U.S. patent application number 17/153666 was filed with the patent office on 2021-12-09 for novel formulations and methods for treating dermatological disorders or diseases.
The applicant listed for this patent is Vapogenix, Inc.. Invention is credited to Danguole Spakevicius.
Application Number | 20210378936 17/153666 |
Document ID | / |
Family ID | 1000005787308 |
Filed Date | 2021-12-09 |
United States Patent
Application |
20210378936 |
Kind Code |
A1 |
Spakevicius; Danguole |
December 9, 2021 |
NOVEL FORMULATIONS AND METHODS FOR TREATING DERMATOLOGICAL
DISORDERS OR DISEASES
Abstract
The present invention provides compositions and methods for
treating a dermatological disorder or disease.
Inventors: |
Spakevicius; Danguole;
(Houston, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vapogenix, Inc. |
Houston |
TX |
US |
|
|
Family ID: |
1000005787308 |
Appl. No.: |
17/153666 |
Filed: |
January 20, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15979056 |
May 14, 2018 |
10933009 |
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17153666 |
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14129017 |
Feb 26, 2014 |
9968540 |
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PCT/US12/43493 |
Jun 21, 2012 |
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15979056 |
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61500909 |
Jun 24, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/107 20130101;
A61Q 19/004 20130101; A61K 9/127 20130101; A61K 8/69 20130101; A61K
31/075 20130101; A61K 9/1075 20130101; A61K 9/0014 20130101; A61Q
19/007 20130101; A61K 8/14 20130101; A61K 47/22 20130101 |
International
Class: |
A61K 8/69 20060101
A61K008/69; A61K 8/14 20060101 A61K008/14; A61K 9/00 20060101
A61K009/00; A61K 47/22 20060101 A61K047/22; A61K 9/107 20060101
A61K009/107; A61K 9/127 20060101 A61K009/127; A61K 31/075 20060101
A61K031/075; A61Q 19/00 20060101 A61Q019/00 |
Claims
1. A pharmaceutically acceptable composition for treating or
ameliorating a dermatological disorder or disease, wherein said
composition comprises a pharmaceutically acceptable excipient and
at least one component selected from the group consisting of: (a) a
metered amount of a volatile anesthetic dissolved in a solution in
an amount effective to treat said dermatological disorder or
disease, wherein said solution further comprises at least one
extractive solvent in an amount effective to reduce volatility of
said volatile anesthetic, wherein said solution is a component of
an emulsion; (b) a metered amount of a liposome suspension
comprising a volatile anesthetic in an amount effective to treat
said dermatological disorder or disease; (c) a metered amount of a
volatile anesthetic dissolved in a solution in an amount effective
to treat said dermatological disorder or disease, wherein said
solution further comprises at least one extractive solvent in an
amount effective to reduce volatility of said volatile anesthetic,
wherein said composition further comprises a solubilizing agent;
(d) a metered amount of a micro-droplet suspension, wherein said
micro-droplet suspension comprises a sphere of a volatile
anesthetic in an amount effective to treat said dermatological
disorder or disease, wherein said sphere is surrounded by a
stabilizing layer of a phospholipid; and any combinations
thereof.
2. The composition of claim 1, wherein said at least one extractive
solvent is selected from the group consisting of dimethyl sulfoxide
(DMSO), N-methyl-2-pyrrolidone (NMP), dimethylformamide,
dimethylacetamide, dimethylisosorbide, ethanol, propanol, PEG-400,
PEG-300, diethylene glycol monoethyl ether, isopropanol, and any
combinations thereof.
3. The composition of claim 1, wherein said composition is
formulated for an administration route selected from the group
consisting of topical, transdermal, mucosal, rectal, vaginal, and
any combinations thereof.
4. The composition of claim 1, wherein said volatile anesthetic is
selected from the group consisting of isoflurane, halothane,
enflurane, sevoflurane, desflurane, methoxyflurane, xenon and any
mixtures thereof.
5. The composition of claim 1, wherein said dermatological disorder
or disease is selected from the group consisting of eczema,
dermatitis, psoriasis, itching, urticaria, allodynia, dry skin,
sunburn, topical bacterial infections, topical fungal infections,
hidradenitis suppurativa, scab healing, scar growth, development or
emergence of moles, pimples, ingrown hair, punctate palmoplantar
keratoderma, dandruff and any combinations thereof.
6-10. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application is a continuation of, and claims
priority to, U.S. patent application Ser. No. 15/979,056, filed May
14, 2018, now allowed, which is a continuation of, and claims
priority to, U.S. patent application Ser. No. 14/129,017, filed
Feb. 26, 2014, now issued as U.S. Pat. No. 9,968,540, which is the
U.S. national phase application filed under 35 U.S.C. .sctn. 371
claiming priority to International Patent Application No.
PCT/US2012/043493, filed Jun. 21, 2012, which claims priority
pursuant to 35 U.S.C. .sctn. 119(e) to U.S. Provisional Application
No. 61/500,909, filed Jun. 24, 2011, all of which applications are
hereby incorporated by reference herein in their entireties.
BACKGROUND OF THE INVENTION
[0002] Skin is the soft outer covering of animals. In mammals, the
skin is the largest organ of the integumentary system and is made
up of multiple layers of ectodermal tissue. Because it interfaces
with the environment, the skin has the important function of
protecting the underlying muscles, bones, ligaments and internal
organs from outside contact or injury. The skin further plays a key
role in protecting the body against pathogens and excessive water
loss. Among the skin's other functions are thermal insulation and
regulation, gas absorption, sensation (the skin contains nerve
endings that respond to heat and cold, touch, pressure, vibration,
and tissue injury), and synthesis of vitamin D folates.
[0003] The skin may be affected by disorders or diseases that are
diverse in terms of cause, presentation and/or treatment. Among the
most common skin disorders or diseases are dermatitis/eczema,
psoriasis and itching.
[0004] Dermatitis is generally caused by an allergic reaction to
specific allergens. The term "dermatitis" is often used
interchangeably with the term "eczema," which is also called
dermatitis eczema or eczematous dermatitis. Dermatitis comprises
conditions such as: contact dermatitis (caused by an allergen or an
irritating substance); atopic dermatitis; dermatitis herpetiformis
(which appears as a result of celiac disease); seborrheic
dermatitis; nummular dermatitis (which tends to appear more
frequently in middle-aged people); stasis dermatitis (an
inflammation on the lower legs which is caused by buildups of blood
and fluid and more likely to occur in people with varicose); and
perioral dermatitis (which is similar to rosacea and often observed
in women between 20 and 60 years old).
[0005] Dermatitis symptoms range from skin rashes to bumpy rashes,
including blisters. Although every type of dermatitis has different
symptoms, there are presentations that are common for all of them,
including redness of the skin, swelling, itching, skin lesions and
sometimes oozing and scarring. Also, the area of the skin on which
the symptoms appear may be different with each type of dermatitis.
The symptoms of contact dermatitis usually appear at the site where
the allergen got into contact with the skin. Although the symptoms
of atopic dermatitis vary from person to person, the most common
symptoms are dry, itchy, red skin. Typically affected skin areas
include the folds of the arms, the back of the knees, wrists, face
and hands. Less commonly there may be cracks behind the ears, and
various other rashes on any part of the body.
http://en.wikipedia.org/wiki/Dermatitis-cite_note-5 Itching is the
primary symptoms of this condition.
[0006] Treatment of dermatitis is made accordingly with the
particular cause of the disease. Application of corticosteroidal
creams or wet compresses and avoidance of allergens and irritants
are part of most treatment plans. For some types of dermatitis,
non-steroidal medications and occasional use of over-the-counter
antihistamines may help relieve signs and symptoms.
[0007] Psoriasis is a chronic immune-mediated skin disease that
appears when the immune system sends out faulty signals that speed
up the growth cycle of skin cells. Psoriasis is not contagious and
is commonly seen as red and white hues of scaly patches (plaques)
appearing on the top first layer of the epidermis. Some patients,
though, have no dermatological symptoms. Plaques frequently occur
on the skin of the elbows and knees, but can affect any area,
including the scalp, palms of hands and soles of feet, and
genitals. In contrast to eczema, psoriasis is more likely to be
found on the outer side of the joint.
[0008] Psoriasis is a chronic recurring condition that varies in
severity from minor localized patches to complete body coverage.
Fingernails and toenails are frequently affected (psoriatic nail
dystrophy) and can be seen as an isolated symptom. Psoriasis can
also cause inflammation of the joints, which is known as psoriatic
arthritis. Between 10% and 40% of all people with psoriasis have
psoriatic arthritis.
[0009] The cause of psoriasis is not fully understood, but it is
believed to have a genetic component and local psoriatic changes
can be triggered by an injury to the skin. Various environmental
factors have been suggested as aggravating to psoriasis, including
stress and withdrawal of systemic corticosteroid. There are
treatments available (such as topical agents, phototherapy, and
systemic agents, such as methotrexate, cyclosporine and retinoids)
but psoriasis treatment is challenging because of the chronic
recurrent nature of the disease.
[0010] Itching is a sensation that causes the desire or reflex to
scratch. The behavioral response patterns of pain and itching are
intrinsically different: pain creates a withdrawal reflex, while
itch leads to a scratch reflex. Unmyelinated nerve fibers for itch
and pain both originate in the skin; however, information for them
is conveyed centrally in two distinct systems that both use the
same peripheral nerve bundle and spinothalamic tract. Itching may
be triggered by infections and infestations, environmental and
allergic triggers, dermatological disorders (such as dry skin,
psoriasis, eczema, sunburn, topical fungal infections (such as but
not limited to athlete's foot, ringworm, and onychomycosis),
hidradenitis suppurativa, scab healing, scar growth, development or
emergence of moles, pimples and ingrown hairs from below the
epidermis, punctate palmoplantar keratoderma and dandruff), medical
disorders (malignancy or internal cancer such as lymphoma and
Hodgkin's disease), jaundice and cholestasis, polycythemia, thyroid
illness, hyperparathyroidism, uraemia, diabetes mellitus, iron
deficiency anemia, menopause or changes in hormonal balances
associated with aging), medication (morphine and other opiates,
chloroquine) and conditions related to pregnancy (intrahepatic
cholestasis of pregnancy, pruritic urticarial papules and plaques
of pregnancy (PUPPP) and gestational pemphigoid).
[0011] Itching is often treated with over-the-counter and
prescription anti-itch drugs, such as antihistamines (such as
diphenhydramine), corticosteroids (such as hydrocortisone topical
cream), counterirritants (such as mint oil, menthol, or camphor),
and crotamiton. Phototherapy is helpful for severe itching,
especially if caused by renal failure.
[0012] Volatile anesthetics have been used safely for decades as
general anesthetics. Recently, volatile anesthetics have been shown
to be useful in the treatment of pain by administration routes
rather than inhalation. For example, International Application
Publication No. WO 2009/094460 discloses compositions and methods
useful for reducing pain in a subject in need thereof by delivering
a volatile anesthetic in a solution or an emulsion to the subject.
Besides producing analgesia, volatile anesthetics affect other
receptors and have been shown to have anti-inflammatory and muscle
relaxing properties. For example, International Application
Publication No. WO 2010/129686 discloses compositions and methods
useful for treating inflammation or a wound in a subject in need of
such wound treatment or inflammation treatment by delivering a
volatile anesthetic to the wound or the inflammation site. Volatile
anesthetics have been further shown to reduce cytokine production
and release in both in vivo and in vitro inflammation model, and
downregulate lipopolysaccharide (LPS)-induced production of
pro-inflammatory cytokines. Additionally, volatile anesthetics have
been shown to inhibit neutrophil function and decrease time to
resolution of inflammation. However, volatile anesthetics have not
been so far successfully used in the treatment of skin disorders or
diseases.
[0013] There is a need in the art for improved formulations that
may be used in the treatment of dermatological disorders or
diseases. There is also a need in the art for improved methods for
treating dermatological disorders or diseases. The current
invention fulfills these needs.
BRIEF SUMMARY OF THE INVENTION
[0014] The invention includes a pharmaceutically acceptable
composition for treating a dermatological disorder or disease. The
composition comprises a pharmaceutically acceptable excipient and
at least one component selected from the group consisting of: (a) a
metered amount of a volatile anesthetic dissolved in a solution in
an amount effective to treat the dermatological disorder or
disease, wherein the solution further comprises at least one
extractive solvent in an amount effective to reduce volatility of
the volatile anesthetic, wherein the solution is a component of an
emulsion; (b) a metered amount of a liposome suspension comprising
a volatile anesthetic in an amount effective to treat the
dermatological disorder or disease; (c) a metered amount of a
volatile anesthetic dissolved in a solution in an amount effective
to treat the dermatological disorder or disease, wherein the
solution further comprises at least one extractive solvent in an
amount effective to reduce volatility of the volatile anesthetic,
wherein the composition further comprises a solubilizing agent; (d)
a metered amount of a micro-droplet suspension, wherein the
micro-droplet suspension comprises a sphere of a volatile
anesthetic in an amount effective to treat the dermatological
disorder or disease, wherein the sphere is surrounded by a
stabilizing layer of a phospholipid; and any combinations
thereof.
[0015] In one embodiment, the at least one extractive solvent is
selected from the group consisting of dimethyl sulfoxide (DMSO),
N-methyl-2-pyrrolidone (NMP), dimethylformamide, dimethylacetamide,
dimethylisosorbide, ethanol, propanol, PEG-400, PEG-300, diethylene
glycol monoethyl ether, isopropanol and any combinations thereof.
In another embodiment, the composition is formulated for an
administration route selected from the group consisting of topical,
transdermal, mucosal, rectal, vaginal and any combinations thereof.
In yet another embodiment, the volatile anesthetic is selected from
the group consisting of isoflurane, halothane, enflurane,
sevoflurane, desflurane, methoxyflurane, xenon and any mixtures
thereof. In yet another embodiment, the dermatological disorder or
disease is selected from the group consisting of eczema,
dermatitis, psoriasis, itching, urticaria, allodynia, dry skin,
sunburn, topical bacterial infections, topical fungal infections,
hidradenitis suppurativa, scab healing, scar growth, development or
emergence of moles, pimples, ingrown hair, punctate palmoplantar
keratoderma, dandruff and any combinations thereof.
[0016] The invention also includes a method of treating a
dermatological disorder or disease in a subject in need thereof.
The method comprises administering to the subject a
pharmaceutically acceptable composition, wherein the composition
comprises a pharmaceutically acceptable excipient and at least one
component selected from the group consisting of: (a) a metered
amount of a volatile anesthetic dissolved in a solution in an
amount effective to treat the dermatological disorder or disease,
wherein the solution further comprises at least one extractive
solvent in an amount effective to reduce volatility of the volatile
anesthetic, wherein the solution is a component of an emulsion; (b)
a metered amount of a liposome suspension comprising a volatile
anesthetic in an amount effective to treat the dermatological
disorder or disease; (c) a metered amount of a volatile anesthetic
dissolved in a solution in an amount effective to treat the
dermatological disorder or disease, wherein the solution further
comprises at least one extractive solvent in an amount effective to
reduce volatility of the volatile anesthetic, wherein the
composition further comprises a solubilizing agent; (d) a metered
amount of a micro-droplet suspension, wherein the micro-droplet
suspension comprises a sphere of a volatile anesthetic in an amount
effective to treat the dermatological disorder or disease, wherein
the sphere is surrounded by a stabilizing layer of a phospholipid;
and any combinations thereof.
[0017] In one embodiment, the at least one extractive solvent is
selected from the group consisting of dimethyl sulfoxide (DMSO),
N-methyl-2-pyrrolidone (NMP), dimethylformamide, dimethylacetamide,
dimethylisosorbide, ethanol, propanol, PEG-400, PEG-300, diethylene
glycol monoethyl ether, isopropanol and any combinations thereof.
In another embodiment, the administering is performed by a route
selected from the group consisting of topical, transdermal,
mucosal, rectal, vaginal and any combinations thereof. In yet
another embodiment, the volatile anesthetic is selected from the
group consisting of isoflurane, halothane, enflurane, sevoflurane,
desflurane, methoxyflurane, xenon and any mixtures thereof. In yet
another embodiment, the dermatological disorder or disease is
selected from the group consisting of eczema, dermatitis,
psoriasis, itching, urticaria, allodynia, dry skin, sunburn,
topical bacterial infections, topical fungal infections,
hidradenitis suppurativa, scab healing, scar growth, development or
emergence of moles, pimples, ingrown hair, punctate palmoplantar
keratoderma, dandruff and any combinations thereof.
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 illustrates a flowchart representing general methods
for making compositions for the delivery of a formulated volatile
anesthetic to the affected area of a subject.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present invention relates to the unexpected discovery
that the compositions and methods of the invention are useful to
treat, ameliorate or prevent a dermatological disorder or disease,
such as but not limited to eczema, psoriasis and itching. In one
embodiment, the itching is associated with pain. In another
embodiment, the itching is not associated with pain.
Definitions
[0021] As used herein, each of the following terms has the meaning
associated with it in this section.
[0022] Unless defined otherwise, all technical and scientific terms
used herein generally have the same meaning as commonly understood
by one of ordinary skill in the art to which this invention
belongs. Generally, the nomenclature used herein and the laboratory
procedures in cell culture, molecular genetics, organic chemistry,
and peptide chemistry are those well-known and commonly employed in
the art.
[0023] 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.
[0024] As used herein, the term "about" will be understood by
persons of ordinary skill in the art and will vary to some extent
on the context in which it is used. As used herein when referring
to a measurable value such as an amount, a temporal duration, and
the like, the term "about" is meant to encompass variations of
.+-.20% or .+-.10%, more preferably .+-.5%, even more preferably
.+-.1%, and still more preferably .+-.0.1% from the specified
value, as such variations are appropriate to perform the disclosed
methods.
[0025] 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."
[0026] The terms "inhibiting," "reducing," "preventing,"
"diminishing," and variations of these terms, as used herein
include any measurable decrease, including complete or
substantially complete inhibition.
[0027] The term "effective," as that term is used in the
specification and/or claims, means adequate to accomplish a
desired, expected, or intended result.
[0028] The phrase "extractive solvent," as used herein, refers to a
solvent that may interact with a volatile anesthetic in solution to
reduce the volatility of the volatile anesthetic without chemically
reacting to the volatile anesthetic, and/or enhances permeability
of volatile anesthetic into the tissue of interest, favoring either
achievement or enhancement of an intended pharmacological outcome.
Extractive solvents also comprise compounds that do not necessarily
extract, including vehicles and functional components that may
affect properties such as, but not limited to, permeability or
penetration.
[0029] As used herein, the term "enhanced permeability" refers to
increase in (a) amount of volatile anesthetic delivered to the
tissue of interest and/or (b) rate of delivery (i.e., rapid
delivery) to the tissue of interest and/or (c) residence time of
volatile anesthetic in the tissue of interest. Increase in
residence time refers to a delay in elimination of volatile
anesthetic from tissue of interest.
[0030] 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.
[0031] As used herein, the term "dermatological disorder or
disease" refers to a condition associated with the skin. Examples
of these disorders or diseases include, but are not limited to,
eczema, dermatitis, psoriasis, itching, urticaria, dry skin,
sunburn, topical bacterial infections (such as but not limited to
impetigo, folliculitis, furunculosis, carbunculosis, ecthyma,
erysipelas, cellulitis and necrotizing fasciitis), topical fungal
infections (such as but not limited to athlete's foot, toe fungus,
tinea corporis, tinea cruris, tinea faciei, tinea manuum, tinea
pedis, any other form of ringworm, and onychomycosis), hidradenitis
suppurativa, scab healing, scar growth, development or emergence of
moles, pimples, ingrown hair, punctate palmoplantar keratoderma and
dandruff. Itching may be associated with one or more of these
dermatological disorders or diseases, as well as allodynia,
malignancy or internal cancer such as lymphoma and Hodgkin's
disease, jaundice, cholestasis, polycythemia, thyroid illness,
hyperparathyroidism, uraemia, diabetes mellitus, iron deficiency
anemia, menopause or changes in hormonal balances associated with
aging, use of morphine and other opiates, use of chloroquine, and
conditions related to pregnancy (intrahepatic cholestasis of
pregnancy, pruritic urticarial papules and plaques of pregnancy
(PUPPP) and gestational pemphigoid).
[0032] As used herein, the term "allodynia" refers to a form of
pain due to a stimulus which does not normally provoke pain.
Allodynia may be either thermal or mechanical in origin, and often
occurs after injury to a site. Allodynia is distinct from
hyperalgesia, an extreme reaction to a stimulus that is normally
painful. There are different kinds or types of allodynia:
mechanical allodynia (also known as tactile allodynia), which
includes atatic mechanical allodynia (pain in response to light
touch/pressure) and dynamic mechanical allodynia (pain in response
to brushing); and thermal (hot or cold) allodynia (pain from
normally mild skin temperatures in the affected area).
[0033] The term "topical," as used herein, refers to the
administration of the compositions of the invention to the skin and
underlying tissues, as well as to administration to the mucosa and
underlying tissues.
[0034] The term "treat" or "treatment," as used herein, refers to
the alleviation (i.e., "diminution") and/or the elimination of a
sign/symptom or a source of a sign/symptom. By way of several
non-limiting examples, a dermatological disorder or disease may be
treated by alleviating or eliminating a sign/symptom of the
dermatological disorder or disease. By way of a further example, a
dermatological disorder or disease may be treated by aiding (e.g.,
accelerating) the healing process of the dermatological disorder or
disease.
[0035] As used herein, "additional ingredients" include, but are
not limited to, one or more of the following: excipients; surface
active agents; dispersing agents; inert diluents; granulating and
disintegrating agents; binding agents; lubricating agents;
sweetening agents; flavoring agents; coloring agents;
preservatives; physiologically degradable compositions such as
gelatin; aqueous vehicles and solvents; oily vehicles and solvents;
suspending agents; dispersing or wetting agents; emulsifying
agents; demulcents; buffers; salts; thickening agents; fillers;
emulsifying agents; antioxidants; antibiotics; antifungal agents;
stabilizing agents; and pharmaceutically acceptable polymeric or
hydrophobic materials. Other "additional ingredients" that may be
included in the pharmaceutical compositions used in the practice of
the invention are known in the art and described, for example in
Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing
Co., 1985, Easton, Pa.), which is incorporated herein by
reference.
Description
[0036] The invention includes a pharmaceutically acceptable
composition comprising a metered amount of a volatile anesthetic
dissolved in an aqueous solution in an amount effective to treat,
ameliorate or prevent a dermatological disorder or disease, wherein
the solution further comprises at least one extractive solvent in
an amount effective to reduce volatility of the volatile
anesthetic, wherein the solution is a component of an emulsion,
wherein the composition further comprises a pharmaceutically
acceptable excipient.
[0037] The invention further includes a pharmaceutically acceptable
composition comprising a metered amount of a volatile anesthetic
emulsion.
[0038] The invention also includes a pharmaceutically acceptable
composition comprising a metered amount of a volatile anesthetic
dissolved in a solution in an amount effective to treat, ameliorate
or prevent a dermatological disorder or disease, wherein the
solution further comprises at least one extractive solvent in an
amount effective to reduce volatility of the volatile anesthetic,
wherein the composition further comprises a solubilizing agent,
wherein the composition further comprises a pharmaceutically
acceptable excipient.
[0039] The invention further includes a pharmaceutically acceptable
composition comprising a metered amount of a micro-droplet
suspension, wherein the micro-droplet suspension comprises a sphere
of a volatile anesthetic surrounded by a stabilizing layer of a
phospholipid, wherein the composition further comprises a
pharmaceutically acceptable excipient.
[0040] The invention also included a pharmaceutically acceptable
composition comprising a metered amount of a volatile anesthetic
dissolved in an aqueous solution in an amount effective treat,
ameliorate or prevent a dermatological disorder or disease, wherein
the solution is a component of an emulsion, wherein the composition
further comprises a pharmaceutically acceptable excipient.
[0041] In one embodiment, the at least one extractive solvent is
selected from the group consisting of dimethyl sulfoxide (DMSO),
N-methyl-2-pyrrolidone (NMP), dimethylformamide, dimethylacetamide,
dimethylisosorbide, ethanol, propanol, PEG-400, PEG-300, diethylene
glycol monoethyl ether, isopropanol, and mixtures thereof.
Preferably, the at least one extractive solvent comprises from
about 0.1% to about 75% of the solution.
[0042] In one embodiment, the solution is sterile. This may be
achieved by ensuring that all starting materials are sterile and
maintaining them under sterile conditions prior to administration.
This may also be achieved by incorporation of an antimicrobial
filter as has been done with various types of infusions (see, for
example, U.S. Pat. No. 5,695,490).
[0043] In one embodiment, the composition is formulated for an
administration by a route selected from the group consisting of
topical, transdermal, mucosal, rectal, and vaginal.
[0044] In one embodiment, the volatile anesthetic is selected from
the group consisting of isoflurane, halothane, enflurane,
sevoflurane, desflurane, methoxyflurane, xenon and mixtures
thereof. In another embodiment, the volatile anesthetic is
isoflurane. Many of these agents are racemic mixtures. In some
embodiments, the racemic mixtures are used. In other embodiments,
only the d-isomer or the 1-isomer of an agent is used (for
examples, see U.S. Pat. Nos. 5,114,715; 5,114,714 and 5,283,372).
In yet another embodiment, the solution may comprise from about 1%
to about 99% v/v, from about 5% to about 70% v/v, or about 50% v/v,
or about 25% v/v, or about 10% v/v volatile anesthetic in
solution.
[0045] In one embodiment, the emulsion comprises a lipid. In
another embodiment, the lipid comprises an agent selected from the
group consisting of soybean oil, olive oil, peanut oil, castor oil,
corn oil and sesame oil. The emulsion may further comprise an
emulsifier.
[0046] In one embodiment, the volatile anesthetic is in the form of
a suspension, a cream, a paste, an oil, a lotion, a gel, a foam, a
hydrogel, an ointment, a liposome, an emulsion, a liquid crystal
emulsion, or a nano-emulsion.
[0047] In one embodiment, the composition further comprises an
antibiotic.
[0048] In one embodiment, the solution comprises at least one
constituent selected from the group consisting of water and a
saline solution.
[0049] In one embodiment, the diameter of the microdroplet ranges
from about 200 Angstroms up to about 10,000 Angstroms. In another
embodiment, the micro-droplets are produced by sonication,
homogenization, microfluidization or other processes involving high
shear, wherein the ratio of the volume of the volatile anesthetic
to the weight of the phospholipid layer is at least 1.0 ml/g and
the composition contains at least 3% w/v of the volatile
anesthetic.
[0050] The invention further includes a method of treating,
ameliorating or preventing a dermatological disorder or disease in
a subject in need thereof, wherein the method comprises
administering to the subject a volatile anesthetic dissolved in a
solution in an amount effective to treat, ameliorate or prevent the
dermatological disorder or disease, wherein the solution further
comprises at least one extractive solvent in an amount effective to
reduce volatility of the volatile anesthetic, wherein the solution
is a component of an emulsion, wherein the route of administration
is selected from the group consisting of topical, transdermal,
mucosal, rectal, and vaginal.
[0051] The invention also includes a method of treating,
ameliorating or preventing a dermatological disorder or disease in
a subject in need thereof, wherein the method comprises
administering to the wound of the subject a volatile anesthetic
dissolved in a solution in an amount effective to treat, ameliorate
or prevent the dermatological disorder or disease, wherein the
solution further comprises at least one extractive solvent in an
amount effective to reduce volatility of the volatile anesthetic,
wherein the composition further comprises a solubilizing agent,
wherein the administration route is selected from the group
consisting of topical, transdermal, mucosal, rectal, and
vaginal.
[0052] The invention further includes a method of treating,
ameliorating or preventing a dermatological disorder or disease in
a subject in need thereof, wherein the method comprises
administering to the subject a volatile anesthetic dissolved in a
solution in an amount effective to treat, ameliorate or prevent the
dermatological disorder or disease, wherein the solution is a
component of an emulsion, wherein the administration route is
selected from the group consisting of topical, transdermal,
mucosal, rectal, and vaginal.
[0053] The invention also includes a method of treating,
ameliorating or preventing a dermatological disorder or disease in
a subject in need thereof, wherein the method comprises
administering to the subject a liposome suspension comprising a
volatile anesthetic in an amount effective to treat, ameliorate or
prevent the dermatological disorder or disease, wherein the
administration route is selected from the group consisting of
topical, transdermal, mucosal, rectal, and vaginal.
[0054] The invention further includes a method of treating,
ameliorating or preventing a dermatological disorder or disease in
a subject in need thereof, the method comprising administering to
the subject a micro-droplet suspension comprising a sphere of a
volatile anesthetic surrounded by a stabilizing layer of a
phospholipid in an amount effective to treat, ameliorate or prevent
the dermatological disorder or disease, wherein the administration
route is selected from the group consisting of topical,
transdermal, mucosal, rectal, and vaginal.
[0055] In one embodiment, the dermatological disorder or disease is
selected from the group consisting of eczema, dermatitis,
psoriasis, itching, urticaria, allodynia, dry skin, sunburn,
topical bacterial infections (such as but not limited to impetigo,
folliculitis, furunculosis, carbunculosis, ecthyma, erysipelas,
cellulitis and necrotizing fasciitis), topical fungal infections
(such as but not limited to athlete's foot, tinea faciei, any other
form of ringworm, and onychomycosis), hidradenitis suppurativa,
scab healing, scar growth, development or emergence of moles,
pimples, ingrown hair, punctate palmoplantar keratoderma and
dandruff. In another embodiment, itching may be associated with a
condition selected from the group consisting of eczema, dermatitis,
psoriasis, urticaria, dry skin, sunburn, topical bacterial
infections, topical fungal infections (such as but not limited to
athlete's foot, tinea faciei, any other form of ringworm, and
onychomycosis), hidradenitis suppurativa, scab healing, scar
growth, development or emergence of moles, pimples, ingrown hair,
punctate palmoplantar keratoderma, dandruff, malignancy or internal
cancer such as lymphoma and Hodgkin's disease, jaundice,
cholestasis, polycythemia, thyroid illness, hyperparathyroidism,
uraemia, diabetes mellitus, iron deficiency anemia, menopause or
changes in hormonal balances associated with aging, use of morphine
and other opiates, use of chloroquine, and conditions related to
pregnancy (intrahepatic cholestasis of pregnancy, pruritic
urticarial papules and plaques of pregnancy (PUPPP) and gestational
pemphigoid).
[0056] In a non-limiting aspect, the presence of an extractive
solvent in the composition of the invention comprising the volatile
anesthetic may provide substantial advantages, including improving
the physical characteristics, pharmacological properties, and/or
the ease of use of the composition. The extractive solvent may
interact with the volatile anesthetic (in a non-limiting example,
isoflurane) in a non-azeotropic fashion to effectively reduce
vaporization or evaporation of the volatile anesthetic. This effect
of reducing volatility may be referred to as volatility attenuating
effect (VAE). In this way, the shelf-life, durability, and/or ease
of use of a volatile anesthetic composition may be improved.
[0057] In a non-limiting aspect, the pharmacokinetics of the
volatile anesthetic may be altered by the presence of an extractive
solvent. For example, without wishing to be bound by any theory,
the extractive solvent may function in certain embodiments as a
reservoir for the volatile anesthetic such that the amount of
volatile anesthetic retained and/or the duration of retention is
enhanced as compared to the application of pure non-formulated
volatile anesthetic. Hence an extractive solvent renders delivery
of the volatile anesthetic to a particular site of action more
effective. Similarly, in one embodiment where the volatile
anesthetic composition contains an extractive solvent, the
extractive solvent may facilitate absorption, in terms of rate
and/or extent, of the volatile anesthetic into the site of action.
Additionally, presence of an extractive solvent may have additive
or synergistic contributions to the volatility attenuation effect
(VAE) rendered by the vehicle. In this aspect, the formulation may
facilitate retention of the volatile anesthetic, which otherwise
would be prone to rapidly escape from the site of action due to its
highly volatile nature, even at room temperature.
[0058] In a non-limiting aspect, when the formulation 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. In yet another non-limiting aspect, the delivery of the
volatile anesthetic may be tailored as a sustained release. This
may eliminate or reduce the need for repeated dosing, and/or allow
the achievement of the desired steady-state drug levels. Reduced
volatility of the volatile anesthetic in composition may also
improve the ease of handling the volatile anesthetic compositions.
This may facilitate manufacturing and packaging the compositions of
the invention. This may also avoid the possibility of inhalation of
the volatile anesthetic by the patient, health care provider or
packaging facility worker. Further, the reduced vaporization of a
volatile anesthetic in solution due to the presence of an
extractive solvent may also reduce any potential concerns of a
possible risk of fire and/or exposure at the medical facility.
[0059] In a non-limiting embodiment, when administered topically to
an affected area, it is desirable to achieve a clinically effective
concentration, which in some, but not necessarily all, cases may
range, for example, from about 5 .mu.g/mL to about 2,000,000
.mu.g/mL of active agent in a formulation. In another non-limiting
embodiment, in topical administration it is desirable to achieve a
clinically effective concentration, which in some, but not
necessarily all, cases may range, for example, from about 2 .mu.L
to about 50 .mu.L of solution per centimeter square of area of
application.
[0060] The invention further includes a sealed container comprising
a volatile anesthetic solution of the present invention. The
interior of the container may be sterile. The container may be, for
example, a syringe, a plastic bag, a collapsible plastic bag, a
glass bottle, a glass ampoule or a plastic bottle. The container
may be itself a skin dressing or part of a skin dressing. In
another aspect of present invention, a container that offers many
advantages, such as, for example, ease of application, unit dose
configuration, and excellent container-closure compatibility
profile, is contemplated. This container may be such that the
volatile anesthetic solution is contained in a crushable sealed
ampoule. The ampoule is in turn enclosed in protective covering on
which pressure is applied to crush the ampoule, which then releases
volatile anesthetic solution for percolation through a flint-type
tip which capped the ampoule in protective covering. When such
packaging configuration is employed, care is taken to leave as
little as possible or ideally no headspace in ampoule for the
volatile anesthetic to escape and cause a change in solution
composition over a period of shelf life.
Extractive Solvents
[0061] 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 that may interact
with a volatile anesthetic in the compositions of the invention to
reduce the volatility of the volatile anesthetic without chemically
reacting with the anesthetic. This phrase also includes compounds
that do not necessarily extract, including vehicles and functional
components, which may affect properties such as, but not limited
to, permeability or penetration.
[0062] 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, or mixtures thereof, 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. Extractive solvents are
also expected to attenuate volatility of volatile anesthetics such
that the time required for a given amount of anesthetic to escape
from a given surface at a given temperature is increased, resulting
in appreciable increase in time of contact of volatile anesthetic
with the site of application before complete evaporation of
unabsorbed portion, as compared with the application of pure
volatile anesthetic under similar conditions. In another
embodiment, formulations of current invention may contain an
extractive solvent such that this extractive solvent enhances
permeability of volatile anesthetic into the tissue of interest
thus favoring either achievement of or enhancement of an intended
pharmacological outcome. By way of example, but not limitation, the
tissue of interest described above may be skin or any other tissue
involved or believed to be involved, directly or indirectly, in the
intended pharmacological outcome. Enhanced permeability, as it
applies to current invention, refers to increase in: (a) amount of
volatile anesthetic delivered to the tissue of interest, and/or (b)
rate of delivery (i.e., rapid delivery) to the tissue of interest,
and/or (c) residence time of volatile anesthetic in the tissue of
interest. Increase in residence time refers to a delay in
elimination of volatile anesthetic from tissue of interest.
[0063] As described below by chemical class as well as individual
examples, various extractive solvents are envisioned for use with
the present invention. The chemical classes contemplated in this
invention comprise fatty alcohols, fatty acids, fatty amines, fatty
acid esters, polyols, terpenes, esters, ethers, alkoxylated amides,
poly propylene glycol ethers, polyethylene glycols, poly propylene
glycols and poly propylene glycol ethers. Selected examples of
individual ingredients contemplated in current invention comprise
of polyethylene glycol 400, polyethylene glycol 300, diethylene
glycol monoethyl ether, Labrasol, oleoyl macrogolglycerides
(Labrafil M 1944), linoleoyl macrogolglycerides (Labrafil M2125),
lauroyl macrogoglycerides (Labrafil M 2130), propylene glycol
dicaprylocaprate, propylene glycol monocaprylate (Capryol 90,
Capryol PGMC), polypropylene glycol monolaurate (Lauroglycol 90,
Lauroglycol FCC), polyglyceryl-3-dioleate, Peceol, isostearyl
isostearate, propylene glycol dipelargonate, polyglyceryl-3
dioleate, propylene glycol dipelargonate, octyldodecyl myristate,
diethyl sebacate, diisopropyl adipate, ethyl oleate, glyceryl
isostearate, isopropyl isostearate, isopropyl myristate, isostearyl
alcohol, isostearic acid, oleyl alcohol, eicosapentanenoic acid,
docosahexaenoic acid, olive oil, peanut oil, soybean oil, castor
oil, corn oil, cottonseed oil, peppermint oil, safflower oil,
sesame oil, soybean oil, hydrogenated soybean oil, hydrogenated
vegetable oil, medium chain triglycerides coconut oil, palm oil,
liquid lanolin, DMSO, NMP, and the like.
[0064] 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 is 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 select a concentration of
an extractive solvent that 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.
[0065] Including an extractive solvent in an anesthetic composition
may increase the ease with which one may mix the solution prior to
administration. For example, in certain embodiments, mixing prior
to administration may be desirable if final formulation is selected
to be self-emulsifying drug delivery system (SEDDS). 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 a
volatile anesthetic composition according to the present invention.
The reduction in the bulk associated with the presence of a
sonicator may 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 may improve mobility since the patient is not
required to additionally move a sonicator. In certain embodiments,
sonication of the anesthetic solution prior to administration is
required when an extractive solvent is included in the volatile
anesthetic composition.
[0066] 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, for
example, for reating, ameliorating or preventing a dermatological
disorder or disease.
[0067] 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.
[0068] 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.
[0069] 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.
[0070] In certain embodiments, the extractive solvent is
polyethylene glycol 400 (PEG 400) or polyethylene glycol 300 (PEG
300). In other embodiments, vehicle is olive oil or peanut oil or
liquid lanolin or diethylene glycol monoethyl ether.
[0071] In certain embodiments, the extractive solvent is diethylene
glycol monoethyl ether. In other embodiments, functional component
is ethyl oleate, glyceryl isostearate, isopropyl isostearate,
isopropyl myristate, isostearyl alcohol, isostearic acid or oleyl
alcohol.
[0072] 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.
[0073] Other extractive solvents include PEG-400, PEG-300, and
diethylene glycol monoethyl ether.
[0074] 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
irritation or neuron death occurs as a result of injection of the
solution near a nerve.
[0075] A single extractive solvent, or multiple extractive
solvents, may be present in an anesthetic composition of the
present invention. For example, in certain embodiments, only a
single extractive solvent (e.g., DMSO, NMP or PEG 400) is present
in a composition comprising a volatile anesthetic. In other
embodiments, two, three, four 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 an anesthetic composition of the present
invention; in other embodiments, two, three, four or more volatile
anesthetics may be present in an anesthetic composition of the
present invention. In certain embodiments, only a single extractive
solvent (e.g., diethylene glycol monoethyl ether) is present in an
anesthetic composition of the present invention. In other
embodiments, two, three, four or more extractive solvents may be
present in an anesthetic composition of the present invention.
N-Methyl pyrrolidone:
[0076] N-methyl-2-pyrrolidone (NMP) is a solvent that 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.
[0077] 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.
[0078] 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, transdermal 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).
Dimethyl Sulfoxide (DMSO):
[0079] 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 non-polar compounds and is miscible in a wide range
of organic solvents as well as water.
[0080] DMSO is a relatively non-toxic compound, which makes it
particularly suitable for use as a solvent within the present
invention. The relative lack of toxicity of DMSO is well
established, and the potential use of DMSO for medical purposes was
established by 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.
[0081] 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 rate and/or extent of volatile anesthetic
delivered.
Volatile Anesthetics
[0082] 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 may treat dermatological
disorders or diseases without significant side effects. It may be
desirable, for example, to select a volatile anesthetic 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 may
easily adjust the delivery amount for the dermatological disorder
or disease he or she is experiencing). An active agent gas that
does not produce tolerance (unlike opioids or local volatile
anesthetics) or dependence (like opioids) may also be
desirable.
[0083] 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.
[0084] 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 procedure, such
as transdermally, topically, mucosally, rectally, orally, or
vaginally. Importantly, the gaseous volatile anesthetic is not
administrated by inhalation. Gaseous volatile anesthetics other
than halogenated anesthetics are contemplated, and examples include
xenon, nitrous oxide, cyclopropane, and ether, all of which may 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) may be
delivered in a solution to a subject according to the present
invention.
[0085] 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,
two, three, four 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 volatile anesthetics depending on their physical
and physiological properties. In certain clinical scenarios, a
shorter acting agent may be desirable to treat acute dermatological
disorders or diseases, whereas a longer lasting agent may be more
suited to chronic dermatological disorders or diseases.
Antibiotics
[0086] Antibiotics useful in the compositions and methods of the
invention include known antibiotics, as well as those yet to be
discovered. Non-limiting examples include Amikacin, Aminoglycoside,
Amoxicillin, Ampicillin, Azithromycin, Bacampicillin, Candicidin,
Carbenicillin, Cefaclor, Cefadroxil, Cefamandole, Cefazolin,
Cefdinir, Cefditoren, Cefepime, Cefonicid, Cefoperazone,
Cefotaxime, Cefotetan, Cefoxitin, Cefpodoxime, Cefprozil,
Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime,
Cephalexin, Cephalosporins, Cephapirin, Cephradine, Ciprofloxacin,
Clarithromycin, Clindamycin, Clotrimazole, Cloxacillin,
Crysticillin, Cuprimyxin, Pentids, Permapen, Pfizerpen,
Pfizerpen-AS, Wycillin, Demeclocycline, Dicloxacillin,
Dirithromycin, Doxycycline, Enoxacin, Erythromycin, Flucloxacillin,
Fluoroquinolone, Gatifloxacin, Gemifloxacin, Gentamicin,
Haloprogin, Iodochlorohydroxyquin, Kanamycin, Ketolide,
Levofloxacin, Lipopeptides, Lomefloxacin, Macrolides,
Metronidazole, Mezlocillin, Minocycline, Moxifloxacin, Nafcillin,
Neomycin, Netilmicin, Norfloxacin, Nystatin, Ofloxacin, Oxacillin,
Oxytetracycline, Paromomycin, Penicillin G, Penicillin V,
Penicillins, Piperacillin, Pivampicillin, Pivmecillinam,
Roxithromycin, Sparfloxacin, Streptomycin, Sulfamethizole,
Sulfamethoxazole, Sulfisoxazole, Sulfonamides, Telithromycin,
Tetracyclines, Ticarcillin, Tobramycin, Tolnaftate,
Trimethoprim-Sulfamethoxazole, Trovafloxacin, and Vancomycin.
Emulsions
[0087] As would be understood by one skilled in the art, 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.
[0088] 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 volatile
anesthetic 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
anesthetic. For example, lipid compositions, lipid emulsions,
water-in-oil emulsions, and/or oil-in-water emulsions may be useful
for the transdermal, topical, mucosal, rectal, or vaginal delivery
of the volatile anesthetic compositions of the present invention.
Certain emulsions of isoflurane have been prepared previously for
intravenous (da Silva Telles 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., 2006,
Anesthesiology 105:A743), both for inducing anesthesia.
[0089] 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 of the invention also include, but are not
limited to, liquid crystal emulsions, such as those disclosed, for
example, in U.S. Patent Application Nos. 20070149624 and
20050238677, U.S. Pat. No. 5,183,585 and International Patent
Application No. WO 05108383.
[0090] In certain embodiments, the emulsion of the invention may
have a lipid component. In various embodiments, the lipid component
may 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 may 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..
[0091] In other embodiments, the emulsion further comprises an
emulsifier. An emulsifier is a substance that stabilizes an
emulsion. An emulsifier may also known as an emulgent. An
emulsifier may also be a surfactant. In various embodiments, the
emulsifier may 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.
[0092] In other embodiments, the emulsion of the invention has a
perfluorocarbon component. In various embodiments, the
perfluorocarbon component may 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 Micro-Droplets
[0093] In various embodiments, the volatile anesthetics of the
present invention may 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 non-limiting examples, liposomes may 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
(dioleoylphosphatidyl-ethanolamine). Liposomes may 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) 12:1363-1365;
incorporated herein by reference in its entirety).
[0094] Liposomes are useful as drug carriers or for topical use
(Gehring et al., 1990, Drug Res. 40 (II) 12:1368-1371; 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 may also be injected, and when they are modified with
lipids, their surfaces become more hydrophilic and hence their
ability to persist may 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.
[0095] Liposome compositions of the invention may 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.
[0096] In various embodiments, the volatile anesthetics of the
present invention may also be a component of a microdroplet. A
micro-droplet 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.
[0097] Micro-droplets may 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, micro-droplets may 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.
Micro-droplets may 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. Nos. 4,622,219,
4,725,442, and 5,091,188, Haynes et al. (1989, J. Contr. Rel.
9:1-12) and Haynes et al. (1985, Anesthesiology 63:490-499), all of
which references are incorporated herein in their entirety.
Dosing
[0098] The amount of the volatile anesthetic to be administered
depends on the particular indication desired. For example, the dose
will depend on the type of dermatological disorder or disease
intended to be treated. The dose may be different, for instance, if
the delivery of the volatile anesthetic is intended to reduce a
chronic dermatological disorder or disease as opposed to an acute
dermatological disorder or disease. 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.
[0099] 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 solution. For
example, increases in temperature may increase the solubility, and
thus potency, of the volatile aesthetic 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.
[0100] Volatile anesthetics (for example, halogenated volatile
anesthetic compounds) may be applied in amounts leading to
concentrations in the range of about 250 to about 50,000
nanograms/cm.sup.2 of target site of action, depending on the
volatile anesthetic selected and the desired effect. In certain
embodiments, a halogenated volatile anesthetic or volatile
anesthetic may be administered to achieve a concentration of from
about 5 to about 5,000,000 nanograms/cm.sup.2 of target site of
action. 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/cm.sup.2 of
target site of action are more suitable for treating, ameliorating
or preventing a moderate dermatological disorder or disease, while
higher doses such as from about 10,000 nanogram/cm.sup.2 of target
site of action to about 500,000 nanogram/cm.sup.2 of target site of
action or more are suitable for treating a severe dermatological
disorder or disease. Of course, the doses may be given once (for
example, for a minor single occurrence of dermatological disorder
or disease), repeatedly (for example, for a moderate or chronic
dermatological disorder or disease), or continuously (for example,
for a severe dermatological disorder or disease). Combinations of
these dosing regimes may also be used. For example, a subject
suffering from a severe dermatological disorder or disease may
require continuous dosing with periodic additional dosing.
[0101] In embodiments where an volatile anesthetic (for example, a
volatile anesthetic, 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 a volatile anesthetic, for example,
isoflurane, and the solution may be water, a saline solution,
artificial cerebrospinal fluid (ACSF), or other fluid.
[0102] The dosing and manner of delivery of the compositions of the
invention may be adjusted to treat, ameliorate or prevent a
dermatological disorder or disease, for example, by varying the
amount, concentration, frequency of administration, and timing of
administration.
[0103] The volatile anesthetic solution may also contain one or
more additives, such as a surfactant, PVP, a polymer, 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 sevoflurane, 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.
[0104] In various embodiments, a solution of about 10% volatile
anesthetic, such as isoflurane, may be used; this solution may be
administered as a one-time, continuously, and/or repeatedly to
treat, ameliorate or prevent a dermatological disorder or disease.
A further aspect of the compositions and methods of the invention
for the treatment of a dermatological disorder or disease is the
analgesic activity of the volatile anesthetics. Thus, a 10% v/v
solution of a volatile anesthetic may be used to treat, ameliorate
or prevent a dermatological disorder or disease. Higher
concentrations and/or longer durations of volatile anesthetic may
be used, in various embodiments, as necessary.
Methods of Active Agent Delivery
[0105] Volatile anesthetics of the present invention may be
delivered topically. In some embodiments, specific concentrations
of volatile anesthetics which may be used for topical delivery
include from about 100 to about 500,000 nanogram/cm.sup.2 of target
site of action, from about 100 to about 250,000 nanogram/cm.sup.2
of target site of action, from about 100 to about 100,000
nanogram/cm.sup.2 of target site of action, from about 100 to about
50,000 nanogram/cm.sup.2 of target site of action, from about 100
to about 25,000 nanogram/cm.sup.2 of target site of action, or from
about 100 to about 10,000 nanogram/cm.sup.2 of target site of
action. 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 and/or
the particular characteristics of the patient such as sensitivity
to the volatile anesthetic.
[0106] In some embodiments, specific concentrations of volatile
anesthetics which may be used to treat, ameliorate or prevent a
dermatological disorder or disease include from about 100 to about
500,000 nanogram/cm.sup.2 of target site of action, from about 100
to about 250,000 nanogram/cm.sup.2 of target site of action, from
about 100 to about 100,000 nanogram/cm.sup.2 of target site of
action, from about 100 to about 50,000 nanogram/cm.sup.2 of target
site of action, from about 100 to about 25,000 nanogram/cm.sup.2 of
target site of action, or from about 100 to about 10,000
nanogram/cm.sup.2 of target site of action.
[0107] The pharmaceutical compositions of the invention may be
dispensed to the subject under treatment with the help of an
applicator. The applicator to be used may depend on the specific
medical condition being treated, amount and physical status of the
pharmaceutical composition, and choice of those skilled in the
art.
[0108] The pharmaceutical compositions of the invention may be
provided to the subject or the medical professional in charge of
dispensing the composition to the subject, along with instructional
material. The instructional material includes a publication, a
recording, a diagram, or any other medium of expression, which may
be used to communicate the usefulness of the composition and/or
compound used in the practice of the invention in a kit. The
instructional material of the kit may, for example, be affixed to a
container that contains the compound and/or composition used in the
practice of the invention or shipped together with a container that
contains the compound and/or composition. Alternatively, the
instructional material may be shipped separately from the container
with the intention that the recipient uses the instructional
material and the compound cooperatively. Delivery of the
instructional material may be, for example, by physical delivery of
the publication or other medium of expression communicating the
usefulness of the kit, or may alternatively be achieved by
electronic transmission, for example by means of a computer, such
as by electronic mail, or download from a website.
[0109] Other routes of administration to the affected area which
are contemplated include: transdermal, mucosal, rectal, and
vaginal, or topical (for example, in a carrier vehicle, a topical
control release patch, in a wound dressing, a hydrocolloid, a foam,
or a hydrogel, a cream, a gel, a lotion, an ointment, a liquid
crystal emulsion (LCE), and/or a micro-emulsion). An appropriate
biological carrier or pharmaceutically acceptable excipient may be
used. Compounds administered may, in various embodiments, be
racemic, isomerically purified, or isomerically pure.
Transmucosal Administration.
[0110] Transmucosal administration is carried out using any type of
formulation or dosage unit suitable for application to mucosal
tissue. For example, the selected active agent may be administered
to the buccal mucosa in an adhesive tablet or patch, sublingually
administered by placing a solid dosage form under the tongue,
lingually administered by placing a solid dosage form on the
tongue, administered nasally as droplets or a nasal spray, a
non-aerosol liquid formulation, or a dry powder, placed within or
near the rectum ("transrectal" formulations), or administered to
the urethra as a suppository, ointment, or the like.
Transrectal Administration.
[0111] Transrectal dosage forms may include rectal suppositories,
creams, ointments, and liquid formulations (enemas). The
suppository, cream, ointment or liquid formulation for transrectal
delivery comprises a therapeutically effective amount of the
selected active agent and one or more conventional nontoxic
carriers suitable for transrectal drug administration. The
transrectal dosage forms of the present invention may be
manufactured using conventional processes. The transrectal dosage
unit may be fabricated to disintegrate rapidly or over a period of
several hours. The time period for complete disintegration may be
in the range of from about 10 minutes to about 6 hours, e.g., less
than about 3 hours.
Vaginal or Perivaginal Administration.
[0112] Vaginal or perivaginal dosage forms may include vaginal
suppositories, creams, ointments, liquid formulations, pessaries,
tampons, gels, pastes, foams or sprays. The suppository, cream,
ointment, liquid formulation, pessary, tampon, gel, paste, foam or
spray for vaginal or perivaginal delivery comprises a
therapeutically effective amount of the selected active agent and
one or more conventional nontoxic carriers suitable for vaginal or
perivaginal drug administration. The vaginal or perivaginal forms
of the present invention may be manufactured using conventional
processes as disclosed in Remington: The Science and Practice of
Pharmacy, supra (see also drug formulations as adapted in U.S. Pat.
Nos. 6,515,198; 6,500,822; 6,417,186; 6,416,779; 6,376,500;
6,355,641; 6,258,819; 6,172,062; and 6,086,909). The vaginal or
perivaginal dosage unit may be fabricated to disintegrate rapidly
or over a period of several hours. The time period for complete
disintegration may be in the range of from about 10 minutes to
about 6 hours, e.g., less than about 3 hours.
[0113] Topical Formulations.
[0114] Topical formulations may be in any form suitable for
application to the body surface, and may comprise, for example, an
ointment, cream, gel, lotion, solution, paste or the like, and/or
may be prepared so as to contain liposomes, micelles, and/or
microspheres. In certain embodiments, topical formulations herein
are ointments, creams and gels.
[0115] Transdermal Administration.
[0116] Transdermal compound administration, which is known to one
skilled in the art, involves the delivery of pharmaceutical
compounds via percutaneous passage of the compound into the
systemic circulation of the patient. Topical administration may
also involve the use of transdermal administration such as
transdermal patches or iontophoresis devices. Other components may
be incorporated into the transdermal patches as well. For example,
compositions and/or transdermal patches may be formulated with one
or more preservatives or bacteriostatic agents including, but not
limited to, methyl hydroxybenzoate, propyl hydroxybenzoate,
chlorocresol, benzalkonium chloride, and the like. Dosage forms for
topical administration of the compounds and compositions may
include creams, sprays, lotions, gels, ointments, eye drops, nose
drops, ear drops, and the like. In such dosage forms, the
compositions of the invention may be mixed to form white, smooth,
homogeneous, opaque cream or lotion with, for example, benzyl
alcohol 1% or 2% (wt/wt) as a preservative, emulsifying wax,
glycerin, isopropyl palmitate, lactic acid, purified water and
sorbitol solution. In addition, the compositions may contain
polyethylene glycol 400. They may be mixed to form ointments with,
for example, benzyl alcohol 2% (wt/wt) as preservative, white
petrolatum, emulsifying wax, and tenox II (butylated
hydroxyanisole, propyl gallate, citric acid, propylene glycol).
Woven pads or rolls of bandaging material, e.g., gauze, may be
impregnated with the compositions in solution, lotion, cream,
ointment or other such form may also be used for topical
application. The compositions may also be applied topically using a
transdermal system, such as one of an acrylic-based polymer
adhesive with a resinous crosslinking agent impregnated with the
composition and laminated to an impermeable backing.
[0117] Examples of suitable skin contact adhesive materials
include, but are not limited to, polyethylenes, polysiloxanes,
polyisobutylenes, polyacrylates, polyurethanes, and the like.
Alternatively, the drug-containing reservoir and skin contact
adhesive are separate and distinct layers, with the adhesive
underlying the reservoir that, in this case, may be either a
polymeric matrix as described above, or be a liquid or hydrogel
reservoir, or take some other form.
Additional Administration Forms.
[0118] Additional dosage forms of this invention include dosage
forms as described in U.S. Pat. Nos. 6,340,475; 6,488,962;
6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage
forms of this invention also include dosage forms as described in
U.S. Patent Application Nos. 20030147952, 20030104062, 20030104053,
20030044466, 20030039688, and 20020051820. Additional dosage forms
of this invention also include dosage forms as described in PCT
Application Nos. WO 03/35041, WO 03/35040, WO 03/35029, WO
03/35177, WO 03/35039, WO 02/96404, WO 02/32416, WO 01/97783, WO
01/56544, WO 01/32217, WO 98/55107, WO 98/11879, WO 97/47285, WO
93/18755, and WO 90/11757.
Solutions
[0119] After a halogenated ether volatile anesthetic has been
selected, it may be dissolved into a solution. The solution may be
an aqueous-based solution, such as water, saline, or the like. In
some variations, other fluids and solutions may be appropriate.
[0120] 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).
[0121] 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. 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.
[0122] In various embodiments, a preservative or stabilizer may be
included in the composition or solution. For example, the
prevention of the action of microorganisms may 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 that may be included suitable for use include sterile
aqueous solutions or dispersions and sterile powders for the
extemporaneous preparation of sterile 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, and the like. Appropriate stabilizers or
preservatives may be selected according to the route of
administration desired. A particle filter or microbe filter may be
used, and may be necessary according to the route of administration
desired.
[0123] 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 treatment of dermatological disorders
or diseases.
[0124] 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.
[0125] The active agent gas may be formulated into a 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 such as a halogenated ether or a volatile anesthetic may
be measured in liquid form and directly admixed into a solution. Of
course, other suitable methods of dissolving the volatile
anesthetic into solution may also be used. After the halogenated
ether volatile anesthetic has been solubilized, it may be
administered to a subject in need of treatment of a dermatological
disorders or disease. In certain embodiments, a volatile anesthetic
is admixed 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.
[0126] In certain embodiments, solutions of the present invention
may 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. Certain emulsions of isoflurane have been
prepared previously for intravenous (da Silva Telles, et al., 2004,
Rev. Bras. Anaestesiol Campianas 54(5):2004) or epidural
administration (Chai et al. 2008, British J Anesthesia
100:109-115).
[0127] Pharmaceutical compositions of the present invention
comprise an effective amount of one or more volatile anesthetics 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.
[0128] 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 (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 may be used as a
solubilizing agent.
[0129] In various other embodiments, compositions of the present
invention may comprise human serum albumin purified from plasma, or
recombinant human serum albumin. In certain embodiments, human
serum albumin may be used as a solubilizing agent. In other
embodiments, the compositions of the invention may comprise
propylene glycol. In other embodiments, the compositions of the
invention may comprise perfluorooctyl bromide. In other
embodiments, the compositions of the invention may comprise
perfluorocarbon. In certain embodiments, perfluorocarbon may be
used as a solubilizing agent.
[0130] In various embodiments, a preservative or stabilizer may be
included in the composition or solution. For example, the
prevention of the action of microorganisms may 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 use include sterile
aqueous solutions or dispersions and sterile powders for the
extemporaneous preparation of sterile 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 may be used and may be necessary
according to the route of administration desired.
Pharmaceutical Compositions and Therapies
[0131] Administration of compositions of the invention in a method
of treatment may be achieved in a number of different ways, using
methods known in the art. Such methods include, but are not limited
to, topically administering solutions, suspensions, creams, pastes,
oils, lotions, gels, foam, hydrogel, ointment, liposomes,
emulsions, liquid crystal emulsions, and nanoemulsions.
[0132] The therapeutic and prophylactic methods of the invention
thus encompass the use of pharmaceutical compositions of the
invention. The formulations of the pharmaceutical compositions
described herein may be prepared by any method known or hereafter
developed in the art of pharmacology. In general, such preparatory
methods include the step of bringing the active ingredient into
association with a carrier or one or more other accessory
ingredients, and then, if necessary or desirable, shaping or
packaging the product into a desired single- or multi-dose unit.
For example unit dose container may be such that volatile
anesthetic solution is contained in a crushable sealed ampoule
which in turn is enclosed in protective covering on which pressure
is applied to crush the ampoule which then releases volatile
anesthetic solution for percolation through a flint-type tip which
capped the ampoule in protective covering. When such packaging
configuration is employed, care is taken to leave as little as
possible or ideally no headspace in ampoule for the volatile
anesthetic to escape and cause a change in solution composition
over a period of shelf life.
[0133] Although the description of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for ethical administration to
humans, it will be understood by the skilled artisan that such
compositions are generally suitable for administration to animals
of all sorts, including mammals. Modification of pharmaceutical
compositions suitable for administration to humans in order to
render the compositions suitable for administration to various
animals is well understood, and the ordinarily skilled veterinary
pharmacologist may design and perform such modification with merely
ordinary, if any, experimentation. Subjects to which administration
of the pharmaceutical compositions of the invention is contemplated
include, but are not limited to, humans and other primates, mammals
including commercially relevant mammals such as non-human primates,
cattle, pigs, horses, sheep, cats, and dogs.
[0134] Pharmaceutical compositions that are useful in the methods
of the invention may be prepared, packaged, or sold in formulations
suitable for ophthalmic, vaginal, topical, intranasal, buccal, or
another route of administration.
[0135] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in bulk, as a single unit dose, or as a
plurality of single unit doses. A unit dose is discrete amount of
the pharmaceutical composition comprising a predetermined amount of
the active ingredient. The amount of the active ingredient is
generally equal to the dosage of the active ingredient which would
be administered to a subject or a convenient fraction of such a
dosage such as, for example, one-half or one-third of such a
dosage.
[0136] The relative amounts of the active ingredient, the
pharmaceutically acceptable carrier, and any additional ingredients
in a pharmaceutical composition of the invention will vary,
depending upon the identity, size, and condition of the subject
treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0137] In addition to the active ingredient, a pharmaceutical
composition of the invention may further comprise one or more
additional pharmaceutically active agents. One non-limiting example
of such an additional pharmaceutically active agent is an
antimicrobial agent, such as an antibiotic.
[0138] Controlled- or sustained-release formulations of a
pharmaceutical composition of the invention may be made using
conventional technology.
[0139] Formulations of a pharmaceutical composition suitable for
topical administration comprise the active ingredient combined with
a pharmaceutically acceptable carrier, such as sterile water or
sterile isotonic saline. Formulations may be prepared, packaged, or
sold in unit dosage form, such as in ampules, crushable or
otherwise, or in multi-dose containers containing a preservative.
Formulations for topical administration include, but are not
limited to, suspensions, solutions, emulsions in oily or aqueous
vehicles, solutions, suspensions, creams, pastes, oils, lotions,
gels, foam, hydrogel, ointment, liposomes, emulsions, liquid
crystal emulsions, nanoemulsions, implantable sustained-release or
biodegradable formulations. Such formulations may further comprise
one or more additional ingredients including, but not limited to,
suspending, stabilizing, or dispersing agents.
[0140] The pharmaceutical compositions may be prepared, packaged,
or sold in the form of a sterile aqueous or oily suspension or
solution. This suspension or solution may be formulated according
to the known art, and may comprise, in addition to the active
ingredient, additional ingredients such as the dispersing agents,
wetting agents, or suspending agents described herein. Such sterile
formulations may be prepared using a non-toxic acceptable diluent
or solvent, such as water or 1,3-butane diol, for example. Other
acceptable diluents and solvents include, but are not limited to,
Ringer's solution, isotonic sodium chloride solution, and fixed
oils such as synthetic mono- or di-glycerides. Other formulations
that are useful include those which comprise the active ingredient
in a liposomal preparation, or as a component of a biodegradable
polymer system. Compositions for sustained release or implantation
may comprise pharmaceutically acceptable polymeric or hydrophobic
materials such as an emulsion, an ion exchange resin, a sparingly
soluble polymer, or a sparingly soluble salt.
[0141] In some embodiments, the pharmaceutical compositions of the
invention may be contained in a crushable ampule irrespective of
the route of delivery to the patient.
[0142] Throughout this disclosure, various aspects of this
invention may 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 sub-ranges 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 sub-ranges 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.
[0143] It is contemplated that any embodiment discussed in this
specification may be implemented with respect to any method or
composition of the invention, and vice versa. Furthermore,
compositions of the invention may be used to achieve methods of the
invention.
[0144] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures, embodiments, claims, and
examples described herein. Such equivalents were considered to be
within the scope of this invention and covered by the claims
appended hereto. For example, it should be understood, that
modifications in reaction conditions, including but not limited to
reaction times, reaction size/volume, and experimental reagents,
such as solvents, catalysts, pressures, atmospheric conditions,
e.g., nitrogen atmosphere, and reducing/oxidizing agents, with
art-recognized alternatives and using no more than routine
experimentation, are within the scope of the present
application.
[0145] It is to be understood that wherever values and ranges are
provided herein, all values and ranges encompassed by these values
and ranges, are meant to be encompassed within the scope of the
present invention. Moreover, all values that fall within these
ranges, as well as the upper or lower limits of a range of values,
are also contemplated by the present application.
[0146] The following examples further illustrate aspects of the
present invention. However, they are in no way a limitation of the
teachings or disclosure of the present invention as set forth
herein.
EXPERIMENTAL EXAMPLES
[0147] The invention is now described with reference to the
following Examples. These Examples are provided for the purpose of
illustration only, and the invention is not limited to these
Examples, but rather encompasses all variations that are evident as
a result of the teachings provided herein.
Example 1
Preparation of Isoflurane Dissolved in Saline
[0148] Isoflurane was dissolved into saline using the following
method (also referred to as the "bubbling" method). 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.
Example 2
Isoflurane Dissolved in Artificial Cerebrospinal Fluid
[0149] 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.
Example 3
Preparation of Anesthetic Compositions Comprising an Extractive
Solvent
[0150] The following solutions were prepared. Isoflurane was
obtained. NMP was obtained from Sigma-Aldrich Chemical company. A
40% (v/v) isoflurane-NMP solution was made adding 40 ml of
isoflurane to 60 ml of NMP. A 40% (v/v) isoflurane-ethanol solution
was made adding 40 ml of isoflurane to 60 ml of ethanol.
[0151] Saline compositions with varying concentrations of
isoflurane and NMP were made by mixing the above NMP-isoflurane
solution with saline as follows:
TABLE-US-00001 Saline Base-Isoflurane % % Sample (ml)
Compositions(ml) Isoflurane NMP A 0 10 40% 60% B 2 8 32 48 C 4 6 24
36 D 5 5 20 30 E 6 4 16 24 F 8 2 8 12 G 10 0 0 0
[0152] Control compositions with varying concentrations of
isoflurane-ethanol were made by mixing the above isoflurane-ethanol
compositions with saline as follows:
TABLE-US-00002 Saline Control-Isoflurane % % Sample (ml)
Compositions(ml) Isoflurane Ethanol H 0 10 40% 60% I 2 8 32 48 J 4
6 24 36 K 5 5 20 30 L 6 4 16 24 N 8 2 8 12 M 10 0 0 0
[0153] To determine the stability of the compositions, the
following experiment may be performed. Each sample is divided into
two containers containing 5 mls of the sample. One of the samples
is capped. The other sample is left uncapped. Over time (1 hour, 6
hour, 24 hour, etc.), the samples are examined to see if the
isoflurane has separated from solution. Furthermore, the
concentration of isoflurane in each solution may be determined at
each time point. The uncapped sample may be compared to the capped
sample to determine the stability of the solution. Furthermore, the
isoflurane-NMP compositions may then be compared to the control
compositions. It is anticipated that the anesthetic compositions
will remain miscible at all concentrations.
Example 4
Preparation of Anesthetic Compositions Comprising an Emulsion
[0154] Solutions of emulsified isoflurane are prepared at room
temperature (20.degree. C.) by adding liquid isoflurane to 30%
Intralipid.RTM. (Sigma-Aldrich) in gas-tight glass bottles fitted
with Teflon stoppers. The bottles are then vibrated on a vibrator
at 50 Hz for 30 minutes. (For examples see, Zhou et al, 2006,
Anesth Analg 102:129-34; Taheri et al., 1991, Anesth Analg 1991;
72:627-34).
TABLE-US-00003 30% Intralipid Isoflurane % Sample (ml) (ml)
Isoflurane A 40 1.28 3.1 B 40 2.55 6.0 C 40 3.48 8.0 D 40 4.45 10.0
E 40 10.0 20.0 F 40 26.67 40.0
[0155] To determine the stability of the compositions, the
following experiment is performed. Each sample is divided into two
containers containing 5 ml of the sample. One of the samples is
capped. The other sample is left uncapped. Over time (1 hour, 6
hour, 24 hour, etc.), the samples are examined to see whether the
isoflurane has separated from solution, or whether the lipid phase
has separated from the aqueous phase. Furthermore, the
concentration of isoflurane in each solution may be determined at
each time point. The uncapped sample may be compared to the capped
sample to determine the stability of the solution. It is
anticipated that the anesthetic compositions will not separate at
all concentrations.
[0156] One of skill in the art will realize that emulsions of
isoflurane may be made using other lipids, including other emulsion
preparations, such as 10% (w/v) Intralipid.RTM. or 20% (w/v)
Intralipid.RTM., 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).
[0157] One of skill in the art will also realize that emulsions of
desflurane, sevoflurane, isoflurane, enflurane, methoxyflurane and
halothane may be produced using variations of the methods described
herein.
Example 5
Preparation of Anesthetic Compositions Comprising an Extractive
Solvent and an Emulsion
[0158] The following solutions and emulsions are prepared.
Isoflurane is obtained. NMP is obtained from Sigma-Aldrich Chemical
company. A 40% (v/v) isoflurane-NMP solution is made by adding 40
ml of isoflurane to 60 ml of NMP (as in Example 4).
[0159] Emulsion compositions with varying concentrations of
isoflurane and NMP are prepared by mixing the above NMP-isoflurane
solution with 30% Intralipid (Sigma-Aldrich) at room temperature
(20.degree. C.) in gas-tight bottles fitted with Teflon stoppers as
follows:
TABLE-US-00004 40% (v/v) 30% Intralipid isoflurane-NMP % % Sample
(ml) (ml) Isoflurane NMP A 40 3.37 3.1 4.7 B 40 7.06 6.0 9.0 C 40
10.0 8.0 12.0 D 40 13.34 10.0 15.0 E 40 40.0 20.0 30.0
[0160] After mixing, the bottles are vibrated on a vibrator at 50
Hz for 30 minutes. To determine the stability of the compositions,
the following experiment is performed. Each sample is divided into
two containers containing 5 ml of the sample. One of the samples is
capped. The other sample is left uncapped. Over time (1 hour, 6
hour, 24 hour, etc.), the samples are examined to see whether the
isoflurane has separated from solution, or whether the lipid phase
has separated from the aqueous phase. Furthermore, the
concentration of isoflurane in each solution is determined at each
time point. The uncapped sample may be compared to the capped
sample to determine the stability of the solution. It is
anticipated that the anesthetic compositions will not separate at
all concentrations.
[0161] One of skill in the art will realize that emulsions of
isoflurane may be made using other lipids, including other emulsion
preparations, such as 10% (w/v) Intralipid.RTM. or 20% (w/v)
Intralipid.RTM., 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).
[0162] One of skill in the art will also realize that emulsions of
desflurane, sevoflurane, isoflurane, enflurane, methoxyflurane and
halothane may be produced using variations of the methods described
herein.
Example 6
Stability of Isoflurane Formulations
[0163] 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.
[0164] 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-00005 Pure form 0 h 0.25 h 1 h 2 h 3 h 5 h of (% (% (% (%
(% (% isoflurane remaining remaining remaining remaining remaining
remaining (g) iso) iso) iso) iso) iso) iso) 7 h 8 h 0.7893 100 85
52 14 0 3.4825 100 96 86 75 62 38 13 3
Example 7
[0165] Preparation of Isoflurane Solution (v/v) with NMP
[0166] 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-00006 NMP Saline Isoflurane Appearance of (%) (%) (%)
solutions 1 90 -- 10 Clear 2 60 -- 40 Clear 3 63 27 10 Clear 4 72
20 8 Clear
TABLE-US-00007 Isoflurane 0 h 0.25 h 1 h 16 h 24 h concen- (% (% (%
(% (% tration remaining remaining remaining remaining remaining in
NMP iso) iso) iso) iso) iso) 10 100 99 99 94 91 30 100 99 98 90
86
[0167] 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 6.
Example 8
[0168] Preparation of Emulsified Isoflurane (v/v) in Intralipid
[0169] Pure isoflurane USP (Forane) liquid is mixed with Intralipid
20% or 30% (Baxter) at the indicated concentrations; the mixture
was vortexed vigorously and sonicated for 30 minutes to prepare
homogenous isoflurane-intralipid emulsion.
TABLE-US-00008 Isoflurane Appearance of Lipid Emulsion
Concentration Emulsions 1 20% Intralipid 1-6% Homogenous 2 30%
intralipid 6-10% Homogenous
TABLE-US-00009 Isoflurane concen- 0 h 0.25 h 1 h 16 h 24 h tration
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
[0170] Intralipid emulsions with the indicated amount of isoflurane
looked homogenous and uniform. Moreover, intralipid reduced the
volatility of isoflurane, as compared with Example 6.
[0171] One of skill in the art will realize that emulsions of
isoflurane may 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 may be produced using variations of the methods described
herein.
Example 9
[0172] Preparation of Emulsified Isoflurane (v/v) in Intralipid and
NMP
[0173] 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-00010 20% Intralipid NMP Isoflurane Appearance of (%) (%)
(%) emulsions 1 75 15 10 Homogenous 2 80 10 10 Homogenous
TABLE-US-00011 0 h 0.25 h 1 h 16 h 24 h (% (% (% (% (% Isoflurane
remaining remaining remaining remaining remaining Vehicle (%) iso)
iso) iso) iso) iso) 20% 5 100 98 94 88 85 intralipid + 1 5% NMP 20%
10 100 98 97 93 89 intralipid + 1 5% NMP
[0174] 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 6.
[0175] One of skill in the art will realize that emulsions of
isoflurane may 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 may be produced using variations of the methods described
herein.
Example 10
Preparation of Polysorbate 80 (Tween 80)-Based Emulsified
Isoflurane
[0176] 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-00012 3% Tween 80 DMPC Isoflurane Appearance of (%) (%)
(%) emulsions 1 95 -- 5 Homogenous 2 93 0.3 7 Homogenous 3 93 0.6 7
Homogenous
TABLE-US-00013 0 h 0.25 h 1 h 16 h 24 h (% (% (% (% (% Isoflurane
remaining remaining remaining remaining remaining Vehicle (%) iso)
iso) iso) iso) iso) 3% Tween 7 100 97 95 91 85 3% Tween + 7 100 98
96 94 89 0.3% DMPC 3% Tween + 7 100 100 100 99 94 0.6% DMPC
[0177] 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 6.
Example 11
[0178] Preparation of Isoflurane Solution (v/v) with Propylene
Glycol
[0179] 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-00014 Propylene Glycol Saline Isoflurane Appearance of (%)
(%) (%) solutions 1 90 -- 10 Clear 2 70 -- 30 Clear 3 72 20 8
Clear
TABLE-US-00015 Isoflurane concen- 0 h 0.25 h 1 h 16 h 24 h tration
(% (% (% (% (% 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
[0180] 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 6.
Example 12
Preparation of Cremophor EL-Based Emulsified Isoflurane
[0181] 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-00016 10% Cremophor EL Isoflurane Appearance of (%) (%)
the emulsion 1 95 5 Milky 2 90 10 Milky
TABLE-US-00017 0 h 0.25 h 1 h 16 h 24 h (% (% (% (% (% Isoflurane
remaining remaining remaining remaining remaining Vehicle
Concentration iso) iso) iso) iso) iso) 10% 5 100 90 85 68 54
Cremophor 10% 10 100 91 87 73 60 Cremophor
[0182] 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 6.
Example 13
[0183] Preparation of Isoflurane Solution (v/v) with Dimethyl
Sulfoxide (DMSO)
[0184] 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-00018 DMSO Saline Isoflurane Appearance of (%) (%) (%)
solutions 1 90 -- 10 Clear 2 50 -- 50 Clear 3 72 20 8 Clear
Example 14
[0185] Preparation of Isoflurane Solution (v/v) in Perfluorooctyl
Bromide
[0186] 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-00019 Perfluorooctyl Bromide Isoflurane Appearance of (%)
(%) solutions 1 90 10 Clear 2 80 20 Clear
Example 15
[0187] Preparation of Isoflurane Solution (v/v) in PEG 400
[0188] Isoflurane (2 mL) was mixed with PEG-400 (2 mL) in a vial
and contents were shaken resulting in a clear solution. The
volatility of the resulting solution was compared to the volatility
of pure isoflurane using Exetech Heavy Duty Differential Pressure
Manometer Model 407910. At least a 3 fold reduction of vapor
pressure was observed when heated to about 39.degree. C.
Example 16
[0189] Preparation of Isoflurane Solution (v/v) in PEG 300
[0190] Isoflurane (2 mL) was mixed with PEG-300 (2 mL) in a vial
and contents were shaken resulting in a clear solution. The
volatility of the resulting solution was compared to the volatility
of pure isoflurane using Exetech Heavy Duty Differential Pressure
Manometer Model 407910. At least a 3 fold reduction of vapor
pressure was observed when heated to about 39.degree. C.
Example 17
[0191] Preparation of Isoflurane Solution (v/v) in Diethylene
Glycol Monoethyl Ether
[0192] Isoflurane (2 mL) was mixed with diethylene glycol monoethyl
ether (2 mL) in a vial and contents were shaken resulting in a
clear solution. The volatility of the resulting solution was
compared to the volatility of pure isoflurane using Exetech Heavy
Duty Differential Pressure Manometer Model 407910. At least a 3
fold reduction of vapor pressure was observed when heated to about
39.degree. C.
[0193] The disclosures of each and every patent, patent
application, and publication cited herein are hereby incorporated
herein by reference in their entirety.
[0194] All of the compositions and methods disclosed and claimed
herein may 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.
[0195] 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.
* * * * *
References