United States Patent: 4,652,557
( 8 of 13 )
United States Patent 4,652,557
Sandborn * March 24, 1987
Pharmaceutical solutions comprising dimethyl sulfoxide
Abstract
Novel pharmaceutical solutions and particularly novel pharmaceutical
solutions
comprising dimethyl sulfoxide (DMSO).
Inventors: Sandborn; Edmund (Burlington, CA)
Assignee: Clark Pharmaceutical Laboratories Ltd. (Weston, CA)
[*] Notice: The portion of the term of this patent subsequent to March
11,
2003 has been disclaimed.
Appl. No.: 791102
Filed: October 24, 1985
Current U.S. Class:514/164; 514/159; 514/936
Intern'l Class: A61K 031/10; A61K 031/60; A61K 031/605
Field of Search: 514/708,936,647
References Cited [Referenced By]
U.S. Patent Documents
3551554Dec., 1970Herschler424/45.
3711602Jan., 1973Herschler424/45.
3740420Jun., 1973Herschler et al.424/45.
3743727Jul., 1973Herschler514/936.
4353896Oct., 1982Levy514/936.
4369190Jan., 1983Schulte514/936.
4575515Mar., 1986Sandborn514/708.
Foreign Patent Documents
1001075Dec., 1976CA.
1005761Feb., 1977CA.
Primary Examiner: Griffin; Ronald W.
Attorney, Agent or Firm: Fornari; James D.
Parent Case Text
FIELD OF INVENTION
This is a continuation-in-part application of
U.S. application Ser. No. 06/610,,590 filed May 15, 1984, now U.S. Pat.
No.
4,575,515, issued Nov. 11, 1986.
Claims
The embodiments of the invention in which an exclusive property or
privilege is
claimed are as follows:
1. A deep and rapidly penetrating homogeneous solution for topical
application
causing medicine to penetrate deeply into affected parts of the body
without
irritating the skin or leaving a greasy film on the skin when the
solution is
applied topically, the solution comprising:
(a) between about 40% and about 85% DMSO by weight of the solution;
(b) a polyalcohol for assisting to retain moisture in the skin and
prevent the
skin from dehydrating;
(c) a dispersant for assisting to disperse the components in the
solution to
provide a homogeneous solution when applied and when penetrating the
skin;
(d) triethanolamine salicylate;
(e) water.
2. The solution of claim 1, wherein the polyalcohol has 3 to 5 carbon
atoms.
3. The solution of claim 1, wherein the polyalcohol is glycerol (glycerine).
4. The solution of claim 3, wherein the DMSO is present between about
60% and
about 70% by weight of the solution.
5. The solution of claim 3, wherein the DMSO constitutes about 65% by
weight of
the solution.
6. The solution of claim 3 wherein the dispersant is propylene glycol.
7. The solution of claim 1, wherein the DMSO is present between about
60% and
about 70% by weight of the solution.
8. The solution of claim 1, wherein the DMSO constitutes about 65% by
weight of
the solution.
9. The solution of claim 1, wherein the dispersant is propylene glycol.
Description
This invention relates to novel pharmaceutical solutions and
particularly novel
pharmaceutical solutions comprising dimethyl sulfoxide (DMSO).
BACKGROUND OF THE INVENTION
If one rubs a few drops of DMSO on any part of his/her person, it is
usually
absorbed very rapidly and a taste resembling garlic is immediately
present. This
finding subsequently led to a most important finding of pharmacologic
ability of
pure DMSO of various strengths to reduce inflammation and pain in a wide
range
of conditions to penetrate into the skin after topical application of
DMSO for
the lessening of pain and swelling of inflammation. Many clinicians have
reported particularly gratifying results by the use of DMSO in the
management of
arthritis.
U.S. Letters Pat. No. 3,549,770, teaches the topical application of
undiluted
dimethyl sulfoxide, and dimethyl sulfoxide with appropriate
pharmaceutical
diluents, excipients and adjuvants in the treatment of tissue damage,
pain,
abnormal muscle contraction and vascular insufficiency.
The facility with which DMSO penetrates the skin and other membranes has
spawned
considerable research into the use of DMSO as a vehicle for the
administration
of drugs through topical application. In the course of that research a
number of
different products were added to DMSO with ranging degrees of success.
U.S. Pat. No. 3,711,606 teaches the use of DMSO as a carrier in
concentrations
of 50% and over by weight with a steroid in lotion, cream, gel and
ointment
forms to penetrate rapidly to and saturate the stratum corneum, the
highly
resistant "horny layer" of the skin which is the major barrier to
penetration.
According to this patent "The Steroid continues to penetrate through the
skin
from `this reservoir` in the stratum corneum to the underlying tissue
and into
the circulatory system" (Column 3, line 50-53).
U.S. Pat. No. 3,711,602 also teaches the compositions (creams,
suppositories,
ointments and gels) for topical application for enhancing tissue
penetration of
physiologically active agents (for example, physiologically active
steroids,
antineoplastic agents, antigens, antihistamine agents,
neuropharmacologic
agents, anti-inflammatory agents, anticoagulants, vasodilators,
ultra-violet
screening agents and agents with DMSO.
However, these compositions are extremely greasy and are solely for
surface
penetration, very little penetrating deeply into affected areas where
the
greatest need arises. See also U.S. Pat. Nos. 3,551,554; 3,740,420;
3,743,727;
3,790,682; 4,369,190 and 3,499,961 and Canadian Pat. Nos. 1,001,075;
1,011,255;
1,043,704; 980,252 and 1,005,761.
Furthermore these compositions are not suitable for direct application
to an
afflicted part of the body (joints etc.). In addition, DMSO also
captures water
from the skin, being a hydroxyl ion scavenger thereby dehydrating the
skin.
It is therefore, an object of this invention to provide penetrating
solutions,
allowing penetration deeply into affected parts of the body, comprising
DMSO,
preferably another medicine which may be applied topically and which
rapidly
penetrates deeply into the body carrying the medication in the solutions
with it
while protecting the skin against dehydration.
Further and other objects of the invention will be realized by those
skilled in
the art from the following summary of the invention and detailed
description of
the embodiments thereof.
SUMMARY OF THE INVENTION
According to one aspect of the invention, a deeply and rapidly
penetrating
homogeneous solution for topical application causing medicine to
penetrate
deeply and rapidly into affected parts of the body without irritating
the skin
or leaving a greasy film on the skin when the solution is applied
topically is
provided, the solution comprising:
(a) between about 40% and about 85% DMSO by weight of the solution, more
preferably between about 60% and about 70% DMSO by weight of the
solution and
most preferably about 65% DMSO by weight of the solution;
(b) a polyalcohol, preferably having 3-5 carbon atoms, for the retention
of
moisture in the skin, in one embodiment, glycerol or glycerine;
(c) A dispersant for assisting to disperse the components in solution to
provide
a homogeneous solution when applied to the skin, in one embodiment
propylene
glycol;
(d) a medicine for example naproxen and diclofenac dissolved in the
solution;
(e) water.
Because the medicine must be dissolved in the solution, a solubilizing
agent may
be added to the solution to dissolve the medicament. For example,
naproxen is
not soluble in DMSO. Therefore, ethanol is used to solubilize also be
added to
the solution where desired.
When the penetrating solutions of the invention are employed in topical
applications unexpected results from treatment therewith are obtained.
This is
because of the ability of the solution to penetrate quickly and deeply
into the
body through the skin and tissue below the point of topical application.
Furthermore, because of the nature of the solution, the skin is not
dried out.
Where glycerol is employed, glycerol is a hydroxyl radical scavenger (as
is
DMSO) and assists in the medicinal effect of the DMSO in the solution.
The
dispersant propylene glycol is also a hydroxyl radical scavenger.
The formulations are prepared by combining the requisite amounts of the
ingredients together (adding solubilizing agents, for example ethanol
where
naproxen is to be included). The medicines that may be used with the
DMSO may be
manufactured according to the processes taught in the following patents
or other
such suitable processes: NAPROXEN: Canadian Pat. Nos. 1,122,603;
1,004,226;
1,142,957; 1,137,108; 879,118; 879,719; 936,171; 955,600; 960,668;
960,689;
983,517; 991,655; 1,000,725; 1,000,726; 1,020,575; and 1,124,735.
DICLOFENAC:
Canadian Pat. Nos. 850,133; 811,738; 829,910; 918,175; 765,432; 827,708;
1,126,746; and 1,050,565. NIFEDIPINE: Canadian Pat. Nos. 981,582;
934,758;
868,911; 921,035; and 1,080,223. Triethanolamine salicylate may also be
used.
The invention will now be illustrated having regard to the following
embodiments
and exemplary test cases.
EMBODIMENTS
DMSO with diclofenac as a treatment for arthritis
300 ml 90% DMSO
60 ml glycerine
25 ml propylene glycol
100 ml water
15 ml ethyl alcohol
75 gm diclofenac
Solution as a treatment for psoriasis
65 ml 90% DMSO
3.375 gm diclofenac
80 ml H.sub.2 O
5 ml 2% xylocaine
250 ml ethyl alcohol
65 ml glycerine
30 ml propylene glycol
5 ml tar
DMSO with diclofenac and urea as a treatment for Arthritis with added
skin
protection
325 ml DMSO 90%
70 ml H.sub.20
50 gm urea
25 ml glycerine
75 gm diclofenac
25 ml propylene glycol
Solution for treatment of herpes
335 ml DMSO 90%
25 ml glycerol
25 ml propylene glycol
100 ml H.sub.2 O
15 ml ethyl alcohol
75 gm diclofenac
DMSO with triethanolamine salicylate in 500 c.c. solution
315 ml 90% dimethyl sulfoxide
30 ml glycerine
55 ml propylene glycol
100 ml distilled water
52 g triethanolamine salicylate.
The following case histories are offered where penetrating solutions
according
to the invention were employed.
In each of cases 1 to 8 inclusive the anti-inflammatories used were
naproxen or
diclofenac.
Case 1. Mrs. E. G.--Age 58 Years--Rheumatoid Arthritis
Severe pain in left tarsal joint, then late in May, right foot then
rapidly
involved righ tleg, both shoulders, elbows and wrists. Was first treated
with
phenylbutazone, then naproxen, but four months later was becoming
severely
disabled with acute symptoms, particularly shoulders, wrists, and right
foot -
33 joints involved. Thereafter, treatment with penetrating solution
comprising
DMSO with naproxen, application thereof. Indocid was administered by
mouth. By
the next month some improvement in mobility, but shoulders still only
slight
(10) abduction. Treatment was continued five times daily. Three months
later
remarkable improvement in mobility. Three months later, returned to work
part-time.
This patient has shown steady improvement with essentially full return
to range
of motion in all joints. Still employs DMSO by itself for flare-ups. Can
go
without medication.
Case 2. Mrs. B. W.--Age 52 Years--Post Traumatic Arthritis
Ankle-skiing accident with comminuted fracture. Repaired by surgical
intervention with numerous screws and plates-one screw later removed.
After 13
years of restricted movement and acute pain, patient was advised that if
she was
not prepared to tolerate the pain, the only alternatives were fusion or
amputation. Began trial with topical application of a penetrating
solution of
DMSO anti-inflammatories, propylene glycol, water and glycerine. Within
days
mobility began to improve and this was gradually followed by a reduction
in
pain. Four months later almost complete return of function and was
pain-free.
Now only employs DMSO at irregular intervals.
Case 3. Mrs. J. F.--Age 52 Years--Traumatic Arthritis
Fractured left ankle on three occasions - each repaired by open
reduction.
Movements severely restricted and pain severe. Employed crutches--has
done so
for three years. Began topical treatment with formulation used in Case
1. After
treatment, flexibility and comfort both improving--can bear some weight.
A month
later flexibility improving but still a long way to go. However, lateral
and
medial movement of tarsal joints had improved considerably but
dorsiflection
still quite limited. Four months later could finally touch heel to
floor. Some
months later, ankle greatly improved. Both mobility improved and pain
quite
tolerable. Has been able to live normally, walks, dances, etc. Has had
bouts of
gouty arthritis in other foot but this is also under satisfactory
control.
Case 4. Mr. H. B.--Age 63 Years--Arthritis
Arthritis in wrists, hands, ankle, feet and back.
Has reached the point where wrists and ankles are almost Has reached the
point
where wrists and ankles are almost completely ankylosed--very little
movement
obtainable. Is not able to continue at work. Barely able to walk. Began
topical
application of penetrating solution comprising DMSO anti-inflammatory,
propylene
glycol, glycerin and water. Improvement was seen quite rapidly by
reduction of
effusion and slow increase of mobility over the years. In spite of
exacerbations
of acute arthritis his mobility has increased until he can walk much
better.
Lifestyle closer to normal.
Case 5. Mr. M. L.--Age 51 Years--Osteoarthritis
Right knee--began following a football injury 30 years ago. Had meniscus
excised. Activities quite limited due to pain. Began topical application
of
penetrating solution comprising DMSO, anti-inflammatory, propylene
glycol,
glycerine and water. Exercise tolerance and comfort improved steadily.
Patient
has been able to participate in sports in more comfort.
Case 6. Mr. K. L.--Age 62 Years--Osteoarthritis
Knees. Has had one cartilage removed. Unable to participate in sports
without
pain. Began typical application of formulation used in Case 1. Increased
ability
to participate in sports. Improvement still maintained in spite of acute
flare-ups on occasion.
Case 7. Mr. B. P.--Age 59 Years--Acute Bursitis and Arthritis
Acute Bursitis left shoulder. Abduction only 150. Acute pain in both
knees from
degenerated cartilages and osteoarthritis. Patient began topical
treatment with
penetrating solution comprising DMSO, anti-inflammatory, propylene
glycol,
glycerine and water after arthroscopy and by the time his surgical
booking had
arrived, he was so much improved he refused the surgical procedure. His
pain
gradually receded, mobility of knees and shoulder increased until he was
able to
live in comfort and return to active work and sports without pain. He
now only
requires occasional application of DMSO solution for slight discomfort.
Case 8. Age 64 Years
Patient diagnosed as having neuromuscular rheumatism and advised
prolonged bed
rest--suggested period, three years. Patient has marked crepitus joints.
Had
been told `her chances of working again were non-existent` (Mayo
Clinic).
Patient was a practical nurse who had re-entered a registered nursing
training
course but was forced to stop due to illness. When first seen was in a
wheel
chair and even had great difficulty in swallowing. After treatment with
penetrating solution comprising DMSO, anti-inflammatory, propylene
glycol,
glycerin and water for several days, a slight increase in movement of
joints was
detectable. A month later, felt immensely better and flexion and
rotation of
shoulders had increased dramatically. She had an excellent response.
Subsequently returned to nursing school. Works three nights a week and
has
returned to driving an automobile. This patient has obtained full
function of
joints and muscles. Has completed her nursing training and has worked
full-time
since. She has now entered the B.Sc. nursing training course and is
doing very
well.
Case 9
Patient was diagnosed as having chondromalacia and osteoarthritis in the
knee of
many years duration. She had considerable limitation of movement and
pain.
Crepitations felt on knee movements. After treatment with penetrating
solution
comprising dimethyl sulfoxide, triethanolamine salicylate, glycerine,
propylene
glycol and distilled water for about four months, the knee was greatly
improved
and pain relieved. While the knee was still slightly stiff, mobility was
greatly
improved. Her knee was still slightly affected by the weather.
Case 10
Patient was diagnosed as having arthritis in her left knee of many years
duration. After treatment with the penetrating solution comprising
dimethyl
sulfoxide, triethanolamine salicylate, glycerine, propylene glycol and
distilled
water, there was a very marked improvement over the first four months.
Now she
uses the solution on a prn basis.
Case 11
Patient was in extreme pain from post herpetic neuritis. She had a band
of scars
C8 to T3- medial arm, back exilla and upper breast. Patient had a
previous
history of Graves Disease and cancer of the bladder. After treatment
with the
penetrating solution of dimethyl sulfoxide, triethanolamine salicylate,
glycerine, propylene glycol and distilled water, within two weeks there
was
great improvement of post herpetic neuritis. After one week only
itchiness and
tenderness remained.
Case 12
Patient was diagnosed as having post herpetic neuritis left forearm and
hand.
She had had this condition for seven years duration. After treatment
with a
penetrating solution of dimethyl sulfoxide, diclofenac, glycerine,
propylene
glycol, and distilled water, there was considerable improvement.
However, after
treatment with the penetrating solution of dimethyl sulfoxide,
triethanolamine
salicylate, glycerine, propylene glycol and distilled water, there were
excellent results.
Case 13
Patient was diagnosed as having rheumatoid arthritis since 1974. The
patient had
extreme deformity of the wrists, hands, knees and elbows with rheumatoid
nodules
on forearms and elbows. After treatment with both (a) dimethyl sulfoxide,
diclofenac, glycerine, propylene glycol, and distilled water and (b)
dimethyl
sulfoxide, triethanolamine salicylate, glycerine, propylene glycol, and
distilled water, great improvement in mobility and comfort was the
result. He
has returned to work as a furniture restorer, something he was unable to
do for
some time before the treatments.
Case 14
The patient, a former football player, was diagnosed as having
osteoarthritis of
the knee and ankle, chondromalacia. The patient had arthroscopic removal
of part
of his semilunar cartilages. He was in extreme pain, unable to continue
playing
golf or other activities for a period of at least two years prior to
treatment.
After treatment with dimethyl sulfoxide, triethanolamine salicylate,
glycerine,
propylene glycol, and distilled water, even though there was X-ray
evidence of
moderate degeneration of knee cartilages, he has improved his range of
mobility
and comfort to the extent that he is now able to golf 18 holes
regularly.
As many changes can be made to the embodiments disclosed without
departing from
the scope of the invention, it is intended that all material contained
herein be
interpreted as illustrative of the invention and not in a limiting
sense.
* * * * *
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