CA2055683A1 - Complexes containing s(+) phenyl alkane acids and .alpha.-amino acids - Google Patents
Complexes containing s(+) phenyl alkane acids and .alpha.-amino acidsInfo
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- CA2055683A1 CA2055683A1 CA002055683A CA2055683A CA2055683A1 CA 2055683 A1 CA2055683 A1 CA 2055683A1 CA 002055683 A CA002055683 A CA 002055683A CA 2055683 A CA2055683 A CA 2055683A CA 2055683 A1 CA2055683 A1 CA 2055683A1
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- Prior art keywords
- alpha
- amino acids
- ibuprofen
- phenyl
- acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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Abstract
P 47?7 Abstract:
New complexes of S(+)-ibuprofen and amino acids are described. Said complexes have anti-inflammatory, antipyretic and antimicrobial properties and analgesic effects.
New complexes of S(+)-ibuprofen and amino acids are described. Said complexes have anti-inflammatory, antipyretic and antimicrobial properties and analgesic effects.
Description
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_s Com~lexes containinq S~+) Phenvl alkane acids and a-amino acids The present invention relates to hydrogen-bridge-bound complexes having a stoichiometrv of 1:1, comprising S(+)-phenyl alkane acids and basic a-amino acids.
Compounds o S(-)-phenyl alkane acids and a-amino acids are already known. However, they are not the specific comple~es according to the inventlon but salts.
Lvsinate salts, both racemic (D, ~) or onlv L salts of basic a-amino acids, have been described inter alia bv Bru~zese et al., US patent specification ~,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 phaxmaceutical forms described by Bruzzese et al. and consisting of S(+)-ibuprofen and (D, L)-lvsine or (R, S)-ibuprofen with (D, L) or L( )-lvsine, as salts, i.e. consisting of an anion and cation.
Specification as laid open to inspection DE 29 224~1, ~1, describes pharmaceutical preparations of ibuprofen and S(s)-ibuprofen with a low neutral or acidic a-amino acid which are added to an amount of up to ~0 ~ bv weight to the active substance ibuprofen (S-ibuprofen). The a-amino acld 30/ amount added may even be up to 60 % (g/g) if acidic or neutral amino acids are involved. No particulars are yiven on the weight ratios for basic a-amino acids nor on their stereo-onemistr~f, ~.~ater solubilicy, stability and pharmacokinetic behaviour.
Publication DE 3814887, Cl (1988), does not describe either salts or comple~es with D, L or D and L a-amino acids, or , "-, ' : , ;-. ~' ~, , ~.3~
...
with basic a-amino acids; only a racemate separation with the aid of threo-l-p-nitrophenyl-2-aminoProPane-1,3-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 ?roble~ is sol~ed according to the inventio-n b~
hvdrogen-bridge-bound complexes having a stoichiometrv of 1:1 comprisins S(-)-pnen~l alkane acids and basic a-amino acids in ~hich the complex bond is based on carboxvlate-carboxyl interactions ~ith a proton s~ ch of the form Rl-COOH.... OOC-R2 Rl-C00 ....... HOOC-R2 ~-here Rl-C00.I denotes the S(-)-phenvl alkane acids and R2-COOH the basic a-amino acids and the pKa values relating to the carboxyl group of the S(+)-phenyl alXane acids lie in the range of 3.5 to 3.g and the pKa values relating to the carboxyl group of the basic ~-amino acids lie in the range, of 1.9 - 2.9.
Preferably, the pKa values relating to the carboxvl group of the basic ~-amino acids lie in the range of 1.9 - 2.2.
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. _3 _ Preferably, as S(~)-phenyl alkan0 acids hereln S(+~-lbuprofen or S(~)-naproxen shall be unders~ood and are used.
Preferably as S(~)-phenyl alcane acids herein the subst~nces as detailed below shall be understood and are used. These substances comprise the following structure:
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, ~-C4 alkyls, benzyl, hydroxy, Cl-Cz 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- hloro-phenyl, 4-difluoro-metho~y-phenyl, 6-hydroxy-2-naphthyl, and 5-bromo-6-hydroxy-2-naphthyl.
- 3~ )J
. .
Preferably, the D-form of the basic a-amino acids is used.
Preferably, the a-amino acids have the following structure:
Z-A-C~C ~
¦ ~ OH
.. . . . .. . . .
, , with X = NH2, NHCH3, NHC2H5, C1-C6 alkanyl amino z = H, OH, NH2 A = a bond or an alkylene chain which contains 1 - 10 carbon atoms and if required an amino group of 1 - 6 hydroxyl groups.
Preferably, as basic D-a-amino acids D-lysine, D-arginine, D-histidine or D-ornithine are used.
Preferably, the comple~ according to the invention contains valine, leucine, isoleucine, asparaginic acid, glutamine acid, asparagine, glutamine, phenylalanine, serine, threonine or hydroxylysine.
According to the invention the comple~es 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 (20C) a buffered aqueous solution, for example a 0.01 M - 0.001 M-K2HP04/KH2P04 buffer pH 6.0-7.5 (20C) is prepared and into it an 2S equivalent amount S(+)-phenyl alkane acid is introduced with constant stirring;
b3 the solution is heated with constant stirring to 40C
(water bath) until a clear transparent solution is obtained (normally after 20 minutes) and all the 3~ S(~)-phenyl alkane acid has gone into solution;
c1 thereafter the pH of the solution is adjusted to pH
5.~ - 6.0 by addition o~ diluted phosphoric acid (H3P04) (20C1 and then the equivalent (corresponding) amount of the a-amino acid is introduced with constant stirring, ensuring that the neutral ~-amino acids are introduced and not the hydrochloric acid ~HC1)-a~amino - , ~ ., : :, :. " ~, . , : -- - . - ~ : , .
1 acids!;
d) the complex formation is terminated after 20 minutes whereupon after cooling to 0 - 4C the complexes precipitate in crystalline for~ and can be separated from the mother liquor via a sintered glass funnel or glass filter (lG4);
e) alternatively to method step d) the clear solution can be reduced in a rotary evaporator (water bath temperature 25 - 30C) in the water jet vacuum to half the volume, whereupon a colourless (amorphous~ deposit forms which is filtered off via a lG~ glass filter and can be recrystallized from water/ethanol (70/30 V/V) or from ethyl acetate (lO0 %).
The substances according to the invention do not represent a salt formation between an acidic group (carbo~yl 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-carboxvl interactions, the two carboxyl radicals of the a-amino acid and for e.Yample the ibuprofen sharing a proton. This means that the complex is formed in accordance with the ~-ray structure analvsis bv a hydrogen bridge Wl thout any participation of the a-amino ~ group or other basic group (guanido, ~ -amino group) being observed (Fig. l). The complexes of S(+)-ibuprofen and D(-)-lysine or of S(+)-ibuprofen and L(+)-lysine crystallize in the chiral space group P2l2l2l as l:l complexes with four molecules per unit cell. ~ithin 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 (H20) because only the pKa values of the a-amino acid with regard to the carboxyl group, i.e. pKa = 2.18 - l.92, and the .
phenyl alkane acids, i.e. pKa = 3.5 - 3.9, are decisive.
The pKa values of the a-amino group of the ~-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 contrary a "proton switch" of the form R.-COOH...-OOC-R2 R1-COO- ...HOOC-R2 and therefore the "complex" appears neutral in solution without influencing the water solubilitv of these complexes, as is for example the case with alkaline and alkaline earth salts of phenyl alkane acids, in particular ibuprofen, since they are soluble and dissociated only above pH > 7Ø
The dissociation of these alkaline or alkaline earth salts also disadvantageously affects the resorbability and consequently the therapeutic advantages (for e~ample no precipitation of the ibuprofen in the stomach, resorption in the gastro-intestinal region bv 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 ~-amino group i9 not complexly bound because no N-H stretch vibrations are present, although non-hydrogen-bridge-bound carbonyl groups are present at 1680 - 1700 cm 1. 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 ,., .,, .,.,. ; ~ . . . .. . .
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 anti-inflammatory, 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 au~iliary substances, in which the active substance comple~ consists of S(+)-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 anti-inflammatory, antipyretic, antimicrobial and analgesic effect, containing an active substance complex comprising an ibuprofen or napro~en and basic a-amino acids and possibly additionally usual physiologically compatible auxiliary substances, in which the active substance comple~
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 doses for a topical administration of the comple~ lies in the range of 10 - 200 mg daily.
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1 Hereina~ter, 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 unitarv 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 a~ueous or oily suspensions. Tablets may for example be prepared by 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 50 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 admini~tration include aqueous solutions containing the .
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, . . . ~ .
active pharmaceutical compound in the presence of a non-toxic 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.
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 e~ample 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 matri~ 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 ~ith 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.
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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 e~ample colloidal solutions or particulate suspensions of the order of magnitude of O.l - l ~m (colloid mill).
If desired, in accordance with this invention compositlons may also be prepared with other compatible pharmaceutical active suhstances.
These comple~es according to the invention have anti-inflammatory, 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 relieYing pain, for example headache, dysmenorrhea, postoperative pain, postpartum pain and pain related to influenza and colds.
Accordin~ly, the invention describes in particular another aspect of the treatment of pain or inflammatory fever after ~ `
'' - ' ' '~ ' ' ' . ~ .
. .
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 doqe both for oral and parenteral adminstrations of S(~)-ibuprofen comple~ is in the range of 50 to 1200 mg daily, normally batween 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 comple~ 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 Pr~æ ration of the complex accordin~ to the invention.
146.2 mg ~1 mol) R~+)-lysine are dissolved while stirring in 2 l 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 lyophili~ed. The solid mass obtained is ground, sifted and subsequently dried for 3 hours at 105C. Yield ~98 - 99% of theoretical), melting point 173.5 - 176.0C.
Exa Ele 2:
Pre~aration of a table~ according_ o ~he invention-Composition: 1 tablet contain~
t ~
active constituents .
S(+)-ibuprofen-(R)-lysine 171 mg = S(+)-ibuprofen 100 mg non-a_tive constituents.~
gelatin 3 mg crosslinked sodium carboxymethyl cellulose 13 mg magnesium stearate 3 mg weight per tablet 190 mg Preparatlon:
The gelatin is dissolved to 10 % in purified water whilst heating (max. 40C) and slowly added to the active substance in the mixer with low mixing power. The granulate obtained is dried in ths fluidized bed at about ~0C 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.
Exam~le 3-Use example Maximum plasma levels of S(+j-ibuprofen (Cmax in ug/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 Sl+)-ibuprofen and 150 mg S(+)-ibuprofen complex accor~ing to this inYention in the form of an amorphous powder (see Table below) ~
-l Table The powder was enclosed in a gelatin capsule and the following results were obtained:
tmax (h ) CmaX (~g/ml) St+)-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 German application DE 40 15 794.6. 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 trans-parent liquid;
c) determination of the refractive index;
d) setting the desired concentration of the pharma-ceutical active substances whilst observing the molar fraction, which at 37C must lie between 0.001 and 0.67;
e) introduction of the pharmaceutical active sub-stance 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 differeDtial refractive index increment [(~n/~c)T~p=cOn9tant] for determining the monomolecular solution and/or h) checking the native conformation and the mono-~J ~ ~3~J ~ ~
~, . ~
1 molecularity of the pharmaceutical active sub-stance in the solution by measuring the molar e~tinction 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,V=constant] for controllin~ 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 temp-erature until the solution has solidified.
The comple~es described according to the invention and being o a non-salt nature, consisting for ex~ ple of S(+)- -ibuprofen and a basic D(~ -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), 13~ 263; Paradies, H.H., J. Phys, Chem. 9O, 5956, (1986). By the change in the fluorescence of the ibuprofen and the ibuprofen-~-amino acid complexes the fast proton transfer was detected: kp =
1.7 x 1012 M 1 sec~1, which moreover is of the same order of magnitude for (R, S)-ibuprofen, kp = 2.0 x 1012 M~1 sec~1, S(+) or R(-)-ibuprofen kp - 2.3 x 1012 M-1 se -1, caused by the interactions of the carboxyl groups, which 1 also manifest themselves again in the crystal structures J (Fig. 2). Salts consisting of cation and anion (ibuprofen , .
, ' ' ' ' ' , .
'' .' ' ,~
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 e~periments on 24 test persons.
Pharmacokinetics of S(~)-ibuprofen-D-~-)-lvsinate The plasma level values of S(~)-ibuprofen measured in 2~
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). ~s can be seen, in all other cases typical plasma level ~ariations occurred, as are to be expected after taking a drug. ~ rapid resorption phase, reaching a maximum value, was followed by a rapid drop in the plasma level, apparent in the semilogarithmic represer.tation 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.~5 mg/l ~ 12 h as mean value for all the female test persons. The maximum plasma level Cmax is 2G.47 mg/l 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 tTl/2~) for the total mean value curve is 107.4 minutes (1.79 hours). In tahle 3 all the important pharmacokinetic characteristics for all the test persons and the particular 3 subgroups are summarized.
Pha_macod ~amics _ S(+)_ibuprofen_~ _ sinate In a monocentering study the pharmacodynamics were invsstigated for 24 female test persons for primary dysmenorrhea. The mean values of all the female test , . 17 1 /persons ~re 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.
.~s apparent frcm Fig. a, the me~n pain int ~sitv at the time zero was ~.7; the analgesic efflcacy s~ rted ~it:~ln 5 minutes and within the rirst ~5 mi~utes theYe ~as a :~
reduc~ion to a value of 1.65 on the averase. T~e maY-mum analsesic effec' ~as achieved af.er t~o houYs ~ith a value of 0.36. Thereafter, the pain intensitv: asain slowly increased to a value of 0.83 a~ter 6 hours. Figure a shows the pain intensity curve of the female tes. persons.
~ _ . .
Na undesired drug effects occurred in any or the female participants in the study. Likewise, all the chemical laboratorv parameters and the results of the medical subsequent e~amination showed ~o patholosical findings. It may be concluded therefrom that the taking onc~ or several times of St+)-lbupro~en D-1ysiDate ~in this studv up to 3 ~ dailv 200 mg for 3 davs) did not lead ~o any undesired drug effects except for the pseudoallergic reaction observed in the one test person The rela~ive oral bioa~ailabilitV of S(;)-ibuprofen-D
.
, ' ~ ~ ~3 ~!3 1 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/l x 12 h was calculated. The maximum level was 26.g7 mg/l 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 (tmaX 0.6 + 0.3 h, lysinate) and the high Cma~ 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.
.
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Plasma level of S(+)-ibuprofen foc female test persons ater 200 mg - ' (oral) S(~)-ibuprofen (concentration in mg/l) . . _ Time A B
h (min.) geometric mean values -O 0,10 ~ 0,10- 0,'10) 0,10 t 0,10- 0,10~
0,08 ( 5)0,14 t 0,11- 0,18)0,1~ ~ 0,10- 0,10) 0,~66(~,36 t 0,~6- 3,30)1,q9 ( 0,~9- ~,21) 0,33 ~2~)12,18 ( ~,36-17,75), a,s~ ( 5,43-13,343 0,5 (30)15,66 (11,70-20,94)21,Z2 (19,33-23,31) 0,75(45)20,89 (19,28-22,63)18,49 (14,G6-23,33) 119,06 (17,27-21,03) l9,~D ~18,52-19,91) 1,517,16 (15,23-19,34) 13,78 (12,99-14,62) 2lZ,40 (1~,89-14,13) 9,12 ( 9,11-10,35) 45,7~ ~ 4,96- 6,70) 4,15 t 2,~5- 5,72 63,07 t 2,3~- 3,97) Z,g~ t 2,6~- 3,2~) ~1,52 t 1,23- ?,83) 1,25 ~ 0,98- l,SB) 100,~9 ( 0,~3- 1,08) 0,62 ( 0,4g- 0,7~) 120,39 ( 0,~8- 0,53) 0,27 ~ 0,22- 0,34) C D
0,10 ~ 0,1~- 0,10) ~,10 ~ 0,10- 0,1~) 0,08 ( 5)0,62 ~ 0,26- 1,4g)0,45 ( 0,21- 0,97) 0,156(10)7,28 t 4,23-12,55)3,54 t l,~S- 7,62 0,33 (20)26,6a ~22,69-31,36j15,19 (10,70-21,57 0,5 (30)27,19 (2~,17-30,60)17,26 (13,00-22,~1~
0,75(45)21,53 tl9,10-~4,48)19,08 tl6,69-21,~0) 116,23 t94,42~18,27) 14,01 tll,61-16,90) 1,5~1,69 tlO,00-13,66) g,36 ~ ~,00-10,95) 27,93 ~ 7,09- 8,88) 6,09 ~ 4,88- 7,6~) 43,92 t 2,67- 3,4~) 2,~9 ( 2,0a~ ~,98) 61,29 ( 1,16- 1,44~ 0,~8 ~ 0,75- 1,03) 8 -0,67 1 0!62- 0,73) 0,53 ~ 0,4~- 0,64) ~0 Og28 ~ 0,24- 0,33~ 0,23 ~ 0,17- O,~O) 12 ~,13 1 0,11- 0,153 0,14 ~ 0,11- 0,17) ., _ .
, ~
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' 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 n 6 plasma - x 24.1 value~mg/1) S 3.45 min 19.5 max 28.8 P
Time of max n 6 plasma value x 44,2 (min) ~ 27,3 min 20 max 4 P
AUC n 6 (Traps~ium) x 69,55 (mg~lxlZh) S 15,9 min 44,73 max g5,7s P
:
: .
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,: ' ' ~ ' `
2 ~ J
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 ~ No contraceptives n = 6 n = 6 N = 12 O min 3,70 4,76 3,95 5 min 3,63 ~,73 3,88 lo min 3,21 4,40 3,39 20 min 2,52 3,20 2,a6 30 m~n 2,15 2,88 2,33 45 min 1,90 1,27 1,53 60 min 1,18 0,55 0,87 90 min 0,55 0,28 0,39 2 h 0,35 0,18 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 -h 1,02 Og63 o,a3 Group A: Non-smoker/no contraceptive taken Group B: Smoker/no contraceptive taken . ~; .
' Table 5 Pharmacokinetic parameters af~er administration of a single oral dose of 150 mg (+)(S)-ibuprofen (I) and as D-lysinate S(+)-ibuprofen free acid Mean + SD tablet Lysinate max'h 2,0 + U,20,33 ~ 0,20 Cmax,~g~ml 10,1 + 4~723,8 ~ 5,2 ~UC, ~gtml ~ h ~4,5 + 10,557,0 + 10,2 tlag' h 0,5 + 0,10,1 + 0,02 tl~ h 2,2 + 0,3 1,5 ~ 0,3 Ae, free 1 ~ of do~e 0,6 ~ 0,2 0,6 + 0,5 Ae con~. I 8,0 t 2,9 9,3 + ~,4 , ~ ,
. .
;,1 P ~
_s Com~lexes containinq S~+) Phenvl alkane acids and a-amino acids The present invention relates to hydrogen-bridge-bound complexes having a stoichiometrv of 1:1, comprising S(+)-phenyl alkane acids and basic a-amino acids.
Compounds o S(-)-phenyl alkane acids and a-amino acids are already known. However, they are not the specific comple~es according to the inventlon but salts.
Lvsinate salts, both racemic (D, ~) or onlv L salts of basic a-amino acids, have been described inter alia bv Bru~zese et al., US patent specification ~,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 phaxmaceutical forms described by Bruzzese et al. and consisting of S(+)-ibuprofen and (D, L)-lvsine or (R, S)-ibuprofen with (D, L) or L( )-lvsine, as salts, i.e. consisting of an anion and cation.
Specification as laid open to inspection DE 29 224~1, ~1, describes pharmaceutical preparations of ibuprofen and S(s)-ibuprofen with a low neutral or acidic a-amino acid which are added to an amount of up to ~0 ~ bv weight to the active substance ibuprofen (S-ibuprofen). The a-amino acld 30/ amount added may even be up to 60 % (g/g) if acidic or neutral amino acids are involved. No particulars are yiven on the weight ratios for basic a-amino acids nor on their stereo-onemistr~f, ~.~ater solubilicy, stability and pharmacokinetic behaviour.
Publication DE 3814887, Cl (1988), does not describe either salts or comple~es with D, L or D and L a-amino acids, or , "-, ' : , ;-. ~' ~, , ~.3~
...
with basic a-amino acids; only a racemate separation with the aid of threo-l-p-nitrophenyl-2-aminoProPane-1,3-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 ?roble~ is sol~ed according to the inventio-n b~
hvdrogen-bridge-bound complexes having a stoichiometrv of 1:1 comprisins S(-)-pnen~l alkane acids and basic a-amino acids in ~hich the complex bond is based on carboxvlate-carboxyl interactions ~ith a proton s~ ch of the form Rl-COOH.... OOC-R2 Rl-C00 ....... HOOC-R2 ~-here Rl-C00.I denotes the S(-)-phenvl alkane acids and R2-COOH the basic a-amino acids and the pKa values relating to the carboxyl group of the S(+)-phenyl alXane acids lie in the range of 3.5 to 3.g and the pKa values relating to the carboxyl group of the basic ~-amino acids lie in the range, of 1.9 - 2.9.
Preferably, the pKa values relating to the carboxvl group of the basic ~-amino acids lie in the range of 1.9 - 2.2.
., "-. , - , ~
~ .
.
. _3 _ Preferably, as S(~)-phenyl alkan0 acids hereln S(+~-lbuprofen or S(~)-naproxen shall be unders~ood and are used.
Preferably as S(~)-phenyl alcane acids herein the subst~nces as detailed below shall be understood and are used. These substances comprise the following structure:
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, ~-C4 alkyls, benzyl, hydroxy, Cl-Cz 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- hloro-phenyl, 4-difluoro-metho~y-phenyl, 6-hydroxy-2-naphthyl, and 5-bromo-6-hydroxy-2-naphthyl.
- 3~ )J
. .
Preferably, the D-form of the basic a-amino acids is used.
Preferably, the a-amino acids have the following structure:
Z-A-C~C ~
¦ ~ OH
.. . . . .. . . .
, , with X = NH2, NHCH3, NHC2H5, C1-C6 alkanyl amino z = H, OH, NH2 A = a bond or an alkylene chain which contains 1 - 10 carbon atoms and if required an amino group of 1 - 6 hydroxyl groups.
Preferably, as basic D-a-amino acids D-lysine, D-arginine, D-histidine or D-ornithine are used.
Preferably, the comple~ according to the invention contains valine, leucine, isoleucine, asparaginic acid, glutamine acid, asparagine, glutamine, phenylalanine, serine, threonine or hydroxylysine.
According to the invention the comple~es 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 (20C) a buffered aqueous solution, for example a 0.01 M - 0.001 M-K2HP04/KH2P04 buffer pH 6.0-7.5 (20C) is prepared and into it an 2S equivalent amount S(+)-phenyl alkane acid is introduced with constant stirring;
b3 the solution is heated with constant stirring to 40C
(water bath) until a clear transparent solution is obtained (normally after 20 minutes) and all the 3~ S(~)-phenyl alkane acid has gone into solution;
c1 thereafter the pH of the solution is adjusted to pH
5.~ - 6.0 by addition o~ diluted phosphoric acid (H3P04) (20C1 and then the equivalent (corresponding) amount of the a-amino acid is introduced with constant stirring, ensuring that the neutral ~-amino acids are introduced and not the hydrochloric acid ~HC1)-a~amino - , ~ ., : :, :. " ~, . , : -- - . - ~ : , .
1 acids!;
d) the complex formation is terminated after 20 minutes whereupon after cooling to 0 - 4C the complexes precipitate in crystalline for~ and can be separated from the mother liquor via a sintered glass funnel or glass filter (lG4);
e) alternatively to method step d) the clear solution can be reduced in a rotary evaporator (water bath temperature 25 - 30C) in the water jet vacuum to half the volume, whereupon a colourless (amorphous~ deposit forms which is filtered off via a lG~ glass filter and can be recrystallized from water/ethanol (70/30 V/V) or from ethyl acetate (lO0 %).
The substances according to the invention do not represent a salt formation between an acidic group (carbo~yl 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-carboxvl interactions, the two carboxyl radicals of the a-amino acid and for e.Yample the ibuprofen sharing a proton. This means that the complex is formed in accordance with the ~-ray structure analvsis bv a hydrogen bridge Wl thout any participation of the a-amino ~ group or other basic group (guanido, ~ -amino group) being observed (Fig. l). The complexes of S(+)-ibuprofen and D(-)-lysine or of S(+)-ibuprofen and L(+)-lysine crystallize in the chiral space group P2l2l2l as l:l complexes with four molecules per unit cell. ~ithin 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 (H20) because only the pKa values of the a-amino acid with regard to the carboxyl group, i.e. pKa = 2.18 - l.92, and the .
phenyl alkane acids, i.e. pKa = 3.5 - 3.9, are decisive.
The pKa values of the a-amino group of the ~-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 contrary a "proton switch" of the form R.-COOH...-OOC-R2 R1-COO- ...HOOC-R2 and therefore the "complex" appears neutral in solution without influencing the water solubilitv of these complexes, as is for example the case with alkaline and alkaline earth salts of phenyl alkane acids, in particular ibuprofen, since they are soluble and dissociated only above pH > 7Ø
The dissociation of these alkaline or alkaline earth salts also disadvantageously affects the resorbability and consequently the therapeutic advantages (for e~ample no precipitation of the ibuprofen in the stomach, resorption in the gastro-intestinal region bv 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 ~-amino group i9 not complexly bound because no N-H stretch vibrations are present, although non-hydrogen-bridge-bound carbonyl groups are present at 1680 - 1700 cm 1. 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 ,., .,, .,.,. ; ~ . . . .. . .
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 anti-inflammatory, 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 au~iliary substances, in which the active substance comple~ consists of S(+)-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 anti-inflammatory, antipyretic, antimicrobial and analgesic effect, containing an active substance complex comprising an ibuprofen or napro~en and basic a-amino acids and possibly additionally usual physiologically compatible auxiliary substances, in which the active substance comple~
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 doses for a topical administration of the comple~ lies in the range of 10 - 200 mg daily.
, . , "
r~~ 93~
1 Hereina~ter, 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 unitarv 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 a~ueous or oily suspensions. Tablets may for example be prepared by 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 50 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 admini~tration include aqueous solutions containing the .
,:
~ ~3 ~J~
, . . . ~ .
active pharmaceutical compound in the presence of a non-toxic 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.
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 e~ample 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 matri~ 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 ~ith 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.
::
:.' ' ' `: ~ '' , ` ' ~' , -3,~ '~J ~J ~.
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 e~ample colloidal solutions or particulate suspensions of the order of magnitude of O.l - l ~m (colloid mill).
If desired, in accordance with this invention compositlons may also be prepared with other compatible pharmaceutical active suhstances.
These comple~es according to the invention have anti-inflammatory, 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 relieYing pain, for example headache, dysmenorrhea, postoperative pain, postpartum pain and pain related to influenza and colds.
Accordin~ly, the invention describes in particular another aspect of the treatment of pain or inflammatory fever after ~ `
'' - ' ' '~ ' ' ' . ~ .
. .
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 doqe both for oral and parenteral adminstrations of S(~)-ibuprofen comple~ is in the range of 50 to 1200 mg daily, normally batween 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 comple~ 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 Pr~æ ration of the complex accordin~ to the invention.
146.2 mg ~1 mol) R~+)-lysine are dissolved while stirring in 2 l 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 lyophili~ed. The solid mass obtained is ground, sifted and subsequently dried for 3 hours at 105C. Yield ~98 - 99% of theoretical), melting point 173.5 - 176.0C.
Exa Ele 2:
Pre~aration of a table~ according_ o ~he invention-Composition: 1 tablet contain~
t ~
active constituents .
S(+)-ibuprofen-(R)-lysine 171 mg = S(+)-ibuprofen 100 mg non-a_tive constituents.~
gelatin 3 mg crosslinked sodium carboxymethyl cellulose 13 mg magnesium stearate 3 mg weight per tablet 190 mg Preparatlon:
The gelatin is dissolved to 10 % in purified water whilst heating (max. 40C) and slowly added to the active substance in the mixer with low mixing power. The granulate obtained is dried in ths fluidized bed at about ~0C 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.
Exam~le 3-Use example Maximum plasma levels of S(+j-ibuprofen (Cmax in ug/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 Sl+)-ibuprofen and 150 mg S(+)-ibuprofen complex accor~ing to this inYention in the form of an amorphous powder (see Table below) ~
-l Table The powder was enclosed in a gelatin capsule and the following results were obtained:
tmax (h ) CmaX (~g/ml) St+)-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 German application DE 40 15 794.6. 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 trans-parent liquid;
c) determination of the refractive index;
d) setting the desired concentration of the pharma-ceutical active substances whilst observing the molar fraction, which at 37C must lie between 0.001 and 0.67;
e) introduction of the pharmaceutical active sub-stance 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 differeDtial refractive index increment [(~n/~c)T~p=cOn9tant] for determining the monomolecular solution and/or h) checking the native conformation and the mono-~J ~ ~3~J ~ ~
~, . ~
1 molecularity of the pharmaceutical active sub-stance in the solution by measuring the molar e~tinction 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,V=constant] for controllin~ 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 temp-erature until the solution has solidified.
The comple~es described according to the invention and being o a non-salt nature, consisting for ex~ ple of S(+)- -ibuprofen and a basic D(~ -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), 13~ 263; Paradies, H.H., J. Phys, Chem. 9O, 5956, (1986). By the change in the fluorescence of the ibuprofen and the ibuprofen-~-amino acid complexes the fast proton transfer was detected: kp =
1.7 x 1012 M 1 sec~1, which moreover is of the same order of magnitude for (R, S)-ibuprofen, kp = 2.0 x 1012 M~1 sec~1, S(+) or R(-)-ibuprofen kp - 2.3 x 1012 M-1 se -1, caused by the interactions of the carboxyl groups, which 1 also manifest themselves again in the crystal structures J (Fig. 2). Salts consisting of cation and anion (ibuprofen , .
, ' ' ' ' ' , .
'' .' ' ,~
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 e~periments on 24 test persons.
Pharmacokinetics of S(~)-ibuprofen-D-~-)-lvsinate The plasma level values of S(~)-ibuprofen measured in 2~
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). ~s can be seen, in all other cases typical plasma level ~ariations occurred, as are to be expected after taking a drug. ~ rapid resorption phase, reaching a maximum value, was followed by a rapid drop in the plasma level, apparent in the semilogarithmic represer.tation 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.~5 mg/l ~ 12 h as mean value for all the female test persons. The maximum plasma level Cmax is 2G.47 mg/l 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 tTl/2~) for the total mean value curve is 107.4 minutes (1.79 hours). In tahle 3 all the important pharmacokinetic characteristics for all the test persons and the particular 3 subgroups are summarized.
Pha_macod ~amics _ S(+)_ibuprofen_~ _ sinate In a monocentering study the pharmacodynamics were invsstigated for 24 female test persons for primary dysmenorrhea. The mean values of all the female test , . 17 1 /persons ~re 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.
.~s apparent frcm Fig. a, the me~n pain int ~sitv at the time zero was ~.7; the analgesic efflcacy s~ rted ~it:~ln 5 minutes and within the rirst ~5 mi~utes theYe ~as a :~
reduc~ion to a value of 1.65 on the averase. T~e maY-mum analsesic effec' ~as achieved af.er t~o houYs ~ith a value of 0.36. Thereafter, the pain intensitv: asain slowly increased to a value of 0.83 a~ter 6 hours. Figure a shows the pain intensity curve of the female tes. persons.
~ _ . .
Na undesired drug effects occurred in any or the female participants in the study. Likewise, all the chemical laboratorv parameters and the results of the medical subsequent e~amination showed ~o patholosical findings. It may be concluded therefrom that the taking onc~ or several times of St+)-lbupro~en D-1ysiDate ~in this studv up to 3 ~ dailv 200 mg for 3 davs) did not lead ~o any undesired drug effects except for the pseudoallergic reaction observed in the one test person The rela~ive oral bioa~ailabilitV of S(;)-ibuprofen-D
.
, ' ~ ~ ~3 ~!3 1 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/l x 12 h was calculated. The maximum level was 26.g7 mg/l 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 (tmaX 0.6 + 0.3 h, lysinate) and the high Cma~ 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.
.
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Table 2 ~ ~ ~ r~ ~ ~J fJ
Plasma level of S(+)-ibuprofen foc female test persons ater 200 mg - ' (oral) S(~)-ibuprofen (concentration in mg/l) . . _ Time A B
h (min.) geometric mean values -O 0,10 ~ 0,10- 0,'10) 0,10 t 0,10- 0,10~
0,08 ( 5)0,14 t 0,11- 0,18)0,1~ ~ 0,10- 0,10) 0,~66(~,36 t 0,~6- 3,30)1,q9 ( 0,~9- ~,21) 0,33 ~2~)12,18 ( ~,36-17,75), a,s~ ( 5,43-13,343 0,5 (30)15,66 (11,70-20,94)21,Z2 (19,33-23,31) 0,75(45)20,89 (19,28-22,63)18,49 (14,G6-23,33) 119,06 (17,27-21,03) l9,~D ~18,52-19,91) 1,517,16 (15,23-19,34) 13,78 (12,99-14,62) 2lZ,40 (1~,89-14,13) 9,12 ( 9,11-10,35) 45,7~ ~ 4,96- 6,70) 4,15 t 2,~5- 5,72 63,07 t 2,3~- 3,97) Z,g~ t 2,6~- 3,2~) ~1,52 t 1,23- ?,83) 1,25 ~ 0,98- l,SB) 100,~9 ( 0,~3- 1,08) 0,62 ( 0,4g- 0,7~) 120,39 ( 0,~8- 0,53) 0,27 ~ 0,22- 0,34) C D
0,10 ~ 0,1~- 0,10) ~,10 ~ 0,10- 0,1~) 0,08 ( 5)0,62 ~ 0,26- 1,4g)0,45 ( 0,21- 0,97) 0,156(10)7,28 t 4,23-12,55)3,54 t l,~S- 7,62 0,33 (20)26,6a ~22,69-31,36j15,19 (10,70-21,57 0,5 (30)27,19 (2~,17-30,60)17,26 (13,00-22,~1~
0,75(45)21,53 tl9,10-~4,48)19,08 tl6,69-21,~0) 116,23 t94,42~18,27) 14,01 tll,61-16,90) 1,5~1,69 tlO,00-13,66) g,36 ~ ~,00-10,95) 27,93 ~ 7,09- 8,88) 6,09 ~ 4,88- 7,6~) 43,92 t 2,67- 3,4~) 2,~9 ( 2,0a~ ~,98) 61,29 ( 1,16- 1,44~ 0,~8 ~ 0,75- 1,03) 8 -0,67 1 0!62- 0,73) 0,53 ~ 0,4~- 0,64) ~0 Og28 ~ 0,24- 0,33~ 0,23 ~ 0,17- O,~O) 12 ~,13 1 0,11- 0,153 0,14 ~ 0,11- 0,17) ., _ .
, ~
i ~, ":, `, f`~ ?,~ ~ t-~
' 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 n 6 plasma - x 24.1 value~mg/1) S 3.45 min 19.5 max 28.8 P
Time of max n 6 plasma value x 44,2 (min) ~ 27,3 min 20 max 4 P
AUC n 6 (Traps~ium) x 69,55 (mg~lxlZh) S 15,9 min 44,73 max g5,7s P
:
: .
,, ~ - ':
,: ' ' ~ ' `
2 ~ J
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 ~ No contraceptives n = 6 n = 6 N = 12 O min 3,70 4,76 3,95 5 min 3,63 ~,73 3,88 lo min 3,21 4,40 3,39 20 min 2,52 3,20 2,a6 30 m~n 2,15 2,88 2,33 45 min 1,90 1,27 1,53 60 min 1,18 0,55 0,87 90 min 0,55 0,28 0,39 2 h 0,35 0,18 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 -h 1,02 Og63 o,a3 Group A: Non-smoker/no contraceptive taken Group B: Smoker/no contraceptive taken . ~; .
' Table 5 Pharmacokinetic parameters af~er administration of a single oral dose of 150 mg (+)(S)-ibuprofen (I) and as D-lysinate S(+)-ibuprofen free acid Mean + SD tablet Lysinate max'h 2,0 + U,20,33 ~ 0,20 Cmax,~g~ml 10,1 + 4~723,8 ~ 5,2 ~UC, ~gtml ~ h ~4,5 + 10,557,0 + 10,2 tlag' h 0,5 + 0,10,1 + 0,02 tl~ h 2,2 + 0,3 1,5 ~ 0,3 Ae, free 1 ~ of do~e 0,6 ~ 0,2 0,6 + 0,5 Ae con~. I 8,0 t 2,9 9,3 + ~,4 , ~ ,
Claims (16)
1. Hydrogen-bridge-bound complexes having a stoichiometry of 1:1 comprising S(+)-phenyl alkane acids and basic .alpha.-amino acids in which the complex bond is based on carboxylate-carboxyl interactions with a proton switch of the form R1-COOH...-OOC-R2 ? R1-COO- ... HOOC-R2 where R1-COOH denotes the S(+)-phenyl alkane acids and R2-COOH the basic .alpha.-amino acids and the pKa values relating to the carboxyl group of the S(+)-phenyl alkane acids lie in the range of 3.5 - 3.9 and the pKa values relating to the carboxyl group of the basic .alpha.-amino acids lie in the range of 1.9 - 2.9.
2. Complexes according to claim 1, characterized in that pKa values relating to the carboxyl group of the basic .alpha.-amino acids lie in the range of 1.9 - 2.2.
3. Complexes according to claim 1 or 2, characterized in that as S(+)-phenyl alkane acids S(+)-ibuprofen or S(+)-naproxen are used.
4. Complexes according to one or more of the preceding claims, characterized in that the D form of the basic .alpha.-amino acids is used.
5. Complexes according to one or more of the preceding claims, characterized in that the .alpha.-amino acids have the following structure:
where X NH2, NHCH3, NHC2H5, C1-C6 alkanyl amino Z = H, OH, NH2 A = a bond or an alkylene chain which contains 1 - 10 carbon atoms and if required an amino group or 1 - 6 hydroxyl groups.
where X NH2, NHCH3, NHC2H5, C1-C6 alkanyl amino Z = H, OH, NH2 A = 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 one or more of the preceding claims, characterized in that as basic D-.alpha.-amino acids D-lysine, D-arginine, D-hystidine or D-ornithine are used.
7. Complexes according to one or more of the preceding claims, characterized in that the complex contains valine, leucine, isoleucine, asparaginic acid, glutamine acid, asparagine, glutamine, phenylalanine, serine, threonine or hydroxylysine.
8. Method for the preparation of the complexes according to one or more 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 - 7.5 (20°C) a buffered aqueous solution, for example a 0.01 M -0.001 M-K2HPO4/KH2 PO4 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 (H2PO4) (20°C) and then the equivalent (corresponding) amount of the .alpha.-amino acid is introduced with constant stirring, ensuring that the neutral .alpha.-amino acids are introduced and not the hydrochloric acid (HCl)-.alpha.-amino 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 %).
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-K2HPO4/KH2 PO4 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 (H2PO4) (20°C) and then the equivalent (corresponding) amount of the .alpha.-amino acid is introduced with constant stirring, ensuring that the neutral .alpha.-amino acids are introduced and not the hydrochloric acid (HCl)-.alpha.-amino 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 %).
9. Pharmaceutical preparation containing one or more complexes according to one or more of the preceding claims and possibly optionally additionally physiologically compatible extenders or carriers.
10. Pharmaceutical preparation according to claim 9 on the basis of phenyl alkane acids having anti-inflammatory, antipyretic, antimicrobial and analgesic effect, containing an active substance complex comprising a phenyl alkane acid and an .alpha.-amino acid and possibly additionally usual physiologically compatible auxiliary substances, characterized in that the active substance complex consists of S(+)-phenyl alkane acids and basic .alpha.-amino acids, preferably D-.alpha.-amino acids.
11. Pharmaceutical preparation according to claim 9 or 10 on the basis of ibuprofen or naproxen with anti-inflammatory, antipyretic, antimicrobial and analgesic effect, containing an active substance complex comprising an ibuprofen or naproxen and basic .alpha.-amino acids and possibly additionally usual physiologically compatible auxiliary substances, characterized in that the active substance complex consists of S(+)-ibuprofen or S(+)-naproxen and a basic .alpha.-amino acid and represents an amount by weight of 0.1 to 90 (w/w) of the composition.
12. Pharmaceutical composition according to one or more of claims 9 to 11, characterized in that it contains 50 to 800 mg, preferably 100 to 600 mg, in particular 100 to 300 mg S(+)-ibuprofen or S(+)-naproxen.
13. Pharmaceutical composition according to one or more of claims 9 to 12, consisting of one or more active sub-stance complexes and a water-soluble carrier, in particular polyethylene glycol, which solidifies in the range between 20 and 80°C and is water-soluble, characterized in that it is an isotropic solution, 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 iso-tropic at body temperature, e) the isotropic solution, consisting of carrier and active substance, solidifies at room temperature, f) the solidified solution is crystalline or non-crystalline 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 freezing point reduction h) the dissolved active substance within the polymer electrolyte has a temperature-dependent diffusion coefficient and a temperature-dependent specific conductivity.
14. Pharmaceutical preparation according to one or more of claims 9 to 13, characterized in that 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 doses for a topical administration of the complex lies in the range of 10 - 200 mg daily.
15. Complexes according to one or more of the preceding claims, characterized in that the S(+) phenyl alcane acids have a structure of the form in which R is lower alkyl, Ar is a monocyclic, polycyclic or ortho-condensed polycyclic aromatic group having up to twelve carbons in the aromatic system, as phenyl, diphenyl, and naphthyl, whereby the substituents of these aromatic groups comprise one or more halogen atoms, C1-C4-alkyls, benzyl, hydroxy, C1-C2 alkoxy, phenoxy and benzoyl groups.
16. Complexes according to claim 15, characterized in that the 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.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4036458 | 1990-11-15 | ||
DEP4036458.5 | 1990-11-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2055683A1 true CA2055683A1 (en) | 1992-05-16 |
Family
ID=6418339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002055683A Abandoned CA2055683A1 (en) | 1990-11-15 | 1991-11-15 | Complexes containing s(+) phenyl alkane acids and .alpha.-amino acids |
Country Status (16)
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---|---|
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) | DE4137675A1 (en) |
HU (1) | HUT59656A (en) |
MX (1) | MX9102088A (en) |
NZ (1) | NZ240617A (en) |
PL (1) | PL292413A1 (en) |
ZA (1) | ZA919077B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5510385A (en) * | 1993-06-21 | 1996-04-23 | Zambon Group S.P.A. | Pharmaceutical compositions containing the salts of S(+)-2-(4-isobutylphenyl)propionic acid with basic aminoacids |
US11642329B2 (en) | 2005-11-09 | 2023-05-09 | Novartis Pharmaceuticals Corporation | Amorphous solid form of compounds containing S—N-valeryl-N- {[2′-( 1 H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
EP0577725A4 (en) * | 1991-03-29 | 1996-04-17 | Univ Florida | Targeted drug delivery via mixed phosphate derivatives |
ATE151740T1 (en) * | 1992-12-02 | 1997-05-15 | Knoll Ag | METHOD FOR PRODUCING ESSENTIAL ENANTIOMERS OF PHENYLPROPIONIC ACIDS |
IT1272149B (en) * | 1993-03-26 | 1997-06-11 | Zambon Spa | PHARMECEUTICAL COMPOSITION WITH ANALGESIC ACTIVITY |
DE69918977T2 (en) * | 1998-05-15 | 2005-07-28 | Warner-Lambert Co. Llc | AMINO ACID-STABILIZED GABAPENTIN AND PREGABALINE PREPARATIONS AND METHOD FOR THE PRODUCTION THEREOF |
CN101455653B (en) * | 2007-12-13 | 2013-03-06 | 天津医科大学 | Arginine ibuprofen oral disintegrating tablets and preparation method thereof |
CN116621689A (en) * | 2023-04-24 | 2023-08-22 | 山东省药学科学院 | L-lysine-biphenyl acetate, and preparation method and application thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1497044A (en) * | 1974-03-07 | 1978-01-05 | Prodotti Antibiotici Spa | Salts of phenyl-alkanoic acids |
ATE50493T1 (en) * | 1986-11-14 | 1990-03-15 | Puetter Medice Chem Pharm | MEDICATION 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 CA CA002055683A patent/CA2055683A1/en not_active Abandoned
- 1991-11-15 NZ NZ240617A patent/NZ240617A/en unknown
- 1991-11-15 DE DE4137675A patent/DE4137675A1/en not_active Withdrawn
- 1991-11-15 KR KR1019910020368A patent/KR920009774A/en not_active Withdrawn
- 1991-11-15 CS CS913464A patent/CS346491A3/en unknown
- 1991-11-15 PL PL29241391A patent/PL292413A1/en unknown
- 1991-11-15 EP EP91119522A patent/EP0486045B1/en not_active Revoked
- 1991-11-15 JP JP3354099A patent/JPH0656737A/en active Pending
- 1991-11-15 CN CN91110739A patent/CN1061404A/en active Pending
- 1991-11-15 MX MX9102088A patent/MX9102088A/en unknown
- 1991-11-15 BG BG095490A patent/BG95490A/en unknown
- 1991-11-15 ZA ZA919077A patent/ZA919077B/en unknown
- 1991-11-15 AU AU87905/91A patent/AU8790591A/en not_active Abandoned
- 1991-11-15 DE DE59107790T patent/DE59107790D1/en not_active Revoked
- 1991-11-15 AT AT91119522T patent/ATE137733T1/en not_active IP Right Cessation
- 1991-11-18 BR BR919104996A patent/BR9104996A/en not_active Application Discontinuation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5510385A (en) * | 1993-06-21 | 1996-04-23 | Zambon Group S.P.A. | Pharmaceutical compositions containing the salts of S(+)-2-(4-isobutylphenyl)propionic acid with basic aminoacids |
US11642329B2 (en) | 2005-11-09 | 2023-05-09 | Novartis Pharmaceuticals Corporation | Amorphous solid form of compounds containing S—N-valeryl-N- {[2′-( 1 H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations |
Also Published As
Publication number | Publication date |
---|---|
EP0486045A2 (en) | 1992-05-20 |
CN1061404A (en) | 1992-05-27 |
BG95490A (en) | 1993-12-24 |
PL292413A1 (en) | 1993-01-25 |
DE59107790D1 (en) | 1996-06-13 |
EP0486045B1 (en) | 1996-05-08 |
BR9104996A (en) | 1992-06-23 |
EP0486045A3 (en) | 1992-12-09 |
JPH0656737A (en) | 1994-03-01 |
ATE137733T1 (en) | 1996-05-15 |
ZA919077B (en) | 1992-08-26 |
MX9102088A (en) | 1993-01-01 |
NZ240617A (en) | 1994-12-22 |
CS346491A3 (en) | 1992-06-17 |
DE4137675A1 (en) | 1992-05-21 |
AU8790591A (en) | 1992-05-21 |
KR920009774A (en) | 1992-06-25 |
HUT59656A (en) | 1992-06-29 |
HU913571D0 (en) | 1992-01-28 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |