CH694451A5 - Pharmaceutical preparations containing hydrosoluble ketoprofen salts - Google Patents

Pharmaceutical preparations containing hydrosoluble ketoprofen salts Download PDF

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CH694451A5
CH694451A5 CH00618/99A CH61899A CH694451A5 CH 694451 A5 CH694451 A5 CH 694451A5 CH 00618/99 A CH00618/99 A CH 00618/99A CH 61899 A CH61899 A CH 61899A CH 694451 A5 CH694451 A5 CH 694451A5
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ketoprofen
pharmaceutical preparations
glucosamine
salt
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CH00618/99A
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Paolo Luca Maria Giorgetti
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Errekappa Euroterapici S P A
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Priority to CH00618/99A priority Critical patent/CH694451A5/en
Priority to JP55142299A priority patent/JP2002510336A/en
Priority to CN99800474A priority patent/CN1263464A/en
Priority to EP99910606A priority patent/EP1024808A1/en
Priority to PCT/IB1999/000626 priority patent/WO1999052528A1/en
Priority to US09/445,672 priority patent/US6291527B1/en
Priority to CA002293605A priority patent/CA2293605A1/en
Priority to KR1019997011727A priority patent/KR20010013712A/en
Publication of CH694451A5 publication Critical patent/CH694451A5/en

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars

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  • General Chemical & Material Sciences (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Pharmaceutical preparations containing hydrosoluble ketoprofen salts obtained by reaction of ketoprofen and glucosamine and/or proline and/or hydroxyproline are new. An independent claim is included for hydrosoluble salts contained in the pharmaceutical preparations characterized by the fact that they are obtained from ketoprofen and amino acids, in 0.8-1.2 times the equimolar quantities. ACTIVITY : Antiinflammatory; Analgesic. The results obtained for the carrageenan edema test in the rat indicate that ketoprofen glucosamine salt, administered orally at doses of 0.5, 1 and 2 mg/kg, possesses antiinflammatory activity. The anti-edematogenic effect of the test compound is dose-dependent. Ketoprofen glucosamine significantly inhibits the reaction process by 30%, 48% and 72% at oral doses of 0.5, 1 and 2 mg/kg, respectively.

Description

       

  



   L'invenzione si riferisce a preparazioni farmaceutiche contenenti sali idrosolubili ottenuti mediante reazione fra il ketoprofene e la glucosamina e/o la prolina e/o l'idrossiprolina, e al loro uso per le terapie antiinfiammatorie ed antalgiche, come caratterizzato nelle rivendicazioni. 



   L'invenzione si basa sul brevetto CH 692 939 della stessa richiedente. 



   In particolare l'invenzione si riferisce a prodotti come menzionati negli esempi 1 34 e ai metodi di sintesi dei sali descritti nel brevetto menzionato, con l'aggiunta delle specificazioni seguenti. 1. Materiali e metodi 



   L'attività anti infiammatoria del ketoprofene sale di glucosammina e del ketoprofene sale di lisina, in paragone a quella del ketoprofene, è stata valutata nel ratto utilizzando il metodo dell'edema da carragenina e il metodo dell'edema da corpo estraneo (sponge). 1.1. Edema da carragenina nel ratto. 



   Per queste prove sono state utilizzati 80 ratti maschi di ceppo Wistar (Charles River, Calco, LC, Italia) del peso corporeo di 160 + 5 g. E stata seguita la metodica descritta da Winter e Coll. (1) che permette di valutare l'attività dei farmaci ella fase acuta del processo flogistico essenzialmente legato ad un aumento della permeabilità vascolare (edema) e a prevalente infiltrazione di granulociti polimorfonucleati nell'essudato. 



   In particolare, 100  mu l di carragenina sciolta all'1% in soluzione fisiologica sterile sono stati iniettati nell'aponeurosi plantare posteriore di animali digiuni (acqua ad libitum) dalla sera precedente l'esperimento. Allo scopo di ottenere una maggiore uniformità nello sviluppo dell'edema, gli animali sono stati trattati per via orale con 5 ml di soluzione fisiologica 2 ore prima dell'esperimento. 



   L'evoluzione dell'edema indotto dalla somministrazione di carragenina è stata valutata con il metodo pletismografico utilizzando apparecchiatura (plethysmometer, mod. 7150) della ditta U. Basile (Comerio, VA, Italia). Il rilievo del volume della zampa è stato eseguito immediatamente dopo l'iniezione dell'agente flogogeno (tempo 0) e ad ogni ora sino alla 6<a> ora. Gli animali, suddivisi con metodo random in 8 gruppi sperimentali (10 animali per gruppo), sono stati trattati per via orale (tramite sonda    gastrica) con il ketoprofene sale di glucosammina, il ketoprofene sale di lisina e con il ketoprofene, 30 minuti prima della carragenina secondo il seguente protocollo sperimentale: 



   



   Controlli (Sol. fisiol., 1 ml/kg); n 10 



   Ketoprofene sale di glucosammina (0.5 mg/kg); n=10 



   Ketoprofene sale di glucosammina (1 mg/kg); n=10 



   Ketoprofene sale di glucosammina (2 mg/kg); n-10 



   Ketoprofene sale di lisina (0.5 mg/kg); n-10 



   Ketoprofene sale di lisina (1 mg/kg); n-10 



   Ketoprofene sale di lisina (2 mg/kg); n-10 



   Keloprofene (10 mg/kg); n-10 1.2. Edema da corpo estraneo: test delle "sponge" nel ratto. 



   Poiché il ketoprofene, come tutti i derivati dell'acido propionico, deve gran parte della sua attività antiflogistica all'inibizione dell'enzima cicloossigenasi e quindi al blocco della cascata ossidativa dell'acido arachidonico, il modello sperimentale nel ratto delle "sponge" descritto da Higgs e Coll. (2) si presta molto bene a valutare il fenomeno vasculoessudativo e la neoformazione di prostaglandine primarie ad esso correlato. 



   Per queste prove sono stati utilizzati 100 ratti maschi di ceppo CD (Charles River, Calco, LC, Italia) del peso corporeo di 180  +/- 8 g. Gli animali hanno osservato un periodo di 12 ore di digiuno (acqua ad libitum) prima dell'accesso all'esperimento. 



   La reazione infiammatoria con formazione di essudato è stata indotta utilizzando spugne di poliestere sterilizzate (4  x  1.5  x  0.5 cm) imbevute in carragenina disciolta al 2% in soluzione fisiologica sterile. Due spugne    per ogni ratto sono state impiantate sottocute (zona dorsale) agli animali in leggera anestesia eterea dopo un'accurata depilazione. Gli animali, suddivisi con metodo random in 10 gruppi sperimentali (10 animali per gruppo), sono stati trattati per via orale (tramite sonda gastrica) con il ketoprofene sale di giucosammina, il ketoprofene sale di lisina e con il ketoprofene, immediatamente dopo l'impianto delle spugne (tempo 0) secondo il seguente protocollo sperimentale: 



   



   Controlli (Sol. fisiol., 1 ml/kg); n 10 



   Ketoprofene sale di glucosammina (0.5 mg/kg); n-10 



   Ketoprofene sale di glucusammina (1 mg/kg)); n=10 



   Ketoprofene sale di glucosammina (2 mg/kg); n-10 



   Ketoprofene sale di glucosammina (4 mg/kg); n-10 



   Ketoprofene sale di lisina (0.5 mg/kg); n-10 



   Ketoprofene sale di lisina (1 mg/kg); n-10 



   Ketoprofene sale di lisina (2 mg/kg); n-10 



   Ketoprofene sale di lisina (4 mg/kg); n-10 



   Ketoprofene (10 mg/kg): n-10 



   



   L'espianto delle spugne è stato eseguito 8 ore più tardi dopo aver sacrificato gli animali mediante "eutanasia eterea". 



   Le spugne rimosse, sono state immediatamente immerse in provettoni di polietilene (50 ml) contenenti 10 ml di soluzione fisiologica eparinizzata. Successivamente tali provettoni sono stati sottoposti a centrifugazione (1000 g; 15 min) e dopo aver tolto dai medesimi le spugne, il volume del fluido rimasto è stato accuratamente misurato. Sempre seguendo la metodica di Higgs e Coll. (2), i lipidi acidi presenti nel fluido sono stali estratti in cloroformio previa diluizione in etanolo e acidificazione a pH 3. Dopo completa evaporazione del cloroformio, il residuo secco rimasto    è stato ripreso in soluzione fisiologica ed utilizzato per il dosaggio immunoenzimatico della prostaglandina E 2 (PGE 2 ). 1.3. Sostanze. 



   Per questi esperimenti sono state utilizzate le seguenti sostanze: ketoprofene sale di glucosammina e ketoprofene sale di lisina (forniti della ditta ...); ketoprofene e carragenina tipo IV (Sigma-Aldrich, MI, Italia); kit per il dosaggio immunoenzimatico della PGE 2  (Amersham, MI, Italia). Tutti gli altri reagenti utilizzati per queste prove sono stati acquistati dalla Merck-Bracco (MI, Italia). 1.4. Statistica. 



   I dati ottenuti in questi esperimenti sono stati processati mediante l'analisi della varianza (ANOVA) e lo Student's "t" test per dati non appaiati considerando significative le differenze con p<0.05. La comparazione multipla tra i diversi gruppi sperimentali è stata effettuata utilizzando il test statistico di Tukey-Kramer. L'area sotto la curva (AUC) è stata calcolata con il metodo dei trapezoidi utilizzando un programma computerizzato (Microcal Origin, versione 3.5). 2.  Risultati 2.1. Edema da carragenina nel ratto. 



   I risultati ottenuti da questi esperimenti indicano che il ketoprofene sale di glucosammina, somministrato per via orale nel ratto alla dose di 0.5, 1 e 2 mg/kg, è provvisto di attività antiinfiammatoria. L'effetto antiedemigeno del composto in esame è in misura proporzionale alla dose impiegata. Infatti, considerando i valori ottenuti misurando le aree sotto la curva (AUC), il ketoprofene sale di glucosammina inibisce in significativamente (p<0.001) del 30%, del 48% e del 72% il processo reattivo rispettivamente alla dose di 0.5, 1 e 2 mg/kg os (Fig. 1 e Tab. 1-2). 



   L'attività antiinfiammatoria osservata con il ketoprofene sale di glucosammina e del tutto paragonabile a quello ottenuto somministrando ai ratti il ketoprofene sale di lisina alla dose di 0.5, 1 e 2 mg/kg os. Infatti, i valori delle ED 50  dei due composti (estrapolate dai dati ottenuti con le AUC) sono risultate pari a 1.104 mg/kg os (lim. fìd. = 95%: 0.733-1.474) e 1.383 mg/kg os (lim. fid. = 95%: 1.198-1.567) rispettivamente per il ketoprofene sale di glucosammina e per il ketoprofene sale di lisina (Tab. 2 e Fig. 3). 



   Anche il ketoprofene in questo test (utilizzato come standard interno positivo) ha dato reperti di attività antiinfiammatoria. Infatti, tale composto somministrato ai ratti alla dose di 10 mg/kg os, inibisce (54.1%; p<0.001) il processo reattivo flogistico causato dall'iniezione di carragenina nell'aponeurosi plantare (Fig. 1-2 e Tab. 1-2). 2.2. Edema da corpo estranco: test delle "sponge" nel ratto. 



   I risultati ottenuti da queste prove, riportati in Tab. 3, indicano chiaramente che il ketoprofene sale di glucosammina controlla in misura    dose dipendente (0.5, 1, 2 e 4 mg/kg os) la risposta infiammatoria vasculo-essudativa nel ratto. Infatti, il ketoprofene sale di glucosammina è in grado di opporsi significativamente all'evoluzione del processo reattivo soprattutto in termini di minor formazione di essudato infiammatorio correlata ad una significatica inibizione dell'attività della PGE 2 in questi essudati (Tab. 3). 



   Anche il ketoprofene sale di lisina, somministrato agli animali alla dose di 0.5, 1, 2 e 4 mg/kg os ha dimostrato di ben controllare la risposta infiammatoria dell'ospite all'impianto sottocutaneo di un corpo estraneo (Tab. 3). 3. Bibliografia 



   1) Winter C.A. et al. Proc. Soc. Exp. Biol. Med. 1962; 111: 544. 



   2) Higgs G.A et al. In: Samuelsson B., Paoletti R. (eds). Advance in Prostaglandin and Thromboxane Research. New York: raven Press Vol. 1, pp. 105, 1976. 



   Tabella 1. Attività antiinfiammatoria del ketoprofene sale di glucosammina (KSG), del ketoprofene sale di lisina (KSL) e del ketoprofene (KETO) nel ratto: edema da carragenina. 



   <tb><TABLE> Columns = 7 <tb>Head Col 1: Trattamento (mg/kg os) <tb>Head Col 2: Andamento del volume della zampa (delta in ml) ai tempi: <tb>Head Col 3: I<a> ora <tb>Head Col 4: II<a> ora <tb>Head Col 5: III<a> ora <tb>Head Col 6: IV<a> ora <tb>Head Col 7: V<a> ora <tb>Head Col 8: VI<a> ora <tb><SEP> Controlli<SEP> 0.40  +/- 0.02<SEP> 0.71  +/-  0.02<SEP> 0.87  +/-  0.03<SEP> 0.93  +/-  0.03<SEP> 0.90  +/-  0.04<SEP> 0.84  +/-  0.04 <tb><SEP> KSG 0.5<SEP> 0.28 +/-  0.02<SEP> 0.51  +/-  0.03<SEP> 0.62  +/-  0.04<SEP> 0.65  +/- 0.04<SEP> 0.62  +/-  0.05<SEP> 0.56  +/-  0.05 <tb><SEP> KSG 1<SEP> 0.23  +/-  0.01<SEP> 0.39  +/-  0.02<SEP> 0.46  +/-  0.02<SEP> 0.48 +/-  0.02<SEP> 0.45  +/-  0.02<SEP> 0.39  +/-  0.03 <tb><SEP> KSG 2<SEP> 0.11  +/-  0.02<SEP> 0.20  +/-  0.02<SEP> 0.26  +/-  0.03<SEP> 0.28  +/-  0.03<SEP> 0.25  +/-  0.03<SEP> 0.16  +/-  0.02 <tb><SEP> KSL 0.5<SEP> 0.32  +/- 

   0.02<SEP> 0.53  +/-  0.03<SEP> 0.66  +/- 0.04<SEP> 0.70  +/-  0.03<SEP> 0.68  +/-  0.02<SEP> 0.64  +/-  0.03 <tb><SEP> KSL 1<SEP> 0.24  +/-  0.02<SEP> 0.43  +/-  0.03<SEP> 0.54  +/-  0.03<SEP> 0.59  +/-  0.03<SEP> 0.57  +/-  0.03<SEP> 0.49  +/-  0.03 <tb><SEP> KSL 2<SEP> 0.13  +/-  0.02<SEP> 0.23  +/-  0.02<SEP> 0.28  +/-  0.02<SEP> 0.29  +/-  0.02<SEP> 028  +/-  0.02<SEP> 0.23  +/-  0.03 <tb><SEP> Keto 10<SEP> 0.19  +/-  0.02<SEP> 0.33  +/-  0.03<SEP> 0.41  +/- 0.02<SEP> 0.42  +/-  0.02<SEP> 0.40  +/-  0.03<SEP> 0.37  +/-  0.03 <tb></TABLE> 



   I dati rappresentano la media  +/-  ESM di 10 ratti per gruppo. I composti sono stati somministrati per via orale 60 min prima dell'agente flogogeneo (carragenina 1%). Volume della zampa di base: 1.70  +/- 0.02 ml (n=80). Tabella 2. Aree sotto la curva (AUC) relative all'andamento nel tempo degli aumenti del volume della zampa riportati in Fig. 1 e 2 



   <tb><TABLE> Columns = 6 <tb>Head Col 1: Trattamento <tb>Head Col 2: Dose (mg/kg os) <tb>Head Col 3: n DEG ratti <tb>Head Col 4: Auc (media  +/-  ESM) <tb>Head Col 5: % inibizione vs controlli <tb>Head Col 6: ED 60  in mg/kg os (lim. fiduciali = 95%) <tb><SEP> Controlli<SEP>  - <SEP> 10<SEP> 4.23  +/-  0.26<SEP> - <SEP>  - <tb><SEP> KSG<SEP> 0.5<SEP> 10<SEP> 2.96  +/-  0.15<SEP> 30.0 <tb><SEP> KSG<SEP> 1<SEP> 10<SEP> 2.20  +/-  0.13<SEP> 48.0<SEP> 1.104 <tb><SEP> KSG<SEP> 2<SEP> 10<SEP> 1.18  +/-  0.06<SEP> 72.1<SEP> (0.733-1.474) <tb><SEP> KSL<SEP> 0.5<SEP> 10<SEP> 3.21  +/-  0.17<SEP> 24.1 <tb><SEP> KSL<SEP> 1<SEP> 10<SEP> 2.62  +/-  0.12<SEP> 38.0<SEP> 1.383 <tb><SEP> KSL<SEP> 2<SEP> 10<SEP> 1.33  +/-  0.07<SEP> 68.6<SEP> (1.198-1.567) <tb><SEP> KETO<SEP> 10<SEP> 10<SEP> 1.94  +/-  0.10<SEP> 54.1<SEP> - <tb></TABLE> 



   I composti sono stati somministrati per via orale 60 min prima della carragenina. Le AUC sono state calcolate con il metodo dei trapezoidi (in ordinata: volume della zampa (detta in ml); in ascissa: tempo (da 0 a 6 ore)]. 



   Tutte le differenze vs. i controlli sono risultate altamente (p<0.001) significative (ANOVA + Tukey-Kramer test). Tabella 3. Effetto dei ketoprofene sale di glucosammina (KSG), del ketoprofene sale di lisina (KSL) e del ketoprofene (KETO) sulla concentrazione di prostaglandina E 2  (PGE 2 ) presente nell essudato infiammatorio (EI) ottenuto 8 ore dopo l'impianto ai ratti di due spugne di poliestere imbevute in carragenina (0.5%). 



   <tb><TABLE> Columns = 5 <tb>Head Col 1: Trattamento <tb>Head Col 2: Dose (mg/kg os) <tb>Head Col 3: n DEG ratti <tb>Head Col 4: EI (ml) <tb>Head Col 5: PGE 2 (ng/ml) <tb><SEP> Controlli<SEP> - <SEP> 10<SEP> 5.15  +/-  0.28 ( - )<SEP> 98.7  +/-  4.7 ( - ) <tb><SEP> KSG<SEP> 0.5<SEP> 10<SEP> 3.87  +/-  0.27 (24.8)<b><SEP> 67.6  +/- 4.1 (31.5)<c> <tb><SEP> KSG<SEP> 1<SEP> 10<SEP> 3.56  +/-  0.28 (30.9)<c><SEP> 60.5  +/-  3.0 (38.7)<c> <tb><SEP> KSG<SEP> 2<SEP> 10<SEP> 2.53  +/-  0.22 (50.9)<c><SEP> 49.9  +/-  2.1 (49.4)c <tb><SEP> KSG<SEP> 4<SEP> 10<SEP> 1.05  +/-  0.09 (79.6)<c><SEP> 24.9  +/- 2.3 (74.8)<c> <tb><SEP> KSL<SEP> 0.5<SEP> 10<SEP> 4.33  +/-  0.26 (15.9)<a><SEP> 78.1  +/-  3.7 (20.9)<b> <tb><SEP> KSL<SEP> 1<SEP> 10<SEP> 3.82  +/-  0.15 (25.8)<b><SEP> 67.9  +/-  3.5 (31.2)<c> <tb><SEP> KSL<SEP> 2<SEP> 10<SEP> 2.97  +/-  0.19 (42.3)<c><SEP> 55.6  +/- 2.3 (43.7)

  <c> <tb><SEP> KSL<SEP> 4<SEP> 10<SEP> 1.68  +/-  0.14 (67.4)c<SEP> 32.8  +/-  1.8 (66.8)<c> <tb><SEP> KETO<SEP> 10<SEP> 10<SEP> 2.13  +/-  0.15 (58.6)c<SEP> 49.6  +/-  3.0 (49.7)<c> <tb></TABLE> 



   I composti sono stati somministrati per via orale immediatamente dopo l'impianto delle spugne. I valori sono espressi come media +/-  errore standard della media. In parentesi: % inibizione vs i controlli. 



   a, p<0.05; b, p<0.01; e, p<0.001 ((ANOVA + Tukey-Kramer test). Tabella 4. Valori di ED 50  del ketoprofene sale di glucosammina (KSG) e del ketoprofene sale di lisina (KSL) sulla concentrazione di prostaglandina E 2  (PGE 2 ) presente nell essudato infiammatorio (El) ottenuto 8 ore dopo l'impianto ai ratti di due spugne di poliestere imbevute in carragenina (0.5%). 



   <tb><TABLE> Columns = 4 <tb>Head Col 1: Trattamento <tb>Head Col 2: Dose (mg/kg os) <tb>Head Col 3: El (ED 50  in mg/kg os) <tb>Head Col 4: PGE 2 (ED 50  in mg/kg os) <tb><SEP> KSG<SEP> 0.5 <tb><SEP> KSG<SEP> 1<SEP> 2.092<SEP> 1.989 <tb><SEP> KSG<SEP> 2<SEP> (1.802-2.381)<SEP> (1.848-2.131) <tb><SEP> KSG<SEP> 4<ROW> <tb><SEP> KSL<SEP> 0.5 <tb><SEP> KSL<SEP> 1<SEP> 2.714<SEP> 2.610 <tb><SEP> KSL<SEP> 2<SEP> (2.334-3.094 )<SEP> (2.215-3.005) <tb><SEP> KSL<SEP> 4 <tb></TABLE> 



   I composti sono stati somministrati per via orale immediatamente dopo l'impianto delle spugne. l valori della Dose Efficace 50 (ED 50 ) sono stati calcolati utilizzando i dati riportati In Tab. 3. In parentesi: limiti fiduciali = 95% 



   <tb><TABLE> Columns = 5  <PAR AL=L>DL 50  (Limiti di confidenza al 95% <tb><SEP> Ketoprofene sale di glucosammina<SEP> i.pl.<SEP> Maschi<SEP> 171<SEP> (85-240)<ROW><SEP> l.p.<SEP> Femmine<SEP> 289<SEP> (211-401)<ROW><SEP> p.o.<SEP> Maschi<SEP> 268<SEP> (131-352)<ROW><SEP> p.o.<SEP> Femmine<SEP> 447<SEP> (384-524) <tb><SEP> Ketoprofene sale di lisina<SEP> i.p.<SEP> Maschi<SEP> 187<SEP> (103-252)<ROW><SEP> i.p.<SEP> Femmine<SEP> 273<SEP> (199-352) <tb></TABLE>



  



   The invention relates to pharmaceutical preparations containing water-soluble salts obtained by reaction between ketoprofen and glucosamine and / or proline and / or hydroxyproline, and to their use for anti-inflammatory and analgesic therapies, as characterized in the claims.



   The invention is based on the patent CH 692 939 of the same applicant.



   In particular the invention relates to products as mentioned in Examples 1 34 and to the salt synthesis methods described in the mentioned patent, with the addition of the following specifications. 1. Materials and methods



   The anti-inflammatory activity of ketoprofen salt of glucosamine and of ketoprofen lysine salt, in comparison with that of ketoprofen, was evaluated in the rat using the carrageenan edema method and the foreign body edema (sponge) method. 1.1. Carrageenin edema in the rat.



   For these tests, 80 male Wistar strain rats (Charles River, Calco, LC, Italy) of body weight of 160 + 5 g were used. The method described by Winter and Coll. (1) which allows to evaluate the activity of drugs in the acute phase of the inflammatory process essentially linked to an increase in vascular permeability (edema) and to a prevalent infiltration of polymorphonuclear granulocytes in exudate.



   In particular, 100 mu of carrageenan dissolved at 1% in sterile physiological solution were injected into the posterior plantar aponeurosis of fasted animals (water ad libitum) from the evening before the experiment. In order to achieve greater uniformity in the development of the edema, the animals were treated orally with 5 ml of physiological solution 2 hours before the experiment.



   The evolution of edema induced by the administration of carrageenan was evaluated with the plethysmographic method using equipment (plethysmometer, mod. 7150) of the company U. Basile (Comerio, VA, Italy). The relief of the paw volume was performed immediately after the injection of the phlogogenic agent (time 0) and at every hour up to the 6th hour. The animals, randomly divided into 8 experimental groups (10 animals per group), were treated orally (by gavage) with the ketoprofen salt of glucosamine, the ketoprofen lysine salt and with ketoprofen, 30 minutes before carrageenan according to the following experimental protocol:



   



   Controls (Sol. Fisiol., 1 ml / kg); n 10



   Ketoprofen glucosamine salt (0.5 mg / kg); n = 10



   Ketoprofen glucosamine salt (1 mg / kg); n = 10



   Ketoprofen glucosamine salt (2 mg / kg); n-10



   Ketoprofen lysine salt (0.5 mg / kg); n-10



   Ketoprofen lysine salt (1 mg / kg); n-10



   Ketoprofen lysine salt (2 mg / kg); n-10



   Keloprofen (10 mg / kg); n-10 1.2. Foreign body edema: "sponge" test in the rat.



   Since ketoprofen, like all propionic acid derivatives, owes much of its anti-inflammatory activity to the inhibition of the cyclooxygenase enzyme and therefore to the blockage of the oxidative cascade of arachidonic acid, the experimental model in the "sponge" rat described by Higgs et al. (2) lends itself very well to evaluating the vasculoessudative phenomenon and the neoformation of primary prostaglandins related to it.



   For these tests 100 male rats of CD strain (Charles River, Calco, LC, Italy) of body weight of 180 +/- 8 g were used. The animals observed a 12-hour fasting period (ad libitum water) before accessing the experiment.



   The inflammatory reaction with exudate formation was induced using sterilized polyester sponges (4 x 1.5 x 0.5 cm) soaked in 2% carrageenan dissolved in sterile physiological solution. Two sponges for each rat were implanted subcutaneously (dorsal area) to animals in slight ethereal anesthesia after careful hair removal. The animals, randomly divided into 10 experimental groups (10 animals per group), were treated orally (by gavage) with the ketoprofen giucosamine salt, the ketoprofen lysine salt and with ketoprofen, immediately after the sponges implantation (time 0) according to the following experimental protocol:



   



   Controls (Sol. Fisiol., 1 ml / kg); n 10



   Ketoprofen glucosamine salt (0.5 mg / kg); n-10



   Ketoprofen glucusamine salt (1 mg / kg)); n = 10



   Ketoprofen glucosamine salt (2 mg / kg); n-10



   Ketoprofen glucosamine salt (4 mg / kg); n-10



   Ketoprofen lysine salt (0.5 mg / kg); n-10



   Ketoprofen lysine salt (1 mg / kg); n-10



   Ketoprofen lysine salt (2 mg / kg); n-10



   Ketoprofen lysine salt (4 mg / kg); n-10



   Ketoprofen (10 mg / kg): n-10



   



   The sponges were removed 8 hours later after sacrificing the animals by "ethereal euthanasia".



   The removed sponges were immediately immersed in test tubes of polyethylene (50 ml) containing 10 ml of heparinized physiological solution. Subsequently these test tubes were subjected to centrifugation (1000 g; 15 min) and after removing the sponges from them, the volume of the remaining fluid was carefully measured. Still following the method of Higgs et al. (2), the acidic lipids present in the fluid are extracted in chloroform after dilution in ethanol and acidification at pH 3. After complete evaporation of the chloroform, the remaining dry residue was taken up in physiological solution and used for immunoenzymatic determination of prostaglandin E 2 (PGE 2). 1.3. Substances.



   For these experiments the following substances were used: ketoprofen salt of glucosamine and ketoprofen lysine salt (supplied by the company ...); ketoprofen and type IV carrageenan (Sigma-Aldrich, MI, Italy); immunoassay kit for PGE 2 (Amersham, MI, Italy). All the other reagents used for these tests were purchased by Merck-Bracco (MI, Italy). 1.4. Statistics.



   The data obtained in these experiments were processed through the analysis of variance (ANOVA) and the Student's "t" test for non-paired data considering the differences with p <0.05 significant. The multiple comparison between the different experimental groups was carried out using the Tukey-Kramer statistical test. The area under the curve (AUC) was calculated using the trapezoid method using a computer program (Microcal Origin, version 3.5). 2. Results 2.1. Carrageenin edema in the rat.



   The results obtained from these experiments indicate that the glucosamine ketoprofen salt, administered orally in the rat at a dose of 0.5, 1 and 2 mg / kg, is provided with anti-inflammatory activity. The anti-edema effect of the test compound is in proportion to the dose used. In fact, considering the values obtained by measuring the areas under the curve (AUC), the ketoprofen salt of glucosamine inhibits the reactive process at a dose of 0.5, 1 significantly (p <0.001) by 30%, 48% and 72% respectively and 2 mg / kg os (Fig. 1 and Tab. 1-2).



   The anti-inflammatory activity observed with the ketoprofen glucosamine salt is completely comparable to that obtained by administering ketoprofen lysine salt to the rats at a dose of 0.5, 1 and 2 mg / kg os. In fact, the ED 50 values of the two compounds (extrapolated from the data obtained with the AUC) were equal to 1,104 mg / kg os (limit fìd. = 95%: 0.733-1.474) and 1,383 mg / kg os (lim. fid. = 95%: 1.198-1.567) respectively for the ketoprofen glucosamine salt and for the ketoprofen lysine salt (Tab. 2 and Fig. 3).



   Also the ketoprofen in this test (used as a positive internal standard) gave evidence of anti-inflammatory activity. In fact, this compound administered to rats at a dose of 10 mg / kg os inhibits (54.1%; p <0.001) the inflammatory reactive process caused by the injection of carrageenan in the plantar aponeurosis (Fig. 1-2 and Tab. 1- 2). 2.2. Foreign body edema: "sponge" test in the rat.



   The results obtained from these tests, reported in Tab. 3, clearly indicate that the glucosamine ketoprofen salt controls the vascular-exudative inflammatory response in the rat to a dose dependent extent (0.5, 1, 2 and 4 mg / kg os). In fact, the ketoprofen salt of glucosamine is able to significantly oppose the evolution of the reactive process especially in terms of less formation of inflammatory exudate correlated to a significant inhibition of the activity of PGE 2 in these exudates (Table 3).



   Also the ketoprofen lysine salt, administered to animals at a dose of 0.5, 1, 2 and 4 mg / kg os has been shown to well control the inflammatory response of the host to the subcutaneous implantation of a foreign body (Table 3). 3. Bibliography



   1) Winter C.A. et al. Exp. Biol. Proc. Med. 1962; 111: 544.



   2) Higgs G.A et al. In: Samuelsson B., Paoletti R. (eds). Advance in Prostaglandin and Thromboxane Research. New York: raven Press Vol. 1, pp. 105, 1976.



   Table 1. Anti-inflammatory activity of ketoprofen glucosamine salt (KSG), ketoprofen lysine salt (KSL) and ketoprofen (KETO) in the rat: carrageenin edema.



   <tb> <TABLE> Columns = 7 <tb> Head Col 1: Treatment (mg / kg os) <tb> Head Col 2: Trend of the volume of the paw (delta in ml) at the time: <tb> Head Col 3: I <a> now <tb> Head Col 4: II <a> time <tb> Head Col 5: III <a> time <tb> Head Col 6: IV <a> time <tb> Head Col 7: V < a> time <tb> Head Col 8: VI <a> time <tb> <SEP> Controls <SEP> 0.40 +/- 0.02 <SEP> 0.71 +/- 0.02 <SEP> 0.87 +/- 0.03 <SEP> 0.93 +/- 0.03 <SEP> 0.90 +/- 0.04 <SEP> 0.84 +/- 0.04 <tb> <SEP> KSG 0.5 <SEP> 0.28 +/- 0.02 <SEP> 0.51 +/- 0.03 <SEP> 0.62 + / - 0.04 <SEP> 0.65 +/- 0.04 <SEP> 0.62 +/- 0.05 <SEP> 0.56 +/- 0.05 <tb> <SEP> KSG 1 <SEP> 0.23 +/- 0.01 <SEP> 0.39 +/- 0.02 <SEP> 0.46 +/- 0.02 <SEP> 0.48 +/- 0.02 <SEP> 0.45 +/- 0.02 <SEP> 0.39 +/- 0.03 <tb> <SEP> KSG 2 <SEP> 0.11 +/- 0.02 <SEP > 0.20 +/- 0.02 <SEP> 0.26 +/- 0.03 <SEP> 0.28 +/- 0.03 <SEP> 0.25 +/- 0.03 <SEP> 0.16 +/- 0.02 <tb> <SEP> KSL 0.5 <SEP> 0.32 +/-

   0.02 <SEP> 0.53 +/- 0.03 <SEP> 0.66 +/- 0.04 <SEP> 0.70 +/- 0.03 <SEP> 0.68 +/- 0.02 <SEP> 0.64 +/- 0.03 <tb> <SEP> KSL 1 < SEP> 0.24 +/- 0.02 <SEP> 0.43 +/- 0.03 <SEP> 0.54 +/- 0.03 <SEP> 0.59 +/- 0.03 <SEP> 0.57 +/- 0.03 <SEP> 0.49 +/- 0.03 <tb> <SEP> KSL 2 <SEP> 0.13 +/- 0.02 <SEP> 0.23 +/- 0.02 <SEP> 0.28 +/- 0.02 <SEP> 0.29 +/- 0.02 <SEP> 028 +/- 0.02 <SEP> 0.23 + / - 0.03 <tb> <SEP> Keto 10 <SEP> 0.19 +/- 0.02 <SEP> 0.33 +/- 0.03 <SEP> 0.41 +/- 0.02 <SEP> 0.42 +/- 0.02 <SEP> 0.40 +/- 0.03 <SEP> 0.37 +/- 0.03 <tb> </TABLE>



   Data represent the mean +/- ESM of 10 rats per group. The compounds were administered orally 60 min before the phlogogenic agent (carrageenan 1%). Basis leg volume: 1.70 +/- 0.02 ml (n = 80). Table 2. Areas under the curve (AUC) related to the trend over time of increases in the volume of the paw reported in Fig. 1 and 2



   <tb> <TABLE> Columns = 6 <tb> Head Col 1: Treatment <tb> Head Col 2: Dose (mg / kg os) <tb> Head Col 3: n DEG rats <tb> Head Col 4: Auc ( media +/- ESM) <tb> Head Col 5:% inhibition vs controls <tb> Head Col 6: ED 60 in mg / kg os (trust limits = 95%) <tb> <SEP> Controls <SEP> - <SEP> 10 <SEP> 4.23 +/- 0.26 <SEP> - <SEP> - <tb> <SEP> KSG <SEP> 0.5 <SEP> 10 <SEP> 2.96 +/- 0.15 <SEP> 30.0 <tb> <SEP> KSG <SEP> 1 <SEP> 10 <SEP> 2.20 +/- 0.13 <SEP> 48.0 <SEP> 1.104 <tb> <SEP> KSG <SEP> 2 <SEP> 10 <SEP> 1.18 +/- 0.06 <SEP> 72.1 <SEP> (0.733-1.474) <tb> <SEP> KSL <SEP> 0.5 <SEP> 10 <SEP> 3.21 +/- 0.17 <SEP> 24.1 <tb> <SEP> KSL <SEP> 1 <SEP> 10 <SEP> 2.62 +/- 0.12 <SEP> 38.0 <SEP> 1.383 <tb> <SEP> KSL <SEP> 2 <SEP> 10 <SEP> 1.33 +/- 0.07 <SEP> 68.6 <SEP > (1.198-1.567) <tb> <SEP> KETO <SEP> 10 <SEP> 10 <SEP> 1.94 +/- 0.10 <SEP> 54.1 <SEP> - <tb> </TABLE>



   The compounds were administered orally 60 min before carrageenan. The AUC were calculated using the trapezoid method (in ordinate: volume of the paw (called in ml); in the abscissa: time (from 0 to 6 hours)].



   All the differences vs. the controls were highly significant (p <0.001) (ANOVA + Tukey-Kramer test). Table 3. Effect of ketoprofen salt of glucosamine (KSG), of ketoprofen lysine salt (KSL) and of ketoprofen (KETO) on the concentration of prostaglandin E 2 (PGE 2) present in the inflammatory exudate (EI) obtained 8 hours after the rat implantation of two polyester sponges soaked in carrageenan (0.5%).



   <tb> <TABLE> Columns = 5 <tb> Head Col 1: Treatment <tb> Head Col 2: Dose (mg / kg os) <tb> Head Col 3: n DEG rats <tb> Head Col 4: EI ( ml) <tb> Head Col 5: PGE 2 (ng / ml) <tb> <SEP> Controls <SEP> - <SEP> 10 <SEP> 5.15 +/- 0.28 (-) <SEP> 98.7 +/- 4.7 (-) <tb> <SEP> KSG <SEP> 0.5 <SEP> 10 <SEP> 3.87 +/- 0.27 (24.8) <b> <SEP> 67.6 +/- 4.1 (31.5) <c> <tb> < SEP> KSG <SEP> 1 <SEP> 10 <SEP> 3.56 +/- 0.28 (30.9) <c> <SEP> 60.5 +/- 3.0 (38.7) <c> <tb> <SEP> KSG <SEP> 2 <SEP> 10 <SEP> 2.53 +/- 0.22 (50.9) <c> <SEP> 49.9 +/- 2.1 (49.4) c <tb> <SEP> KSG <SEP> 4 <SEP> 10 <SEP> 1.05 + / - 0.09 (79.6) <c> <SEP> 24.9 +/- 2.3 (74.8) <c> <tb> <SEP> KSL <SEP> 0.5 <SEP> 10 <SEP> 4.33 +/- 0.26 (15.9) < a> <SEP> 78.1 +/- 3.7 (20.9) <b> <tb> <SEP> KSL <SEP> 1 <SEP> 10 <SEP> 3.82 +/- 0.15 (25.8) <b> <SEP> 67.9 + / - 3.5 (31.2) <c> <tb> <SEP> KSL <SEP> 2 <SEP> 10 <SEP> 2.97 +/- 0.19 (42.3) <c> <SEP> 55.6 +/- 2.3 (43.7)

  <c> <tb> <SEP> KSL <SEP> 4 <SEP> 10 <SEP> 1.68 +/- 0.14 (67.4) c <SEP> 32.8 +/- 1.8 (66.8) <c> <tb> <SEP> KETO <SEP> 10 <SEP> 10 <SEP> 2.13 +/- 0.15 (58.6) c <SEP> 49.6 +/- 3.0 (49.7) <c> <tb> </TABLE>



   The compounds were administered orally immediately after the sponges were implanted. Values are expressed as an average +/- standard error of the average. In parentheses:% inhibition vs controls.



   a, p <0.05; b, p <0.01; e, p <0.001 ((ANOVA + Tukey-Kramer test). Table 4. ED 50 values of ketoprofen glucosamine salt (KSG) and ketoprofen lysine salt (KSL) on the concentration of prostaglandin E 2 (PGE 2) present in the inflammatory exudate (El) obtained 8 hours after the implantation to the rats of two polyester sponges soaked in carrageenan (0.5%).



   <tb> <TABLE> Columns = 4 <tb> Head Col 1: Treatment <tb> Head Col 2: Dose (mg / kg os) <tb> Head Col 3: El (ED 50 in mg / kg os) <tb > Head Col 4: PGE 2 (ED 50 in mg / kg os) <tb> <SEP> KSG <SEP> 0.5 <tb> <SEP> KSG <SEP> 1 <SEP> 2.092 <SEP> 1.989 <tb> < SEP> KSG <SEP> 2 <SEP> (1.802-2.381) <SEP> (1.848-2.131) <tb> <SEP> KSG <SEP> 4 <ROW> <tb> <SEP> KSL <SEP> 0.5 <tb > <SEP> KSL <SEP> 1 <SEP> 2.714 <SEP> 2.610 <tb> <SEP> KSL <SEP> 2 <SEP> (2.334-3.094) <SEP> (2.215-3.005) <tb> <SEP> KSL <SEP> 4 <tb> </TABLE>



   The compounds were administered orally immediately after the sponges were implanted. The values of the Effective Dose 50 (ED 50) were calculated using the data reported in Table 3. In brackets: fiducial limits = 95%



   <tb> <TABLE> Columns = 5 <PAR AL = L> DL 50 (95% confidence limits <tb> <SEP> Ketoprofen glucosamine salt <SEP> i.pl. <SEP> Males <SEP> 171 < SEP> (85-240) <ROW> <SEP> lp <SEP> Females <SEP> 289 <SEP> (211-401) <ROW> <SEP> po <SEP> Males <SEP> 268 <SEP> (131 -352) <ROW> <SEP> po <SEP> Females <SEP> 447 <SEP> (384-524) <tb> <SEP> Ketoprofen lysine salt <SEP> ip <SEP> Males <SEP> 187 <SEP > (103-252) <ROW> <SEP> ip <SEP> Females <SEP> 273 <SEP> (199-352) <tb> </TABLE>

Claims (9)

1. Preparazioni farmaceutiche, contenenti i sali idrosolubili ottenuti mediante reazione fra il ketoprofene e la glucosammina e/o la prolina e/o l'idrossiprolina. 1. Pharmaceutical preparations containing the water-soluble salts obtained by reaction between ketoprofen and glucosamine and / or proline and / or hydroxyproline. 2. Preparazioni farmaceutiche secondo i la rivendicazione 1, contenenti da 0,01 a 30% di massa dei sali idrosolubili di ketoprofene. 2. Pharmaceutical preparations according to claim 1, containing from 0.01 to 30% of mass of the water-soluble salts of ketoprofen. 3. Uso delle preparazioni farmaceutiche secondo la rivendicazione 1 per la preparazione di medicinali per le terapie antiinfiammatorie ed antalgiche, specialmente delle articolazioni con somministrazione orale, transcutanea o intramuscolare di dette preparazioni. 3. Use of the pharmaceutical preparations according to claim 1 for the preparation of medicines for anti-inflammatory and analgesic therapies, especially of the joints with oral, transcutaneous or intramuscular administration of said preparations. 4. Uso secondo la rivendicazione 3 sotto forma di preparazioni iniettabili, compresse, capsule, granulati o sospensioni. 4. Use according to claim 3 in the form of injectable preparations, tablets, capsules, granulates or suspensions. 5. 5. Uso delle preparazioni farmaceutiche secondo la rivendicazione 1 per la preparazione di medicinali per le terapie antiinfiammatorie ed antalgiche specialmente delle mucose con somministrazione iniettiva o topica di dette preparazioni.  Use of the pharmaceutical preparations according to claim 1 for the preparation of medicines for anti-inflammatory and analgesic therapies especially of the mucous membranes with injective or topical administration of said preparations. 6. Uso secondo la rivendicazione 5 sotto forma di soluzione, lavanda, collutorio, suppositorio, candeletta, gel, crema o schiuma. 6. Use according to claim 5 in the form of a solution, lavender, mouthwash, suppository, glow plug, gel, cream or foam. 7. Sali idrosolubili contenuti nelle preparazioni secondo la rivendicazione 1, caratterizzati dal fatto che sono ottenuti da ketoprofene e aminoacidi, in quantità essenzialmente equimolari. 7. Water-soluble salts contained in the preparations according to claim 1, characterized in that they are obtained from ketoprofen and amino acids, in essentially equimolar amounts. 8. Sali idrosolubili secondo la rivendicazione 7, ottenuti in forma di soluzione acquosa, caratterizzati dal fatto che la sintesi è eseguita a pH neutro a temperature fra 5 DEG e 60 DEG C e che la concentrazione dei sali prodotti è >= 300 g.l<-1>. 8. Water-soluble salts according to claim 7, obtained in the form of aqueous solution, characterized in that the synthesis is carried out at neutral pH at temperatures between 5 DEG and 60 DEG C and that the concentration of the salts produced is> = 300 gl <- 1>. 9. 9. Sali idrosolubili secondo la rivendicazione 7, ottenuti in forma di solidi, caratterizzati dal fatto che la sintesi è eseguita in almeno un solvente organico adatto, il quale, dopo la reazione viene eliminato mediante temperatura elevata e/o pressione ridotta.  Water-soluble salts according to claim 7, obtained in the form of solids, characterized in that the synthesis is carried out in at least one suitable organic solvent, which, after the reaction is eliminated by high temperature and / or reduced pressure.
CH00618/99A 1998-04-11 1999-03-31 Pharmaceutical preparations containing hydrosoluble ketoprofen salts CH694451A5 (en)

Priority Applications (8)

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CH00618/99A CH694451A5 (en) 1999-03-31 1999-03-31 Pharmaceutical preparations containing hydrosoluble ketoprofen salts
JP55142299A JP2002510336A (en) 1998-04-11 1999-04-09 Pharmaceutical preparations containing water-soluble ketoprofen salts and methods of using the same
CN99800474A CN1263464A (en) 1998-04-11 1999-04-09 Pharmaceutical preparations containing hydrosoluble ketoprofen salts and their application
EP99910606A EP1024808A1 (en) 1998-04-11 1999-04-09 Pharmaceutical preparations containing hydrosoluble ketoprofen salts and their application
PCT/IB1999/000626 WO1999052528A1 (en) 1998-04-11 1999-04-09 Pharmaceutical preparations containing hydrosoluble ketoprofen salts and their application
US09/445,672 US6291527B1 (en) 1998-04-11 1999-04-09 Pharmaceutical preparations containing hydrosoluble ketoprofen salts and their application
CA002293605A CA2293605A1 (en) 1998-04-11 1999-04-09 Pharmaceutical preparations containing hydrosoluble ketoprofen salts and their application
KR1019997011727A KR20010013712A (en) 1998-04-11 1999-04-09 Pharmaceutical preparation containing hydrosoluble ketoprofen salts and their application

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