Note: Descriptions are shown in the official language in which they were submitted.
1228l33L6
This invention relates to pharmaceutical compositions
and dosage forms and their use in the treatment of chronic
disease. More particularly it concerns pharmaceutical come
positions and dosage forms and their use in the treatment of
the pain and locomotor dysfunction of rheumatoid arthritis.
Rheumatoid arthritis is a serious, often crippling,
disease characterized by pain and locomotor dysfunction.
As pointed out by Nickander et at in their article "Nonsteroidal
Antiinflammatory Agents" which appeared at Ann. Rev. Pharmacol.
Topical., 1979. 19:469-90, this sort of pain and locomotor dysfunc-
lion are among man's most common and frustrating afflictions.
The gravity of this disease has led to the investigation and/or
adoption of a wide range of drugs for its alleviation. Aspirin
has been commonly used since the turn of this century. Other
major drugs for arthritis have historically included indomethacin,
other salicylates, phenylbutazone, steroids and gold. While
more recently, fenoprofen, ibuprofen, naproxen, sulindac and
tolmetin have been approved for use in the United States.
While these compounds can offer antiinflammatory, anti-
paretic and analgesic effects and have proven helpful in the
management of rheumatoid arthritis in many patients, when
combined with other modalities such as proper rest, exercise,
1228~3~6
physical therapy and surgery, they are less than ideal. Many
exhibit serious side-effects with many patients, particularly
gastrointestinal damage and renal toxicity. Each of these
materials have the failing of being far from universal -- some
patients will respond to one material while others respond
favorably only to others.
Cocaine and cocaine free base have been employed in the
management of rheumatoid arthritis for a number of years. I
have demonstrated, through clinical experiments on a range of
patients suffering from rheumatoid arthritis, the effective-
news of this treatment.
Unfortunately for this possible therapeutic use, cocaine
and cocaine free base are widely regarded as materials of
abuse. It is most unlikely that the regulatory and drug enforce-
mint agency issues will ever be resolved to a point that cocaine
or its free base can be available on as widespread a basis as would
be required for their use in the treatment of sufferers of
rheumatoid arthritis. In addition, certain individuals can
develop dependence upon these materials and/or exhibit symptoms
of intoxication when using them.
What is needed is a pharmaceutical preparation and/or
dosage form and a method for its use that does not involve
cocaine or its free base, that does not present the untoward
physiological effects of cocaine but Which acts therapeutically
in the manner of cocaine to alleviate the pain and motor
dysfunction of rheumatoid arthritis.
l;~Z88~
It has now been found that benzoylecgonine and its
related compound benzoylnorecgonine are therapeutically effective
for alleviation of the pain of rheumatoid arthritis and restore-
lion of motor dysfunction of rheumatoid arthritis in humans
and other manuals. The compounds are preferably administered
in carriers as pharmaceutically acceptable formulations.
Benzoylecgonine and benzoylnorecgonine are the active
agents employed herein. wish and Wilson, in J. Harm.
Pharmacy 1969 21 Supply issue - 138S. presented results showing
formation of benzoylecgonine
SHEA
\ I --I C2H
OCOPh
by mammals as a metabolize of cocaine. Micra et at summarized
and reported at Volume 13, No. 4, Research Communications in
Chemical Pathology and Pharmacology (April, 1976, page 579)
the finding of benzoylnorecgonine,
C02H
U I-
OCOPh
-- 3 --
122~3816
as a mammalian cocaine metabolize, as well.
Routes for the compounds' synthesis have been published.
Schmidt and Werner disclose in Ann. 653, 184-94 (1962) the
conversion of benzoylecgonine (I) to benzoylnorecgonine (II) by,
for example, putting 1.16 g of I in 250 cc HO, adding, over
30 minutes, 48 cc of 3% KMnO4 and stirring for 5 hours at a
pi held below 8 by gradual H2SO4 addition and thereafter
filtering and recovering (II) by freeze drying and repeated
recrystallization from ethanol. Fondly in J. Amer. Chum.
Sock 82 (1960) 4642-4644 discloses that benzoylecgonine can
be formed by refluxing cocaine in water for 10 hours and
then cooling to recover the benzoylecgonine by crystallization.
Administration of a therapeutically effective dose of
the active compounds to a human or other warm-blooded patient
afflicted with rheumatoid arthritis can be via appropriate
pharmaceutical formulation and any of the accepted modes for
repeated administration of agents for the treatment of inflame-
lion or pain and the prophylaxis thereof. Thus, administration
can be for example orally, rectally, Buckley, nasally, vaginal
topically (for transdermal delivery) or via inhalation. The
formulations suitable for such modes of administration include
solid, semisolid and liquid formulations which can include
tablets, pills, capsules, powders, solutions, suspensions,
creams, lotions, ointments or the
like, preferably in unit dosage forms suitable for simple
administration of precise dosages.
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Oral administration is effected using a convenient
daily dosage regimen, such as from 3 to 8 doses per day,
preferably 4-6 doses per day, which can be adjusted accord-
in to the degree of affliction. Generally, a daily dose
of from 1.5 to about 15 my of the active benzoylecgonine
and/or benyoylnorecgonine per kilogram of body weight is
used. Most conditions respond to treatment comprising a
dosage level of the order of 2.5 to 10 my. per kilogram of
body weight per day. In such an oral mode of administration,
a pharmaceutically acceptable nontoxic composition is formed
by the incorporation of any of the normally employed
excipients, such as, for example, pharmaceutical grades of
minutely, lactose, starch, magnesium Stewart, talcum, eel-
lulls, glucose, gelatin, sucrose, magnesium carbonate, and
the like. Of course, if desired, other pharmacologically
active materials can be incorporated into such formulations to
give a combination product.
Transdermal delivery of the benzoylecgonine and/or
benzoylnorecgonine compounds, effected by topical administer-
lion of a solution, suspension, cream, lotion or similar
formulation to the skin of the patient is also effective.
Formulations for such use include a carrier which should be
a liquid or semisolid that is inert to the active compound
and not irritating to the skin. Suitable carriers for soul-
lions include water, aqueous mixed solvents, lower alkanols
and alkandiols, for example, ethanol, methanol, isopropanol,
ethylene glycol, glycerine, propylene glycol and the like.
Suitable bases for salves and creams include pharmaceutically
~2288~L6
acceptable oils and cream bases and golfs. In addition,
topical formulations can contain nontoxic auxiliary substances
such as wetting or emulsifying agents, pi buffering agents
and the like. In general, it is preferred to use formulations
in which the active compounds are soluble, preferably at least
to an extent of about I by weight.
In the transdermal (topical mode of administration,
typically from 50 to 500 square centimeters of skin surface
is contacted with a 1 to 10~ by weight solution or cream of
the active compound at least once a day and preferably from
three to eight times per day, and preferably four to six times
per day, the exact dosage depending upon the degree of afflict
lion. The formulations employed in the transdermal mode of
application can, if desired, contain materials to promote
transdermal transport. The aforesaid alkanols and alkandiols
for example, may promote such transport as many DMSO, sun-
fact ants, and the like. In addition, other materials may be
added to minimize skin irritation or to treat other conditions
or side reactions.
A third mode of administration that is useful is via the
mucous membranes of the oral and nasal cavities. This method
of administration can be effected using biaxial patches or the
like for sublingual administration or by inhaling the active
benzoylecgonine or benzoylnorecgonine compound as a finely
divided powder or atomized solution. With inhalation therapy,
the benzoylecgonine compound can be delivered to the nasal
membranes and to the lungs as a solid powder or as a solution.
In either method, the patient can supply the driving force by
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inhaling or an external force can be used such as a pump, a
propellant gas or liquid, or the like. In this mode of therapy,
a daily dosage regimen of at least one does per day is followed,
with three to eight doses per day being preferred. Generally,
the amount of active benzoylecgonine compound delivered per
day is at least 0.5 my. per kilogram of body weight. Prefer-
ably, the amount of benzoylecgonine compound administered per
day by inhalation is from 1 to about 8 my. per kilogram of body
weight.
In addition, the benzoylecgonine or benzogylnorecgonine
active compound can be administered via vaginal or utterly
routes wherein the active compound in a suitable liquid or
ointment carrier is applied to the vaginal or utterly membranes.
This method of administration employs similar dosages and
dosage regimens described above for biaxial or nasal ad minis-
traction.
The invention will be further illustrated by the follow-
in EXAMPLES. These are presented to exemplify and make clear
the invention and are not to be construed as limiting its
scope which is defined solely by the claims.
EXAMPLE 1
A. Benzoylecgonine and benzoylnorecgonine are prepared
from commercial cocaine by the above-described methods of Finley
and Schmidt and Werner, respectively. The two active compounds
are formulated with sorbitol as a powder containing 50% active
agent, in sterile water as a 4% solution, and in a carboxymethl-
cellulose jelly at a 2% concentration.
-- 7 --
foe
The active compounds could also, if desired, be presented
in association with other pharmaceutically acceptable carriers
in pharmaceutical formulations suitable for transdermal, in-
halation, nasal, oral or rectal administration. Suitable carriers
include solids such as lactose, starch (pharmaceutical grade),
dicalcium phosphate, calcium sulfate, kaolin, minutely and
powdered sugar and liquids such as sterile saline or the like.
The formulations for oral, rectal or vaginal administer-
lion are advantageously presented in discrete unit dosage forms,
such as tablets, capsules, cachets, suppositories, each con-
twining a predetermined amount of the compound, but may also
be presented as a powder, or as granules. They may as well be
presented as a solution or suspension in an aqueous or non-
aqueous liquid such as would be useful for admix-
istration. The formulations may be made by any of the known
methods and may include one or more of the following accessory
ingredients: buffers, flavoring, binding, dispersing, surface-
active, thickening, lubricating and coating materials, pro-
servatives, bacteriostats, antioxidant, suppository and joint-
mint bases, coloring agents, and any other acceptable excipients.
Unit dosage forms may typically contain from about 0.01 to about
0.1 gram of active compound.
Any skilled artisan can prepare these dosage forms by
simply referring to the oral dosage form preparatory prove-
dune outline in "Remington's Pharmaceutical Sciences," Fourteenth
Edition (1970), pages 1624 through 1698 inclusive, and the
rectal dosage form preparatory procedure outline in the same
text at pages 1617 through 1624, inclusive.
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B. A group of patients afflicted with rheumatoid
arthritis is assembled. They are in pain and have pronounced
motor dysfunction as results of their disease. A control group
is taken from this group and left untreated. The members of
the control group show no improvement during the test. A
first test group is selected at random from the patient group.
Each member of this first test group rubs 2-4 g quantities of
the jelly (40-80 my of the active Caine compound) on their skin
three times a day. A second test group takes by inhalation
lo my. doses of the powder six times a day. A third test
group rubs 1-2 ml quantities of the 4% solution or- their skin
and allows it to evaporate to dryness. This is carried out six
times a day. A fourth test group takes orally six times a
day capsules made up to contain 80 my. of the active compound.
The patients in each of the four test groups report a reduction
of their pain and an improvement in mobility and motor function
during the period that the treatment is being administered to
them. They report no adverse effects of their treatment.
EXAMPLE 2
The active compounds are individually formulated into
5% by weight ointments in a water-miscible ointment vehicle
consisting of polyethylene glycols and propylene glycol.
When l g of either of these ointments is rubbed into the
skin of test patients suffering from rheumatoid arthritis
in a treatment program of six doses per day or 300 my of active
compound per day the patients report improvement in mobility
and a decrease in the pain that they normally associate with
their arthritic condition.
12288~
A series of biaxial patches is prepared each incorporate
in 0.5 g of this ointment. When four to six of these patches
are serially placed on the mucous membrane under the tongue
they administer the compound throughout the day. Test subjects
afflicted with rheumatoid arthritis report a decrease in pain
and an increase in mobility when they are receiving this treat-
mint.
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