ITPD20090360A1 - COMPOSITION FOR TOPICAL USE - Google Patents
COMPOSITION FOR TOPICAL USE Download PDFInfo
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- ITPD20090360A1 ITPD20090360A1 IT000360A ITPD20090360A ITPD20090360A1 IT PD20090360 A1 ITPD20090360 A1 IT PD20090360A1 IT 000360 A IT000360 A IT 000360A IT PD20090360 A ITPD20090360 A IT PD20090360A IT PD20090360 A1 ITPD20090360 A1 IT PD20090360A1
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- composition
- dermatitis
- treatment
- vaginitis
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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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
- A61K9/10—Dispersions; Emulsions
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Description
COMPOSIZIONE PER USO TOPICO COMPOSITION FOR TOPICAL USE
I cannabinoidi, tra cui il principale principio attivo della cannabis delta-9-tetraidrocannabinolo (THC), sono da tempo noti possedere, oltre ai loro effetti psicoattivi, proprietà farmacologiche di interesse nel trattamento di diverse patologie o sintomatologie ad esse associate (Ameri A., 1999 Progress in Neurobiol. 58: 315-348). Tra queste, esistono oggi concrete evidenze sperimentali che i cannabinoidi, come ad esempio il cannabidiolo od altri derivati del THC, sono in grado di esercitare effetti di tipo antidolorifico ed anti-infiammatorio in patologie, anche di tipo autoimmunitario, a carico di diversi distretti corporei acute o croniche associate ad infiammazione e/o stati algici come ad esempio le artriti, ivi inclusa l’artrite reumatoide, dolore cronico, radiculopatie, asma, colite ulcerosa, dermatiti (Ameri A., 1999 ref. cit.). Cannabinoids, including the main active ingredient in cannabis delta-9-tetrahydrocannabinol (THC), have long been known to have, in addition to their psychoactive effects, pharmacological properties of interest in the treatment of various pathologies or symptoms associated with them (Ameri A. , 1999 Progress in Neurobiol. 58: 315-348). Among these, there is now concrete experimental evidence that cannabinoids, such as cannabidiol or other THC derivatives, are able to exert pain-relieving and anti-inflammatory effects in pathologies, including autoimmune ones, affecting different body districts. acute or chronic associated with inflammation and / or painful states such as arthritis, including rheumatoid arthritis, chronic pain, radiculopathies, asthma, ulcerative colitis, dermatitis (Ameri A., 1999 ref. cit.).
Inoltre, vi sono, oggi, anche numerosi altri sintomi o patologie per le quali recenti evidenze sperimentali suggeriscono un potenziale utilizzo medicoterapeutico dei derivati del THC. E' il caso della sclerosi multipla, patologia nella quale i cannabinoidi sono potenzialmente in grado di esercitare non solo effetti antinfiammatori ma anche di tipo anti-spastico suggerendo un effetto farmacologico sul controllo del tono muscolare (Baker D. et. al. Furthermore, today there are also numerous other symptoms or pathologies for which recent experimental evidence suggests a potential medicotherapeutic use of THC derivatives. This is the case of multiple sclerosis, a pathology in which cannabinoids are potentially able to exert not only anti-inflammatory but also anti-spastic effects, suggesting a pharmacological effect on the control of muscle tone (Baker D. et. Al.
2000, Nature 404, 84- 87; Ameri A.1999 ref.cit. ) 2000, Nature 404, 84-87; Ameri A.1999 ref. Cit. )
Altri campi promettenti per le proprietà neuroprotettive ed anticonvulsivanti dei cannabinoidi o loro derivati, includono quello della terapia dell’ictus o traumi cerebrali e spinali. Inoltre, sempre a livello del SNC, esistono delle evidenze sperimentali che dimostrano che derivati cannabinoidomimetici potrebbero essere di interesse in associazione con altri farmaci (ad esempio oppiodi) nella terapia del dolore (Mas-Nieto M. et al. 2001, Brit. J. Pharmacol.132: 1809-16). Other promising fields for the neuroprotective and anticonvulsant properties of cannabinoids or their derivatives, include that of stroke therapy or brain and spinal trauma. Furthermore, again at the CNS level, there is experimental evidence showing that cannabinoidomimetic derivatives could be of interest in association with other drugs (for example opioids) in pain therapy (Mas-Nieto M. et al. 2001, Brit. J. Pharmacol. 132: 1809-16).
Per le loro proprietà broncodilatatrice e antipertensiva sono anche promettenti nel campo della terapia dell’insufficienza respiratoria e/o cardiovascolare e dell’ipertensione (Ameri A.1999 ref. cit.), mentre, vista la loro efficacia sia nell'inibire la crescita che nel promuovere la morte delle cellule tumorali (effetto anti-proliferativo e pro-apoptotico) si mostrano promettenti nella terapia dei tumori (Ameri A.1999 ref. cit.). Due to their bronchodilator and antihypertensive properties they are also promising in the field of therapy of respiratory and / or cardiovascular insufficiency and hypertension (Ameri A.1999 ref. Cit.), While, given their efficacy both in inhibiting growth and in promoting the death of cancer cells (anti-proliferative and pro-apoptotic effect) they show promise in cancer therapy (Ameri A.1999 ref. cit.).
Inoltre, sono numerose le evidenze, sebbene aneddotiche, di un benefico utilizzo del THC o suoi derivati sia nel stimolare l’appetito in pazienti con sindrome da deperimento causate dall’AIDS (Ameri A.1999 ref. cit.) sia nel ridurre la nausea ed il vomito secondari a chemioterapia nei malati di tumore (effetto anti-emetico) (Ameri A. 1999 ref. cit.), suggerendo un effetto nel controllo dell’appetito. Furthermore, there are numerous evidences, although anecdotal, of a beneficial use of THC or its derivatives both in stimulating the appetite in patients with wasting syndrome caused by AIDS (Ameri A.1999 ref. Cit.) And in reducing nausea. and vomiting secondary to chemotherapy in cancer patients (anti-emetic effect) (Ameri A. 1999 ref. cit.), suggesting an effect on appetite control.
Infine, molecole endocannabinoido-simili come la palmitoiletanolamide (PEA) sono stati descritti esercitare effetti inibitori sul rilascio, IgE mediato, di mediatori mastocitari, indicando un possibile ruolo di queste molecole nella cura di stati allergici (Facci L. et al. 1995 Proc. Natl. Acad. Sci. USA Vol 92: 3376-80 ). Finally, endocannabinoid-like molecules such as palmitoylethanolamide (PEA) have been described to exert inhibitory effects on the IgE mediated release of mast cell mediators, indicating a possible role of these molecules in the treatment of allergic states (Facci L. et al. 1995 Proc. Natl. Acad. Sci. USA Vol 92: 3376-80).
Tuttavia nonostante i derivati del THC ed il THC stesso siano, sperimentalmente molto promettenti, attualmente l’unico uso clinico approvato è nel ridurre la pressione intraoculare nei malati di glaucoma (Ameri A.1999 ref. cit.). However, although THC derivatives and THC itself are experimentally very promising, currently the only approved clinical use is to reduce intraocular pressure in glaucoma patients (Ameri A.1999 ref. Cit.).
Parallelamente alle evidenze sperimentali succitate che portano a ipotizzare diverse applicazioni cliniche di derivati dei cannabinoidi, negli ultimi anni gli studi sul possibile meccanismo d'azione di queste molecole hanno subito un'improvvisa accelerazione con la scoperta nel 1990 dell’esistenza di specifici recettori per il THC (denominati recettori CB) e nel 1992 di ligandi endogeni per tali recettori (denominati endocannabinoidi). Parallel to the aforementioned experimental evidence that leads to hypothesize different clinical applications of cannabinoid derivatives, in recent years the studies on the possible mechanism of action of these molecules have undergone a sudden acceleration with the discovery in 1990 of the existence of specific receptors for the THC (called CB receptors) and in 1992 of endogenous ligands for these receptors (called endocannabinoids).
Ad oggi, sebbene recentemente sia stato identificato e caratterizzato un nuovo recettore, GPR55, il quale per il THC e la PEA mostra affinità dell’ordine delle nano moli (Ryberg E, et al. Br J Pharmacol. 2007 Sep 17; Epub ahead of print), i recettori considerati essere coinvolti nella mediazione degli effetti del THC e dei suoi derivati sintetici sono due: il recettore CB1 prevalentemente espresso nel sistema nervoso ed in alcuni tessuti periferici (Piomelli D. et al. 2000, TIPS 21: 218-24) e il recettore CB2, identificato sopratutto in cellule del sistema immunitario dei mammiferi, individuato per la prima volta solo nel 1993 (Piomelli D. et al. To date, although a new receptor, GPR55, has recently been identified and characterized, which for THC and PEA shows affinity of the order of nano moles (Ryberg E, et al. Br J Pharmacol. 2007 Sep 17; Epub ahead of print), the receptors considered to be involved in mediating the effects of THC and its synthetic derivatives are two: the CB1 receptor mainly expressed in the nervous system and in some peripheral tissues (Piomelli D. et al. 2000, TIPS 21: 218-24 ) and the CB2 receptor, identified mainly in cells of the mammalian immune system, identified for the first time only in 1993 (Piomelli D. et al.
2000 ref. cit.). Inoltre, nonostante l’identificazione del recettore GRP55 ci sono evidenze dell’esistenza di ulteriori recettori CB che ad oggi non sono ancora stati caratterizzati (Wiley J.L., Martin B.R.2002, Chem. Phys. Lipids 121: 57-63). 2000 ref. cit.). Furthermore, despite the identification of the GRP55 receptor, there is evidence of the existence of additional CB receptors that have not yet been characterized (Wiley J.L., Martin B.R. 2002, Chem. Phys. Lipids 121: 57-63).
A seguito della scoperta del recettore CB1, nel 1992 è stato isolato, dal cervello di maiale, il primo composto endogeno in grado di legarsi selettivamente a tale recettore. Si tratta dell'ammide tra l'acido arachidonico e l'etanolammina, due componenti ubiquitari delle membrane cellulari animali, che venne chiamata anandamide suggerendo così per questa classe di molecole, le N-acilamidi, un ruolo di mediatori endogeni di tipo cannabinoido-mimetico (Martin et al. 1999, Life Sci. 65, 573-595). Successivamente fu isolato un altro tipo di molecola, appartenente alla classe degli intermedi metabolici noti come monoacilgliceroli, il 2-arachidonoilglicerolo con attività cannabinoido-mimetiche e con affinità elevata per i recettori CB1 e CB2 (Martin et al. 1999 ref. cit.). Infine, l’ultimo endo-cannabinoide isolato e caratterizzato risulta molto simile al precedente, 2-arachidonilglicerolo, ma con un legame etereo tra il radicale arachidonico e il carbonio 2 del glicerolo (Hanus L. et al. 2001, Proc. Natl. Following the discovery of the CB1 receptor, in 1992 the first endogenous compound capable of selectively binding to this receptor was isolated from pig brains. It is the amide between arachidonic acid and ethanolamine, two ubiquitous components of animal cell membranes, which was called anandamide thus suggesting for this class of molecules, the N-acylamides, a role of endogenous mediators of the cannabinoid-mimetic type. (Martin et al. 1999, Life Sci. 65, 573-595). Subsequently another type of molecule was isolated, belonging to the class of metabolic intermediates known as monoacylglycerols, 2-arachidonoylglycerol with cannabinoid-mimetic activity and with high affinity for CB1 and CB2 receptors (Martin et al. 1999 ref. Cit.). Finally, the last isolated and characterized endo-cannabinoid is very similar to the previous one, 2-arachidonylglycerol, but with an ethereal bond between the arachidonic radical and the 2 carbon of glycerol (Hanus L. et al. 2001, Proc. Natl.
Acad. Sci. USA; 98, 3662-5). Studi sperimentali con queste molecole suggeriscono che sebbene i tre endocannabinoidi identificati siano caratterizzati da differenti gruppi funzionali, tutti e tre sono in grado di interagire, sebbene con diversa affinità, con i recettori CB1 e CB2 con effetti sovrapponibili a quelli dei cannabinoidi naturali, come il THC, e loro derivati sintetici (Martin et al. 1999 ref. cit.). Infine in questi ultimi anni sono emerse evidenze sperimentali che fanno supporre che questa famiglia di molecole (endocannabinoidi) interagisca anche con il recettore dei vanilloidi (TRPV) (De Petrocellis et al.2000, Chem. Phys Lipids; 108, 191-209), mentre è da poco noto che molecole cannabinomimetiche riconducibili alla classe degli aminoalchilindoli (ad esempio WIN 55.212) possono interagire, oltre che con i recettori CB, con altri recettori noti (ad esempio il recettore 5-HT3a) (Barann M. et al 2002, Brit. J. Pharmacol.:137, 589-96). Non è possibile quindi escludere che gli endocannabinoidi possano interagire con molti altri sistemi recettoriali o enzimatici. Nel loro insieme, queste scoperte hanno, in questi ultimi anni, dato vita a una notevole attività di ricerca scientifica sui cannabinoidi ed endocannabinoidi, la quale ha portato non solo a un notevole avanzamento sul potenziale ruolo terapeutico dei cannabinoidi e loro derivati, ma anche alla sintesi e sviluppo di svariati composti in grado di agire come agonisti recettoriali e/o potenziando gli effetti degli endocannabinoidi interferendo, ad esempio, con gli enzimi implicati nella sintesi e degradazione degli endocannabinoidi, nonché con i sistemi cellulari implicati nel loro rilascio e re-uptake. Acad. Sci. USA; 98, 3662-5). Experimental studies with these molecules suggest that although the three identified endocannabinoids are characterized by different functional groups, all three are able to interact, albeit with different affinities, with the CB1 and CB2 receptors with effects comparable to those of natural cannabinoids, such as THC, and their synthetic derivatives (Martin et al. 1999 ref. Cit.). Finally, in recent years experimental evidence has emerged which suggests that this family of molecules (endocannabinoids) also interacts with the vanilloid receptor (TRPV) (De Petrocellis et al. 2000, Chem. Phys Lipids; 108, 191-209), while it is recently known that cannabinomimetic molecules attributable to the class of aminoalkylindoles (for example WIN 55.212) can interact, in addition to the CB receptors, with other known receptors (for example the 5-HT3a receptor) (Barann M. et al 2002, Brit. J. Pharmacol.:137, 589-96). It is therefore not possible to exclude that endocannabinoids may interact with many other receptor or enzymatic systems. Taken together, these discoveries have, in recent years, given rise to considerable scientific research on cannabinoids and endocannabinoids, which has led not only to a significant advance on the potential therapeutic role of cannabinoids and their derivatives, but also to the synthesis and development of various compounds capable of acting as receptor agonists and / or enhancing the effects of endocannabinoids by interfering, for example, with the enzymes involved in the synthesis and degradation of endocannabinoids, as well as with the cellular systems involved in their release and re-uptake .
A titolo esemplificativo vengono di seguito riportati alcuni esempi di composti a cui è attribuita un’attività cannabinoido-simile: a) derivati del THC (ad es. HU-210, CP55940) (Patel S. e Hillard C. J.2001, J. Pharmacol. Exp. Ther. 297, 629-37); b) derivati degli aminoalchilindoli (es. WIN 55.212) (Patel S. e Hillard C.J. 2001, ref. cit); c) derivati degli endocannabinoidi sia saturi che insaturi (ad es. oleiletanolamide OEA, palmitoiletanolamide PEA, metanandamide, olvanil, arvanil, nada) (Calignano A. et al. 2001, Eur. J. Pharmacol. 419, 191-198 ); d) inibitori dell’enzima FAAH, fatty acid amido-hydrolase, (ad es. AM 374) (Gifford A.N. et al. 1999, Eur. J. Pharmacol. 383, 9-14); e) inibitori del re-uptake degli endocannabinoidi (ad es. AM404) (Giuffrida A. et al. 2001, J. Pharmacol. Exp. Ther., 298, 7-14);. Inoltre ad oggi sono stati sintetizzati e sviluppati alcuni antagonisti recettoriali per i recettori noti, es. CB1 e CB2, (ad es. SR141716 e SR144528) (Francisco M.E. et al. 2002, J. Med. Chem.45, 2708-19 ). By way of example, some examples of compounds to which a cannabinoid-like activity is attributed are given below: a) THC derivatives (eg HU-210, CP55940) (Patel S. and Hillard C. J.2001, J. Pharmacol. Exp. Ther. 297, 629-37); b) derivatives of aminoalkylindoles (eg WIN 55.212) (Patel S. and Hillard C.J. 2001, ref. cit); c) derivatives of both saturated and unsaturated endocannabinoids (eg oleylethanolamide OEA, palmitoylethanolamide PEA, methanandamide, olvanil, arvanil, nada) (Calignano A. et al. 2001, Eur. J. Pharmacol. 419, 191-198); d) inhibitors of the FAAH enzyme, fatty acid amido-hydrolase, (eg. AM 374) (Gifford A.N. et al. 1999, Eur. J. Pharmacol. 383, 9-14); e) endocannabinoid re-uptake inhibitors (eg AM404) (Giuffrida A. et al. 2001, J. Pharmacol. Exp. Ther., 298, 7-14); Furthermore, to date some receptor antagonists for known receptors have been synthesized and developed, eg. CB1 and CB2, (e.g. SR141716 and SR144528) (Francisco M.E. et al. 2002, J. Med. Chem. 45, 2708-19).
Inoltre sebbene siano state sintetizzate molecole con l’intento di ottenere composti con attività agonista specifica per il recettore periferico CB2 (recettore ritenuto coinvolto nel controllo dei processi infiammatori periferici), ad oggi i risultati ottenuti sono modesti in quanto in molti casi questi derivati interagiscono, sebbene con minore ma non trascurabile affinità, con il recettore centrale CB1, oppure come la PEA o derivati dell’anandamide con un numero di doppi legami inferiore a 4, come pure omologhi inferiori (ad es. steraoiletanonolamide SEA, OEA) dimostrano di avere effetti di tipo centrale quando somministrati in vivo (Lambert D.M. Di Marzo V 1999, Curr. Med. Chem. 6, 757-73). Furthermore, although molecules have been synthesized with the aim of obtaining compounds with specific agonist activity for the peripheral CB2 receptor (receptor believed to be involved in the control of peripheral inflammatory processes), to date the results obtained are modest as in many cases these derivatives interact, although with minor but not negligible affinity, with the central receptor CB1, or as PEA or derivatives of anandamide with a number of double bonds lower than 4, as well as lower homologs (e.g. steraoyletanonolamide SEA, OEA) are shown to have effects central type when administered in vivo (Lambert D.M. Di Marzo V 1999, Curr. Med. Chem. 6, 757-73).
In questo scenario le N-acetil-etanolamidi (NAE) sature rappresentano una famiglia di derivati lipidici che, sebbene non presentino affinità apprezzabile per i recettori dei cannabinoidi noti, sono dotate di attività cannabinoidosimile sicuramente di interesse farmacologico. In this scenario, saturated N-acetyl-ethanolamides (NAEs) represent a family of lipid derivatives which, although they do not have appreciable affinity for known cannabinoid receptors, are endowed with cannabinoid-like activity certainly of pharmacological interest.
Fra queste molecole la più nota e studiata è sicuramente la palmitoiletanolamide (PEA). È noto infatti fin dagli anni ’50, che questa molecola è dotata di differenti attività farmacologiche (vedi sopra) e in modo particolare di attività antinfiammatoria. (Ganley O.H: et al. 1958; Perlik F. et al. 1971). PEA, sotto il nome di Impulsin, è stata largamente impiegata nell’uomo negli anni ’70 (Masek K., et al., 1974 Europ. J. Clin. Pharmacol. 7, 415-419; Hurych J et al., 1980 Czecoslovak Medicine, 8, 218-225) per la prevenzione e la cura di affezioni delle prime vie aeree. Negli anni novanta, a seguito della scoperta dell’anandamide, PEA è tornata di attualità in quanto dimostratasi efficace nel ridurre la degranulazione mastocitaria in diversi modelli sperimentali (Facci L. rif. citato; Mazzari S., 1996, Eur J Pharmacol. 300, 227-36). Inoltre va qui rilevato che è stato recentemente pubblicato (Ryberg E, rif. citato) che PEA ha un’affinità a livello nanomolare per il recettore recentemente identificato GPR55. Among these molecules, the best known and most studied is certainly palmitoylethanolamide (PEA). In fact, it has been known since the 1950s that this molecule has different pharmacological activities (see above) and in particular an anti-inflammatory activity. (Ganley O.H: et al. 1958; Perlik F. et al. 1971). PEA, under the name of Impulsin, was widely used in humans in the 1970s (Masek K., et al., 1974 Europ. J. Clin. Pharmacol. 7, 415-419; Hurych J et al., 1980 Czecoslovak Medicine, 8, 218-225) for the prevention and treatment of diseases of the upper airways. In the nineties, following the discovery of anandamide, PEA became topical again as it proved effective in reducing mast cell degranulation in various experimental models (Facci L. ref. Cited; Mazzari S., 1996, Eur J Pharmacol. 300, 227-36). It should also be noted here that it has recently been published (Ryberg E, ref. Cited) that PEA has an affinity at the nanomolar level for the recently identified GPR55 receptor.
L’omologo superiore della PEA, la stearoiletanolamide (SEA), forse a causa della sua estremamente scarsa solubilità in ambienti acquosi, sebbene sia utilizzato industrialmente da molti anni come agente perlante in preparati cosmetici con il nome più comune di Comperlan HS è stato ad oggi molto poco studiato per quanto riguarda la sua attività biologica. I pochi dati disponibili sull’attività biologica di SEA sono riportati, per quanto attiene all’attività antinfiammatoria, in tre brevetti (US5,990,170; US5,679,667 e US5,506,224) dove risulta essere sempre molto meno attivo del suo omologo inferiore la PEA. Inoltre SEA è riportata interferire con il sistema degli endocannabinoidi (Maccarrone et al. 2002 Biochem J. 366:137-44. Maccarrone M. et al. 2002 Mol Cell Neurosci. 21:126-40.) e con l’espressione dell’enzima SCD-1 (Terrazzino S. et al. 2004 FASEB J. PEA's superior counterpart, stearoylethanolamide (SEA), perhaps due to its extremely poor solubility in aqueous environments, although it has been used industrially for many years as a pearling agent in cosmetic preparations with the more common name of Comperlan HS to date very little studied regarding its biological activity. The few data available on the biological activity of SEA are reported, as regards the anti-inflammatory activity, in three patents (US5,990,170; US5,679,667 and US5,506,224) where PEA is always much less active than its lower counterpart. . Furthermore, SEA is reported to interfere with the endocannabinoid system (Maccarrone et al. 2002 Biochem J. 366: 137-44. Maccarrone M. et al. 2002 Mol Cell Neurosci. 21: 126-40.) And with the expression of SCD-1 enzyme (Terrazzino S. et al. 2004 FASEB J.
18:1580-2). 18: 1580-2).
Da sempre interessata allo sviluppo di molecole derivanti dalla classe degli endocannabinoidi, con lo scopo di ottenere composti attivi senza gli effetti cannabinoido-simile indesiderati, la Richiedente ha sorprendentemente scoperto che l’associazione dei due derivati PEA e SEA esercita un azione sinergica con effetti antinfiammatori, in un modello di infiammazione immunogenica in vitro, superiori a quelli dei singoli derivati. Always interested in the development of molecules deriving from the class of endocannabinoids, with the aim of obtaining active compounds without the unwanted cannabinoid-like effects, the Applicant has surprisingly discovered that the association of the two derivatives PEA and SEA exerts a synergistic action with anti-inflammatory effects. , in an in vitro immunogenic inflammation model, superior to those of single derivatives.
È quindi oggetto della presente invenzione l’impiego di una miscela di PEA e SEA per la preparazione di composizioni per il trattamento terapeutico o paramedico preventivo di stati patologici che possono trarre vantaggio dall’attività endocannabinoido-simile di questi composti. Therefore, the subject of the present invention is the use of a mixture of PEA and SEA for the preparation of compositions for the preventive therapeutic or paramedical treatment of pathological states that can benefit from the endocannabinoid-like activity of these compounds.
La Richiedente ha infatti sorprendentemente trovato che il trattamento in vitro con una miscela dei composti oggetto dell’invenzione esplica un’attività farmacologica cannabinoido-mimetica e superiore a quella esercitata dai singoli componenti. Questa miscela può quindi essere utilmente impiegata in preparati per il trattamento di stati patologici che possono beneficiare dell’utilizzo medico terapeutico e paramedico preventivo dei cannabinoidi/endocannabinoidi. The Applicant has in fact surprisingly found that the in vitro treatment with a mixture of the compounds object of the invention carries out a cannabinoid-mimetic pharmacological activity which is superior to that exerted by the individual components. This mixture can therefore be usefully used in preparations for the treatment of pathological states that can benefit from the medical, therapeutic and paramedical preventive use of cannabinoids / endocannabinoids.
Gli scopi ed i vantaggi dell’impiego medico terapeutico o paramedico di questa miscela di derivati acilici saturi condensati con etanolamina, in stati patologici che possono essere controllati dai cannabinoidi e dai endocannabinoidi o molecole affini, oggetto della presente invenzione, saranno meglio compresi nel corso della descrizione dettagliata seguente. La Richiedente ha infatti trovato che, dopo trattamento in vitro, con la miscela oggetto dell’invenzione, si assiste ad una riduzione marcata e altamente significativa del rilascio di mediatori infiammatori da cellule mastocitarie stimolate con stimoli immunogenici indicando che la miscela, oggetto della presente invenzione esplica una potente attività antiinfiammatoria. The purposes and advantages of the therapeutic or paramedical medical use of this mixture of saturated acyl derivatives condensed with ethanolamine, in pathological states that can be controlled by cannabinoids and endocannabinoids or similar molecules, object of the present invention, will be better understood in the course of the detailed description below. The Applicant has in fact found that, after in vitro treatment, with the mixture object of the invention, there is a marked and highly significant reduction in the release of inflammatory mediators from mast cells stimulated with immunogenic stimuli, indicating that the mixture, object of the present invention exerts a powerful anti-inflammatory activity.
Più in particolare si è utilizzata la linea cellulare RBL-2H3, linea mastocitaria che esprime i recettori ad alta affinità per le immunoglobuline IgE. L’interazione degli antigeni con le molecole di IgE, presenti sulla superficie cellulare, stimola queste cellule a secernere il contenuto proinfiammatorio dei loro granuli intra-citoplasmatici, tra cui quantità significative di: istamina, leucotrieni, prostaglandine e TNF-alfa. Pertanto, le RBL-2H3 rappresentano un ottimo modello cellulare per studiare i meccanismi di esocitosi e di rilascio dei mediatori infiammatori e l’eventuale loro modulazione. In particolare, è stata misurata l’attività dell’enzima b-esosaminidase, il rilascio del quale correla positivamente con la secrezione di mediatori pro-infiammatori molto potenti come l’istamina e il TNF-alfa. More specifically, the RBL-2H3 cell line was used, a mast cell line that expresses high-affinity receptors for IgE immunoglobulins. The interaction of antigens with IgE molecules, present on the cell surface, stimulates these cells to secrete the pro-inflammatory content of their intra-cytoplasmic granules, including significant amounts of: histamine, leukotrienes, prostaglandins and TNF-alpha. Therefore, RBL-2H3 represent an excellent cellular model for studying the mechanisms of exocytosis and release of inflammatory mediators and their possible modulation. In particular, the activity of the enzyme b-hexosaminidase was measured, the release of which correlates positively with the secretion of very powerful pro-inflammatory mediators such as histamine and TNF-alpha.
Questi risultati, nel loro insieme e mai riportati in precedenza, dimostrano che derivati acilici saturi posseggono effetti cannabinoido/endocannabinoido-simili che, visto l’effetto sinergico ottenuto dalla loro associazione, probabilmente vengono esercitati da sistemi recettoriali diversi Tali effetti, valutati in vitro, sono di seguito descritti in dettaglio. These results, taken as a whole and never previously reported, demonstrate that saturated acyl derivatives possess cannabinoid / endocannabinoid-like effects which, given the synergistic effect obtained from their association, are probably exerted by different receptor systems. are described in detail below.
a. Valutazione, in vitro, degli effetti antinfiammatori cannabinoido-mimetici Come già indicato, si è utilizzata la linea cellulare RBL-2H3, linea mastocitaria che esprime i recettori ad alta affinità per le immunoglobuline IgE, mentre la valutazione della vitalità cellulare è stata rilevata con il metodo dell’MTT. Le cellule RBL-2H3 vengono messe in coltura ad una densità di 20.000 cellule/pozzetto (96 wells) ed incubate con IgE-anti-DNP. Dopo circa un’ora, nella coltura viene introdotto l’antigene (DNP) e dopo ulteriori 30 minuti viene raccolto il terreno di coltura. Su questo viene misurata l’attività dell’enzima b-esosaminidase del quale la secrezione correla positivamente con il rilascio di mediatori pro-infiammatori molto potenti come l’istamina e il TNF-alfa. Una riduzione dell’attività enzimatica nel terreno di coltura è indice di minore degranulazione cellulare e quindi di attività antinfiammatoria. Le molecole oggetto del presente brevetto sono state solubilizzate DMSO e aggiunte entrambe a concentrazioni variabili alle colture cellulari 1 ora prima dell’aggiunta dell’antigene. to. In vitro evaluation of cannabinoid-mimetic anti-inflammatory effects As already indicated, the cell line RBL-2H3 was used, a mast cell line that expresses the high affinity receptors for IgE immunoglobulins, while the evaluation of cell viability was detected with the MTT method. RBL-2H3 cells are cultured at a density of 20,000 cells / well (96 wells) and incubated with IgE-anti-DNP. After about an hour, the antigen (DNP) is introduced into the culture and after a further 30 minutes the culture medium is collected. On this, the activity of the enzyme b-hexosaminidase is measured, of which the secretion positively correlates with the release of very powerful pro-inflammatory mediators such as histamine and TNF-alpha. A reduction in enzymatic activity in the culture medium is an indication of lower cell degranulation and therefore of anti-inflammatory activity. The molecules object of this patent were solubilized DMSO and both added at varying concentrations to cell cultures 1 hour before the addition of the antigen.
b. Risultati b. Results
I risultati ottenuti, in termine di riduzione del rilascio di b-esosaminidase sono riportati nella tabella 1 alla pagina seguente. The results obtained, in terms of reduction of the release of b-hexosaminidase, are reported in table 1 on the following page.
Tabella 1 – inibizione del rilascio di b-esosaminidase in terreno di coltura derivante da celluleRBL-2H3 stimolate. Table 1 - Inhibition of b-hexosaminidase release in culture medium resulting from stimulated RBL-2H3 cells.
Visti quindi gli effetti cannabinomimetici, in vitro, dimostrati da queste molecole, le miscele di PEA e SEA oggetto della presente invenzione possono essere utilmente impiegabili per la preparazione di composizioni farmaceutiche per il trattamento terapeutico, da soli o in associazione con altri agenti terapeutici di elezione per lo stato patologico specifico, come ad esempio farmaci antiepilettici, neurolettici, neurolettici atipici, antidepressivi, dopaminergici, dopamino-agonisti, gaba-agonisti, contro l’eccesso ponderale, per il miglioramento della memoria, antinfiammatori/antidolorifici (es. oppiodi, salicilati, pirazolici, indolici, arilantranilici, arilpropionici, arilacetici, oxicami, piranocarbossilici, glucocorticoidi, anti-cox2, nimesulide e acetaminofene), di stati patologici che possono beneficiare di un effetto cannabinomimetico come ad esempio: • per il loro effetto anti-infiammatorio, in patologie infiammatorie croniche, in diversi distretti corporei inclusa la cute, di tipo autoimmunitario e non; Given therefore the cannabinomimetic effects, in vitro, demonstrated by these molecules, the mixtures of PEA and SEA object of the present invention can be usefully used for the preparation of pharmaceutical compositions for the therapeutic treatment, alone or in association with other therapeutic agents of choice. for the specific pathological state, such as antiepileptic drugs, neuroleptics, atypical neuroleptics, antidepressants, dopaminergics, dopamine agonists, gaba-agonists, against excess weight, for memory improvement, anti-inflammatory / painkillers (eg opioids, salicylates , pyrazoles, indoles, arylanthranyls, arylpropionics, arylacetics, oxicams, pyranocarboxyls, glucocorticoids, anti-cox2, nimesulide and acetaminophen), of pathological states that can benefit from a cannabinomimetic effect such as: • for their anti-inflammatory effect, in chronic inflammatory diseases, in various parts of the body including the skin, d autoimmune and non-autoimmune types;
• per la loro capacità di inibire la degranulazione mastocitaria, nella cura di stati allergici. • for their ability to inhibit mast cell degranulation, in the treatment of allergic states.
Le vie di somministrazione che possono essere usate per il trattamento preventivo o terapeutico degli stati patologici secondo la presente invenzione possono essere la via topica, transdermica, rettale e nasale. La miscela secondo l’impiego terapeutico può essere somministrata in composizioni farmaceutiche in combinazione con eccipienti, disperdenti e diluenti noti o nuovi, compatibili con gli impieghi farmaceutici, al fine di ottenere una migliore veicolazione del principio attivo al sito d’azione e di ottenere un effetto rapido, sostenuto o ritardato nel tempo. Allo scopo quindi possono essere impiegate forme farmaceutiche a fast, sustained o slow release. I dosaggi sono dipendenti dalla gravità della patologia e della via di somministrazione scelta, come pure dallo stato (età, peso corporeo, condizioni generali di salute) del paziente ed a scopo illustrativo ma non limitativo della presente invenzione, possono essere compresi tra 1 mg/Kg di peso corporeo e 50 mg/Kg di peso corporeo in somministrazioni giornaliere ripetute per un periodo compreso tra 2 e 16 settimane. Per la somministrazione orale possono essere adatte composizioni sotto forma di polveri disperdibili, compresse, confetti, capsule di gelatina molle o rigida, sospensioni; per la somministrazione topica transdermica, rettale, nasale o sublinguale possono essere adatte composizioni in opportuni eccipienti o disperdenti sotto forma di creme, emulsioni, sospensioni, soluzioni, geli, cerotti, supposte, ovuli, candelette, aereosol o spray. The administration routes which can be used for the preventive or therapeutic treatment of the pathological states according to the present invention can be the topical, transdermal, rectal and nasal route. The mixture according to the therapeutic use can be administered in pharmaceutical compositions in combination with known or new excipients, dispersants and diluents, compatible with pharmaceutical uses, in order to obtain a better delivery of the active principle to the site of action and to obtain a rapid, sustained or delayed effect over time. For this purpose, fast, sustained or slow release pharmaceutical forms can be used. The dosages depend on the severity of the pathology and the chosen route of administration, as well as on the state (age, body weight, general health conditions) of the patient and for illustrative but not limitative purposes of the present invention, they can be comprised between 1 mg / Kg of body weight and 50 mg / Kg of body weight in repeated daily administrations for a period between 2 and 16 weeks. For oral administration, compositions in the form of dispersible powders, tablets, dragees, soft or hard gelatin capsules, suspensions, may be suitable; compositions in suitable excipients or dispersants in the form of creams, emulsions, suspensions, solutions, gels, patches, suppositories, ovules, candles, aerosols or sprays may be suitable for topical transdermal, rectal, nasal or sublingual administration.
A titolo di esempio il trovato trova particolare impiego nella preparazione di composizioni farmaceutiche utili nella cura o prevenzione per il trattamento di patologie ginecologiche come le vulvovaginiti non infettive, lichen sclerosus, iperplasia squamosa, lichen simplex cronico, lichen planus, psoriasi, dermatite eczematosa cronica, vulvite, patologia irritativa vulvare, vulvodinia, craurosi vulvare, patologia infiammatoria vaginale, vaginiti, vaginite nodulare, vaginite papillare, vaginite cistica, vaginite atrofica, vestibulite vulvare, eritema vestibolare, annessite, salpingovarite, endometrite, vaginiti croniche, metriti, parametriti. La composizione può essere in forma di gel vaginale. secondo la seguente formulazione nelle seguenti proporzioni: By way of example, the invention finds particular use in the preparation of pharmaceutical compositions useful in the treatment or prevention for the treatment of gynecological diseases such as non-infectious vulvovaginitis, lichen sclerosus, squamous hyperplasia, chronic lichen simplex, lichen planus, psoriasis, chronic eczematous dermatitis, vulvitis, vulvar irritative pathology, vulvodynia, vulvar craurosis, vaginal inflammatory pathology, vaginitis, nodular vaginitis, papillary vaginitis, cystic vaginitis, atrophic vaginitis, vulvar vestibulitis, vestibular erythema, adnexitis, salpingovaritis, endometritis, vaginitis. The composition can be in the form of a vaginal gel. according to the following formulation in the following proportions:
Glicole Butilenico 10-50% Butylene Glycol 10-50%
− Acqua 50-90% - Water 50-90%
− Sodio Propilacrilato o idrossipropilcellulosa 0.1-0.5% - Sodium Propylacrylate or hydroxypropylcellulose 0.1-0.5%
La composizione trova altro particolare impiego per la preparazione di composizioni farmaceutiche utili nella cura o prevenzione delle patologie cutanee, come dermatite, dermatite atopica, dermatite da contatto, dermatite erpetiforme, dermatite allergica, dermatite seborroica, dermatosi acantolitica o malattia di Grover, penfigo bolloso, psoriasi, cheratosi lichenoide benigna, porpora di Henoch-Schonlein, lupus eritematoso, necrobiosi lipidica diabeticorum, penfigo volgare, fascite eosinofila, eritema nodoso, prurito, orticaria, orticaria pigmentosa, orticaria papulosa, xantoma, sclerosi sistemica, sindrome di Sweet, sindrome di Sjögren, sarcoidosi, eczema, eczema discoide o nummulare, intertrigine, lupus eritematoso discoide, lichen simplex, lichen planus, eczema varicoso, eczema disidrosico, pelle secca, dermatite irritativa primaria, dermatite da pannolino, fotodermatiti, prurigo nodulare, linfoma cutaneo. Detta composizone farmaceutica è preferibilmente in forma di crema dermoprotettiva e comprende composti che sono presenti nella formulazione nelle seguenti proporzioni The composition finds another particular use for the preparation of pharmaceutical compositions useful in the treatment or prevention of skin diseases, such as dermatitis, atopic dermatitis, contact dermatitis, herpetiform dermatitis, allergic dermatitis, seborrheic dermatitis, acantholytic dermatosis or Grover's disease, bullous penphigus, psoriasis, benign lichenoid keratosis, Henoch-Schonlein purpura, lupus erythematosus, diabeticorum lipid necrobiosis, penphigus vulgaris, eosinophilic fasciitis, erythema nodosum, pruritus, urticaria, urticaria pigmentosa, urticaria papulosa, xanthoma, systemic sclerosis syndrome , sarcoidosis, eczema, discoid or nummular eczema, intertrigo, discoid lupus erythematosus, lichen simplex, lichen planus, varicose eczema, dyshydrosis eczema, dry skin, primary irritant dermatitis, diaper rash, photodermatitis, nodular prurigo, cutaneous lymphoma. Said pharmaceutical composition is preferably in the form of a skin protective cream and comprises compounds which are present in the formulation in the following proportions
− Glicole propilenico 40-50% - Propylene glycol 40-50%
− Acqua 40-50% - Water 40-50%
− Polysorbate 60 1-5% - Polysorbate 60 1-5%
− Isopropilmiristato 1-5% - Isopropyl myristate 1-5%
− Glicerilmonostearato 1-10% - Glyceryl monostearate 1-10%
− Sodio Propilacrilato 0.1-0.5% - Sodium Propylacrylate 0.1-0.5%
La composizione trova ulteriore particolare impiego anche nella forma di emulsione gel, dove i seguenti composti sono presenti nella formulazione nelle proporzioni: The composition finds further particular use also in the form of gel emulsion, where the following compounds are present in the formulation in the proportions:
− Glicole propilenico 40-50% - Propylene glycol 40-50%
− Acqua 40-50% - Water 40-50%
− Glicerilmonostearato 1-10% - Glyceryl monostearate 1-10%
− Sodio Poliacrilato 0.1-0.5% - Sodium Polyacrylate 0.1-0.5%
Claims (15)
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Citations (4)
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WO1999060987A2 (en) * | 1998-05-29 | 1999-12-02 | Neurosciences Research Foundation, Inc. | Control of pain with endogenous cannabinoids |
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2009
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WO1999060987A2 (en) * | 1998-05-29 | 1999-12-02 | Neurosciences Research Foundation, Inc. | Control of pain with endogenous cannabinoids |
US7083933B1 (en) * | 2003-05-09 | 2006-08-01 | Prosidion Limited | Methods for identification of modulators of OSGPR116 activity |
WO2008075978A2 (en) * | 2006-12-20 | 2008-06-26 | Seperex Nutritionals Limited | An extract |
WO2009133574A1 (en) * | 2008-04-28 | 2009-11-05 | Vermont Italia Srl | Pharmaceutical formulation containing palmitoyl ethanolamide and stearoyl ethanolamide |
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