Note: Descriptions are shown in the official language in which they were submitted.
ANALGES IC METHOD AND COMPOS ITION 1 ~ 8 7 6 8
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of S(+)
ibuprofen-enriched compositions to elicit an onset hastened and
enhanced analgesic response in ~r~lian organisms in need of
such treatment, and to certain pharmaceutical compositions
comprising an effective amount of an enriched S(+) ibuprofen
composition.
2. Description of the Prior Art
Ibuprofen, or (+) 2-(p-isobutylphenyl)propionic acid,
has the structural formula:
c u--c u ~ a ~111 .
~ .
C~
The compound is well known as a nonsteroidal an-
ti-inflammatory drug having analgesic and antipyretic activity.
Ibuprofen is currently a prescription drug in the United States
and it is marketed as a prescription drug under various trade-
names, such as Motrin . Ibuprofen has recently also become
available in this country as a non-prescription drug under a
variety of tradenames, including AdvilR and Nuprin .
As is well-known, the drug ibuprofen has utility as an
analgesic for the treatment of mild to moderate pain and, at ,
lower doses, for minor aches and pains.
As can be seen from the structural formula, ibuprofen
has an asymmetric carbon atom which allows the compounds to be
isolated in its S(+) or R(-) enantiomeric forms. However, it is
the racemic mixture that is marketed under the above-mentioned
tradenames.
Recently, a number of patents have issued directed to
the use of the S(+) enantiomer in an analgesic composition. For
example, U.S. Patent No. 4,851,444 to Sunshine et al., discloses
that an onset hastened and enhanced analgesic response is
elicited in a mammalian organism in need of such~treatment,
i.e., a mammal suffering pain, by administering thereto a unit
-2- 21187~8
dosage onset-hastening/~nhancing analgesically effective amount
of the S(+) ibuprofen enantiomer, said enantiomer being substan-
tially free of its R(-) ibuprofen antipode.
In U.S. Patent No. 4,877,670 to Loew et al., an
ibuprofen-containing medicament is disclosed which contains
ibuprofen only in the (s) (+)-form. The patent notes that
(S)-(+)-ibuprofen is more active than the racemate.
However, both patents teach that by using such highly
concentrated quantities of the S(+) enantiomer, beneficial
analgesic effects are produced using lesser amounts of material
than known from the prior art.
Howeverj to attain an ibuprofen composition comprised
as required by the prior art of substantially free-R(-)
ibuprofen is very difficult and costly.
.
.
Sunshine et al. of the U.S. Patent No 4,851,444 from 7/25/1989
disclosed a method of using the S-(+)-enantiomer of ibuprofen to
elicit an onset-hastened and analgesic response in mammalian
organisms. Furthermore, they teach a weight ratio of S-
enantiomer to R-(-)-enantiomer of at least 90:10, respectively.
The disclosure of Slln-chine et. al. considers the R-(-)-
enantiomer as a enatiomeric impurity, or as a non-biologically
active material, because the analgesic activity is believed to
reside entirely on the S-(+)-ibuprofen. This implies that the
different ratios as mentioned by Slln-chine et al. are related to
the contamination of a S-(+)-ibuprofen formulation by the R-(-)-
ibuprofen on unspecified reasons. The authors did not disclose
any manufacturing or production reasons for their claimed
ratios, or optical activity as well as melting diagrams, for
discriminating between a racemic compound or a racemic mixture.
, _ _ . ,,
The Sllnchine et.al. patent did not teach the use and the amount
of R-(-)-i~u~ofen needed to optimize the active ingredients for
a short term analgesic and long term antiphlogistic or
antipyretic effects for the S-(+)-ibuprofen in the presence of
the R-(-)-enantiomer. Their ratios are 9/1, 2 9, S/R 2 20/1; S/R
2 97/3, and S/R 2 99/1, so A 1 WA~S 1 Arger or e~lAl ~hAn 9.
21~76~
-- --3--
SUMMARY OF THE INVENTION
Surprisingly, the present inventor has found that compositions
of ibuprofen enriched in the S( t ) enantiomer but still
containing some R(-) enantiomer can be advantageously
administered to mammals suffering from pain, especially
humans; they do not only elicit the same potent analgesic
response but they also evoke such response similar rapidly by
administration of the same dose of ibuprofen in its pure S(+)-
form. Preferably, the ratio of R(-) enantiomer to S(~)
enantiomer ranges from 11:89 to about 30:70.
Accordingly, in our studies the preferred ratios of the
S enantiomer to the R enantiomer are ranging from 70/30 to
80/20, so alwaYs below 9, reveiling the same efficacy as S10O-
~ (+)ibuprofen to SgO-(+)-ibuprofen. This can also be confirmed
by pharmacokinetic arguments, showing almost the same AUC for
S10O-(+)-ibuprofen comparable to the Sx-(+)-ibuprofen with x =
8g.0-70.
.... .
Thi5 is particularly surprising in light of the prior ~~
art' 8 reliance on enhanced effectiveness of S(+) ibuprofen
versus the racemic mixture.
In one aspect, the present invention-thus provides a
method of hastening the onget of analge~ia in a mammal, said
method comprising administering to a mammal in need of such
treatment an effective analgesic amount of S(+) ibuprofen in
combination with R(-) ibuprofen.
In another aspect, the present invention provides a
method of eliciting an enh~ced analgesic response in a mammal~
Raid method comprising administering to a mammal in need of ~uch
treatment an effective analgesia enhancing amount of racemic
ibuprofen enriched with S(+) ibuprofen.
In yet another aspect, the present invention provides
a pharmaceutical composition of matter for use in eliciting an
I
~!
21 1~768 -
enhanced analgesic response in mammals, especially humans, said
composition comprising an effective analgesic amount of racemic
ibuprofen enriched with the S(+) enantiomer. Typically, the
S(+)-enriched compositions are associated with a non-toxic,
pharmaceutically acceptable, inert carrier or diluent therefor.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention encompasses pharmaceutical
compositions containing enantiomeric ibuprofen, wherein said
enantiomeric ibuprofen is from about 80 to about 95% S(+) -
ibuprofen relative to R(-) ibuprofen. Preferably, the present
invention encomPa~sses pharmaceutical compositions containing from
about 70-89.0, , S(+)-ibuprofen relative to the R-ibuprofen.
By use of the term "enantiomeric ibuprofenn, or
"S(+)-enriched ibuprofen", it is meant that the ibuprofen is
enriched in the S-enantiomer such th~at the ratio of S-enantiomer
to R-enantiomer ranges from about 70:30 to 89.0 : 11.
- The S(+) -ibuprofen of use in the methods and composi-
tion of the present invention can be prepared by a variety of
- methods, such as by resolution of racemic ibuprofen. S(+)
-ibuprofen may be prepared by following the procedures disclosed
in U.S. Patent Nos. 4,831,444, 4,877,620 5,266,723 and
5,248,813, the contents of which are incorporated herein by
reference.
Racemic ibuprofen is a true racemic compound where a
homogenous solid phase of the two enantiomers co-exists in the
same unit cell. The mixture may be separated by, for example,
diastereomer crystallization or kinetic resolution. This
generally involves reaction of the racemate with an optically
pure acid or base (the resolving agent) to form a mixture of
diastereomeric salts which is separated by crystallization.
The theoretical once-through yield of a resultion via
diastere~mer crystallization is 50 percent. However, in
practice a single recrystallization produces a composition that
is simply an enantiomerically enriched racemate.
Another method for the resultion of racemic ibuprofen
is kinetic resolution, the success of which depends on the
differential in rate that the two enantiomers react with a added
A~lenA .
Kinetic resolutions can also be effected using chira~
-5-
~etal comple:ces such as chemocatalys~s, e.g., the
enantioselective rhodium-BINAP-catalyzed isomerization of the
chiral allyl1c alcohol to the analogous prostaglandin intermedi-
ates. See, for example, Hamilton et al., Trends in
Biotechnology 3, 64-58 (1985).
The enantioselective conversion of a prochiral
substrate to an optically active product, by reaction with a
chiral addend, is referred to as asymmetric synthesis. From an
economic viewpoint, the chiral addend functions in catalystic
quantities. This may involve a simple chemocatalyst or a
biocatalyst. An example of the former is the well-known
Monsanto process for the manufacture of L-dopa by catalytic
asymmetric hydrogenation, See. Knowles et al., J. Am. Chem.
Soc., 97, 2567 ~1975). An example of the latter is the Genex
process for the esynthesis of L-phenylalanine by the addition of
ammonia of transcinn~ric acid in the presence of L-phenylalanine
ammonia lyase (PAL). See Hamilton et al., ibid.
In U.S. Patent No. 5,248,815, the contents of which is
incorporated herein, a method of obtaining highly pure
enantiomers of ibuprofen is described. By carryinq o~t this ,-~
process using ibuprofen having a composition of 70-75 % of the
S(+) enantiomer, (a 25%enriched racemic composition), a
composition of a 80-89.0 % S(+) pure produce can be obtained.
When compositions of
greater enrichment are used in this process, the S(+) isomer
content of the-final product is even higher, i.e., starting with
an 80~ S(+) composition, the final product contain-~ 87% S(+)
product. Of course, starting compositions having smaller
amounts of enrichment than the above noted 76~ S(+) produces
final product of less than 9o% S(+). The relationship between
composition of the starting ibuprofen and composition of the
final ~buprofen is surprisingly linear. The process disclosed
in U.S. Patent No. 5,248,815 provides, in one step, a product
that ~an be used directly in the compositions of the present
invention. However, it should be noted that other prior art
processes typically produce a first mixture that is essentially
an enantiomerically enriched racemic composition. If the
resulting compositions have an S(+) ibuprofen concentration of
at least 90~, these processes are also useful in carrying out
the method of the present invention.
I
-6- ~ 768
- Once the rati~ of S(+) enantiomer to R(-) enantiomer
is determined in the synthesized product, it can be modified to
the appropriate level by adding additional R(-) or S(+)
enantiomers. For example if R(-)-enantiomer is added, obviously
the ratio of S-(+)-enantiomer to R-(-)-enantiomer decreases,
while if additional S-(+)-enantiomer is added, this ratio
increases.
The present invention also includes compositions
containing pharmaceutically basic salts of the enantiomeric
ibuprofen and the use thereof. Salts include saltR with alkali
metal, such as sodium or potassium, salts with alkaline earth
metals, such as calcium, or salts with other metals such as
. . . .. ... . . _ ,
magnesium, aluminum, iron, zinc, copper, nickel or cobalt,
.. . . . _ _
Complexes of S~(+~ih~fen also ~nclude ~e dias~w~,.ic complexes ~h~n a~no acids,
1 . C ~
par~cular~ for L,lysi~, Irar~ynine, L,his~dine and I,ll~ho,~y a-amino aads, e.g saine ~d
- tbreonine, as ~ d by Paladies et aL in Pbam~ ~., 141-144 (1993). Th~e comp s
are not salts in a pl~;^~ ucal sense as ~ ,1O.~d in the EPO 4860451 A 2 (1-992) and EPO
486046 A 2 (1992), as well as in the '~nt. Symp. on Moleallar Chila~, 151-156, (19941 Kyoto-
U~ ~y, Kyoto (Japan) by Pa~dies et al. ~ m)lt;, the present i~ n~;Qn in~h~les also
compos~ons a~ntain~g S~(+~ih~o~n and a-L~Jlu~ a~cawic a~ids, e.~ S- or R-lac~c acid as
1: ~43~ in the US-patent No 5,254,728 (1993).
If the cationic portion of the salt exists in
enantiomeric or diastereomeric forms, all of the various
enantiomers or diastereomers of the salts as well as mixtures
thereof are contemplated by the present invention. THus, for
example, the present invention would include both the R- a~d the
S amino acid salts.
Metal salts of ibuprofen may be obtained by contacting
the hydroxide or carbonate with ibuprofen.
-7- 21 ~ 8 768
- It has al~o been found that S-(+)-ibuprofen has side
effects associated therewith. The allergic contraindictionQ
sometimes associated with S-(+)-ibuprofen, however, is reduced
by addition of up to 20% (w/w) of R(-)-ibuprofen to the
S(+)-ibuprofen, in accordance with the present invention.
Preferred unit dosage compositions for use in the
treatment of mild to moderate pain, contain for 50 to 1000 mg,
preferably 50, 100, 200, 400, 600, or 800 mg of the S(+)
ibuprofen-enriched compositions of the present invention.
While the compositions for use in the invention are
preferably for oral use, they may be formulated for and adminis-
tered by other routes which are known for administering
non-narcotic analgesics and/or nonsteroidal anti-inflammatory
drugs, e.g., as suppositories or parenteral solutions, or as
topical formulations such as ointments, gels, creams, lotions,
solutions, impregnated bandages, or other topical delivery
devices, and so forth. Also, it should be noted that the pre-
ferred human dosage levels indicated above are for use in adults
preferably weighing about 70 Kg; pediatric compositions would
contain proportionately less of the active ingredients.
The compositions for use herein are conveniently
administered to mammals by any route of administration that has
been suitable for racemic ibuprofen, e.g., oral, rectal, top-
ical, or parenteral. Preferably, S(+) ibuprofen-enriched
compoQitions are formulated with any suitable nontoxic, pharma-
ceutically acceptable, inert carrier material. Such carrier
materials are well-known to those skilled in the art of pharma-
ceutical formulations. For those not skilled in the art,
reference is made to the text entitled Remington's Pharmaceuti-
cal Sciences, 17th edition, 1985, ed. Alfonso R. Gennaro, Mack
Publishing Company, Easton, Pa, 18042, the contents of which are
incorporated by reference.
2ll~7~8
In a typical preparation for oral administration, e.g,
tablet, capsule or caplet, elixirs, syrups, drops, granules,
liquids, or suspension enriched S(+) ibuprofen in a liquid
composition, ethyl alcohol, and the like. Additionally, when
required, suitable binders, lubricants, disintegrating agents,
and coloring agents can also be included. Typical binders
include starch, PVP, gelatin, sugars such as sucrose,-molasses,
and lactose, corn sweeteners, natural and synthetic gums such as
acacia, sodium alginate, extract of Irish moss,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
polyethylene glycol, ethylcellulose and waxes. Typical
lubricants for use in those dosage forms can
include, without limitation, magnesium, stearic acid, talc,
boric acid, sodium benzoate, sodium acetate, sodium chloride,
leucine, and polyethylene glycoI. Suitable disintegrators can
also be added, and include, without limitation, starch
methylcellulose, agar, bentonite, cellulose, wood products,
alginic acid, guar gum, citrus pulp, carboxymethylcellulose, and
sodium lauryl sulfate, If desired, a conventional pharmaceuti-
cally acceptable dye can be incorporated into the unit dosage
form, i.e., any of the st~n~rd FD&C dyes. Sweetening and
flavoring agents as well as preservatives can also be included,
particularly when a liquid dosage form is formulated, e.g, an
~1~8768
g
elixir, suspension or syrup. Where necessary, super disintegra-
tors, such as docusate sodium, starch glycolate or cross-linked
PVP may also be included. Also, when the dosage form is a
capsule, it may contain, in addition to materials of the above
type, a liquid carrier such as a fatty oil. Various other
materials may be present as coatings or to otherwise modify the
physical form of the dosage unit. For instance, tablets, pills
or capsules may be coated with sheilac and/or sugar.
The active components may also be formulated in
sustained release formulations. These formulation may be
employed in oral, dermal, rectal, or vaginal administrations.
Such sustained release forms also include layered formulations ~-
which provide for distant release ratio and thus may be more
beneficial in allowing for shortened long-term relief.
Such pharmacutical compositions should preferably
contain at least 0.1% of the enriched S(+) ibuprofen composi-
tion; generally, the composition will be from about 2% to about
- 60% of the weight of the total unit dosage. Typical unit dosage
forms for oral administration will contain about 50 to 1000 mg,
preferably 100 to 800 mg, most preferably 100 to 600 mg, of the
enriched S(+) ibuprofen, if formulated for immediate release, as
is preferred. If the composition is intended for sustained
release, much larger amounts of the active ingredient would of
course be incorporated into an individual unit; in such case, at
least 50, and preferably up to 600 or 800 mg of the total amount
of enriched S(+) ibuprofen, should be formulated for the
sustained release formulations so as to obtain the desired
degree of enhanced analgesia and hastened onset.
A typical tablet of oral administration may contain,
in addition to the selected amount of enriched S(+) ibuprofen,
the following combination of inactive ingredients/carrier
material: acacia, acetylated monoglycerides, beeswax, calcium
sulfate, colloidal silicon dioxide, dimethicone, iron oxide,
lecithin, pharmaceutical glaze, povidone, sodium benzoate,
sodium carboxymethylcellulose, starch, stearic acid, sucrose,
titanium disoxide, carnauba wax, cornstarch, D&C Yellow No. 10,
FD&C Yellow No. 6, hydroxpropylmethylcellulose, propylene
glycol, silicon dioxide, stearic acid and titanium dioxide, and
the like.
-10- 21~8768
Mor~ov~r, th~ compositions for use in obtaining
- analgesia and hastened onset in accord and with the present
invention may, in addition to the selected doses of the composi-
tions of the present invention, also contain other active
ingredients and/or enhancing agents. Thus, for example, the
enriched compositions may be combined with such ingredients and
agents as have been previously described for combination with
racemic ibuprofen, e.g., caffeine or other xanthine derivative,
a narcotic analgesic (with or without caffeine), a skeletal
muscle rel~Y~nt~ an antihistamine, decongestant, cough
suppressant and/or expectorant, and the like. However, the
compositions of the present invention excludes the presence of
antitussive agents in combination with the enantiomeric
ibuprofen. Further, it is to be understood that the method of
the present invention additionally excludes the administration
of the enantiomeric ibuprofen and an anti-tussive agent.
The following examples illustrate the compositions of
the present invention and as such are not to be considered as
limiting the invention as set forth in the claims appended
~ hereto.
EXAMPLES
In the following examples, the S(+)-ibuprofen and the
R(-)-ibuprofen are prepared in accordance with the procedures
described in u.S. Patent Nos. 5,266,723 and 5,248,815, the
contents of which, including the examples, are incorporated by
reference as set forth hereinbelow.
Example 1
1000 tablets each containing 100 mg of ~5 ~
S-(+)-ibuprofen and15% R-(-)-ibuprofen are produced from the
following ingredients:
S-(+)-ibuprofen 85 g
R-(-)-ibuprofen 5 g
Corn Starch 50 g
Gelatin 7.5 g
Avicel (microcrystalline cellulose) 25 g
Magnesium stearate 2.5 g
The R(-) ibuprofen and S(+) ibuprofen and corn starch
are admixed with an aqueous solution of gelatin. The mixture is
21~876~
dried and ground to fine powder. The Avicel and then the
magnesium stearate are admixed with the granulation. This is
then compressed in a tablet press to form 1000 tablets each
contain 100 mg of active ingredients.
Example 2
1000 tablets each contA;~ing 200 mg of 89.0 %
S-(+)-ibuprofen and 11% R-(-)-ibuprofen are produced from the
following ingredients.
S-(+)-ibuprofen 178 g
R-(-)-ibuprofen 22 g
Lactose 100 g
Avicel 150 g
Corn Starch 50 g
Magnesium stearate 5 g
The S-(+)-ibuprofen, R-(-)-ibuprofen, lactose, and
Avicel are admixed, then blen~eA with the corn starch. Magne-
sium stearate is added. The dry mixture is compressed in a
table press to form 1000, 505 mg tablets each containing 200 mg
of active ingredient. The tablets are coated with a solution of
Methocel E 15 (Methyl cellulose) including as a color a lake
contA;ning Yellow No. 6.
Example 3
Two piece No. 1 gelatin capsules each contAi~i~g 225
mg of S-(+)-ibuprofen and 25 mg of R-(-)-ibuprofen are filled
with a mixture of the following ingredients.
S-ibuprofen 225 mg
R-ibuprofen 25 mg
Magnesium stearate 7 mg -
usp lactose 193 mg
Example 4
An enantiomeric ibuprofen containing S-(+)-ibuprofen
and R-(-)-ibuprofen in a ratio of 95:5 (5mg) is dissolved in a
solution of water (2.5 ml) and an equivalent amount of lN sodium
hydroxide. The solution is freeze dried to obtain the sodium
-12- _ 2I ~ ~ 76~
sal t.
~ An in jectable solution is produced as follows:
S-(~)-ibuprofen 450 g
R-(-)-ibuprofen 50 g
Methyl paraben 5 g
Propyl paraben 1 g
Sodium chloride 25 g
Water for injections q.s. 5 g
The active substance, preservatives and sodium
chloride are dissolved in 3 liters of water for injection and
then the volume is brought up to 5 liters. The solution is
filtered through a sterile filter and aseptically filled into
pre~terilized vials which are then closed with presterilized
rubber closures. Each vial contains 5 ml of solution in a
concentration of 100 mg of active ingredient per ml of solution
for injection.
' The different ratios of S-(+)-ibuprofen to
- R-(-)-ibuprofen, weight by weight, e.g.89.a%(w/w) S-(+) and ll.Q%
R-(-), or 80% (w/w) and 20% (w/w), can easily be manufactured by
mixing optically pure S-(+)-ibuprofen with racemic
(R,S)-ibuprofen. The different ratios of the above described
constituents can be achieved by mixing 60 parts by weight of
S-(~)-ibuprofen with 40 parts of (R,S)-ibuprofen, by weight also,
either in solution or in the solid state through thorough mixing
of the powdered materials. The mixing can be performed in
solutions, e.g. ethanol or n-hexane, by dissolving the equivalent
amounts of S-(+)-ibuprofen and racemic (R,S)-ibuprofen at
moderate temperatures between 20-38C., however below 45C. due
to phase separations which has to be avoided. After vigorous
agitation of the solutions for 15 minutes the mixing is
finalized. Subsequent crystalization at 40C., or evaporation of
the solvent under reduced pressure with subsequent drying of the
powder having the desired ratio by weight of S-(+)-ibuprofen to
R-(-)-ibuprofen yields the wanted product at almost 100% yield.
It is also possible to mix the dry powders of S-(+)-ibuprofen and
racemic (R,SJ-ibuprofen in appropriate apparatus, e.g. a dry
drum, to obtain the desired product after intense mixing.
Moreover, it is also possible to obtain the desired ratios by
adding the appropriate amount of R-(-)-ibuprofen to
21 1~7~8
- -13-
~ S-(+)-ibuprofen, all enantiomers in optically pure form.
Due to the different compositions of S-(+)-ibuprofen
and R-(-)-ibuprofen prepared by either method, through addition
of racemic (R,S)-ibuprofen to optica~ly pure S-(+)-ibuprofen, or
by addition of optically pu2r5e R-(-)-ibuprofen, the physical
parameters, e.g. m.p., [a ]D, change when compared to optically
pure S-(+)-ibuprofen. This can be used within the method of
producing the various ratios of S-(+)/R-(-) (w/w) of ibuprofen in
addition to quantitative analysis by HPLC-techniques using
chiral analytical columns, characterizing the compositions in a
quantative and quantative way.
The melt-diagram and the solubility diagram of racemic
(R,S)-ibuprofen including the pure enantiomers inhibit the
typical form of a racemic compound e.g. m.p. (R,S)-ibuprofen
76-77C, (R)-(-)- ibuprofen or S-(+)-ibuprofen of 51-52C.
respectively. It has been found that the mixtures of 95% (w/w)
of S-(+)-ibuprofen to 30% (w/w) of R-(-)-ibuprofen and 5% (w/w/)
to 20% (w/w) of R-(-)-ibuprofen crystallizes as a racemic
compound having a melting point of 45-48C., whereas above this
melting temperature and different ratios of
S-(+)/R-(-)-ibuprofen as disclosed have to form racemic
mixtures. However, this is dependent on the
nature of the solvent using ethanol as a solvent for preparation
of the various ratios in the absence of water, racemic compounds
above 45C. are obtained, in the presence of H2O racemic mixtures
are observed. In the presence of n-hexane or other apolar
solvents above 45C. racemic mixtures are observable,
however, within the disclosed ratios of S-(+)-ibuprofen to
R-(-)-ibuprofen always racemic compounds are formed between the
weight amount of R-(-)-iburpofen and the equisolvent weight
amount of S-(+)-ibuprofen. Table I illustrates some of the
features of the above disclosed ratios of S-(+)-/R-(-) (w/w~,
ibuprofen.
2l~768
-14-
Melt and solibility curves, andFT-IR as well as x-ray
crystal structure determinations are consistent with a racemic
compound rather than a racemic conglomerate or racemic mixture.
So it is eoneeivable to mix S-(+)-ibuprofen (60% w/w) with
raeemie (R,S)-ibuprofen (40~ w/w) yielding a eomposition (binol)
of 80% (w/w) S-(+)-ibuprofen, containing 20% (w/w)
R-(-)-ibuprofen which i~ not ~t random in a prior art product
since it is ~ound to the eguivalent amount of S-(+)-ibuprofen.
Aceording to the melting and solubility diagrams we eonsider the
raeemie (R,S)-ibuprofen a raeemie eom~o~,~ arising from ~e~ea~ed
heterochiral interaetions (Fig. 1). This is also eonfirmed by
single erystal X-ray diffraetion analysis of (R,S)-ibuprofen, R-
(-)- and S-(+)-ibuprofen, respectively.
Homoehiral crystals, made of moleeules of the same hande~necc,
e.g. S-(+)-ibuprofen 100~ pure, accept the incorporation of the
opposite enantiomer e.g. R-(-)-ibuprofen in their lattiee.
How_ve~, molecules having similar stru~L~es and hydrodynamie
8ize8 ean ~o _-~stallize to form solid solutions, whieh is the
ease here with S~-(+)-ibu~oren with x=90-70, and R-(-)-ibuprofen
-of 10-30 ~ (w/w). So a small guantity of R-(-)ibuprofen ean be
i,.~o~o-a~ed into the lattiee of S-(+)-ib~o~en. The degree of
- similarity of two moleeules ean be quantified by means of a
-15- 2 ~4~ 768
"isosterism" coefficient, (~ vno/v~) with vna and vO representing
the non-overlap and overlap volume of the enantiomeric molecules
of ibuprofen. ~ is normally unity for identical molecules, and
the formulation of a solid solution between two molecules e.g.
S-(/+)- and R-(-)-ibuprofen, would require that ~ be in the
range of 0.8-1Ø However due to the melting profile (~ig. 1)
between Sr-(+)-ibuprofen with x=90-70, we notice a "racemic solid
solution", having different optical activity and a melting point
close to the of the enantiomer of ibuprofen although not
identical (m.p. S~ +)-ibuprofen 52-53 C). This is consistent -
with the view that isomorphism of the two crystal species, e.g.
S~-(+)-ibuprofen or ~-(-)-ibuprofen with x=90-70 or 10-30
respec~ively, is occuring, so allowing the existence of a
continuous solid solution ~etween them. ~ was found to be of the-
order of O.9-0.95, so very close to unity. Identical melting
diagrams were obtained for crystalline Sx-(+)-ibuprofen samples
recrystallized from n-hexan, ethylacetate or ethanol,
-respectively.
By melting the appropiate amounts of S ~-(+)-ibuprofen and Rloo-
.
(-)-ibuprofen, or of S1~-(+)-ibuprofen with racemic (R,S)-
ibuprofen giving the Sl~-(+)-ibuprofen compositions yielded also
the same melting and solubility profiles.
Example 5:
Preparation of S89-(+)-Ibuprofen-L-Serine.
O.25 moles (=26.3 g) L-Serine is dissolved in 150 mL
H20 under continuous stirring until a clear solution is obtained
(20-25C.) 0.25 moles S89 (+)-ibuprofen in ethanol (52.5 g in 100
mL EtOH) are added dropwise to the aqueous L-Serine solution
over a period of time of 10 minutes at 25-30C., or until the
solution becomes transparent. Sometimes it is necessary to add
additional 100 mL EtOH under agitation at 30C. Stirring is
continued for 15 minutes at 30C., filtered through a sintered
glass funnel (lG4) to remove any insoluble or particulate
material. To this clear solution 250 mL EtOH were added until
the solution becomes transparent (20C.). The solution was left
-16- 21 1~768
at 20C. for one hour under stirring, cooled to 0C. and lef~
for 12 hours at 0-4C. The crystalline product was filtered
off, washed with cold EtOH, and dried in vacuo at 30C. Yield
71g (81%), [a]D + 21.5 (C-l, EtOH) m.p. 153-157C., 1~ ]D +
30.5 (C=1.5, H2O).
Example 6:
Preparation of S8~ (+)-Ibuprofen-D-Serine.
Thi~ complex can be prepared complex can be prepared
according to the Example 1 with L-serine but substituting the
equivalent amount of D-Serine for L-Serine [a ]D = -1.5 (C=1,
H2Ol after re-crystallization from EtOH/H2O (80/20 v/v); yield
70g (80%), m.p. 154C.
Example 7:
Preparation of S8o-(~J-Ibuprofen-D,L-Serine.
60g of S-(+)-ibuprofen (S100), having la ]D + 58, 95%
EtOH, m.p. 51C. was dissolved in 500 mL EtOH under continuou~
stirring (20-25C.) until a clear solution is obtained. Under
agitation 40g of (R,S)-ibuprofen (mp 72C.) dissolved in 100 mL
EtOH was added over a period of time of 15 minutes. Normally, a -
clear, transparent solution is obtained at 20-25C., if not some
additional EtOH (about 20-30 mL) is added until a clear solution
is obtained. Upon crystallization at 0-4C., or by removing the
EtOH by distillation under reduced pressure, and
re-crystallization from n-heYA~e or n-hexane/n-pentane (60/40
v/v), one obtains a product which has a melting point (mp) of
46C. [a 1D + 40~ (C=2, EtOH).
0.25 moles (=26.3g) of D,L-serine is dissolved in 150
mL H20 under agitation at 20C. un2til a clear solution is
obtained . Yield: 75g (85%) [ a]D + 35 (C=l.EtOH).
Example 8:
Preparation of S80-(+)-Ibuprofen-L-Threonine.
This compound can be prepared according to Example 3,
however, using 29.8g L-threonine (-0.25 moles) in 150 ml H2O.
The final product has an ta]2D5+ 1.7 (C=0.5, H2O) after
re-crystallization from EtOH. Yield: 70g (80%), m.p. 171C.
2l~7&8
-17-
Example 9:
Preparation of S89 (+J-Ibuprofen-L-Cysteine.
This complex can be prepared according to Example 3,
however, using 30.3g L-cysteine (=0.25 moles) in de-aerated H2O
(150 ml), or water N2- atmosphere. The final product has an
~ alD + 31.5 (C=l, H2O), m.p. 171C. after re-crystallization
from ethyl acetate/EtOH (80/20 v/v) at 0-4C. The product is
not hygroscopic.
Example 10:
Preparation of S80-~+~-Ibuprofen-L-Glutamine.
36.5g (=0.25 moles) of L-glutamine ([ a]D + 6.9, C=4.0,
water) are dissolved in 500 ml deaerated H2O at 25-30C -water
with continuous stirring. 52.5g S80-(+)-ibuprofen (=0.25 molesJ
dissolved in 100-200 mL EtOH are being added dropwise to the
aqueous L-glutamine solution over a period of time of 20
minutes. The solution has to be stirred because mixing is very
important, keeping the temperature around 35C., but below 50C.
in order to avoid decomposition of the L-glutamine. The clear
solution becomes cloudy ~pon cooling to 4C. and platelet
cystals appear on the bottom of the vessel. The solution is left
for 8 hours at 4C., the crystalline material filtered ff,2~
dried in vacuo at 20C. (10 mm Hg). Yield: 70g, (80%), ta ]D +
33.0 (C=1.5, EtOH), m.p. 152C.
.
Example 11:
Preparation of S8Q~-(+)-Ibuprofen-D,L-Glutamine.
D,L-glutamine (m.p. 173/73C.), which is more soluble
in H2O than L-glutamine, is dissolved in H2O (200 ml, 30C.).
Under agitation 52,5g S80-(+)-ibuprofen, dissolved in 150 ml
EtOH are added dropwise to the D,L-glutamine solution under
continuous stirring at 30-35C. The work-up of the
S80-(+)-ibuprofen-D,L-glutamine product is the same as disclosed
ln Example 3. The final product has an la ]D + 31 (C=l, dilute
acetone/water ~60/40 v/v/) after re-crystallization. Yield: 65g
(71%), m.p. 151C.
-18- 21 ~3 7~8
Example 12:
-- s89 -(+)-Ibuprofen-L-Asparagine.
26.4g (=0.20 mole asparagine) are dissolved in an
aqueous solution containing Na(K)OH (0.001M) in 500 ml at 22C.
under continuous stirring since a transparent solution of this
enantiomeric d=amine acid amide is obtained. 41.25g
S90-(+)-ibuprofen dissolved in 200 mL EtOH is added dropwise to
a dropping funnel over a period of time of 30 minutes to the
AlkAline aqueous solution. ~22-25C.). Upon cooling to 4C.
after the reaction i8 completed (30 minutes) small needle-like
crystals of the complex appear on the wall of the reaction
vessel. Continuous cooling at 4C. for 20 hours, or after
seeding with crystals ofS~g~~(+)-ibuprofen-L-asparagine, the
J final product crystallizes. Upon drying and re-crystallization
from aqueous ethanolic solution at 4C., 61g of the product-is
obtained (75%), m.p. 171 [ ]25+ 21.3 (C=l,H2O).
- Example 13:
S80-(+)-Ibuprofen-D-Asparagine.
The preparation of this product can be performed as
disclosed in Example 8, by substituting SgO-(+)-ibuprofen through
\ S80-(+)-ibuprofen, and L-asparagine with D-asparagine. The final
product (61g, 68-70~ yield) after re-crystallization from
ethylacetate at 4C.
Example 14:
S80-(+)-Ibuprofen-1-Amino-l-Deoxy-D-glucitol.
(Meglumine).
206-3g (1.0 mol) S80-(+)-ibuprofen and 195.2g-(1.0 mol)
2-D-(-)-N-methylglucamine are dissolved in 1000 ml EtOH or
isopropanol under continuous stirring at 25C. Upon gentle
heating to 50C. of the reaction vessel, normally one contains a
clear solution after 20 minutes. The work-up of this solution
consists of adding 2.5L n-hexane, stirring, cooling to 4C.,
filter off the crystals of the complex through a glas-funnel
(164), and washing the crystals with n-hexane. After drying of
the product formed and purified through re-crystallization.
Yield: 398-400g (99.1-99.6%, m.p. 106.5C. [ ~D + 11.5 (C=1,
H20) .
-19- 2l~8768
Example 15:
S89-(+)-Ibuprofen-l-Amino-l-Deoxy-D-Glucitol.
The preparation of this complex can be conducted as
described in Example 10 by substituting the amount of
S80-(+)-ibuprofen through S89-(+)-ibuprofen. Yield: 395g (90%),
m.p. 104.5C., la ~ + 10.0 (C=l,H2O).
Example 16:
Formulation of a.~Table 1:
S80-(+)-Ibuprofen-N-Methylglucitol. --
Active Ingredients:
S80-(~)-N-Methyl-Glucitol 390 mg
- S80-(+)-Ibuprofen ~ . 200 mg ~ ,,f, ,`
Inactive Ingredients:
- Gelatine
Cross-linked Sodium 10 mg
Carboxymethyl cellulose 40 mg
Magnesium stearate 10 mg
Total weight of the table 1450 mg
Example 17:
Formulation of a Table 1: SgO-(+)-Ibuprofen-N-Methylglucitol
(Meglumine).
Active Ingredients:
S89-(+)-ibuprofen-N-Methyl-Glucitol 185 mg
=S89- (+)-ibuprofen 100 mg
Inactive Ingredients:
Gelatine
Cross-Linked Sodium 5.0 mg
- Carboxymethyl cellulose 20 mg
Magnesium stearate 5.0 mg
Total weight of the Table 1 225 mg
2ll~768
-20-
Preparation:
The gelatine (10~ w/w) is dis301ved in double-distilled water at
40-45C. The active ingredient is added slowly through a
constant mixer at low mixing performance. The granulated
material obtained is processed through a whirl-heat at 35C. for
drying, and sieved (pore size 1.6 mm). The dry granules are
pressed through plates by pistons (diameter 24 mm) having a
final weight of 200 mg or 400 mg, respectively.
Some interesting pharmacokinetic results for this
preparation are listed in the following Table II.
-21- 21~ 8 768
Example 18;
s8o-(+)-I~uprofen-2-Amino-2-Deoxyglucose (Glucosamine).
44.8g (= 0.25 moles) of a-D-glucosamine ( ~-form,
crystalline material, m.p. 88-38C.) has been dissolved in 250
ml at 20-25C. under continuous stirring through a dropping
funnel 52.5g S80-(+)-ibuprofen, dissolved in 200 ml EtoH has
been added over a period of time of 30 minutes. The complex
formulation between S80-(+)-ibuprofen and a-D-glucosamine is
completed after 1 hour ~20C.) 400 mL EtOH are added under -
agitation to the solution, cooled to 40C., whereupon a~ter
seeding the solution rapidly crystallizes. Crystallization of
- the fine n~eAle~ of the com~ex from ethylacetate, yielded a
- ;~ product of m.p. 71C., 1 alD = 70 (C=l, H2O), upon stAn~in~ in
H2O after 1 hour [a 12+ 41.5C. = 1, H2O), yield 71g l80-81~
The equivalent ~-D-complex of S80-(+)-ibuprofen with
the 2-amino-2-deoxyglucose can be obtA~ne~ in the presence of
0.001 MHCl or catalytic20amounts of ZnC12. The yield is 68g
- ~(78~), m.p. 91C., ra lD s 51.9C. (C=l,H2O) without changing
C51.9~ith time in H2O.
Example 19: 1
.- S80-(+)-Ibuprofen-D-Glucitol-Complex Formati2o0n.
45.5g glucitol (anhydrous, m.p. 91C., [ a]D - 2.5
(H2OlC=10) are dissolved in 200 ml of double distilled water at
ambient temperature. To this solution 52,5g of
S80-(+)-ibuprofen dissolved in 200-300 ml EtOH are added through
a dropping funnel over a period o-f time of 30 minutes.
Continuous mixing is essential to increase complex formation, or
achieving an almost stoichiometric amount of the complex at
20C. - Addition of further 300 ml cold EtOH (4C.) resulted in
a cloudy solution which upon standing at 4C. started to
crystallize. The crystalline material is filtered off (16g),
washed with cold ethanol, re-crystallizea from n-hexane, dried
under reduced pressure (lOmm Hg) at 32-35C., yielded a product
of m.p. 88-90C, t ~]D + 1~ (C=l, H2O). Yield: 89g (90~).
The product is freely soluble in water, upon stAn~ing
at 45C. no precipitation of S80-(+)-ibuprofen has been
21 l~ 768
-22-
observed. According to spectroscopic analyses of these
complexes, and x-ray diffraction analyses of single crystals of
these materials, it is evident from these studies that these
complexes are best described as strong hydrogen-bonding
complexes between the carboxyl-group of the S80-(+)-ibuprofen
and the complex partners, e.g. amino acids, amino-sugars, or
sugar-alcohols.
Example 20:
S80-(+)-ibuprofen-D-Gluconic acid ~S-Lactone
44.5g of gluconoLactone (m.p. 151C., [ a]D + 60, C=l
H2O) waQ dissolved at ambient temperature in 100 mL H2O. Upon
addition of 52.5g S90-(+)-ibuprofen dissolved in 200 ml methanol
or ethanol, the solution turns to be turbid, but under
continuou~ stirring the solution becomes transparent again until
- the complex formation is finalized. This is normally achieved
after 30-45 minutes. The solution has been cooled to 4-10C.,
- 200 ml ether is added whereupon the solution immediately
crystallizes. The crystrals are filtered off, washed with cold
ethanol (methanol) to remove any sugar-like material, e.g.
glucolactone, gluconic acid, and recrystallized from ethanol25
solutions or n-hexane. Yield: 89g (81%), m.p. 87.5C., la ]D +
81.9 (C=l,H2O).
- Example 21:
S80-(+)-iburpofen-D-Gluconic acid. 20
49g D-glucomic acid (m.p. 131C, t a]D~7-0 (C=l,H2OJ are
dissolved in 200 ml double distilled water. To this solution at
ambient temperature a solution of 52.5g S80-(+)-ibuprofen
dissolved in 200 ml EtOH are added through a dropping funnel
over a period of time of 30 minutes under continuous stirring.
Upon raising the temperature to 50C. any turbidity can be
removed. Complex formation is finalized within one hour at
50C., the solution cooled to 4C, precipitated with ether (250
ml) at 4C. When crystallization of the complex between
S8~(+)-ibuprofen and D-gluconic acid has subsided, they were
~ltered off, washed with cold ether, re-crystallized from a
mixture of cold EtOH/ETHER 80/20 (v/v) at 4C. yielded a pure
-- 21~8768
-23- 25
_ product of 90.5g (~0t), m.p. 91.5~., [ ~1D + 13-1 (0.5g, H2O),
with no transformation or equilibrium Wit~ r.i ~ -
gluconolactose according to NMR-measurements. Th~ product is
stable in aqueous solutions without any changes of the optical
activity with time within a temperature range of 30-40C.
Example 22:
S80 -(~)-Ibuprofen-D-Gluconic Acid.
A different procedure can be used for the preparation
of the above mentioned complex by applying the magnesium salt of
gluconic acid which is commercially available as the magnesium
salt dihydrate C12H22Mgl4 g 14 2
112.7g (=0.25 moles) of the magnesium salt dihydrate
of a-D-gluconic acid is dissolved in 500 ml solution,
comprising of 60 volume parts of water and 40 volume parts of
EtOH at ambient temperatuxe. Through a dropping funnel a
solution of 52.5g S80(+)-ibuprofen (-~0.25 moles) disposed in 200
mL Ethanol (EtOH) are added slowly at constant temperature
(20-25C.) and continuous stirring (at about 800 rpm) to the
solution containing the Mg salt of gluconic acid. 1 ml of 0.01M
HCl is added through another funnel by keeping the temperature
constant at 20-25C. over a period of time of 30 minutes. Upon
! addition of 2~0 ml of isopropanol the complex of
S80-(~)-ibuprofen- a-gluconic acid precipitates as a crystalline
material, whereas the magnesium chloride resides in the
isopropanol/EtOH phase. Upon re-crystallization as disclosed in
Example 21 an optically pure product can be obtained at almost
quantitative yield.
The same process can be applied also for the zinc
complex or ammonium complex of D-gluconic acid.
Similar complexes between Sx-(+)-ibuprofen with
x=89.0 to 70 ~, and a-D- mannosamine, a-D-galactosamine/ as well
as mannitol, and l-amino-l-deoxy-D-ribitol (ribamine) or ribitol
have been prepared and analyzed. They reveal the same chemical,
physical and pharmalogical features as disclosed for the above
examples. Particularly for oral pharmaceutical formulations the
non-dissociative complex are important since only the free, i.e.
unbound material (not bound to protein), and neutral in charge is
capable of crossing membranes. Charged ibuprofen, e.g. as a salt
2~:~8768
-24-
which dissociates into cdtion and anion, cannot cross th~
membranes, it would be repelled from the membrane barriers, or
precipitates in the stomach due to insolubility problems at the
acidic pH. Furthermore, it has been found that only the
S-(+)-ibuprofen penetrates quickly from plasma into the synovial
fluid according tg these disclosed pharmaceutical formulations,
which results in short time, high C max for SgO-(+)-ibuprofen to
- s~ ibuprofen equivalent effective as Sloo-(+)-ibuprofen~TableII)
This is also true for the synovial kinetics by furni~hing rapid
hastened onset of analgesia.
:, ;;~--, .. .
Towards preparing a better ib~profen, particularly Sx-(+)-
ibuprofen with high clinical efficacy, less side effects and
high tolerance, the role of R-(-)-ibuprofen with regard to its
pharmacodynamic activity has-to be considered also. Most of the
investigators are concerned with the uni-directional conversion
of R-(-)-ibuprofen to its enantiomer S-(+)-ibuprofen in man,
attributing the biological activities only to the amounted S-
(+)-ibuprofen brought about by the converted R-(-)-ibuprofen.
This is more or less dependent on the pharmaceutical ~ormulation
as shown ~ery recently by Jamali et.al., J.Pharm. Sci.,81, 221-
225,(1992). Due to the unknown me~h~;sm of the uni-directional
conversion and the so far uncuveled action of R-~-)-ibuprofen,
it is not surprising by considering the state of art that the
benificial aspects as well as the unwanted side effects of the
~ ~ .
R-(-)-enantiomer has not been studied in such a detail as the
analgetically active s-(+)-ibuprofen.
-25- 21 ~ ~ 768
Whereas S-(+)-ibuprofen as well as indomethacin and aspirin are
~less active against Cox-2 than Cox-l ( Maede et.al.J.Biol~
Chem.,268, 6610-6614, 1993 ), R-(-)-ibuprofen has a stronger positive
activity on Cox-l ~ almost 7,0 fold, when compared to S-(+)-
ibuprofen considering the in-vitro assays. This range of
distinct activities of S-(+)- or R-(-)-ibuprofen can explain the
variations in side effects of S-(+)-ibuprofen at their
equivalent anti-inflammatory doses, e.g. osteo-arthritis of 800-
1,000 mg per day of optically pure Sl~-(+)-ibuprofen vs. 1,600-
, ~ . . .
2,000mg of racemic ibuprofen. Since R-(-)-ibuprofen has also a
protective effect on Cox-l particularly in the p~e_cnce of S-
(+)-ibuprofen since it reduces the unwanted side effects
(irritation of the stomach lining and toxic effects on the
kidneys) in a col.~e-.L ~ion ~e~ nt manner re~c~ing a pl~teau,-
~starting at a R/S-ratio of 0.42. Due to the concentration
~epen~?nt activation of Cox-2 at a R/S-ratio of 0.42 the
physiological functions of Cox-l,e.g. anti-thrombogenic
activities and the cytoprotective activity by the gastric mucosa
are enhAnceA when compared to S~-(+)-ibuprofen alone. Some of
the well received R,S-ibuprofen preparations can well be
explained by the existance of different activities of R-(-) or ~
S-(+)-ibuprofen on the two isoforms,e.g. Cox-l and Cox-2, for
each enantiomer having different inhibitory S-(+)- and
activating R-(-)-ibuprofen effects, although at concentrations
of 50 ~M R-(-)-ibuprofen the mec~Anism of action of R-(-)-
ibuprofen is com~ou"ded by a suppression of the induction of
Cox-l, and activation of Cox-2, which is enhanced by S-(+)-
ibuprofen.
While the S/R AUC-ratios of 90/10, 80/20 and 70/30 are very
similar for all S~-(+)-ibuprofen-meglumine complexes
with x = 70-90 as well as for the correspon~ing diastereomeric
lysine complexes, con~A;ning 200 mg Sy-(+)-ibuprofen as active
substance, these AUC-ratios are uneffected when increasing the
dose (100, 200, 300 and 400 mg). IIou~ver they are significantly
greater for tablets contAin~ng of 100, 200, 300 and 400 mg
racemic ibuprofen as compared with solutions of racemic
ibuprofen (1.35 ~ 0.15 vs. 0.90 ~ 0.15). This sL~o~,~ly indicates
a greater extent of chiral inversion for the tablet due to a
-26- 21 ~8768
longer residence time in the gut, therefore more presystemic
inversion. Furthermore, chiral inversion of R-(-)- to S-(+)-
ibuprofen was according to our studies completed after 2.s to 3
hours, where 20 - 25 % is being inverted to S-(+)-ibuprofen.
Surprisingly, this is just the amont of R-(-)-ibuprofen in the
tablet comprising of S70 "-(+)-ibuprofen-meglumine compleY
revealing the same efficacy and AUC-values (Table 2 + 3)as SgO-(+)-or
sloo-(+ ~buprofen-meglumine complex. As a result the AUC of S-(+)-
ibuprofen in the dosage forms between 90/10 to 70/30 (S/R) is
enriched ell~U~l -t ârds S-(+)-ibuprofen to be e~v~l~nt
Qf~ect~ve a~ SlOO-(+)-ibuprofen, and to influence the ~ atelet
a~eyàtional behaviour in a more moderate mode (Fig.2-4) which
is not the case for SlOO-(+)-ibuprofen which appparentiy is
- significantly stonger. The maximum cQncentrations of Sx-(+)-
iLuy Gfen for maximal inhibitory effects was found to b~20r
~g/mL for S1OO-(+)-iL~oren, for S90-(+)-ibuprofen to 30 ~g/mL,---
SO-(+)-ibuprofen to 40 ~g/mL, and S70-(+)-ibuprofen to 45 ~g/mL.
By contrast racemic ibuprofen and R-(-)-ibuprofen showed very
little activation. These results were also obtained in in-vivo
experiments.
_ -27- 219 8768
To demonstrate the pharmacokinetic relationship between the
preparation of SlO~-(+)-ibuprofen more closely with respect to
the various S/R-ratios, we investigated the plasma levels of S-
(+)-ibuprofen produced by the different S/R-mixtures ranging
from 90/10 to 70/30, and racemic R,S- ibuprofen. The results
obtained are listed in Table 2.
The results of this study (N=8) reveal no superiority of the
S~-(+)-ibuprofen, S~+-ibuprofen over the S~-(+)-ibuprofen to
S,0-(+)-ibuprofen in the production of high, efficient:
concentrations of S-(+)-ibuprofen in plasma after administering
200mg pharmaceutically active ingredient S~-(+)-ibuprofen. With
the S~-(+)- or S,~-t+)-ibuprofen mi~Lule~ there are practical ~ -
significant S-(+)-ibuprofen concentrations in plasma at the same
time, having the same c~y and almost the same AUC's. However,
considering e.g. S~-(+)-ibuprofen only, plasma concentrations-
(AUC) are approximately 15-17% higher taking the chiral
inversion into consideration. So the overall AUC for
formulations of Sy-(+)-ibuprofen with x=80-70% when in complex
with meglumine or lysine,respectively, yielded the same AUC's
compared to S~-(+)-ibuprofen within the time frame of 3-4 hours
(Fig.s~. This is consistent with the observation that the t~2
for R-(-)-ibuprofen is significantly shorter when compared to S-
(+)-ibuprofen following 100 - 400mg doses (1.60 vs. 2.09), and
does not change with higher doses (600 - l,OOOmg, 1.70 vs.
2.15), so t~2 does not change with dose. Furthermore, the
conversion of R-(-)-ibuprofen-meglumine or lysine, is
considerably ~nhAnced resulting in a significant increase of S-
~+)-ibuprofen Plasma levels having also prolonged duration
effects (Fig.5). So no significant decrease in S-(+)-ibuprofen
plasma levels were produced by increasing the optical purity
from 75 % to 100 %, revealing a threshold preparation of R-(-)-
ibuprofen of 15-20 % (w/w) where the converted R-(-)-ibuprofen
to S-(+)-ibuprofen becomes readily available in the blood.
Therefore, it shows the same onset of analgesia as S~-(+)-
ibuprofen but it also reveals an enhancement of the reversal of
the inhibitory effects of the platelet aggregation , reducing 5-
-28- 21~8768
HETE concentrations, reduction of bleeding time to values
similar known for racemic ibuprofen.
Furthermore, the stereoselectivity in the tl,2 observed after 100
to 400 mg S70-(+)-ibuprofen due to R,0-(-)-ibuprofen in the
pharmaceutical preparations as disclosed in this invention is
unlikely to result from a difference in the protein binding of
the two enantiomers of ibuprofen; such an effect would be more
pronounced using higher doses where nonlinearity is more evident
as shown by Jamali et. al also (Jamali et. al., J.Pharm. Sci,
81, 221-225, 1992)
Means for Qnset, c~, and AUC are summarized in Table 3 and in
Figs. 6-8, respectively, for the various S~-(+)-ibuprofen
formulations in complex with meglumine according to the examples
disclosed here. Similar results have been obtained for Sy~(+)~
ibuprofen-L-lysine preparations. (Fig. 9)
The results obtained for onset, c~y, and AUC closely agree with
and support the conclusions based on the time-course information
and the in-vivo studies, e.g. platelet a~Le~ation, biochemistry
of action and pharmacokinetics. The 90/10 composition is found
not to be superior over the 95/5 or 80/20 (w/w) composition with
regard to c~, AUC and t~; for all three of the variables namely
c~,AUC and onset, there was no significant regression when
comparing the 95/5, 90/10, 80/20, and 75/25 compositions.
Furthermore, the assessment ot the analgesic activity of S~-
(+)-ibuprofen, as well as for R-(-)-ibuprofen and racemic
ibuprofen in the Writhing Test was found to be ED~=38.8-39.72
for S,~(+)-ibuprofen, ED~=79.1-89.8 for R-(-)-ibuprofen and
ED~=250-260 for racemic ibuprofen (in mg/Kg) where ED~ is the
dose leading to a 50 % reduction in writhing score (1 % acetic
acid, intraperitonial). Taking chiral conversion into account R-
(-)-ibuprofen is 2.5 times more active than the racemic, and
S,~-(+)-ibuprofen is six times more effective than the racemic
ibuprofen. However using composites of Sy-(+)-ibuprofen with x=
70-go, still reveals the same ED~ as the one determined for
-29- 21~876~
racemic ibuprofen of 38.8-39.7 (35-40).
Furthermore, the relative oral bioavailability of Sy~(+)~
ibuprofen-R-lysinate, or Sy-(+)-ibuprofen-meglumine with x = 100,
90, 80, and 70 can be estimated by comparison with published
data on racemic ibuprofen. After taking 200mg Sy-(+)-ibuprofen-
meglumine in a capsule form, a mean value of AUC of s5.s
mg/L-12h for x = 100, 55.0 + 5.5 mg/L-12h; x = 90, 55.0 + 5.0
mg/L-12h; x = 80, 53 + 7.0 mg/L-12h, and for x = 70 52.7 + 8.2
- mg/L-12h have been calculated. Por all preparations the maximum
level was computed to be of the order of 25.5 mg/L, and was
r~rhe~ on the average in 2.3-2.5 minutes (N=8).The mean pain
intensity at zero time was 5.1 as ~se~ through an~
arbitrarily pain intensity scale by patients suffering from
primary dysmenorrhoe. The analgesic effect for all
pharmaceutica~ preparations of S~-(+)-ibu~oren-meglumine (200mg
active il~y~edient) started within 5-7 minutes, a reduction in
value to 1.5 on the average have been found throughout all
ratios which have been tested. The maximum analgesic effect was
achieved for the ratios 80 to 70 after 2.5 hours with a value of
0.27. Thereafter the pain intensity slowly increA~e~ to a value
of 1.0 again after 8 hours. The maximum analgesic effect for a
preparation comprising of 100 or 90 % pure S-(+)-ibuprofen was
achieved after 2 hours having a value of 0.25 on the pain scale,
and lasted 5-6 hours.
The differences in the Acceæsments of Sl~-(+)-ibuprofen, the S~-
(+)-ibuprofen compositions vs. racemic and R~-(+)-ibuprofen has
been investigated on PGE2 and 6-keto-PGF~-synthesis, also. These
different compositions including (R,S)-ibuprofen, R-(-)-
ibuprofen and typical standards (e.g. indomethacin, aspirin)
have been tested for their c~F~city to i nh i hi t the ionophore-
induced release of PGE2 from mouse peritoneal macrophages in the
cell culture. (Paradies et. al.; Eur. J. Med. Chem. 25, 143-156,
1990; H. H. Paradies, K.E. Schulte; Ann. N. Y. Acad. Sci., 529,
221-227, 1988). The mean values for the 50 % inhibitation (IC~)
which are obtained from concentration depe~ent activity ~ve3
-30- 21~ 8 75
- are listed in Table 4. The results in Table 4 show that the S~-
(+)-ibuprofen compositions with x= 90-70 are not very different
in the IC50 values nor in potency when compared to the Sl~-(+)-
ibuprofen. However, there is a large difference between R~-(-)-
ibuprofen and the S~-(+)-ibuprofen compositions. However,
comparing these results obtained in in-vivo studies, e.g. the
pain threshold as ~ sed through an arbitrarily pain scale
from patients suffering from primary dysmenorrhoe as alre ~ -
~disclosed in this description, we noticed a significant increase
in pain threshold when compared to (R,S)-ibuprofen or R-(-)-
ibuprofen, but no significant indication of a less effective
biological action (e.g. pain threshold) with the different Sy~~
(+)~ fen compositions. The results obt~ne~ are not oniy~
valid for Sy-(+)-ibuprofen-meglumine (or lysine) formulations,
but also for the Sy-(+)-ibuprofen free acid revealing the same
trend, however, dose dependent after correction for chiral
inversion.
Noreover, determinations of the 6-keto-PGFl~ synthesis in the
presence of Sy-(+)-ibuprofen, R-(-)-ibuprofen as well as (R,S)-
ibuprofen (all of them were administrated as D-meglumine-or
lysinate complexes, 50 mg/kg, to male rates of approx. 200-250
g weigth), was measured from the gastric mucosal tissue and
sectioning. The levels determined of the gastric mucosal
prostaglandin production yielded a reduction in activity of 50
- % for (R;S)-ibuprofen, 58-62 % of S~-(+)-ibuprofen and 50-5S
% of Sy-(+)-ibuprofen, whereas R-(-)-ibuprofen shows a reduction
of 15-20 % only after 5 minutes, however, after 30 minutes of
30-35 %, indicating a presystemic inversion of R-(-)- to S-(+)-
ibuprofen.
We can conclude from these data which are consistent with the
incidents of low numbers of reported serious side effects of
racemic ibuprofen formulations, which are one of the reasons for
the low ul~e o~enicity. This can be related to the effects that
S-(+)- and R-(-)-ibuprofen have partly an inhibitory effect on
the 5- and 15-lipoxygenase activity in the gastric mucosa,
thereby producing a balanced inhibitation of both Cox-1 and Cox-
.- ,, ' 1
2l~87~
-31-
_ 2 and lipoxygenases, particularly for threshold-levels of 15 %
(w/w) at least in the presence of S-(+)-ibuprofen, whereas the
platelet level for optimal performance for R-(-)-ibuprofen is of
the order of 15-20 % (w/w) in the presence S-(+)-ibuprofen. It
seems that this is an association between the propensity of the
ulcerogenic ibuprofen, probably residing mostly on S-(+)-
ibuprofen but also on R-(-)-ibuprofen due to intracellular
chiral inversion, to inhibit platelet a~Le~ation, and t;he~ ~h~
appearance of mucovascular damage. Because the ~L~-~cnce of R-
(-)-ibuprofen, particularly, in the pre-cqnce of meglumine or
lysine as complexing agents, there is neither little tendency of
the S~-(+)-ibuprofen to produce fine structural changes in the
mucosa, so no-microvascular r~ngeC~ nor do they ~nhihit~
platelet ~ ey~tion. This has been shown here, especially the
reversibility of platelet inhibition by applying a threshold
CO~ ation of at least 10-15 % (w/w) R-(-)-ibuprofen. The
reduction of Sl~-(+)-ibuprofen changes in microvascular
integrity in the presence of 10-30 % (w/w) R~ ibuprofen,
might be related to their effects on platelet a~Leyation, and
may contribute to a reduction of ischaemic reactions in the
mucosa during very early stages of S-(+)-ibuprofen induced
mucosal injury.
Since the toxicities of S-(+)- and R-(-)-ibuprofen so far
tested, particularly those for the occurence of gastric ulcers
(tested in 80 male Sprague Dawley rats) are almost the same
(3.10-3.10), but for the racemic much less (1.2-1.3). The
presence of R-(-)-ibuprofen in a formulation does not seem to
provide any obvious benefit at a first look. However, a closer
examination reveals that there is a pharmakodynamic influence of
R-(-)-ibuprofen, e.g. acute toxicity, platelet aggregation,
biochemical infl~enaec on the leukotriene pathways. It can be
conæidered, e.g. that S-(+)-ibuprofen significantly reduced the
ADP, adrenaline, and collagen induced platelet a~ e~ation (20
~g/mL), whereas R~ )-ibuprofen does not show any in-vitro
platelet d~ e~dtion of the same type as S~-(+)-ibuprofen at
all. However, con~l~cting the same studies in the presence of 10-
2l4876~
-32-
30 ~ (w/w) R-(-)-ibuprofen, and in the same concentration ranges
as for S~0O-(+)-ibuprofen, we noticed an almost normal
aggregational behaviour with respect to platelet aggregation by
having the same effect on analgesia as for Sl~-(+)-ibuprofen.
Whereas S-t+)-ibuprofen reduces also the adhesion of platelets,
PF-3 availability but not the total PF-3. However, R-(-)-
ibuprofen do act differently in the ~L~-en~e of 10-30 % (w/w)
and 90-70 % (w/w) of S-(+)-ibuprofen, revealing no reduction of
adhesion and PF-3 availability, so an almost normal behaviour is
to be seen with Le_~e~L to platelet ay~Leyation.
-33_ ~1 4 ~ 768
C~ ree systems was used to demonstrate the
R-(-)-ibuprofen and S-(+)-ibuprofen concentration dependency
within this disclosed pharmaceutical formulations in which a
Fe2+- included oxidation of arachidonic acid (AA) has been
followed by nitroblue-tetrazolium absorbance using human
platelet lysates. The results demonstrate that
S-(+)-ibuprofen-Fe2+ complex dissociates in the presence of
endogeneous or enogeneous AA, which was not the case for
R-(-)-ibuprofen-Fe2 complex at concentrations of 55-80 M.
Furthermore, upon addition of O-phenanthroline , a Fé2~
ion chelate, the Fe2+- enzyme , `system is protected for the
inhibitory effect of S-(~)-ibuprofen or aspirin, whereas
R-(-)-ibuprofen reveals ~effects aæ measured by protease and
PGE2 inhibition! The same experiment conducted with ~
R-(-)-ibuprofen at ~M concentrations revealed little-inhibitory
effects on thromboxane A2 biosynthesis. The same results can be
achieved by incubating the in vitro system with aspirin
following administration of different ratios of S-(~)/R-(-)
ibuprofen as measured through the amounts generated by
thromboxane A2 and PGE2. S;ince it is known that aspirin and
S10O-(+)-ibuprofen are strongly active on the cyclooxygenase-1
(MAEDE, E.A., et. ol. J. Biol. Chem. 268, 6610-6514, 1983), and
less active on cyclooxygenase-2, it can be inferred that
R-(-)-ibuprofen at the applied in-vitro concentrations exhibits
biological activity on cyciooxygenase-2, but less on
cyclooxygenase-l. This is further substantiated in the
microphage assay system and mast cell system. The differences
in biological activities of the various ratios of S-(~)/R-(-)
ibuprofen can be demonstrated by the AA induced platelet
'
. i
.
_34_ 21 ~ 8 76~
aggregation in the presence of metal (Fe ) complexing agents
also. These experiments to show a protective effect of
R-(-)-ibuprofen on cyclooxygenase at ~M levels. To evaluate if
R-(-)-ibuprofen was competing in this assay system for the same
site as aspirin on S-(+)-ibuprofen, they were subjected for this
effect on heme-AA interaction. The results reveal that
R-(-)-ibuprofen, a weak inhibitor for cyclooxygenase-l, was as
potent as S-(+)-ibuprofen or aspirin (as a control, minimally
inhibits cyclooxygenase -1) in preventing the oxidation of AA by
ferous ions, however, at higher concentration than
S-(+)-ibuprofen. This is consistent with in vivo studies that
at concentration ratios of S-(+)/R-(-) ibuprofen, particularly
for 90/10 to approx. 80/20, can effectively block the
irreversible inhibition of cyclooxygenase-1 by aspirin or
S10O-(+)-ibuprofen, suggesting two active sites on platelet
cyclooxygenase, as seen in the reversible AA induced platelet
aggregation and the platelet aggregational phenomens. This
suggests that R-(-)-ibuprofen at the different ratios exerts
some inhibitory action, anti-inflammatory action due to
inhibition of cyclooxygenase-2. This is also in support by
results obtained from inhibition studies on AA induced
aggregation of washed platelets, and the second wave response of
platelets to the action of epinephrine and ADP. In addition
12-HETE as well as 15-HETE can al~er prostaglandin metabolism
due to the various ratios of S-(+)/R-(-)-ibuprofen:
i.) they can substitute for endogenous AA, and
form prostaglandins of the 3-series;
.
.) as seen here can compete for the enzyme
(cox-l, cox-2), and act as a competitive
inhibitors of natural AA;
(iiii.) they can form hydroperoxy acids via
lipoxygenase, and exert inhibitory effects on
the reversibility of platelet function but
still have the antiinflammatory effects due
to the action of these metabolic compound.
It is known that non-steroidal antiinflammatory
compounds, e.g. aspirin, indomethacin and ibuprofen, are highly
bound drugs to serum albumin and ~ -acid glycoprotein,
respectively. However, R-(-)-ibu~rofen is less bound to human
~l8768
-35-
plasma protein than (S-(+)-ibuprofen, having a ratio of 1.5-1.7
of S-(+) to R-(-)-ibuprofen. Since only the free unbound
compound is capable of crossing the membranes the less bound
R-(-)-ibuprofen can be taken up by damaged or inflamed tissues at
concentrations which are relevant and comparable to the in-vitro
experiments through R-(-)-ibuprofen is converted undirectionally
to S-(+)-ibuprofen in humans ( 20-30%). Furthermore, the
selective passage of the S-(+)-enantiomer into the synovial
fluid, and the uptake of R-(-)-ibuprofen into fatty tissues and
inflamed tissues, influence how S-(+)- and R-(-)-ibuprofen can
exert this pharmacyclonamic action after reaching the target
cells at concentration for R) which are compatible to in vitro
experiments. Due to the pharmaceutical formulation applying
various ratios of S-(+)-ibuprofen to R-(-)-ibuprofen,
particularity for 90:10 and 80:20, respectively, including the
superiority of the various complexes over the free acid, e.g.
water-solubility, start T-max with high C max, rapid onset of
analgesic, rapid absorption, it is possible to infer from in
vitro studies to mucosal concentraions which clearly adequate
inhibit prostaglandin synthesis (based on the in vitro potency),
though the absorption of the complexes are fast. Since
R~ ibuprofen does inhibit or reduce 5-HETE levels also in the
gastric mucosa, the consequence of this inhibition of
5-lipogenase activity by S-(+)/R-(-)-ibuprofen which is also a
cylo-oxygenase inhibitor, might be to balance arachidonat~
metabolism, and prevent excess tissue-destruc~ive oxygen-radicals
derived from those hydroperoxyarachidonic acids produced through
the lipoxygenase pathway. It is also known that these kind of
drugs because they inhibit platelet aggregation, induce
microvascular injury. Since the prostaglandin cyclooxygenase
(cox-l) is in inhibited by this pharmaceutical preparation and
this production of pro-aggregatory thromboxane A2, is balanced
by inhibitory effects of this combination of S-(+)-ibuprofen and
R-(-)-ibuprofen on endothelial cell production of the
antiaggregatory PGI2 (prostacyclin). Therefore, it is
conceivable that these two effects virtually cancel out one
another assuming equipotent antagonism of platelet thromboxane A2
by PGI2 with these ratios of S-(+)-ibuprofen to R-(-)-ibuprofen.
As the result the low expected ulcerogenicity of this
21~76~,
-36-
~ pharm~ceutical formulation cdn be relat~d to the effects this
continuation of S-(+)-ibuprof~n to R-(-)-ibuprofen have on
inhibiting 5-lipooxygenase activity in the nucosa and of the two
cyclooxygenases, thereby producing balanced inhibition of both
cyclooxygenase (cox 1 and cox 2) and lipooxygenase pathways.
It is known that human enzymes and cell surface
receptors are bonded by some sort of stereochemical mechanism,
so the two enantiomers of a racemic drug, e.g. S-(+) and
R-(-)-ibuprofen within the (R,S)-compound, may be adsorbed,
activated, or metabolized at different rates. So it is possible
that the two enantiomers can possess equal pharmaceutical
activity, or one may be inactive (or be toxic), or the two can
have unequal degrees or very different kinds of activities. So
it is known that R-(-)-ketoprofen reveals activities against
bone loss in periodontal disease whereas the S-(+)-ketoprofen is
an analgesic/antiinflammatory compound. Moreover, most of the
nonsteriodal antiinflammatory compounds, so also S-(~)-ibuprofen
lead to inhibition of the prostaglandin
H2-synthestase-llcyclo-oxogenase-11, resulting in "shooting" off
the arachidonic acid (AA) into the lipoxygenase pathway result-
ing in increased leukotriene production in several epithelial
systems. Therefore, some of the pharmacodynamic effects previ-
ously descri~ed for cyclo-oxygenase-1 inhibitors, e.g.
S-(+)-ibuprofen, are most likely secondary to the increased
production of one lipoxygenase product or another. These
products have important roles in inflammatory and allergic
reactions (Kuehl, F.A., Egan, R.W., Science (Wash. D.C.) 210,
978-984, 1980). The influence of S-(+) and R-(-)-ibuprofen can
be demonstrated in vitro and in vivo in studying the activation
of the 15-lipoxygenase pathway which produce 5-HETE
(5-hydroxy-6, 8, 11, 14-eicosatetraenoic acid), di-HETEs, LTB4,
LTC4, LTD4, and LTE4 (Samuelson, s., Science (Wash. D.C.), 220,
568-575, 1983). It is known, e.g. LTs"is a very potent
chemokinetic and chemotactic agent 4 neutrophils where 5-HETE
is approximately 100-fold less active whereas that LTC4, LTD4
and LTE4 are the most active compounds of slow reacting
substance of anaphylaxis (SRA). However, the 15-lipoxygenase
pathway forms initially 15-HPETE which can be reduced by
cellular peroxidases to 15-HETE, or metabolized to other
-37_ 21 ~ ~ 768
products of the 15-series leukotrienes, 15-HPETE inhibits
platelet aggregation, and vascular prostacyclin synthesis
~Moncada, S. et al. Prostaglandins 12, 715-737, 1976).
Moreover, cellular lipoxygenases are modulated by 15-HPETE and
15-HETE as well as lymphocyte mitogenesis. According to Table V
15-HETE and the 15-lipoxygenase is a valuable monitor to expose
the role of R-(-)-ibuprofen and their concentration dependant
role in conjunction with S-(+)-ibuprofen. This is further
manifasted by the time course of (R,S)-ibuprofen
R-(-)-ibuprofen, and S-(+)-ibuprofen (Fig.10,11) activation
of 15-lipoxygenase in human polymorphonuclear leucotyes ~PMN)
(R,S)-, S-~+)- or R-(-)-, and the 10% (w/w) R-(-)-J9o%
S-(+)-ibuprofens were added either before (Fig 11) or after -
(Fig.10) the addition Of t C]-AA to the PMNs. The results ``
clearly show that the stir~ tion of the 15-lipoxygenase by
R-(-)-ibuprofen as well as by 10% (w/w) R-(-)-ibuprofen/90%
(w/w) S-(+)-ibuprofen occurs within minutes (almost within 1
minute). Furthermore PMN cells treated with the combination of
10% (w/w) R-(-)-ibuprofen /90% (w/w) S-(+)-ibuprofen show a
remarkable enhanced formation of 114C]-15 HETE and very low
formation of [14C]-5-HETE. In addition the stimulation of the
PMN 15-lipoxygenase by addition of the ibuprofen is reversible.
Furthermore, this in vivo study reveals that a further increase
of the concentration of R-(-)-ibuprofen ~above 20% (w/w) does not
change the shape of the curves in Fig.ll. Apparently full
stimulation of the 15-lipoxygenase of the human PMNs is achieved
approximately between 45-50 M R-(-)-ibuprofen, whereas inhibi-
tion effects of S-(~)-ibuprofen alone are observed at concen-
tration of 0.150 mM which are not compatible with serum plasma
levels under therapeutic dosages in treatment of acute and
- chronic pain. Furthermore, by comparison with aspirin the
result obtained for this ibuprofens including the one containing
10 % (w/w) R-(-)-ibuprofen and 90 % S~ ibuprofen under the
same experimental conditions (however from 10 patients) reveals
a very low enhancement of 15-lipoxygenase for aspirin but a
considerable enhancement for the 90/10 ibuprofen composition.
- The low activities for aspirin and for other non-steroidal
antiinflammatory compounds with respect to 15-lipoxygenase are
in agreement with results obtain by Vanderhoek and Bailey
-38- 21 ~ 7~8
- (Vanderhock, J.Y., sailey, J. M., J. siol. Chem., 259,
6752-6756, 1984J, recently.
Fig.4 shows the collagen induced platelet aggregation
after administration of 200 mg S-(+)-ibuprofen and 200 mg
S-(+)-ibuprofen /R-(-)-ibuprofen (90/10), respectively to 10
healthy volunteers with time (h). It can be noticed, that the
platelet aggregation is reversible, and reduced in the presence
of 10% (w/w) R-(-)-ibuprofen. The same trend is seen in the
epinephrine-induced platelet aggregation in vitro (Fig.3) as
well as in the ADP induced platelet aggregation assay (Fig.2).
Moreover, platelet aggregation is decreased by S-(+)-ibuprofen
at daily dosages between 100 and 200 mg in a reversible
response. ~owever, by addition of 10% (w/w) of R-(-)-ibuprofen
the aggregational status is much less effected as seen in
clinical trails of 50 volunteers and 20 patients suffering from
rheumatism which is consistent with the results shown in Figs. 4
- and 2 also.
Table VI shows that the concentration of 12-HPETE
- required to produce half-maximum inhibition of platelet
aggregation induced at 5(10) mM ibuprofen in humans. It can be
noticed that the thrombin-induced aggregation was not inhibited
by 12-HPETE. However, aggregation induced by AA, collagen and
thrombin reveal together with the fact that higher concen-
trations of 12-HPETE are needed to abolish TxB2 biosynthesis an
antagonistic effect of R-(-)-ibuprofen v. S-(+)-ibuprofen on
formation of 12-HPETE. Furthermore, this antagonistic effect of
12-HPETE on endoperoxide- and for thromboxane (TxB2) induced
aggregation is seen particularly in the presence of 15-20% (w/w)
R-(-)-ibuprofen / 80-85% (w/w) S-(+)-ibuprofen. In addition
S-(+)-ibuprofen and R-(-)-ibuprofen have a dual effect on shape
and aggregational behavior of human platelets, namely inhibiting
both cyclooxygenase and the peroxidase in a stereochemical
manner concomitantly regulating the 12-HPETE level. Maximal
activity in the presence of R-(-)-ibuprofen is achieved between
50-55 M accounting for approximately 20% (w/w) of
R-(-)-ibuprofen, and 80% S-(+)/R-(-)-ibuprofen ratio, and does
not increase the activity any further, whereas the plateau-level
is reached at concentrations of 45 ~M e~uivalent to 10-15
R-(-)-ibuprofen (Table VII).
- -39-
Th~ rever~ible ln~lbltlon o~ platelet aggreg~tion ln
th13 si~uation ~or 80-903 (~ ) S-(+)=ibuprofan contai,~ing
10-20~ ~w/wJ R~ ibup~o~en result~ from ~he com~ined effects
of abol~shlng pro~taglandin ~ynthesls, ar~d acc~mulati~n of 12
HPETE, ~he inhlbltton of -his chemotax_s cf human PMN cells in
the presence of S-~+)-ibuprofen 1~ linear, for the racemic
(~,S)-lbuprofen i~ biphasic ~n an exper~mental sy~tem ~tudied as
de~cribed by Paradies et al ~Eur. J. Med. Chem 2S 143-156,
199~. However, at concentration level3 of 45
R-(-)-ibuprofen ~n the p~e6ence o~ the corre~ponding
S~ lbupro~n conce~tration (O. ~50 mM) ~he l~nearlty ove~ a
total concentration range between 10 4-103 M o~ S-~)-ibuprofen
and R~ ibuprofen i~ p~e~er~d. ~en ln the pr~se~ce of human
~e~um ~lbumin ~here ~5 no decxea~e ln mo~eme~t o~serv~ble in
contra~t ~o mos~ other observations ln chemotax~ 6 expc3rim~nt~.
~ t ~ g known that drugs like asplrin, ~ndomethacln,
~ollnda~ and (R, S) -ibuprofen have d~ual effect~ on platelet~,
lnhi~iting both the cyclooxygena~e ar~d ~he ~erox~ d~se, thus
r ~ising the 12-~PETE to abnormal high levQl~ re~ulting in the
known adverse effect~. The inhibiti~n o~ pl~t~l~t asgregAtion
by thesQ drugs ~a~ hyphothesized to reslult ~rom the combined
effects of abol ishlng pxo6taglindin biosynthesis, particularly
for the enant~omer S~ lbupro~en an~ accumulatio~ of 12-~P~T~.
In additlon r~cemic ibuprofsn $~ le~s ac~lve than indomethacln,
A 23187 and 8RIJ 56 wit~ respect to ~m~lian 5-lipoxyg~nase
uslng pleural neutrophils a~ the cell sou~ce.
~ t ha~ been found tha~ 15-lipoxygenase from peripheral
polymorpho-nuclear cell~ ~P.~) is in A relative~y 6tate ~ince
t~e~e c~119 oxygenate only ~m~ll a~.ounts of exogeneous-
~rachldonic acid (AA) to 15-HETE. However, R~ -ibuprofen
~elect~vely actl~ate~ in a concsnt~tion d~pondent manner the
human PMN 15-lipoxygenase. Pre~reatmen~. of the PMNs with
1.0-2.0 mM R-~-)-lbu~rofen ~rior to the add~tion of exogeneous
[14C]-AA reaulted ~n the ~timul~tion of 15-~ETE form~tior. up to
25-30 fold, wherea~ no enhAncement of th~ 15-l~poxygenase
actlvlty ha~ been ob~erved under these conditio~6.
S-(l)-ibupr~fen reveals no activities under ~he a~say con-
d~tlons. Fu~thormora, ~he ac~lva~lon was revers~ble, and
maxlmum 8~ mulatio~ of the 15-lipoxygenase ~a~ observed when the
_40_ 21 ~ 8768
time interval between the addition of R~ ibuprofen and
- arachidonic acid was less than 2 min Comparing the effects of
aspirin, indomethacin and R-(-)-ibuprofen on the ls-lipoxygenase
activities, R-(-)-ibuprofen produced an 20-fold increase,
whereas aspirin and indomethacin produces only 1.5-twofold
enhancement, S-(+)-ibuprofen none.
Since both enantiomers of ibuprofen do not produce
LTC4 and LTD4, no increase in vasopermeability in the skin is
being observed.
Platelets from asthmatics and patients sufferinq from ~;~:
chron~c idiopathic thrombocytopenia purpura synthesizes increasë`~
amounts of 12-HETE and lessTX and HHT than those from healthy
volunteerg, 12-HETE and 15-HETE inhibit both AA-induced platelet
aggregation and thrombin-in~-~c~ TXB2 formation in platelet~
Since 15-HETE is being synthesized and enhanced by
R-(-)-ibuprofen (not by R-(-)-naproxen) endogeneously, the
platelets do not form TX and HHT in a concentration manner,
- revealing a 10% (w/w) of R-(-)-ibuprofen with respect to
S-(+)-ibuprofen suppressing the side effects due to platelet
- activities. In addition the re-esterification of
5,8,11-sicosatrienoic acid (lipoxygenase product) within the
platelet membrane is reduced due to R-(-)-ibuprofen, the in-
creased platelet susceptibility to thrombin-indued aggregation
is reduced.
Lipoxygenase, but not cyclooxygenase, seems to be
involved in the incorporation of phosphatidic acid into mast
cell membrane phospholipides which is inhibited by
R-(-)-ibuprofen. Lipoxygenase peroxidation of mitochondrial
membrane lipids of reticulocytes appeared to be involved in the
process of inactivation and degradation of cell organelles which
can also be inhibited by R-(-)-ibuprofen, not by S-(+)-ibuprofen
at all. This results in a disactivation of the release of
aggressive radicals due to interference of R-(-)-ibuprofen.
This is important for chronic treatment, as well as for the
en~nced onset.
Most importantly R-(-)-ibuprofen has only a postlipase
control point in the formation of lipoxygenase products which
S-t+)-ibuprofen does not have. This second regulatory feature
involves the Ca2+ dependent conversion of inactive lipoxygenase
-41~ 8 7~8
(~5-) to an active lipoxygenase species which is necessary for
the formation of specific lipoxygenase metabolites, resulting in
a certain modulation of inflammatory reactions.
S~ lisinyly the analgetic response bet~veen 5:95 20:80 and 70:30 is identically to
100% S~+)-ibuprofen however it drops significantly below 30:70 as the pha,n,ac~
dynamic and pl,d"nacokinetic data indicate. FulU~em~or~ the red~ction of 5-HETE due
to the p~e ~ of R~-~ibuprofen, the side effects - as n ~ ~1 e.g. through in vivou~i.~ns by platelet a~ti~) and TxAQ determinations - are significantly less and
reversible when administerin~ pure S (~)~ibuprofen without loosin~ clinical efficien~
Noreover the stimulation of 15-Ht 1 E through Rt-tibupiofen affects the function of the
cells and tissues involved in l~,~o~tasis and ir~ .nation which includes platelets,
endo~elial celb, ..~ytes and ~ranuloc3~tes. Therefore, it was l--~ted and
obvious aooordin~ to the state of art that those ~npositions of S`x (~) ibuprofen (X = 89
70) in the p.~s~ of Rt-) ibuprofen at U l-~hold oonoentration of 11-25% (W/w) inhibit
the pro~tion of pr~i,dl~ml.~tory leukotrienes B4, C4, and D4, which are strong
,~; ~ion of urnNanted side effects.
(R,S~ibuprofen is a weak inhibitor of COX-2, strong on COX-1, so is S100t 1 )-ibuprofen.
However, the inhibito~y effects on COX-1 is redl~ by Rt-~ibuprofen within the
c~nb~dti~l range of 10-20% (W/w) as seen through TxAQ inhibition which is
cons;d~rdbly re~l ~1 in the pr~s~ce of S100 ~)ibuprofen. Less than 10% (Wlw) of R~-
~ibuprofen has no effect, more than 30% (W/w) of the R~-)-ibuprofen does not affect either
the reversal of TxA2 prod~tion nor stimulation of the 15-HETE pro~ ~tion, since it levels
off at 1~20h (Wlw) of R~-~ibuprofen. The Ulr~l.old dose for R~-~ibuprofen t~U~rwith the analgetic compound S~ibuprofen is of the order of 10-20% (W/w) R~-)-
ibuprofen and 80 90h (W/w) S~+)-ibuprofen, and does not ,~por,J to higher concen-
trdtions of R~-) ibuprofen anymore. This is particularly i,npo.t~t for long termadministraUon of S~(+~ibuprofen, e.g. o~ U"it,s or muscle a,U"itis and re!ated
rheumatic complex ~ ~s Appa~dly law doses of R~-) ibupr~ren (10 30%) does
selectively effect COX-1 in platelets t~aU,er with S~+~ibuprofen. So R~-)-ibuprofen
has the advant~ to reduce TxA2 ~l~tion t~U ~r with a large amount of S~+~
ibuprofen ( R/S = 0.12-0.43 ) to a certain level that the inhibited pl~t~let enymes can
~e ~dte within a certain period of time during anti-i. Ibmmat~y be~bl enl wiff out
loosing analgebc n~sponse having the ~ame analgetic efficac3~ as S,00 ~ibup~fen.FurU ~n~ore, as R~-) ibuprofen is ab~ L~ into the presystemic cira ~'~ion, so platel~t
and platelet enyrnes in tne blood meet R~-~ibuprofen in much higher cona3nbdlionbhan in bhe arterial circulation.
.
2l~8768
_ -42-
In terms for long treatment of chronic inflammatory
process~s the sid~ effects due to S-(~)-ibuprofen can be reduced
by addition of up to 20% ~w/w) of R-(-)-ibuprofen.
This pharmaceutical composition of ibuprofen compris-
ing of 80-95% S-(+)-ibuprofen and 20-5% R-(-)-ibuprofen w/w for
treating acute pain, particularly in a suitable complex with
aminosugars, o~-hydroxy acids, e.g. (R,S)-lactate described in
the US Patent No. 5,254,728 or in the corresponding EP-0486045
A2 given an onset-hastened, analgesic response in humans.
From the foregoing description, one of ordinary skill
in the art can easily ascertain the essential characteristics of
the instant invention, and without departing from the spirit and
scope thereof, can make various changes and/or modifications of
the invention to adapt it to various usages and conditions. As
such, these changes and/or modifications are intended to be
within the full range of equivalence of the following claims.
.. . .. . . . . . . .
2I~8768
~3
TABLE
Melting points (mp) and optical rotation ~~ in
ethanol for various ratios of S-(+)-ibuprofen/R-(-)-ibuprofen
(weight/weight).
Ratio m.p.C. ~]D
100% S 52-53 +58
95% S/ 5% R 49-50 +53
90% S/109~ R 46-47 +45
95~ S/15% R 45--46 +42
80% S/20% R 45-48 +40
75% S!~5% R 45-48 ~ +35
7096S/30~ R 45-48 +30
... . . ..
- : - - -, - . . . - . . . -
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TABLE V
Relative enhancement of ( R, S ) - ibuprofen, R - (-) ibuprofen, and S - (~) ibuprofen by stimulation of the PMN 15 - lipo~ygenase in
human~ in comparison to aspirin.
Stimulation of [14C] 15 - HETE form~ tiQn by aspirin or il~u~lor~l in rnM
0.05 mM 1.0 mM 2.0mM 5.0mM
Aspir~ 0.05 0.21 - 0.4 - 0.9 - fold
(R,S)-il~u~ uÇ~ 2.15 5.1 8.5- 16-fold
S - (-) - il~u~.~lr~ 0.08 0. 19 0.37 0.8 - fold
R - (+) - ib~lofi_. 2.0 4.8 8.0 12 - f~ld
.
~R--(--)- ibu~lùf~ ( 30%) ~
S--(+)- ibul~of~ ( 70%) ~ 2.1 3.5 5.2 10.5 -f~ld ~ :
~R--(--)--ibu~lùr~u ( 40/O)
S--(+ )--ibUl lul~ ( 60%) ~ 2.0 4.5 8.0 14 - f~ld
R- (--)--ibu~ )r~ ( 10%)~
S~ (+)~ ibu~lufi~(90%)¦ 1.7 3.4 5.7 11 -fold
~R- (--)~ ul~lur~ ( 20%)~
S--(+)- i~ul.lur~ (8oo/o)J 2.0 3.5 5.5 10.7-fold
R- (- )- ibu~luf~,.l ( 5%)~
S- (+ )- ibu~ of ~ ( 95/O)J 0.8 1.6 2.7 9.0 - fold
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