carrier (or excipients). A
pharmaceutically-acceptable excipient is a substance that is
non-toxic and otherwise biologically suitable for administration to
a subject. Such excipients facilitate administration of the
compounds described herein and are compatible with the active
ingredient. Examples of pharmaceutically-acceptable excipients
include stabilizers, lubricants, surfactants, diluents,
anti-oxidants, binders, coloring agents, bulking agents,
emulsifiers, or taste-modifying agents. In some embodiments, the
pharmaceutical composition is sterile.
[0075] Also provided here are unit dosage forms comprising a
pharmaceutical compositions useful for treating muscle weakness
described herein. These unit dosage forms can be stored in a
suitable packaging in single or multiple unit dosages and may also
be further sterilized and sealed. Unit dosage forms can be
provided, for example, in the form of tablets, capsules, vials, and
any other forms described herein.
[0076] In some embodiments, there is provided a composition (such
as a pharmaceutical composition, for example a unit dosage) useful
for treating muscle weakness comprising oxprenolol or a
pharmaceutically acceptable salt thereof, wherein the composition
is enantiomerically enriched for S-oxprenolol (for example
comprising an enantiomeric excess of at least about 99% of
S-oxprenolol), wherein the amount of S-oxprenolol in the
composition (such as pharmaceutical composition) is included in any
of the following ranges: about 5 to about 10 mg, about 10 to about
20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40
to about 50 mg, about 50 to about 60 mg, about 60 to about 70 mg,
about 70 to about 80 mg, about 80 to about 90 mg, about 90 to about
100 mg, about 100 to about 110 mg, about 110 to about 120 mg, about
120 to about 130 mg, about 130 to about 140 mg, about 140 to about
150 mg, about 150 to about 160 mg. In some embodiments, the amount
of S-oxprenolol in the composition is about 20 to about 160 mg,
including for example about 50 to about 150 mg, 80 to about 150 mg,
about 90 to about 140 mg, about 100 to about 120 mg. In some
embodiments, the amount of S-oxprenolol in the composition is about
80 to about 160 mg. In some embodiments, the composition is
suitable for oral administration.
[0077] In sonic embodiments, the composition useful for treating
muscle weakness is provided in a slow release form. For example,
oxprenolol can be administered in slow release form. (Eur J Drug
Metab Pharmacokinet. 1998 April-June; 23(2):178-84; Bennett P N,
Bennett Bradbrook I, Francis J, John V A, Rogers H, Turner P,
Warrington S J. Br J Clin Pharmacol. 1985; 19 Suppl. 2:1715-1755;
and Woods K L, Jack D B, Kendall M J, Halsey A, O'Donnell M L,
Warrington S J, John V A. Br J Clin Pharmacol. 1985; 19 Suppl
2:177S-184S.)
[0078] Also provided are articles of manufacture comprising the
compositions, formulations, and unit dosages described herein in
suitable packaging for use in the methods of treatment, methods of
administration, and dosage regimens described herein. Suitable
packaging for compositions described herein are known in the art,
and include, for example, vial (such as sealed vials), vessels
(such as sealed vessels), ampules, bottles, jars, flexible
packaging (e.g., sealed Mylar or plastic bags), and the like. These
articles of manufacture may further be sterilized and/or
sealed.
Dosages and Administration Route
[0079] The dosage of the compositions described herein administered
to an individual (such as a human) may vary with the particular
composition, the method of administration, and the particular stage
of muscle weakness. The amount should be sufficient to produce a
desirable response, such as a therapeutic or prophylactic response
against muscle weakness. In some embodiments, the amount of the
composition is a therapeutically effective amount. In some
embodiments, that amount of the composition is a prophylactically
effective amount. In some embodiments, the amount of total
oxprenolol in the composition is below the level that induces a
toxicological effect (i.e., an effect above a clinically acceptable
level of toxicity) or is at a level where a potential side effect
can be controlled or tolerated when the composition is administered
to the individual.
[0080] In some embodiments, the amount of an S-enantiomerically
enriched composition of a beta blocker or a pharmaceutically
acceptable salt thereof (e.g., S-oxprenolol) in the composition is
included in any of the following ranges: about 0.5 to about 5 mg,
about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about
20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25
to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg,
about 75 to about 100 mg, about 100 to about 125 mg, about 125 to
about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg.
In some embodiments, the amount of an S-enantiomerically enriched
composition of a beta blocker or a pharmaceutically acceptable salt
thereof (e.g., S-oxprenolol) in the composition is included in any
of the following ranges: about 5 to about 10 mg, about 10 to about
20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40
to about 50 mg, about 50 to about 60 mg, about 60 to about 70 mg,
about 70 to about 80 mg, about 80 to about 90 mg, about 90 to about
100 mg, about 100 to about 110 mg, about 110 to about 120 mg, about
120 to about 130 mg, about 130 to about 140 mg, about 140 to about
150 mg, about 150 to about 160 mg. In some embodiments, the amount
of an S-enantiomerically enriched composition of a beta blocker or
a pharmaceutically acceptable salt thereof (e.g., S-oxprenolol) in
the composition is about 20 to about 160 mg, including for example
about 50 to about 150 mg, 80 to about 150 mg, about 90 to about 140
mg, about 100 to about 120 mg. In some embodiments, the amount of
an S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof (e.g., S-oxprenolol) in
the composition is about 80 to about 160 mg.
[0081] In some embodiments, the amount of an S-enantiomerically
enriched composition of a beta blocker or a pharmaceutically
acceptable salt thereof (e.g., S-oxprenolol) in the composition
includes at least about any of 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2.5
mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg. In some
embodiments, the amount of an S-enantiomerically enriched
composition of a beta blocker or a pharmaceutically acceptable salt
thereof (e.g., S-oxprenolol) in the composition includes less than
about any of 35 mg/kg, 30 mg/kg, 25 mg/kg, 20 mg/kg, 15 mg/kg, 10
mg/kg, 5 mg/kg, 2.5 mg/kg, 2 mg/kg, 1 mg/kg, 0.5 mg/kg, or 0.1
mg/kg.
[0082] Exemplary dosing frequencies include, but are not limited
to, daily without break; weekly without break; weekly, three out of
four weeks; once every three weeks; once every two weeks; weekly,
two out of three weeks. In some embodiments, the composition is
administered about once every 2 weeks, once every 3 weeks, once
every 4 weeks, once every 6 weeks, or once every 8 weeks. In some
embodiments, the composition is administered at least about any of
1.times., 2.times., 3.times., 4.times., 5.times., 6.times., or
7.times. (i.e., daily) a week. In some embodiments, the intervals
between each administration are less than about any of 6 months, 3
months, 1 month, 20 days, 15, days, 12 days, 10 days, 9 days, 8
days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In
some embodiments, the intervals between each administration are
more than about any of 1 month, 2 months, 3 months, 4 months, 5
months, 6 months, 8 months, or 12 months. In some embodiments,
there is no break in the dosing schedule. In some embodiments, the
interval between each administration is no more than about a week.
In some embodiments, the composition is administered daily. In some
embodiments, the composition is administered twice daily. In some
embodiments, the composition is administered at least once (such as
at least any of 2.times., 3.times., or 4.times.) daily.
[0083] The administration of the composition can be extended over
an extended period of time, such as from about a month up to about
seven years or life-long. In some embodiments, the composition is
administered over a period of at least about any of 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months or
life-long. In some embodiments, the composition is administered
over a period of at least one month, wherein the interval between
each administration is no more than about a week.
[0084] The compositions described herein can be administered to an
individual (such as human) via various routes, including, for
example, intravenous, intra-arterial, intraperitoneal, intraportal,
intrapulmonary, oral, inhalation, intravesicular, intramuscular,
intra-tracheal, subcutaneous, intraocular, intrathecal,
transmucosal, and transdermal. In some embodiments, sustained
continuous release formulation of the composition may be used.
[0085] Once improvement of the patient's condition has occurred,
the dose may be adjusted for preventative or maintenance treatment.
For example, the dosage or the frequency of administration, or
both, may be reduced as a function of the symptoms, to a level at
which the desired therapeutic or prophylactic effect is maintained.
Of course, if symptoms have been alleviated to an appropriate
level, treatment may cease. Patients may, however, require
intermittent treatment on a long-term basis upon any recurrence of
symptoms. Patients may also require chronic treatment on a
long-term basis.
Pharmaceutical Formulations and Administration
[0086] The pharmaceutical compositions described herein may be
formulated as solutions, emulsions, suspensions, dispersions, or
inclusion complexes such as cyclodextrins in suitable
pharmaceutical solvents or carriers, or as pills, tablets,
lozenges, suppositories, sachets, dragees, granules, powders,
powders for reconstitution, or capsules along with solid carriers
according to conventional methods known in the art for preparation
of various dosage forms. Pharmaceutical compositions of the
embodiments may be administered by a suitable route of delivery,
such as oral, parenteral, rectal, nasal, topical, or ocular routes,
or by inhalation. Preferably, the compositions are formulated for
intravenous or oral administration.
[0087] For oral administration, the compositions may be provided in
a solid form, such as a tablet or capsule, or as a solution,
emulsion, or suspension. Oral tablets may include the active
ingredient(s) mixed with compatible pharmaceutically acceptable
excipients such as diluents, disintegrating agents, binding agents,
lubricating agents, sweetening agents, flavoring agents, coloring
agents and preservative agents. Suitable inert fillers include
sodium and calcium carbonate, sodium and calcium phosphate,
lactose, starch, sugar, glucose, methyl cellulose, magnesium
stearate, mannitol, sorbitol, and the like. Exemplary liquid oral
excipients include ethanol, glycerol, water, and the like. Starch,
polyvinyl-pyrrolidone (PVP), sodium starch glycolate,
microcrystalline cellulose, and alginic acid are exemplary
disintegrating agents. Binding agents may include starch and
gelatin. The lubricating agent, if present, may be magnesium
stearate, stearic acid, or talc. if desired, the tablets may be
coated with a material such as glyceryl monostearate or glyceryl
distearate to delay absorption in the gastrointestinal tract, or
may be coated with an enteric coating. The oral formulations may be
presented as discrete units such as capsules, cachets or tablets,
each containing a predetermined amount of the active ingredient; as
a powder or granules; as a solution or a suspension in an aqueous
liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient
may also be presented as a bolus, electuary or paste.
[0088] Capsules for oral administration include hard and soft
gelatin capsules. To prepare hard gelatin capsules, active
ingredient(s) may be mixed with a solid, semi-solid, or liquid
diluent. Soft gelatin capsules may be prepared by mixing the active
ingredient with water, an oil such as peanut oil or olive oil,
liquid paraffin, a mixture of mono and di-glycerides of short chain
fatty acids, polyethylene glycol 400, or propylene glycol.
[0089] A tablet may be made by compression or moulding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(e.g., sodium starch glycolate, cross-linked povidone, cross-linked
sodium carboxymethyl cellulose), surface-active or dispersing
agent. Moulded tablets may be made by moulding in a suitable
machine a mixture of the powdered compound moistened with an inert
liquid diluent. The tablets may optionally be coated or scored and
may be formulated so as to provide slow or controlled release of
the active ingredient therein using, for example,
hydroxypropylmethylcellulose in varying proportions to provide
desired release profile.
[0090] Liquids for oral administration may be in the form of
suspensions, solutions, emulsions, or syrups, or may be lyophilized
or presented as a dry product for reconstitution with water or
other suitable vehicle before use. Such liquid compositions may
optionally contain: pharmaceutically-acceptable excipients such as
suspending agents (for example, sorbitol, methyl cellulose, sodium
alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
aluminum stearate gel and the like); non-aqueous vehicles, e.g.,
oil (for example, almond oil or fractionated coconut oil),
propylene glycol, ethyl alcohol, or water; preservatives (for
example, methyl or propyl p-hydroxybenzoate or sorbic acid);
wetting agents such as lecithin; and, if desired, flavoring or
coloring agents.
[0091] For parenteral use, including intravenous, intramuscular,
intraperitoneal, intranasal, or subcutaneous routes, the
compositions may be provided in sterile aqueous solutions or
suspensions, buffered to an appropriate pH and isotonicity or in
parenterally acceptable oil. Suitable aqueous vehicles include
Ringer's solution and isotonic sodium chloride. Such forms may be
presented in unit-dose form such as ampoules or disposable
injection devices, in multi-dose forms such as vials from which the
appropriate dose may be withdrawn, or in a solid form or
pre-concentrate that can be used to prepare an injectable
formulation. Formulations suitable for parenteral including
intravenous administration include aqueous and non-aqueous sterile
injection solutions which may contain anti-oxidants, buffers,
bacteriostats and solutes which render the formulation isotonic
with the blood of the intended recipient; and aqueous and
non-aqueous sterile suspensions which may include suspending agents
and thickening agents. The formulations may be presented in
unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in a freeze-dried (lyophilised) condition
requiring only the addition of the sterile liquid carrier, for
example water for injections, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared
from sterile powders, granules and tablets of the kind previously
described.
[0092] Preferred unit dosage formulations are those containing a
daily dose or unit, daily sub-dose or an appropriate fraction
thereof, of an active ingredient.
Drug Combinations
[0093] The methods of the embodiments comprise administering an
effective amount of at least one compound of the embodiments;
optionally the compound may be administered in combination with one
or more additional therapeutic agents, particularly therapeutic
agents known to be useful for treating muscle weakness afflicting a
subject.
[0094] The additional active ingredients may be administered in a
separate pharmaceutical composition from a compound of the
embodiments or may be included with a compound of the embodiments
in a single pharmaceutical composition. The additional active
ingredients may be administered simultaneously with, prior to, or
after administration of a compound of the embodiments.
[0095] In certain embodiments, the additional therapeutic agent is
selected from the group consisting of anabolic steroids,
testosterone, nandrolone, oxandrolone, megestrol acetate, ghrelin
agonists, selective androgen receptor modulators (SARMs), amino
acid or other nutritional supplements.
Kits
[0096] The present application also provides kits, medicines,
compositions, and unit dosage forms for use in any of the methods
described herein.
[0097] Kits provided herein include one or more containers
comprising any one of the compositions described herein and/or
other agent(s), and in some embodiments, further comprise
instructions for use in accordance with any of the methods
described herein. The kit may further comprise a description of
selection of individual suitable for treatment. Instructions
supplied in the kits of the invention are typically written
instructions on a label or package insert (e.g., a paper sheet
included in the kit), but machine-readable instructions (e.g.,
instructions carried on a magnetic or optical storage disk) are
also acceptable.
[0098] For example, in some embodiments, the kit comprises a) an
S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof (e.g., S-oxprenolol) and a
pharmaceutically acceptable carrier and b) instructions for
administering the composition for treatment of muscle weakness. The
present disclosure provides, in some embodiments, a kit comprising
a pharmaceutical composition comprising oxprenolol or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier, wherein the composition is enantiomerically
enriched for S-oxprenolol, and instruction for using the
pharmaceutical composition for treating muscle weakness.
[0099] The kits of the invention are in suitable packaging.
Suitable packaging include, but is not limited to, vials, bottles,
jars, flexible packaging (e.g., sealed Mylar or plastic bags), and
the like. Kits may optionally provide additional components such as
buffers and interpretative information. The present application
thus also provides articles of manufacture, which include vials
(such as sealed vials), bottles, jars, flexible packaging, and the
like.
[0100] The instructions relating to the use of the compositions
generally include information as to dosage, dosing schedule, and
route of administration for the intended treatment. The containers
may be unit doses, bulk packages (e.g., multi-dose packages) or
sub-unit doses. For example, kits may be provided that contain
sufficient dosages of S-oxprenolol as disclosed herein to provide
effective treatment of an individual for an extended period, such
as any of a day, a week, 8 days, 9 days, 10 days, 11 days, 12 days,
13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4
months, 5 months, 7 months, 8 months, 9 months, or more. Kits may
also include multiple unit doses of the pharmaceutical compositions
and. instructions for use and packaged in quantities sufficient for
storage and use in pharmacies, for example, hospital pharmacies and
compounding pharmacies.
[0101] Also provided are medicines, compositions, and unit dosage
forms useful for the methods described herein. For example, the
present disclosure provides, in some embodiments, an
S-enantiomerically enriched composition of a beta blocker or a
pharmaceutically acceptable salt thereof (e.g., S-oxprenolol) for
treating muscle weakness in an individual. The present disclosure
also provides, in some embodiments, an S-enantiomerically enriched
composition of a beta blocker or a pharmaceutically acceptable salt
thereof (e.g., S-oxprenolol) for preventing body weight loss in an
individual with muscle weakness; preventing and treating muscle
wasting in an individual with muscle weakness; or improving quality
of life in an individual with muscle weakness.
[0102] For example, the present disclosure provides, in some
embodiments, a pharmaceutical composition comprising oxprenolol or
a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier, wherein the composition is enantiomerically
enriched for S-oxprenolol for use in treating muscle weakness.
[0103] For example, the present disclosure provides, in some
embodiments, an S-enantiomerically enriched composition of a beta
blocker or a pharmaceutically acceptable salt thereof (e.g.,
S-oxprenolol) for the manufacture of a medicament for treating
muscle weakness in an individual. The present disclosure also
provides, in some embodiments, an S-enantiomerically enriched
composition of a beta blocker or a pharmaceutically acceptable salt
thereof (e.g., S-oxprenolol) for the manufacture of a medicament
for preventing body weight loss in an individual with muscle
weakness; preventing and treating muscle wasting in an individual
with muscle weakness; or improving quality of life in an individual
with muscle weakness.
[0104] Those skilled in the art will recognize that several
embodiments are possible within the scope and spirit of this
invention. The invention will now be described in greater detail by
reference to the following non-limiting examples. The following
examples further illustrate the invention but, of course, should
not be construed as in any way limiting its scope.
EXAMPLES
Example 1
[0105] The effect of a disclosed composition can be evaluated in
patients suffering from one or more of the causes of acute muscle
weakness disclosed herein by comparing patients treated to their
pre-treatment strength or to patients not so treated. Muscle
weakness improvement can be assessed by asking the patient their
opinion of muscle strength and/or by measuring one or more of the
tests of muscle strength mentioned above. The tests can include
measuring muscle strength by hand grip strength, leg extension
force, weight lifting, stair climbing power, short physical
performance battery (SPPB) test, 6 minute corridor walk test
distance, shuttle test speed or other tests of muscle strength,
force, fatiguability or power. The tests can also evaluate muscle
bulk, by measurement by CT scan, MRI or bioimpedance. The patients
can be compared after treatment to before treatment or can be
compared to other patients not so treated. The trial may be
designed as a parallel group or cross-over design. Muscle
improvement can be shown either by reducing the rate of muscle
getting weaker or more wasted or by the muscle getting stronger or
having an increase in mass and/or bulk.
* * * * *