Note: Descriptions are shown in the official language in which they were submitted.
WO 95/07079 217 0 4 8 5 pCT~S94109582
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COMI'OSTTIONS CONTABVIrIG AN AI~VO ACID SALT OF PROPIONIC ACID NON-STEROIDAL
ANT~INFLAMMAT'ORY AGENTS AND CAFI'E1NE
TECHNICAL FIELD
The present invention relates to compositions and methods for providing
improved analgesic and/or anti-inflammatory effect by administering a safe and
ef
festive amount of a composition comprising certain amino acid salts of
propionic
acid non-steroidal anti-inflammatory agents along with an amount of caffeine
sufficient to hasten the onset.
1o BACKGROUND OF THE I1WENTION
Inflammation, or the "inflammatory response", is the result of complex in-
terconnected physiological events, including increased vascular permeability,
fluid
accumulations, aad the migration of a changing population of inflammatory
cells
into the inflamed area. The clinical manifestations of inflammation include
swelling
I5 (edema), increased local temperature, erythema, and pain. The inflammatory
re
sponse can be triggered by any of a number of causative factors, including
certain
bacteria, radiation, hypersensitivity to chemical agents, arthritis-like
conditions, and
the like. The inflammatory response is generally believed to be a primary
defense
mechanism in the body, but, unchecked, can become excessive and can result in
2o functional impairment.
The use of non-steroidal anti-inflammatory, anti-pyretic and analgesic drugs,
especially the salicylates, which include aspirin and aspirin derivatives, to
combat
inflammation and attendant pain is accepted medical practice. The non-
steroidals
are commonly employed to relieve pain and inflammation associated with, for
25 example, bursitis, arthritis, and the like.
While pain is incapable of precise definition due to its basically subjective
nature, it can generally be said that the term refers to feelings of distress
or suffering
cause~by stimulation of specialized nerve endings. A great variety of drugs
have
been developed to reduce pain in man and other animals, some directed to
3o eliminating pain at its source, and others directed to blocking the
perception of pain
by the brain. Among the latter group of drugs that are designed to block the
sensation of pain, are the analgesics, which generally relieve pain without
causing
unconsciousness. Analgesics can be further classified into two main
categories:
opioid analgesics, including morphine, codeine, levorphanol, and the morphine-
like
35 analgesics meperidine, and methadone; and antipyretic analgesics, such as
aspirin,
ibuprofen, phenacetin, acetaminophen, phenylbutazone, and indomethacin.
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2
Although the precise pharmacological action of these analgesics is uncertain,
there
are certain effects which readily distinguish the opioid analgesics from the
antipyretics. In
particular, the antipyretics are weak analgesics, with much of their effect in
the peripheral
nervous system, so that behavioral changes do not usually occur. Generally,
these analgesics
relieve only pain originating from muscles, joints, tendons and fasciae, and
are ineffective
against deep visceral pain. However, the opioid analgesics are quite effective
against all
types of pain, with broad-based action in the central nervous system. Aside
from potent
analgesia, the opioids, also known as narcotics, often produce effects on mood
and other
behavioral changes. Perhaps the most notable side effect of opioid analgesics
is the fact that
their repeated use is associated with tolerance, as well as psychic and
physical dependence.
The ornithine, lysine and arginine salts of ibuprofen useful for providing
relief from
pain and inflammation have been disclosed in, for example, U.S. 4,279,926 to
Bruzzese et
al., issued July 21, 1981. A process for the preparation of ibuprofen lysine
tablets has been
disclosed in EP 505,180, published March 19, 1992.
The use of the racemic mixture of ibuprofen together with caffeine has been
disclosed in, for example, in U.S. Patent 4,464,376 to Sunshine et al. issued
August, 7, 1984.
The use of ibuprofen, as well as other of the newer non-steroidal anti-
inflammatory agents
(i.e., excluding aspirin, acetaminophen and phenacetin) in the preparation of
cough/cold
pharmaceutical compositions containing sympathomimetic amines, has been
disclosed in, for
example, U.S. Patent 4,552,899 to Sunshine et al. issued November 12, 1985.
The use of
the S(+) form of ibuprofen has been disclosed in, for example, U.S. Patent
4,851,444 to
Sunshine et al. issued July 25, 1989 and in combination with antihistamines in
WO
9,205,783 to Gates et al. published April 16, 1992.
The present inventors have found that selected compositions comprising certain
amino acid salts of the propionic acid NSAIDs in combination with caffeine
provides further
improved analgesic and/or anti-inflammatory effect.
It is therefore an object of the present invention to provide such
compositions and
methods for the treatment of pain and/or inflammation.
SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical composition adapted
to elicit an onset-hastened and enhanced analgesic response in a mammalian
organism in need of such . treatment and adapted for unit dosage
administration,
said composition comprising: a. an analgesically and anti-inflammatory
effective
amount of the S(+) enantiomer of an amino acid salt or a propionic
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acid nonsteroidal anti-inflammatory agent; and b. an amount of caffeine
sufficient to hasten
the onset of and enhance the analgesic response.
All percentages and ratios used herein are by weight unless otherwise
indicated.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compositions and methods of eliciting a
sustained,
enhanced analgesic response in a human or lower animal in need of such
treatment,
comprising administering to such human or lower animal a safe and effective
amount of a
composition comprising ibuprofen lysinate, and an amount of caffeine
sufficient to hasten
the onset of and enhance the analgesic response.
The term "amino acid salt" refers to salts derived from pharmaceutically
acceptable
organic non-toxic bases of primary, secondary, tertiary and quaternary amines,
substituted
amines including naturally occurring substituted amines, cyclic amines and
basic ion
exchange resins, such as triethylamine, tripropylamine, 2-
dimethylaminoethanol,
2-diethylaminoethanol, lysine, ornithine, arginine, histidine, caffeine,
procaine, N-
ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,
methylglycamine, theobromine, purines, piperazine, piperidine, polyamine
resins and the like.
The propionic acid derivatives of the non-steroidal anti-inflammatory agents
which
are useful in the compositions of the present invention are well-known to
those skilled in the
art and are disclosed in, for example, U.S. Patent 4,552,899 to Sunshine et
al., issued
November 12, 1985. For detailed disclosure of the chemical structure,
synthesis, side
effects, etc., of non-steroidal anti-inflammatory agents, reference may be had
to standard
texts, including Anti-inflammatory and Anti-Rheumatic Drugs, K.D. Rainsford,
Vol. I-III,
CRC Press, Boca Raton, (1985), and Anti-inflammator~r Agents, Chemistry and
Pharmacolo~y, 1, R.A. Scherrer, et al., Academic Press, New York (1974).
The preferred non-steroidal anti-inflammatory agents useful in the composition
of
the present invention include the amino acid salts of the propionic acid
derivatives such as
naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,
indoprofen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen,
suprofen,
alminoprofen, and tiaprofenic. Mixtures of these non-steroidal anti-
inflammatory
agents may also be employed. Of these propionic acid NSAIDs, ibuprofen,
naproxen, and ketoprofen are most preferred.
Most preferred for use herein is the S(+) isomer of these NSA1D salts. The
term
"S(+)" as applied to the analgesic agents herein is intended to encompass the
dextrorotatory
or S(+) isomer of the amino acid salt derivatives thereof. The expression
"substantially free
r
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4
of the R(-) antipode" as used in conjunction with the term "S(+)" means that
the S(+)
enantiomer is sufficiently free it is R(-) antipode to exert the desired onset-
hastened and
enhanced analgesic effect. Practically speaking, this means that the active
ingredient should
contain at least 90% by weight of the S(+) enantiomer and 10% or less weight
R(-)
enantiomer. Preferably, the weight ratio of S(+) enantiomer to R(-) enantiomer
is greater
than 20:1, more preferably greater than 97:3. Most preferably the S(+)
enantiomer is 99 or
more % by weight free of R(-) enantiomer, i.e., the weight ratio of S to R is
approximately
equal to or greater than 99:1.
The safe and effective amount of the amino acid salts of ibuprofen, naproxen,
benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen,
pirprofen,
carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen,
alminoprofen, and
tiaprofenic generally ranges from about 7.5 mg to about 1000 mg, and are
generally the
same as their acid derivatives counterparts. Useful dosage of these agents can
be found in
The Physicians' Desk Reference, 47th Edition (1993) and in U.S. Patent
4,552,899 to
Sunshine et al., issued November 12, 1985.
For example, the safe and effective amount of the amino acid salt of ibuprofen
used
in the compositions of the present invention generally ranges from about 50 to
about
800 mg, preferably from about 50 to about 400 mg, more preferably from about
50 to about
200 mg and most preferably from about 50 to about 100 mg. The safe and
effective amount
of the amino acid salt of flurbiprofen used in the compositions of the present
invention
generally ranges from about 12.5 to about 300 mg, preferably from about 12.5
to about
200 mg, more preferably from about 12.5 to about 100 mg and most preferably
from about
12.5 to about 50 mg. The safe and effective amount of the amino acid salt of
ketoprofen
useful in the compositions of the present invention generally ranges from
about 5 to about
100 mg, preferably from about 5 to about 75 mg, more preferably from about 5
to about
50 mg and most preferably from about 5 to about 25 mg. Generally, the amount
of the S(+)
isomers of these agents will be about half of the amount of the racemic
mixture.
Preferably, the pharmaceutical compositions of the present invention comprise
the
analgesic agent and caffeine in a ratio of from about 10:1 to about 1:10,
preferably from
about 5:1 to about 1:5 and most preferably from about 2:1 to about 1:5.
Various oral dosage forms can be used, including such solid forms as tablets,
gelcaps
capsules, granules, lozenges and bulk powders and liquid forms such as syrups
and
suspensions. These oral forms comprise a safe and effective amount, usually at
least about
5% of the active component. Solid oral dosage forms preferably contain from
about 5% to
B
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S
about 95%, more preferably from about 10% to about 95%, and most preferably
from about
25% to about 95% of the active component. Liquid oral dosage forms preferably
contain
from about I% to about 50% and more preferably from about 1% to about 25% and
most
preferably from about 3% to about 10% of the active component.
Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated,
film-coated
or multiple compressed, containing suitable binders, lubricants, diluents,
disintegrating
agents, coloring agents, flavoring agents, preservatives and flow-inducing
agents.
Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions,
suspensions, and solutions and/or suspensions reconstituted from non-
effervescent granules,
containing suitable solvents, preservatives, emulsifying agents, suspending
agents, diluents,
sweeteners, taste-masking agents, coloring agents, and flavoring agents.
Specific examples
of pharmaceutically acceptable carriers and excipients that may be used to
formulate oral
dosage forms, are described in U.S. Patent 3,903,297, Robert, issued September
2, 1975.
Techniques and compositions for making solid oral dosage forms are described
in Marshall,
"Solid Oral Dosage Forms," Modern Pharmaceutics, Vol. 7, (Banker and Rhodes,
editors),
359-427 (1979). Techniques and compositions for making tablets (compressed and
molded),
capsules (hard and soft gelatin) and pills are described in Remin , on's
Pharmaceutical
Sciences (Arthur Osol, editor), 1553-1593 (1980).
In preparing the liquid oral dosage forms, the active component is
incorporated into
an aqueous-based orally acceptable pharmaceutical carrier consistent with
conventional
pharmaceutical practices. An "aqueous-based orally acceptable pharmaceutical
carrier" is one
wherein the entire or predominant solvent content is water. Typical carriers
include simple
aqueous solutions, syrups, dispersions and suspensions, and aqueous based
emulsions such
as the oil-in-water type. The most preferred carrier is a suspension of the
pharmaceutical
composition in an aqueous vehicle containing a suitable suspending agent.
Suitable
suspending agents include Avicel RC-591 (a microcrystal line cellulose/sodium
carboxymethyl
cellulose mixture available from FMC), guar gum and the like. Such suspending
agents are
well known to those skilled in the art. While the amount of water in the
compositions of
this invention can vary over quite a wide range depending upon the total
weight and volume
of the active component and other optional non-active ingredients, the total
water content,
based on the weight of the final composition, will generally range from 2
about 20 to about
75%, and, preferably, from about 20 to about 40%, by weight/volume.
Although water itself may make up the entire carrier, typical liquid
formulations
preferably contain a co-solvent, for example, propylene glycol, glycerin,
sorbitol solution and
B
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6
the like, to assist solubilization and incorporation of water-insoluble
ingredients, such as
flavoring oils and the like into the composition. In general, therefore, the
compositions of
this invention preferably contain from about 5 to about 25 volume/volume
percent and, most
preferably, from about 10 to about 20 volume/volume percent, of the co-
solvent.
The compositions of this invention may optionally contain one or more other
known
therapeutic agents, particularly those commonly utilized in cough/cold
preparations, such as,
for example, a cough suppressant such as dextromethorphan, chlophedianol,
carbetapentane,
caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone,
fominoben, their pharmaceutically-acceptable salts; an expectorant or
mucolytic such as
glyceryl guaiacolate, tenpin, ammonium chloride, N-acetylcysteine and
bromhexine,
ambroxol, their pharmaceutically acceptable salts; and an antihistamine such
as chlor-
pheniramine brompheniramine, dexchlorpheniramine, dexbrompheniramine,
triprolidine,
doxylamine, tripelennamine, cyproheptadine, carbinoxamine,
bromodiphenhydramine,
phenindamine, pyrilamine, azatadine, their pharmaceutically acceptable salts,
as well as the
1 S non-sedating antihistamines which include acrivastine, AHR-11325,
phenindamine,
astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide,
loratidine, levocabastine,
mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine,
their
pharmaceutically acceptable salts: all of these components, as well as their
acceptable
dosage ranges are described in the following: U.S. Patent 4,783,465 to
Sunshine et al.,
issued November 8, 1988, U.S. Patent 4,619,934 to Sunshine et al., issued
October 28, 1986.
Also useful are bronchodilators such as theophylline and albuterol as well as
other analgesic
agents such as acetaminophen and AspirinT~''. A highly preferred optional
component is
caffeine, which is preferably present at a level of from about 10% to about
50%.
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WO 95107079 PCT/LTS94/09582
2110485
Other optional ingredients well known to the pharmacist's art may also be
included in amounts generally known for these ingredients, for example,
natural or
artificial sweeteners, flavoring agents, colorants and the like to provide a
palatable
and pleasant looking final product, antioxidants, for example, butylated
hydroxy
anisole or butylated hydroxy toluene, and preservatives, for example, methyl
or
propyl paraben or sodium benzoate, to prolong and enhance shelf life.
METHOD OF TREATMENT
The amount of the pharmaceutical composition administered depends upon the
percent of active ingredients within its formula, which is a function of the
amount of
1o the ibuprofen and caffeine and any optional components such as a
decongestant,
expectorant and/or antihistamine required per dose, stability, release
characteristics
and other pharmaceutical parameters.
Usually from about 1 mg/kg to about 50 mg/kg per day, preferably from
about 2 mg/kg to about 30 mg/kg per day and most preferably from about 3 mg/kg
per day to about 20 mg/kg per day of the pharmaceutical composition is adminis-
tered as described herein. This amount can be given in a single dose, or,
preferably,
in multiple (two to six) doses repeatedly or sustained release dosages over
the
course of treatment. Generally, each individual dosage of the pharmaceutical
compositions of the present invention range from about 1 mg/kg to about 25
mglkg,
2o preferably from about 2 mg/kg to about 15 mg/kg and most preferably from
about 3
mg/kg to about 10 mg/kg. Typical unit dosage forms for oral administration
generally comprise from about 50 mg to about 2000 mg, preferably from about
100
mg to about 600 mg and most preferably from about 100 mg to about 400 mg of
the ibuprofen and from about 25 mg to about 200 mg, preferably from about 50
mg
a to about 200 mg and most preferably from about 50 mg to about 100 mg of
caffeine. While dosages higher than the foregoing are effective to provide
analgesic
relied care must be taken, as with any drug, in some individuals to prevent
adverse
side efltcts.
The following examples illustrate embodiments of the subject invention
3o wherein both essential and optional ingredients are combined.
EXAMPLE I
A hard gelatin capsule composition for oral administration is prepared by
combining the following ingredients:
In edi n Amoun
35 Ibuprofen Lysinate 200 mg
Caffeine 100 mg
Triturate active ingredients and q.s. with lactose to selected capsule size.
WO 95/07079 PCT/US94/09582
g
Administration of 1 or 2 of the above capsules to a human in need of
treatment provides improved analgesic and/or anti-inflammatory effect.
EXAMPLE II
A hard gelatin capsule composition for oral administration is prepared by
combining the following ingredients:
In edient Amoun
Naproxen Lysinate 200 mg
Astemizole 5 mg
1o Caffeine 50 mg
Glyceryl guaiacolate 100 mg
Triturate active ingredients and q.s. with lactose to selected capsule size.
Administration of 1 or 2 of the above capsules to a human in need of
treatment provides improved analgesic and/or anti-inflammatory effect.
EXAMPLE III
A liquid composition for oral administration is prepared by combining the
following ingredients:
Ingredient % W
Ketoprofen Lysinate I.00
Caffeine 1.00
Alcohol (95%) 25.000
Propylene Glycol 25.000
Sodium Citrate 2.000
Citric Acid 0.250
Liquid Sugar (Simple Syrup) 25.00
Glycerin 7.000
Colorants 0.008
Flavor 0.500
Water, Purified QS 100.000
3o The puri5ed water (approximately 10% of the final batch volume) is poured
into a batch container equipped with a lightnin' mixer. The sodium citrate,
citric
acid and Caffeine are added sequentially and dissolved with agitation. The
glycerin
and uquid sugar are then colorants added. In a separate container the
colorants are
added to purified water (approximately 0.5% of the final batch volume). This
colorant solution is then added to the first batch container. In a separate
container
the Ketoprofen lysinate is added to the alcohol while stirring. The propylene
glycol
and flavors are added to this alcohol premix and the resulting mixture is
stirred until
WO 95/07079 pCTlUS94109582
2170485
homogeneous and then added to the first container. The remaining purified
water is
added to the resulting mixture and stirred.
Administration of 10 ml to 20 ml (2 to 4 teaspoonsful) to a human in need of
treatment provides improved analgesic and/or anti-inflammatory effect.
EXAMPLE IV
A liquid composition for oral administration is prepared by combining the
following ingredients:
In in °/W
Ibuprofen Argininate 1.00
1o Caffeine 1.00
Chlorpheniramine Maleate 0.02
Pseudoephedrine HCl 0.30
Alcohol (95%) 25.00
Propylene Glycol 25.00
Sodium Citrate 2.00
Citric Acid 0.25
Liquid Sugar (Simple Syrup) 25.00
Glycerin 7.00
Colorants 0.008
2o Flavor ' 0.50
Water, Purified QS 100.00
The purified water (approximately 10% of the final batch volume) is poured
into a batch container equipped with a lightnin' mixer. The sodium citrate,
citric
acid, pseudoephedrine HCl and chlorpheniramine maleate are added sequentially
2S and dissolved with agitation. The glycerin and liquid sugar are then added.
In a
separate container the colorants are added to purified water (approximately
0.5% of
the final batch volume). This colorant solution is then added to the first
batch
container. In a separate container the ibuprofen argininate is added to the
alcohol
while stirring. The propylene glycol and flavors are added to this alcohol
premix
3o and the resulting mixture is stirred until homogeneous and then added to
the first
container. The remaining purified water is added to the resulting mixture and
stirred.
Administration of 10 ml to 20 ml(2 to 4 Teaspoonsful) to a human in need
of treatment provides improved analgesic and/or anti-inflammatory effect.
35 EXAMPLE V
A liquid composition for oral administration is prepared by combining the
following ingredients:
WO 95/07079 PCT/US94/09582
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io
In reg diem % WN
S(+) Ibuprofen Lysinate 1.00
Caffeine 1.00
Pseudoephedrine HCI 0.30
Chlorpheniramine Maleate 0.02
Dextromethorphan HBr 0.15
Alcohol (95%) 25.00
Propylene Glycol 25.00
Sodium Citrate 2.00
1o Citric Acid 0.25
Liquid Sugar (Simple Syrup) 25.00
Glycerin 7.00
Colorants 0.008
Flavor 0.50
Water, Purified QS 100.00
The purified water (approximately 10% of the final batch volume) is poured
into a batch container equipped with a lightnin' mixer. The sodium citrate,
citric
acid, pseudoephedrine HCl and chlorpheniramine maleate are added sequentially
and dissolved with agitation. The glycerin and liquid sugar are then added. In
a
2o separate container the colorants are added to purified water (approximately
0.5% of
the final batch volume). This colorant solution is then added to the first
batch
container. In a separate container the (S) + ibuprofen lysinate and dextro-
methorphan HBr are added sequentially to the alcohol while stirring.
The propylene glycol and Savors are added to this alcohol premix and the
resulting mixture is stirred until homogeneous and then added to the first
container.
The remaining purified water is added to the resulting mixture and stirred.
Administration of 10 ml to 20 ml (2 to 4 teaspoonsful) to a human in need of
treatment provides improved analgesic and/or anti-inflammatory effect.
