NZ240617A - Hydrogen-bridge-bound complexes comprising a 1:1 stoichiometric proportion of s(+)-phenyl alkane acid and a basic alpha-amino acid; and pharmaceutical compositions thereof - Google Patents
Hydrogen-bridge-bound complexes comprising a 1:1 stoichiometric proportion of s(+)-phenyl alkane acid and a basic alpha-amino acid; and pharmaceutical compositions thereofInfo
- Publication number
- NZ240617A NZ240617A NZ240617A NZ24061791A NZ240617A NZ 240617 A NZ240617 A NZ 240617A NZ 240617 A NZ240617 A NZ 240617A NZ 24061791 A NZ24061791 A NZ 24061791A NZ 240617 A NZ240617 A NZ 240617A
- Authority
- NZ
- New Zealand
- Prior art keywords
- amino acid
- acid
- ibuprofen
- active substance
- phenyl
- Prior art date
Links
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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Abstract
Novel complexes of S-(+)-ibuprofen and amino acids are described. These complexes have anti-inflammatory, antipyretic and antimicrobial properties and also analgesic effects.
Description
0
240617
Priority Date(s): ... .t^V.
Complete Specification Filed:
Class:
Publication Date: ..?.?.?£?. }?$.
P.O. Journal, No: ... J2>^71
NEW ZEALAND
PATENTS ACT, 1953
No.: Date:
COMPLETE SPECIFICATION
N.Z. PATENT Oi
NOV 1991
RECEivuO
COMPLEXES CONTAINING S(+)-PHENYL ALKANE ACIDS AND a-AMINO ACIDS
♦/We, MEDICE CHEM.-PHARM. FABRIK POTTER GMBH & CO. KG, of Kuhloweg 37-39, 5860 Iserlohn/Westfalen, Federal Republic of Germany, a German company hereby declare the invention for which i/ we pray that a patent may be granted to zaae/us, and the method by which it is to be performed, to be particularly described in and by the following statement: -
(followed by page la)
.
240617
- la "
The present invention relates to hydrogen-bridge-bound complexes having a stoichiometry of 1:1, comprising S( + )-phenyl alkane acids and basic a-amino acids-
Compounds of SM -phenyl alkane acids and a-amino acids are already known. However, they are not the specific complexes according to the invention but salts.
Lvsinate salts, both racemic (D, L) or only L salts of basic a-amino acids, have been described inter alia by Bruzzese et al., US patent specification 4,279,926 with anti-inflammatory phenyl alkane acids, in particular with (R, S)-ibuprofen. Both European patent application 0 267 321 of Loew et al. (1986) and the pharmaceutical forms described by Bruzzese et al. and consisting of S(+)-ibuprofen and (D, L)-lysine or (R, S)-ibuprofen with (D, L) or L(-)-lysine, as salts, i.e. consisting of an anion and cation.
Specification as laid open to inspection DE 29 22441, Al,
describes pharmaceutical preparations of ibuprofen and
S (-r)-ibuprofen with a low neutral or acidic a-amino acid which are added to an amount of up to 40 % by weight to the active substance ibuprofen (S-ibuprofen). The a-amino acid amount added may even be up to 60 % (g/g) if acidic or neutral amino acids are involved. No particulars are given on the weight ratios for basic a-amino acids nor on their stereo-
cnemistry, water solubility/ stability and pharmacokinetic behaviour.
Publication DE 3814887, CI (1988), does not describe either salts or complexes with D, L or D and L a-amino acids, or
240617
with basic a-amino acids; only a racemate separation with the aid of threo-l-p-nitrophenyl-2-aminopropane-l,3-diol is disclosed.
One problem underlying the present invention is to provide new substances on the basis of S(+)-phenyl alkane acids and a-amino acids and to develop their advantageous use in pharmaceutical preparations.
This problem is solved according to the invention by hydrogen-bridge-bound complexes having a stoichiometry of 1:1 comprising S(+)-phenyl alkane acids and basic a-amino acids in which the complex bond is based on carboxvlate-carbcxyl interactions with a proton switch of the form R-|-COOH.. . "OOC-Rg R^-COO" ... HOOC-R2 where R-|-C00II denotes the S(+)-phenyl alkane acids and R2-COOH the basic a-amino acids and the pKa values relating to the carboxyl group of the S (•*•) -phenyl alkane acids lie in the range of 3.5 to 3.9 and the pKa values relating to the carboxyl group of the basic a-amino acids lie in the range of 1.9 - 2.9.
Preferably, the pKa values relating to the carboxyl group of the basic a-amino acids lie in the range of 1.9 - 2.2.
240 6 1 7
Preferably, as S(+)-phenyl alkane acids herein S(+)-ibuprofen or S(+)-naproxen shall be understood and are used.
Preferably as S(+)-phenyl alcane acids herein the substances as detailed below shall be understood and are used. These substances comprise the following structure:
R
I
Ar C COOH
I
H
in which R is lower alkyl, Ar is preferably a monocyclic, polycyclic or ortho-condensed polycyclic aromatic group having up to twelve carbons in the aromatic system, e.g. phenyl, diphenyl, and naphthyl. The substituents of these aromatic groups comprise one or more halogen atoms, C^-C4 alkyls,
benzyl, hydroxy, C^-Cj alkoxy, phenoxy and benzoyl groups. Examples of such substituted aryls are: 4-isobutyl-phenyl, 3-phenoxy-phenyl, 2-fluoro-4-diphenyl, 4'-fluoro-4-diphenyl, 6-methoxy-2-naphthyl, 5-chloro-6-methoxy-2-naphthyl and 5-bromo-6-methoxy-naphthyl, 4-chloro-phenyl, 4-difluoro-methoxy-phenyl, 6-hydroxy-2-naphthyl, and 5-bromo-6-hydroxy-2-naphthyl.
Preferably, the D-form of the basic a-amino acids is used.
Preferably, the a-amino acids have the following structure:
H
i .y3
Z-A-C-C
| OH X
24 0 6 1
- 4
with X = NH- or C,-Cc alkyl amino;
2. JL b
Z = H, OH or NH2; and
A = a bond or an alkylene chain which
contains 1-10 carbon atoms and if required an amino group or 1 - 6
hydroxyl groups.
Preferably X = NHCH or NHC_H_
3 2 5
Preferably, as basic D-a-amino acids, D-lysine, "D-arginine, *0 D-histidine or D-ornithine are used.
Preferably, the complex according to the invention contains valine, leucine, isoleucine, asparaginic acid, glutamine acid, asparagine, glutamine, phenylalanine, serine,
threonine or hydroxylysine.
According to the invention the complexes are prepared by the following method steps:
a) for the preparation from aqueous medium (only water)
or weakly buffered aqueous solutions covering a pH range between pH 5.5 - 7.5 (20°C) a buffered aqueous solution, for example a 0.01 M - 0.001 M-K2HP04/KH2P04 buffer pH 6.0-7.5 (20°C) is prepared and into it an
equivalent amount S(+)-phenyl alkane acid is introduced with constant stirring;
b) the solution is heated with constant stirring to 40°C (water bath) until a clear transparent solution is obtained (normally after 20 minutes) and all the
S(+)-phenyl alkane acid has gone into solution;
c) thereafter the pH of the solution is adjusted to pH 5.5 - 6.0 by addition of diluted phosphoric acid (H-jPO^) (20°C) and then the equivalent (corresponding) amount of the a-amino acid is introduced with constant
stirring, ensuring that the neutral a-amino acids are introduced and not the hydrochloric acid Uf&d Ncpfckgiino r
240 6 17
acids!;
d) the complex formation is terminated after 20 minutes whereupon after cooling to 0 - 4°C the complexes precipitate in crystalline form and can be separated from the mother liquor via a sintered glass funnel or glass filter (1G4);
e) alternatively to method step d) the clear solution can be reduced in a rotary evaporator (water bath temperature 25 - 30°C) in the water jet vacuum to half the volume, whereupon a colourless (amorphous) deposit forms which is filtered off via a 1G4 glass filter and can be recrystallized from water/ethanol (70/30 V/V) or from ethyl acetate (100 %).
The substances according to the invention do not represent a salt formation between an acidic group (carboxyl group of the ibuprofen) and a basic radical of the a-amino acid (a-amino and/or £ -amino group or guanido group of lysine or arginine) but, as the X-ray structure analysis and FT-IR spectra show, carboxylate-carboxyl interactions, the two carboxyl radicals of the a-amino acid and for example the ibuprofen sharing a proton. This means that the complex is formed in accordance with the X-ray structure analysis by a hydrogen bridge without any participation of the a-amino group or other basic group (guanido, 6 -amino group) being observed (Fig. 1). The complexes of S(+)-ibuprofen and D(-)-lysine or of S ( + )-ibuprofen and L( + )-lysine crystallize in the chiral space group as 1:1
complexes with four molecules per unit cell. Within the crystal lattice the hydrogen bridge formation mentioned and designated above and the hydrophobic forces of the p-isobutyl phenyl radical are the decisive interacting forces keeping the crystalline form together (long-range order).
This also applies to the structure .in solution (H2O)
because only the pKa values of the a-amino acid with regard to the carboxyl group, i.e. pKa = 2.18 - 1.92, and the
? 4 0 6 1 7
1
phenyl alkane acids, i.e. pKa = 3.5 - 3.9, are decisive. The pKa values of the a-amino group of the a-amino acids in question here are pKa = 8.9 - 9.10, of the -amino group of lysine for example pKa = 10.53, of arginine (guanido group)
12.48. It follows from this that the amino groups of the a-amino acids do not play any part in the disclosed preparation of these complexes and consequently no salt formation can be present, not even as intramolecular ion pair, but on the contrarv a "proton switch" of the form
R.-COOH...~OOC-R2 R^-COO ...H00C-R2 and therefore the "complex" appears neutral in solution without influencing the water solubility of these complexes, as is for example the case with alkaline and alkaline earth salts of phenvl alkane acids, in particular
ibuprofen, since they are soluble and dissociated only above pH > 7.0.
The dissociation of these alkaline or alkaline earth salts also disadvantageously affects the resorbability and consequently the therapeutic advantages (for example no precipitation of the ibuprofen in the stomach, resorption in the gastro-intestinal region by formation of the anion of the ibuprofen membrane barrier) of the present complexes are considerable, the undesired secondary effects being reduced for a given dosage. FT-IR investigations of these complexes clearly show that the a-amino group is not complexly bound because no N-H stretch vibrations are present, although non-hydrogen-bridge-bound carbonyl groups are present at 1680 - 1700 cm~^. Similar results were obtained by Raman spectroscopic investigations which furthermore confirm that the structure of the complexes described here involves carboxyl-carboxylate interactions.
The complexes according to the invention may advantageously be used in pharmaceutical preparations containing one or
2 4 0 6 1 7
more complexes and possibly optionally additionally physiologically compatible usual extenders or carriers.
Particularly advantageous is a pharmaceutical preparation on the basis of phenyl alkane acids having antiinflammatory, antipyretic, antimicrobial and analgesic effect, containing an active substance complex comprising a phenyl alkane acid and an a-amino acid and possibly additionally usual physiologically compatible auxiliary substances, in which the active substance complex consists of S(-r)-phenyl alkane acids and basic a-amino acids, preferably D-a-amino acids.
Particularly advantageous is a pharmaceutical preparation on the basis of ibuprofen or naproxen with antiinflammatory, antipyretic, antimicrobial and analgesic effect, containing an active substance complex comprising an ibuprofen or naproxen and basic a-amino acids and possibly additionally usual physiologically compatible auxiliary substances, in which the active substance complex consists of S(+)-ibuprofen or S(+)-naproxen and a basic a-amino acid and represents an amount by weight of 0.1 to 90 % (w/w) of the composition.
Particularly advantageous is a pharmaceutical composition which contains 50 to 800 mg, preferably 100 to 600 mg, in particular 100 to 300 mg S(+)-ibuprofen or S(+)-naproxen.
Particularly advantageous is a pharmaceutical preparation in which the suitable dose for oral or parenteral administration is in the range of 50 - 1200 mg daily, normally between 100 and 800 mg daily, preferably between 200 and 600 mg S ( + )-ibuprofen daily and that the suitable do.ses for a topical administration of the complex lies in the range of 10 - 200 mg daily.
24 0 6 1
1 Hereinafter, the "pharmaceutically active compound" in the broader sense is denoted as a complex. In medical use said pharmaceutically active compound may be administered orally, rectally, parenterally or topically, in particular however orally or topically. Thus, the therapeutical composition of the present invention may be any pharmaceutical preparation known per se for oral, rectal, parenteral or topical administrations. Pharmaceutically usual carriers which can be used in such pharmaceutical compositions are frequently described in pharmacy. The composition of this invention may correspond to 0.1 - 90% (w/w) of the active compound. The compositions represent normal unitary dosage forms. These dosage forms contain 50 - 800 mg, preferably 100 - 600 mg or 100 - 300 mg, S(+)-ibuprofen.
Oral administration forms according to this invention are preferred, such as tablets, capsules, syrup and aqueous or oily suspensions. Tablets may for example be prepared by 20 mixing the active compound with inert extenders such as for example calcium phosphate in the presence of a disintegrating agent, for example starch, or lubricant, for example magnesium stearate, with subsequent conversion to tablet form in the normal production sense. The tablets ^ may be prepared in the form of a retard formulation of the-
active compound by known methods. If desired, such tablets may be prepared by correspondingly known methods so that they do not disintegrate in the stomach, for example with the aid of cellulose, acetate, phthalate. Correspondingly, capsules may be made, for example soft or hard gelatin capsules, which contain the pharmaceutically active compound alone or in the presence of added auxiliary agents. These capsules may be made by conventional pharmaceutical technology, with or without stomach-resistant coating. Other compositions for oral administration include aqueous solutions containing the
240 6
active pharmaceutical compound in the presence of a nontoxic suspension agent, for example carboxymethyl cellulose and oily suspensions which contain the active pharmaceutical compound in the presence of a vegetable oil.
In accordance with this invention pharmaceutical formulations may be employed for topical administration of the active pharmaceutical compound. The pharmaceutically active compound in this case is dispersed in a pharmaceutically suitable cream, ointment or gel. A suitable cream can for example be prepared in that the active pharmaceutical compound is dispersed in a topical carrier, for example readily volatile paraffin in an aqueous medium with the aid of surfactants (detergents). An ointment can for example be prepared by mixing the pharmaceutically active compound with a topical carrier, for example mineral oil or paraffin or beeswax. A gel-like formulation can be prepared by mixing an active pharmaceutical compound with a topical carrier, for example Carbomer BP, in the presence of water. Topically administratable compositions may consist inter alia of a matrix which is able to disperse the active pharmaceutical compound in such a manner that the latter is administered transdermally by its close contact with the skin. A suitable transdermal composition may be prepared inter alia by mixing the pharmaceutically active compound with a topical carrier, as described above, together with a possible transdermal accelerator, for example dimethyl sulfoxide or propylene glycol.
Pharmaceutical formulations in accordance with this invention which are suitable for rectal administration are inter alia suppositories on the basis of polyethylene glycol or cocoa butter.
O I
-
4 0 6 1 7
Pharmaceutical formulations for parenteral administration contain known pharmaceutical formulations, for example sterile suspensions or sterile solutions in a suitable solvent.
In some specific pharmaceutical formulations it appears expedient to have the pharmaceutical active compounds in the size of small particles, for example colloidal solutions or particulate suspensions of the order of magnitude of 0.1 - 1 urn (colloid mill).
If desired, in accordance with this invention compositions may also be prepared with other compatible pharmaceutical active substances.
These complexes according to the invention have antiinflammatory, antipyretic and interesting antimicrobial properties as well as analgesic effects. These complexes have inter alia the advantage that after oral administration after a relatively short time they result in a substantially higher plasma level of S(+)-ibuprofen than S(+)-ibuprofen in the form of the free acid. These complexes are therefore particularly important in practice for treating acute pain; rapid onset with immediate freedom from pain can be achieved. The treatment of inflammations and pain is particularly important in rheumatic patients exhibiting indications such as primary chronic polyarthritis, arthridites of rheumatic origin, articular rheumatism and muscle rheumatism with their corresponding degrees of severity. These new complexes are particularly valuable for relieving pain, for example headache, dysmenorrhea, postoperative pain, postpartum pain and pain related to influenza and colds.
Accordingly, the invention describes in particular another aspect of the treatment of pain or inflammatory fever after
2 4 0 6
- 11
administering a therapeutically effective dose of said complex. Although the exact dose of the pharmaceutically active compound depends on a number of parameters, for example age of the patient, state of the patient, case history and compliance, a suitable dose both for oral and parenteral adminstrations of S(+)-ibuprofen complex is in the range of 50 to 1200 mg daily, normally between 100 and 800 mg daily, preferably between 200 and 600 mg S( + )-ibuprofen administered daily at one time or at several times.
With topical administration of this complex the corresponding dose lies in the range of 10 - 200 mg daily, generally being 20 - 100 mg daily, as ordered by the physician.
Further features of the invention will be apparent from the following description of examples of embodiment:
Example 1:
Preparation of the complex according to the invention: 146.2 mg (1 mol) R(+)-lysine are dissolved while stirring
in 2 1 dimineralized water and to this solution 206.2 g (1 mol) S(+)-ibuprofen are added. After subsequent stirring for 10 minutes the clear solution is lyophilized. The solid mass obtained is ground, sifted and subsequently dried for 3 hours at 105°C. Yield (98 - 99% of
theoretical), melting point 173.5 - 176.0°C.
Example 2:
Preparation of a tablet according to the invention:
Composition:
1 tablet contains
2406 17
active constituents
S ( + )-ibuprofen-(R)-lysine 171 mg
= S{+)-ibuprofen 100 mg non-active constituents:
gelatin 3 mg crosslinked sodium carboxymethyl cellulose 13 mg magnesium stearate 3 mg weight per tablet 190 mg
Preparation:
The gelatin is dissolved to 10 % in purified water whilst heating (max. 40°C) and slowly added to the active substance in the mixer with low mixing power. The granulate obtained is dried in the fluidized bed at about 40°C and sifted via a screening machine (mesh width 1.6 mm). The dried granulate is compacted with the aid of rams (diameter 7.8 mm) to tablets of 190 mg final weight.
Example 3:
Use example:
Maximum plasma levels of S(+)-ibuprofen (Cmax in yg/ml) and the time at which maximum plasma levels of S(+)-ibuprofen were reached (tmax, h.) were measured for four healthy male test persons after administration of 150 mg S(+)-ibuprofen and 150 mg S(+)-ibuprofen complex according to this invention in the form of an amorphous powder (see Table below).
24 0 6 1
Table
The powder was enclosed in a gelatin capsule and the following results were obtained:
fcmax ^ cmax (W9/ml)
S ( + )-ibuprofen, free acid 2.0 10.9
S(+)-ibuprofen in the complex 0.6 17.6
Advantageously, according to the invention the complexes of the invention may also be used in pharmaceutical preparations as are described in European Publication No. 0398387. Such isotropic solutions can be prepared by the following method steps:
a) heating of the carrier whilst stirring to above the melting point until an isotropic transparent liquid is present;
b) measuring the electrical conductivity and the viscosity at the temperature of the melting point to ensure the presence of an isotropic transparent liquid;
c) determination of the refractive index;
d) setting the desired concentration of the pharmaceutical active substances whilst observing the molar fraction, which at 37°C must lie between 0.001 and 0.67;
e) introduction of the pharmaceutical active substance into the solvent with constant stirring;
f) stirring the mixture until the pharmaceutical active substance is dissolved and a transparent solution obtained;
g) measuring the differential refractive index increment [(&n/£c)(jyp_constant] for determining the monomolecular solution and/or h) checking the native conformation and the mono-
ff * v
14
(followed by page 14a)
24 0 6 1
molecularity of the pharmaceutical active substance in the solution by measuring the molar extinction coefficient in the UV range and taking the absorption spectrum and detection of the chiral configuration by measuring in the polarimeter and/or i) measuring the opacification to ensure a homogeneous solution and/or k) measuring the specific conductivity
[(__/—) t tv=constant^ for controlling the ional concentration in the isotropic solution; 1) cooling the clear solution and preparing a galenic formulation;
m) further cooling of the solution to room temperature until the solution has solidified.
Using this method a pharmaceutical preparation according to the invention, consisting of one or more active substance complexes and a water soluble carrier, in particular polyethylene glycol, can be prepared. For example, the method provides a preparation which solidifies in the range between 20 and 80°C and is water-soluble, characterized in that it is an isotropic solution, wherein a) the active substance is dissolved in the carrier in monomolecular form or as ion,
b) the active substance is present in its native conformation and/or its biologically active chiral (enantiomeric) conformation,
c) the active substance has a molar fraction of 0.001 to 0.67 at 37°C.
d) the carrier is molten, phase-uniform and isotropic at body temperature,
e) the isotropic solution, consisting of carrier and active substance, solidifies at room temperature,
f) the solidified solution is crystalline or noncrystalline and contains the active substance in
/■'' ,
J ~ 1
/ •!
22FEBS994;
24 0 6 1 ?
14a crystalline form or can crystallize the active substance out,
g) the monomolecular or ionic solution has an osmotic pressure and effects a molar freezing point reduction, and h) the dissolved active substance within the polymer electrolyte has a temperature-dependent diffusion coefficient and a temperature-dependent specific conductivity.
The complexes described according to the invention and being of a non-salt nature, consisting for example of S( + )-ibuprofen and a basic D(-)-a-amino acid, which in the organism are converted and metabolized to the corresponding L(+)-amino acid, can be incorporated into natural membranes to detect
1) the resorbability mentioned above and
2) aforementioned proton switch.
The experimental execution is described in the publications Paradies, H.H., Colloids Surf., (1985), ^3, 263; Paradies,
H.H., J. Phys, Chem. gQ, 5956, (1986). By the change in the fluorescence of the ibuprofen arid the ibuprofen-a-amino acid complexes the fast proton transfer was detected: kp =
I.7 x lO1^ sec-1, which moreover is of the same order of magnitude for (R, S)-ibuprofen, kp = 2.0 x lO1^ M"*1 sec-1, S (+) or R(-)-ibuprofen kp. = 2.3 x lO1^ m~1 sec-1, caused by the interactions of the carboxyl groups, which also manifest themselves again in the crystal structures (Fig. 2). Salts consisting of cation and anion (ibuprofen
:22FEBt??l
4 0 6 1
-
carboxylate) do not exhibit these effects! The fast onset of pain relief after administration of S(+)-ibuprofen-D-(-) lysinate, as well as the pharmacokinetics are the consequence of the aforementioned results which can be proved, as will be shown below, in in vivo experiments on 24 test persons.
Pharmacokinetics of S(+)-ibuprofen-D-(-)-lysinate
The plasma level values of S(+)-ibuprofen measured in 24 test persons are summarized in tables 1 and 2 as individual values and mean values. Fig. 3 shows a representative plasma level curve after administration of S{-)-ibuprofen-D lysinate (200 mg S(+)-ibuprofen). As can be seen, in all other cases typical plasma level variations occurred, as are to be expected after taking a drug. A rapid resorption phase, reaching a maximum value, was followed by a rapid drop in the plasma level, apparent in the semilogarithmic representation as linear elimination phase. The mean plasma level curve calculated for all test persons with the lower region of the simple standard deviations was calculated by the trapezium rule and is 56.45 mg/1 x 12 h as mean value for all the female test persons. The maximum plasma level Cmax is 26.47 mg/1 and is reached after a tmax of 33 minutes. The delay time (lag time) of the resorption is 2.33 minutes on average. The elimination half value (Ti/23) for the total mean value curve is 107.4 minutes (1.79 hours). In table 3 all the important pharmacokinetic characteristics for all the test persons and the particular subgroups are summarized.
Pharmacodynamics of S(+)-ibuprofen-D lvsinate
In a monocentering study the pharmacodynamics were investigated for 24 female test persons for primary dysmenorrhea. The mean values of all the female test
240617
persons are shown in table 4 and graphically in Figure 4 as evaluation of a pain intensity scale. Pain intensity was specified with the aid of the visual analog scale (a scale open from 0 - 10) by the female test persons within a self-assessment.
As apparent from Fig. 4, the mean pain intensity at the time zero was 4.7; the analgesic efficacy started within 5 minutes and within the first 45 minutes there was a reduction to a value of 1.65 on the average. The maximum analgesic effect was achieved after two hours with a value of 0.36. Thereafter, the pain intensity again slowly increased to a value of 0.83 after 6 hours. Figure 4 shows the pain intensity curve of the female test persons.
No undesired drug effects occurred .in any of the female participants in the study. Likewise, all the chemical laboratory parameters and the results of the medical subsequent examination showed no- pathological findings. It may be concluded therefrom that the taking once or several times of S(+)-ibuprofen D-iysinate (in this study up to 3 x daily 200 mg for 3 days) did not lead to any undesired drug effects except for the pseudoallergic reaction observed in the one test person.
The relative oral bioavailability of s (-*-) -ibuprofen-D
240617
lysinate can be estimated by comparison with published literature data. After taking 200 mg S(+)-ibuprofen-D lysinate in capsule form a mean AUC of 56.45 mg/1 x 12 h was calculated. The maximum level was 26.47 mg/1 and was reached on average after 33.59 minutes. The elimination half time for our female test persons was 1.79 hours and the lag time 2.33 minutes.
A pharmacokinetic comparison of 150 mg S(+)-ibuprofen, free acid tablet, with S(+)-ibuprofen-C lysinate (150 mg S(+)-ibuprofen) is summarized in table 5. The rapid onset time (troax 0.6 + 0.3 h, lysinate) and the high Cmax value (17.6 + 5.2) with high AUC of 57.0 mg/ml x h show the superiority of the S(+)-ibuprofen-D lysinate complex over the free acid of the S(+)-ibuprofen.
Table 1; P1asma level of all test persons as individual values and arithmetic mean values (5) with standard deviations (s, s- ), median values (Me) with minimum (Mi) and maximum (Ma).
Cons. Initial Minutes No. value 5 10
1
2
3
4
6
7 B 9
U
12
13
14
16
17 IB
19
21
22
23
24
n X s Sx
Me Mi Ma
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
24 0.000 0.000 0.000
0.000 0.000 0.000
0.050 0.000 0.300 0.000 0.000 0.290 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 10.600 5.240 0.000 1.050 0.000 7.260 0.000 0.360 3.050 0.000
24
1.175 2.720 0.555
0.000 0.000 10.600
3.050 0.000 9.400 0.000 1.450 14.900 7.160 0.310 0.000 1.000 11.400 4.360 0.730 8.550 26.100 25.700 4.140 8.610 0.220 26.700 1.580 5.730 26.400 1.410
24 7.871 9.302 1.899
4.250 0.000 26.700
24.500 2.110 20.800 10.900 12.300 22.700 35.100 •2.720 4.700 12.700 la.500 17.000 17.100 36.500 24.300 38.300 16.500 37.600 2.650 20.900 13.900 19.BOO 29.300 25.600
24 19.445 10.063 2.217
19.150 2.110 36.300
21.400 4.950 IB.000 18.900 19.500 24.100 29.100 14.600 20.200 24.500 21.000 20.700 23.200 37.400 19.300 30.700 21.200 37.100 24.500 16.100 24.400 24.100 27.600 22.900
24 22.727 6.B07 1.389
22.150 4.950 37.400
.400 21.600 16.200 22.200 18.200 28.800 24.400 22.000 24.400 25.000 22.900 23.000 19.300 32.000 13.500 22.800 19.500 27.600 17.100 11.800 21.300 27.300 26.500 15.500
24 21.637 4.939 1.006
22.100 11.000 32.000
17.000 24.000 13.200 24.400 16.700 20.200 20.000 21.700 17.700 19.400 17.300 18.700 12.100 27.200 12.200 15.900 17.200 16.100 14.000 6.230 17.500 19.600 21.500 11.100
24 17.672 4.718 0.963
17.600 6.230 27.200
14.000
9.710
4.550
26.400
18.500
8.700
11.900
8.290
3.140
21.700
16.200
6.280
.300
.400
7.290
17.500
14.500
6.400
16.900
.100
7.230
18.000
12.700
.290
14.000
9.800
7.210
12.700
0.200
4.030
13.900
9.650
.080
11.900
8.460
4.120
9.150
6.120
3.990
21.800
12.900
4.750
7.560
6.380
2.230
9.450
7.430
2.280
12.500
7.310
2.720
14.300
9.100
2.920*
9.030
8.050
2.920
.650
3.390
1.560
12.200
7.420
3.700
11.900
9.650
3.740
13.900
8.850
2.740
6.010
2.760
1.350
24
24
24
13.685
9.445
4.303
4.965
3.591
1.997
1.014
0.733
0.408
13.300
0.975
4.055
.650
2.760
1.350
26.400
18.500
B.780
1.920
1.140
0.690
4.810
11.870
0.940
1.050
O.710
0.460
4.230
1.210
0.730
4.540
2.520
1.500
4.490
2.690
1.540
3.510
1.950
0.960
4.380
1.600
0.840
2.250
0.400
0.200
2.540
1.170
0.620
2.580
1.740
1.010
2.740
1.400
0.570
1.010
0.730
0.200
1.630
0.960
0.560
0.'890
0.610
0.390
1.240
0.520
0.220
1.500
0.660
0.250
1.710
0.640
0.200
0.610
0.410
0.000
0.730
0.500
0.240
1.050
0.680
0.290
1.150
0.770
0.530
1.490
0.850
0.390
0.580
0.250
0.000
24
24
24
2.193
1.502
0.555
1.405
2.302
0.414
0.287
0.470
0.005
1.670
0.010
0.495
0.580
0.250
0.000
4.810
11.870
1.540
0.350 0.550 0.290 0.000 0.770 0.760 0.460 0.330 0.000 0.310 0.340 0.250 0.000 0.240 0.200 0.000 0.000 0.000 0.000 0.000 0.000 0.320 0.200 0.000
24
0.224 0.239 0.049
0.220 .0.000 0.770
00
1
-J3*>
o
^4
?. 4 0 6 1 7
Table 2
Plasma level of s(+)-ibuprofen for female test persons after 200 mg -(oral) S(+)-ibuprofen (concentration in mg/1)
Time h (min.)
A
B
geometric mean values
0
0,10
( 0,10- 0,10)
0,10
( 0,10
- 0,10)
0,08 ( 5}
0,14
( 0»11"
- 0,18)
0,10
( 0,10
- o,io)
0,166(10)
1,36
( 0,56-
- 3,30)
1,49
( 0,69-
- 3,21)
0,33 (20)
12,18
( 8,36-
-17,75)
. 8,51
( 5,43-
-13,34)
0,5 (30)
,66
(11,70-
-20,94)
21,22
(19,33-23,31)
0,75(45)
,89
(19,28-22,63)
18,49
(14,66-
-23,33)
1
19,06
(17,27-
-21,03)
19,20
(18,52-
-19,91)
1,5
17,16
(15,23-
-19,34)
13,78
(12,99-
-14,62)
2
12,40
(10,89-
-14,13)
9,12
( 9,11-
-10,35)
4
,77
( 4,96-
' 6/70)
4,15
( 2,95- 5,72)
6
3,07
( 2,38- 3,97)
2,92
( 2,64-
- 3,23)
8
1,52
( 1,23-
1,88)
1,25
( 0,98-
• 1,58)
0,89
( 0,73-
1,08)
0,6 2
( 0,49-
0,79)
12
0,39
( 0,28-
0,53)
0,27
( 0,22-
0,34)
C
'
O
0
0,10
( 0,10-
0,10)
0,10
0,10-
0,10)
0,08 ( 5)
0,62
( 0,26-
1/49)
0,45
0,21-
0,97)
0,166(10)
7,28
( 4,23-
12,55)
3,54
1,65-
7,62)
0,33 (20)
26,68
(22,69-
31,36) •
,19
,70-
21,57)
0,5 (30)
27,19
(24,17-
,60)
17,26
13,00-
22,91)
0,75(45)
21/63
(19,10-
24,48)
19,08
16,69-
21,80)
1
16,23
(14,42-
18,27)
14,01
11,61-
16,90)
1,5
11,69
(10,00-
13,66)
9,36
8,00-
,95)
2
7,93
( 7,09-
8,88)
6,09
4,88-
7,60)
4
3,02
( 2,67-
3,43)
2,49
2,08-
2,98)
6
1,29
( 1,16-
1.44)
0,88
0,75-
1,03)
8
0,67
( 0,62-
0,73)
0,53
0,44-
0,64)
0,28
( 0,24-
0,33)
0,23
0,17-
0,30)
12
0,13
( 0,11-
0,15)
0,14
0,11-
0,17)
"MQ 6
Table 3
Study for pharmacokinetics and dynamics of s(+)-ibuprofen D-lysinate capsules as analgesic after single administration to patients with dismenorrhea Kinetic parameters for S(+)-ibuprofen D-lysinate
Item a
Maximum measured 5
plasma x 24.1
value(rag/l) S 3.45
min 19.5
max 28.8 P /
Time of max n_ s plasma value x 44,2
(min) S 27/3
min 20
max 45 P /
AUC n 6
(Trapezium) x 69,55
(mg/lxl2h) S 15,9
min 44,73
max 85,75 P /
"*436
Table 4
Subjective estimation of the pain intensity with the aid of the visual analog scale
Data on pain intensity (mean values)
Time Group A Group B No contraceptives n = 6 n = 6 N = 12
0
min
3,70
4,76
3,95
min
3,63
4,73
3,88
min
3,21
4,40
3,39
min
2,52
3,20
2,86
min
2,15
2,88
2,33
45
min
1,90
1,27
1,58
60
min
1,18
0,55
0,87
90
min
0,55
0,28
0,39
2
h
0,35
GO H
O
0,27
3
h
0,27
0,08
0,18
4
h
0,62
0,08
0,35
h
0,92
0,40
0,66
6
ft
1,02
0,63
0,83
Group A: Non-smoker/no contraceptive taken Group B: Smoker/no contraceptive taken
?40 6
Table 5
Pharmacokinetic parameters after administration of a singl oral dose of 150 mg (+)(S)-ibuprofen (I) and as D-lysinate
Mean + SD
rmax'h
Cmax'"9/,,d AUC, ng/ral x h tlag' h *1/2' h
Ae, free 1 % of dose Ae conj. I
S(+)-ibuprofen free acid tablet
2,0 + 0,2 10,1 + 4,7 44,5 ± 10,5 0,5 + 0,1 2,2 ± 0,3 0,6 ± 0,2 8,0 ± 2,9
Lysinate
0*33 + 0,20 23,8 ± 5,2 57,0 ± 10,2 0,1 ± 0,02 1,5 + 0,3 0,6 + 0,5 9,3 ± 5,4 1.
240617
Claims (29)
1 . Hydrogen-bridge-bound complexes having a stoichiometry of 1:1 comprising a S(+)-phenyl alkane acid and a basic a-amino acid in which the complex bond is based on carboxylate-carboxyl interactions with a proton switch of the form -COOH... OOC- ^ -COO" ... HOOC- where -COOH is representative of the S(+)-phenyl alkane acid and "OOC- is representative of the basic a-amino acid and the pKa values relating to the carboxyl group of the S(+)-phenyl alkane acid lies in the range of 3.5 - 3.9 and the pKa values relating to the carboxyl group of the basic a-amino acid lies in the range of 1.9 - 2.9.
2. Complexes according to claim 1, characterized in that the pKa values relating to the carboxyl group of the basic a-amino acid lies in the range of 1.9 -2.2.
3. Complexes according to claim 1 or 2, characterized in that as the S(+)-phenyl alkane acid, S(+)-ibuprofen or S(+)-naproxen is used.
4. Complexes according to any one of the preceding claims, characterized in that the D form of the basic a-amino acid is used.
5. Complexes according to any one of the preceding claims, characterized in that the a-amino acid has the following struc^r^5t ' 0 fv * * - 24 - 240617 H Z-A- X where X is NH2 or Ci-C6 alkyl amino; Z is H, OH or NH2; and A is a bond or an alkylene chain which contains 1 - 10 carbon atoms and if required an amino group or 1 - 6 hydroxyl groups.
6. Complexes according to claim 5, characterized in that X is NHCH3 or NHC2H5.
7. Complexes according to any one of the preceding claims, characterized in that as the basic cr-amino acid, D-lysine, D-arginine, D-hystidine or D-ornithine is used.
8. Complexes according to any one of claims 1 to 6, characterized in that the complex contains valine, leucine, isoleucine, asparaginic acid, glutamic acid, asparagine, glutamine, phenylalanine, serine, threonine or hydroxylysine.
9. A method for the preparation of the complexes according to any one of the preceding claims, characterized by the following method steps: a) for the preparation from aqueous medium (only water) or weakly buffered aqueous solutions covering a pH range between pH 5.5 a buffered aqueous solution is prep y - 25 - into it an equivalent amount by mole of a S(+)-phenyl alkane acid is introduced with constant stirring; b) the solution is heated with constant stirring to 40°C (water bath) until a clear transparent solution is obtained and all the S(+)-phenyl alkane acid has gone into solution; c) thereafter the pH of the solution is adjusted to pH 5.5 - 6.0 by addition of diluted phosphoric acid (H2P04) (20°C) and then the equivalent amount by mole of an a-amino acid is introduced with constant stirring, ensuring that a neutral a-amino acid is introduced and not a hydrochloric acid (HCl)-a-amino acid; and d) the complex formation is terminated after 20 minutes, whereupon after cooling to 0 - 4°C the complex precipitates in crystalline form and can be separated from the mother liquor via a sintered glass funnel or glass filter (1G4); or e) alternatively to method step d) the clear solution can be reduced in a rotary evaporator (water bath temperature 25-30°C) in a water jet vacuum to half the volume, whereupon a colourless (amorphous) deposit forms which is filtered off via a 1G4 glass filter and can be recrystallized from water/ethanol (70/30 v/v) or from ethyl acetate.
10. A method according to claim 9, characterized in that the buffered aqueous solution is a 0.01 M -0.001 M K2HP04/KH2P04 buffer of pH 6.0 - 7.5 (20°C) .
11. A pharmaceutical preparation containing one or more complexes according to any one of claims 1 to 8 and optionally at least one additional physiologi compatible extender or carrier. - 26 - i
12. A pharmaceutical preparation according to' claim 11 comprising a phenyl alkane acid having an antiinflammatory, antipyretic, antimicrobial and analgesic effect, containing an active substance complex comprising a phenyl alkane acid and an a-amino acid, characterized in that the active substance complex consists of a S(+)-phenyl alkane acid and a basic a-amino acid.
13. A pharmaceutical preparation according to claim 12, characterized in that the basic a-amino acid is in the D form.
14. A pharmaceutical preparation according to claim 11, 12 or 13 on the basis of ibuprofen or naproxen with an antiinflammatory, antipyretic, antimicrobial and analgesic effect, containing an active substance complex comprising ibuprofen or naproxen and a basic a-amino acid, characterized in that the active substance complex represents an amount by weight of 0.1 to 90% (w/w) of the composition.
15. A pharmaceutical preparation according to any one of claims 11 to 14, characterized in that it further includes at least one physiologically compatible auxiliary substance.
16. A pharmaceutical preparation according to any one of claims 11 to 15, characterized in that it contains 50 to 800 mg of S(+)-ibupro^ S(+)-naproxen. \ 27 2406 J7
17. A pharmaceutical preparation according to claim 16, characterized in that it contains 100 to 600 mg of S(+)-ibuprofen or S(+)-naproxen.
18. A pharmaceutical preparation according to claim 17, characterized in that it contains 100 to 300 mg S(+)-ibuprofen or S(+)-naproxen.
19. A pharmaceutical preparation according to any one of claims 11 to 18, consisting of at least one active substance complex and a water-soluble carrier, which solidifies in the range between 20 and 80°C and is water-soluble, characterized in that it is an isotropic solution, wherein a) the active substance is dissolved in the carrier in monomolecular form or as ion, b) the active substance is present in its native conformation and/or its biologically active chiral (enantiomeric) conformation, c) the active substance has a molar fraction of 0.001 to 0.67 at 37°C. d) the carrier is molten, phase-uniform and isotropic at body temperature, e) the isotropic solution, consisting of carrier and active substance, solidifies at room temperature, f) the solidified solution is crystalline or noncrystalline and contains the active substance in crystalline form or can crystallize the active substance out, g) the monomolecular or ionic solution has an osmotic pressure and effects a molar point reduction, and 240617 - 28 - h) the dissolved active substance within the polymer electrolyte has a temperature-dependent diffusion coefficient and a temperature-dependent specific conductivity.
20. A pharmaceutical preparation according to claim 19, characterized in that the water-soluble carrier is polyethylene glycol.
21. A pharmaceutical preparation according to any one of claims 11 to 20, characterized in that it provides a suitable dose for oral, parenteral or topical administration, wherein the suitable dose for oral or parenteral administration is in the range of 50 - 1200 mg of S (+)-ibuprofen daily and the suitable dose for topical administration of the complex is in the range of 10 - 200 mg daily.
22. A pharmaceutical preparation according to claim 21, characterized in that the suitable dose for oral or parenteral administration is in the range of 100 - 800 mg daily.
23. A pharmaceutical preparation according to claim 21, characterized in that the suitable dose for oral or parenteral administration is in the range of 200 - 600 mg daily.
24. Complexes according to any one of claims 1 to 8, characterized in that the S( + ) -phenyl alkane acid has a strucfr^^Jfiw^V the form I* ' Vj ocr w \ - 29 - Ar C COOH H in which R is C-|-C5 alkyl and Ar is a monocyclic, polycyclic or ortho-condensed polycyclic aromatic group having up to twelve carbons in the aromatic system, optionally substituted by at least one of a halogen atom or a Ci-C4alkyl, benzyl, hydroxy, C^-C2 alkoxy, phenoxy or benzoyl group.
25. Complexes according to claim 24, characterized in that the aromatic group is phenyl, diphenyl or naphthyl.
26. Complexes according to claim 24 or 25, characterized in that Ar is: 4-isobutyl-phenyl, 3-phenoxy-phenyl, 2-fluoro-4-diphenyl, 4' -fluoro-4-diphenyl, 6-methoxy-2-naphthyl, 5-chloro-6-methoxy-2-naphthyl, 5-bromo-6-methoxy-naphthyl, 4-chloro-phenyl, 4-difluoro-methoxy-phenyl, 6-hydroxy-2-naphthyl, or 5-bromo-6-hydroxy-2-naphthyl.
27. Hydrogen-bridge-bound complexes having a stoichiometry of 1:1 substantially as herein described with reference to Example 1.
28. A method for the preparation of a hydrogen-bridge-bound complex substantially as herein described with reference to Example 1.
29. A pharmaceutical claims 11 to 23, - 30 - - t preparation according to any one of substantially as herein described. OAT ED THIS <21^ DAY OF QCt&W A. J. PARK & SON AGENTS FOR THE APPDCANTS S.
Applications Claiming Priority (1)
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DE4036458 | 1990-11-15 |
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Family
ID=6418339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NZ240617A NZ240617A (en) | 1990-11-15 | 1991-11-15 | Hydrogen-bridge-bound complexes comprising a 1:1 stoichiometric proportion of s(+)-phenyl alkane acid and a basic alpha-amino acid; and pharmaceutical compositions thereof |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP0486045B1 (en) |
JP (1) | JPH0656737A (en) |
KR (1) | KR920009774A (en) |
CN (1) | CN1061404A (en) |
AT (1) | ATE137733T1 (en) |
AU (1) | AU8790591A (en) |
BG (1) | BG95490A (en) |
BR (1) | BR9104996A (en) |
CA (1) | CA2055683A1 (en) |
CS (1) | CS346491A3 (en) |
DE (2) | DE59107790D1 (en) |
HU (1) | HUT59656A (en) |
MX (1) | MX9102088A (en) |
NZ (1) | NZ240617A (en) |
PL (1) | PL292413A1 (en) |
ZA (1) | ZA919077B (en) |
Families Citing this family (9)
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HUT59653A (en) * | 1990-11-15 | 1992-06-29 | Puetter Medice Chem Pharm | Process for producing complexes containing s/+/-phenyl-alcanoic acids and alpha-hydroxy-alcanoic acids and pharmaceutical compositions containing them as active components |
HUT59692A (en) * | 1990-11-15 | 1992-06-29 | Puetter Medice Chem Pharm | Process for producing complexes containing s/+/-phenyl-alkanoic acids and aminosugars |
WO1992017185A1 (en) * | 1991-03-29 | 1992-10-15 | University Of Florida | Targeted drug delivery via mixed phosphate derivatives |
RU2133733C1 (en) * | 1992-12-02 | 1999-07-27 | Дзе бутс компани ПЛС. | Method of synthesis of phenylpropionic acid |
IT1272149B (en) * | 1993-03-26 | 1997-06-11 | Zambon Spa | PHARMECEUTICAL COMPOSITION WITH ANALGESIC ACTIVITY |
IT1264855B1 (en) * | 1993-06-21 | 1996-10-17 | Zambon Spa | PHARMACEUTICAL COMPOSITIONS CONTAINING S (+) - 2- (4-ISOBUTYLPHENYL) PROPIONIC ACID SALTS WITH BASIC AMINO ACIDS |
DK1077692T3 (en) * | 1998-05-15 | 2004-12-06 | Warner Lambert Co | Amino acid stabilized gabapentin and pregabalin preparations and methods for their preparation |
AR057882A1 (en) | 2005-11-09 | 2007-12-26 | Novartis Ag | DOUBLE ACTION COMPOUNDS OF ANGIOTENSIN RECEPTOR BLOCKERS AND NEUTRAL ENDOPEPTIDASE INHIBITORS |
CN101455653B (en) * | 2007-12-13 | 2013-03-06 | 天津医科大学 | Arginine ibuprofen oral disintegrating tablets and preparation method thereof |
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GB1497044A (en) * | 1974-03-07 | 1978-01-05 | Prodotti Antibiotici Spa | Salts of phenyl-alkanoic acids |
ES2055685T3 (en) * | 1986-11-14 | 1994-09-01 | Puetter Medice Chem Pharm | PROCEDURE FOR OBTAINING A MEDICINAL PRODUCT CONTAINING IBUPROFEN. |
DK0424028T3 (en) * | 1989-10-17 | 1996-01-29 | Merck & Co Inc | S (+) - ibuprofen-L-amino acid and S (+) - ibuprofen-D-amino acid as an improved analgesic with accelerated onset |
-
1991
- 1991-11-14 HU HU913571A patent/HUT59656A/en unknown
- 1991-11-15 DE DE59107790T patent/DE59107790D1/en not_active Revoked
- 1991-11-15 AU AU87905/91A patent/AU8790591A/en not_active Abandoned
- 1991-11-15 PL PL29241391A patent/PL292413A1/en unknown
- 1991-11-15 EP EP91119522A patent/EP0486045B1/en not_active Revoked
- 1991-11-15 NZ NZ240617A patent/NZ240617A/en unknown
- 1991-11-15 AT AT91119522T patent/ATE137733T1/en not_active IP Right Cessation
- 1991-11-15 CN CN91110739A patent/CN1061404A/en active Pending
- 1991-11-15 ZA ZA919077A patent/ZA919077B/en unknown
- 1991-11-15 KR KR1019910020368A patent/KR920009774A/en not_active Application Discontinuation
- 1991-11-15 MX MX9102088A patent/MX9102088A/en unknown
- 1991-11-15 JP JP3354099A patent/JPH0656737A/en active Pending
- 1991-11-15 CA CA002055683A patent/CA2055683A1/en not_active Abandoned
- 1991-11-15 BG BG095490A patent/BG95490A/en unknown
- 1991-11-15 CS CS913464A patent/CS346491A3/en unknown
- 1991-11-15 DE DE4137675A patent/DE4137675A1/en not_active Withdrawn
- 1991-11-18 BR BR919104996A patent/BR9104996A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
CA2055683A1 (en) | 1992-05-16 |
EP0486045B1 (en) | 1996-05-08 |
AU8790591A (en) | 1992-05-21 |
ZA919077B (en) | 1992-08-26 |
BR9104996A (en) | 1992-06-23 |
DE4137675A1 (en) | 1992-05-21 |
EP0486045A2 (en) | 1992-05-20 |
EP0486045A3 (en) | 1992-12-09 |
BG95490A (en) | 1993-12-24 |
ATE137733T1 (en) | 1996-05-15 |
CS346491A3 (en) | 1992-06-17 |
KR920009774A (en) | 1992-06-25 |
HU913571D0 (en) | 1992-01-28 |
DE59107790D1 (en) | 1996-06-13 |
HUT59656A (en) | 1992-06-29 |
CN1061404A (en) | 1992-05-27 |
PL292413A1 (en) | 1993-01-25 |
MX9102088A (en) | 1993-01-01 |
JPH0656737A (en) | 1994-03-01 |
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