Inclusion complexes of racemic ibuproxam and of optically active ibuproxam with cyclodextrin derivatives, pharmaceutical preparations containing said inclusion complexes and methods for using same

Inclusion Complexes of Racemic Ibuproxam and of Optically Active Ibuproxam with Cyclodextrin Derivatives, Process for the Preparation Thereof, Pharmaceutical Preparations Containing these Inclusion Complexes or Containing Optically Active S-(+)-Ibuproxam, and Use Thereof There are disclosed novel inclusion complexes of racemic ibuproxam and of optically active S-(+)-ibuproxam with hydrophilic and hydrophobic cyclodextrin derivatives and, in the case of optically active S-(+)-ibuproxam, also with .beta.-cyclodextrin alone. Further a process for preparing S-(+)-ibuproxam and inclusion complexes of racemic ibuproxam and of optically active S-(+)-ibuproxam with hydrophilic and hydrophobic derivatives of .beta.-cyclodextrin and, in the case of optically active S-(+)-ibuproxam, also with .beta.-cyclodextrin alone, is disclosed. Disclosed are also pharmaceutical compositions containing these inclusion complexes or optically active S-(+)-ibuproxam. Optically active S-(+)-ibuproxam and novel inclusion complexes of racemic ibuproxam and of optically active ibuproxam with cyclodextrin derivatives and, in the case of optically active S-(+)-ibuproxam, also with .beta.-cyclodextrin alone, are better soluble in water and have improved biopharmaceutical properties such as lesser toxicity, better antiinflammatory action and non-irritation of the gastric mucous membrane.

TECHNICAL FIELD 
(IPC A 61K 31/185) 
The present invention belongs to the field of pharmaceutical industry and 
relates to novel inclusion complexes of racemic ibuproxam and optically 
active S-(+)-ibuproxam with cyclodextrin derivatives such as 
methyl-.beta.-cyclodextrin, dimethyl-.beta.-cyclodextrin, 
hydroxypropyl-.beta.cyclodextrin, hydroxyethyl-.beta.-cyclodextrin, 
triacetyl-.beta.-cyclodextrin and, in the case of optically active 
S-(+)-ibuproxam, also with .beta.-cyclodextrin. The invention also relates 
to a process for the preparation thereof, to pharmaceutical compositions 
containing these inclusion complexes or optically active S-(+)-ibuproxam, 
and to the use thereof in the treatment of inflammations and febrile 
conditions as well as in alleviating pain. 
TECHNICAL PROBLEM 
There exists a constant need for preparing novel galenic forms of 
ibuproxam, racemic as well as optically active one, having improved 
biopharmaceutical properties such as low toxicity, better antiinflammatory 
action and non-irritation of gastric mucous membrane. 
PRIOR ART 
Ibuproxam is a generic name for 2-(4-isobutylphenyl)-propiohydroxamic acid 
of the formula 
##STR1## 
The substance was described for the first time in U.S. Pat. No. 4,082,707 
as a solid crystalline substance in the form of white shining thin 
platelets having analgetic, antipyretic and antiinflammatory properties. 
The substance is soluble in methanol, ethanol, acetone and ethyl ether and 
is insoluble in water and petroleum ether. 
The substance is ibuprofen (2-(4-isobutylphenyl)-propionic acid) prodrug. 
It has been experimentally confirmed that, irrespective of the ibuproxam 
application route, there occurs a rapid and almost complete metabolic 
conversion into ibuprofen. In the article by Orzalesi G. et al., 
Arzneim.-Forsch./Drug Res. 30 (II), the determination of ibuproxam and 
ibuprofen in blood is disclosed. The presence of ibuproxam and ibuprofen 
in blood was measured 15 minutes after application. The value of ibuprofen 
was 2.5 times higher than the value of ibuproxam, thus indicating a high 
rate of the conversion of ibuproxam into ibuprofen. In the article by 
Orzalesi G. et al., Arzneim.-Forsch./Drug Res. 27 (I) there are disclosed 
comparisons between the properties of ibuprofen and ibuproxam evidencing 
the same analgetic, antipyretic and antiinflammatory action of both 
substances. The introduction of hydroxylamine radical into the ibuprofen 
molecule increases the tolerance of the molecule, which is especially the 
result of different pharmakinetics of ibuproxam. The latter is less toxic 
for the mucous membrane of the alimentary tract with the result that the 
by-effects and toxicity of the active substance are essentially reduced. 
Simultaneously, the chemical conversion of ibuprofen into ibuproxam makes 
possible an increase of the transfer rate and an increase of ibuprofen 
concentration in blood in comparison with ibuprofen. The better 
bioavailability of ibuproxam in comparison with ibuprofen is the result of 
different physicochemical properties of either substance. In the same 
article a comparison between parenteral and peroral application of 
ibuprofen and ibuproxam is also disclosed. At parenteral application 
LD.sub.50 is the same for both substances, whereas LD.sub.50 at peroral 
application of ibuproxam is twice to three times greater than that of 
ibuprofen. 
It is well-known that several biologically active substances exist in the 
form of a stereoisomeric mixture whereas usually only one isomer is 
biologically active. It has been proven that only S-(+)-enantiomer of 
ibuprofen is pharmacologically active. In the body of mammals (in liver 
and kidneys) R-(-)-enantiomer is to a varying extent converted by means of 
metabolic steroisomeric inversion into the active form of S-(+)-ibuprofen 
(Ching-Shih C. et al., Biochimica et Biophysica Acta, 1078 (1991)). 
According to data from the article by Geisslinger G. et al., Agents and 
Actions, Vol. 27, 3/4 (1989), in humans only R-(-)-enantiomer, yet only 
one third thereof, is converted to S-(+)-enantiomer. 
In the literature there are disclosed several advantages of S-(+)-ibuprofen 
over racemic ibuprofen. From EP-B1-267 321 there are known 
sustained-release medicaments in the form of tablets or capsules 
containing ibuprofen only in the optically active form. In WO 89/00421 
methods for increasing analgetic response in the organisms of mammals by 
means S-(+)-enantiomer of ibuprofen are disclosed. A pharmaceutical 
preparation for the treatment of fever and inflammations and for 
alleviating pain, said preparation containing S-(+)-ibuprofen sodium salt, 
is disclosed in WO 92/20334. In U.S. Pat. No. 5,100,918 a method for the 
treatment of sunburns with S-(+)-ibuprofen is disclosed. 
Combinations of optically active ibuprofen with other optically active 
substances are disclosed as well. Thus in WO 92/05783 there is disclosed a 
combination with antihistaminics, in WO 92/17177 a combination with 
antitussives and expectorants and in WO 92/17171 a combination with 
sympathomimetics. 
Ibuprofen as well as ibuproxam are very poorly soluble in water, which 
affects the rate and extent of absorption from the gastrointestinal tract 
and the bioavailability after peroral application. 
Inclusion complexes with cyclodextrins are known from numerous literature 
sources such as J. Szejtli, Cyclodextrins and their Inclusion Complexes, 
Akademiai Kiado, Budapest, 1982, and J. Szejtly, Cyclodextrin Technology, 
Kluwer Academic Publishers, 1988. Cyclodextrins are cyclic compounds 
comprising 6, 7 or 8 glucopyranose units bound with .alpha.-1,4-glycosidic 
bonds. They are characterized by a cylindrical structure and special 
arrangement of hydroxylic groups, the outer surface of cyclodextrin ring 
being hydrophilic, which ensures water solubility, whereas its interior 
surface is lipophilic, which allows other molecules known as "guest 
molecules" or parts thereof that are less polar than water (hydrophobic 
molecules) and are of suitable dimensions, to be bound into the lipophilic 
cavity in the interior of the cylindrical cyclodextrin molecule and to 
form an inclusion complex. 
An inclusion complex of S-(+)-ibuprofen with cyclodextrin and/or its 
derivatives, a process for the preparation thereof and its use in 
pharmaceutical formulations are disclosed in WO 92/09308. For ibuprofen 
bound into a complex with cyclodextrin, there are given better dissolution 
characteristics, a reduced offensive smell, taste and effect to the mucous 
membrane as well as better bioavailability. 
The advantages of binding substances into inclusion complexes with 
cyclodextrin are also known in other active substances. Thus in U.S. Pat. 
No. 4,603,123 an inclusion complex of piroxicam with .beta.-cyclodextrin 
and advantages thereof are disclosed: a four times greater solubility, 
increased therapeutic activity together with a lesser effect upon the 
gastric mucous membrane, a greater therapeutic index, the level of the 
active substance in plasma is higher and it appears soon after 
application. In U.S. Pat. No. 5,079,237 an inclusion complex of 
nicardipine or of its salt with .beta.-cyclodextrin is disclosed. There 
are stated better characteristics of the rate and extent of dissolution 
and a twice better bioavailability whereas no difference in toxicity 
between nicardipine hydrochloride bound into a complex and free 
nicardipine hydrochloride can be noticed. 
The inclusion complex of racemic ibuproxam with .beta.-cyclodextrin is 
disclosed in U.S. Pat. No. 4,952,565, wherein essential physicochemical 
and pharmacokinetic properties of the complex of ibuproxam with 
.beta.-cyclodextrin in comparison to non-complexed ibuproxam are stated: 
by binding ibuproxam into the cyclodextrin molecule the solubility in 
water is significantly increased, the inclusion complex is less toxic than 
ibuproxam alone, the complexing significantly increases the dissolution 
rate, the absorption constant of the complex is greater than the constant 
of the commercial preparation--tablets IBUDROS.RTM., the relative 
bioavailability of the complex is 100% greater than that of the standard 
tablet preparation IBUDROS.RTM., statistically significant differences are 
demonstrated with regard to the time periods necessary for the achievement 
of maximum concentrations and to average plasma concentrations, the same 
activity being achieved by half a dose of ibuproxam. 
TECHNICAL SOLUTION 
The problem to be solved by the present invention is to convert the racemic 
ibuproxam and optically active S-(+)-ibuproxam into a form better soluble 
in water, which would make possible the preparation of galenic forms 
having improved pharmacological properties. The object of the invention 
was especially to prepare inclusion complexes of .beta.-cyclodextrin 
derivatives with optically active S-(+)-ibuproxam of high purity as well 
as to prepare S-(+)-ibuproxam, all of them having lower toxicity, better 
antiinflammatory action and better water solubility than the free racemic 
form of ibuproxam. 
This object is achieved by binding racemic ibuproxam and optically active 
S-(+)-ibuproxam into the structure of derivatives of cyclodextrin 
molecules. Thus novel inclusion complexes in the form of a white powder 
are obtained. 
The first object of the invention is thus an inclusion complex of racemic 
2-(4-isobutylphenyl)-propiohydroxamic acid and of optically active 
S-(+)-2-(4isobutylphenyl)-propiohydroxamic acid (ibuproxam) of the formula 
##STR2## 
with cyclodextrin derivatives and, in the case of optically active 
S-(+)-2-(4-isobutylphenyl)-propiohydroxamic acid, also with 
.beta.-cyclodextrin alone. 
For the preparation of the inventive inclusion complexes 
.alpha.-cyclodextrin, .beta.-cylodextrin and .gamma.-cyclodextrin, 
preferably .beta.-cyclodextrin, and their hydrophilic and hydrophobic 
derivatives may be used. As hydrophilic cyclodextrin derivatives all such 
known compounds may be used such as hexakis-(2,3,6tri-O 
-methyl).alpha.-cyclodextrin dextrin (abbr. TRIMEA), heptakis-(2,6di-O 
-methyl)-.beta.-cyclodextrin (abbr. DIMEB), 
monomethyl-.beta.-cyclodextrin, methyl-.beta.-cyclodextrin (abbr. RAMEB), 
heptakis-(2,3,6-tri-O-methyl)-.beta.-cyclodextrin (abbr. TRIMEB), 
hydroxyethyl-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, 
branched .beta.-cyclodextrin derivatives such as 
glucosyl-.beta.-cyclodextrin, dimaltosyl-.beta.-cyclodextrin, 
diglucosyl-.beta.-cyclodextrin, succinyl-.beta.-cyclodextrin and others. 
As hydrophobic .beta.-cyclodextrin derivatives all such known compounds 
may be used such as heptakis-(2,3,6-tri-O-acetyl)-.beta.-cyclodextrin 
(abbr. triacetyl-.beta.-CD), heptakis-(2,6-di-O-ethyl)-.beta.-cyclodextrin 
(abbr. DE-.beta.-CD), heptakis-(2,3-di-O-ethyl)-.beta.-cyclodextrin, 
heptakis-(2,3,6-tri-O-ethyl)-.beta.-cyclodextrin (abbr. TE-.beta.-CD), 
O-carboxymethyl-O-ethyl-.beta.-cyclodextrin, 
heptakis-2,6-di-O-pentyl-.beta.-cyclodextrin, 
heptakis-2,3,6-tri-O-pentyl-.beta.-cyclodextrin, 
heptakis-(3-O-acetyl-2,6-di-O-pentyl)-.beta.-cyclodextrin and others. 
Further, for the preparation of the inclusion complexes there can be used 
hydrophilic dihydroxyalkyl polymer derivatives of cyclodextrin, which are 
cyclodextrin polymers, or ionic cyclodextrin polymers such as 
aminoalkyl(C.sub.1 -C.sub.3)-, or dialkyl(C.sub.1 
-C.sub.3)-aminoalkyl(C.sub.1 -C.sub.3)-substituted polymers. 
Inclusion complexes of racemic ibuproxam and of optically active 
S-(+)-ibuproxam with .beta.-cyclodextrin derivatives and, in the case of 
optically active S-(+)-ibuproxam, also with .beta.-cyclodextrin alone are 
novel compounds hitherto not disclosed in the literature. 
Optically active S-(+)-ibuproxam of high purity was prepared from 
commercial S-(+)-ibuprofen of 99.4% purity (Ethyl Corporation) in such a 
way that at first in methanol at the temperature of about 30.degree. C. 
S-(+)-ibuprofen methyl ester was prepared, which was then converted with 
hydroxylamine hydrochloride at the temperature of about 0.degree. C. into 
S-(+)-ibuproxam. The percentage of optical purity did not change during 
the reaction so that for preparing inclusion complexes with 
.beta.-cyclodextrin and with derivatives thereof 99.4% S-(+)-ibuproxam was 
used. 
The above process is also an object of the present invention. 
Optically active S-(+)-ibuproxam of high purity could also be prepared from 
the commercial S-(+)-ibuprofen of 99.4% purity (Ethyl Corporation) in such 
a way that S-(+)-ibuprofen was converted in an organic solvent into 
S-(+)-ibuprofen anhydride (bis-2-(4-isobutylphenyl)-propionic 
acid!-anhydride) at a temperature of about 30.degree. C. according to the 
process disclosed in EP-A-0203379, which anhydride was then at the room 
temperature converted with hydroxylamine in an organic solvent such as 
e.g. dichloromethane, chloroform and acetonitrile, into S-(+)-ibuproxam. 
Also in this reaction the percentage of the optical purity did not change. 
The above process is also an object of the present invention. 
Inclusion complex of optically active S-( +)-ibuproxam with 
.beta.-cyclodextrin was prepared in such a way that into a boiling 
.beta.-cyclodextrin aqueous solution S-(+)-ibuproxam was added and after 
the completed reaction the undissolved ibuproxam was filtered off, the 
filtrate was cooled and the complex so formed was isolated. The reaction 
could also take place in an aqueous-methanolic medium instead in an 
aqueous medium, wherein .beta.-cyclodextrin was dissolved in water at a 
temperature of about 70 .degree. C., methanolic solution of 
S-(+)-ibuproxam was added and after the completed reaction the solvent was 
evaporated and then the inclusion complex formed was isolated and dried in 
vacuo at the temperature of 40 .degree. C. 
The above process is also an object of the present invention. 
Inclusion complexes of racemic ibuproxam and optically active 
S-(+)-ibuproxam with hydrophilic derivatives of .beta.-cyclodextrin were 
prepared in such a way that to an alcoholic solution such as e.g. 
methanolic solution of the hydrophilic derivative of .beta.-cyclodextrin 
at room temperature, racemic ibuproxam or its S-(+)-enantiomer was added 
and after the completed reaction the obtained inclusion complex was 
isolated. The reaction could also take place in an aqueous medium, whereat 
the hydrophilic derivative of .beta.-cyclodextrin was dissolved in water, 
the solution was heated to a temperature of about 70.degree. C., racemic 
ibuproxam or its S-(+)-enantiomer was added and it was vigorously stirred. 
The obtained solution was frozen in liquid nitrogen and lyophilized. 
The above process is also an object of the present invention. 
The inclusion complexes of racemic ibuproxam and optically active 
S-(+)-ibuproxam with hydrophobic derivatives of .beta.-cyclodextrin were 
prepared in such a way that a hydrophobic derivative of 
.beta.-cyclodextrin was dissolved in an organic solvent and then racemic 
or optically active ibuproxam was added while stirring at room 
temperature. After the completed stirring the obtained clear solution was 
evaporated in vacuo at the temperature of 40.degree. C. and the residue 
was isolated and dried in a vacuum drier at room temperature to the 
desired oily product. As the organic solvent acetone, ethyl acetate, 
dichloromethane, chloroform and other solvents could be used. Also a 
mixture of an organic solvent with water (e.g. acetone/water mixture) 
could be used. In this case a hydrophobic derivative of 
.beta.-cyclodextrin was dissolved in the organic solvent at a temperature 
of about 40.degree. C. and then there were added racemic or optically 
active ibuproxam and more water under vigorous stirring. The obtained 
solution was cooled to a temperature between 0.degree. and 5.degree. C. 
The formed precipitate was filtered off and dried in vacuo at the 
temperature of 40.degree. C. 
The above process is also an object of the present invention. 
The yield in both cases, for inclusion complexes of .beta.-cyclodextrin 
derivatives with racemic as well as with optically active ibuproxam, was 
high i.e. over 94%. 
Inclusion complexes of racemic and optically active ibuproxam with 
.beta.-cyclodextrin derivatives and, in the case of optically active 
S-(+)-ibuproxam, also with .beta.-cyclodextrin alone could be formed in a 
ratio of 1:5 to 5:1, preferably in a ratio of 1:2 to 2:1. 
The present invention also relates to pharmaceutical preparations 
containing a therapeutically active amount of inclusion complexes of 
racemic ibuproxam or optically active S-(+)-ibuproxam with cyclodextrin 
derivatives, in the case of optically active S-(+)-ibuproxam, also with 
.beta.-cyclodextrin alone, together with a conventional pharmaceutically 
acceptable carrier and other adjuvants. To provide a systemic action of 
ibuproxam the following application routes are possible: peroral, rectal, 
transnasal, transbuccal, transdermal, and parenteral application, in an 
adequate pharmaceutical form such as tablets, capsules, dragees, and in 
forms such as sustained-release forms, effervescent forms, dispersion 
forms, gastroresistent forms, syrups, suspensions, solutions, 
suppositories, ointments, gels, emulsions, injections, infusions etc. 
Tablets may also be lacquered, whereat the usual process for applying a 
lacquer coating onto the tablet surface by means of the spraying method is 
used. To provide a topical action of ibuproxam the following application 
routes are possible: dermal, occular, vaginal application, in an adequate 
pharmaceutical form such as cremes, ointments, gels, solutions and 
suspensions, eye ointments, eye drops, vagitories etc. In addition to the 
active substance, these preparations also contain pharmaceutically 
acceptable adjuvants in their optimum concentrations such as carriers, 
stabilizers, preservatives, colourants etc. The preparations are prepared 
according to known methods specific for a certain pharmaceutical form. 
The present invention further relates to pharmaceutical preparations 
containing a therapeutically active amount of the optically active 
S-(+)-ibuproxam together with a conventional pharmaceutically acceptable 
carrier and other adjuvants. 
The present invention also relates to the use of optically active 
S-(+)-ibuproxam and novel inclusion complexes of racemic ibuproxam and of 
optically active S-(+)-ibuproxam with cyclodextrin derivatives and, in the 
case of optically active S-(+)-ibuproxam, with .beta.-cyclodextrin alone 
as a medicine as well as to their use in the treatment of inflammations 
and febrile conditions and for alleviating pain.

The invention is illustrated by the following Examples which in no way 
represent a limitation thereof. 
EXAMPLE 1 
Preparation of S-(+)-ibuproxam 
Optically active S-(+)-ibuproxam may be prepared in two ways 
a) S-(+)-ibuprofen (5.0 g; 0.024 mole) was shed into methanol (35 ml), 
concentrated sulfuric acid (1 ml) was added and the reaction mixture was 
heated for 3 hours at the reflux temperature of the reaction mixture. Then 
it was evaporated in vacuo at the temperature of 30.degree. C. to dryness. 
S-(+)-ibuprofen methyl ester (5.1 g) was obtained. 
Hydroxylamine hydrochloride (1.7 g; 0.024 mole) was poured over with 
methanol (38 ml) and cooled to the temperature of 0.degree. C. A 
methanolic solution (13 ml) of sodium hydroxide (4.7 g of NaOH/13 ml of 
methanol) and S-(+)-ibuprofen methylester (5.1 g) were slowly added and it 
was stirred for 4 hours at the temperature of 20.degree. C. The reaction 
mixture was evaporated in vacuo at the temperature of 30.degree. C. to 
dryness. Then demineralized water (70 ml) was added. The reaction mixture 
was neutralized with a hydrochloric acid aqueous solution (20%) up to the 
pH value of 6. The product was filtered off and the filtrate was dried in 
vacuo at a temperature up to 30.degree. C. The product was crystallized 
first from a methanol/water mixture and then from a petroleum 
ether/acetone mixture. There was obtained S-(+)-ibuproxam (4.5 g) in the 
form of a white powder, m.p. 119.degree. to 121.degree. C. 
b) S-(+)-ibuprofen (2.3 g; 0.011 mole) was dissolved in dichlorometane (15 
ml) and then N,N'-dicyclohexylcarbodiimide (DCC) (1.15 g) was added. The 
reaction mixture was stirred for 1 hour at the temperature of 30.degree. 
C., then filtered and the filtrate was evaporated in vacuo. 
S-(+)-ibuprofen anhydride (2.19 g; 100%) was obtained in the form of an 
oily product. 
S-(+)-ibuprofen anhydride (2 g; 0.005 mole) was dissolved in 
dichloromethane (10 ml) and hydroxylamine (0.18 g; 0.0055 mole) was added. 
The reaction mixture was stirred for 1 hour at room temperature, then the 
solvent was evaporated in vacuo, the residue was poured over with 
petroleum ether (15 ml) and stirred for two hours. The obtained product 
was filtered off and washed with petroleum ether. S-(+)-ibuproxam (1.13 g; 
92%) was obtained in the form of a white powder, m.p. 119.degree. to 
121.degree. C. 
Specific rotation: 
.alpha.!.sup.23.sub.Na (ethanol abs., 0.30)=+44.4.degree. 
IR and NMR spectra of S-(+)-ibuproxam corresponded to the spectra of 
racemic ibuproxam. 
FIG. 1 shows IR spectrum of racemic ibuproxam and S-(+)-ibuproxam. 
FIGS. 2A and 2B show NMR spectrum of racemic ibuproxam and S-(+)-ibuproxam. 
FIG. 3 shows DSC (differential scanning calorimetry) thermogram of racemic 
ibuproxam and S-(+)-ibuproxam. 
EXAMPLE 2 
Preparation of inclusion complex of optically active S-(+)-ibuproxam with 
.beta.-cyclodextrin 
a) Procedure in aqueous medium 
.beta.-cyclodextrin (1.135 g; 1.0 mmole) in water (10 ml) was heated to 
boiling temperature. Into the boiling solution S-(+)-ibuproxam (0.221 g; 
1.0 mmole) was added and it was vigorously stirred for 2 minutes. 
Undissolved S-(+)-ibuproxam was filtered off and the filtrate was cooled 
during stirring to a temperature between 0 .degree. and 5.degree. C. The 
obtained complex was filtered off by suction and dried in vacuo at the 
temperature of about 40.degree. C. Inclusion complex (1.28 g; 94.4%) of 
S-(+)-ibuproxam with .beta.-cyclodextrin was obtained in the form of a 
white powder in the molar ratio of 1:1. 
Data on reaction yields, ibuproxam content in the complex (determined 
theoretically and experimentally-spectrophotometric determination at the 
wavelength of 220 nm) and specific rotation .alpha.!.sup.23.sub.Na of the 
complex formed are summarized in Table 2. 
Differential scanning calorimetry (DSC thermogram) 
In the curve of the obtained product there was not detected any endothermic 
transition for a melting point, characteristic of a physical mixture of 
ibuproxam/.beta.-cyclodextrin at a temperature from 120.degree. to 
130.degree. C. (FIGS. 4A and 4B). 
NMR spectrum 
In the .sup.1 H-NMR spectrum of the title complex in DMSO-D.sub.6 solution 
the following change in the ibuproxam moiety was observed: at 7.19-7.25 
ppm the signal for proton resonances in phenyl ring shifted to a higher 
field. 
FIG. 5 shows NMR spectrum of the complex of S-(+)-ibuproxam with 
.beta.-cyclodextrin. 
b) Procedure in a solvent mixture (methanol/water in the ratio 5:20) 
.beta.-cyclodextrin (1.135 g; 1.0 mmole) was dissolved in water (20 ml) at 
a temperature of about 70.degree. C. During stirring a solution of 
S-(+)-ibuproxam (0.221 g; 1.0 mmole) in methanol (5 ml) was added. At the 
temperature of 70.degree. C. it was stirred for another 5 minutes, when 
the solvents were evaporated. The obtained complex was dried in vacuo at a 
temperature about 40.degree. C. Inclusion complex (1.26 g; 92.9%) of 
S-(+)-ibuproxam with .beta.-cyclodextrin was obtained in the form of a 
white powder in the molar ratio of 1:1. 
Differential scanning calorimetry and NMR spectrum showed the same results 
as in the process for preparing the inclusion complex in an aqueous 
medium. 
EXAMPLE 3 
Preparation of inclusion complex of racemic ibuproxam with 
methyl-.beta.-cyclodextrin 
a) Procedure in methanolic medium 
Racemic ibuproxam (0.221 g; 1.0 mmole) was added to a solution of 
methyl-.beta.-cyclodextrin (1.31 g; 1.0 mmole) in methanol (10 ml). The 
obtained solution was stirred for another 5 minutes at room temperature. 
Methanol was then evaporated and the obtained complex was dried in vacuo 
at the temperature of 40.degree. C. Inclusion complex (1.51 g; 98.6%) of 
racemic ibuproxam with methyl-.beta.-cyclodextrin was obtained in the form 
of a white powder in the molar ratio of 1:1. 
Data on reaction yields, ibuproxam content in the complex (determined 
theoretically and experimentally-spectrophotometric determination at the 
wavelength of 220 nm) and specific rotation .alpha.!.sup.23.sub.Na of the 
complex formed are summarized in Table 1. 
Differential scanning calorimetry (DSC thermogram) 
In the curve of the obtained product there was not detected any endothermic 
transition for a melting point, characteristic of a physical mixture of 
ibuproxam/methyl-.beta.-cyclodextrin at a temperature from 120.degree. to 
130.degree. C. (FIGS. 6A and 6B). 
NMR spectrum 
In the .sup.1 H-NMR spectrum of the title complex in DMSO-D.sub.6 solution 
the following change in the ibuproxam moiety was observed: at 7.19-7.25 
ppm the signal for proton resonances in phenyl ring shifted to a higher 
field. 
FIG. 7 shows NMR spectrum of the complex of racemic ibuproxam with 
methyl-.beta.-cyclodextrin. 
b) Procedure in aqueous medium 
Methyl-.beta.-cyclodextrin (1.31 g; 1.0 mmole) was dissolved in water (10 
ml). The obtained solution was heated to the temperature of 70.degree. C. 
and racemic ibuproxam (0.221 g; 1.0 mmole) was added. It was vigorously 
stirred for another 5 minutes. The solution was frozen in liquid nitrogen 
and lyophilized. Inclusion complex (1.48 g; 96.7%) of racemic ibuproxam 
with methyl-.beta.-cyclodextrin was obtained in the form of a white powder 
in the molar ratio of 1:1. 
Differential scanning calorimetry and NMR spectrum showed the same results 
as in the process for preparing inclusion complex in the methanolic 
medium. 
EXAMPLE 4 
Preparation of inclusion complex of S-(+)-ibuproxam with 
methyl-.beta.-cyclodextrin 
a) Procedure in methanolic medium 
S-(+)-ibuproxam (0.221 g; 1.0 mmole) was added to a solution of 
methyl-.beta.-cyclodextrin (1.31 g; 1.0 mmole) in methanol (10 ml). The 
obtained solution was stirred for another 5 minutes at room temperature. 
Methanol was then evaporated and the obtained complex was dried in vacuo 
at the temperature of 40.degree. C. Inclusion complex (1.51 g; 98.6%) of 
S-(+)-ibuproxam with methyl-.beta.-cyclodextrin was obtained in the form 
of a white powder in the molar ratio of 1:1. 
Data on reaction yields, ibuproxam content in the complex (determined 
theoretically and experimentally-spectrophotometric determination at the 
wavelength of 220 nm) and specific rotation .alpha.!.sup.23.sub.Na of the 
complex formed are summarized in Table 2. 
Differential scanning calorimetry (DSC thermogram) 
In the curve of the obtained product there was not detected any endothermic 
transition for a melting point, characteristic of a physical mixture of 
ibuproxam/methyl-.beta.-cyclodextrin at a temperature from 120.degree. to 
130.degree. C. (FIGS. 8A and 8B). 
NMR spectrum 
In the .sup.1 H-NMR spectrum of the title complex in DMSO-D.sub.6 solution 
the following change in the ibuproxam moiety was observed: at 7.19-7.25 
ppm the signal for proton resonances in phenyl ring shifted to a higher 
field. 
FIG. 9 shows NMR spectrum of the complex of S-(+)-ibuproxam with 
methyl-.beta.-cyclodextrin. 
b) Procedure in aqueous medium 
Methyl-.beta.-cyclodextrin (1.31 g; 1.0 mmole) was dissolved in water (30 
ml). The obtained solution was heated to the temperature of 70.degree. C. 
and S-(+)-ibuproxam (0.221 g; 1.0 mmole) was added and it was vigorously 
stirred for another 15 minutes. The solution was frozen in liquid nitrogen 
and lyophilized. Inclusion complex (1.33 g; 86.9%) of S-(+)-ibuproxam with 
methyl-.beta.-cyclodextrin was obtained in the form of a white powder in 
the molar ratio of 1:1. 
Differential scanning calorimetry and NMR spectrum showed the same results 
as in the process for preparing inclusion complex in the methanolic 
medium. 
EXAMPLE 5 
Preparation of inclusion complex of racemic ibuproxam with 
hydroxypropyl-.beta.-cyclodextrin 
a) Procedure in methanolic medium 
Racemic ibuproxam (0.221 g; 1.0 mmole) was added to a solution of 
hydroxypropyl-.beta.-cyclodextrin (1.38 g; 1.0 mmole) in methanol (10 ml) 
and the obtained solution was stirred for another 5 minutes at room 
temperature. Methanol was then evaporated and the obtained complex was 
dried in vacuo at the temperature of 40.degree. C. Inclusion complex (1.57 
g; 98.1%) of racemic ibuproxam with hydroxypropyl-.beta.-cyclodextrin was 
obtained in the form of a white powder in the molar ratio of 1:1. 
Data on reaction yields, ibuproxam content in the complex (determined 
theoretically and experimentally-spectrophotometric determination at the 
wavelength of 220 nm) and specific rotation .alpha.!.sub.23.sub.Na of the 
complex formed are summarized in Table 1. 
Differential scanning calorimetry (DSC thermogram) 
In the curve of the obtained product there was not detected any endothermic 
transition for a melting point, characteristic of a physical mixture of 
ibuproxam/hydroxypropyl-.beta.-cyclodextrin at a temperature from 
120.degree. to 130.degree. C. (FIGS. 10A and 10B). 
NMR spectrum 
In the .sup.1 H-NMR spectrum of the title complex in DMSO-D.sub.6 solution 
the following change in the ibuproxam moiety was observed: at 7.19-7.25 
ppm the signal for proton resonances in phenyl ring shifted to a higher 
field. 
FIG. 11 shows NMR spectrum of the complex of racemic ibuproxam with 
hydroxypropyl-.beta.-cyclodextrin. 
b) Procedure in aqueous medium 
Hydroxypropyl-.beta.-cyclodextrin (1.38 g; 1.0 mmole) was dissolved in 
water (40 ml) and the obtained solution was heated to the temperature of 
70.degree. C. and racemic ibuproxam (0.221 g; 1.0 mmole) was added. It was 
vigorously stirred for another 15 minutes and then the solution was 
filtered. The filtrate was frozen in liquid nitrogen and lyophilized. 
Inclusion complex (1.40 g; 87.4%) of racemic ibuproxam with 
hydroxypropyl-.beta.-cyclodextrin was obtained in the form of a white 
powder in the molar ratio of 1:1. 
Differential scanning calorimetry and NMR spectrum showed the same results 
as in the process for preparing inclusion complex in the methanolic 
medium. 
EXAMPLE 6 
Preparation of inclusion complex of S-(+)-ibuproxam with 
hydroxypropyl-.beta.-cyclodextrin 
a) Procedure in methanolic medium 
S-(+)-ibuproxam (0.221 g; 1.0 mmole) was added to a solution of 
hydroxypropyl-.beta.-cyclodextrin (1.38 g; 1.0 mmole) in methanol (10 ml) 
and the obtained solution was stirred for another 5 minutes at room 
temperature. Methanol was then evaporated and the obtained complex was 
dried in vacuo at the temperature of 40.degree. C. Inclusion complex (1.56 
g; 97.4%) of S-(+)-ibuproxam with hydroxypropyl-.beta.-cyclodextrin was 
obtained in the form of a white powder in the molar ratio of 1:1. 
Data on reaction yields, ibuproxam content in the complex (determined 
theoretically and experimentally-spectrophotometric determination at the 
wavelength of 220 nm) and specific rotation .alpha.!.sup.23.sub.Na of the 
complex formed are summarized in Table 2. 
Differential scanning calorimetry (DSC thermogram) 
In the curve of the obtained product there was detected no endothermic 
transition for a melting point, characteristic of a physical mixture of 
ibuproxam/hydroxypropyl-.beta.cyclodextrin at a temperature from 
120.degree. to 130.degree. C. (FIGS. 12A and 12B). 
NMR spectrum 
In the .sup.1 H-NMR spectrum of the title complex in DMSO-D.sub.6 solution 
the following change in the ibuproxam moiety was observed: at 7.19-7.25 
ppm the signal for proton resonances in phenyl ring shifted to a higher 
field. 
FIG. 13 shows NMR spectrum of the complex of S-(+)-ibuproxam with 
hydroxypropyl-.beta.-cyclodextrin. 
b) Procedure in aqueous medium 
Hydroxypropyl-.beta.-cyclodextrin (1.38 g; 1.0 mmole) was dissolved in 
water (40 ml). The obtained solution was heated to the temperature of 
70.degree. C. and S-(+)-ibuproxam (0.221 g; 1.0 mmole) was added. It was 
vigorously stirred for another 15 minutes and the solution was filtered. 
The filtrate was frozen in liquid nitrogen and lyophilized. Inclusion 
complex (1.49 g; 9 3.1%) of S-(+)-ibuproxam with 
hydroxypropyl-.beta.-cyclodextrin was obtained in the form of a white 
powder in the molar ratio of 1:1. 
Differential scanning calorimetry and NMR spectrum showed the same results 
as in the process for preparing inclusion complex in the methanolic 
medium. 
EXAMPLE 7 
Preparation of inclusion complex of racemic ibuproxam with 
hydroxyethyl-.beta.-cyclodextrin 
a) Procedure in methanolic medium 
Racemic ibuproxam (0.221 g; 1.0 mmole) was added to a solution of 
hydroxyethyl-.beta.-cyclodextrin (1.44 g; 1.0 mmole) in methanol (10 ml) 
and the obtained solution was stirred for another 5 minutes at room 
temperature. Methanol was then evaporated and the obtained complex was 
dried in vacuo at the temperature of 40.degree. C. Inclusion complex (1.58 
g; 95.1%) of racemic ibuproxam with hydroxyethyl-.beta.-cyclodextrin was 
obtained in the form of a white powder in the molar ratio of 1:1. 
Data on reaction yields, ibuproxam content in the complex (determined 
theoretically and experimentally-spectrophotometric determination at the 
wavelength of 220 nm) and specific rotation .alpha.!.sup.23.sub.Na of the 
complex formed are summarized in Table 1. 
Differential scanning calorimetry (DSC thermogram) 
In the curve of the obtained product there was not detected any endothermic 
transition for a melting point, characteristic of a physical mixture of 
ibuproxam/hydroxyethyl-.beta.-cyclodextrin at a temperature from 
120.degree. to 130.degree. C. (FIGS. 14A and 14B). 
NMR spectrum 
In the .sup.1 H-NMR spectrum of the title complex in DMSO-D.sub.6 solution 
the following change in the ibuproxam moiety was observed: at 7.19-7.25 
ppm the signal for proton resonances in phenyl ring shifted to a higher 
field. 
FIG. 15 shows NMR spectrum of the complex of racemic ibuproxam with 
hydroxyethyl-.beta.-cyclodextrin. 
b) Procedure in aqueous medium 
Hydroxyethyl-.beta.-cyclodextrin (1.44 g; 1.0 mmole) was dissolved in water 
(40 ml). The obtained solution was heated to the temperature of 70.degree. 
C. and racemic ibuproxam (0.221 g; 1.0 mmole) was added. It was vigorously 
stirred for another 15 minutes and then the solution was filtered. The 
filtrate was frozen in liquid nitrogen and lyophilized. Inclusion complex 
(1.53 g; 92.1%) of racemic ibuproxam with hydroxyethyl-.beta.-cyclodextrin 
was obtained in the form of a white powder in the molar ratio of 1:1. 
Differential scanning calorimetry and NMR spectrum showed the same results 
as in the process for preparing inclusion complex in the methanolic 
medium. 
EXAMPLE 8 
Preparation of inclusion complex of S-(+)-ibuproxam with 
hydroxyethyl-.beta.-cyclodextrin 
a) Procedure in methanolic medium 
S-(+)-ibuproxam (0.221 g; 1.0 mmole) was added to a solution of 
hydroxyethyl-.beta.-cyclodextrin (1.44 g; 1.0 mmole) in methanol (10 ml) 
and the obtained solution was stirred for another 5 minutes at room 
temperature. Methanol was then evaporated and the obtained complex was 
dried in vacuo at the temperature of 40.degree. C. Inclusion complex (1.57 
g; 94.5%) of S-(+)-ibuproxam with hydroxyethyl-.beta.-cyclodextrin was 
obtained in the form of a white powder in the molar ratio of 1:1. 
Data on reaction yields, ibuproxam content in the complex (determined 
theoretically and experimentally-spectrophotometric determination at the 
wavelength of 220 nm) and specific rotation .alpha.!.sup.23.sub.Na of the 
complex formed are summarized in Table 2. 
Differential scanning calorimetry (DSC thermogram) 
In the curve of the obtained product there was not detected any endothermic 
transition for a melting point, characteristic of a physical mixture of 
ibuproxam/hydroxyethyl-.beta.-cyclodextrin at a temperature from 
120.degree. to 130.degree. C. (FIGS. 16A and 16B). 
NMR spectrum 
In the .sup.1 H-NMR spectrum of the title complex in DMSO-D.sub.6 solution 
the following change in the ibuproxam moiety was observed: at 7.19-7.25 
ppm the signal for proton resonances in phenyl ring shifted to a higher 
field. 
FIG. 17 shows NMR spectrum of the complex of S-(+)-ibuproxam with 
hydroxyethyl-.beta.-cyclodextrin. 
b) Procedure in aqueous medium 
Hydroxyethyl-.beta.-cyclodextrin (1.44 g; 1.0 mmole) was dissolved in water 
(40 ml). The obtained solution was heated to the temperature of 70.degree. 
C. and S-(+)-ibuproxam (0.221 g; 1.0 mmole) was added. It was vigorously 
stirred for another 15 minutes and the solution was filtered. The filtrate 
was frozen in liquid nitrogen and lyophilized. Inclusion complex (1.52 g; 
91.5%) of S-(+)-ibuproxam with hydroxyethyl-.beta.-cyclodextrin was 
obtained in the form of a white powder in the molar ratio of 1:1. 
Differential scanning calorimetry and NMR spectrum showed the same results 
as in the process for preparing inclusion complex in the methanolic 
medium. 
EXAMPLE 9 
Preparation of inclusion complex of racemic ibuproxam with 
triacetyl-.beta.-cyclodextrin 
a) Procedure in organic solvent 
Triacetyl-.beta.-cyclodextrin (2.018 g; 1.0 mmole) was dissolved in acetone 
(10 ml) and to the solution racemic ibuproxam (0.221 g; 1.0 mmole) was 
added during stirring at room temperature. It was stirred for another 5 
minutes, then the clear solution was evaporated in vacuo at the 
temperature of 40.degree. C. and the residue was dried in a vacuum drier 
at room temperature to the dry product. The title complex (2.23 g; 99.6%) 
was obtained in the form of a white powder in the molar ratio of 1:1, 
containing ibuproxam (9.6%). 
Data on reaction yields, ibuproxam content in the complex (determined 
theoretically and experimentally-spectrophotometric determination at the 
wavelength of 220 nm) and specific rotation .alpha.!.sup.23.sub.Na of the 
complex formed are summarized in Table 1. 
Differential scanning calorimetry (DSC thermogram) 
In the curve of the obtained product there was not detected any endothermic 
transition for a melting point, characteristic of a physical mixture of 
ibuproxam/triacetyl-.beta.-cyclodextrin at a temperature from 120.degree. 
to 130.degree. C. (FIGS. 18A and 18B). 
NMR spectrum 
In the .sup.1 H-NMR spectrum of the title complex in DMSO-D.sub.6 solution 
the following change in the ibuproxam moiety was observed: at 7.19-7.25 
ppm the signal for proton resonances in phenyl ring shifted to a higher 
field. 
FIG. 19 shows NMR spectrum of the complex of racemic ibuproxam with 
triacetyl-.beta.-cyclodextrin. 
b) Procedure in solvent mixture (acetone/water in the ratio 1:1) 
Triacetyl-.beta.-cyclodextrin (2.018 g; 1.0 mmole) was dissolved in acetone 
(3 ml) at the temperature of 40.degree. C. and then to the obtained 
solution racemic ibuproxam (0.221 g; 1.0 mmole) was added under stirring. 
To the obtained clear solution water (5 ml) was added under vigorous 
stirring, it was cooled to a temperature from 0.degree. to 5.degree. C. 
and the formed precipitate was filtered off, dried in vacuo at the 
temperature of 40.degree. C. and the title complex was obtained. 
Differential scanning calorimetry and NMR spectrum showed the same results 
as in the process for preparing inclusion complex in organic solvent. 
EXAMPLE 10 
Preparation of inclusion complex of S-(+)-ibuproxam with 
triacetyl-.beta.-cyclodextrin 
a) Procedure in organic solvent 
Triacetyl-.beta.-cyclodextrin (2.018 g; 1.0 mmole) was dissolved in acetone 
(10 ml) and to the solution S-(+)-ibuproxam (0.221 g; 1.0 mmole) was added 
during stirring at room temperature. It was stirred for another 5 minutes, 
then the clear solution was evaporated in vacuo at the temperature of 
40.degree. C. and the residue was dried in a vacuum drier at room 
temperature to the dry product. The title complex (2.22 g; 99.2%) was 
obtained in the form of a white powder in the molar ratio of 1:1, 
containing S-(+)-ibuproxam (9.8%). 
Data on reaction yields, ibuproxam content in the complex (determined 
theoretically and experimentally-spectrophotometric determination at the 
wavelength of 220 nm) and specific rotation .alpha.!.sup.23.sub.Na of the 
complex formed are summarized in Table 2. 
Differential scanning calorimetry (DSC thermogram) 
In the curve of the obtained product there was detected no endothermic 
transition for a melting point, characteristic of a physical mixture of 
ibuproxam/triacetyl-.beta.-cyclodextrin at a temperature from 120.degree. 
to 130.degree. C. (FIGS. 20A and 20B). 
NMR spectrum 
In the .sup.1 H-NMR spectrum of the title complex in DMSO-D.sub.6 solution 
the following change in the ibuproxam moiety was observed: at 7.19-7.25 
ppm the signal for proton resonances in phenyl ring shifted to a higher 
field. 
FIG. 21 shows NMR spectrum of the complex of S-(+)-ibuproxam with 
triacetyl-.beta.-cyclodextrin. 
b) Procedure in solvent mixture (acetone/water in the ratio 1:1) 
Triacetyl-.beta.-cyclodextrin (2.018 g; 1.0 mmole) was dissolved in acetone 
(3 ml) at the temperature of 40.degree. C. and then to the solution 
S-(+)-ibuproxam (0.221 g; 1.0 mmole) was added under stirring. To the 
clear solution water (5 ml) was added under vigorous stirring, it was 
cooled to a temperature from 0.degree. to 5.degree. C. The formed 
precipitate was filtered off and dried in vacuo at the temperature of 
40.degree. C. to obtain the title complex. 
Differential scanning calorimetry and NMR spectrum showed the same results 
as in the process for preparing inclusion complex in organic solvent. 
TABLE 1 
______________________________________ 
Reaction yield, ibuproxam content in the complex and specific rotation 
for 
inclusion complex of racemic ibuproxam with different derivatives of 
.beta.-cyclodextrins in the ratio 1:1. Procedure in methanolic medium 
except 
for triacetyl-.beta.-cyclodextrin where 
the results are summarized from the procedure in acetone. 
Inclusion complex 
reaction theor. exper. 
of racemic yield cont. cont. 
ibuproxam with 
(%) (%)* (%)** spec. rotation 
______________________________________ 
methyl- 98.6 14.5 14.4 +127.8.degree. 
.beta.-cyclodextrin (ethanol abs., 0.30) 
hydroxyethyl- 
95.1 13.3 13.2 +108.7.degree. 
.beta.-cyclodextrin (ethanol abs., 0.30) 
hydroxypropyl- 
98.1 13.8 13.6 +103.1.degree. 
.beta.-cyclodextrin (ethanol abs., 0.30) 
triacetyl- 99.6 9.9 9.6 +109.5.degree. 
.beta.-cyclodextrin (ethanol abs., 0.30) 
______________________________________ 
*theoretical content of ibuproxam in the complex 
**experimentally determined content of ibuproxam in the complex 
TABLE 2 
______________________________________ 
Reaction yield, ibuproxam content in the complex and specific rotation 
for 
inclusion complex of S-(+)-ibuproxam with different derivatives of 
.beta.-cyclodextrins in the ratio 1:1. Procedure in methanolic medium 
except 
for .beta.-cyclodextrin where the medium is 
water, and for triacetyl-.beta.-cyclodextrin where the the medium is 
acetone 
Inclusion complex 
reaction theor. exper. 
of S-(+)- yield cont. cont. 
ibuproxam with 
(%) (%)* (%)** spec. rotation 
______________________________________ 
.beta.-cyclodextrin 
94.4 16.3 16.2 +133.1.degree. 
(H.sub.2 O, 0.29) 
methyl- 98.6 14.5 13.5 +133.9.degree. 
.beta.-cyclodextrin (ethanol abs. 0.30) 
hydroxyethyl- 
94.5 13.3 13.2 +113.8.degree. 
.beta.-cyclodextrin (ethanol abs., 0.30) 
hydroxypropyl- 
97.4 13.8 13.6 +109.2.degree. 
.beta.-cyclodextrin (ethanol abs., 0.30) 
triacetyl- 99.2 9.9 9.8 +113.9.degree. 
.beta.-cyclodextrin (ethanol abs., 0.30) 
______________________________________ 
*theoretical content of ibuproxam in the complex 
**experimentally determined content of ibuproxam in the complex 
EXAMPLE 11 
Water solubility 
A suspension having the concentration of 200 mg inclusion complex of 
racemic or optically active S-(+)-ibuproxam in 10 ml water and having pH 
5.8 was stirred for 1 hour (500 rpm) at room temperature. Then a sample 
was filtered through filter paper (blue ribbon) and diluted with absolute 
ethanol. The concentration of ibuproxam was determined 
spectrophotometrically at the wavelength of 220 nm and at room 
temperature. 
TABLE 3 
______________________________________ 
Solubility of ibuproxam in water 
______________________________________ 
Solubility of racemic ibuproxam 
0.11 mg/ml 
inclusion complex of solubility (mg/ml) 
racemic ibuproxam with 
methyl-.beta.-cyclodextrin 
2.8 
hydroxyethyl-.beta.-cyclodextrin 
2.8 
hydroxypropyl-.beta.-cyclodextrin 
2.5 
triacetyl-.beta.-cyclodextrin 
0.4 
Solubility of S-(+)-ibuproxam 
0.2 (mg/ml) 
inclusion complex of solubility (mg/ml) 
S-(+)-ibuproxam with 
.beta.-cyclodextrin 2.6 
methyl-.beta.-cyclodextrin 
2.5 
hydroxyethyl-.beta.-cyclodextrin 
2.5 
hydroxypropyl-.beta.-cyclodextrin 
2.0 
triacetyl-.beta.-cyclodextrin 
0.4 
______________________________________ 
As evident from the above data the solubility of ibuproxam is significantly 
increased by binding its molecule into a cyclodextrin complex. There is no 
noticeable difference in solubilities of individual hydrophilic 
derivatives, but the solubility of ibuproxam is greater in the case of 
hydrophilic derivatives than in the case of hydrophobic derivatives of 
.beta.-cyclodextrins. 
EXAMPLE 12 
Acute toxicity 
In toxicological evaluation acute toxicity of S-(+)-ibuprofen, 
S-(+)-ibuproxam and inclusion complex of S-(+)-ibuproxam with 
.beta.-cyclodextrin was established. The S-(+)-ibuproxam content in 
complex was 14.4%. In the test mice of Han-NMRI strain of both sexes, 
weight 19 to 24 g, and female rats of Han-WISTAR strain, weight 220 to 250 
g, were used. The active substance was suspended in arachis oil and 
applied perorally. The volume of the applied suspension was 0.2 ml/20 g 
body weight in mice and 0.2 ml/200 g body weight in rats. Before the test 
the animals were fasted for 24 hours and after application, water and food 
were available ad libitum. The results of testing are summarized in Table 
4. 
TABLE 4 
______________________________________ 
Acute toxicity of selected substances after peroral application 
% of 
No. of % of deaths 
animals in 
Dosis deaths 
after 15 
LD.sub.50 
Substance the group 
mg/kg in 24 h 
days mg/kg 
______________________________________ 
1. Male mice 
S-(+)-ibuprofen 
10 2000 0 30 &gt;2000 
S-(+)-ibuproxam 
10 2000 0 0 &gt;2000 
S-(+)-ibuproxam 
10 2000 0 0 &gt;2000 
in inclusion complex 
with .beta.-cyclodextrin 
2. Female mice 
S-(+)-ibuprofen 
10 1000 10 10 &gt;2000 
S-(+)-ibuprofen 
10 2000 10 10 &gt;2000 
S-(+)-ibuproxam 
10 2000 0 0 &gt;2000 
S-(+)-ibuproxam 
10 1000 0 0 &gt;2000 
in inclusion complex 
10 2000 0 0 &gt;2000 
with .beta.-cyclodextrin 
3. Female rats 
S-(+)-ibuprofen 
6 1000 0 83.3 &lt;1000 
S-(+)-ibuproxam 
6 1000 0 50 .apprxeq.1000 
S-(+)-ibuproxam 
6 2000 0 0 &gt;2000 
in inclusion complex 
with .beta.-cyclodextrin 
______________________________________ 
It is evident from the above table that acute toxicity of S-(+)-ibuprofen 
in all test animals is greater than acute toxicity of S-(+)-ibuproxam, 
irrespective of its being free or bound in the complex with 
.beta.-cyclodextrin. At the dosis of 2000 mg/kg of S-(+)-ibuprofen 30% of 
male mice died in 15 days and no animal died at the dosis of 
2000 mg/kg of S-(+)-ibuproxam or inclusion complex of S-(+)-ibuproxam with 
.beta.-cyclodextrin. At the dosis of 2000 mg/kg of S-(+)-ibuprofen 10% of 
female mice died in 15 days and again no animal died at the dosis of 1000 
mg/kg or 2000 mg/kg of S-(+)-ibuproxam or inclusion complex of 
S-(+)-ibuproxam with .beta.-cyclodextrin. 
The difference in acute toxicity between free S-(+)-ibuproxam and 
S-(+)-ibuproxam bound into inclusion complex with .beta.-cyclodextrin 
showed in rats which were more susceptible to test substances. At the 
dosis of 1000 mg/kg of S-(+)-ibuprofen 83.3% of the animals died in 15 
days, at the dosis of 1000 mg/kg of S-(+)-ibuproxam 50% of the animals 
died after 15 days, whereas also at the increased dosis of 2000 mg/kg of 
S-(+)-ibuproxam bound into inclusion complex with .beta.-cyclodextrin no 
animal died. 
A comparative analysis of the toxicological results for different test 
animals shows that rats are much more susceptible to ibuprofen than mice, 
but equally susceptible to ibuproxam as mice. The mean lethal dosis 
(LD.sub.50) for S-(+)-ibuprofen for mice of both sexes is greater than 
2000 mg/kg at peroral application, but for female rats it is under 1000 
mg/kg. The mean lethal dosis for S-(+)-ibuproxam for mice of both sexes is 
greater than 2000 mg/kg at peroral application, yet for femal rats it is 
approximately 1000 mg/kg. The mean lethal dose for inclusion complex of 
S-(+)-ibuproxam with .beta.-cyclodextrin is for mice of both sexes and for 
female rats greater than 2000 mg/kg. 
After peroral application of S-(+)-ibuprofen to male mice in the dosis of 
2000 mg/kg, 30% of animals died in 48 hours, whereas in female mice at 
1000 mg/kg and at the dosis of 2000 mg/kg 10% of animals died already in 
the first 24 hours. In female rats after peroral application of ibuprofen 
in the dosis of 1000 mg/kg, even 83.3% of the animals died in 6 days. 
After peroral application of S-(+)-ibuproxam in mice of both sexes at the 
dosis of 2000 mg/kg, no animal died in 15 days, whereas in female rats at 
the same dosis 50% of the tested animals died in 15 days. 
After peroral application of inclusion complex of S-(+)-ibuproxam no test 
animal died irrespective of the dosis, which was 1000 mg/kg or 2000 mg/kg. 
It is evident from the above data that the inclusion complex of optically 
active S-(+)-ibuproxam is less toxic than S-(+)-ibuproxam alone, which is 
in turn less toxic than S-(+)-ibuprofen, which is also the priority aim of 
the present invention. 
EXAMPLE 13 
Antiinflammatory action 
Antiinflammatory action was measured in vivo by the inhibition of oedema 
caused by carrageenin. 
Rats, which were fasted overnight, were given 100 mg/kg of the test 
substance 1 hour before the injection of 0.1 ml 1% carrageenin suspension. 
The inhibition of the formed oedema was measured 3 hours after injecting 
carrageenin. 
TABLE 5 
______________________________________ 
Measurement of antiinflammatory action in vivo at the dosis of 
100 mg/kg of the active substance applied perorally 
Substance antiinflammatory action 
______________________________________ 
S-(+)-ibuproxam 37 
complex of S-(+)-ibuproxam 
75 
with .beta.-cyclodextrin 
______________________________________ 
The measurement in vivo of the antiinflammatory action showed that the 
inclusion complex of S-(+)-ibuproxam with .beta.-cyclodextrin exhibited a 
twice greater antiinflammatory action than free optically active 
S-(+)-enatiomer. 
It is evident from the above data that the inclusion complex of optically 
active S-(+)ibuproxam with .beta.-cyclodextrin showed greater 
antiinflammatory action than free optically active S-(+)-ibuproxam, which, 
however, showed greater antiinflammatory action than free racemic 
ibuproxam, which is also the priority aim of the present invention. 
EXAMPLE 14 
Effect on gastric mucous membrane 
Effect of S-(+)-ibuprofen, S-(+)-ibuproxam and inclusion complex of 
S-(+)-ibuproxam with .beta.-cyclodextrin on gastric mucous membrane was 
measured. 
Rats, which were fasted overnight, were given perorally 100 mg/kg of the 
active substance. After 4 hours its effect on irritation of gastric mucous 
membrane was measured in a way that the rate of bleeding in stomach and 
frequency of ulcers was determined. 
TABLE 6 
______________________________________ 
Measurement of the effect on gastric mucous membrane 
dose 
Substance (mg/kg) irritation 
______________________________________ 
S-(+)-ibuprofen 30 12 
S-(+)-ibuproxam 30 0 
inclusion complex of 
15 0 
S-(+)-ibuproxam with 
.beta.-cyclodextrin 
______________________________________ 
The above data show that free S-(+)-ibuproxam and S-(+)-ibuproxam bound 
into an inclusion complex with .beta.-cyclodextrin did not exhibit an 
irritating effect on gastric mucous membrane of the animals. 
EXAMPLE 15 
Antiinflammatory action and effect on gastric mucous membrane 
Testing antiinflammatory action was carried out according to the method of 
Winter C. A. et al., Proc. Soc. Exp. Biol. Med., 111 (1962). The effect on 
gastric mucous membrane was measured in such a way that changes on gastric 
mucous membrane were observed under magnifying glass. In the test 120 male 
rats (Wistar), weight 140 to 170 g, were used. 
Animals were fasted 24 hours before the beginning of the test with water at 
libitum. Active substances to be tested were applied in the dosis of 25 
mg/kg, 50 mg/kg and 100 mg/kg perorally in the form of a suspension in a 
10% gum arabic solution. Control group of rats was given only the vehicle 
(i.e. the 10% gum arabic solution). After 60 minutes the rats were 
administered a subcutaneous injection of 0.1 ml of 1.5% carrageenin 
suspension in 0.9% NaCl solution into a subplantar part of the right hind 
paw. 0.1 ml of 0.9% NaCl solution only was injected into a subplantar part 
of the left hind paw as a control. Volumes of both paws were measured by 
means of plethysmometer meter (Model 7150, Ugo Basile) immediately and 
then in intervals of 1 to 5 hours after carrageenin application. The 
percentage of the swelling of the hind paw was calculated according to the 
following equation: 
##EQU1## 
The testing of the antiinflammatory action was concluded 6 hours after 
peroral application of the active substance or 5 hours after injecting 
carrageenin. Then the rats were decapitated and the stomachs were removed 
and washed with 0.9% NaCl solution. By incision along the lesser bend the 
stomach was opened and gastric mucous membrane was observed under 
magnifying glass and possible changes were evaluated according to the 
following scale (Cashin C. H. et al., J. Pharm. Pharmac. 29 (1977): 
______________________________________ 
0 no lesions 
0.5 hyperaemia 
1 one or two indistinct lesions 
1.5 more than two indistinct lesions 
2 frequent lesions 
3 very frequent lesions 
4 lesions are noticeable over the whole gastric mucous 
______________________________________ 
membrane 
TABLE 7 
______________________________________ 
Therapeutic index: ratio of UD.sub.50 /ED.sub.30 
UD.sub.50 /ED.sub.30 
Substance (95% confidence limit) 
______________________________________ 
S-(+)-ibuprofen 0.54 
racemic ibuproxam 1.37 
S-(+)-ibuproxam 1.63 
inclusion complex of S-(+)-ibuproxam 
2.21 
with .beta.-cyclodextrin 
______________________________________ 
UD.sub.50 calculated dosis of the active substance in mg per 1 kg of the 
animal, which dosis caused a change of the gastric mucous membrane at 
least with the note 1 at 50% animals 
ED.sub.30 calculated dosis of the active substance in mg per 1 kg of the 
animal, which dosis caused a 30% inhibition of carrageenininduced oedema 
It is evident from the above table that the therapeutic index was the most 
advantageous (the greatest) at the inclusion complex of S-(+)-ibuproxam 
with .beta.-cyclodextrin since it was four times greater than for 
S-(+)-ibuprofen, 1.6 times greater than for racemic ibuproxam and 
1.4-times greater than for S-(+)-ibuproxam. This means that at the dosis 
of the active substance which caused a 30% inhibition of 
carrageenin-induced oedema, in the case of the inclusion complex of 
S-(+)-ibuproxam with .beta.-cyclodextrin a lesser irritation of the 
gastric mucous membrane occurred in comparison with S-(+)-ibuproxam, which 
caused a 1.2 times lesser irritation of the gastric mucous membrane in 
comparison with racemic ibuproxam, which in turn caused a 2.5 times lesser 
irritation than S-(+)-ibuprofen. 
EXAMPLE 16 
Alleviation of pain 
The effect of alleviating pain was tested with the number of convulsions 
caused by phenylbenzoquinone. Female mice, weight 15 to 22 g, were fasted 
before the test for 24 hours and after the application water and food were 
ad libitum. 30 minutes after peroral introduction of the suspension of 
active substance in 10% gum arabic solution, individual mice were 
intraperitoneally administered 0.25 ml of 0.02% phenylbenzoquinone 
solution. Only the vehicle was applied to a control group of animals. The 
number of phenylbenzoquinone-induced convulsions was pursued 5 to 20 
minutes after the application thereof. 
TABLE 8 
______________________________________ 
Measurement of the effect of alleviating pain 
ED.sub.50 (mg/kg) 
Substance (95% confidence limit) 
______________________________________ 
S-(+)-ibuproxam 73.0 
S-(+)-ibuproxam in inclusion complex 
25.0 
with .beta.-cyclodextrin 
______________________________________ 
ED.sub.50 calculated dosis of the active substance in mg per 1 kg of the 
animal, which dosis caused a 50% pain protection 
It is evident from the above table that ED.sub.50 value in the case of 
S-(+)-ibuproxam bound into the inclusion complex with .beta.-cyclodextrin 
was even three times lesser than the value for S-(+)-ibuproxam alone, 
which means that in the case of S-(+)-ibuproxam bound into the inclusion 
complex with .beta.-cyclodextrin the same effect as with S-(+)-ibuproxam 
alone could be achieved by a three times lesser dosis. 
EXAMPLE 17 
X-ray powder diffraction 
In Table 9 there are demonstrated lattice spacings d (nm) and intensities 
(I) of X-ray diffraction for S-(+)-ibuproxam, racemic ibuproxam, 
.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, 
triacetyl-.beta.-cyclodextrin, for physical mixtures of S-(+)-ibuproxam 
with .beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin and 
triacetyl-.beta.-cyclodextrin, for physical mixtures of racemic ibuproxam 
with hydroxypropyl-.beta.-cyclodextrin and triacetyl-.beta.-cyclodextrin, 
for inclusion complexes of S-(+)-ibuproxam with .beta.-cyclodextrin, 
hydroxypropyl-.beta.-cyclodextrin and triacetyl-.beta.-cyclodextrin, and 
for inclusion complexes of racemic ibuproxam with 
hydroxypropyl-.beta.-cyclodextrin and triacetyl-.beta.-cyclodextrin. The 
analysis was made on Philips PW 1710 diffractometer on Al-substrate at the 
wavelength of .lambda.=0.15418 nm (CuK.alpha.). 
TABLE 9 
______________________________________ 
Characteristic diffraction maximums 
physical mixture 
inclusion complex 
of S-(+)- of S-(+)- 
S-(+)- ibuproxam + ibuproxam + 
.beta.-cyclodextrin 
ibuproxam .beta.-cyclodextrin 
.beta.-cyclodextrin 
d(nm) I d(nm) I d(nm) I d(nm) I 
______________________________________ 
0.701 75 0.383 52 0.699 72 0.508 68 
0.687 100 0.380 53 0.493 74 0.502 91 
0.657 53 0.369 100 0.471 65 0.497 100 
0.495 51 0.354 45 0.467 88 0.489 78 
0.487 68 0.264 46 0.418 79 0.477 72 
0.472 55 0.237 51 0.392 95 0.472 81 
0.205 50 0.387 99 0.468 83 
0.327 73 0.368 59 
0.257 100 0.236 67 
0.204 92 0.204 84 
______________________________________ 
physical mixture 
inclusion complex 
of S-(+)- of S-(+)- 
ibuproxam + ibuproxam + 
hydroxypropyl-.beta.- 
S-(+).beta.- 
hydroxypropyl-.beta.- 
hydroxypropyl-.beta.- 
cyclodextrin 
ibuproxam cyclodextrin 
cyclodextrin 
d(nm) I d(nm) I d(nm) I d(nm) I 
______________________________________ 
0.500 86 0.383 52 0.493 80 0.488 92 
0.490 89 0.380 53 0.478 81 0.469 91 
0.486 89 0.369 100 0.467 89 0.458 87 
0.470 100 0.354 45 0.456 86 0.458 92 
0.454 88 0.264 46 0.442 84 0.448 81 
0.237 51 0.205 100 0.204 100 
0.205 50 
______________________________________ 
physical mixture 
inclusion complex 
of S-(+)- of S-(+)- 
ibuproxam + ibuproxam + 
triacetyl-.beta.- 
S-(+)- triacetyl-.beta.- 
triacetyl-.beta.- 
cyclodextrin 
ibuproxam cyclodextrin 
cyclodextrin 
d(nm) I d(nm) I d(nm) I d(nm) I 
______________________________________ 
0.470 68 0.383 52 0.474 92 0.416 78 
0.441 72 0.380 53 0.468 98 0.408 78 
0.438 61 0.369 100 0.445 99 0.399 84 
0.401 68 0.354 45 0.403 90 0.385 80 
0.204 100 0.264 46 0.387 100 0.390 78 
0.237 51 0.385 85 0.204 100 
0.205 50 
______________________________________ 
physical mixture 
inclusion complex 
of racemic of racemic 
ibuproxam + ibuproxam + 
hydroxypropyl-.beta.- 
racemic hydroxypropyl-.beta.- 
hydroxypropyl-.beta.- 
cyclodextrin 
ibuproxam cyclodextrin 
cyclodextrin 
d(nm) I d(nm) I d(nm) I d(nm) I 
______________________________________ 
0.500 86 1.225 95 0.480 82 0.480 80 
0.490 89 1.133 74 0.473 92 0.464 80 
0.486 89 0.634 43 0.468 100 0.457 79 
0.470 100 0.471 83 0.462 89 0.448 79 
0.454 88 0.382 100 0.382 87 0.204 100 
______________________________________ 
physical mixture 
inclusion complex 
of racemic of racemic 
ibuproxam + ibuproxam + 
triacetyl-.beta.- 
racemic triacetyl-.beta.- 
triacetyl-.beta.- 
cyclodextrin 
ibuproxam cyclodextrin 
cyclodextrin 
d(nm) I d(nm) I d(nm) I d(nm) I 
______________________________________ 
0.470 68 1.225 95 0.473 94 0.424 80 
0.441 72 1.133 74 0.464 89 0.407 79 
0.438 61 0.634 43 0.438 100 0.404 79 
0.401 68 0.471 83 0.402 94 0.394 80 
0.204 100 0.382 100 0.388 88 0.204 100 
______________________________________ 
FIGS. 22A to 22D show the comparison of recordings of X-ray powder 
diffraction for .beta.-cyclodextrin (FIG. 22A), S-(+)-ibuproxam (FIG. 
22B), physical mixture of S-(+)-ibuproxam and .beta.-cyclodextrin (FIG. 
22C) and inclusion complex of S-(+)-ibuproxam with .beta.-cyclodextrin 
(FIG. 22D). 
FIGS. 23A to 23D show the comparison of recordings of X-ray powder 
diffraction for hydroxypropyl-.beta.-cyclodextrin (FIG. 23A), 
S-(+)-ibuproxam (FIG. 23B), physical mixture of S-(+)-ibuproxam and 
hydroxypropyl-.beta.-cyclodextrin (FIG. 23C) and inclusion complex of 
S-(+)-ibuproxam with hydroxypropyl-.beta.-cyclodextrin (FIG. 23D). 
FIGS. 24A to 24D show the comparison of recordings of X-ray powder 
diffraction for triacetyl-.beta.-cyclodextrin (FIG. 24A), S-(+)-ibuproxam 
(FIG. 24B), physical mixture of S-(+)-ibuproxam and 
triacetyl-.beta.-cyclodextrin (FIG. 24C) and inclusion complex of 
S-(+)-ibuproxam with triacetyl-.beta.-cyclodextrin (FIG. 24D). 
FIGS. 25A to 25D show the comparison of recordings of X-ray powder 
diffraction for hydroxypropyl-.beta.-cyclodextrin (FIG. 25A), racemic 
ibuproxam (FIG. 25B), physical mixture of racemic ibuproxam and 
hydroxypropyl-.beta.-cyclodextrin (FIG. 25C) and inclusion complex of 
racemic ibuproxam with hydroxypropyl-.beta.-cyclodextrin (FIG. 25D). 
FIGS. 26A to 26D show the comparison of recordings of X-ray powder 
diffraction for triacetyl-.beta.-cyclodextrin (FIG. 26A), racemic 
ibuproxam (FIG. 26B), physical mixture of racemic ibuproxam and 
triacetyl-.beta.-cyclodextrin (FIG. 26C) and inclusion complex of racemic 
ibuproxam with triacetyl-.beta.-cyclodextrin (FIG. 26D). 
EXAMPLE 18 
Preparation of tablets with 200 mg of active substance (inclusion complex 
of S-(+)-ibuproxam with .beta.-cyclodextrin) 
Tablets of the following composition were prepared 
______________________________________ 
inclusion complex of S-(+)-ibuproxam 
1300.0 mg 
with .beta.-cyclodextrin 
poliviniylpyrrolidone 5.0 mg 
crospovidone (cross-linked polyvinylpyrrolidone) 
96.0 mg 
colloidal silicon dioxide 
3.2 mg 
stearic acid 16.0 mg 
microcrystalline cellulose 
ad 1600.0 mg 
______________________________________ 
Preparation of tablets 
The active substance was homogeneously stirred with additives. The mixture 
was sieved through a sieve and pressed into tablets on a rotating 
tableting machine. 
EXAMPLE 19 
Preparation of dispersion tablets with 200 mg of active substance 
(inclusion complex of S-(+)-ibuproxam with .beta.-cyclodextrin) 
Dispersion tablets of the following composition were prepared 
______________________________________ 
inclusion complex of S-(+)-ibuproxam 
1300.0 mg 
with .beta.-cyclodextrin 
low substituted hydroxypropyl cellulose 
100.0 mg 
saccharin 2.0 mg 
flavours 10.0 mg 
coloidal silicon dioxide 
1.6 mg 
stearic acid 16.5 mg 
microcrystalline cellulose 
ad 1650.0 
mg 
______________________________________ 
The preparation of dispersion tablets 
The active component was homogeneously blended with additives. The mixture 
was sieved through a sieve and pressed into tablets on a rotating 
tableting machine. The tablets rapidly disintegrated in water, the 
obtained suspension had a pleasant taste and was appropriate for 
consumption. 
EXAMPLE 20 
Preparation of tablets with 200 mg of active substance (S-(+)-ibuproxam) 
Tablets of the following composition were prepared 
______________________________________ 
S-(+)-ibuproxam 200.0 mg 
maize starch 22.0 mg 
crospovidone (POLYPLASDONE .RTM. XL 
16.2 mg 
povidone 16.2 mg 
colloidal silicon dioxide (Aerosil 200) 
1.4 mg 
talcum 9.7 mg 
stearic acid 6.5 mg 
microcrystalline cellulose 
ad 325.0 mg 
______________________________________ 
Preparation of tablets 
The active component was homogeneously stirred with a part of the 
ingredients (maize starch, crospovidone, microcrystalline cellulose) and 
granulated with polyvinylpyrrolidone aqueous solution. The obtained 
granulate was dried, sieved, blended with the remaining amount of the 
additives (colloidal silicon dioxide, talcum, stearic acid) and pressed 
into tablets on a rotating tableting machine.