Note: Descriptions are shown in the official language in which they were submitted.
WO 94/07541 2 1 4 ~ 1 5 5 PCI'/US93/08947
TITLE OF THE INV~ENTION
IBUPROFEN-H2 ANTAGONIST COMBINATIONS
BACKGROUND OF THE INVENTION
The non-steroidal anti-infl~mm~tory drugs (NSAID) have
been utilized in the treatment of pain/infl~mm~ion and a number of
other symptoms including stiffness that are associated with painful
conditions affecting muscles, bones, and joints. NSAIDs have been
prescribed to relieve back pain, arthritic pain, gout, menstrual pain,
headaches, mild pain following surgery, and pain from soft tissue
injuries such as sprains and strains. NSAIDs are within the broader
class of non-narcotic analgesics which also includes acetyl salicyclic acid
(aspirin) and acetaminophen. NSAIDs, except for acetaminophen, are
generally considered to exert their effect by blocking the production of
prost~gl~ndins at the site of pain, irritation or injury so that the pain
signal does not reach the brain.
Ibuprofen (2-(4-isobutylphenyl)propionic acid) is a well
known and commonly employed NSAID. Amino acid salts of racemic
ibuprofen including the lysine or arginine salt are also known pain
relievers. See U.S. Pat. No. 4,279,926. Recently, it has been found that
a faster onset of pain relief and an enhanced analgesic response can be
obtained by l~tili7ing the single enantiomer (S)-ibuprofen (also known as
(+)-ibuprofen or dexil,uplofen) rather than the racemic mixture of
ibuprofen. See U.S. Patent 4,877,620.
H2 antagonists are commonly prescribed to treat and
prevent ulcers in the walls of the stomach, duodenum or esophagus. H2
antagonists are also used to treat non-ulcerative conditions. Damage to
the mucus lining surrolln-ling these tissues enables destructive action of
stomach acids which erodes the underlying tissue. Commonly known
H2 antagonists for the treatment of ulcers include cimetidine, ranitidine,
nizatidine, roxatidine and famotidine.
Combinations of ibuprofen with H2 antagonists have been
disclosed. See EPO App. No. 426479A which discloses a
pharmaceutical composition for treating the symptoms of
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overindulgence (hP~ rhe and acid indigestion) using H2 antagonists
including famotidine and an analgesic effective amount of a NSAID
including ibuprofen wherein the term is defined to include
~dmini~tration of both the racemic mixture or the pure S enantiomer of
5 ibuprofen. There is a need to employ a compound with faster acting and
enhanced analgesic capability such as (i) an analgesically and anti-
infl~mm~tory effective amount of a salt of (S)-ibuprofen subst~nti~lly
free of (R)-ibuprofen wherein the salt is selected from (S)-ibuprofen-
(S)-lysine and (S)-ibuprofen-(R)-lysine; in combination with an H2
o antagonist such as famotidine to treat and prevent the pain and
discomfort associated with headaches, indigestion, sour stomach,
heartburn or other gastrointestinal disorders. There is a need to employ
a combination wherein an advantage is that the (S)-ibuprofen lysine salt
is more stable than the free acid of ibul~rofen and is extremely soluble
15 in water to give subst~nti~lly neutral (versus acidic) aqueous solutions.
The ibuprofen/lysine salt is therefore more suitable for ~-lmini~tration
to patients than the free acid because of its enhanced solubility in water
(and in plasma) and because of its neutrality. Because of these
improved and advantageous physical properties, ~clminictration of the
20 combination is more effective in the treatment of pain, infl~mm~tion,
and overindulgence. In addition, an advantage of the (S)-ibuprofen-
(S)-lysine in the combination claimed in the instant invention is that this
salt is neutral and not acidic and, therefore, unlike the prior art
disclosures of H2 antagonist and ibuprofen, does not both acerbate and
25 treat stomach conditions siml~lt~neously.
The present invention provides both faster onset and
enhanced relief of aches and pains associated with the body, head and
stomach to provide broad and con~;u"ellt symptomatic relief. The
combination with famotidine is especially advantageous since (S)-
30 ibuprofen-lysine does not interfere with the metabolism of famotidine
nor does famotidine interfere wi~ the metabolism of alcohol.
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DETAILED DESCRIPTION OF THE INVENTION
This invention claims pharmaceutical compositions for use
in the treatment of pain and infl~mm~tion and the treatment of mild
stomach and esophagus disorders including the treatment of heartburn.
5 The composition comprises:
(i) an analgesically and anti-infl~mm~tory effective amount of a
salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt
is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine;
and
(ii) an amount effective in relief of gastrointestinal or esophagus
disorders of at least one of the H2 antagonists.
This invention is also directed to a method of treating pain
and iILfl~mm~tion and concurrently treating indigestion, sour stomach,
5 heartburn, overindulgence and other gastrointestinal disorders in
m~mm~ls, including hllm~n~, in need thereof, comprising ~lmini.~tering
to such org~nism:
(i) an analgesically and anti-infl~mm~tory effective amount of a
salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt
20 iS selected from (S)-ibul rofen-(S)-lysine and (S)-ibuprofen-(R)-lysine;
and
(ii) an amount effective in relief of gastrointestinal or esophagus
disorders of at least one of the H2 antagonists.
This invention is further directed to a method of eliciting
25 an onset hastened and enhanced response for the treatment of pain and
infl~mm~tion and the treatment of gastrointestinal or esophagus
disorders in m~mm~l.s, including hllm~n.s, in need thereof, comprising
lmini.stering to such organism:
(i) an analgesically and anti-infl~mm~tory effective amount of a
30 salt of (S)-ibuprofen substantially free of (R)-ibuprofen wherein the salt
- is selected from (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-lysine;
and
(ii) an amount effective in relief of gastrointestinal or esophagus
disorders of at least one of the H2 antagonists.
WO 94/07541 PCI/US93/0~
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Substantially free of (R)-ibuprofen means that the ratio of
(S)-ibuprofen to (R)-ibuprofen is at least 90:10.
Salts of (S)-ibuprofen include ph~rm~ceutically acceptable
salts such as alkali metals (sodium or potassium), ~lk~line earth metals
5 (calcium), or salts with other metals such as m~gnesium, al1-minllm,
iron, zinc, copper, nickel or cobalt.
Pharmaceutically acceptable salts of (S)-ibuprofen further
include the amino acid salts, particularly the basic amino acids such as
lysine or arginine. Specifically included within the composition of the
o instant invention is (S)-ibuprofen-(S)-lysine and (S)-ibuprofen-(R)-
lysine.
The term m~mm~l~ or m~mm~ n organism includes but is
not limited to man, dog, cat, horse and cow.
The term treatment encompasses the complete range of
15 therapeutically positive effects associated with pharmaceutical
medication including reduction of, alleviation of and relief from the
symptoms or illness which affect the org~ni~m
(S)-ibuprofen may be prepared following the procedures
disclosed in U.S. Patent 4,877,620. Metal salts of ibuprofen may be
20 obtained by contacting a hydroxide, or carbonate with ibuprofen.
Amino acid salts of ibuprofen may be obtained by contacting an amino
acid in solution with ibuprofen. U.S. Patent No. 4,994,604 describes a
process for the formation and resolution of (S)-ibuprofen-(S)-lysine that
employs preferential cryst~lli7~tion to separate a pair of diastereomeric
25 salts, (S)-ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine. The basic
procedure involves (a) contacting (R),(S)-ibuprofen and (S)-lysine in an
aqueous-organic solvent mixture; (b) separating any suspended solid
from the mixture; and (c) cooling the clear mixture until the mixture is
supersaturated with respect to each of the (S)-ibuprofen-(S)-lysine and
30 (R)-ibuprofen-(S)-lysine salts; (d) contacting the supersaturated mixture
with a slurry of (S)-ibuprofen-(S)-lysine in an aqueous-organic solvent;
and (e) separating the formed crystalline (S)-ibuprofen-(S)-lysine.
Specifically, the racemic ibuprofen starting material is
mixed with an organic solvent that is miscible with water. The (S)-
WO 94/07541 PCl/US93/08947
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lysine is mixed with water and the ibuprofen and lysine solutions arecombined.
The mixture is agitated for a time period sufficient to
crystallize all the salts, if any, in excess of the solubility limit. The
5 suspended salts are separated to obtain a clear mother liquor which is
generally saturated with respect to the diastereomeric salts (S)-
ibuprofen-(S)-lysine and (R)-ibuprofen-(S)-lysine. Filtration may be
employed to effect the separation. The liquor is then cooled to a
temperature at which it is supersaturated with respect to each of the
o diastereomeric salts. It is preferred that the liquor be cooled to the
point at which maximllm supersaturation is obtained with respect to
each salt without nucleation of either cryst~lli7~ble species. Typically
the temperature of the mother liquor must be lowered by about 5C to
reach maximl1m supersaturation without precipitation of either salt.
5 However, the degree of cooling will depend on the particular solvent
composition. The supersaturated liquor is then passed into a vessel
cont~ining a slurry of (S)-ibuprofen-(S)-lysine, hereafter referred to as
the (S,S) salt, in the same solvent system employed above for the
n~ e of racemic ibuprofen and (S)-lysine. In the presence of the
20 (S,S) salt crystals acting as a seed, the supersaturation of the (S,S)-salt in
the feed liquor is released by the growth of further crystals of the (S,S)-
salt. Conversely, there is little or no change in the (R)-ibuprofen-(S)-
lysine supersaturation because the growth rate of the (R,S) crystals is
essentially zero in the absence of any initial (R,S) salt seed. The (S,S)
25 crystals are then separated by filtration or centrii~ugation and washed
with aqueous-organic solvent to yield (S)-ibuprofen-(S)-lysine of purity
approxim~ting 98%.
The pharmaceutical compositions of the present invention
are useful in the rapid and enhanced treatment of pain and infl~mm~tion
3~ and in the treatment of various mild gastrointestinal disorders including
indigestion, sour stomach, overindulgence and heartburn. In particular,
the (S)-ibuprofen-(S)-lysine combined with an H2 antagonist such as
famotidine is useful for the treatment of pain, infl~mm~tion, and the
various gastrointestinal disorders such as indigestion, sour stomach, or
WO 94/07541 ? ~4 4~S~ PCI/US93/0*
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heartburn. The l-tili7~tion of (S)-ibuprofen and in particular (S)-
ibuprofen-(S)-lysine in an analgesic/H2 antagonist combination offers
significant advantages over the combination of racemic ibuprofen and
an H2 antagonist or (S)-ibuprofen and an H2 antagonist.
(S)-ibuprofen and in particular the (S)-lysine salt of (S)-
ibuprofen provides a faster onset of pain and infl~mm~tion relief and an
eIlh~nced degree of relief compared to racemic ibuprofen. These
benefits contribute to overall enhanced and faster relief of symptoms
associated with headaches and other aches and pains that often
o accompany gastrointestinal disorders and overindulgence when the (S)-
ibuprofen-(S)-lysine is combined with an H2 antagonist such as
famotidine.
The absence or reduction of (R)-ibuprofen also provides
significant benefits. The allergic contraindications sometimes associated
15 with ibu~rofen ~lmini,stration are absent or reduced in a (R)-ibuprofen-
free or subst~nti~lly-free composition. An additional advantage may be
that less metabolic energy will be used to convert the inactive (R)-
ibuprofen to the active (S)-ibuprofen. In addition, a reduced burden
may be placed on the urogenital system since ~lministration of the pure
20 (S)-ibuprofen elimin~tes the need to excrete the (R)-ibuprofen or its
metabolites. The absence of the (R)-enantiomer also reduces or
elimin~tes the incorporation of this molecule into fatty tissue. The renal
burden and renal toxicities sometimes associated with racemic il~u~rofen
therapy may be reduced or elimin~ted in a (S)-ibuprofen composition
25 that is subst~nti~lly free of the (R) enantiomer.
H2 antagonists are well known in the treatment of ulcers
and other gastrointestinal disorders and may be used in combination
with (S)-ibuprofen-(S)-lysine. H2 antagonists used for ulcer therapy
fall into four major structural classes: imidazole derivatives; substituted
30 furans; aminoalkylphenoxy derivatives and guanidinothiazole
compounds. Famotidine (N'-(aminosulfonyl)-3-[[[2-[(cli~mino-
methylene)amino]-4-thiazolyl]methyl]thio] propanimidamide), a
member of the latter class, is a competitive inhibitor of histamine H2-
receptors and its primary pharmacological activity is the inhibition of
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21~155
gastric acid secretion. Famotidine suppresses both the acid
concentration and the volume of gastric acid secretion. Famotidine is
well tolerated and has minim~l side effects and thus advantageously may
be used in the present invention in combination with (S)-ibuprofen-(S)-
5 lysine. Famotidine is also the most potent and selective H2 antagonist.The combination of famotidine and (S)-ibù~rofell-(S)-lysine provides a
combination which simlllt~neously and selectively provides relief from
headaches, pain, infl~mm~tion, and discomfort and injury to the
stomach, esophagus, or duodenum from excess production of gastric
o acid. Furthermore, famotidine may not interact with alcohol so that it
may be ~clminictered prior to or during ingestion of meals or beverages
which contain alcohol. The combination of (S)-ibuprofen-(S)-lysine
with famotidine provides rapid and enhanced relief of pain while also
providing long acting relief from and treatment of gastrointestinal
15 disorders associated with gastric acid secretion.
The absence of inactive enantiomers, particularly (R)-
ibu~rofell provides for significant size and weight advantages in a
combination dosage form, particularly a sustained release dosage form.
Where a sustained release dosage of ibuprofen may have required 800
20 to 1000 mg, the employment of (S)-ibuprofen-(S)-lysine reduces the
weight to 400 to 500 mg, and provides for a more practical size tablet
for an ibuprofen/H2 antagonist combination. In particular, the
combination of famotidine which is a highly potent H2 antagonist with
(S)-ibuprofen-(S)-lysine reduces the size and weight of all
25 pharmaceutical delivery forms or combination form~ tions and
therefore improves patient compliance or tolerance. The tablet or
capsule form of this combination is more readily swallowable by
patients in need of treatment thereof.
An effective amount of (S)-ibuprofen, or a salt thereof, for
30 use in a unit dose composition of this invention may range from 50-800
mg of (S)-ibuprofen equivalents. The preferred amount of (S)-
ibuprofen is about 100 to 400 mg. The amount of a salt such as (S)-
ibuprofen-(S)-lysine is determined based on the amount of (S)-
ibuprofen contained therein.
WO 94/07541 PCI`/US93/0
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The H2 antagonist employed herein may be selected from
any of the commercially available or known H2 antagonists such as
cimetidine, ranitidine, roxatidine, nizatidine or famotidine. Famotidine
is advantageously used in the present invention in combination with (S)-
5 ibuprofen-(S)-lysine. The amount of famotidine used in the present
invention in hl-m~n~ may range from 2.5 mg/day to 40 mg/day.
Advantageously, 2.5 to 20 mgs/day is ~rlminictered in combination with
100 to 400 mg of (S)-ibuprofen-(S)-lysine. The combination claimed in
the instant invention is advantageously ~lmini.~tered orally. However,
o in patients with hypersecretory conditions, intractable ulcers, or in
patients who are unable to take oral medication, the claimed
combination may be ~lmini~tered intravenously in a suitable dosage
within the limits described for oral treatment.
The present composition may be ~flmini~tered in the form
15 of tablets, caplets, gelcaps, capsules, elixirs, syrups, or suspensions. For
oral ~lmini~tration~ the active ingredients may be admixed with a
pharmaceutically acceptable diluent such as lactose, sucrose, cellulose,
dicalcium phosphate, calcium sulfate, m~nnitol, and, in a liquid
composition, ethyl alcohol. Acceptable emulsifying or suspending
agents such as PVP, gelatin, natural sugars, corn sweeteners, natural
and synthetic gums such as acacia, sodium alginate, guar gum, agar,
bentonite, carboxymethylcellulose sodium, polyethylene glycol and
waxes, may also be admixed with the active components. Where
necessary, lubricants such as m~nesium stearic acid talc or m~gnesium
stearate, and disintegrators or superdisintegrators such as starch,
sodium starch glycolate or cross-linked PVP may also be included.
Electrolytes such as dicalcium phosphate, sodium benzoate, sodium
acetate and sodium chloride may also be used.
The active components may also be formulated in sustained
release oreffervescentform~ tions. These formulations depending
upon whether they are sustained release or effervescent may be
employed in oral, dermal, rectal or vaginal ~lmini~trations. The
sustained release formulations also include layered formulations which
WO 94/07S41 PCI /US93/08947
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provide for distinct release ratio and thus may be more effective in
allowing for short and long term relief.
The following examples illustrate ~e compositions of the
present invention which may be readily prepared and as such are not to
be considered as limiting the invention set forth in the claims.
EXAMPLE 1
(S)-Ibuprofen Iysine/famotidine Tablet
(S)-ibuprofen-(S)-lysine342 mg
famotidine 40 mg
PVP 15 mg
Avicel PH101 40 mg
15 Magnesium Stearate4 mg
EXAMPLE 2
(S)-Ibuprofen lysine/famotidine Tablet
(S)-ibuprofen-(S)-lysine342 mg
famotidine 20 mg
PVP 15 mg
Avicel PH101 40 mg
Magnesium Stearate4 mg
-
WO 94/07541 PCr/US93/0
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EXAMPLE 3
(S)-Ibuprofen Iysine/famotidine Tablet
5 (S)-ibuprofen-(S)-lysine 342 mg
famotidine 15 mg
PVP 15 mg
Avicel PH101 40 mg
Magnesium Stearate 4 mg
EXAMPLE 4
(S)-Ibuprofen Iysine/famotidine Tablet
15 (S)-ibuprofen-(S)-lysine 342 mg
famotidine 10 mg
PVP 15 mg
Avicel PH101 40 mg
Magnesium Stearate 4 mg
EXAMPLE 5
(S)-Ibuprofen Iysine/famotidine Tablet
25 (S)-ibuprofen-(S)-lysine 342 mg
famotidine 5 mg
PVP 15 mg
Avicel PH101 40 mg
Magnesium Stearate 4 mg
PCI~/US93/08947
WO 94/07541
2i4~ls5
EXAMPLE 6
(S)-Ibuprofen Iysine/famotidine Sustained Release
(S)-ibuprofen-(S)-lysine400 mg
famotidine 40 mg
PVP 30 mg
Avicel PH101 80 mg
Magnesium Stearate 8 mg
o Methocel ElOMCR 66 mg
Methocel KlOOMLV 200 mg
EXAMPLE 7
(S)-Ibuprofen (S)-lysine/famotidine Sustained Release
(S)-ibuprofen-(S)-lysine 400 mg
famotidine 20 mg
PVP 30 mg
Avicel PH101 80 mg
Magnesium Stearate 8 mg
Methocel ElOMCR 66 mg
Methocel KlOOMLV 200 mg
EXAMPLE 8
(S)-Ibuprofen-(S)-lysine/famotidine Solution
(S)-ibuprofen-(S)-lysine 342 mg
famotidine 10 mg
g.s. syrup 5 ml
WO 94/07541 PCI'/US93/0~
2l4~l~3
FXAMPLE 9
(S)-Ibuprofen-(S)-lysine/farnotidine Solution
5 (S)-ibuprofen-(S)-lysine 342 mg
famotidine 20 mg
g.s. syrup 5 ml
