U.S. patent application number 12/863757 was filed with the patent office on 2011-06-30 for volatile anesthetic compositions and methods of use.
This patent application is currently assigned to VAPOGENIX, INC. Invention is credited to Allen Burton, Hatice Ozsoy, Phillip C. Phan.
Application Number | 20110159078 12/863757 |
Document ID | / |
Family ID | 40901623 |
Filed Date | 2011-06-30 |
United States Patent
Application |
20110159078 |
Kind Code |
A1 |
Burton; Allen ; et
al. |
June 30, 2011 |
Volatile Anesthetic Compositions and Methods of Use
Abstract
The present invention provides methods for reducing pain in a
subject in need thereof by delivering a volatile anesthetic in a
solution or an emulsion that can additionally include an extractive
solvent in an amount effective to reduce pain without substantially
interfering with motor function. Chronic or acute pain may be
treated, or the volatile anesthetic may be delivered as a regional
anesthetic to a subject to anesthetize a portion of the subject
prior to surgery. Dosing regimes including a one-time
administration, continuous and/or periodic administration are
contemplated.
Inventors: |
Burton; Allen; (Houston,
TX) ; Phan; Phillip C.; (Houston, TX) ; Ozsoy;
Hatice; (Houston, TX) |
Assignee: |
VAPOGENIX, INC
Houston
TX
|
Family ID: |
40901623 |
Appl. No.: |
12/863757 |
Filed: |
January 22, 2009 |
PCT Filed: |
January 22, 2009 |
PCT NO: |
PCT/US09/31707 |
371 Date: |
March 9, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61011898 |
Jan 22, 2008 |
|
|
|
Current U.S.
Class: |
424/450 ;
514/722 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 9/107 20130101; A61P 19/02 20180101; A61P 29/00 20180101; A61K
47/20 20130101; A61K 31/075 20130101; A61P 23/00 20180101; A61K
9/0019 20130101; A61P 25/04 20180101; A61K 9/0085 20130101; A61K
31/08 20130101; A61K 9/0024 20130101; A61K 47/22 20130101 |
Class at
Publication: |
424/450 ;
514/722 |
International
Class: |
A61K 31/08 20060101
A61K031/08; A61K 9/127 20060101 A61K009/127; A61P 23/00 20060101
A61P023/00; A61P 29/00 20060101 A61P029/00 |
Claims
1-323. (canceled)
324. A method for reducing pain in a subject in need thereof, the
method comprising delivering to the subject by a route other than
orally, intravenously or by inhalation, a volatile anesthetic
dissolved in a solution in an amount effective to reduce pain, and
wherein the solution further comprises an extractive solvent in an
amount effective to reduce volatility of the volatile anesthetic,
and wherein the solution is a component of an emulsion.
325. The method of claim 324, wherein the extractive solvent is at
least one selected from the group consisting of dimethyl sulfoxide
(DMSO), dimethylformamide, dimethylacetamide,
N-methyl-2-pyrrolidone (NMP), dimethylisosorbide, ethanol,
propanol, and isopropanol.
326. The method of claim 324, wherein the volatile anesthetic is
selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
327. The method of claim 324, wherein the volatile anesthetic is
delivered by at least one route from the group selected from
intrathecally, epidurally, transdermally, topically, mucosally,
buccally, rectally, vaginally, intramuscularly, subcutaneously, by
local skin infiltration, and in a nerve block procedure.
328. The method of claim 324, wherein the subject is a human
patient or an animal patient.
329. A method for reducing pain in a subject in need thereof, the
method comprising delivering to the subject by a route other than
orally, intravenously or by inhalation, a volatile anesthetic
emulsion.
330. The method of claim 329, wherein the volatile anesthetic is
selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
331. A method for reducing pain in a subject in need thereof, the
method comprising delivering to the subject by a route other than
orally, intravenously or by inhalation, a liposome suspension
comprising a volatile anesthetic in an amount effective to reduce
pain.
332. The method of claim 331, wherein the volatile anesthetic is
selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
333. A method for reducing pain in a subject in need thereof, the
method comprising delivering to the subject by a route other than
orally, intravenously or by inhalation, a volatile anesthetic
dissolved in a solution in an amount effective to reduce pain, and
wherein the solution further comprises an extractive solvent in an
amount effective to reduce volatility of the volatile anesthetic,
and wherein the composition further comprises a solubilizing
agent.
334. The method of claim 333, wherein the volatile anesthetic is
selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
335. A method for reducing pain in a subject in need thereof, the
method comprising delivering to the subject by a route other than
orally, intravenously or by inhalation, a microdroplet suspension
comprising a sphere of a volatile anesthetic surrounded by a
stabilizing layer of lipid in an amount effective to reduce
pain.
336. The method of claim 335, wherein the volatile anesthetic is
selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
337. A pharmaceutically acceptable composition comprising a metered
amount of a volatile anesthetic dissolved in an aqueous solution in
an amount effective to reduce pain, and wherein the solution
further comprises an extractive solvent in an amount effective to
reduce volatility of the volatile anesthetic, and wherein the
solution is a component of an emulsion, and wherein the composition
further comprises a pharmaceutically acceptable excipient.
338. The composition of claim 337, wherein the volatile anesthetic
is selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
339. A pharmaceutically acceptable composition comprising a metered
amount of a volatile anesthetic emulsion, wherein the composition
further comprises a pharmaceutically acceptable excipient.
340. The composition of claim 339, wherein the volatile anesthetic
is selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
341. A pharmaceutically acceptable composition comprising a metered
amount of a liposome suspension comprising a volatile anesthetic;
wherein the composition further comprises a pharmaceutically
acceptable excipient.
342. The composition of claim 341, wherein the volatile anesthetic
is selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
343. A pharmaceutically acceptable composition comprising a metered
amount of a volatile anesthetic dissolved in a solution in an
amount effective to reduce pain, and wherein the solution further
comprises an extractive solvent in an amount effective to reduce
volatility of the volatile anesthetic, and wherein the composition
further comprises a solubilizing agent and wherein the composition
further comprises a pharmaceutically acceptable excipient.
344. The composition of claim 343, wherein the volatile anesthetic
is selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
345. A pharmaceutically acceptable composition comprising a metered
amount of a microdroplet suspension comprising a microdroplet
suspension comprising a sphere of a volatile anesthetic surrounded
by a stabilizing layer of a phospholipid; wherein the composition
further comprises a pharmaceutically acceptable excipient.
346. The composition of claim 345, wherein the volatile anesthetic
is selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and
mixtures thereof.
Description
BACKGROUND OF THE INVENTION
[0001] Millions of people suffer from pain. The pain may be minor,
such as headaches, acute lower back pain, and acute muscle pain, or
severe, such as chronic pain. Chronic pain may be associated with
cancer treatment, HIV, diabetes, or other conditions. Chronic pain
can be difficult to treat, with many chronic pain sufferers noting
that their pain is not well controlled with current pain
medications or that their medications have significant associated
adverse effects (for example, nausea and vomiting, dependence,
tolerance, etc.).
[0002] In an attempt to address the problem of chronic pain
management, intrathecal infusion pumps and neurostimulators have
been developed. Intrathecal infusion pumps are aimed at continuous,
or near continuous delivery of liquid analgesic agents. Many of
these infusion pumps are totally implantable, which helps to reduce
the risk of infection when compared to the long-term use of
external systems. The infusion pump may also be programmable to
allow patients or their clinicians to adjust dosing amounts or
daily delivery schedule, helping to meet a patient's changing
needs.
[0003] Neurostimulators are available in various forms and
stimulate nerves to relieve pain. Both intrathecal pumps and
neurostimulators have drawbacks, including the onset of tolerance,
with the treatments becoming less effective over time.
[0004] Various approaches for inducing anesthesia or analgesia are
known. Systemic delivery of a general anesthetic renders a patient
unconscious and unaware of the surgery. In contrast, anesthetics
may be applied regionally, for example, to the spine, to the spinal
cord (intrathecally or epidurally), or near a nerve in a nerve
block to anesthetize only a portion of the patient's body. For
general anesthesia, delivery of a general anesthetic to a patient
prior to surgery is typically performed using an initial i.v.
injection of an induction agent followed by intubation and
administration of an inhaled anesthetic gas. It is worthwhile to
note that the mechanism of action for general anesthesia is still
not completely understood.
[0005] Considerable negative side effects may result from
administration of general anesthesia. A tube has to be placed into
the trachea, necessary to protect against vomiting, which can
result in trauma to the upper airway. Many patients report
postoperative hoarseness and tenderness of the mouth and throat. In
addition, the dose of gases required to reach the targeted neural
organs can have an adverse affect on the non-targeted organs,
especially the heart, with an increased risk of cardiopulmonary
morbidity during general anesthesia. Especially in the elderly,
there is substantial evidence for prolonged cognitive dysfunction
following general anesthesia (Moller et al., 1988, Lancet.,
351:857-861). Additionally, regional anesthetic techniques appear
to lead to less overall morbidity and mortality from
cardiopulmonary causes as compared to general anesthesia (Rasmussen
et al., 2003, Acta Anaesthesiologica Scandinavica, 47:260-266;
Rogers et al., 2000, BMJ, 321:1-12).
[0006] Certain risks are also associated with inhalation
administration of a volatile anesthetic, for example, during
general anesthesia. Volatile anesthetic compositions formulated for
inhalation generally have relatively low boiling points and high
vapor pressures. Older, volatile anesthetic compositions (including
ether and cyclopropane) are often flammable or explosive in both
their liquid and vapor states, with newer agents much less see (see
Williams and Lemke, 2002, Foye's Principles of Medicinal Chemistry,
Lippincott Williams & Wilkins, NY). Further, inhalation of
vapors by health care personnel in trace amounts have unknown
health consequences, and have been the subject of much debate. In
the larger amounts used in pediatric operating room's, large
amounts of gas can escape during inhalational induction and can
cause frank drowsiness or headaches, which is not desirable in an
operating room environment. Thus, substantial care must be taken to
safely handle volatile anesthetics (including venting of operating
rooms) in order to minimize both the risk of inhalation by medical
personnel and the risk of fire and care must be taken to try to
ensure that there is little or no release of the volatile
anesthetic into the atmosphere at all stages of handling.
[0007] Clearly, there exists a need for improved methods for pain
management and local and regional anesthesia. Further, there exists
a need for volatile anesthetic compositions that have reduced
risks, as described above, associated with their use. There is also
a need for methods for delivering such improved volatile anesthetic
compositions for treating pain without substantially interfering
with motor function. The current invention fulfills these
needs.
SUMMARY OF THE INVENTION
[0008] The present invention contemplates compositions and methods
for reducing pain in a subject in need thereof by delivering to the
subject by a route other than orally, intravenously, or by
inhalation a volatile anesthetic. The present invention overcomes
limitations in the prior art by providing improved volatile
anesthetic compositions and methods for administering volatile
anesthetics and reducing pain in a subject, such as a human or
animal patient or laboratory animal such as a mouse or rat, in need
of such pain reduction. In one embodiment, the present invention
provides a volatile anesthetic composition comprising a volatile
anesthetic dissolved in a aqueous-based solution, wherein the
solution further comprises a pharmaceutically acceptable extractive
solvent (e.g., DMSO, etc.). In another embodiment, the present
invention provides a volatile anesthetic composition comprising a
volatile anesthetic in an emulsion. In still another embodiment,
the present invention provides a volatile anesthetic composition
comprising a volatile anesthetic in a liposome or in a
microdroplet.
[0009] The presence of an extractive solvent in the composition
comprising the volatile anesthetic may provide substantial
advantages, including improving the physical characteristics,
pharmacological properties, and/or the ease of use of the volatile
anesthetic. The extractive solvent may interact with the volatile
anesthetic in a non-azeotropic fashion to effectively reduce
vaporization or evaporation of the volatile anesthetic. In this
way, the shelf-life, durability, and/or ease of use of a volatile
anesthetic composition may be improved. The presence of an
extractive solvent in the volatile anesthetic composition may also
improve the ease of mixing the composition prior to administration.
Additionally, the pharmacokinetics of the volatile anesthetic may
be altered by the presence of an extractive solvent to provide
improved pain relief. For example, without wishing to be bound by
any theory, the inventors anticipate that the extractive solvent
may function in certain embodiments as a reservoir for the volatile
anesthetic to maintain the volatile anesthetic in a particular
region more effectively and/or help deliver the volatile anesthetic
to site(s) of action. Reduced volatility of the volatile anesthetic
may also improve the ease of handling the volatile anesthetic
compositions. Further, the reduced vaporization of a volatile
anesthetic in the composition, due to the presence of an extractive
solvent, may also reduce concerns regarding a possible risk of fire
and/or inhalation by medical personnel.
[0010] It is understood that the methods of the invention include
administration of the volatile anesthetic compositions by a route
other than orally, intravenously, or by inhalation. The methods
preferably comprise the local or regional delivery, such as, for
example, transdermal, topical, mucosal, buccal, rectal, vaginal,
intramuscular, subcutaneous, intrathecal or epidural delivery, of a
volatile anesthetic composition to the subject in an amount
effective to reduce chronic or acute pain. In other embodiments, a
volatile anesthetic composition of the present invention may be
administered topically in an amount sufficient to reduce pain. More
specifically, the inventors have discovered that, in certain
embodiments, volatile anesthetic compositions of the present
invention may be administered topically to a human subject to
achieve local pain reduction. It should be understood, that as used
herein, the phrase "pain reduction" is intended to cover pain
reduction as a result of anesthesia, analgesia, and/or the
inhibition of neural impulses involved in pain perception, e.g.,
via partial nerve conduction block. In certain embodiments, the
volatile anesthetic compositions of the invention may be delivered
to a portion of the subject in an amount and in a manner effective
to reduce pain. In other embodiments, the compositions of the
invention may be delivered to a portion of the subject in an amount
and in a manner effective to reduce pain without substantially
interfering with motor function of the subject.
[0011] The present invention has several substantial advantages
over previously used methods for regional anesthesia. These
advantages include: (1) the volatile anesthetics of the present
invention are rapidly titratable, thus administration of a volatile
anesthetic according to the present invention can result in a very
quick onset of analgesia or regional anesthesia. (2) The present
invention allows for the quick dissipation of the volatile
anesthetics after administration; thus the anesthesia or analgesia
may be rapidly ended. These properties are of particular value to a
practitioner, as it may be desirable for a practitioner to quickly
alter the dosing of a regional anesthesia or analgesia as desired.
(3) Certain drugs presently used for regional anesthesia may not be
effectively used on various individuals for a variety of reasons,
including tolerance, drug interactions, paradoxical responses, etc.
Additionally, (4) the volatile anesthetics of the present invention
are generally non-opioid compounds, which provides various benefits
for a practitioner, as opioids possess certain disadvantages,
including tolerance, drug interactions, and dependence etc.
[0012] Various extractive solvents may be used with the present
invention. For example, dimethyl sulfoxide (DMSO),
N-methyl-2-pyrrolidone (NMP), dimethylisosorbide, ethanol,
propanol, or isopropanol may be the extractive solvent. The
extractive solvent may comprise from about 0.1% to about 75% of the
composition, 25% to about 75% of the composition, 10% to about 50%
of the composition, from about 0.1% to about 25% of the
composition, or from about 25% to about 50% of the composition.
[0013] An aspect of the present invention relates to a method for
reducing pain in a subject in need of such pain reduction
comprising regionally or locally delivering to the subject a
volatile anesthetic composition in an amount effective to reduce
pain. If the administration is intrathecal or epidural, then the
composition may be free or essentially free of a lipid emulsion. In
preferred embodiments, the volatile anesthetic is delivered by
routes other than intravenously in that intravenous delivery could
potentially give rise to general anesthesia that, while not
specifically excluded from the present invention, is not a
preferred aspect. Preferred volatile anesthetics are the
halogenated ether anesthetics. The volatile anesthetic composition
may preferably be delivered intrathecally, epidurally, or in a
nerve block procedure, to relieve, for example, chronic pain or
acute pain. In certain embodiments, the volatile anesthetic
composition may be administered locally or topically prior to a
procedure such as a venipuncture, an injection (e.g., Botox.TM.), a
peripheral venous cannulation, incision, hair removal, tattoo
application and removal, mammography, or other procedure; in other
embodiments, the volatile anesthetic composition may be
administered via non-topical routes. In certain embodiments, the
volatile anesthetic composition may be delivered to the subject to
anesthetize the subject prior to a surgery.
[0014] The volatile anesthetic may be a halogenated volatile
anesthetic selected from the group consisting of isoflurane,
halothane, enflurane, sevoflurane, desflurane, methoxyflurane, and
mixtures thereof. In certain embodiments, isoflurane is used. The
volatile anesthetic composition can be prepared with a volatile
anesthetic in a concentration of about 5 ng/ml to about 100 ng/ml.
The volatile anesthetic may comprise from about 0.1% to about 15%
v/v, 1% to about 75% v/v, 1% to about 50% v/v, 5% to about 50% v/v,
5% to about 75% v/v, from about 10% to about 50% v/v, or about 10%
v/v volatile anesthetic in the composition. When administered
epidurally or intrathecally it is desirable to achieve a
concentration of from about 250 ng/ml to about 50,000 ng/ml of the
volatile anesthetic in the spinal fluid. The delivery of the
volatile anesthetic composition may be continuous, periodic, a
one-time event, or the volatile anesthetic composition may be both
periodically administered and continuously administered to the
subject on separate occasions.
[0015] The reduction of pain may comprise elimination of pain
perception of a portion of the body of the subject. In certain
embodiments, the compositions of the invention may be delivered to
a portion of the subject in an amount and in a manner effective to
reduce pain without substantially interfering with motor function
of the subject, for example, by varying the dosage, amount,
concentration, frequency of administration, and/or timing of
administration.
[0016] Preferably, in that the compositions of the invention are
intended for administration by a route other than orally,
intravenously, or by inhalation, the composition comprising the
volatile anesthetic is sterile. This can be achieved by ensuring
that all starting materials are sterile and maintaining them under
sterile conditions prior to administration.
[0017] It is contemplated that any embodiment discussed in this
specification can be implemented with respect to any method or
composition of the invention, and vice versa. Furthermore, any of
the compositions of the invention described herein can be used to
achieve any of the methods of the invention described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] For the purpose of illustrating the invention, there are
depicted in the drawings certain embodiments of the invention.
However, the invention is not limited to the precise arrangements
and instrumentalities of the embodiments depicted in the
drawings.
[0019] FIG. 1 depicts a flowchart representing general methods for
making compositions for the delivery of an volatile anesthetic to a
subject.
[0020] FIG. 2 depicts the results of an example experiment
examining the inhibition of pain via intrathecal administration of
isoflurane solution as measured using the hotplate test.
[0021] FIG. 3 depicts the results of an example experiment
examining the inhibition of pain using intrathecal isoflurane in
artificial cerebrospinal fluid (ACSF) and/or DMSO. The time course
for Isoflurane-ACSF and Isoflurane-DMSO/ACSF, at a dose of 1.46 mg
isoflurane, is shown.
[0022] FIG. 4 depicts the results of an example experiment
evaluating the stimulus response (SR) of the maximal possible
effect (MPE) by dose for the time point of 10 minutes after
intrathecal injection of isoflurane-ACSF.
[0023] FIG. 5 depicts the results of an example experiment
examining the inhibition of pain via subcutaneous administration of
isoflurane.
DETAILED DESCRIPTION OF THE INVENTION
[0024] While compounds utilized as a general anesthetic reduce
pain, at least in part, by producing a loss of consciousness, local
anesthetics reduce pain by producing a loss of sensation or sensory
blockade in a localized area or region of a subject. The mechanism
by which local anesthetics reduce pain, while not having been
determined definitively, is generally thought to involve the
ability to interfere with the initiation and/or transmission of
nerve impulses primarily via sodium channel blockade. In certain
embodiments, the present invention may be used to reduce or
eliminate pain in a subject without also causing a loss of
consciousness of the subject. In other embodiments, the present
invention may be used to reduce or eliminate pain in a subject
without also substantially interfering with motor function of the
subject.
[0025] The present invention provides improved volatile anesthetic
compositions and methods for administering volatile anesthetics and
reducing pain in a subject, such as a human or animal patient or
laboratory animal such as a mouse or rat, in need of such pain
reduction. In certain embodiments, the present invention provides a
composition comprising a volatile anesthetic dissolved in an
aqueous-based solution, wherein the solution further comprises a
pharmaceutically acceptable extractive solvent, for example, but
not limited to, DMSO. In certain embodiments, the present invention
provides a composition comprising a volatile anesthetic dissolved
in a aqueous-based solution, wherein the solution comprises a
pharmaceutically acceptable extractive solvent, for example, but
not limited to, DMSO, and wherein the solution is a component of an
emulsion. In certain additional embodiments, the present invention
provides a composition comprising a volatile anesthetic dissolved
in a aqueous-based solution, wherein the solution comprises a
pharmaceutically acceptable extractive solvent, for example, but
not limited to, DMSO, and wherein the solution is a component of a
liposome. In yet other embodiments, the present invention provides
a composition comprising a volatile anesthetic dissolved in a
aqueous-based solution. In certain embodiments, the present
invention provides a composition comprising a volatile anesthetic
dissolved in a aqueous-based solution, and wherein the solution is
a component of an emulsion. In additional embodiments, the present
invention provides a composition comprising a volatile anesthetic
dissolved in a aqueous-based solution, and wherein the solution is
a component of a liposome.
[0026] The presence of an extractive solvent in the composition
comprising the volatile anesthetic may provide substantial
advantages, including improving the physical characteristics,
pharmacological properties, and/or the ease of use of the volatile
anesthetic composition. The extractive solvent may interact with
the volatile anesthetic (for example, isoflurane) in a
non-azeotropic fashion to effectively reduce vaporization or
evaporation of the volatile anesthetic. In this way, the
shelf-life, durability, and/or ease of use of a volatile anesthetic
composition may be improved. The presence of an extractive solvent
in the volatile anesthetic composition may also improve the ease of
mixing the composition prior to administration. Additionally, the
pharmacokinetics of the volatile anesthetic may be altered by the
presence of an extractive solvent to provide improved pain relief.
For example, without wishing to be bound by any theory, the
inventors anticipate that the extractive solvent may function in
certain embodiments as a reservoir for the volatile anesthetic to
maintain the volatile anesthetic in a particular region more
effectively and/or help deliver the volatile anesthetic to site(s)
of action. Similarly, in certain embodiments where the volatile
anesthetic solution is a component of an emulsion or of a liposome,
the emulsion or the liposome may function as a reservoir for the
volatile anesthetic to retain the volatile anesthetic in a
particular region more effectively and/or help deliver the volatile
anesthetic to site(s) of action. Reduced volatility of the volatile
anesthetic in solution may also improve the ease of handling the
volatile anesthetic compositions. Further, the reduced vaporization
of a volatile anesthetic in solution due to the presence of an
extractive solvent may also reduce concerns, as described above,
regarding a possible risk of fire and/or inhalation by medical
personnel.
[0027] An aspect of the present invention relates to a method for
reducing pain in a subject in need thereof comprising regionally or
locally delivering to the subject by a route other than orally,
intravenously or by inhalation, a volatile anesthetic dissolved in
a solution comprising an extractive solvent in an amount effective
to reduce pain. In preferred embodiments, the volatile anesthetic
is delivered by routes other than intravenously in that intravenous
delivery could potentially give rise to general anesthesia that,
while not specifically excluded from the present invention, is not
a preferred aspect. Preferred volatile anesthetics are the
halogenated ether anesthetic dissolved in an aqueous,
pharmaceutically acceptable solution. In certain embodiments, the
volatile anesthetic can be a component of an emulsion or of a
liposome.
[0028] It is understood that the invention does not include
administration of the volatile anesthetic to a subject orally,
intravenously or by inhalation of the volatile anesthetic vapor
alone. The methods preferably comprise the local or regional
delivery, such as, for example, transdermal, topical, mucosal,
buccal, rectal, vaginal, intramuscular, subcutaneous, perineural
infiltration, intrathecal or epidural delivery, of a volatile
anesthetic in an aqueous-based solution, which in some embodiments
can be a component of an emulsion or of a liposome, to the subject
in an amount effective to reduce chronic or acute pain. In other
embodiments, a composition of the present invention may be
administered topically in an amount sufficient to reduce pain. In
certain embodiments, the volatile anesthetic may be delivered to
the subject to anesthetize the subject prior to a surgery or other
medical procedure. In certain embodiments, the compositions of the
invention may be delivered to a portion of the subject in an amount
and in a manner effective to reduce pain. In other embodiments, the
compositions of the invention may be delivered by a route other
than orally, intravenously or by inhalation, to a portion of the
subject in an amount and in a manner effective to reduce pain
without substantially interfering with motor function of the
subject.
[0029] The present invention has several substantial advantages
over previously used methods for regional anesthesia. These
advantages include: (1) the volatile anesthetics of the present
invention are rapidly titratable, thus administration of a volatile
anesthetic according to the present invention can result in a very
quick onset of analgesia or regional anesthesia. (2) The present
invention allows for the quick dissipation of volatile anesthetics
after administration; thus the anesthesia or analgesia may be
rapidly ended. These properties are of particular value to a
practitioner, as it may be desirable for a practitioner to quickly
alter the dosing of a regional anesthesia or analgesia as desired.
(3) Certain drugs presently used for regional anesthesia may not be
effectively used on various individuals for a variety of reasons,
including tolerance, drug interactions, paradoxical responses, etc.
Additionally, (4) the volatile anesthetics of the present invention
are generally non-opioid compounds, which provides various benefits
for a practitioner, as opioids possess certain disadvantages,
including respiratory depression, pruritis, addiction, tolerance,
drug interactions, and dependence etc.
[0030] In certain embodiments, a volatile anesthetic in solution is
delivered to anesthetize a portion of the subject prior to a
surgery or other medical procedure. The volatile anesthetic may be
a halogenated volatile anesthetic selected from the group
consisting of isoflurane, halothane, enflurane, sevoflurane,
desflurane, methoxyflurane, xenon and mixtures thereof. Many of
these agents are racemic mixtures. In some embodiments, the racemic
mixtures can be used. In other embodiments, only the d-isomer or
the 1-isomer of an agent can be used (for examples, see U.S. Pat.
Nos. 5,114,715, 5,114,714 and 5,283,372). In certain embodiments,
isoflurane is used. The solution, such as an isoflurane solution,
may be prepared in a concentration of about 5 ng/ml solution to
about 100 ng/ml solution. The solution may comprise from about 1%
to about 99% v/v, from about 5% to about 50% v/v, or about 10% v/v
volatile anesthetic in solution. The volatile anesthetic may be
isoflurane and/or the solution may be water, saline or artificial
cerebrospinal fluid. In certain embodiments, the solution can be a
component of an emulsion, which can further comprise an extractive
solvent. In other embodiments, the solution can be a component of
an liposome, which can further comprise an extractive solvent. When
administered epidurally or intrathecally it is desirable to achieve
a concentration of from about 250 ng/ml to about 50,000 ng/ml of
active agent in the spinal fluid. The delivery of the volatile
anesthetic composition may be continuous, periodic, a one-time
event, or the volatile anesthetic composition may be both
periodically administered and continuously administered to the
subject on separate occasions. The reduction of pain may comprise
the reduction or elimination of pain perception of a portion of the
body of the subject. The reduction of pain may comprise the
reduction or elimination of pain sensation of a portion of the body
of the subject. The reduction or elimination of pain may be
achieved without also substantially interfering with motor
function.
[0031] In some embodiments, the compositions of the invention may
be delivered by a route other than orally, intravenously or by
inhalation, to a portion of the subject in an amount and in a
manner effective to reduce pain without substantially interfering
with motor function of the subject, for example, by varying the
dosage, amount, concentration, frequency of administration, and/or
timing of administration. Tests useful for the evaluation of motor
function include, for example, but are not limited to, the
Minnesota Rate of Manipulation (MRM) test (Fleishman, 1964,
Abilities and motor skill. In: The structure and measurement of
physical fitness Prentice-Hall, Inc.: Englewood Cliffs, N.J., 1964,
pp. 23-24), the Upper Extremity Function Test (UEFT) (Carroll,
1965, J Chron Dis 18: 479-491), the Purdue Pegboard test (Tiffin et
al., 1948, J Appl Psychol 32: 234-247), the Jebsen test of hand
function (Jebsen et al., 1969, Arch Phys Med Rehab 50: 311-319),
the Nine-Hole Peg test (Kellor et al., 1971, Am J Occup Ther 25:
77-83), the Smith hand function evaluation (Smith, 1973, Am J Occup
Ther 27: 244-251), the Box and Block Test (BBT) (Holser et al.,
1960, Box and Block test. In: Cromwell FS (ed) Occupational
therapists manual for basic skills assessment: primary
prevocational evaluation Fair Oaks Printing Company Pasadena,
Calif., pp. 29-31), the Physical Capacities Evaluation of Hand
Skill (PCE) (Bell et al., 1976, Am J Occup Ther 30: 80-86), the
Action Research Arm (ARA) test (Lyle, 1981, Int J Rehabil Res 4:
483-492), the Sollerman hand function test (Sollerman et al., 1995,
Scand J Plast Reconstr Surg Hand Surg 29: 167-176), Lower Extremity
MOtor COordination Test (LEMOCOT) (Desrosiers et al., 2005, Arch
Phys Med Rehabil 86, 993-98), the Fugl-Meyer Assessment (Fugl-Meyer
et al., 1975, Scand J Rehabil Med 7:13-31), Berg Balance Scale
(Berg et al., 1995, Scand J Rehabil Med 27:27-36; Berg et al.,
1989, Physiother Can 41:304-11, Berg et al, 1992, Arch Phys Med
Rehabil 73:1073-80; Stevenson et al., 1996, Arch Phys Med Rehabil
77:656-62), 5-meter walking test (5MWT) (Salbach et al., 2001, Arch
Phys Med Rehabil 82:1204-12), 2-minute walking test (Wade, 1992,
Measurement in neurological rehabilitation. New York: Oxford Univ
Pr; Guyatt et al., 1984, Thorax 39:818-22), and the Functional
Autonomy Measurement System (Hebert, 1988, Age Ageing 17:293-302),
all of which references are incorporated herein in their entirety.
The motor function of a subject is not substantially interfered
with when the subject's motor function, when measured after
delivery of the compostions of the invention, is at least about 40%
of that of a comparator value, preferably at least about 60% of
that of a comparator value, more preferably at least about 75% of
that of a comparator value, and even more preferably about 90% of
that of a comparator value. Useful comparator values include, but
are not limited to, a value obtained by measuring the subject's
motor function prior to administration of the compositions of the
invention, a value obtained by measuring the motor function of an
untreated but otherwise similarly-situated subject, a value
obtained by measuring the motor function of an untreated control
subject, or a value known or derived from historical norms or
averages.
[0032] Preferably, in that the solution is intended for
administration by a route other than orally, intravenously or by
inhalation, the aqueous solution comprising the volatile anesthetic
is sterile. This can be achieved by ensuring that all starting
materials are sterile and maintaining them under sterile conditions
prior to administration. This can also be achieved by incorporation
of an antimicrobial filter as has been done with other types of
infusions (see, for example, U.S. Pat. No. 5,695,490). As for the
underlying aqueous solution, the nature of the solution is not
believed to be critical, and solutions such as normal saline or
even solutions formulated to mimic natural body fluids, such as
artificial cerebrospinal fluids, are contemplated.
[0033] Yet another aspect of the present invention involves a
sealed container comprising an volatile anesthetic solution of the
present invention. The interior of the container may be sterile.
The container may comprise a rubber stopper which can be easily
pierced by an injection needle. The container may comprise the
chamber portion of a syringe. The container may comprise a drip
chamber. The drip chamber may be coupled to a catheter. The
catheter may be an epidural catheter or an intrathecal catheter.
The container can be a syringe, a plastic bag, a collapsible
plastic bag, a glass bottle, a glass ampoule, or a plastic bottle.
The container may be coupled to an infusion pump. The infusion pump
may be an intrathecal pump, an epidural delivery infusion pump, or
a patient control analgesia (PCA) pump. The infusion pump may be
programmable.
[0034] The present invention overcomes limitations in the art by
providing improved volatile anesthetic compositions comprising a
volatile anesthetic dissolved in an aqueous-based solution, wherein
the solution further comprises a pharmaceutically acceptable
extractive solvent. The presence of the extractive solvent may
provide certain advantages for the volatile anesthetic composition,
including a reduction in the volatile anesthetic vapors emitted
from the solution (for example, reducing risks associated with the
flammability of the vapors and/or inhalation by medical personnel),
improvements in the shelf-life or durability of the composition,
and/or improved pharmacokinetics of the volatile anesthetic
composition. For example, the extractive solvent may interact with
the volatile anesthetic (for example, isoflurane) in a
non-azeotropic fashion to effectively reduce vaporization or
evaporation of the volatile anesthetic. In this way, the shelf-life
and/or durability of a volatile anesthetic in solution may be
improved. Additionally, the pharmacokinetics of the volatile
anesthetic may be altered to provide improved pain relief. For
example, without wishing to be bound by any theory, the inventors
anticipate that the extractive solvent may function in certain
embodiments as a reservoir for the volatile anesthetic to maintain
the volatile anesthetic in a particular region more effectively
and/or help deliver the volatile anesthetic to site(s) of
action.
[0035] The present invention also provides methods for using such
volatile anesthetic compositions for reducing pain in a subject in
need thereof. Specifically, although volatile anesthetics have been
delivered by inhalation to produce general anesthesia, the
inventors have discovered that the volatile anesthetics of the
invention may be dissolved in a solution and delivered regionally
or locally (for example, transdermally, topically, mucosally,
buccally, rectally, vaginally, intramuscularly, subcutaneously,
perineurally, intrathecally, epidurally, or in a nerve block, etc.)
to reduce or inhibit pain or block or inhibit pain perception.
Further, by varying the dosage, amount, concentration, frequency of
administration, and/or timing of administration, for example, of a
volatile anesthetic in solution, or a volatile anesthetic emulsion,
a reduction of pain can be achieved without at the same time
substantially interfering with motor function in the subject. In
general, the methods may involve the delivery of a volatile
anesthetic, which in certain embodiments can be a component of a
solution, an emulsion, or a liposome, to the subject in an amount
effective to reduce pain. The present invention may be used for
pain management of chronic or acute pain. In other embodiments, the
volatile anesthetic may be delivered to a subject to anesthetize at
least a portion of the subject prior to a surgery or other medical
procedure.
Extractive Solvents
[0036] The volatile anesthetic compositions of the present
invention may contain a solvent, such as an extractive solvent, in
combination with a volatile anesthetic. The phrase "extractive
solvent," as used herein, refers to a solvent which may interact
with a volatile anesthetic in the compositions of the invention to
reduce the volatility of the volatile anesthetic without chemically
reacting to the anesthetic. Certain extractive solvents interact in
a non-azeotropic fashion with a volatile anesthetic; nonetheless,
the term "extractive solvent," as used herein, may include certain
compounds which interact with a volatile anesthetic to form an
azeotropic or pseudoazeotropic solution as long as the vapor
pressure or evaporation of the volatile anesthetic from the
solution is reduced. As described below, various extractive
solvents are envisioned for use with the present invention, e.g.,
DMSO, NMP, etc. The exact concentration of an extractive solvent
may be determined empirically and may vary according to the
specific volatile anesthetic used. In certain embodiments, the
extractive solvent will be present in the composition in an amount
effective to reduce volatility of the volatile anesthetic in the
composition. Particular care should also be taken to choose a
concentration of an extractive solvent which results in little or
no toxicity when administered. It will be understood that, although
certain extractive solvents may exhibit properties which might be
used in various separation procedures (e.g., extractive
distillation), extractive solvents according to embodiments of the
present invention are preferably included in pharmacological
mixtures or solutions comprising a volatile anesthetic in order to
reduce the volatility of, rather than "extract," the volatile
anesthetic.
[0037] Including an extractive solvent in an anesthetic composition
may increase the ease with which one can mix the solution prior to
administration. For example, in certain embodiments, sonication of
the anesthetic solution prior to administration is not required
when an extractive solvent is included in the volatile anesthetic
composition. This advantage may be particularly useful in instances
(e.g., chronic administration) where the presence of a sonicator
could be noisy or distracting, such as an operating room, and the
elimination in the noise of a sonicator may also create an improved
environment for a conscious patient receiving a volatile anesthetic
composition, e.g., chronically or intermittently for pain relief.
Eliminating the need for a sonicator, or other similar device, may
also be particularly useful for reducing costs associated with
administration of an volatile anesthetic composition according to
the present invention. The reduction in the bulk associated with
the presence of a sonicator can beneficially improve patient
mobility. For example, in instances where a patient may receive
repeated administrations of an anesthetic composition via a pump
for analgesia, the reduced amount of equipment can improve mobility
since the patient is not required to additionally move a
sonicator.
[0038] Extractive solvents are known in the art and are typically
used in extractive distillation for separating compounds with
similar boiling points by retarding the vapor pressure of the
principal component, thereby making possible an efficient
separation which would not at all occur in the absence of such
solvent. For example, U.S. Pat. No. 5,230,778 describes the
purification of isoflurane by extractive distillation using
extractive solvents such as dimethylformamide. U.S. Pat. No.
5,336,429 describes solvents for cleaning electronic components and
for degreasing metals comprising isoflurane and a lower alcohol or
an ester, although these compositions are described as azeotropic
mixtures with virtually constant boiling points. In contrast, the
present invention provides pharmaceutical preparations, e.g., for
inducing analgesia and/or regional anesthesia.
[0039] Certain extractive solvents known in the art, such as
acetone as described in U.S. Pat. No. 5,230,778, may be
sufficiently toxic to limit their inclusion in pharmaceutical
preparations at higher concentrations.
[0040] In certain embodiments, an extractive solvent may interact
as an azeotropic mixture with an anesthetic and reduce the
volatility of the anesthetic. For example, ethanol may interact in
an azeotropic fashion with a volatile anesthetic as described in
U.S. Pat. No. 5,230,778.
[0041] Various concentrations of an extractive solvent may be used
with the present invention. For example, a composition of the
present invention comprising a volatile anesthetic may comprise
about 0.1%-99%, 0.1%-60%, 5%-50%, 10%-40%, 5%-25%, 10%-30%,
10%-25%, 25%-50%, 10%-75%, 25%-75%, 10%-65%, 25%-65%, 10%-60%,
25%-60%, 0.1%, 1%, 5%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 65%, 70%, 75%, 80% or any range derivable therein, of an
extractive solvent.
[0042] In certain embodiments, the extractive solvent is
dimethylsulfoxide (DMSO) or N-methyl-2-pyrrolidone (NMP). In other
embodiments, an extractive solvent such as dimethylformamide,
dimethylacetamide, or dimethylisosorbide may be used. In instances
where acetone is used, care should be taken to choose an
appropriate dose in order to minimize any possible toxicity.
[0043] In various embodiments, it is envisioned that a medically
acceptable alcohol, such as ethanol, propanol, or isopropanol may
be used. In these embodiments, the concentration of the alcohol
used is sufficiently dilute in solution such that little or no
neuron death occurs as a result of injection of the solution near a
nerve.
[0044] A single extractive solvent or multiple extractive solvents
may be present in an volatile anesthetic composition of the present
invention. For example, in certain embodiments, only a single
extractive solvent (e.g., DMS or NMP) is present in a composition
comprising a volatile anesthetic. In other embodiments, 2, 3, 4, or
more extractive solvents may be present in a composition comprising
a volatile anesthetic. In certain embodiments, only a single
volatile anesthetic (e.g., isoflurane) is present in a volatile
anesthetic composition of the present invention; in other
embodiments, 2, 3, 4 or more volatile anesthetics may be present in
a volatile anesthetic composition of the present invention.
N-methyl pyrrolidone
[0045] N-methyl-2-pyrrolidone (NMP) is a solvent which may be
included in the volatile anesthetic compositions according to the
present invention. NMP is a chemical compound with 5-membered
lactam structure. It is a clear to slightly yellow liquid miscible
with water and solvents including ethyl acetate, chloroform,
benzene and lower alcohols or ketones. NMP is also referred to by
the chemical names 1-methyl-2-pyrrolidone or
N-methyl-2-pyrrolidinone and m-pyrrole. NMP belongs to the class of
dipolar aprotic solvents which also includes dimethylformamide,
dimethylacetamide and dimethyl sulfoxide. Due to its good solvency
properties, NMP has been used to dissolve a wide range of
chemicals, particularly in the polymers field. It also used as a
solvent for surface treatment of textiles, resins and metal coated
plastics or as a paint stripper.
[0046] NMP has been used in the medical industry to improve the
solubility of poorly soluble drugs in certain pharmaceutical
formulations. For example, NMP has been used with various drugs in
veterinary medicine. Several patents have been issued, claiming
improvements in drug solubility by the use of NMP, as well as its
applicability in topical and transdermal pharmaceutical products
for humans.
[0047] The relatively non-toxic properties of NMP make it
particularly suitable for use as a solvent with the present
invention. NMP has a favorable toxicity profile making it a
suitable candidate for use in a variety of topical, transdeinial
and parenteral dosage forms. NMP is available in GMP grade under
the trademark Pharmasolve N-methyl-2-pyrrolidone sold by
International Specialty Products (ISP; New Jersey, USA).
DMSO
[0048] Dimethyl sulfoxide (DMSO) is used in certain embodiments of
the present invention as a solvent. DMSO has the formula
(CH.sub.3).sub.2SO. DMSO is a polar aprotic solvent that dissolves
both polar and nonpolar compounds and is miscible in a wide range
of organic solvents as well as water.
[0049] DMSO is a relatively non-toxic compound, which makes it
particularly suitable for use as a solvent with the present
invention. The relative lack of toxicity of DMSO is well
established, and the potential use of DMSO for medical purposes was
established Stanley Jacob at the University of Oregon Medical
School team, who discovered DMSO could penetrate the skin and other
membranes without damaging them and could carry other compounds
into a biological system. DMSO has also been used as a
cryoprotectant and as an anti-inflammatory agent. Dimethyl
sulfoxide dissolves a variety of organic substances, including
carbohydrates, polymers, peptides, as well as many inorganic salts
and gases.
[0050] In various embodiments, it is envisioned that lower
concentrations, for example, as low as from about 0.1% to about
10%, of DMSO in a composition comprising a volatile anesthetic may
be sufficient to eliminate the need for sonication of the
composition prior to administration. Higher concentrations, for
example, from about 10% to about 75% or higher, of DMSO in a
composition comprising a volatile anesthetic may be sufficient to
alter the pharmacokinetics of the volatile anesthetic in such a way
to allow for an increased duration of analgesic or anesthetic
effects.
Volatile Anesthetics
[0051] In general, the halogenated ether anesthetics or volatile
anesthetics suitable for use with the described compositions and
methods include agents which, although often liquid at room
temperature, are capable of easily being becoming gaseous or are
already gaseous at room temperature and can reduce pain without
significant side effects. It may be desirable, for example, to
select an agent that is minimally metabolized by the body or is
otherwise inert. In this way, liver and kidney toxicity may be
minimized. Similarly, it may be desirable for the volatile
anesthetic to have a short half-life, or be fast acting to promote
titratability (i.e., the subject can easily adjust the delivery
amount for the amount of pain he or she is experiencing). An active
agent gas that does not produce tolerance (unlike opioids) or
dependence (like opioids) may also be desirable.
[0052] Volatile anesthetics useful in the compositions and methods
of the invention include halogenated ether compounds, isoflurane,
sevoflurane, halothane, enflurane, desflurane, methoxyflurane, and
diethyl ethers. In certain embodiments xenon may also be used with
the present invention. A single agent or mixtures of agents may be
particularly suitable for use with the methods described
herein.
[0053] In various embodiments, a gaseous volatile anesthetic may be
used with the present invention. For example, the gaseous volatile
anesthetic may be dissolved in a solution according to the present
invention and administered in a regional or local anesthesia
procedure, such as transdermally, topically, mucosally, buccally,
rectally, vaginally, intramuscularly, subcutaneously, epidurally,
intrathecally, or in a nerve block procedure. Gaseous volatile
anesthetics other than halogenated anesthetics are contemplated,
and examples include xenon, nitrous oxide, cyclopropane, and ether,
all of which can be used, in various embodiments, in racemic
mixture form, or in d-isomer or 1-isomer forms. In various
embodiments, other biologically active gases (for example, nitric
oxide, etc.) may be delivered in a solution to a subject according
to the present invention.
[0054] More than one volatile anesthetic may be administered at one
time, and different volatile anesthetics may be administered at
various times throughout a single treatment cycle. For example, 2,
3, 4 or more volatile anesthetics may be simultaneously or
repeatedly administered to a subject. When compounds are repeatedly
administered to a subject, the duration between administration of
compounds may be about 1-60 seconds, 1-60 minutes, 1-24 hours, 1-7
days, 1-6 weeks or more, or any range derivable therein. In some
instances, it may be desirable to stage the delivery of different
volatile anesthetics depending on their physical and physiological
properties. In certain clinical scenarios, a shorter acting agent
may be desirable to treat acute pain, whereas a longer lasting
agent may be more suited to chronic pain applications.
[0055] In certain embodiments, a volatile anesthetic of the present
invention is a component of an emulsion, such as a water-in-oil or
an oil-in-water emulsion, including, but not limited to a lipid
emulsion, such as a soybean oil emulsion. For example, a
composition comprising a volatile anesthetic dissolved in a
solution comprising an extractive solvent may also comprise a lipid
emulsion or an oil-in-water emulsion. In various embodiments, the
emulsion of the invention may contain an aqueous solution
comprising a volatile anesthetic dissolved in a solution, which may
further comprise an extractive solvent. Inclusion of a water-in-oil
or an oil-in-water emulsion, such as, for example, a lipid
emulsion, in an volatile anesthetic composition may be used, for
example, to favorably affect the stability of the volatile
anesthetic composition and/or alter the pharmacokinetics of the
volatile anesthetic. For example, lipid compositions, lipid
emulsions, water-in-oil emulsions, and/or oil-in-water emulsions
may be useful for the intrathecal, epidural, transdermal, topical,
mucosal, buccal, rectal, vaginal, intramuscular, or subcutaneous
delivery of the volatile anesthetic compositions of the present
invention. Certain emulsions of isoflurane have been prepared
previously for intravenous (da Sila Telles Mathias L, et al., 2004,
Rev. Bras. Anaestesiol Campianas 54(5), 2004) or epidural
administration (Chai et al. 2008, British J Anesthesia 100:109-115;
Chai et al. Anesthesiology 105: A743, 2006), both for inducing
anesthesia.
[0056] In certain embodiments, the emulsion of the invention
comprises a volatile anesthetic and water, and may further comprise
an emulsifier. Emulsions of the invention also include, but are not
limited to, nanoemulsions, which are emulsions with a mean droplet
size less than those of emulsions. Nanoemulsions are sometimes
referred to as microemulsions and submicroemulsions. Often, the
physical appearance of a nanoemulsion is transparent, rather than
the often milky appearance of an emulsion, due to the reduced mean
droplet size.
Emulsions
[0057] As would be understood by one of skill, an emulsion consists
of a mixture of two or more immiscible liquids (i.e., contains
multiple phases) and emulsions are distinct from solutions, which
contain one or essentially only one phase. One of the liquids (the
dispersed phase) is dispersed in the other (the continuous phase).
In one type of emulsion, a continuous liquid phase surrounds
droplets of water (for example, a water-in-oil emulsion). In
another type of emulsion, oil is dispersed within a continuous
water phase (for example, an oil-in-water emulsion). Similarly,
emulsification is the process by which emulsions are prepared.
[0058] In certain embodiments, a volatile anesthetic of the present
invention is a component of an emulsion, such as a water-in-oil or
an oil-in-water emulsion, including, but not limited to a lipid
emulsion, such as a soybean oil emulsion. For example, a
composition comprising a volatile anesthetic dissolved in a
solution comprising an extractive solvent may also comprise a lipid
emulsion or an oil-in-water emulsion. In various embodiments, the
emulsion of the invention may contain an aqueous solution
comprising a volatile anesthetic dissolved in a solution, which may
further comprise an extractive solvent. Inclusion of a water-in-oil
or an oil-in-water emulsion, such as, for example, a lipid
emulsion, in an volatile anesthetic composition may be used, for
example, to favorably affect the stability of the volatile
anesthetic composition and/or alter the pharmacokinetics of the
volatile anesthetic. For example, lipid compositions, lipid
emulsions, water-in-oil emulsions, and/or oil-in-water emulsions
may be useful for the intrathecal, epidural, transdermal, topical,
mucosal, buccal, rectal, vaginal, intramuscular, or subcutaneous
delivery of the volatile anesthetic compositions of the present
invention. Certain emulsions of isoflurane have been prepared
previously for intravenous (da Sila Telles Mathias L, et al., 2004,
Rev. Bras. Anaestesiol Campianas 54(5), 2004) or epidural
administration (Chai et al. 2008, British J Anesthesia 100:109-115;
Chai et al. Anesthesiology 105: A743, 2006), both for inducing
anesthesia.
[0059] In certain embodiments, the emulsion of the invention
comprises a volatile anesthetic and water, and may further comprise
an emulsifier. Emulsions of the invention also include, but are not
limited to, nanoemulsions, which are emulsions with a mean droplet
size less than those of emulsions. Nanoemulsions are sometimes
referred to as microemulsions and submicroemulsions. Often, the
physical appearance of a nanoemulsion is transparent, rather than
the often milky appearance of an emulsion, due to the reduced mean
droplet size.
[0060] In certain embodiments, the emulsion of the invention can
have a lipid component. In various embodiments, the lipid component
can comprise an amount ranging from about 1% to 99%, from about 5%
to about 75%, from about 10% to about 60%, from about 20% to about
50%, or from about 30% to about 40%, v/v of the emulsion. In
various embodiments, the lipid component of the emulsion can be
soybean oil, long chain triglyceride, castor oil, corn oil,
cottonseed oil, olive oil, peanut oil, peppermint oil, safflower
oil, sesame oil, soybean oil, hydrogenated soybean oil,
hydrogenated vegetable oil, medium chain triglycerides coconut oil,
palm see oil and derivatives, medium chain (C8/C10) mono- and
diglycerides, d-alpha-tocopherol, soy fatty acids, or combinations
thereof. In certain embodiments, the lipid component of the
emulsion is soybean oil. Commercially available lipid compositions
that may be useful for the production of the volatile anesthetic
compositions of the present invention include, but are not limited
to, Intralipid.RTM., Liposyn.RTM., and Nutrilipid.RTM..
[0061] In other embodiments, the emulsion further comprises an
emulsifier. An emulsifier is a substance which stabilizes an
emulsion. An emulsifier may also known as an emulgent. An
emulsifier may also be a surfactant. In various embodiments, the
emulsifier can be egg phospholipid, purified egg phospholipids,
Polyoxyl 35 castor oil (Cremophor EL), Polyoxyl 40 hydrogenated
castor oil (Cremophor RH 40), Polyoxyl 60 hydrogenated castor oil
(Cremophor RH 60), Polysorbate 20, Polysorbate 80,
d-alpha-tocopheryl polyethylene glycol 1000 succinate, Solutol
HS-15, propylene glycol or combinations thereof. Various
concentrations of an emulsifier may be used with the present
invention. For example, a composition of the present invention
comprising a volatile anesthetic may comprise about 0.1%-99%,
0.1%-60%, 5%-50%, 10%-40%, 5%-25%, 10%-30%, 10%-25%, 25%-50%,
10%-75%, 25%-75%, 10%-65%, 25%-65%, 10%-60%, 25%-60%, 0.1%, 1%, 5%,
10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,
80% or any range derivable therein, of an emulsifier.
[0062] In other embodiments, the emulsion of the invention has a
perfluorocarbon component. In various embodiments, the
perfluorocarbon component can comprise an amount ranging from about
0.1% to 99%, from about 5% to about 75%, from about 10% to about
60%, from about 20% to about 50%, or from about 30% to about 40%,
v/v of the emulsion. In various embodiments, perfluorocarbon may
provide additional advantages due to its limited toxicity and
ability to scavenge a large amount of gas. In one embodiment, the
emulsion of the invention comprises a volatile anesthetic, a
perfluorocarbon, water and an emulsifier. A perfluorocarbon,
specifically perfluoro-n-octane, has been used clinically, in cases
of retinal detachment, by its instillation into the eye in place of
the aqueous humor (see Chang, 1992, S. Intl Ophthalmol Clinic
32:153-163).
Liposomes and Microdroplets
[0063] In various embodiments, the volatile anesthetics of the
present invention can be a component of a liposome suspension. A
liposome (for example, multilamellar, unilamellar, and/or
multivesicular liposomes) is a microscopic, spherical, fluid-filled
structure, with walls comprising one or more layers of
phospholipids and molecules similar in physical and/or chemical
properties to those that make up mammalian cell membranes. By way
of nonlimiting examples, liposomes can be formed from a variety of
natural membrane components, such as cholesterol, stearylamine, or
phosphatidylcholine (see, for example, U.S. Pat. Nos. 5,120,561 and
6,007,838, each of which is incorporated herein by reference in its
entirety), or of pure surfactant components like DOPE
(dioleoylphosphatidylethanolamine). Liposomes can be formulated to
incorporate a wide range of materials as a payload either in the
aqueous or in the lipid compartments or in both. Generally,
lipophilic active substances dissolve in the bilayer, amphiphilic
substances become associated with the phospholipid membrane and
hydrophilic substances occur in solution in the enclosed aqueous
volume (Artmann et al., 1990, Drug Res. 40 (II) Nr. 12 pp.
1363-1365; incorporated herein by reference in its entirety).
[0064] Liposomes useful as drug carriers or for topical use that
are non-toxic and available in industry (Gehring et al., 1990, Drug
Res. 40 (II) Nr. 12, pp. 1368-1371; incorporated herein by
reference in its entirety). Liposomes have been used as carriers
for lipophilic drugs like the anti-tumor and the anti-viral
derivatives of azidothymidine (AZT) (Kamps, et al., 1996, Biochim.
Biophys. Acta. 1278:183-190). Insulin has also been delivered via
liposomes (Muramatsu et al., 1999, Drug Dev. Ind. Pharm.
25:1099-1105). For medical uses as drug carriers, the liposomes can
also be injected, and when they are modified with lipids, their
surfaces become more hydrophilic and hence their ability to persist
can be increased. Polyethylene glycol-modified liposomes have been
used as carriers for hydrophilic (water-soluble) anti-cancer drugs
like doxorubicin. Liposomal derivatives of mitoxantrone and others
are especially effective in treating diseases that affect the
phagocytes of the immune system because they tend to accumulate in
the phagocytes, which recognize them as foreign invaders (Rentsch
et al., 1997, Br. J. Cancer 75:986-992). Liposomes have also been
used to carry normal genes into a cell to treat diseases caused by
defective genes (Guo et al., 2000, Biosci. Rep. 20:419-432). The
versatility of liposomes, due to the variable composition, enables
liposomes to be used to deliver vaccines, proteins, nucleotides,
plasmids, drugs, cosmetics, or the volatile anesthetics of the
invention to the body.
[0065] Liposome compositions of the invention can comprise any
range of liposome and volatile anesthetic components, according to
the methods and detailed description set forth herein. By way of a
non-limiting example, a liposome component of a composition of the
invention may include from 0.1% to 99.9% liposome component, or
more preferably, from 0.1%-50% liposome component, and even more
preferably, from 0.1%-30% liposome component. In various
embodiments, the liposome of the invention comprises cholesterol,
stearylamine, phosphatidylcholine,
dioleoylphosphatidylethanolamine, or combinations thereof.
[0066] In various embodiments, the volatile anesthetics of the
present invention can also be a component of a microdroplet. A
microdroplet of the invention consists of a sphere of organic
liquid phase drug that ranges in diameter from about 200 Angstroms
to about 10,000 Angstroms that is covered by a monolayer of a
suitable lipid. Preferred lipids are phospholipids, which are
natural constituents of biological membranes and as such are
biologically compatible. Compounds useful for preparing
microdroplets include phosphatidylcholine (lecithin),
sphingomyelin, phosphatidic acid, phosphatidyl serine, phosphatidyl
inositol, diphosphatidyl glycerol and phosphatidyl glycerol.
[0067] Microdroplets can be prepared by sonication, including probe
or bath sonication, homogenization, microfluidization or by high
intensity mechanical agitation. The preferred method of preparing
the microdroplets of the invention is by sonication with a probe
sonicator. Alternatively, microdroplets can be prepared in a bath
sonicator. For small scale preparations a 1.0 cm diameter test tube
is suspended, with use of a test-tube clamp, in a bath sonicator
filled with water. The components of the microdroplet are first
grossly mixed by shaking, Vortex mixing, Polytron or other methods.
The suspension is then introduced into the bath sonicator and
sonicated for 1-2 hours. If the preparation is to be done on a
large scale, it is possible to omit the test tube and introduce the
components of the microdroplet directly into a bath sonicator.
Microdroplets can also be produced by high intensity mechanical
agitation. Useful methods include a Waring blender, a Polytron and
high frequency shakers such as a commercial paint shaker. Other
materials and methods useful in the preparation of microdroplets
are known in the art and are described in U.S. Pat. No. 4,622,219,
U.S. Pat. No. 4,725,442, U.S. Pat. No. 5,091,188, Haynes et al.
(1989, J Controlled Release 9:1-12) and Haynes et al. (1985,
Anesthesiology 63:490-499), all of which references are
incorporated herein in their entirety.
Dosing
[0068] The amount of the volatile anesthetic to be administered,
for example, intrathecally or epidurally, depends on the particular
indication desired. For example, the dose will depend on the type
of pain intended to be treated. The dose may be different, for
instance, if the delivery of the volatile anesthetic is intended to
reduce chronic pain as opposed to acute pain. Similarly, the dose
may be different if the volatile anesthetic composition will be
used to anesthetize a subject (generally or locally, including
intrathecally, epidurally, transdermally, topically, mucosally,
buccally, rectally, vaginally, intramuscularly, subcutaneously, by
local skin infiltration, or in a nerve block procedure). The
subject's physical characteristics may also be important in
determining the appropriate dosage. Characteristics such as weight,
age, and the like may be important factors. For example, the
volatile anesthetic may have increased potency with age, as has
been demonstrated in the case of the volatile anesthetic
isoflurane.
[0069] The temperature of the volatile anesthetic may also be
considered as a factor in selecting an appropriate dose, as the
solubility of many volatile anesthetics may be affected by the
temperature of the volatile anesthetic and/or aqueous solution. For
example, increases in temperature may increase the solubility, and
thus potency, of the volatile anesthetic composition; this property
has been demonstrated with certain volatile anesthetics. The
particular dosage may also be dependent on the dosing regime
chosen. For example, the volatile anesthetic composition may be
delivered continuously or periodically. Conversely, the volatile
anesthetic composition may be administered as a single
administration as a one-time event.
[0070] Volatile anesthetics (for example, halogenated anesthetic
compounds) may be infused in amounts leading to spinal fluid levels
in the range of about 250 to about 50,000 nanograms/ml, depending
on the volatile anesthetic selected and the desired effect. In
certain embodiments, a volatile anesthetic may be administered to
achieve cerebrospinal fluid (CSF) concentration of from about 5 to
about 500,000 nanograms/ml. While the dose range will vary
depending on the compound selected and patient variability, it is
generally true that lower doses such as from about 0.01 to about
10,000 nanogram/ml are more suitable for treating minor to moderate
pain, while higher doses such as from about 10,000 nanogram/ml to
about 500,000 nanogram/ml or more are suitable for treating severe
pain and inducing anesthesia. Of course, the doses may be given
once (for example, for a minor single occurrence of pain),
repeatedly (for example, for moderate or chronic pain), or
continuously (for example, for severe pain or anesthesia purposes).
Combinations of these dosing regimes may also be used. For example,
a subject suffering from severe pain may require continuous dosing
with periodic additional dosing needed for breakthrough pain.
[0071] In embodiments where a volatile anesthetic (for example, a
volatile anesthetic, such as isoflurane, etc.) is mixed in a
solution, such as water, saline or an artificial CSF solution, the
concentration of the volatile anesthetic may vary. For example, a
solution may contain volatile anesthetic in a v/v ratio of from
about 1 to about 99%, from about 10 to about 75%, from about 10 to
about 50%, from about 20 to about 50%, from 30 to about 50%, from
about 1 to about 45%, from about 1 to about 40%, from about 1 to
about 35%, from about 1 to about 30%, from about 1 to about 25%,
from about 1 to about 20%, from about 1 to about 15%, from about 1
to about 10%, from about 1 to about 5%, from about 0.5 to about 5%,
from about 0.1 to about 5%, from about 0.1 to about 2.5%, from
about 0.5 to about 2.5%, or any range derivable therein. In these
embodiments, the volatile anesthetic may be, for example,
isoflurane, and the solution may be water, a saline solution or an
artificial cerebrospinal fluid (ACSF) solution.
[0072] The dosing and manner of delivery of the compositions of the
invention may be adjusted to achieve pain reduction without
substantially interfering with motor function of the subject, for
example, by varying the amount, concentration, frequency of
administration, and timing of administration.
[0073] The volatile anesthetic solution may also contain one or
more additives, such as a surfactant, PVP, a polymers, an
antimicrobial agent, a preservative etc. In certain embodiments, an
volatile anesthetic composition of the present invention may
comprise about: 0.1-90% of a volatile anesthetic such as
isoflurane, methoxyflurane, or sevofluorane, 0.1-99% of an
extractive solvent such as NMP or DMSO, 0.1-99% saline, and 0-50%
other additive(s) (for example, glycerol, a surfactant, PVP, etc.).
In some embodiments, it may be desirable to produce a concentrated
formulation which may be subject to a final dilution prior to
administration.
[0074] In various embodiments and as shown in the below examples, a
solution of about 10% volatile anesthetic, such as isoflurane, may
be used; this solution may be administered as a bolus injection,
continuously, and/or repeatedly to achieve analgesia and/or
anesthesia. Thus, as demonstrated in the below examples, a 10% v/v
solution of a volatile anesthetic may be used to induce analgesia.
Higher concentrations of volatile anesthetic may be used, in
various embodiments, to induce a regional anesthesia.
Methods of Active Agent Delivery
[0075] Volatile anesthetics of the present invention may be
delivered regionally or locally by a route other than orally,
intravenously or by inhalation. "Regional" or "local" anesthesia,
as used herein, is distinct from general anesthesia and refers to
anesthetic procedures which allow for the preferential delivery of
an volatile anesthetic to a specific region of the body, such as
near a nerve or a nerve bundle. In contrast, general anesthesia
allows for the systemic administration of a volatile anesthetic,
for example, via intravenous administration. Regional or local
anesthesia typically allows for a lower total body concentration
(although elevated local concentrations) of a volatile anesthetic
to be administered to a subject for analgesia or diminished pain
perception of at least a portion of the subject's body. For
example, intrathecal anesthesia, epidural anesthesia, nerve blocks,
and local skin infiltration are examples of regional or local
anesthesia. In some embodiments, specific concentrations of
volatile anesthetic which may be used for regional or local
anesthesia include from about 100 to about 500,000 nanogram/ml,
from about 100 to about 250,000 nanogram/ml, from about 100 to
about 100,000 nanogram/ml, from about 100 to about 50,000
nanogram/ml, from about 100 to about 25,000 nanogram/ml, or from
about 100 to about 10,000 nanogram/ml. The specific concentration
of volatile anesthetic used may vary depending on the desired
effect, and in various embodiments the volatile anesthetic
composition is titrated for effect: thus the concentration of
volatile anesthetic used or achieved in tissues may vary depending
on the specific desired result (e.g., regional anesthesia as
compared to analgesia) and/or the particular characteristics of the
patient such as sensitivity to the anesthetic.
[0076] The present invention may be used with various nerve block
procedures. Nerve block procedures according to the present
invention may be performed with or without ultrasound
visualization; for example, an ultrasound machine may be used to
visualize the region of the body involved a the nerve block
procedure, such as, for example, various nerve bundles in the
shoulder, neck, lower back, etc. The inventors envision that the
present invention may be used in conjunction with a variety of
surgical procedures, including, for example, but not limited to,
knee replacement, hip replacement, shoulder replacement, and/or
birthing-related procedures.
[0077] In certain embodiments, compositions and methods of the
present invention may be used for pain management. Pain management
is distinct from general anesthesia in that a lower total body
concentration of a volatile anesthetic may be administered to a
subject to increase analgesia or decrease perception of pain,
preferably without rendering the subject unconscious or
substantially interfering with motor function. In some embodiments,
specific concentrations of volatile anesthetics which may be used
for pain management include from about 100 to about 500,000
nanogram/ml, from about 100 to about 250,000 nanogram/ml, from
about 100 to about 100,000 nanogram/ml, from about 100 to about
50,000 nanogram/ml, from about 100 to about 25,000 nanogram/ml, or
from about 100 to about 10,000 nanogram/ml.
[0078] In some embodiments, specific concentrations of volatile
anesthetics which may be used for regional or local anesthesia
include from about 100 to about 500,000 nanogram/ml, from about 100
to about 250,000 nanogram/ml, from about 100 to about 100,000
nanogram/ml, from about 100 to about 50,000 nanogram/ml, from about
100 to about 25,000 nanogram/ml, or from about 100 to about 10,000
nanogram/ml.
[0079] Epidural or intrathecal administration of a volatile
anesthetic may be accomplished via techniques known in the art,
such as the use of an intrathecal or epidural catheter. The
catheter should be placed closer to the nerves critical for the
propagation of any pain sensory information which the practitioner
desires to inhibit, without damaging the nerves.
[0080] Local topical administration to achieve analgesia prior to
or during a medical procedure may be accomplished using techniques
known in the art. Examples of such medical procedures include, but
are not limited to, surgery, venipuncture, injection, peripheral
venous cannulation, incision, suturing, or other procedure.
[0081] Other routes of administration which are contemplated
include: injection, infusion, continuous infusion, localized
perfusion bathing target cells directly, via a catheter, via
nanoparticle delivery, topical administration (for example, in a
carrier vehicle, a topical control release patch, in a wound
dressing, a hydrocolloid, a foam, or a hydrogel), intra-articular,
intracranial, and/or intratumoral. An appropriate biological
carrier or pharmaceutically acceptable excipient may be used.
Compounds administered may, in various embodiments, be racemic,
isomerically purified, or isomerically pure.
[0082] In certain embodiments, volatile anesthetics of the present
invention are not administered intravenously. Intravenous
administration is often used for general anesthesia (Mathias et
al., 2004, Revista Brasileira de Anestesiologia, ISSN 0034-7094)
and typically results in the rapid distribution of the volatile
anesthetic throughout the body of a subject. Thus, in certain
embodiments, intravenous administration is incompatible for use
with regional or local anesthesia.
Solutions
[0083] After a volatile anesthetic has been selected, it may be
dissolved into a solution. The solution may be an aqueous solution,
such as water, saline, artificial cerebrospinal fluid, the
subject's own cerebrospinal fluid, or the like. In some variations,
other solutions may be appropriate.
[0084] Various formulations of saline are known in the art and may
be used with the present invention. For example, the saline may be
lactated Ringer's solution, acetated Ringer's solution, phosphate
buffered saline (PBS), Dulbecco's phosphate buffered saline
(D-PBS), Tris-buffered saline (TBS), Hank's balanced salt solution
(HBSS), or Standard saline citrate (SSC).
[0085] The saline solutions of the present invention are, in
certain embodiments, "normal saline" (i.e., a solution of about
0.9% w/v of NaCl). Normal saline has a slightly higher degree of
osmolality compared to blood; however, in various embodiments, the
saline may be isotonic in the body of a subject such as a human
patient. Normal saline (NS) is often used frequently in intravenous
drips (IVs) for patients who cannot take fluids orally and have
developed severe dehydration. In certain embodiments, "half-normal
saline" (i.e., about 0.45% NaCl) or "quarter-normal saline" (i.e.,
about 0.22% NaCl) may be used with the present invention.
Optionally, about 5% dextrose or about 4.5 g/dL of glucose may be
included in the saline. In various embodiments, one or more salt,
buffer, amino acid and/or antimicrobial agent may be included in
the saline.
[0086] Various artificial cerebrospinal fluid (ACSF) solutions may
be used with the present invention. In certain embodiments, the
ACSF is a buffered salt solution (pH 7.4) with the following
composition (in mM): NaCl, 120; KCl, 3; NaHCO.sub.3, 25;
CaCl.sub.2, 2.5; MgCl.sub.2, 0.5; glucose, 12. ACSF can also be
obtained from various commercial sources, such as from Harvard
Apparatus (Holliston, Mass.).
[0087] In various embodiments, a preservative or stabilizer may be
included in the composition or solution. For example, the
prevention of the action of microorganisms can be brought about by
preservatives such as various antibacterial and antifungal agents,
including but not limited to parabens (for example, methylparabens,
propylparabens), chlorobutanol, phenol, sorbic acid, EDTA,
metabisulfite, benzyl alcohol, thimerosal or combinations thereof.
Agents which may be included suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions (U.S. Pat. No. 5,466,468, specifically incorporated
herein by reference in its entirety). In all cases the composition
is preferably sterile and must be fluid to facilitate easy
injectability. Solutions are preferably stable under the conditions
of manufacture and storage and must be preserved against the
contaminating action of microorganisms, such as bacteria and fungi.
Examples of stabilizers which may be included include buffers,
amino acids such as glycine and lysine, carbohydrates such as
dextrose, mannose, galactose, fructose, lactose, sucrose, maltose,
sorbitol, mannitol, etc. Appropriate stabilizers or preservatives
may be selected according to the route of administration desired. A
particle filter or microbe filter can be used, and may be necessary
according to the route of administration desired.
[0088] The weight ranges of compounds in the solution may vary. For
example, in various embodiments, the composition may comprise about
1-5 wt % volatile anesthetic, about 1-5 wt %
preservative/stabilizer, about 1-5 wt % NaCl, and about 85%-97%
water. The ratio of volatile anesthetic to water may be varied as
needed to achieve the desired effect (pain reduction or analgesia,
regional anesthesia, etc.).
[0089] The solution and/or composition may also be sterilized prior
to administration. Methods for sterilization are well known in the
art and include heating, boiling, pressurizing, filtering, exposure
to a sanitizing chemical (for example, chlorination followed by
dechlorination or removal of chlorine from solution), aeration,
autoclaving, and the like.
[0090] The active agent gas may be dissolved into the solution in
any number of ways. For example, it may be bubbled through the
solution, for example, using a vaporizer, or it may be solubilized
by agitation or by sonication. In certain embodiments, a volatile
anesthetic may be measured in liquid form and directly mixed into a
solution. Of course, other suitable methods of dissolving the
volatile anesthetic into solution may also be used. After the
volatile anesthetic has been solubilized, it may be administered to
a subject in need of pain reduction (including pain reduction in
the form of anesthesia) epidurally or intrathecally using
techniques well known in the art. In certain embodiments, a
volatile anesthetic is mixed with a solution in a closed vacuum
container, and the combined solutions are then mechanically
agitated for 3-5 minutes and held in a thermo-neutral sonicator
until use.
[0091] In certain embodiments, solutions of the present invention
can be a component of an emulsion, such as a water-in-oil or an
oil-in-water emulsion, including a lipid emulsion, such as a
soybean oil emulsion. In certain embodiments, saline, artificial
CSF, or the patients own CSF, alone or as a constituent of an
emulsion, may be used for intrathecal or epidural administration of
a volatile anesthetic according to the present invention. Certain
emulsions of isoflurane have been prepared previously for
intravenous (da Sila Telles Mathias L, et al., 2004, Rev. Bras.
Anaestesiol Campianas 54(5), 2004) or epidural administration (Chai
et al. 2008, British J Anesthesia 100:109-115).
[0092] Pharmaceutical compositions of the present invention
comprise an effective amount of one or more volatile anesthetic or
biologically active gas or additional agent dissolved or dispersed
in a pharmaceutically acceptable carrier. The phrases
"pharmaceutical or pharmacologically acceptable" refers to
molecular entities and compositions that do not produce an adverse,
allergic or other untoward reaction when administered to an animal,
such as, for example, a human, as appropriate. The preparation of a
pharmaceutical composition that contains at least one volatile
anesthetic or biologically active gas in solution or additional
active ingredient will be known to those of skill in the art in
light of the present disclosure, as exemplified by Remington: The
Science and Practice of Pharmacy, 20th Edition (2000), which is
incorporated herein by reference in its entirety. Moreover, for
animal (for example, human) administration, it will be understood
that preparations should meet sterility, pyrogenicity, general
safety and purity standards as required by FDA Office of Biological
Standards.
[0093] In various embodiments, the compositions of the present
invention further comprise cyclodextrin. Cyclodextrins are a
general class of molecules composed of glucose units connected to
form a series of oligosaccaride rings. (See Challa et al., 2005,
AAPS PharmSciTech 6:E329-E357). In nature, the enzymatic digestion
of starch by cyclodextrin glycosyltransferase (CGTase) produces a
mixture of cyclodextrins comprised of 6, 7 and 8 anhydroglucose
units in the ring structure (.alpha.-, .beta.-, and
.gamma.-cyclodextrin, respectively). Commercially, cyclodextrins
are also produced from starch, but different, more specific enzymes
are used. Cyclodextrins have been employed in formulations to
facilitate the delivery of cisapride, chloramphenicol,
dexamethasone, dextromethoraphan, diphenhydramine, hydrocortisone,
itraconazole, and nitroglycerin. (See Welliver and McDonough, 2007,
Sci World J, 7:364-371). In various embodiments, the cyclodextrin
of the invention is hydroxypropyl-Beta-cyclodextrin,
sulfobutylether-beta-cyclodextrin, alpha-dextrin or combinations
thereof. In certain embodiments, cyclodextrin can be used as a
solubilizing agent.
[0094] In various other embodiments, the compositions of the
present invention can comprise human serum albumin purified from
plasma, or recombinant human serum albumin. In certain embodiments,
human serum albumin can be used as a solubilizing agent. In other
embodiments, the compositions of the invention can comprise
propylene glycol. In other embodiments, the compositions of the
invention can comprise perfluorooctyl bromide. In other
embodiments, the compositions of the invention can comprise
perfluorocarbon. In certain embodiments, perfluorocarbon can be
used as a solubilizing agent.
DEFINITIONS
[0095] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e. to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0096] The terms "inhibiting," "reducing," or "preventing," and
variations of these terms, as used herein include any measurable
decrease, including complete or substantially complete
inhibition.
[0097] The term "effective," as that term is used in the
specification and/or claims, means adequate to accomplish a
desired, expected, or intended result.
[0098] The term "extractive solvent," as used herein, refers to a
solvent which may interact with a volatile anesthetic in solution
to reduce the volatility of the volatile anesthetic without
chemically reacting to the volatile anesthetic.
[0099] Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the study subjects.
[0100] The term "or," as used herein, means "and/or" unless
explicitly indicated to refer to alternatives only or the
alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or."
[0101] As used herein, the words "comprising" (and any form of
comprising, such as "comprise" and "comprises"), "having" (and any
form of having, such as "have" and "has"), "including" (and any
form of including, such as "includes" and "include") or
"containing" (and any form of containing, such as "contains" and
"contain") are inclusive or open-ended and do not exclude
additional, unrecited elements or method steps.
[0102] Throughout this disclosure, various aspects of this
invention can be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual and partial numbers within that range, for
example, 1, 2, 3, 4, 5, 5.5 and 6. This applies regardless of the
breadth of the range.
[0103] It is contemplated that any embodiment discussed in this
specification can be implemented with respect to any method or
composition of the invention, and vice versa. Furthermore,
compositions of the invention can be used to achieve methods of the
invention.
[0104] Other objects, features and advantages of the present
invention will become apparent from the detailed description
herein. It should be understood, however, that the detailed
description and the specific examples, while indicating specific
embodiments of the invention, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the invention will become apparent to those skilled in the
art from this detailed description.
EXPERIMENTAL EXAMPLES
[0105] The invention is further described in detail by reference to
the following experimental examples. These examples are provided
for purposes of illustration only, and are not intended to be
limiting unless otherwise specified. Thus, the invention should in
no way be construed as being limited to the following examples, but
rather, should be construed to encompass any and all variations
which become evident as a result of the teaching provided
herein.
Example 1
Intrathecal Administration of Isoflurane and Sevoflurane
[0106] This study was designed to evaluate efficacy of direct
intrathecal injection of volatile anesthetic in reducing pain and
providing analgesia. The study was conducted over a one (1) month
period using the volatile anesthetics isoflurane and sevoflurane
injected directly intrathecally or dissolved in saline as shown in
the studies below. The subject animal used was the rat, since the
rat has a well-established model of pain/analgesia testing. In
particular, Sprague-Dawley rats weighing over 350 gm were used. The
rats were anesthetized with pentobarbital (50 mg/kg), and the
anesthetic depth of the animals was determined by corneal reflex
and paw withdrawal reflex to a noxious stimulus.
[0107] The neck of the rats were shaved and cleaned with
disinfectant solutions in order to avoid bacterial contamination
during surgery. A midline surgical dissection of the posterior neck
muscles was performed to obtain access to the occipito-atlantoid
membrane. This membrane was identified and then dissected. A
sterile polyethylene catheter was introduced in the subarachnoid
space until the lumbar enlargement of the spinal cord
(approximately 7-8 cm measured in each animal). The surgical wound
was closed, first suturing the neck muscles with 3-0 silk sutures
and then closing the skin incision with staples.
[0108] After the surgery, the rats were moved to their cages and a
radiant lamp was placed over the cages so that the rats would not
undergo anesthetic-induced hypothermia. The rats were continuously
monitored from the end of the surgery until they were fully awake.
Rats showing any motor impairment after surgery were
euthanized.
[0109] On the fifth day after surgery, those rats without wound
infection or motor dysfunction were transported to the pain
behavioral lab to enter the intrathecal study with volatile
anesthetics. Twelve rats were selected for the study. All these
rats had intrathecal catheters. Isoflurane
(1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) and
sevoflurane (fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl
ether) were used as the halogenated ether compounds. Both of these
are halogenated volatile anesthetics, with isoflurane manufactured
by Baxter and sevoflurane manufactured by Abbott Laboratories. The
12 rats were divided into 3 groups of four rats each for study A
and B.
[0110] In the first group, 2 microliters of preservative-free
normal saline was injected via the intrathecal catheter into each
rat. This catheter was then flushed with preservative-free normal
saline. Pain behavioral testing on this group was then
performed.
[0111] In the second group, 2 microliters of isoflurane was
injected via the intrathecal catheter into each rat. This catheter
was also flushed with preservative-free normal saline. This group
was then subjected to pain behavioral testing.
[0112] In the third group, 2 microliters of sevoflurane was
injected via the intrathecal catheter into each rat. This catheter
was also flushed with preservative-free normal saline. This group
was then subjected to pain behavioral testing.
[0113] A "hotplate" behavioral test was used to evaluate pain
perception and analgesia. The pain behavioral testing model used in
these studies have been well established by Tony Yaksh. (See, for
example Chaplan et al., 1994, J. Neurosci. Methods, 53:55-63; Yaksh
et al., 2001, J. Appl. Physiol., 90:2386-2402; Kim and Chung, 1992,
Pain, 50:355-363; Sorkin et al., 2001, Anesthesiology, 95:965-973).
This test involves determining how quickly a rat will withdraw its
hind paw in response to a noxious stimulus such as a radiant heat
source placed directly underneath its paw. This time for withdrawal
is known as "thermal withdrawal latency".
[0114] Rats were transferred for testing onto a modified Hargreaves
apparatus with a heated glass plate maintained at 25.degree. C.
(see Hargreaves et al., 1998, Pain, 32:77-88). A focused projection
bulb below the plate was aimed at the mid-plantar surface of the
paw. A photodiode-activated timer measured the withdrawal latency,
and a cutoff time of 25 seconds was used to prevent tissue damage.
Thermal withdrawal latency to radiant heat was measured at 5
minutes and 30 minutes after each intrathecal injection. Each paw
was tested three times, and the results were averaged. The below
data was collected for both the right and left hind paws:
TABLE-US-00001 Group 1: Control Group (Normal Saline) Tested at 5
minutes Test 1 Test 2 Test 3 Right Left Right Left Right Left
Average Rat 1: 9.00 9.26 10.45 6.74 8.42 9.95 8.97 Rat 2: 11.23
9.32 6.34 7.98 10.65 8.73 7.19 Rat 3: 7.83 8.21 9.67 11.90 8.55
6.38 8.76 Rat 4: 9.72 8.04 6.77 8.92 7.88 8.95 8.38 Group 1
Average: 8.33 seconds
TABLE-US-00002 Group 2 Study A: Isoflurane Group Tested at 5
minutes Test 1 Test 2 Test 3 Right Left Right Left Right Left
Average Rat 5: 19.81 7.23 20.38 8.91 20.34 18.82 19.25 Rat 6: 17.19
19.24 15.88 17.65 18.59 20.72 18.21 Rat 7: 19.20 18.11 17.90 19.80
16.71 20.07 18.63 Rat 8: 20.31 19.71 18.34 17.18 16.75 16.38 17.95
Group 2 Average: 18.51 seconds
TABLE-US-00003 Group 3 Study B: Sevoflurane Group Tested at 5
minutes Test 1 Test 2 Test 3 Right Left Right Left Right Left
Average Rat 9: 13.81 14.90 13.23 15.11 16.03 14.83 14.65 Rat 10:
17.19 13.38 14.29 12.31 13.75 12.01 13.82 Rat 11: 14.98 12.34 13.93
11.03 12.37 14.16 13.14 Rat 12: 10.31 11.83 13.20 12.66 17.59 12.31
12.98 Group 3 Average: 13.65 seconds
[0115] These rats were then allowed time to recover from their
intrathecal injection. There were no apparent adverse effects such
as respiratory depression, cardiac, or neurological compromise. At
30 minutes after the injection, the rats were tested again,
according to grouping:
TABLE-US-00004 Group 1: Control Group (Normal Saline) Tested at 30
minutes Test 1 Test 2 Test 3 Right Left Right Left Right Left
Average Rat 1: 7.32 8.02 9.17 8.64 5.89 7.71 7.79 Rat 2: 6.77 5.98
7.81 6.54 9.03 8.20 8.59 Rat 3: 7.08 8.39 7.26 8.49 9.23 9.84 8.38
Rat 4: 8.36 9.44 9.15 9.67 8.54 7.92 8.85 Group 1 Average: 8.40
seconds
TABLE-US-00005 Group 2, Study A: Isoflurane Group Tested at 30
minutes Test 1 Test 2 Test 3 Right Left Right Left Right Left
Average Rat 5: 9.87 9.12 10.59 9.02 8.54 9.77 9.48 Rat 6: 9.08 6.35
7.81 8.22 10.49 11.62 8.93 Rat 7: 6.32 8.37 9.48 8.45 11.03 10.48
10.52 Rat 8: 9.41 10.27 6.76 7.04 7.88 10.32 9.21 Group 2 Average:
9.53 seconds
TABLE-US-00006 Group 3, Study B: Sevoflurane Group Tested at 30
minutes Test 1 Test 2 Test 3 Right Left Right Left Right Left
Average Rat 9: 9.23 8.54 7.30 8.29 9.43 8.87 8.61 Rat 10: 7.38 6.87
8.92 7.99 10.83 8.10 8.35 Rat 11: 10.05 8.44 9.32 11.74 7.66 6.13
8.89 Rat 12: 9.55 10.93 8.67 6.68 9.27 12.11 9.54 Group 3 Average:
8.84 seconds
[0116] The results of this study demonstrated the efficacy of
intrathecal administration of volatile anesthetics in reducing
pain. At the smallest intrathecally delivered dose of 2
microliters, an analgesic effect of isoflurane and sevoflurane was
shown. The thermal latency time was significantly increased, thus
showing that the thermal C-fiber pain pathway was effectively
dampened. This study also shed some light into the safety of
intrathecally delivering active agent gases. None of the rats in
the study experienced adverse effects, and all of them fully
recovered from the intrathecal injection after 30 minutes, as
indicated by the return to thermal latency baseline for all
groups.
Example 2
Intrathecal Administration of Isoflurane Dissolved in Saline
[0117] Isoflurane was dissolved into saline using the following
method (also referred to as the "bubbling" method). Study C: A mock
vaporizing device was created using a 500 ml modified Erlenmeyer
flask (2 inlets and 1 catheter into the liquid phase). The flask
was partially filled with 0.9% normal saline and a stoppered glass
pipette was inserted into the bottom of the liquid phase for
injection of isoflurane. A second egress pipette allowed egress of
gas from the closed container. 2% isoflurane solution in oxygen at
2 L/min was injected through the pipette, saturating the 0.9%
saline solution after approximately 10 minutes of bubbling. 5 mL
was drawn from the saturated saline solution and administered to 10
animals using the procedures outlined in Example I above.
[0118] For study C, all animals were prepared as for experiments A
and B. The inventors injected 4 animals with 5 microliter of
dissolved isoflurane (as prepared in 0030) via intrathecal
catheter. Note, control (baseline) latency to paw withdrawal is
different in Study C due to a different intensity of heat lamp
used. Each animal serves as its own control in study C.
[0119] Study C Data is presented here: in seconds to paw withdrawal
to heat source. Table and graphic format. Results are shown in FIG.
2.
TABLE-US-00007 CONTROL 5 MIN 10 MIN 15 MIN 30 MIN 60 MIN RAT 1 4.8
11 5.4 7.6 6.8 6.1 4.4 15 9 7.3 7.2 5.8 4.8 19.5 9 8.8 4.9 5.1 20
6.8 7 5.2 4.9 RAT 2 3.4 10.9 9.9 10.4 8.2 3.8 4.3 12.6 8.7 9.4 6.9
4.7 3.6 18.1 12 5.4 8.1 7 17.3 9 13.4 6.4 4.1 RAT 3 3.6 14.2 12.2
6.1 5.2 4.2 3.8 20 12 7.1 6.1 3.5 4.7 20 9.1 4.8 5.8 3.3 16 8.9 5.2
6.5 3.8 RAT 5 3:9 9.8 8.8 7.9 4.9 4.2 2.6 11.8 7.8 6.4 4.3 3.5 2.6
9.1 10.2 6.9 4.7 3.8 11.8 8.1 4.3 3.8 3.5 mean 3.875 14.81875
9.18125 7.375 5.9375 4.45625 SD 0.767671 3.809235 1.77067 2.231171
1.266331 1.073293
Example 3
Intrathecal Inhibition of Pain Using Isoflurane Dissolved in
Artificial Cerebrospinal Fluid
[0120] Pain sensitivity was measured after intrathecal
administration of isoflurane in artificial cerebrospinal fluid
(ACSF). Further, as detailed below, the isoflurane was first
dissolved in ACSF and then sonicated before administration. The
dose response relationship was then evaluated by generating a
stimulus-response (SR) graph in order to determine relevant
concentrations of isoflurane that may be administered intrathecally
to achieve analgesia or anesthesia. The characterization of the
pharmacological profile of intrathecal administration of isoflurane
in AC SF was performed in this example using rats; further, as
would be appreciated by one of skill in the art, analogous
approaches may be used to determine the precise pharmacological
profile in humans.
[0121] Isoflurane dissolved in ACSF was prepared by the following
method. Isoflurane was mixed in a closed vacuum container in a v/v
ratio of 10-50% with buffered salt solution that approximates
cerebrospinal fluid (pH 7.4) with the following composition (in
mM): NaCl, 120; KCl, 3; NaHCO.sub.3, 25; CaCl.sub.2, 2.5;
MgCl.sub.2, 0.5; glucose, 12. The combined solutions were
mechanically agitated for 3-5 minutes and then held in a
thermo-neutral sonicator until use.
[0122] Isoflurane in ACSF was then administered to rats
intrathecally via the following method. Treatment solution is
delivered via intrathecal catheter that overlies lumbar segment
L1-2 in a volume of 10 .mu.l followed by a 10 .mu.l flush of
ACSF.
[0123] Pain perception was tested after intrathecal administration
of isoflurane dissolved in artificial CSF using the "hotplate"
behavioral test, as described above, with the modification that a
cutoff time of 20 seconds was used. As stated above the "hotplate"
behavioral test involves testing the hind paw withdrawal latency to
radiant heat (i.e., duration of time between before a rat to lifts
a paw away from a heat source).
[0124] Intrathecal administration of isoflurane in ACSF resulted in
analgesia. As shown in FIG. 3, intrathecal administration of
isoflurane in ACSF (i.e., at a 1.46 mg dose of isoflurane) resulted
in analgesia as measured by testing the hind paw withdrawal
threshold to radiant heat. A 10 .mu.l, solution of isoflurane in
ACSF (10% v/v) was used. As described below, this dose of
isoflurane represents a moderate dose of intrathecal isoflurane.
Further, as shown in FIG. 3, DMSO may be included in the
pharmaceutical composition for intrathecal injection. A
concentration of 1% DMSO was used.
[0125] The dose response relationship was then evaluated by
generating a stimulus-response (SR) graph in order to standardize
responses across animals and determine relevant concentrations of
isoflurane that may be administered intrathecally to achieve
analgesia or anesthesia. FIG. 4 shows an stimulus-response (SR)
graph of the maximal possible effect (MPE) by dose for the time
point of 10 minutes after the injection of isoflurane in ACSF.
Various doses of isoflurane are shown on the x-axis; for example,
the 10% v/v solution of isoflurane used above, as shown in FIG. 3,
corresponds to approximately a 34% MPE as shown in FIG. 4.
Pharmaceutical compositions including ACSF and/or 1% DMSO are shown
in FIG. 3. MPE is used here to standardize responses across
animals. MPE is calculated as ((drug response time-baseline
response time)/(cutoff time-baseline response time))*100. The
cutoff time used here was 20 seconds. As shown in FIG. 4, a
substantial analgesic effect was observed. A concentration of 1%
DMSO was used.
Example 4
Intraplanar Administration of Isoflurane
[0126] Rats are assessed for response to thermal stimulation using
the Plantar Heat Stimulation Test (i.e., radiant heat) (Planar
Analgesia Instrument, Ugo Basile, Italy) by measuring paw
withdrawal latency. 100 .mu.l of pureform Isoflurane or 100 .mu.l
of 2% Lidocaine was injected subcutaneously into the planar surface
of one hindpaw of each rat. For each rat, the untreated,
contralateral hindpaw served as its own control.
[0127] After the rats acclimated for 15 minutes under acrylic boxes
that allow minimal movement, a heat source was positioned beneath
the mid-plantar surface of the hind paw. Withdrawal latency was
defined as the period of time from the beginning of the thermal
stimulation to the brisk withdrawal of the hind paw. To avoid
tissue damage, a cutoff time of 22 seconds was set. Thermal
stimulation was applied three times to each hind paw at an
interstimulus interval of 3-5 minutes. Thermal withdrawal latency
was assessed before and after the treatment. An increase in the
withdrawal latency in the treated paw compared to the control paw
was assessed as analgesic activity of the tested formulation.
[0128] The results of this experiment are shown in FIG. 5. For
statistical comparison, student paired t-test analysis was used.
Differences were considered significant at P<0.05 (# P<0.05
isoflurane versus control n=4; * P<0.05 lidocaine versus control
n=3).
[0129] The administration of isoflurane into the hindpaw produced
significant antinociceptive effect (iso) when compared to the
untreated paw (con.iso). The antinociceptive effect began at 25
minutes after administration and continued throughout the
experiment. The administration of lidocaine (lid versus con.lid)
resulted in significant antinociceptive effect, which began at 5
minutes after administration, peaked at 15 minutes, and returned to
baseline levels at 45 minutes.
Example 5
Isoflurane Stability
[0130] In the Examples that follow, the stability of isoflurane in
the described compositions was determined in two ways. First, the
compositions were examined for the presence of phase separation at
the macroscopic level. Secondly, isoflurane content of the
compositions was determined by weighing the remaining isoflurane in
the composition when they were left uncapped over time. Briefly,
glass vials were filled with 5-10 ml of the composition vehicle and
then weighed; one of them received only vehicle (i.e., no
isoflurane) and served as control. The other vials received varying
amounts of isoflurane. They were left uncapped in the hood. Over
time, the vials were weighed to see if the isoflurane stayed in the
composition or had evaporated. The amount evaporated over time in
the vehicle control was subtracted from that in the
isoflurane-containing composition.
[0131] The pure form of isoflurane is a volatile anesthetic. In
order to assess the volatility of isoflurane, two vials received
the indicated amounts of pure form isoflurane. The vials were
placed in the chemical fume hood and left uncapped. The vials were
weighed at the indicated times to determine the amount of
evaporated isoflurane. As it is shown in the table below 0.7893 g
isoflurane was evaporated within 3 hours, while 3.4825 g isoflurane
took approximately 8 hrs to evaporate completely. These amounts of
isoflurane are similar to the amounts of isoflurane that were used
to prepare the isoflurane compositions in the Examples that
follow.
TABLE-US-00008 5 h Pure (% form 0 h 0.25 h 1 h 2 h 3 h re- of Iso-
(% (% (% (% (% main- flurane remain- remain- remain- remain-
remain- ing (g) ing iso) ing iso) ing iso) ing iso) ing iso) iso) 7
h 8 h 0.7893 100 85 52 14 0 3.4825 100 96 86 75 62 38 13 3
Example 6
Preparation of Isoflurane Solution (v/v) with NMP
[0132] Pure isoflurane USP (Forane) liquid was mixed with NMP
(Sigma-Aldrich) in the indicated concentrations; the mixture was
vortexed vigorously to prepare homogenous isoflurane-NMP solution.
In order to reduce the amount of NMP in the solution, saline (0.9%
NaCl) was added to the mixture.
TABLE-US-00009 Isoflurane Appearance NMP (%) Saline (%) (%) of
solutions 1 90 -- 10 Clear 2 60 -- 40 Clear 3 63 27 10 Clear 4 72
20 8 Clear
TABLE-US-00010 Isoflurane 0 h 0.25 h 1 h 16 h 24 h con- (% (% (% (%
(% centration remaining remaining remaining remaining remaining in
NMP iso) iso) iso) iso) iso) 10 100 99 99 94 91 30 100 99 98 90
86
[0133] As it is shown in the tables above, 10% and 40% of
isoflurane was mixed with NMP, and the resulting solution looked
clear. Moreover, the addition of NMP reduced the volatility of
isoflurane, as compared with Example 5.
Example 7
Preparation of Emulsified Isoflurane (v/v) in Intralipid
[0134] Pure isoflurane USP (Forane) liquid is mixed with Intralipid
20% or 30%
[0135] (Baxter) at the indicated concentrations; the mixture was
vortexed vigorously and sonicated for 30 minutes to prepare
homogenous isoflurane-intralipid emulsion.
TABLE-US-00011 Isoflurane Appearance of Lipid Emulsion
Concentration Emulsions 1 20% Intralipid 1-6% Homogenous 2 30%
intralipid 6-10% Homogenous
TABLE-US-00012 Isoflurane con- 0 h 0.25 h 1 h 16 h 24 h centration
(% (% (% (% (% in intralipid remaining remaining remaining
remaining remaining 20% iso) iso) iso) iso) iso) 2 100 95 95 92
91.7 3 100 93 92 70 69.8 4 100 94 92 55 55.3 5 100 96 95 60
58.9
[0136] Intralipid emulsions with the indicated amount of isoflurane
looked homogenous and uniform. Moreover, intralipid reduced the
volatility of isoflurane, as compared with Example 5.
[0137] One of skill in the art will realize that emulsions of
isoflurane can be made using other lipids, including other emulsion
preparations, such as 10% (w/v) Intralipid, using variations of the
methods described herein. Other commercially available lipid
compositions that may be useful for the production of the volatile
anesthetic compositions of the present invention include, but are
not limited to, Liposyn.RTM. (B. Braun) and Nutrilipid.RTM. (B.
Braun). One of skill in the art will also realize that emulsions of
desflurane, sevoflurane, isoflurane, enflurane, methoxyflurane and
halothane can be produced using variations of the methods described
herein.
Example 8
Preparation of Emulsified Isoflurane (v/v) in Intralipid and
NMP
[0138] Pure isoflurane USP (Forane) liquid is mixed with NMP
(Sigma-Aldrich) in the indicated concentrations; the NMP-Isoflurane
solution was added to intralipid 20% or 30% (Baxter). The mixture
was vortexed vigorously and sonicated for 30 minutes to prepare
homogenous isoflurane-NMP-intralipid emulsion.
TABLE-US-00013 Appearance 20% Intralipid (%) NMP (%) Isoflurane (%)
of emulsions 1 75 15 10 Homogenous 2 80 10 10 Homogenous
TABLE-US-00014 Iso- 0 h 0.25 h 1 h 16 h 24 h flu- (% re- (% re- (%
re- (% re- (% re- rane maining maining maining maining maining
Vehicle (%) iso) iso) iso) iso) iso) 20% 5 100 98 94 88 85
intralipid + 15% NMP 20% 10 100 98 97 93 89 intralipid + 15%
NMP
[0139] Intralipid emulsions with the indicated amount of isoflurane
in the presence of NMP looked homogenous and uniform. In the
presence of NMP, intralipid was able to hold more isoflurane than
in the absence of NMP, as compared with Example 7. In addition, the
combination of intralipid and NMP reduced the volatility of
isoflurane, as compared with Example 5.
[0140] One of skill in the art will realize that emulsions of
isoflurane can be made using other lipids, including other emulsion
preparations, such as 10% (w/v) intralipid, using variations of the
methods described herein. Other commercially available lipid
compositions that may be useful for the production of the volatile
anesthetic compositions of the present invention include, but are
not limited to, Liposyn.RTM. (B. Braun) and Nutrilipid.RTM. (B.
Braun). One of skill in the art will also realize that emulsions of
desflurane, sevoflurane, isoflurane, enflurane, methoxyflurane and
halothane can be produced using variations of the methods described
herein.
Example 9
Preparation of Polysorbate 80 (Tween 80)-Based Emulsified
Isoflurane
[0141] Isoflurane was added to Tween 80 (3% v/v) for a total volume
of 10 ml. The mixture was vortexed vigorously and sonicated for 30
minutes to prepare homogenous isoflurane emulsion. In some cases,
1,2-dimyristoyl-sn-glycero-3-phophocholine (DMPC) was included in
the formulation. First, DMPC (0.3% or 0.6%) was dissolved in Tween
80 (3% v/v), then isoflurane was added to the Tween-DMPC mixture,
which was followed by 30 minutes of sonication.
TABLE-US-00015 Appearance of 3% Tween 80 (%) DMPC (%) Isoflurane
(%) emulsions 1 95 -- 5 Homogenous 2 93 0.3 7 Homogenous 3 93 0.6 7
Homogenous
TABLE-US-00016 0 h 0.25 h 1 h 16 h 24 h Iso- (% re- (% re- (% re-
(% re- (% re- flurane maining maining maining maining maining
Vehicle (%) iso) iso) iso) iso) iso) 3% Tween 7 100 97 95 91 85 3%
7 100 98 96 94 89 Tween + 0.3% DMPC 3% 7 100 100 100 99 94 Tween +
0.6% DMPC
[0142] Tween 80-based emulsions appeared homogenous. When DMPC was
added, the same amount of Tween 80 was able to hold more isoflurane
than without DMPC. Moreover, the combination of isoflurane with
Tween 80 or Tween 80 DMPC reduced the volatility of isoflurane, as
compared with Example 5.
Example 10
Preparation of Isoflurane Solution (v/v) with Propylene Glycol
[0143] Pure isoflurane USP (Forane) liquid was mixed with Propylene
Glycol (Sigma-Aldrich) at the indicated concentrations; the mixture
was vortexed vigorously to prepare homogenous isoflurane-Propylene
Glycol solution.
TABLE-US-00017 Propylene Glycol Appearance of (%) Saline (%)
Isoflurane (%) solutions 1 90 -- 10 Clear 2 70 -- 30 Clear 3 72 20
8 Clear
TABLE-US-00018 Isoflurane con- 0 h 0.25 h 1 h 16 h 24 h centration
(% (% (% (% (% in Propylene remaining remaining remaining remaining
remaining Glycol iso) iso) iso) iso) iso) 10 100 89 86 44 23 30 100
94 90 53 35
[0144] Eight percent, 10% and 30% of isoflurane was mixed with
propylene glycol, and the resulting solutions appeared clear.
Moreover, propylene glycol reduced the volatility of isoflurane, as
compared with Example 5.
Example 11
Preparation of Cremophor EL-Based Emulsified Isoflurane
[0145] Isoflurane was added to an aqueous solution of Cremophor EL
(10% v/v) for a total volume of 10 ml. The mixture was vortexed
vigorously and sonicated for 30 minutes to prepare homogenous
isoflurane emulsion.
TABLE-US-00019 Appearance of the 10% Cremophor EL (%) Isoflurane
(%) emulsion 1 95 5 Milky 2 90 10 Milky
TABLE-US-00020 0 h 0.25 h 1 h 16 h 24 h Isoflurane (% re- (% re- (%
re- (% re- (% re- Concen- maining maining maining maining maining
Vehicle tration iso) iso) iso) iso) iso) 10% 5 100 90 85 68 54
Cremophor 10% 10 100 91 87 73 60 Cremophor
[0146] Cremophor EL-based emulsions with the indicated amount of
isoflurane appeared milky. Moreover, the Cremophor EL-based
emulsions reduced the volatility of isoflurane, as compared with
Example 5.
Example 12
Preparation of Isoflurane Solution (v/v) with Dimethyl Sulfoxide
(DMSO)
[0147] Pure isoflurane USP (Forane) liquid was mixed with DMSO
(BDH) at the indicated concentrations. The mixture was vortexed
vigorously to prepare homogenous isoflurane-DMSO solution. The
isoflurane solutions containing DMSO appeared clear.
TABLE-US-00021 Appearance of DMSO (%) Saline (%) Isoflurane (%)
solutions 1 90 -- 10 Clear 2 50 -- 50 Clear 3 72 20 8 Clear
Example 13
Preparation of Isoflurane Solution (v/v) in Perfluorooctyl
Bromide
[0148] Pure isoflurane USP (Forane) liquid was mixed with
Perfluorooctyl Bromide (Acros Organics) at the indicated
concentrations. The mixture was vortexed vigorously to prepare
homogenous isoflurane-Perfluorooctyl Bromide solution. The
isoflurane solutions containing Perfluorooctyl Bromide appeared
clear.
TABLE-US-00022 Perfluorooctyl Bromide (%) Isoflurane (%) Appearance
of solutions 1 90 10 Clear 2 80 20 Clear
Example 14
Topical Application of Isoflurane for Analgesia
[0149] To evaluate the efficacy of topical isoflurane, a small
amount of (1 cc) of 50% ISO/DMSO solution was applied to the skin
of a human subject. The subject observed local anesthetic
properties where the 50% ISO/DMSO solution was applied, with a
notable local anesthetic response to light touch for approximately
one hour duration. No skin irritation was observed.
[0150] To further quantify this local anesthetic response in human
subjects, clinical studies assessing any of the volatile anesthetic
compositions described herein, may be performed as described below.
Isoflurane (ISO) is a widely used volatile anesthetic agent with a
well established safety profile. Dimethyl sulfoxide (DMSO) is an
organic solvent which has been used as a drug delivery system to
facilitate drug movement across the stratum corneum (the water
impermeable skin layer). Previous work had shown local anesthesia
with lecithin-coated microdroplets of methoxyflurane (Haynes and
Kirkpatrick, 1991, Reg Anesth 16:173-80).
[0151] The following approach may be used to test the analgesia of
any of the volatile anesthetic compositions described herein.
Studies similar to those involving topical amitryptiline studies
(see clinicaltrials.gov/show/NCT00471445) may be performed.
Cutaneous evaluation in human volunteers for efficacy and or local
skin irritation may also be tested. In the example of
amitryptiline, important advances came through pilot human trials
with volunteers comparing different doses and vehicle alone for
skin irritation and pain blocking properties (Gerner et al., 2003,
Reg Anesth Pain Med. 28:289-93). To differentiate between vehicle
and active drug, several sites will be tested as outlined below to
include a vehicle only site versus drug+vehicle (in different
doses).
[0152] Subject Eligibility: Test subjects should be volunteer
adults without health problems including lack of skin sensitivity
or other medical problems. They need to be literate and agree to an
application of test medications to their forearm with a subsequent
testing protocol for 4 hours.
[0153] Treatment Plan: Healthy volunteers may have 3 circles
approximately 10 cm in diameter drawn on their nondominant forearm
with a marking pen. Baseline vital signs may be taken.
[0154] Medication may be applied as follows: Low dose volatile
anesthetic composition, High dose volatile anesthetic composition,
and Vehicle alone, each to one of the three spots respectively, and
covered with a tegaderm (6.times.7 cm, 3M Healthcare, St Paul
Minn.). This may be removed after 15 minutes.
[0155] Testing may be done at the center of the three circles at
baseline (pre-application), 15 minutes (after dressing removal), 60
minutes, 3 hours, and 24 hours. Testing may include sensitivity to
light touch with:
[0156] Touch detection thresholds. (A delta-small myelinated
fibers--"fast pain" touch): Touch detection thresholds may be
determined using the up/down method of Dixon 1 with 6 von Frey
monofilaments that are calibrated to administer a force of 0.1,
0.5, 0.9, 3.2, 6.1 or 8.0 mN. Starting with 0.5 mN, the von Frey
monofilament may be applied for approximately 1 sec. If the subject
fails to detect the stimulus, then the next higher force von Frey
monofilament is applied. When the subject detects the presence of
the stimulus, the next lower von Frey is administered. The up/down
test sequence continues for four additional von Frey applications
after the initial detection. The 50% mechanical detection threshold
is calculated using the procedure described in Dixon 1. If there is
no detection to the highest force von Frey monofilament, then the
50% detection threshold is assigned the value of 19 mN.
[0157] Pain Detection (C Fiber-large unmyelinated "slow pain"),
Sharpness threshold and pain to needle probes: Sharpness detection
may be determined using a weighted needle device 2. The tip of 30
gauge needle (200 im diameter) is filed to produce a flat,
cylindrical end. A cotton tip applicator is inserted into the Luer
connection of the needle, and washers are placed on the shaft of
the cotton tip applicator to achieve the desired force level for
the stimulus. The entire assembly is then placed inside a 30 cc
syringe so that the needle came out of the tip of the syringe and
the assembly moved freely within the syringe. When the needle is
applied to the skin surface, a reliable and consistent force is
applied. Three forces will be used: 100, 200 and 400 mN. Each
stimulus is applied for about 1 second. Each force is applied 10
times within each area of interest in a pseudorandom order. The
subjects are instructed to indicate if the stimulus is sharp. If a
stimulus is sharp, the subject then indicates if the stimulus is
painful.
[0158] To assess for skin irritation, the subjects may be asked to
rate the "local skin irritation" at each location at each time
point on a 0-10 scale (0=not irritated at all and 10=extremely
irritated). Finally, the skin may be examined for redness and
obvious irritation at the site at each time point as a "present or
absent."
[0159] The disclosures of each and every patent, patent
application, and publication cited herein are hereby incorporated
herein by reference in their entirety.
[0160] All of the compositions and methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. More specifically, it will be apparent that certain
agents which are both chemically and physiologically related may be
substituted for the agents described herein while the same or
similar results would be achieved. All such similar substitutes and
modifications apparent to those skilled in the art are deemed to be
within the spirit, scope and concept of the invention as defined by
the appended claims.
[0161] While this invention has been disclosed with reference to
specific embodiments, it is apparent that other embodiments and
variations of this invention may be devised by others skilled in
the art without departing from the true spirit and scope of the
invention. The appended claims are intended to be construed to
include all such embodiments and equivalent variations.
* * * * *