U.S. patent application number 16/773656 was filed with the patent office on 2020-09-24 for dimethyl sulfoxide (dmso) and methylsulfonylmethane (msm) formulations to treat osteoarthritis.
This patent application is currently assigned to Abela Pharmaceuticals, Inc.. The applicant listed for this patent is Abela Pharmaceuticals, Inc.. Invention is credited to Rodney Benjamin, Colette Cozean, Jesse Cozean, Anthony Keller.
Application Number | 20200297625 16/773656 |
Document ID | / |
Family ID | 1000004873644 |
Filed Date | 2020-09-24 |
United States Patent
Application |
20200297625 |
Kind Code |
A1 |
Cozean; Colette ; et
al. |
September 24, 2020 |
DIMETHYL SULFOXIDE (DMSO) AND METHYLSULFONYLMETHANE (MSM)
FORMULATIONS TO TREAT OSTEOARTHRITIS
Abstract
Embodiments of the invention relate generally to the use of
formulations comprising DMSO and MSM to treat arthritis (such as
osteoarthritis), pain, inflammation, and/or degeneration. DMSO and
MSM formulations are administered orally and/or topically in
several embodiments and provide effective treatment of both chronic
and acute symptoms of arthritis (e.g., osteoarthritis), pain,
inflammation, and/or degeneration. Solid forms of DMSO are provided
in several embodiments.
Inventors: |
Cozean; Colette; (Lake
Forest, CA) ; Cozean; Jesse; (Lake Forest, CA)
; Benjamin; Rodney; (Vancouver, WA) ; Keller;
Anthony; (Ashland, OR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abela Pharmaceuticals, Inc. |
Lake Forest |
CA |
US |
|
|
Assignee: |
Abela Pharmaceuticals, Inc.
Lake Forest
CA
|
Family ID: |
1000004873644 |
Appl. No.: |
16/773656 |
Filed: |
January 27, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15821370 |
Nov 22, 2017 |
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16773656 |
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13503626 |
Apr 23, 2012 |
9839609 |
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PCT/US10/54870 |
Oct 29, 2010 |
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15821370 |
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61319203 |
Mar 30, 2010 |
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61256935 |
Oct 30, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 31/7036 20130101; A61K 45/06 20130101; A61K 31/496 20130101;
Y02A 50/30 20180101; A61K 31/133 20130101; A61K 31/17 20130101;
A61K 31/10 20130101; A61K 31/4409 20130101; A61K 31/4965 20130101;
A61K 9/0053 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/10 20060101 A61K031/10; A61K 45/06 20060101
A61K045/06; A61K 31/133 20060101 A61K031/133; A61K 31/17 20060101
A61K031/17; A61K 31/4409 20060101 A61K031/4409; A61K 31/496
20060101 A61K031/496; A61K 31/4965 20060101 A61K031/4965; A61K
31/7036 20060101 A61K031/7036 |
Claims
1. A solid oral formulation comprising dimethylsulfoxide (DMSO) and
methylsulfonylmethane (MSM) as prills, microprills, or flakes,
wherein the prills, microprills, or flakes (a) are prepared by
flacking, prilling and/or freezing a liquid combination of DMSO and
MSM, and (b) stay solid at room temperature.
2. The solid oral formulation of claim 1, comprising about 5 mg to
about 50 mg DMSO.
3. The solid oral formulation of claim 2, comprising about 300 mg
to about 800 mg MSM.
4. The solid oral formulation of claim 1, comprising about 30 mg to
about 50 mg DMSO and about 500 mg to about 800 mg MSM.
5. The solid oral formulation of claim 1, wherein the liquid
combination is prepared by heating a combination of liquid DMSO and
solid MSM.
6. The solid oral formulation of claim 1, wherein the prills,
microprills, or flakes have a diameter of about 75 microns to about
840 microns.
7. A method for reducing inflammation or pain in a human subject in
need thereof, comprising orally administering to the human subject
a solid oral formulation of claim 1.
8. The method of claim 7, where the oral administration reduces
chronic inflammation or pain and reduces osteoarthritis.
9. A method of reducing inflammation or pain in a human subject in
need thereof, comprising topically administering to the human
subject a topical formulation comprising about 65-70% v/v
dimethylsulfoxide (DMSO) and about 25-35% v/v methylsulfonylmethane
(MSM), wherein the topical formulation is provided in a gel, cream,
serum, liquid, spray, ointment, and/or patch form.
10. The method of claim 9, wherein the topical formulation is
administered at a hand, a knee or another joint.
11. The method of claim 9, wherein the topical formulation is
administered at a hand.
12. The method of claim 9, further comprising orally administering
to the human subject a solid oral formulation comprising DMSO and
MSM as prills, microprills, or flakes, wherein the prills,
microprills, or flakes (a) are prepared by flacking, prilling
and/or freezing a liquid combination of DMSO and MSM, and (b) stay
solid at room temperature.
13. The method of claim 9, wherein the topical administration
provides acute relief of pain and inflammation.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/503,626, filed on Apr. 23, 2012, which is
the U.S. National Phase application under 35 U.S.C. .sctn. 371 of
International Application PCT/US2010/054870, filed on Oct. 29,
2010, which claims the benefit of U.S. Provisional Patent
Application Nos. 61/256,935, filed on Oct. 30, 2009; and
61/319,203, filed on Mar. 30, 2010, the disclosure of each of which
is expressly incorporated by reference herein.
BACKGROUND
Field of the Invention
[0002] Embodiments of the invention relate generally to
formulations comprising dimethyl sulfoxide (DMSO) and/or
methylsulfonylmethane (MSM) and the use of those compounds for the
treatment of arthritis (such as osteoarthritis) and other
conditions. Solid formulations comprising DMSO, alone or in
combination with MSM, are provided in several embodiments.
Description of the Related Art
[0003] Cartilage is a protein matrix which functions to lubricate
and cushion the joints. Osteoarthritis, or degenerative arthritis,
refers to a class of diseases and mechanical abnormalities that
result in degradation of joints, structurally and therefore,
functionally. The articular cartilage of joints and the juxtaposed
subchondral bone (e.g., the ends of the bone) are frequently
affected.
[0004] Clinically, osteoarthritis may present with symptoms such as
joint pain or minor tenderness of load bearing joints. Symptoms
range from this level of "everyday aches and pains" to severe
sensitivity of joints, stiffness, inflammation, creaking, and
locking of joints.
[0005] Osteoarthritis is the most common form of arthritis in the
United States, affecting nearly 27 million people, and is the
leading cause of chronic disability. Osteoarthritis is linked to
approximately 25% of visits to primary care physicians, and about
50% of non-steroidal anti-inflammatory prescriptions. Thus, in its
various stages, osteoarthritis accounts for an enormous burden on
those who suffer from the disease, their family and caretakers, as
well as the medical community.
[0006] Severe cases of osteoarthritis may require surgery to
replace joints, remove bone fragments, reposition and/or fuse bones
to increase stability and reduce pain. However, these surgeries are
costly, are associated with long recovery times, and in some cases
do not lead to significant alleviation of symptoms.
[0007] Dimethyl sulfoxide (DMSO; (CH.sub.3).sub.2(SO)) is a polar,
aprotic solvent widely used as a solvent. It is frequently used in
various chemical and biological reactions and as a cryoprotectant
for cell storage. The strong unpleasant odor of DMSO, along with
several undesired side effects, have adversely impacted the use of
DMSO in medical applications.
[0008] Methylsulfonylmethane (MSM; (CH.sub.3).sub.2SO.sub.2)), also
known as dimethyl sulfone, is an organosulfur compound that is a
metabolite of DMSO and certain sulfur-containing amino acids. MSM
has been marketed primarily as a dietary supplement.
SUMMARY
[0009] The etiology of osteoarthritis is varied, and includes
hereditary, developmental, metabolic, and mechanical aspects that
may lead to loss of cartilage. Ironically, the responses generated
by the body (e.g., immune and regrowth processes) may accelerate
damage to the cartilage. For example, when bone surfaces lose
cartilage, subchondral bone may be exposed, damaged, and regrown.
However, regrowth may lead to excessive proliferation of dense bone
in central areas of cartilage loss, further exacerbating the
cartilage loss. As a result, a person suffering from progressive
osteoarthritis may experience increasing pain upon weight bearing,
including walking and standing. Additionally, the decreased
movement because of the pain may cause regional muscles to atrophy
and reduce tension on ligaments, further compromising the
functionality of the joint.
[0010] Several options for therapy are available currently for
those afflicted with osteoarthritis. Paracetamol
(Tylenol.RTM./acetaminophen) is commonly used to treat
osteoarthritis pain and has demonstrated roughly equivalent benefit
to ibuprofen. However, doses demonstrating effective pain relief
(.about.4 g/day) have been associated with alterations in liver
function as well as gastrointestinal bleeding or renal damage when
used chronically.
[0011] Non-steroidal anti-inflammatory (NSAID) drugs may be
prescribed for more severe cases of osteoarthritis. This class of
drugs acts by inhibiting the formation of prostaglandins and may
reduce both the pain and inflammation associated with
osteoarthritis. These drugs, however, are also associated with
adverse events including increased gastrointestinal bleeding,
stomach upset, cramping, diarrhea, and peptic ulcer. Some of these
drugs, namely the cyclooxygenase-2 inhibitors, have been withdrawn
from the market due to their elevated risk for cardiovascular
disease. Several NSAIDS are available for topical use, though the
therapeutic effect is generally minimal and short lived.
[0012] Oral corticosteroids carry a high rate of adverse side
effects and produce limited symptomatic improvement, and therefore
are not typically recommended for osteoarthritis treatment.
Injections of corticosteroids into the intra-articular space may
provide acute (e.g., several weeks) relief of pain, but do not
generally offer a long term therapeutic effect.
[0013] Thus, there remains a need in the art for an effective
treatment for osteoarthritis, particularly one that addresses both
the chronic condition of osteoarthritis as well as the acute
symptoms associated with the illness. Accordingly, in several
embodiments, formulations comprising MSM and DMSO, individually or
combined, are provided for either oral or topical use, either alone
or in combination, to provide efficacious relief of both chronic
and acute symptoms of osteoarthritis, while inducing minimal,
reduced, or no, side effects.
[0014] In several embodiments, formulations comprising DMSO and
MSM, individually or combined, are formulated as solids. A solid
form of DMSO, alone or in combination with MSM is particularly
surprising and beneficial because, in some embodiments, the solid
form is associated with less odor than the liquid form. In several
embodiments, the solid form stays solid at room temperature (e.g.,
about 20.degree. C.-23.degree. C.). In other embodiments, the solid
form stays solid at temperatures up to 30.degree. C., 45.degree.
C., 60.degree. C., 75.degree. C., 100.degree. C., or higher. In
some embodiments, the solid form does not crystallize and/or lose
its texture at temperatures below room temperature, 25.degree. C.,
15.degree. C., 10.degree. C., 5.degree. C., or lower. In several
embodiments, the solid form maintains its chemical stability and/or
integrity (e.g., phase integrity) at a wide range of temperatures,
including but not limited to ranges between about 0.degree. C. to
about 100.degree. C., about 5.degree. C. to about 50.degree. C.,
about 10.degree. C. to about 40.degree. C., about 20.degree. C. and
about 30.degree. C., and overlapping ranges thereof. In several
embodiments, the solid form maintains a similar consistency, e.g.,
maintains one or more of a hardness, firmness, density, texture,
and/or viscosity that is at least 75%, 85%, 95% or 100% the same,
over a range of temperatures from about 0.degree. C. to about
100.degree. C., about 5.degree. C. to about 50.degree. C., about
10.degree. C. to about 40.degree. C., about 20.degree. C. and about
30.degree. C., and overlapping ranges thereof. In several
embodiments, the addition of a coating to the solid form and/or a
stabilizer increases the stability temperature stability range by
at least 10%, 25%, 50% or more. In one embodiment, the solid form
maintains its chemical stability and/or integrity (e.g., phase
integrity) in a range from about 10.degree. C. to about 40.degree.
C. without a coating and about 0.degree. C. to about 50.degree. C.
with a coating. Coatings include, but are not limited to,
vegetable-based coatings, biopolymers, colloidal particles,
multilayer emulsions, colloidosomes, or combinations thereof.
[0015] In several embodiments, solid forms of DMSO, alone or in
combination with MSM, are provided in the form of a capsule. In one
embodiment, the use of solidified DMSO reduces the odor typically
associated with DMSO. In another embodiment, the use of solidified
DMSO reduces the physiological side effects typically associated
with DMSO. In some embodiments, the formulations are consumed
orally to treat osteoarthritis, while in some other embodiments,
the formulations are applied topically. In still other embodiments,
both oral and topical formulations are used. In several other
embodiments, formulations comprising DMSO and MSM, individually or
combined, are formulated as liquids.
[0016] As used herein, the phrase "symptoms of osteoarthritis"
shall be given its ordinary meaning and shall include, but not be
limited to, one or more of the following: cartilage degeneration,
degeneration of subchondral bone, joint pain, tenderness,
stiffness, creaking, locking of joints, inflammation, structural
changes in the joint, swelling, diminished grip strength, bony
enlargement, diminished range of motion, osteophyte (or spur)
formation, and synovial irritation. Symptoms of osteoarthritis can
occur, for example, in the knee, toe, thumb, finger, ankle, spine,
hip, shoulder or other joint.
[0017] In several embodiments, formulations comprising MSM, DMSO
and/or a combination of MSM and DMSO, alone or with other colors,
flavorings, additives, fillers, carriers, excipients, and/or
therapeutics are used to prevent and/or treat osteoarthritis and/or
symptoms thereof, arthritis and/or symptoms thereof, inflammation,
joint pain, and/or structural changes of the joint.
[0018] In several embodiments, formulations comprising MSM, DMSO
and/or a combination of MSM and DMSO, alone or with other carriers,
flavorings, additives, fillers, carriers, excipients, and/or
therapeutics are used to prevent and/or treat the following
conditions that are unrelated to an osteoarthritic etiology: tissue
degeneration, pain (e.g., joint pain), and/or inflammation.
[0019] Due to its physical properties, DMSO exists as a liquid at
room temperature, and is therefore typically utilized as a liquid.
However, there is a long felt and as yet unmet need for a solid
form of DMSO at room temperature. For example, a solid form of DMSO
is particularly advantageous because, in some embodiments, it can
be provided as a pill, tablet or capsule, is suitable for
concentrated dosages, and exhibits reduced side effects as compared
to a liquid form (e.g., less irritation, sensitivities,
gastrointestinal effects, etc.). In several embodiments, solid
forms offer controlled release in the body, and in some
embodiments, are more slowly released and/or more effectively
absorbed. In one embodiment, a solid form that dissolves in a
desired area (e.g., small intestine) is provided, thereby offering
enhanced bioavailability based on targeted delivery. Further, solid
forms of DMSO exhibit reduced or no odor as compared to the liquid
form in some embodiments. Thus, several embodiments of the present
invention provide a formulation comprising DMSO that is solid at
room temperature, and methods of making same.
[0020] In several embodiments, formulations comprising DMSO and MSM
(and/or a compound related to MSM) exhibit reduced odor than
formulations comprising DMSO alone. Formulations in liquid, gel,
solid, and/or gaseous forms exhibit reduced odor when DMSO is
combined with MSM (and/or a compound related to MSM) in some
embodiments.
[0021] In several embodiments, the invention comprises an oral and
topical system for improving the symptoms of arthritis (e.g.,
osteoarthritis), including, but not limited to, pain, osteophytes,
stiffness, grip strength, limited range of motion, tissue
enlargement in joints, inflammation (specific to a joint or
localized to a general region of the body), swollen joints, joint
deformity, and combinations thereof. In one embodiment, the system
comprises a first formulation comprising DMSO and MSM, wherein said
first formulation is suitable for oral administration. In some
embodiments, the first formulation comprises about 300 mg to about
750 mg MSM and about 10 mg to about 50 mg DMSO. In some
embodiments, the first formulation comprises about 300 mg to about
700 mg MSM and about 10 mg to about 50 mg DMSO. The second
formulation comprises DMSO and MSM, and is suitable for topical
administration. In some embodiments, the second formulation
comprises between about 100 mg and about 1500 mg MSM and between
about 500 mg and about 5000 mg DMSO, depending on the volume
applied. The second formulation, in some embodiments, comprises
about 900 mg to about 1200 mg MSM and about 3000 mg to about 5000
mg DMSO. In some embodiments, the second formulation comprises
about 10% to about 15% MSM and about 40% to about 70% DMSO, or
higher (e.g., up to 90% or more DMSO).
[0022] In one embodiment, the first formulation (e.g., oral)
comprises 650 mg MSM and 15 mg DMSO and the second formulation
(e.g., topical) comprises 10% MSM and 50% DMSO. In one embodiment,
the first formulation comprises 500 mg MSM and 15 mg DMSO and the
second formulation comprises 917 mg MSM and 4585 mg DMSO. In one
embodiment, an oral formulation comprises 400-600 mg MSM and 10-20
mg DMSO and a topical formulation comprises 800-1000 mg MSM and
3500-5000 mg DMSO.
[0023] In one embodiment, the first formulation comprises about 900
mg to about 2100 mg MSM and about 30 mg to about 150 mg DMSO and
the second formulation comprises about 10% to about 15% MSM, and
about 50% to about 90% DMSO. In one embodiment, the first
formulation comprises about 900 mg to about 2100 mg MSM and about
30 mg to about 150 mg DMSO and the second formulation comprises
about 2700 mg to about 3600 mg MSM, and about 9000 mg to about
15,000 mg DMSO.
[0024] In one embodiment, the first formulation comprises about
1500 mg MSM and about 45 mg DMSO and the second formulation
comprises about 10% MSM and about 50% DMSO. In one embodiment, the
first formulation comprises about 1500 mg MSM and about 45 mg DMSO
and the second formulation comprises about 2751 mg MSM and about
10,800 mg DMSO.
[0025] In one embodiment, the first formulation comprises about
60-99% MSM, and about 0.1-3% DMSO and the second formulation
comprises about 10-15% MSM, and about 50-70% DMSO, or higher (e.g.,
up to 90% or more DMSO).
[0026] In one embodiment, the first formulation comprises about
60-70% MSM and about 0.1-3% DMSO and the second formulation
comprises about 10%-15% MSM and about 40%-90% (e.g., 50%-70%)
DMSO.
[0027] In one embodiment, the first formulation comprises about
0.045 g/day DMSO and about 1.85 g/day MSM and the second
formulation comprises about 50%-70% DMSO and about 10%-15% MSM. In
one embodiment, an oral formulation comprises about 0.045 g/day
DMSO and about 1.85 g/day MSM and a topical formulation comprises
about 40%-90% DMSO and about 10%-15% MSM.
[0028] In several embodiments herein, only the first formulation
(e.g., oral) is used (alone or combined with other compounds). In
other embodiments, only the second formulation (e.g., topical) is
used (alone or combined with other compounds). In yet other
embodiments, a dual treatment approach is employed. In some
embodiments, the dual treatment approach comprises an oral and
topical therapy comprising DMSO, MSM and one or more additional
compounds.
[0029] In one embodiment, the therapeutic system is suitable for
treating a subject, and is administered (or is suitable for
administration) in the following doses: the first formulation
comprises about 10-30 mg MSM per kg body weight of the subject and
about 0.1-1 mg DMSO per kg body weight and the second formulation
comprises about 30-50 mg MSM per kg body weight and about 125-175
mg DMSO per kg body weight. In one embodiment, the second
formulation comprises about 30-70 mg MSM per kg body weight and
about 125-225 mg DMSO per kg body weight
[0030] In one embodiment, the first formulation and/or the second
formulation are administered (or are suitable for administration)
at least once, twice or thrice daily.
[0031] In several embodiments, the MSM reduces an odor or other
side-effect of the DMSO. In some embodiments, MSM reduces dermal
irritation that may be caused by administration of DMSO. In some
embodiments, DMSO reduces a side-effect of the MSM. In some
embodiments, DMSO enhances the efficacy of the MSM. In some
embodiments, the enhanced efficacy of the MSM is due to the DMSO in
the oral formulation. In some embodiments, DMSO in the oral
formulation reduces the amount of MSM that is required to achieve a
given therapeutic result. MSM used according to any of the
embodiments provided herein may be isolated, purified or processed.
MSM that has been granted a GRAS (Generally Recognized As Safe)
designation is used for several embodiments described herein.
[0032] In some embodiments, the first formulation is in a capsule,
tablet, oral suspension, liquid, inhalant, and/or effervescent
form, wherein said forms are optionally coated and/or flavored. The
second formulation, according to some embodiments, is in a gel,
cream, serum, liquid, spray, ointment, and/or patch form. Heat or
cold therapy may be additionally provided in conjunction with the
second formulation.
[0033] In several embodiments, the first oral formulation treats
the chronic symptoms of osteoarthritis and/or generalized pain
and/or injury and the second topical formulation treats the acute
symptoms of osteoarthritis and/or localized pain and/or injury. The
first and/or the second formulations are optionally provided in
time-released formulations.
[0034] In one embodiment, the invention comprises the use of the
formulations described herein in the preparation of a medicament
for the treatment of osteoarthritis and/or symptoms of
osteoarthritis. In one embodiment, the invention comprises a kit
comprising one or more formulations according to any one of the
preceding claims with instructions to administer the first
formulation orally 1-4 times daily and/or instructions to
administer the second formulation topically 1-4 times daily. In one
embodiment, the instructions instruct the administration of the
first formulation orally 3 times daily. The instructions may also
instruct administration of the second formulation topically 1-4
times daily for up to two weeks. In one embodiment, the
instructions instruct the administration of the second formulation
topically 3 times daily for up to two weeks.
[0035] In several embodiments, the invention comprises a method for
treating the symptoms of arthritis (e.g., osteoarthritis). Symptoms
that are treated in some embodiments include one or more of pain,
osteophytes, stiffness, grip strength, limited range of motion,
tissue enlargement in joints, swollen joints, and joint deformity.
In some embodiments, the invention comprises a method for treating
the symptoms other types of arthritis, such as, for example, adult
onset rheumatoid arthritis. In some embodiments, the invention is
used to treat and/or improve the symptoms of juvenile rheumatoid
arthritis. In one embodiment, the method comprises providing the
first and second formulation as disclosed herein, orally
administering or instructing oral administration of the first
formulation to a subject 1-4 times daily; and topically
administering or instructing topical administration of the second
formulation to said subject 1-4 times daily.
[0036] In several embodiments of the invention, a topical
formulation for improving the symptoms of osteoarthritis is
provided. In one embodiment, the formulation comprises DMSO in an
amount between about 2000 mg to about 5000 mg DMSO per dose (e.g.,
a 5 mL dose) and MSM in an amount between about 300 mg to about
1200 mg MSM per dose (e.g., a 5 mL dose). In one embodiment, the
formulation comprises DMSO in an amount between about 3000 mg to
about 5000 mg DMSO per dose and MSM in an amount between about 900
mg to about 1200 mg MSM per dose. In one embodiment, the DMSO and
MSM are suitable for topical administration to a subject to improve
the symptoms of osteoarthritis. In one embodiment, the DMSO and MSM
are suitable for topical administration to a subject to treat one
or more of joint disorders, inflammation, degeneration, and/or
pain. Optionally, an oral formulation comprises about 300 mg to
about 700 mg MSM and about 10 mg to about 50 mg DMSO per dose is
provided.
[0037] In one embodiment, MSM is configured to act as a lubricant
to reduce irritation associated with topical application of DMSO.
In one embodiment, MSM reduces the odor associated with topical
application of DMSO.
[0038] In one embodiment, the invention comprises a method of
reducing the amount oral DMSO to achieve a therapeutic effect
comprising: providing the oral or topical formulation as described
herein to reduce the amount of DMSO needed to achieve a therapeutic
effect, thereby reducing the side effects of DMSO.
[0039] In several embodiments, the invention comprises an oral
formulation for improving the symptoms of arthritis (e.g.,
osteoarthritis). In one embodiment, the formulation comprises DMSO
and at least one second compound in a solid form that is
encapsulated in a capsule or other encapsulation format. In one
embodiment, the capsule delivers said DMSO and at least one second
compound in a time-released manner. In some embodiments, the oral
formulation is analgesic and anti-inflammatory. The second compound
reduces an odor associated with DMSO and reduces one or more side
effects associated with DMSO. In one embodiment, the second
compound is MSM, urea, a sulfur-binding agent, or combinations
thereof. In one embodiment, the second compound comprises a
nutrient (e.g., an amino acid). In one embodiment, the second
compound comprises a carbonyl group attached to two organic amine
residues. In one embodiment, the second compound includes carbamide
peroxide, allantoin, and hydantoin, biurets, amides, carbamates,
diimides, carbodiimides, thiocarbamides, or combinations thereof.
Preferably, one or more of MSM, urea and/or a sulfur-binding
compound are used, although other compounds are provided in several
embodiments to reduce an odor or side-effect of DMSO.
[0040] In one embodiment, the encapsulated oral formulation is
provided in a dosage of about 1 gram or less. In one embodiment,
the formulation is suitable for administration 1-4 times per day
with or without food. In some embodiments, the synergistic effects
of DMSO and MSM do not require the formulation to be ingested with
food. In several embodiments, the use of MSM permits higher
concentrations of DMSO to be used and tolerated, by for example,
reducing the side-effects of DMSO and/or reducing the odor
associated with DMSO. In one embodiment, the use of MSM in amounts
greater than 800 mg (e.g., in a single or daily dose) increase the
tolerability of DMSO in amounts greater than 200 mg (e.g., in a
single or daily dose).
[0041] In several embodiments of the invention, a formulation
comprising DMSO in a solid form is provided. In some embodiments,
the DMSO is in a solid phase at room temperature. The DMSO in solid
formulation is suitable for the treatment of several disorders,
including arthritis (e.g., osteoarthritis, rheumatoid arthritis),
and other disorders that would benefit from DMSO treatment (e.g.,
osteophyte formation). In some embodiments, the solid formulation
is used for the treatment of inflammation, pain, or a combination
thereof. In several embodiments, DMSO and MSM are combined to form
a solid, wherein the solid remains a solid at room temperature. The
solid formulation includes, but is not limited to, a capsule, a
gel-cap, a tablet, an oral suspension, a powder, an effervescent,
or combinations thereof. A coating is provided in some embodiments.
The coating provides sustained-release, sustained-action,
extended-release, controlled-release, or continuous-release of the
formulation according to several embodiments. In some embodiments,
the coating further provides a flavorant. In one embodiment, DMSO
is between about 0.01% to about 10% by weight of the formulation.
In another embodiment, DMSO is between about 45% to about 55% by
weight of the formulation. In one embodiment, the formulation is
provided in a capsule comprising about 100 mg to about 1000 mg of
said DMSO, wherein said capsule is suitable for delivery 1-4 times
daily.
[0042] In several embodiments, the invention comprises a method for
producing DMSO in a form that is solid at room temperature. In one
embodiment, the method comprises providing DMSO in a liquid form,
combining said liquid DMSO with hydrogen peroxide, heating the
liquid DMSO and the hydrogen peroxide to obtain a combination of
DMSO and MSM, cooling the DMSO and MSM combination into a solid
formulation, wherein said solid formulation is solid at room
temperature. Flaking, prilling and/or freezing is performed
according to some embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0043] FIG. 1 depicts plasma concentrations of MSM after a 5 minute
topical exposure to 10% MSM and varied concentrations of DMSO.
[0044] FIG. 2 depicts the change from baseline of the MSM plasma
concentrations.
DETAILED DESCRIPTION
[0045] The invention, in some embodiments, comprises a formulation
comprising DMSO and MSM, individually or combined, to treat the
chronic effects of osteoarthritis as well the acute symptoms
associated with osteoarthritis. In several embodiments, the
invention comprises a therapeutic system comprising DMSO and MSM,
individually or combined, to treat generalized pervasive pain via
an oral formulation and localized pain via a topical formulation.
In one embodiment, topical formulations of DMSO and/or MSM are also
effective for generalized pain. In several embodiments,
formulations comprising DMSO and MSM, individually or combined, are
multifunctional in that the formulations not only treat the
symptoms of an illness (such as osteoarthritis), but also confer
unrelated benefits (e.g., improvements in skin and other aesthetic
benefits, cardiovascular health, neurological health, immunity,
vision, etc.).
[0046] As discussed herein, in several embodiments, there is
provided an oral and topical dual formulation system for improving
the symptoms of arthritis (including but not limited to
osteoarthritis), the system comprising a first formulation
comprising DMSO and a sulfur-binding and/or sulfur-based agent
(including but not limited to MSM), wherein the first formulation
is suitable for oral administration, wherein the first formulation
comprises about 300 mg to about 750 mg MSM (or other agent) and
about 10 mg to about 50 mg DMSO (e.g., about 650 mg MSM, or other
agent, and about 15 mg DMSO) and a second formulation comprising
DMSO and MSM (or other agent), wherein the second formulation is
suitable for topical administration, wherein the second formulation
comprises about 10% to about 15% MSM (or other agent) about 40% to
about 70% DMSO, or higher (e.g., about 10% MSM, or other agent, and
about 50% DMSO).
[0047] Unless stated otherwise, percentages of MSM, DMSO or other
compounds provided herein are provided as % by weight.
[0048] In one embodiment, a dual formulation system comprising an
oral dosage of 500 mg MSM and 15 mg DMSO together with a topical
dosage of 50% DMSO and 10% MSM is provided. The oral dosage may be
in the form of a tablet, capsule, powder, liquid, oral suspension,
effervescent, or any other form suitable for oral delivery. The
topical dosage may be in the form of a spray, gel, cream, lotion,
patch, or any other form suitable for topical delivery. In some
embodiments, the formulation is administered intravenously or via
inhalation in addition to, or instead of, oral administration.
[0049] In several embodiments, the combined use of MSM reduces or
eliminates the odor normally associated with DMSO. In some
embodiments, the use of solid DMSO reduces or eliminates the odor
normally associated with DMSO. The odor reduction is surprising,
and beneficial in several embodiments because practitioners have
avoided using DMSO in high concentrations (or in any amount)
because of its unpleasant odor.
[0050] In some embodiments, the invention comprises an oral
formulation of DMSO and MSM. In other embodiments, the invention
comprises a topical formulation of DMSO and MSM. According to one
embodiment, the topical formulation is particularly advantageous
because MSM reduces or eliminates the skin irritation that can
result from that topical application of DMSO. For example, in some
embodiments, MSM acts as a lubricant and/or barrier that shields
the skin from DMSO while still permitting penetration. In one
embodiment, topical DMSO in concentrations greater than 25% (e.g.,
50%, 70%, or more) are tolerated because of the presence of MSM. In
one embodiment, the presence of MSM reduces the formation of rash,
redness, dryness of skin, itching, and/or combinations thereof. In
one embodiment, MSM reduces the occurrence, probability or symptoms
associated with a generalized allergic reaction to DMSO, including
heart arrhythmias and breathing difficulties. Because higher
concentrations of DMSO can be administered topically in certain
embodiments, the oral dose of DMSO can be reduced, thereby reducing
the gastrointestinal side effects that can result from the topical
administration of DMSO.
[0051] In several embodiments, the amount of DMSO is reduced when
combined with MSM because of additive or synergistic effects
between DMSO and MSM. In several embodiments, the amount of MSM is
reduced when combined with DMSO because of additive or synergistic
effects between DMSO and MSM. In several embodiments, MSM is
provided in solution in a concentration of less than about 15%. In
some embodiments, oral doses of MSM of less than about 2 grams per
day are administered (e.g., 1 g, 1.5 g, 1.75 g and 1.85 g) to
reduce gastrointestinal side effects in certain applications. In
several embodiments, DMSO increases the penetration of MSM into
tissue (e.g., skin).
[0052] In another embodiment, a formulation comprises, consists or
consists essentially of an oral dosage (e.g., a solid form) of
about 200 mg to about 2000 mg MSM and about 1 mg to about 100 mg
DMSO together with a topical dosage of about 5% to about 90% DMSO
and about 1% to about 50% MSM. In some such embodiments, MSM in the
oral dosage ranges from about 200 to 500 mg, 500 to 800 mg, 800 to
1100 mg, 1100 to 1400 mg, 1400 to 1700 mg, 1700 to 2000 mg, and
overlapping ranges thereof. In some such embodiments, DMSO in the
oral dosage ranges from about 10 to 30 mg, 30 to 50 mg, 50 to 70
mg, 70 to 90 mg, 80 to 100 mg, and overlapping ranges thereof. In
one embodiment, the invention comprises, consists or consists
essentially of about 200 mg to about 2000 mg MSM and about 1 mg to
about 100 mg DMSO, e.g., 400-600 mg MSM and 10-20 mg DMSO, 500 mg
MSM and 15 mg DMSO, or 650 mg MSM and 15 mg DMSO.
[0053] In several embodiments, the invention comprises an oral
formulation (e.g., a solid form) comprising a ratio of MSM to DMSO
of 33:1, and optionally, a topical formulation comprising a ratio
of MSM to DMSO of 1:5. In other embodiments, the invention
comprises an oral formulation having a ratio of MSM to DMSO of
30-50:1, and optionally, a topical formulation having a ratio of
MSM to DMSO of 1:2-10. In yet other embodiments, the invention
comprises an oral formulation having a ratio of MSM to DMSO of
25-35:1, and optionally, a topical formulation having a ratio of
MSM to DMSO of 1:3-7. The ratio of MSM to DMSO in several
embodiments is surprisingly advantageous because the MSM
synergistically improves the efficacy of DMSO. Thus, DMSO, which
may have side effects when administered at certain concentrations,
may be provided at lower concentrations to offer the same or better
therapeutic efficacy. As discussed herein, the presence of MSM in
certain embodiments functions as an emollient. In some embodiments,
MSM reduces the odor normally associated with DMSO.
[0054] In some embodiments, the invention comprises a method of
managing the symptoms of osteoarthritis by administering an oral
dosage of MSM and DMSO daily for at least 1 month, together with a
topical dosage of DMSO and MSM daily for about two weeks. Certain
embodiments are particularly advantageous because they permit
fast-acting symptom relief with the topical dosage, while allowing
the oral dosage to gradually provide long-term relief. In some
embodiments, relief is provided for extended periods of time, e.g.,
a week or more, several weeks, about a month, two months or more.
At the point when the oral dosage becomes effective, patients can
discontinue repetitive use of the topical formulation, thus
reducing the risk of skin irritation and/or localized
bioaccumulation. In still other embodiments, once the oral dosage
has reduced pain and/or symptoms, the topical formulation is not
necessary. In some embodiments, the dosage of the oral or the
topical formulations is adjusted to personalize the therapy for a
particular individual. For example, if an individual normally has
limited chronic symptoms, but severe acute symptoms, a lower dose
oral formulation with a higher dose topical formulation may be
used. In other embodiments, an individual with more severe chronic
symptoms, and few acute symptomatic episodes may benefit from a
higher dose oral formulation and a less concentrated topical
formulation. Thus, a dual formulation comprising both oral and
topical routes of administration are surprisingly advantageous in
several embodiments.
[0055] Oral formulations comprising MSM and DMSO, individually or
combined, are administered multiple times per day in certain
embodiments. In some embodiments, dosing occurs two, three, four or
more times daily, depending on the severity of the osteoarthritis
symptoms. In other embodiments, oral formulations are taken once
per day. Topical formulations, in certain embodiments, are used
multiple times daily, for example two, three, four or more times.
In other embodiments, topical formulations are used only for
treatment of acute exacerbation of symptoms. In some embodiments,
oral formulations are used in conjunction with topical
formulations, while in other embodiments, only oral formulations
are administered.
[0056] In certain embodiments, formulations comprising MSM and
DMSO, individually or combined, (oral, topical, or combinations
thereof) are efficacious in ameliorating one or more symptoms of
osteoarthritis. In some embodiments, formulations comprising MSM
and DMSO, individually or combined, reduce or prevent pain or
stiffness in one or more joints during periods of rest. In some
embodiments, formulations comprising MSM and DMSO, individually or
combined, reduce or prevent pain or stiffness in one or more joints
during periods of light or moderate activity. In still other
embodiments, formulations comprising MSM and DMSO, individually or
combined, reduce or prevent pain or stiffness in one or more joints
during periods of strenuous activity. In several embodiments,
formulations comprising MSM and DMSO, individually or combined,
reduce pain, stiffness and/or inflammation at rest, during
activity, and/or post-activity.
[0057] In several embodiments, the combination of DMSO and MSM in a
single formulation results in a synergistic effect, thereby
lowering the concentration of DMSO, MSM, or both DMSO and MSM
needed to effectively reduce one or more symptoms of
osteoarthritis. Toxicology studies have established that DMSO can
be chronically administered at 5 g/kg daily without any serious
adverse effects. In certain embodiments, the dosage of oral DMSO
ranges from about 0.003 to 0.06 g per day. In some embodiments, the
dosage of oral DMSO is about 0.045 g per day. Assuming an average
of 50 kg per subject, these dosages equate to a range of about
0.00006 to about 0.0012 g/Kg daily (0.0012 to 0.024% of the dose
given in the toxicology studies without serious adverse
effect).
[0058] Oral toxicity of MSM has been previously determined through
standard methods in rats. The LD.sub.50 value was approximately 17
g/kg, which corresponds to an oral dose of 2.6 pounds per day for a
150 pound human. In certain embodiments, the dosage of oral MSM
ranges from about 1.0 to 2.5 g per day. In some embodiments, the
dosage of oral MSM is 1.95 g per day. In other embodiments, MSM is
administered (e.g., orally) in a dosage of up to about 6 g/day.
These doses are well below the range of toxicity determined for
MSM. At this dosage level, MSM reduces inflammation and
radiological changes in the joint in several embodiments.
[0059] In certain embodiments, the synergistic effects between DMSO
and MSM reduce the concentration of DMSO and/or MSM required to
function as an effective anti-inflammatory or to generate analgesic
effects. In certain embodiments, the synergy reduces the
concentration of DMSO and/or MSM required to prevent structural
changes to affected joints, the articular cartilage of joints and
the juxtaposed subchondral bone. In several embodiments, DMSO
functions to facilitate the activity of MSM (e.g., analgesia,
anti-inflammatory effects, and the like). In some embodiments, DMSO
provides further positive effects on the same aspects of a disease
or condition that MSM positively impacts. Thus, in some
embodiments, DMSO supplements and also facilitates the actions of
MSM.
[0060] Further, the synergistic effects of certain embodiments
reduce the amount of time from inception of treatment to
amelioration of osteoarthritis symptoms. In some embodiments, this
time period is reduced several fold, for example from the order of
several months down to the order of several weeks. In certain
embodiments, the synergistic effects result in symptomatic
improvement within about 2 to 6 weeks.
[0061] In several embodiments, a formulation comprising DMSO and
MSM lowers the amount of MSM required orally. In one embodiment,
DMSO allows MSM to penetrate skin more effectively. According to
some embodiments, the combination permits lower amounts of both
DMSO and MSM to be used therapeutically, and optionally lowers
odor, gastrointestinal symptoms, and/or the size of the capsule (or
pill, tablet, or other dosage format). In one embodiment, MSM binds
with DMSO metabolites for further odor reduction. In some
embodiments (e.g., liquid forms for children), a flavor is added to
DMSO and MSM to improve taste. Formulations comprising DMSO and/or
MSM may also be added to therapeutic confectionaries, such as chews
and gummies.
[0062] The synergism of DMSO and MSM according to several
embodiments, allows reductions in the concentrations needed to
effectively reduce osteoarthritis symptoms. In certain embodiments,
the MSM functions as a skin protectant and unexpectedly protects
the skin from the adverse effects of DMSO exposure. In some
embodiments, topical MSM functions primarily as an inactive
ingredient, e.g., it functions primarily to minimize dermal
irritation that may otherwise be induced by topical DMSO
administration. In some embodiments, MSM functions as a lubricant
for the skin (e.g., to prevent excessive drying of the skin). In
certain embodiments, the efficacious concentration of DMSO for
lower limb joint treatment is reduced to 50% DMSO, or lower. In
certain embodiments, the efficacious concentration of DMSO for
upper limb joint treatment is reduced to 25-50% DMSO. In some
embodiments, the duration that the skin is exposed to DMSO is
reduced, because the DMSO/MSM formulation is more efficacious than
DMSO alone. Thus, in certain embodiments, the DMSO/MSM topical
formulation is left on the skin for 2-15 minutes and then removed
(e.g., washed off). In other embodiments, DMSO/MSM topical
formulation is left on the skin for about 5-10 minutes and then
removed (e.g., washed off). In such embodiments, the possibility of
side effects from DMSO exposure is reduced due to the reduction in
exposure time and the protectant effects of MSM. However, in
further embodiments, DMSO/MSM topical formulation is left on the
skin and not removed. In some embodiments, DMSO and/or MSM act as
antioxidants.
[0063] In several embodiments, the penetrant effect of DMSO allows
MSM to achieve greater skin penetration and absorption, allowing
enhanced anti-inflammatory effects. In some embodiments, the
DMSO/MSM topical formulation unexpectedly provides analgesic
effects. Further, the synergism exhibited by DMSO and MSM in the
topical formulations can improve osteoarthritis symptoms in as
little as about 1/2 a day to about 3 days, according to several
embodiments. In some embodiments, DMSO and/or MSM are analgesic
when provided in an oral dosage form.
[0064] In some embodiments, the synergism of DMSO and MSM, and the
associated reduction in doses of both compounds, enables the
simultaneous use of both oral and topical formulations. The reduced
concentrations of DMSO and MSM (as compared to therapies of either
DMSO or MSM alone), according to several embodiments described
herein, reduce the overall occurrence of side effects and thereby
enable simultaneous use of oral and topical formulations. Such
embodiments therefore allow use of a topical formulation to
ameliorate any acute joint pain, while the oral formulation serves
to lower inflammation and pain on a chronic basis with minimal
complications.
[0065] In some embodiments, the combination of DMSO and MSM and/or
the use of solidified DMSO unexpectedly reduces the unpleasant odor
normally experienced with DMSO use. For example, in certain
embodiments, formulations comprising DMSO and MSM produce no
perceptible odor after use. In some embodiments, a formulation
comprising 10%-50% MSM reduces or eliminates the odor of DMSO
provided at a concentration of 50%-90%. Previously, DMSO used at
concentrations approaching 50% (or more) were associated with a
strong unpleasant odor that could be detected through the skin or
on the breath of a patient. Thus, several embodiments of the
compositions described herein are unexpectedly advantageous because
they reduce or eliminate the odor-related side effect.
[0066] According to any of the embodiments disclosed herein, a
therapeutic system comprising MSM and DMSO, individually or
combined, also includes one or more of the following compounds:
ibuprofen, fenoprofen, indomethacin, naproxen, tolmetin, salicylic
acid, and sulindac. In other embodiments, a therapeutic system
comprising DMSO and/or MSM also includes one or more of the
following compounds: antioxidants, glucosamine, chondroitin,
niacinamide, S-adenosylmethionine, curcumin, quercetin, omega-3
fatty acids, papain, hyaluronic acid, and bromelain. In several
embodiments, a formulation comprising DMSO and/or MSM and about
500-2500 mg glucosamine is provided. One or more of the following
compounds may be used in addition to, or in place of, glucosamine:
about 500-5000 mg fish oil, about 500-5000 IU Vitamin D, about
500-2500 mg chondroitin, 500-5000 mg or IU antioxidants (such as
vitamin C, E or beta-carotene), about 500-2500 mg curcumin, and
about 50-2500 mg hyaluronic acid. In some embodiments, formulations
comprising DMSO and/or MSM inhibit the secretion of
pro-inflammatory enzymes that are contribute to the breakdown of
cartilage, including collagenase, hyaluronidase, and elastase. In
some embodiments, formulations consisting or consisting essentially
of DMSO and/or MSM inhibit the secretion of pro-inflammatory
enzymes that are contribute to the breakdown of cartilage.
[0067] In several embodiments, a formulation comprising DMSO and/or
MSM without a gastroprotectant is provided. Thus, several
embodiments of the invention are particularly advantageous because
it is estimated that many severe arthritic patients who are
receiving NSAIDs are also co-prescribed a gastroprotectant.
[0068] In certain embodiments, the amount of DMSO in a topical
formulation ranges from about 0.01% by weight to about 70% by
weight. In other embodiments, the formulation comprises between
about 0.01% and 10% DMSO by weight, and overlapping ranges thereof.
Other embodiments comprise between about 10% and 20% DMSO, about
20-30% DMSO, about 30-40% DMSO, about 40-50% DMSO, about 50-60%, or
about 60-70% DMSO, and overlapping ranges thereof. Still other
embodiments comprise a formulation comprising between about 7% and
15% DMSO, about 15-25% DMSO, about 25-35% DMSO, about 35-45% DMSO,
about 45-55% DMSO, about 55-60%, about 60-65%, or about 65-70%, and
overlapping ranges thereof. In certain embodiments, DMSO is present
in a range between about 45-55% by weight, including 45, 46, 47,
48, 49, 50, 51, 52, 53, 54, and 55%, and overlapping ranges
thereof. In some embodiments, DMSO is provided in a range from
about 70% to about 90%. Higher concentrations of DMSO may also be
used in other embodiments.
[0069] In certain embodiments, the amount of MSM in a topical
formulation ranges from about 0.01% by weight to about 70% by
weight. In some embodiments, the formulation comprises between
about 0.01% and 10% MSM by weight, and overlapping ranges thereof.
Other embodiments comprise a formulation comprising between about
10% and 20% MSM, about 20-30% MSM, about 30-40% MSM, about 40-50%
MSM, about 50-60%, or about 60-70% MSM, and overlapping ranges
thereof. Still other embodiments comprise between about 7% and 15%
MSM, about 15-25% MSM, about 25-35% MSM, about 35-45% MSM, or about
45-55% MSM, and overlapping ranges thereof. In certain other
embodiments, MSM is present in a range between about 5-15% by
weight, including 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15%, and
overlapping ranges thereof. In some embodiments, MSM is provided in
a range from about 70% to about 90%. Higher concentrations of MSM
may also be used in other embodiments. In several embodiments, the
percentages above are based on the volume of MSM used in an
embodiment.
[0070] In several embodiments, a topical formulation MSM and DMSO,
individually or combined, is provided in a concentration sufficient
for application to the body in a thin layer. In one embodiment, the
DMSO/MSM formulation is wiped across the surface of a joint in a
thin layer and removed about five to ten minutes later with, for
example, a wet wash cloth. In one embodiment, the target tissue
(e.g., skin of the knee or other joint) is cleaned to deter the
penetration of contaminants by DMSO. In some embodiments, volumes
of the topical formulation applied range from about 0.5 mL to about
10 mL, depending on the tissue to which the formulation is applied.
Thus, in some embodiments, the amount of the topical formulation
applied in one use is between about 0.5 mL to about 1 mL, about 1
mL to about 3 mL, about 3 mL to about 5 mL, about 5 mL to about 7
mL, about 7 mL to about 10 mL, about 10 mL to about 20 mL, and
overlapping ranges thereof. In some embodiments, a formulation
comprising MSM, DMSO, or a combination of MSM and DMSO is provided
in a topical formulation and a user is instructed to apply about 3
mL to about 15 mL per application per body part (e.g., knee).
[0071] In several embodiments, the topical formulation comprising
MSM and DMSO, individually or combined, further comprises one or
more inactive ingredients including, among others, de-ionized water
and various polymers (for example, carbopol 974 NF). Active
ingredients may also be provided. In some embodiments, a
formulation consisting or consisting essentially of MSM and DMSO,
individually or combined, is provided.
[0072] In some embodiments, formulations comprising DMSO and urea,
and optionally MSM are provided to reduce odor. In some
embodiments, formulations comprising DMSO and sulfur-binding
compounds are used to reduce odor. In some embodiments,
formulations comprising DMSO and at least one odor-reducing
nutrient are used to reduce odor. In several embodiments in which
odor is reduced, odors associated with the oxidation, metabolism,
degradation or other conversion of DMSO are reduced. For example,
in one embodiment, odors associated with methylthiomethane (DMS)
are reduced. In some embodiments, MSM is used to reduce the odor of
DMS that is produced by bacterial transformation of DMSO waste that
is disposed (e.g., into sewage systems).
[0073] In several embodiments in which odor is reduced, odors
associated with the oxidation, metabolism, degradation or other
conversion of DMSO are reduced. In some embodiments, odors are
reduced through the binding of odiferous compounds. In some
embodiments, odors are reduced by reducing the production of
odor-causing compounds. In some embodiments, odors are reduced by
increasing the degradation of odor-causing compounds. According to
one embodiment, compounds such as MSM are provided to reduce the
odor associated with DMSO use by reducing the formation of DMSO
metabolites or by binding to DMSO metabolites (e.g., DMS).
[0074] In several embodiments, a combined topical and oral DMSO/MSM
formulation is used to treat osteoarthritis of the knee. In some
embodiments, the formulation is used to treat a condition in which
the patient has both knee pain and osteophytes (bone spurs)
visualized on radiographs or when the patient is 40 years of age
(or older), has morning knee stiffness lasting 30 minutes or less,
and crepitus (grating, crackling or popping sounds) is detectable
on motion of the knee.
[0075] In several embodiments, a combined topical and oral DMSO/MSM
formulation is used to treat osteoarthritis of the hand. In some
embodiments, the formulation is used to treat a condition in which
a patient has hand pain, aching or stiffness, hard tissue
enlargement of two or more of 10 selected joints, fewer than three
swollen metacarpophalangeal joints, and hard tissue enlargement of
two or more distal interphalangeal joints. In other embodiments,
the formulation is used to treat a condition in which a patient has
deformity of two or more of 10 selected joints (second and third
distal interphalangeal joints, the second and third proximal
interphalangeal joints and the first carpometacarpal joints (of
both hands).
[0076] In several embodiments, a formulation comprising DMSO and
MSM, alone or combined, is used to treat one or more joints of a
patient, including but not limited to the knee, toe, thumb, finger,
ankle, spine, hip, shoulder or other joint. In some embodiments, a
formulation comprising DMSO and MSM, alone or combined, is used to
treat lower back pain (e.g., pain in or associated with spinal
column).
[0077] According to any of the embodiments disclosed herein, a
combined topical and oral formulation comprising MSM and DMSO,
individually or combined, is used to treat cartilage degeneration
and/or degeneration of subchondral bone. In some embodiments, the
formulation prevents, halts or treats bone spur formations,
calcified areas and/or other undesired formations. A combined
topical and oral DMSO/MSM formulation may also be used to treat
joint pain, tenderness, stiffness, creaking, locking of joints,
and/or local inflammation. In several embodiments, a combined
topical and oral DMSO/MSM formulation is used to positively affect
one or more of the following measures: (i) Radiological testing for
both the knee and hand; (ii) Likert pain index on resting for both
the knee and hand; (iii) Fuchs swelling index for both the knee and
hand; (iv) Range of motion for both the knee and hand (or other
joint); (v) Visual analog scale-pain intensity (VAS-PI) with
loading for both the knee and hand and VAS Patient global
assessment; (vi) The Lequesne index for the knee; (vii) WOMAC
(Western Ontario and McMaster Osteoarthritis) physical stiffness
and pain scale for the knee; (viii) Functional Index for Hand
Osteoarthritis; (ix) Grip strength measurement; and (x) Rescue
medication usage. Improvements of about 5%-100% in the identified
measures are provided according to several embodiments (e.g.,
improvements of about 10-25%, 25-50%, 50-75%, 75-100%, and
overlapping ranges thereof). Improvements in pain and inflammation
may also be accompanied by increased range of motion, grip strength
and general ability to perform daily activities according to
several embodiments.
[0078] In several embodiments, a formulation comprising MSM and
DMSO, individually or combined, is used to treat weakness,
inflammation and/or pain in the hand, knee, or other joint. The
formulation can be administered orally, topically, orally, or both
orally and topically.
[0079] According to any of the embodiments disclosed herein, an
oral formulation comprising MSM and DMSO, individually or combined,
is used exclusively (without the topical treatment). According to
any of the embodiments disclosed herein, a formulation comprising
MSM and DMSO, individually or combined, is provided in a form
suitable for administration intravenously, intra-articularly,
and/or via inhalation in addition to or instead of oral
administration. In some embodiments, the formulation is
administration intravenously, intra-articularly, and/or via
inhalation in addition to or instead of topical administration.
[0080] In several embodiments, subjects treated with a formulation
comprising MSM and DMSO, individually or combined, include humans,
non-human mammals, domesticated animals and livestock. In some
embodiments, a formulation comprising MSM and DMSO, individually or
combined, is used to not only treat undesired symptoms and
illnesses, but can also act as a preventative. For example, an oral
and/or topical formulation comprising MSM and DMSO, individually or
combined, may be taken on a regular basis to prevent the onset of
illness. Reversal of osteoarthritis is provided in several
embodiments, while in other embodiments, formulations comprising
MSM and DMSO, individually or combined, prevent the onset or
progression of the disease.
Formulations Comprising Solid DMSO
[0081] In several embodiments, a formulation comprising solid DMSO,
alone or in combination with MSM, is provided. Pure DMSO is
typically a clear and colorless dipolar liquid at room temperature
with a melting point of 18.4.degree. C. (or 65.degree. F.), a flash
point of 95.degree. C., and a boiling point of 189.degree. C. at
sea level. It is an aprotic and very hygroscopic chemical with a
molecular weight of 78.13. However, application or ingestion of
DMSO often yields an unpleasant odor, which "tastes" like garlic
shortly after it contacts the skin. In addition, irritation,
dryness, redness and/or itching of the skin can develop where DMSO
is applied topically in repeated doses or in high concentrations.
Other side effects of DMSO can include sensitivity to light, visual
disturbances, headache, nausea, upset stomach, and diarrhea. Side
effects, such as allergic reactions to DMSO, can occur in certain
cases, e.g., palpitations, arrhythmias, and/or respiratory issues.
Undesired effects of DMSO may be caused by DMSO, its metabolism,
catalysis, oxidation, degradation, and/or other conversion. Due to
its physical properties, DMSO is typically utilized in its liquid
form.
[0082] MSM is an organosulfur compound that is a metabolite of DMSO
and certain sulfur-containing amino acids. It is a white,
water-soluble powder with a melting point of 109.degree. C., a
flash point of 143.degree. C., and a boiling point of 248.degree.
C. It has a molecular weight of 94.13.
[0083] Due to its physical properties, DMSO exists as a liquid at
room temperature, and is therefore typically utilized as a liquid.
However, there is a long felt and as yet unmet need for a solid
form of DMSO at room temperature. For example, solid forms of DMSO
are particularly advantageous because they (i) are able to be
manufactured or packaged into pill, tablet or capsule form; (ii)
are able to achieve concentrated forms (about 2-50 fold more
concentrated than liquid forms per dose size); (iii) exhibit
reduced side effects as compared to the liquid form (e.g., less
irritation, sensitivities, gastrointestinal effects, etc.); and
(iv) exhibit reduced or no odor as compared to the liquid form. In
some embodiments, the use of DMSO that stays solid at room
temperature is particularly advantageous because it permits the
inclusion of DMSO into capsules (or other packaging) that would
normally be degraded by liquid DMSO.
[0084] In some embodiments, DMSO that is solid at room temperature
is provided. In some embodiments, DMSO that is solid at
temperatures between 70-80.degree. F., 80-90.degree. F.,
90-100.degree. F., 100-125.degree. F., and higher than 125.degree.
F. is provided. In other embodiments, DMSO that is solid at room
temperature is provided, wherein said DMSO liquefies at about
65.degree. F.
[0085] In accordance with certain embodiments, surprisingly, the
combination of DMSO and MSM yields a solid form of DMSO at room
temperature. In some embodiments, DMSO and MSM are combined by
mixing hydrogen peroxide with a liquid form of DMSO. In these
embodiments, the hydrogen peroxide and DMSO are heated. In some
embodiments, MSM is formed, but not all of the DMSO is removed. In
certain other embodiments, DMSO and MSM are combined by mixing a
liquid form of DMSO in a MSM solution. In these embodiments, the
solution can be heated and agitated. In some embodiments, DMSO and
MSM are combined by mixing a solid form of MSM in a liquid form of
DMSO. In other embodiments, DMSO and MSM are combined by mixing a
liquid form of DMSO with a molten form of MSM.
[0086] In one embodiment, liquid DMSO is used as a starting
material. The liquid form of DMSO is mixed with hydrogen peroxide
(H.sub.2O.sub.2) at a temperature and time sufficient for
substantially all of the hydrogen peroxide to be consumed and for
MSM and water by-product to form. In certain embodiments, not all
of the DMSO is removed, thereby yielding a molten DMSO/MSM
combination that may subsequently be cooled. For example, in one
embodiment, liquid DMSO at a concentration of about 90-100% is
combined with 30% to 51% H.sub.2O.sub.2 at stoichiometric ratio and
a temperature of about 230-250.degree. F. until at least 90% of the
H.sub.2O.sub.2 is consumed, and a product containing about 0.1%-15%
DMSO and 85%-99.9% MSM is produced. Extreme caution must be
maintained as this is an extremely exothermic reaction.
[0087] In several embodiments, the preparation of MSM involves a
high temperature distillation step which results in molten MSM. In
such embodiments, DMSO may be added back into the molten MSM in
known quantities under agitation. In some embodiments, the DMSO
added back is in liquid form, while in other embodiments, the DMSO
is in solid form. The resultant DMSO/MSM combination is further
agitated and then rapidly cooled in one embodiment.
[0088] In one embodiment, the molten DMSO/MSM combination is sent
to a spray cooler/prilling chamber to form solid prills or
microprills (microspherical pellets). In certain embodiments, the
molten DMSO/MSM combination is fed into the prilling chamber where
the molten DMSO/MSM combination enters a droplet generator to
discharge the material in the form of droplets. As the droplets
fall freely, they are cooled and solidify into spheres or prills.
The spheres or prills have a diameter in the range of about 75
microns to 840 microns (e.g., about 75-150 microns, about 150-300
microns, about 300-450 microns, about 450-600 microns, about
600-840 microns, and overlapping ranges therein).
[0089] In certain embodiments, the droplets are cooled with a flow
of cold gas, such as but not limited to air, nitrogen gas, or
carbon dioxide. In certain other embodiments, the droplets are
cooled with a spray of cold water or cold liquid nitrogen. In other
embodiments, the droplets are cooled by dry ice. In accordance with
certain embodiments described herein, after the droplets are
cooled, since the exteriors of the droplets cool first, the prills
can remain in the cool temperature to solidify the interiors of the
prills.
[0090] In certain other embodiments, the molten DMSO/MSM
combination (e.g., mixture) is sent to a flaking system to form
solid flakes. For example, in one embodiment, the molten DMSO/MSM
combination is sent to a drum flaker, where a thin warm layer of
the molten DMSO/MSM combination is applied to the outside of a
rotating drum. As the drum rotates, a cooling agent housed within
the rotating drum cools and solidifies the layer of material on the
exterior of the drum, and a knife scraper removes the material in
the shape of flakes. Various cooling agents can be used, for
example, liquid nitrogen, liquid oxygen, cooled water, or cooled
water containing polypropylene glycol.
[0091] In accordance with several embodiments described herein, MSM
can be purified prior to combining it with DMSO. In some
embodiments, purification is accomplished by distillation, among
other methods. In certain embodiments, DMSO powders or flakes are
combined with MSM prill. In other embodiments, DMSO powders or
flakes are combined with MSM flakes. In other embodiments, DMSO
powders or flakes are combined with MSM powder. In certain
embodiments, a homogenous mixture of DMSO/MSM is produced, while in
other embodiments, a non-homogenous mixture results.
[0092] In accordance with several embodiments described herein, MSM
may be combined with DMSO to form a DMSO/MSM solution, and the
resultant mixed solution is subsequently frozen and ground into
powder. In some embodiments, the liquid phase of the DMSO/MSM
solution is water. In some embodiments, distilled, deionized, or
distilled-deionized water is used. In other embodiments, other
liquids may used. For example, the DMSO/MSM solution may contain
normal saline, or another acceptable solvent. In certain
embodiments, the ionic characteristics of the liquid may be
adjusted to affect the resultant DMSO/MSM product. In some
embodiments, other ingredients are added into the solution, with
the solution heated and agitated to facilitate mixing. The DMSO/MSM
solution can be cooled and frozen. For example, the liquid DMSO can
be cooled in a cooling chamber containing cold gas, such as but not
limited to air, nitrogen gas, or carbon dioxide. The DMSO/MSM
combination is then ground by any grinding or milling technique
well known in the art or yet to be devised.
[0093] In other embodiments, DMSO is added to molten MSM. In
certain embodiments, the DMSO/MSM combination is formed into a
solid by a spray cooler/prilling chamber as described above. In
other embodiments, the DMSO/MSM combination is formed into a solid
by a flaking system as described herein.
[0094] In some embodiments, the purity of the starting raw
materials can be altered to adjust the purity of the end product.
Depending on the level of purity required, one or more purification
processes may be employed. For example, in some embodiments where
DMSO is the starting material, impurities can exist because DMSO is
a strong solvent. Thus, the starting MSM and/or DMSO may be
purified prior to the manufacture of the DMSO/MSM combination. In
some embodiments, the synthesis of MSM from DMSO yields side
reactions and compounds. In some embodiments, additional
purification can be performed after the DMSO/MSM product is
formed.
[0095] In one embodiment, distillation is employed as the
purification process. Other contaminant/by-product removing
procedures may be used instead of, or in addition to, distillation.
Distillation removes the water and contaminates from the raw
materials and from side reactions. In accordance with some
embodiments described herein, distillation can form a molten MSM
into which DMSO may be added. In some embodiments, the DMSO/MSM
combination is tested after production to reduce potential
hazardous heavy metals, such as lead, mercury, cadmium, and
arsenic, to levels below specified standards.
[0096] In some embodiments, gelatin and/or hydroxypropyl
methylcellulose (HPMC) is used with the organic based solvent
system to form a gel-cap. In other embodiments, the organic based
solvent system is used to form a tablet. In some embodiments, the
tablet is uncoated. In some embodiments, the tablet is coated. In
certain embodiments, the coating is pH stable and provides a
time-release effect, such that the tablet is positioned in a
portion of the gastrointestinal tract that is highly absorptive,
such as the ileum.
[0097] In several embodiments, the organic based solvent system is
used to formulate an orally consumable effervescent DMSO/MSM
formulation, allowing for enhanced absorption of DMSO and MSM. For
example, in certain embodiments, a DMSO/MSM powder is produced that
when added to a consumable liquid, dissolves and yields and
effervescent beverage for consumption. In certain embodiments, the
DMSO/MSM powder is pre-packaged into single-dose serving sizes. In
other embodiments, formulations comprising DMSO and MSM, alone or
combined, are formulated into a tablet that can similarly be
dissolved to produce an effervescent beverage. Any consumable
liquid may be used to dissolve, the powder or tablet, with the
taste of the liquid being driven by the choice of the consumer. In
other embodiments, flavors may be added to the DMSO and/or MSM
powder or tablet, such that, when combined with water, a flavored
effervescent beverage results.
[0098] In accordance with some embodiments described herein, a
DMSO/MSM active capsule is produced. In one non-limiting example,
prior to or during the process to form the DMSO/MSM combination
into a solid, vegetable coating, amorphous silicon dioxide, and
magnesium stearate are blended and added into the DMSO/MSM
combination to produce a formulation comprising 650 mg of MSM, 15
mg of DMSO, 285 mg of Dritex-S Flake coating, 4.75 mg of silicon
dioxide, and 4.75 mg of magnesium stearate. The vegetable coating
may be fully hydrogenated soybean oil that has been further
processed into flake form such as Dritex-S flakes and used as an
encapsulating agent. A placebo capsule can also be produced with a
formulation consisting of 1 mg of DMSO, 950 mg of Pac-Gel 70, 4.75
mg of silicon dioxide, and 4.75 mg of magnesium stearate. In
several embodiments, as discussed herein, greater or lesser
percentages of MSM and/or DMSO are used for active oral
formulations. Placebos are also adjusted accordingly. In some
embodiments, multilayer emulsions are provided as coating
materials. In one embodiment, nano-laminated lipids are used as
coating materials. Polymers are used in some embodiments. In some
embodiments, coatings comprise hydrogels, gelatins, soybean oil,
malitol, or combination thereof.
[0099] In accordance with certain embodiments described herein,
topical formulations, e.g., gels, lotions, and creams, can be
produced by mixing DMSO into a MSM solution. In some embodiments,
distilled, deionized, or distilled-deionized water is used. In
other embodiments, other liquids may used. For example, the MSM
solution may contain normal saline, or another acceptable solvent.
In certain embodiments, other ingredients such as thickening
agents, emulsifiers, and fragrances, used in topical formulations
which are well known in the art or yet to be devised can be mixed
into the solution. In certain embodiments, the solution is heated
and agitated to facilitate dissolution. Once mixed, the solution is
allowed to cool to form a gel, lotion or cream in some
embodiments.
[0100] In one embodiment, an active topical gel is produced. In one
non-limiting example, 50 ml of de-ionized water is warmed on a hot
plate. MSM (12 g) is added to the warm water and dissolved. After
complete dissolution of the MSM, DMSO (60 g) is added to the MSM
solution. Crosslinked acrylic acid polymer (Carbopol 974 NF) is
added to the solution with constant agitation, which serves to wet
the polymer as it is being added. The temperature of the solution
is brought to between about 50-60.degree. C. and agitation is
continued until the polymer is completely dissolved. Sodium
carbonate (Na.sub.2CO.sub.3, 0.02 g) is dissolved in an additional
10 mL of deionized water. Once the Na.sub.2CO.sub.3 is completely
dissolved, it is added to the DMSO/MSM/polymer solution with
simultaneous stirring by hand. Once thoroughly mixed, the solution
is allowed to cool, resulting in a viscous gel of containing 50%
DMSO/10% MSM with 1% Carbopol 974 NF and 39% de-ionized water.
Viscosity is measured at approximately 300,000 cPs at 23.degree. C.
(73.degree. F.). In several embodiments, as discussed herein,
greater or lesser percentages of MSM and/or DMSO are used for
topical formulations. In several embodiments, percentages of DMSO
and/or MSM are by volume, as stated, rather than by weight.
[0101] In certain embodiments described herein, formulations
comprising DMSO and MSM, alone or in combination, are provided the
form of a capsule, a gel-cap, a tablet, oral suspension, a powder,
or an effervescent. Gels, slurries, particles, powders and other
dehydrated forms are also provided in some embodiments. In certain
embodiments, a formulation comprising DMSO and MSM that is not
liquid (e.g., a solid) at room temperature is provided. In some
embodiments, solid formulations are advantageous in that they
maintain their consistency, e.g., maintain one or more of a
hardness, firmness, density, texture, and/or viscosity that is at
least 75%, 85%, 95% or 100% the same, over a wide range of
temperatures (e.g., from about 0.degree. C. to about 100.degree.
C., about 5.degree. C. to about 50.degree. C., about 10.degree. C.
to about 40.degree. C., about 20.degree. C. and about 30.degree.
C., and overlapping ranges thereof). Certain embodiments are
covered with a coating while other embodiments are not coated.
Where a coating is provided, the coating may render a time-release
effect. In certain embodiments, DMSO is between about 0.01% to
about 10% by weight of the formulation. In several embodiments, the
percentages above are based on the volume of DMSO used in an
embodiment.
[0102] In several embodiments, a solid formulation comprising DMSO
is used in several industrial and medical applications. In some
embodiments, solid DMSO is used for storing and transporting
DMSO.
[0103] In several embodiments, the amount of DMSO in a solid
formulation comprising DMSO and MSM (and optionally other
ingredients) ranges from about 0.01% by weight to about 90% by
weight. In other embodiments, the formulation comprises between
about 0.01% and 10% DMSO by weight. In certain embodiments DMSO is
present in about 0.01% to about 5%, about 0.01% to about 2.5%, or
0.01% to about 2.0%. In some embodiments, DMSO is present in about
0.5% to about 1.75%, including 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2,
1.3, 1.4, 1.5, 1.55, 1.6, 1.65, 1.7, and 1.75%, and overlapping
ranges thereof. Other embodiments comprise a formulation comprising
between about 10 and 20% DMSO, about 20-30% DMSO, about 30-40%
DMSO, about 40-50% DMSO, about 50-60% DMSO, about 60-70% DMSO,
about 70-80% DMSO, about 80-90% DMSO. Still other embodiments
comprise from about 7 to about 15% DMSO, about 15-25% DMSO, about
25-35% DMSO, about 35-45% DMSO, about 45-55% DMSO, about 55-65%
DMSO, about 65-75% DMSO, or about 75-85% DMSO, and overlapping
ranges thereof. Several embodiments for capsules, gel-caps,
powders, and effervescents comprise between about 0.01-10% DMSO,
including 0.5, 1, 2, 3, 4, 5, 6, 7, 8, and 9% DMSO. Several
embodiments for gels, lotions, and creams comprise DMSO at a
concentration of between 30% and 90%, for example, about
45-55%.
[0104] In several embodiments, the amount of MSM in a solid
formulation comprising DMSO and MSM (and optionally other
ingredients) ranges from about 0.01% by weight to about 70% by
weight. In other embodiments, the formulation comprises between
about 0.01% and 10% MSM by weight. Other embodiments comprise
between about 10 and 20% MSM, about 20-30% MSM, about 30-40% MSM,
about 40-50% MSM, about 50-60% MSM, or about 60-70% MSM including
60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70% MSM, and
overlapping ranges thereof. Still other embodiments comprise a
formulation comprising about 7 and 15% MSM, about 15-25% MSM, about
25-35% MSM, about 35-45% MSM, about 55-60% MSM, about 60-65% MSM,
or about 65-70% MSM, and overlapping ranges thereof. Some
embodiments for capsules, gel-caps, powders, and effervescents
comprise between about 90-99% MSM, including 91, 92, 93, 94, 95,
96, 97, and 98% MSM. Several embodiments for gels, lotions, and
creams comprise between about 5 to 15% MSM.
[0105] In some embodiments, the solid formulation is uncoated. In
other embodiments, the solid formulation is covered with a coating.
In some embodiments, the coating provides a time-release effect
(e.g., sustained-release, sustained-action, extended-release,
controlled-release, or continuous-release). Coatings, in some
embodiments, incorporate a flavor additive, such that there is no
chalky or medicinal-tasting residue remaining after consuming the
solid formulation. As used herein, "solid" shall be given its
ordinary meaning and shall additionally refer to semi-solids, gels,
viscous solutions, and other compounds that are not in liquid or
gaseous phases. Solidified DMSO, alone or in combination with MSM,
may be provided in the form of oral capsules, gel-caps, tablets,
powders, and effervescents, or topical gels, lotions, and creams.
Other forms may also be manufactured. As used herein, "compound"
shall be given its ordinary meaning and shall include, but not be
limited to, molecules, ingredients, atoms, substances and
elements.
[0106] In some embodiments, one or more additional agents are added
into the DMSO/MSM combination. In certain embodiments,
pharmaceuticals, including but not limited to analgesics and
anti-inflammatory agents, are employed with the DMSO/MSM
combination. In certain embodiments, antimicrobials, such as
penicillin and antibiotics, can be employed with the DMSO/MSM
combination. In certain embodiments, vitamins and supplements are
added.
[0107] In several embodiments, a solid formulation comprising MSM
and DMSO, individually or combined, is provided that optionally
comprises one or more inactive ingredients including, among others,
microencapsulating agents (for example Dritex-S Flake coating),
silicon dioxide, and magnesium stearate. In several embodiments, a
solid formulation comprising MSM and DMSO, alone or in combination,
is encapsulated to, for example, facilitate delivery, bioactivity,
absorption, time-release, and/or palatability. In several
embodiments, non-encapsulated powders facilitate delivery,
bioactivity, absorption, time-release, and/or palatability.
EXAMPLE
[0108] The following example is provided to further illustrate
certain embodiments within the scope of the invention. The example
is not to be construed as a limitation of any embodiments, since
numerous modifications and variations are possible without
departing from the spirit and scope of the invention.
Example 1
Absorption of MSM in Topical Formulation is within Recognized Safe
Levels
[0109] Approximately 17% of DMSO is metabolized into MSM in the
body. DMSO has been established to function as a penetration
enhancer (among other functions). This study investigated the
circulating concentrations of MSM when MSM is topically applied in
combination with one of two concentrations of DMSO. According to
the study, in some embodiments, MSM is not a pharmacologically
active ingredient when applied topically. Rather, in some
embodiments, topical MSM works synergistically with DMSO to reduce
one or more side effects of DMSO. Thus, higher concentrations of
DMSO (which would otherwise be prohibitive because of the undesired
side effects) are able to be used to treat subjects.
[0110] New Zealand White rabbits, which are an accepted animal
model for dermal absorption studies, were used to assess the
absorption and resultant blood levels of MSM. Rabbits were obtained
from Charles River Canada (Saint-Constant, Quebec). Five male
rabbits, ages 12-13 weeks (and ranging in weight from 2.6 kg to 2.7
kg) were used for the dermal absorption studies. Rabbits were used
because of their greater skin permeability as compared to rats,
pigs or humans. Thus, testing on rabbits is a more conservative
approach for the safety of topical products for human use. The size
of rabbit was based on the ethical restriction of collecting
greater than 6 mL/kg body weight of blood within a two week period.
The total volume of blood to be removed during this study was 10 mL
on a single day. One animal per group was used to minimize the
number of animals required. Animals were housed individually in
stainless steel cages with 12 hours light/dark cycles. The animal
room environment was monitored daily (targeted ranges:
18-26.degree. C. and relative humidity 25-50%). Fresh air was
supplied to the room at a sufficient rate to provide approximately
15 to 17 changes of room air per hour. Clinical observations were
conducted for all animals to ensure animals were in good health
prior to dosing. Morbidity and mortality observations were also
conducted during the study period.
[0111] Treatment groups were as shown in Table 1:
TABLE-US-00001 TABLE 1 Study 1 Design Surface Number Area Volume of
Blood Collection Group Test Article Exposed Applied Animals Times
(min) A 10% MSM + 90% Water 6 cm.sup.2 0.5 mL 1 0 (pre-dose), 10,
30, 120, 480 minutes B 50% DMSO + 50% Water 6 cm.sup.2 0.5 mL 1 0
(pre-dose), 10, 30, 120, 480 minutes C 70% DMSO + 30% Water 6
cm.sup.2 0.5 mL 1 0 (pre-dose), 10, 30, 120, 480 minute D 10% MSM +
50% DMSO + 6 cm.sup.2 0.5 mL 1 0 (pre-dose), 10, 30, 40% Water 120,
480 minutes E 10% MSM + 70% DMSO + 6 cm.sup.2 0.5 mL 1 0
(pre-dose), 10, 30, 20% Water 120, 480 minutes
[0112] One day prior to the experiment, the rump of each rabbit was
closely clipped using hair clippers. An area of 6 cm.sup.2 was
measured and marked to ensure equivalence in the application of the
various compositions. Each product was applied by pipetting 0.5 mL
of each composition into the center of the test area and spread to
cover the entire test area. After the 5 minute exposure period, the
compositions were removed by wiping, rinsing and drying the test
area.
[0113] Prior to blood collection, animals were tranquilized with
Acepromazine (1 mg/kg) by intramuscular injection in the right hind
leg muscle, after which EMLA cream (lidocaine/prilocaine) was
applied to both ears along the ear artery. Blood was collected by
insertion of a 21G needle (hub removed) into the ear artery.
Approximately 2 mL of whole blood was collected into 4 mL
Vacutainer.TM. tubes (Becton Dickinson, Mississauga, ON) containing
K.sub.2EDTA. Tubes were inverted to mix with the anticoagulant and
stored refrigerated until plasma was separated by centrifugation.
Plasma was separated from whole blood by centrifugation at
3000.times.g for 10 minutes. Plasma was collected, transferred and
stored in a cryovial at -70.degree. C. until further processing for
MSM analysis.
[0114] Following the 5 minute exposure period to the various test
products (see Table 1), blood was collected after 10 minutes, 30
minutes, 2 hours and 8 hours. Prior to the 2 and 8 hour blood
collections, EMLA cream was applied to the ears (approximately 30
minutes prior to each of these blood draws) as the anesthetic
effects of the EMLA cream lasts approximately 1.2 hours. Both EMLA
cream and Acepromazine were used due to ethical considerations and
to provide for the well being of the animals used in this
project.
[0115] The concentrations of MSM in plasma were quantified by Gas
Chromatography-Mass Spectrometry (GC/MS) based on established
methods. Briefly, 450 .mu.L of plasma sample was mixed with 50
.mu.L of physiological saline and vortexed for 30 seconds.
Following this 1 mL of Acetonitrile (Fisher, HPLC grade) was added
to the mixture. The solution was vortexed vigorously for 60 seconds
and centrifuged at 2000 rpm for 5 minutes. 1 .mu.L of the clear
supernatant was introduced to the GC/MS system (GC/MS QP20108 EI,
Shimadzu, Kyoto, Japan). The analysis was performed on a 8himadzu
SHRSXLB column (0.25 mm ID.times.length 30 m, film 0.25 um, Kyoto,
Japan). The retention time of MSM was 6.1-6.3 minutes. MSM was
detected with MS and m/z 79 (M+-15) was used for monitoring MSM ion
SIM profiles. Helium gas was used as the carrier gas, head pressure
was 0.25 kg/cm2, make-up gas was 30 ml/min, column temperature was
80.degree. C., injector temperature 120.degree. C., separator
temperature 200.degree. C. and ion source temperature 250.degree.
C. The ionization energy was 70 eV. An external standard graph was
prepared with MSM dissolved in acetonitrile at the following
concentrations: 62.5 .mu.g/ml, 31.3 .mu.g/ml, 15.6 .mu.g/ml, 7.8
.mu.g/ml, 3.9 .mu.g/ml, 1.9 .mu.g/ml, 0.98 .mu.g/ml and 0.49
.mu.g/ml. The MSM concentration in plasma samples was calculated
from the slope of the standard curve. The best fitted graph was
linear with a R2 value of 0.998.
[0116] All animals were observed prior to the start of the
experiment and all demonstrated good health. During the course of
the experiment and subsequent to the experiment, all animals
demonstrated good health. Morbidity, mortality and injury were
assessed twice daily. No animals demonstrated any morbidity,
mortality or injury.
[0117] The results of the absorption study are summarized in Table
2 and graphically depicted in FIGS. 1 and 2. Baseline plasma
concentrations of MSM (prior to exposure to test articles) ranged
between 4.2 .mu.g/mL and 104.2 .mu.g/mL (see FIG. 1). The variation
in baseline is within the normal range of variation of natural MSM
concentrations that have been established in prior studies.
Following exposure to the various test articles, the highest plasma
concentrations of MSM measured were less than or equal to
approximately 140 .mu.g/mL (see FIG. 1). This peak concentration
results from exposure to 10% MSM+70% DMSO+20% water. When corrected
for natural variation in baseline MSM concentrations, the largest
change in plasma MSM was detected in the 70% DMSO+30% water group.
These data suggest that variations in MSM, either due to absorption
or due to metabolism of DMSO, are within the natural range of MSM
concentrations.
[0118] As such, in several embodiments, MSM is an inert ingredient
in topical applications, with respect to analgesic function.
However, as discussed herein, MSM does provide several beneficial
effects. In several embodiments, MSM functions to reduce the side
effects normally associated with DMSO (skin effects, odor, etc.).
In several embodiments, MSM functions as an emollient, which also
may aid in reducing irritation of the skin by DMSO. As such, the
combination of MSM with DMSO in the topical formulation embodiments
described herein allow for the use of concentrations of DMSO that
function to reduce one or more symptoms of osteoarthritis without
the normal array of DMSO-associated side effects. Thus, in certain
embodiments, the presence of MSM advantageously allows for the
unexpected use of higher (and more efficacious) concentrations of
DMSO without the side effects.
TABLE-US-00002 TABLE 2 Concentration of MSM in Plasma After
Exposure to MSM and DMSO Time point MSM Concentration Treatment
(minute) (.mu.g/mL) 10% MSM + 90% water 0 25.6 10 17.6 30 16.3 120
14.0 480 15.4 50% DMSO + 50% water 0 4.2 10 6.9 30 6.9 120 7.4 480
12.6 70% DMSO + 30% water 0 56.7 10 89.0 30 98.9 120 128.7 480
120.2 10% MS M + 50% DMSO + 0 104.2 40% water 10 116.5 30 127.9 120
128.4 480 140.4 10% MSM + 70% DMSO + 0 26.8 20% water 10 37.3 30
30.9 120 33.9 480 44.4
[0119] It will be understood by those of skill in the art that
numerous and various modifications can be made without departing
from the spirit of the embodiments of the present invention. Method
steps described herein need not be performed in the order set
forth. It should be clearly understood that embodiments disclosed
herein are illustrative only and are not intended to limit the
scope of the present invention.
* * * * *