IT202100002471A1 - ASSOCIATION OR COMPOSITION COMPRISING STABILIZED LACTOFERRIN - Google Patents
ASSOCIATION OR COMPOSITION COMPRISING STABILIZED LACTOFERRIN Download PDFInfo
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- IT202100002471A1 IT202100002471A1 IT102021000002471A IT202100002471A IT202100002471A1 IT 202100002471 A1 IT202100002471 A1 IT 202100002471A1 IT 102021000002471 A IT102021000002471 A IT 102021000002471A IT 202100002471 A IT202100002471 A IT 202100002471A IT 202100002471 A1 IT202100002471 A1 IT 202100002471A1
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- Prior art keywords
- lactoferrin
- association
- salts
- sialic acid
- composition
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- 102000010445 Lactoferrin Human genes 0.000 title claims description 55
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 title claims description 55
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Description
ASSOCIAZIONE O COMPOSIZIONE COMPRENDENTE LATTOFERRINA COMBINATION OR COMPOSITION INCLUDING LACTOFERRIN
STABILIZZATA STABILIZED
La presente invenzione riguarda l?associazione di lattoferrina, almeno un polisaccaride o sali dello stesso e almeno un acido sialico o sali dello stesso al fine di aumentare la stabilit? della lattoferrina e la conseguente biodisponibilit? della stessa. La presente invenzione riguarda inoltre composizioni farmaceutiche comprendenti detta associazione e l?uso delle stesse. The present invention relates to the association of lactoferrin, at least one polysaccharide or salts thereof and at least one sialic acid or salts thereof in order to increase the stability of lactoferrin and the consequent bioavailability? of the same. The present invention also relates to pharmaceutical compositions comprising said association and the use thereof.
STATO DELLA TECNICA STATE OF THE ART
La recente pandemia globale causata da infezione da SARS-Cov-2 ha causato fino ad oggi pi? di 29.000.000 di infezioni e pi? di 900.000 decessi. The recent global pandemic caused by SARS-Cov-2 infection has caused to date more? than 29,000,000 infections and more? of 900,000 deaths.
Al momento non ? disponibile alcun vaccino per prevenire l?infezione e sono allo studio vari protocolli di trattamento. Not at the moment? no vaccine is available to prevent infection and various treatment protocols are being studied.
SARS-Cov-2 appartiene alla famiglia dei Coronaviridae. SARS-Cov-2 belongs to the Coronaviridae family.
Ad oggi 7 ceppi di coronavirus sono noti infettare gli esseri umani e non sono disponibili terapie o vaccini approvati contro di loro. To date, 7 strains of coronavirus are known to infect humans, and there are no approved therapies or vaccines available against them.
Negli ultimi due decenni, oltre a SARS-CoV-2, altri due ?-coronavirus hanno causato tre delle epidemie pi? gravi al mondo: SARS-CoV e MERS-CoV che causano rispettivamente la Sindrome Respiratoria Acuta Severa (SARS), e la Sindrome Respiratoria del Medio Oriente (MERS). In the past two decades, in addition to SARS-CoV-2, two other ?-coronaviruses have caused three of the world's largest epidemics? serious in the world: SARS-CoV and MERS-CoV causing Severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome (MERS), respectively.
? ben caratterizzato come l?infezione da SARS-CoV sia mediata dalle interazioni ad alta affinit? tra il dominio di legame al recettore (RBD) della glicoproteina spike (S) e il recettore enzima di conversione dell?angiotensina 2 (ACE2) dell?ospite umano. La proteina spike ? situata sull?envelope del virus e promuove l?attacco alla cellula dell?ospite e la fusione tra il virus e la membrana cellulare. ? well characterized how SARS-CoV infection is mediated by high affinity interactions between the receptor binding domain (RBD) of spike (S) glycoprotein and the human host angiotensin converting enzyme 2 (ACE2) receptor. The spike protein? located on the virus envelope and promotes attachment to the host cell and fusion between the virus and the cell membrane.
SARS-CoV-2 ? caratterizzato da un genoma di RNA a singolo filamento e dall?espressione di quattro proteine strutturali essenziali: una glicoproteina spike, una piccola proteina dell?envelope, una proteina della matrice e una proteina del nucleocapside. SARS-CoV-2 ? characterized by a single-stranded RNA genome and the expression of four essential structural proteins: a spike glycoprotein, a small envelope protein, a matrix protein, and a nucleocapsid protein.
La glicoproteina spike (S) ? composta da due subunit? (S1 e S2). Omotrimeri di S sono responsabili del legame con alta affinit? al recettore umano ACE2 che ? espresso sulla superficie delle cellule polmonari, cardiache, renali, intestinali ed endoteliali umane. In particolare, gli epiteli nasali mostrano la pi? alta espressione di ACE2 tra tutte le cellule dell?albero respiratorio indagate. The spike glycoprotein (S) ? composed of two subunits? (S1 and S2). Are homotrimers of S responsible for binding with high affinity? to the human ACE2 receptor that ? expressed on the surface of human lung, heart, kidney, intestinal and endothelial cells. In particular, the nasal epithelia show the most? high expression of ACE2 among all cells of the respiratory tree investigated.
La maggior parte dei pazienti infettati da SARS-Cov-2 mostra sintomi lievi/moderati, ma circa il 15% sviluppa polmonite acuta e circa il 5% progredisce verso sindrome da distress respiratorio acuto, shock settico e/o insufficienza multiorgano, associato ad alta mortalit?. Most patients infected with SARS-Cov-2 show mild/moderate symptoms, but approximately 15% develop acute pneumonia and approximately 5% progress to acute respiratory distress syndrome, septic shock and/or multiple organ failure, associated with high mortality.
Pubblicazioni recenti hanno descritto che la Lattoferrina inibisce l?infezione da SARS-Cov-2 (Carlos Alberto Marques de Carvalho et al ?In Vitro Inhibition of SARS-Cov-2 infection by bovine lactoferrin BioRix prestampato 13 Maggio 2020, Chang et al ?Lactogerrin as potential preventive and adjunct treatment for COVID-19? International Journal of Antimicrobial Agents 5 Agosto 2020, Kell et al ?The biology of Lactoferrin, an iron-binding protein that can help defend against viruses and bacteria? Frontiers in immunology 28 Maggio 2020) e hanno proposto l?uso della Lattoferrina per la prevenzione e/o il trattamento delle infezioni da SARS-Cov-2 e, pi? in generale, per la prevenzione e/o il trattamento delle infezioni batteriche o virali. Recent publications have described that Lactoferrin inhibits SARS-Cov-2 infection (Carlos Alberto Marques de Carvalho et al ?In Vitro Inhibition of SARS-Cov-2 infection by bovine lactoferrin BioRix preprint 13 May 2020, Chang et al ?Lactogerrin as potential preventive and adjunct treatment for COVID-19? International Journal of Antimicrobial Agents 5 August 2020, Kell et al ?The biology of Lactoferrin, an iron-binding protein that can help defend against viruses and bacteria? Frontiers in immunology 28 May 2020) and have proposed the use of Lactoferrin for the prevention and/or treatment of SARS-Cov-2 infections and, more in general, for the prevention and/or treatment of bacterial or viral infections.
Milanetti et al (Milanetti et al ?In-Silico evidence for two receptors based strategy of SARS-CoV-2? Biorix Aprile 2020) hanno recentemente che l?infezione da SARS-Cov-2 delle cellule epiteliali delle vie aeree umane implica non solo interazioni ad alta affinit? con il recettore ACE2 ma anche interazioni a bassa affinit? con polisaccaridi contenenti acido sialico, utilizzando una regione di legame a sialico sulla proteina spike. Milanetti et al (Milanetti et al ?In-Silico evidence for two receptors based strategy of SARS-CoV-2? Biorix April 2020) recently found that SARS-Cov-2 infection of human airway epithelial cells implies not only high affinity interactions? with the ACE2 receptor but also low affinity interactions? with sialic acid-containing polysaccharides, using a sialic-binding region on the spike protein.
SOMMARIO DELL?INVENZIONE SUMMARY OF THE INVENTION
Gli autori della presente invenzione hanno scoperto che a differenza di SARS-CoV ma similmente a MERS-CoV e al virus dell?influenza A, i virioni di SARS CoV 2 possiedono un simile sito di legame a acido sialico e forse interagiscono con oligosaccaridi contenenti acido sialico. Pertanto, la compromissione del legame di oligosaccaridi potrebbe essere una strategia importante per contrastare l?ingresso del virus SARS CoV 2 nelle cellule bersaglio. The authors of the present invention found that unlike SARS-CoV but similar to MERS-CoV and influenza A virus, the virions of SARS CoV 2 possess a similar sialic acid binding site and possibly interact with oligosaccharides containing acid sialic. Thus, impairment of oligosaccharide binding could be an important strategy to counter SARS CoV 2 virus entry into target cells.
La lattoferrina, ovvero lattoferrina bovina (BLf) ? una glicoproteina legante il ferro ripiegata in due lobi globulari simmetrici (N- e C-lobi) con attivit? antimicrobica e immunomodulante. La BLf ? fisiologicamente presente nelle secrezioni esterne, soprattutto nel latte. ? stato mostrato che la BLf possiede attivit? antivirale contro un ampio spettro di virus a RNA e a DNA. Questi virus utilizzano tipicamente molecole comuni sulla membrana cellulare per facilitare la loro invasione nelle cellule. Lactoferrin, or bovine lactoferrin (BLf) ? an iron-binding glycoprotein folded into two symmetrical globular lobes (N- and C-lobes) with activity antimicrobial and immunomodulatory. The BLf? physiologically present in external secretions, especially in milk. ? been shown that the BLf has assets? antiviral against a broad spectrum of RNA and DNA viruses. These viruses typically use common molecules on the cell membrane to facilitate their invasion into cells.
Nel caso del virus dell?influenza, la proteina legante acido sialico emoagglutinina, situata nell?envelope virale (analoga alla proteina spike S1 in SARS CoV 2), svolge un ruolo significativo nelle fasi iniziali dell?infezione virale e rappresenta un bersaglio attraente per lo sviluppo di farmaci antinfluenzali. ? stato dimostrato che l?interazione della lattoferrina con l?emoagglutinina dell?influenza comporta l?inibizione del processo di ingresso virale. In the case of the influenza virus, the sialic acid binding protein hemagglutinin, located in the viral envelope (analogous to the S1 spike protein in SARS CoV 2), plays a significant role in the early stages of viral infection and represents an attractive target for the development of anti-flu drugs. ? The interaction of lactoferrin with influenza hemagglutinin has been shown to inhibit the viral entry process.
Gli autori della presente invenzione hanno sorprendentemente scoperto che la stabilit? termica della lattoferrina pu? essere fortemente aumentata quando la molecola ? combinata con almeno un polisaccaride carico negativamente o sali dello stesso e almeno un acido sialico o sali dello stesso aumentando cos? la biodisponibilit? di detta molecola nelle formulazioni mediche. Inoltre, poich? gli acidi sialici sembrano avere un ruolo chiave nelle vie infettive di diversi virus, incluso Sars-Cov-2, la presenza di un acido sialico nella formulazione pu? competere con l?acido sialico naturalmente presente nella mucina nei dotti aerei, potenziando cos? l?intrappolamento del virus che entra nei dotti aerei esercitato dalla molecola di lattoferrina. The authors of the present invention have surprisingly discovered that the stability? thermal lactoferrin pu? be strongly increased when the molecule ? combined with at least one negatively charged polysaccharide or salts thereof and at least one sialic acid or salts thereof, thus increasing? the bioavailability? of said molecule in medical formulations. Furthermore, since sialic acids seem to have a key role in the infectious pathways of various viruses, including Sars-Cov-2, the presence of a sialic acid in the formulation can compete with the sialic acid naturally present in the mucin in the air ducts, thus enhancing the the trapping of the virus entering the air ducts by the lactoferrin molecule.
L?invenzione fornisce quindi una nuova associazione comprendente lattoferrina, almeno un polisaccaride carico negativamente o sali dello stesso e almeno un acido sialico o sali dello stesso che ? pi? stabile della sola lattoferrina e che, grazie alla presenza di acido sialico intrappola il virus che entra nei dotti aerei arrestando la capacit? del virus di infettare le cellule. The invention thus provides a novel combination comprising lactoferrin, at least one negatively charged polysaccharide or salts thereof and at least one sialic acid or salts thereof which is more stable than lactoferrin alone and which, thanks to the presence of sialic acid, traps the virus that enters the air ducts, stopping the ability? of the virus to infect cells.
In particolare, per virus con un?efficienza infettiva estremamente elevata, quale il Sars-Cov-2, l?associazione fornita nella presente invenzione, quando veicolata nel tratto nasofaringeo e/o orofaringeo, ? un?arma potente nel trattamento o nella prevenzione, o nell?adiuvare il trattamento o la prevenzione di infezioni virali, incluse infezioni da Sars-Cov-2 intrappolando il virus prima della sua penetrazione e replicazione nella cellula. Pertanto, oggetto della presente invenzione sono In particular, for viruses with an extremely high infectious efficiency, such as Sars-Cov-2, the combination provided in the present invention, when conveyed in the nasopharyngeal and/or oropharyngeal tract, is a powerful weapon in the treatment or prevention, or in aiding the treatment or prevention of viral infections, including Sars-Cov-2 infections by trapping the virus before its penetration and replication in the cell. Therefore, the subject of the present invention are
Un?associazione di Lattoferrina, almeno un polisaccaride carico negativamente o sali dello stesso e almeno un acido sialico o sali dello stesso; A combination of Lactoferrin, at least one negatively charged polysaccharide or salts thereof and at least one sialic acid or salts thereof;
Una composizione comprendente detta associazione e uno o pi? veicoli e/o diluenti e/o eccipienti e/o additivi farmaceuticamente/nutraceuticamente accettabili; A composition comprising said association and one or more? pharmaceutically/nutraceutically acceptable carriers and/or diluents and/or excipients and/or additives;
Una composizione o l?associazione comprendente Lattoferrina, almeno un polisaccaride carico negativamente o sali dello stesso e almeno un acido sialico o sali dello stesso come definita nella descrizione e nelle rivendicazioni per uso in un trattamento medico di una malattia virale o come adiuvante in un trattamento medico di una malattia virale o nella prevenzione di un?infezione virale o in un trattamento medico preventivo contro un?infezione virale comprendente la somministrazione della composizione o dell?associazione comprendente Lattoferrina, almeno un polisaccaride carico negativamente o sali dello stesso e almeno un acido sialico o sali dello stesso come definita nella descrizione e nelle rivendicazioni a un individuo che ne necessita; Un dispositivo medico comprendente la composizione o l?associazione comprendente Lattoferrina, almeno un polisaccaride carico negativamente o sali dello stesso e almeno un acido sialico o sali dello stesso come definita nella descrizione e nelle rivendicazioni adatto per la somministrazione della stessa nel tratto nasofaringeo e/o orofaringeo; A composition or combination comprising lactoferrin, at least one negatively charged polysaccharide or salts thereof and at least one sialic acid or salts thereof as defined in the specification and the claims for use in a medical treatment of a viral disease or as an adjuvant in a medical treatment of a viral disease or in the prevention of a viral infection or in a preventive medical treatment against a viral infection comprising the administration of the composition or association comprising Lactoferrin, at least one negatively charged polysaccharide or salts thereof and at least one sialic acid or salts thereof as defined in the specification and claims to an individual in need; A medical device comprising the composition or association comprising Lactoferrin, at least one negatively charged polysaccharide or salts thereof and at least one sialic acid or salts thereof as defined in the description and in the claims suitable for administration thereof in the nasopharyngeal and/or oropharyngeal tract ;
Un procedimento di produzione della composizione come definita nella descrizione e nelle rivendicazioni in cui un?associazione come definita nella descrizione e nelle rivendicazioni ? formulata in unit? di dosaggio adatte con uno o pi? eccipienti e/o additivi farmaceuticamente/nutraceuticamente accettabili. A method of manufacturing the composition as defined in the specification and claims wherein a combination as defined in the specification and claims is formulated in units? dosage suitable with one or more? pharmaceutically/nutraceutically acceptable excipients and/or additives.
GLOSSARIO GLOSSARY
DESCRIZIONE DETTAGLIATA DELLE FIGURE DETAILED DESCRIPTION OF THE FIGURES
Figura 1 Spettri di dicroismo circolare della oloproteina blf (lattoferrina bovina) nativa e non ripiegata in tampone PBS sono mostrati come linea continua insieme con la proteina dispiegata termicamente (95?C per 24 h) nello stesso tampone come linea tratteggiata. Lo spettro CD della proteina dispiegata termicamente ? quindi usato come riferimento per la blf completamente denaturata. Gli spettri CD registrati durante il test di stabilit? sono quindi considerati come una combinazione lineare degli spettri di proteina ripiegata e non ripiegata. Figure 1 Circular dichroism spectra of native and unfolded blf (bovine lactoferrin) holoprotein in PBS buffer are shown as solid line together with thermally unfolded protein (95°C for 24 h) in the same buffer as dashed line. The CD spectrum of the thermally unfolded protein ? hence used as a reference for the fully denatured blf. The CD spectra recorded during the stability test? they are therefore regarded as a linear combination of the folded and unfolded protein spectra.
Figura 2: Curve di denaturazione termica di lattoferrina bovina in tampone PBS in funzione del tempo. Figure 2: Thermal denaturation curves of bovine lactoferrin in PBS buffer as a function of time.
La concentrazione di proteina era 10 mg/mL in tampone PBS pH 7,4. I punti dati cinetici sono stati acquisiti mediante spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?) 25 ?C; (?) 35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. The protein concentration was 10 mg/mL in PBS pH 7.4 buffer. Kinetic data points were acquired by UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?) 25 ?C; (?) 35?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section.
Figura 3 Curve di denaturazione termica di lattoferrina bovina in tampone PBS contenente 1% (p/p) di acido sialico in funzione del tempo. Figure 3 Thermal denaturation curves of bovine lactoferrin in PBS buffer containing 1% (w/w) sialic acid as a function of time.
La concentrazione di proteina era 10 mg/mL in tampone PBS pH 7,4. I punti dati cinetici sono stati acquisiti mediante spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?)25 ?C; (?)35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. The protein concentration was 10 mg/mL in PBS pH 7.4 buffer. Kinetic data points were acquired by UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?)25 ?C; (?)35 ?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section.
Figura 4 Curve di denaturazione termica di lattoferrina bovina in tampone PBS contenente 1% (p/p) di carbossimetilglucano in funzione del tempo. Figure 4 Thermal denaturation curves of bovine lactoferrin in PBS buffer containing 1% (w/w) carboxymethylglucan as a function of time.
La concentrazione di proteina era 10 mg/mL in tampone PBS pH 7,4 e carbossimetilglucano. I punti dati cinetici sono stati acquisiti mediante spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?)25 ?C; (?)35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. The protein concentration was 10 mg/mL in PBS buffer pH 7.4 and carboxymethylglucan. Kinetic data points were acquired by UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?)25 ?C; (?)35 ?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section.
Figura 5 Curve di denaturazione termica di lattoferrina bovina in tampone PBS contenente 1% (p/p) di carbossimetilglucano e 1% di acido sialico in funzione del tempo. Figure 5 Thermal denaturation curves of bovine lactoferrin in PBS buffer containing 1% (w/w) carboxymethylglucan and 1% sialic acid as a function of time.
La concentrazione di proteina era 10 mg/mL in tampone PBS pH 7,4 contenente acido sialico (1%) e carbossimetilglucano (1%). I punti dati cinetici sono stati acquisiti mediante spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?)25 ?C; (?)35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. I valori sono riassunti nella Tabella 1. The protein concentration was 10 mg/mL in PBS pH 7.4 buffer containing sialic acid (1%) and carboxymethylglucan (1%). Kinetic data points were acquired by UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?)25 ?C; (?)35 ?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section. The values are summarized in Table 1.
Figura 6 Curve di denaturazione termica di lattoferrina bovina in tampone PBS contenente 5% (p/p) di carbossimetilglucano e 1% di acido sialico in funzione del tempo. Figure 6 Thermal denaturation curves of bovine lactoferrin in PBS buffer containing 5% (w/w) carboxymethylglucan and 1% sialic acid as a function of time.
La concentrazione della proteina era 10 mg/mL in tampone PBS pH 7,4 contenente acido sialico (1%) e carbossimetilglucano (5%). I punti dati cinetici sono stati acquisiti mediante spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?)25 ?C; (?)35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. I valori sono riassunti nella Tabella 1. The protein concentration was 10 mg/mL in PBS pH 7.4 buffer containing sialic acid (1%) and carboxymethylglucan (5%). Kinetic data points were acquired by UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?)25 ?C; (?)35 ?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section. The values are summarized in Table 1.
DESCRIZIONE DETTAGLIATA DELL?INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
La presente invenzione riguarda un?associazione di Lattoferrina, almeno un polisaccaride carico negativamente o sali dello stesso e almeno un acido sialico o sali dello stesso. L?associazione pu? inoltre comprendere almeno un sale di zinco. The present invention relates to an association of Lactoferrin, at least one negatively charged polysaccharide or salts thereof and at least one sialic acid or salts thereof. The association can further comprising at least one zinc salt.
In una forma di realizzazione dell?invenzione, l?associazione pu? comprendere o essere costituita da In one embodiment of the invention, the association can understand or consist of
Lattoferrina: polisaccaride/i carichi negativamente o sali degli stessi: acido/i sialico/i o sali degli stessi in un rapporto p/p, rispettivamente, da circa 1:1:0,1 a circa 1:5:1. Lactoferrin: Negatively charged polysaccharide(s) or salts thereof: Sialic acid(s) or salts thereof in a w/w ratio, respectively, of about 1:1:0.1 to about 1:5:1.
In una forma di realizzazione, il rapporto p/p Lattoferrina: polisaccaride/i carichi negativamente o sali degli stessi: acido/i sialico/i o sali degli stessi ?, rispettivamente, da circa 1:2:0,1 a circa 1:5:1, da circa 1:3:0,1 a circa 1:5:1; da circa 1:4:0,1 a circa 1:5:1 o da circa 1:5:0,1 a circa 1:5:1. In one embodiment, the w/w ratio of Lactoferrin:negatively charged polysaccharide(s) or salts thereof:sialic acid(s) or salts thereof is, respectively, about 1:2:0.1 to about 1:5 :1, approximately 1:3:0.1 to approximately 1:5:1; approximately 1:4:0.1 to approximately 1:5:1 or approximately 1:5:0.1 to approximately 1:5:1.
In un?ulteriore forma di realizzazione, l?associazione pu? comprendere essere costituita da In a further embodiment, the association can understand be made up of
Lattoferrina: polisaccaride/i carichi negativamente o sali degli stessi: acido/i sialico/i o sali degli stessi: sale/i di zinco in un rapporto p/p, rispettivamente, da circa 1:1:0,1:0 a circa 1:5:1:0,05. Lactoferrin: Negatively charged polysaccharide(s) or salts thereof: Sialic acid(s) or salts thereof: Zinc salt(s) in a w/w ratio of about 1:1:0, 1:0 to about 1, respectively :5:1:0,05.
In una forma di realizzazione, il rapporto p/p Lattoferrina: polisaccaride/i carichi negativamente o sali degli stessi: acido/i sialico/i o sali degli stessi: sale/i di zinco ?, rispettivamente, da circa 1:2:0,1:0 a circa 1:5:1:0,05, da circa 1:3:0,1:0 a circa 1:5:1:0,05; da circa 1:4:0,1:0 a circa 1:5:1:0,05 o da circa 1:5:0,1:0 a circa 1:5:1:0,05. In one embodiment, the w/w ratio of the negatively charged Lactoferrin:polysaccharide(s) or salts thereof:sialic acid(s) or salts thereof:zinc salt(s) is, respectively, from about 1:2:0, 1:0 to approximately 1:5:1:0.05, approximately 1:3:0.1:0 to approximately 1:5:1:0.05; approximately 1:4:0.1:0 to approximately 1:5:1:0.05 or approximately 1:5:0.1:0 to approximately 1:5:1:0.05.
Il peso ? riferito al peso secco di ogni composto. Weight ? referred to the dry weight of each compound.
A titolo di esempio, l?associazione pu? essere un?associazione comprendente o costituita dalle seguenti quantit? di composti in sospensione in acqua sterile o in un altro solvente adatto: By way of example, the association can? be an?association comprising or constituted by the following quantities? of compounds suspended in sterile water or other suitable solvent:
Lattoferrina da 0,01 a 1 % (da 0,1 a 10 mg/mL) Lactoferrin 0.01 to 1% (0.1 to 10 mg/mL)
Polisaccaride/i carichi negativamente o sali degli stessi da 0,01 a 5 % (da 0,1 a 50 mg/mL) Negatively charged polysaccharide(s) or salts thereof 0.01 to 5 % (0.1 to 50 mg/mL)
Acido/i sialico/i o sali degli stessi da 0,001 a 1 % (da 0,01 a 10 mg/mL) Sialic acid(s) or salts thereof 0.001 to 1% (0.01 to 10 mg/mL)
Sale/i di zinco compreso tra 0 e 0,0005 % (da 0 a 0,005 mg/mL) Zinc salt(s) between 0 and 0.0005 % (0 to 0.005 mg/mL)
Secondo la descrizione i sali di ciascun composto sono intesi come sali farmaceuticamente o nutraceuticamente accettabili. According to the description the salts of each compound are intended as pharmaceutically or nutraceutically acceptable salts.
? noto che lo zinco ? un elemento essenziale cruciale per la crescita, lo sviluppo, e il mantenimento della funzione immunitaria. ? noto che lo stato dello zinco ? un fattore critico che pu? influenzare l?immunit? antivirale, in particolare poich? le popolazioni carenti di zinco sono spesso pi? a rischio di contrarre infezioni virali quali da HIV o da virus dell?epatite C e negli ultimi 50 anni si ? accumulata un?abbondanza di prove a dimostrare l?attivit? antivirale dello zinco contro una variet? di virus, e tramite numerosi meccanismi. ? stato recentemente riportato che la maggior parte dei gruppi a rischio descritti per COVID-19 sono allo stesso tempo gruppi associati a carenza di zinco. ? known that the zinc ? an essential element crucial for the growth, development, and maintenance of immune function. ? known that the state of the zinc ? a critical factor that can? affect l? immunity? antiviral, in particular since? populations deficient in zinc are often more? at risk of contracting viral infections such as HIV or hepatitis C virus and in the last 50 years yes? accumulated an abundance of evidence to demonstrate the activity? zinc antiviral against a variety of viruses, and by numerous mechanisms. ? It has recently been reported that most of the described risk groups for COVID-19 are at the same time groups associated with zinc deficiency.
Poich? lo zinco ? essenziale per preservare le barriere naturali dei tessuti quale l?epitelio respiratorio, che impediscono l?ingresso dei patogeni, per una funzione equilibrata del sistema immunitario e del sistema redox, la carenza di zinco pu? probabilmente essere aggiunta ai fattori che predispongono gli individui all?infezione e alla progressione dannosa di COVID-19. Pertanto, l?associazione dell?invenzione pu? vantaggiosamente inoltre comprendere lo Zinco, sotto forma di un sale adatto, per via delle propriet? antivirali di questo ione. Secondo l?invenzione, sali di zinco adatti possono essere zinco solfato, Zn(SO4), zinco acetato, zinco cloruro o una miscela degli stessi. because the zinc ? essential to preserve the natural barriers of tissues such as the respiratory epithelium, which prevent the entry of pathogens, for a balanced function of the immune system and the redox system, zinc deficiency can likely to be added to factors that predispose individuals to infection and harmful progression of COVID-19. Therefore, the association of the invention can? advantageously also understand the Zinc, in the form of a suitable salt, because of the properties? antivirals of this ion. According to the invention, suitable zinc salts can be zinc sulphate, Zn(SO4), zinc acetate, zinc chloride or a mixture thereof.
Secondo l?invenzione, la lattoferrina pu? essere lattoferrina bovina o lattoferrina prodotta per via ricombinante, quale la lattoferrina umana ricombinante. La lattoferrina umana ricombinante pu? essere prodotta in qualsiasi modo noto alla persona esperta, ad es. in cellule batteriche, di lievito, animali o vegetali geneticamente trasformate secondo protocolli noti nella tecnica. According to the invention, lactoferrin can be bovine lactoferrin or recombinantly produced lactoferrin, such as recombinant human lactoferrin. Recombinant human lactoferrin can be produced in any way known to the skilled person, e.g. in bacterial, yeast, animal or vegetable cells genetically transformed according to protocols known in the art.
In una forma di realizzazione preferita, pu? essere utilizzata lattoferrina essiccata, liofilizzata o spray-essiccata. Data la sua facile disponibilit?, si utilizza preferibilmente la lattoferrina bovina. In a preferred embodiment, it can dried, freeze-dried or spray-dried lactoferrin can be used. Given its easy availability, bovine lactoferrin is preferably used.
Sono noti pi? di 50 tipi di acido sialico, ognuno dei quali pu? essere ottenuto da una molecola di acido neuraminico sostituendo il suo gruppo ammino o uno dei suoi gruppi idrossile. In generale, il gruppo ammino porta un gruppo acetile o uno glicolile, ma sono state descritte altre modificazioni. Are they known more? of 50 types of sialic acid, each of which can? be obtained from a neuraminic acid molecule by replacing its amino group or one of its hydroxyl groups. In general, the amino group bears either an acetyl or a glycolyl group, but other modifications have been described.
Sebbene qualsiasi acido sialico sia adatto per la presente invenzione, in una forma di realizzazione preferita l?acido sialico ? come definito nella formula 1 di seguito, While any sialic acid is suitable for the present invention, in a preferred embodiment the sialic acid is as defined in formula 1 below,
In cui In which
R1 ? scelto tra almeno uno di H, CH3, COCH3R1 ? selected from at least one of H, CH3, COCH3
R2 ? scelto tra almeno uno di H, OH, CH3, CH2OH R2 ? selected from at least one of H, OH, CH3, CH2OH
R3 ? scelto tra almeno uno di H, OH, CH3, CH2OH e R3 ? selected from at least one of H, OH, CH3, CH2OH e
R3 ? scelto tra almeno uno di H, OH, CH3, NH COCH3 R3 ? selected from at least one of H, OH, CH3, NH COCH3
come riassunto nella tabella 1 di seguito as summarized in Table 1 below
Sopra sono indicati specifici acidi sialici possibili secondo l?invenzione. Indicated above are specific sialic acids possible according to the invention.
Secondo l?invenzione, polisaccaridi adatti sono polisaccaridi anionici di origine naturale, quali i polisaccaridi estratti da lieviti o da piante o da alghe, incluse frazioni polisaccaridiche di estratti da piante, beta glucani o sali degli stessi, carbossi-metilglucano o sali dello stesso, alginati o sali degli stessi. Un esempio tipico e non vincolante di sali degli stessi ? rappresentato da sali di Na degli stessi. In una forma di realizzazione preferita i polisaccaridi dell?associazione dell?invenzione comprenderanno o saranno costituiti da carbossi-metil-glucano o da sali farmaceuticamente o nutraceuticamente accettabili dello stesso. According to the invention, suitable polysaccharides are anionic polysaccharides of natural origin, such as polysaccharides extracted from yeasts or plants or algae, including polysaccharide fractions of plant extracts, beta-glucans or salts thereof, carboxy-methylglucan or salts thereof, alginates or salts thereof. A typical and non-binding example of salts of the same? represented by Na salts thereof. In a preferred embodiment, the polysaccharides of the combination of the invention will comprise or consist of carboxy-methyl-glucan or pharmaceutically or nutraceutically acceptable salts thereof.
Per via dell?effetto protettivo contro l?infezione virale esercitato dalla lattoferrina, l?associazione in qualsiasi delle forme di realizzazione fornite nella descrizione e nelle rivendicazioni, pu? essere utilizzata in un trattamento medico di una malattia virale o come adiuvante in un trattamento medico di una malattia virale o nella prevenzione di un?infezione virale. Due to the protective effect against viral infection exerted by lactoferrin, the combination in any of the embodiments provided in the description and the claims, may be used in a medical treatment of a viral disease or as an adjuvant in a medical treatment of a viral disease or in the prevention of a viral infection.
Come indicato negli esempi pi? avanti, a seguito dell?associazione con almeno un polisaccaride e almeno un acido sialico come descritto nella presente descrizione, la stabilit? della lattoferrina ? fortemente aumentata, di conseguenza, l?associazione dell?invenzione ? di particolare interesse per uso medico poich? la molecola attiva ? pi? stabile quando associata come descritto nella presente piuttosto che da sola. Pertanto, tra i vantaggi dell?associazione secondo la presente invenzione ci sono i seguenti: As indicated in the examples pi? forward, following the association with at least one polysaccharide and at least one sialic acid as described in the present description, the stability? of lactoferrin? strongly increased, as a consequence, the association of the invention ? of particular interest for medical use since? the active molecule? more stable when combined as described herein rather than alone. Therefore, among the advantages of the association according to the present invention there are the following:
1) la solubilizzazione della lattoferrina e la stabilizzazione della stessa, in particolare in soluzione acquosa; 1) the solubilization of lactoferrin and its stabilization, in particular in aqueous solution;
2) la maggiore stabilit? termica della lattoferrina in soluzione ha costituito un vantaggio dal punto di vista industriale per la produzione di formulazioni liquide. Infatti, questa associazione permette di ottenere un prolungamento della shelf-life della lattoferrina, poich? la molecola non ? soggetta a degradazione o almeno la degradazione ha luogo con modalit? ritardata; 2) the greater stability? of lactoferrin in solution has been an advantage from an industrial point of view for the production of liquid formulations. In fact, this association makes it possible to obtain an extension of the shelf-life of lactoferrin, since it is the molecule not ? subject to degradation or at least the degradation takes place with mode? delayed;
3) a livello produttivo, la solubilizzazione della lattoferrina consente di utilizzare una quantit? inferiore di questa molecola nella produzione di formulazioni liquide di specialit? farmaceutiche, dispositivi medici, integratori dietetici, prodotti cosmetici, alimenti funzionali in pezzi, prodotti veterinari; 3) at the production level, the solubilization of lactoferrin allows you to use a quantity? inferior of this molecule in the production of liquid formulations of specialties? pharmaceuticals, medical devices, dietary supplements, cosmetic products, functional food pieces, veterinary products;
4) la maggiore stabilit? della presente formulazione di lattoferrina consente una migliore biodisponibilit? della stessa. Finora, si raggiungono concentrazioni pi? elevate di questa molecola a livello tissutale in presenza di almeno un polisaccaride e almeno un acido sialico rispetto alla somministrazione della sola lattoferrina, con conseguente aumento dell?efficienza; 4) the greater stability? of this formulation of lactoferrin allows a better bioavailability? of the same. So far, concentrations are reached more? higher levels of this molecule at the tissue level in the presence of at least one polysaccharide and at least one sialic acid compared to the administration of lactoferrin alone, with a consequent increase in efficiency;
5) dato che i polisaccaridi e gli acidi sialici rendono la lattoferrina pi? biodisponibile e di conseguenza pi? efficace, rafforza anche i possibil effetti sinergici tra lattoferrina e altre molecole. 5) given that polysaccharides and sialic acids make lactoferrin more? bioavailable and consequently more? effective, it also strengthens the possible synergistic effects between lactoferrin and other molecules.
Per via del ruolo riportato della lattoferrina e dell?acido sialico nelle infezioni da Coronavirus, l?associazione dell?invenzione ? di particolare interesse quando utilizzata nel trattamento o nella prevenzione, o nell?adiuvare il trattamento o la prevenzione delle infezioni virali causate da un Coronavirus, un rhinovirus, un adenovirus, un virus dell?influenza. Due to the reported role of lactoferrin and sialic acid in Coronavirus infections, the combination of the invention is of particular interest when used in the treatment or prevention, or in aiding the treatment or prevention of viral infections caused by a Coronavirus, a rhinovirus, an adenovirus, an influenza virus.
In una forma di realizzazione preferita delle invenzioni, detto Coronavirus ? Sars-Cov-2, MERS-Cov. In a preferred embodiment of inventions, called Coronavirus ? Sars-Cov-2, MERS-Cov.
L?invenzione comprende quindi anche un metodo per il trattamento o la prevenzione, o per adiuvare il trattamento o la prevenzione di infezioni virali causate da un Coronavirus in cui dosi terapeuticamente efficaci dell?associazione come descritta sopra nella presente e nelle rivendicazioni o della composizione come descritta nella presente pi? avanti e nelle rivendicazioni sono somministrate ad un dosaggio terapeuticamente efficace a un individuo che ne necessita. The invention therefore also comprises a method for the treatment or prevention, or for aiding the treatment or prevention, of viral infections caused by a Coronavirus in which therapeutically effective doses of the combination as described above in the present and in the claims or of the composition as described in this pi? foregoing and in the claims are administered at a therapeutically effective dosage to an individual in need.
La somministrazione pu? essere ripetuta diverse volte al giorno e l?associazione o la composizione pu? essere fornita gi? sotto forma di singole dosi o con un erogatore di singole dosi. The administration can be repeated several times a day and the association or composition can be provided already? in the form of single doses or with a single dose dispenser.
Quantit? terapeuticamente efficace significa una quantit? che ? efficace in terapia, o una quantit? sufficiente a fornire un effetto terapeutico desiderato. Una quantit? che ? efficace in terapia ? una quantit? che produce una o pi? attivit? biologiche desiderate durante il trattamento o la prevenzione di una malattia. Nel presente caso durante il trattamento o la prevenzione di una malattia infettiva virale come definita nella presente. Secondo l?invenzione, l?associazione della composizione pu? essere veicolata nel tratto nasofaringeo e/o orofaringeo dell?individuo trattato. quantity therapeutically effective means a quantity? That ? effective in therapy, or a quantity? sufficient to provide a desired therapeutic effect. A quantity? That ? effective in therapy? a quantity? which produces one or more activity? biological pathways desired during the treatment or prevention of disease. Herein during the treatment or prevention of a viral infectious disease as defined herein. According to the invention, the association of the composition can be conveyed in the nasopharyngeal and/or oropharyngeal tract of the treated individual.
Un ulteriore oggetto della presente invenzione ? una composizione comprendente l?associazione come definita nella descrizione, e nelle rivendicazioni e uno o pi? veicoli e/o diluenti e/o eccipienti e/o additivi farmaceuticamente/nutraceuticamente accettabili. Secondo una forma di realizzazione dell?invenzione, l?unico agente terapeuticamente attivo nella composizione dell?invenzione ? l?associazione come definita nella descrizione e nelle rivendicazioni. In una forma di realizzazione della presente invenzione, la composizione ? in forma di una soluzione, una sospensione uno spray, uno sciroppo, una compressa, una pastiglia, una pillola, una caramella, una gelatina, un granulato (quale un granulato orosolubile), una polvere, una crema, un?emulsione, un gel, una schiuma. A further object of the present invention ? a composition comprising the association as defined in the specification and claims and one or more? pharmaceutically/nutraceutically acceptable carriers and/or diluents and/or excipients and/or additives. According to one embodiment of the invention, the only therapeutically active agent in the composition of the invention is ? the association as defined in the description and in the claims. In one embodiment of the present invention, the composition is in the form of a solution, a suspension, a spray, a syrup, a tablet, a lozenge, a pill, a candy, a jelly, a granulate (such as a buccal granule), a powder, a cream, an emulsion, a gel , a foam.
Quando la composizione ? in forma liquida, la lattoferrina pu? essere opportunamente disciolta in una formulazione liquida comprendente gli altri componenti attivi e facoltativamente uno o pi? eccipienti o carrier aggiuntivi, immediatamente prima dell?uso o dopo l?apertura della fiala contenente la formulazione liquida comprendente gli altri ingredienti attivi. When the composition? in liquid form, lactoferrin pu? be suitably dissolved in a liquid formulation comprising the other active components and optionally one or more? additional excipients or carriers, immediately before use or after opening the vial containing the liquid formulation comprising the other active ingredients.
La composizione pu? anche essere fornita gi? aliquotata in singole dosi o in singole frazioni di dose, o pu? essere fornita in un erogatore atto a rilasciare singola dose o singole frazioni di dose quale, a titolo di esempio, un erogatore atto a rilasciare una quantit? pre-definita di una soluzione sotto forma di spray. The composition can also be provided already? aliquoted in single doses or in single dose fractions, or pu? be supplied in a dispenser suitable for releasing a single dose or single dose fractions such as, by way of example, a dispenser suitable for releasing a quantity pre-defined solution in the form of a spray.
Tra i veicoli e/o i diluenti e/o gli eccipienti accettabili, secondo la via di somministrazione e la pratica degli standard farmaceutici/nutrizionali i seguenti sono adatti per realizzare l?invenzione sebbene la persona esperta in preparazioni di composizioni mediche conoscer? anche altri veicoli e/o diluenti e/o eccipienti accettabili adatti: Of the carriers and/or diluents and/or excipients which are acceptable, depending on the route of administration and practice of pharmaceutical/nutritional standards, the following are suitable for carrying out the invention although the person skilled in the preparation of medical compositions will know also other suitable acceptable vehicles and/or diluents and/or excipients:
- per le formulazioni liquide, preferibilmente un veicolo comprendente: saccarosio o saccarosio con glicerina e/o mannitolo e/o sorbitolo, polisorbato 20, PEG, glicole propilenico; - for liquid formulations, preferably a carrier comprising: sucrose or sucrose with glycerin and/or mannitol and/or sorbitol, polysorbate 20, PEG, propylene glycol;
- per le formulazioni in sospensione e emulsione preferibilmente un veicolo comprendente: una gomma naturale, agar, sodio alginato, carragenina, pectina, metilcellulosa, carbossimetilcellulosa o alcool polivinilico. - for suspension and emulsion formulations preferably a carrier comprising: a natural gum, agar, sodium alginate, carrageenan, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
- per le formulazioni solide preferibilmente un veicolo comprendente uno o pi? diluenti quali: lattosio, destrosio, saccarosio, cellulosa, amido di mais; uno o pi? lubrificanti quali: silice, acido stearico, magnesio o calcio stearato, polietilene glicoli; uno o pi? agenti leganti (agglutinanti) quali: amidi, mucillagini, gelatina, metilcellulosa, carbossimetilcellulosa, o polivinilpirrolidone; uno o pi? agenti disgreganti quali: amido, acido alginico, alginati o glicolati; miscele effervescenti; essiccanti; edulcoranti; uno o pi? agenti umettanti quali: lecitina, polisorbato, laurilsolfato; sostanze note, inattive e non tossiche dal punto di vista farmaceutico/nutraceutico. - for solid formulations preferably a vehicle comprising one or more? diluents such as: lactose, dextrose, sucrose, cellulose, corn starch; one or more lubricants such as: silica, stearic acid, magnesium or calcium stearate, polyethylene glycols; one or more binding agents (caking agents) such as: starches, mucilages, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; one or more disintegrating agents such as: starch, alginic acid, alginates or glycolates; effervescent blends; desiccants; sweeteners; one or more humectant agents such as: lecithin, polysorbate, lauryl sulfate; known, inactive and non-toxic substances from a pharmaceutical/nutraceutical point of view.
I veicolanti, i diluenti e gli eccipienti menzionati sopra vanno intesi esclusivamente a titolo di esempio, non costituendo tuttavia un elenco esaustivo. The carriers, diluents and excipients mentioned above are intended as examples only, however they are not an exhaustive list.
Di seguito vengono forniti esempi della composizione secondo l?invenzione. Examples of the composition according to the invention are given below.
La persona esperta, sulla base della presente descrizione, sar? in grado di preparare altre composizioni aggiungendo all?associazione dell?invenzione composti di formulazione idonei noti nel campo a seconda della forma di composizione desiderata. ESEMPI DI COMPOSIZIONE The expert person, on the basis of this description, will be capable of preparing other compositions by adding to the combination of the invention suitable formulation compounds known in the art depending on the desired composition form. COMPOSITION EXAMPLES
Composizione: Spray nasale: 100 g cont.: Composition: Nasal spray: 100 g cont.:
COMPOSIZIONE #1 COMPOSITION #1
Lattoferrina bovina, 1 g, Carbossimetilglucano sale sodico, 5 g, Acido sialico, sale sodico, 1 g, polisorbato 80, 0,5 g, glicole propilenico, 2 g, Sodio fosfato bibasico, 35 mg, Zinco Solfato, 0,5 mg. Benzalconiocloruro 10 mg, Canfora, 0,1 mg, Eucaliptolo 0,2 mg e acqua purificata fino a 100 g. Bovine Lactoferrin, 1g, Carboxymethylglucan Sodium, 5g, Sialic Acid, Sodium, 1g, Polysorbate 80, 0.5g, Propylene Glycol, 2g, Dibasic Sodium Phosphate, 35mg, Zinc Sulfate, 0.5mg . Benzalkonium chloride 10mg, Camphor, 0.1mg, Eucalyptol 0.2mg and purified water up to 100g.
COMPOSIZIONE #2 COMPOSITION #2
Lattoferrina bovina, 600 mg, Carragenina, 200 mg, Carbossimetilglucano sale sodico, 2,8 g, Acido sialico, sale sodico, 600 mg, potassio sorbato, 0,5 g, glicole propilenico, 2 g, Sodio fosfato bibasico, 35 mg, Zinco solfato, 0,03 mg. Benzalconiocloruro 10 mg, Canfora, 0,1 mg, Xilitolo 0,2 mg e acqua purificata fino a 100 g. Bovine Lactoferrin, 600mg, Carrageenan, 200mg, Carboxymethylglucan Sodium, 2.8g, Sialic Acid, Sodium, 600mg, Potassium Sorbate, 0.5g, Propylene Glycol, 2g, Dibasic Sodium Phosphate, 35mg, Zinc sulphate, 0.03 mg. Benzalkonium chloride 10mg, Camphor, 0.1mg, Xylitol 0.2mg and purified water up to 100g.
COMPOSIZIONE #3 COMPOSITION #3
Lattoferrina bovina, 100 mg, Carbossimetilglucano sale sodico, 500 mg, Acido sialico, sale sodico, 100 mg, potassio sorbato, 0,5 g, glicole propilenico, 2 g, Sodio fosfato bibasico, 35 mg, Zinco solfato, 0,005 mg. Clorexidina gluconato 10 mg, estratto di Phyllantus emblica, 0,2 mg e acqua purificata fino a 100 g Bovine lactoferrin, 100 mg, Carboxymethylglucan sodium salt, 500 mg, Sialic acid, sodium salt, 100 mg, Potassium sorbate, 0.5 g, Propylene glycol, 2 g, Dibasic sodium phosphate, 35 mg, Zinc sulphate, 0.005 mg. Chlorhexidine gluconate 10mg, Phyllantus emblica extract, 0.2mg and purified water up to 100g
Secondo l?invenzione, per le ragioni fornite sopra con riferimento all?associazione, la composizione secondo qualsiasi delle forme di realizzazione fornite nella descrizione o nelle rivendicazioni ? utile in un trattamento medico di una malattia virale o come un adiuvante in un trattamento medico di una malattia virale o nella prevenzione di un?infezione virale. According to the invention, for the reasons given above with respect to the association, the composition according to any of the embodiments provided in the description or in the claims is useful in a medical treatment of a viral disease or as an adjuvant in a medical treatment of a viral disease or in the prevention of a viral infection.
Di conseguenza, in una forma di realizzazione preferita, detta malattia virale o detta infezione virale ? causata da un Coronavirus come pure da altri virus del tratto respiratorio quali rhinovirus, adenovirus, virus dell?influenza etc. In un ulteriore forma di realizzazione preferita detto Coronavirus ? Sars-Cov-2, MERS-Cov come pure altri virus del tratto respiratorio quali rhinovirus, adenovirus, virus dell?influenza etc. Accordingly, in a preferred embodiment, said viral disease or said viral infection is caused by a Coronavirus as well as other respiratory tract viruses such as rhinovirus, adenovirus, influenza virus etc. In a further preferred embodiment called Coronavirus? Sars-Cov-2, MERS-Cov as well as other respiratory tract viruses such as rhinoviruses, adenoviruses, influenza viruses, etc.
Un ulteriore oggetto dell?invenzione riguarda un dispositivo medico comprendente un?associazione o una composizione come definita nella descrizione e nelle rivendicazioni. A further object of the invention relates to a medical device comprising an association or composition as defined in the description and in the claims.
Secondo una forma di realizzazione dell?invenzione, detto dispositivo medico pu? essere un inalatore, un nebulizzatore o un dispositivo che veicola aerosol, per veicolazione di farmaci nasale e/o buccale. According to an embodiment of the invention, said medical device can be an inhaler, nebulizer or aerosol delivery device, for nasal and/or buccal drug delivery.
In una forma di realizzazione, il dispositivo pu? essere atto a miscelare una quantit? adeguata di lattoferrina secca con una quantit? adeguata di una formulazione liquida comprendente o costituita dai rimanenti composti dell?associazione come definita nella descrizione e nelle rivendicazioni e uno o pi? carrier farmaceuticamente efficaci. In one embodiment, the device can be able to mix a quantity? adequate dry lactoferrin with a quantity? suitable preparation of a liquid formulation comprising or consisting of the remaining compounds of the association as defined in the specification and claims and one or more? pharmaceutically effective carriers.
Oggetto dell?invenzione ? anche un procedimento di produzione della composizione secondo una qualsiasi delle forme di realizzazione fornite nella presente descrizione, comprendente il passo di formulare l?associazione come definita in una qualsiasi delle forme di realizzazione fornite nella descrizione e nelle rivendicazioni in unit? di dosaggio adatte con uno o pi? eccipienti e/o additivi farmaceuticamente/nutraceuticamente accettabili. Object of the invention ? Also a method of producing the composition according to any of the embodiments provided in the present description, comprising the step of formulating the association as defined in any of the embodiments provided in the description and in the claims in units? dosage suitable with one or more? pharmaceutically/nutraceutically acceptable excipients and/or additives.
Gli esempi che seguono forniscono dati scientifici che dimostrano l?aumento di stabilit? della lattoferrina nell?associazione dell?invenzione ed esempi specifici e non limitanti dell?associazione e della composizione rivendicate. The following examples provide scientific data demonstrating the increase in stability? of lactoferrin in the combination of the invention and specific and non-limiting examples of the claimed combination and composition.
ESEMPI EXAMPLES
Materiali e Metodi Materials and methods
L?apolattoferrina bovina e lo zinco solfato sono stati ottenuti da Merck. Carbossimetilglucano ? stato ottenuto da e acido sialico ? stato ottenuto da Merck. Gli esperimenti di denaturazione termica sono stati condotti ponendo soluzioni contenenti lattoferrina 10 mg/mL in fiale da 1 mL sterili, sigillate e messe in una stufa termostatabile a 35 o 45 ?C. Gli spettri di dicroismo circolare sono stati misurati su uno spettropolarimetro Jasco 650 (Jasco Europe srl) dotato di un?unit? di controllo termico Peltier. Gli spettri di fluorescenza sono stati misurati su uno spettrofluorimetro Shimazu. Gli spettri CD sono stati acquisiti sui campioni giornalmente o settimanalmente e sono stati deconvoluti secondo il metodo di Chang [. Chang, C. T.; Wu, C. S.; Yang, J. T. Anal Biochem 1978, 91, 13?31.] per stimare la % di strutture secondarie presenti nella soluzione. Si stima che la proteina nativa al 100% contenga il 48% di contenuto ad alfa-elica, il 28% di beta-struttura e il 24% assegnato a spirale estesa. La proteina completamente denaturata ? stata considerata spirale estesa al 100 %, corrispondente alla proteina riscaldata a 95 ?C di 1 ora e poi centrifugata a 10000 RPM in una minicentrifuga eppendorf. Bovine apolactoferrin and zinc sulfate were obtained from Merck. carboxymethylglucan? was obtained from and sialic acid ? been obtained from Merck. Thermal denaturation experiments were conducted by placing solutions containing 10 mg/mL lactoferrin into sterile, sealed 1 mL vials and placed in a heat-settable oven at 35 or 45°C. The circular dichroism spectra were measured on a Jasco 650 spectropolarimeter (Jasco Europe srl) equipped with a unit? Peltier thermal control. The fluorescence spectra were measured on a Shimazu spectrofluorometer. The CD spectra were acquired on the samples daily or weekly and were deconvolved according to Chang's method [. Chang, C.T.; Wu, C.S.; Yang, J. T. Anal Biochem 1978, 91, 13?31.] to estimate the % of secondary structures present in the solution. The 100% native protein is estimated to contain 48% alpha-helical content, 28% beta-structure, and 24% allotted extended coil. The completely denatured protein ? was considered 100% extended spiral, corresponding to the protein heated at 95 ?C for 1 hour and then centrifuged at 10000 RPM in an eppendorf minicentrifuge.
Il pattern di degradazione del prodotto, assumendo che si degradi con una reazione di primo-ordine, pu? essere descritto da un decadimento esponenziale semplice come segue: Y = esp(-kT) [1] The degradation pattern of the product, assuming that it degrades with a first-order reaction, can be described by a simple exponential decay as follows: Y = esp(-kT) [1]
Dove Y rappresenta la frazione di proteina nativa rispetto alla proteina totale, k ? una costante cinetica di primo ordine in giorni<-1>, Where Y represents the fraction of native protein to total protein, k ? a first order kinetic constant in days<-1>,
Il risultato osservato (Y) da ciascun lotto ? stato adattato all?esponenziale singolo [1] con il metodo dei minimi quadrati utilizzando il programma Matlab The observed result (Y) from each batch ? has been adapted to the single exponential [1] with the least squares method using the Matlab program
RISULTATI RESULTS
Lo stato nativo della oloproteina blf ? stato interpretato come quello avente un contenuto di alfa-elica al 48%, beta struttura al 28% e il 24% assegnato a spirale estesa. La quantit? di struttura secondaria, come ottenuta da spettri CD (si veda la Figura 1) ? in discreto accordo con i dati della struttura tridimensionale [https://www.rcsb.org/structure/2HCA, The native state of the blf holoprotein ? interpreted as having an alpha-helix content of 48%, beta structure at 28%, and 24% assigned to extended spiral. The quantity? of secondary structure, as obtained from CD spectra (see Figure 1) ? in fair agreement with the three-dimensional structure data [https://www.rcsb.org/structure/2HCA,
Nella Figura 1, lo spettro della proteina blf nativa in tampone PBS ? mostrato insieme alla proteina dispiegata termicamente (95 ?C per 24 h) nello stesso tampone. Lo spettro CD della proteina dispiegata termicamente viene quindi utilizzato come riferimento per la blf completamente denaturata. Gli spettri CD registrati durante il test di stabilit? sono quindi considerati come una combinazione lineare degli spettri di proteina ripiegata e non ripiegata. Il grado di denaturazione Y ? stato quindi stabilito come la frazione di proteina nativa versus la proteina totale (ripiegata pi? non ripiegata). In Figure 1, the spectrum of native blf protein in PBS buffer ? shown together with the thermally unfolded protein (95 ?C for 24 h) in the same buffer. The CD spectrum of the thermally unfolded protein is then used as a reference for the fully denatured blf. The CD spectra recorded during the stability test? they are therefore regarded as a linear combination of the folded and unfolded protein spectra. The degree of denaturation Y ? was then determined as the fraction of native protein versus total protein (folded plus unfolded).
Pertanto, la proteina blf filtrata sterile e sigillata ? stata sottoposta a un regime di riscaldamento in funzione del tempo e gli spettri CD sono stati registrati a intervalli regolari. La funzione Y ? stata quindi riportata in funzione del tempo come descritto pi? avanti nella sezione dei metodi. La Figura 2 rappresenta la proteina in tampone PBS a 25, 35 e 45 ?C. Therefore, the sterile filtered and sealed blf protein ? was subjected to a heating regime as a function of time and the CD spectra were recorded at regular intervals. The Y function? was then reported as a function of time as described pi? continue in the methods section. Figure 2 represents the protein in PBS buffer at 25, 35 and 45°C.
Le curve di denaturazione termica in funzione del tempo di lattoferrina bovina in tampone PBS contenente 1% (p/p) di acido sialico o carbossimetilglucano (1% o 5 %) in funzione del tempo sono rappresentate nelle figure 2-6. Thermal denaturation versus time curves of bovine lactoferrin in PBS buffer containing 1% (w/w) sialic acid or carboxymethylglucan (1% or 5%) versus time are shown in Figures 2-6 .
I dati relativi alla cinetica della denaturazione di proteina a diverse temperature sono stati quindi adattati a un decadimento esponenziale singolo e riassunti nella TABELLA I. I valori delle costanti cinetiche del primo ordine indicavano che (t1/2 = ln(2)/k) la shelflife (tempo di dimezzamento per la denaturazione) delle formulazioni di lattoferrina variava da un minimo di 69 giorni in tampone non addizionato a 45 ?C a un massimo di 368 giorni in presenza di Carbossimetilglucano e acido sialico. Va detto che ad una temperatura di 45 ?C o superiore (non riportato) si osserva un colore giallastro accompagnato da rilascio di ammonio in presenza di acido sialico dopo 4-5 settimane. Esperimenti di controllo su soluzioni di acido sialico non addizionate hanno dimostrato che l?effetto ? dovuto alla co-presenza di acido sialico e lattoferrina indicando parziale degradazione di acido sialico a T ? 45 ?C. Alla temperatura di conservazione raccomandata di 25?3 ?C, si osserva un netto aumento della stabilit? della struttura secondaria della lattoferrina in presenza di almeno l?1% di CMG o l?1% di acido sialico. La presenza combinata di acido sialico e CMG ciascuno alla concentrazione dell?1% offre solo un modesto aumento della stabilit? (Fig.5 e 6). The data relating to the kinetics of protein denaturation at different temperatures were then fitted to a single exponential decay and summarized in TABLE I. The values of the first order kinetic constants indicated that (t1/2 = ln(2)/k) the shelf life (half-life for denaturation) of lactoferrin formulations ranged from a minimum of 69 days in unspiked buffer at 45°C to a maximum of 368 days in the presence of carboxymethylglucan and sialic acid. It should be noted that at a temperature of 45 ?C or higher (not reported) a yellowish color is observed accompanied by ammonium release in the presence of sialic acid after 4-5 weeks. Control experiments on non-added sialic acid solutions have shown that the effect is ? due to the co-presence of sialic acid and lactoferrin indicating partial degradation of sialic acid at T ? 45?C. At the recommended storage temperature of 25?3?C, a marked increase in stability is observed. of the secondary structure of lactoferrin in the presence of at least 1% CMG or 1% sialic acid. The combined presence of sialic acid and CMG each at a 1% concentration offers only a modest increase in stability. (Fig.5 and 6).
Come mostrato nella figura 2, la concentrazione di proteina era 10 mg/mL in tampone PBS pH 7,4. I punti dati cinetici sono stati acquisiti mediante spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?) 25 ?C; (?) 35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. I valori sono riassunti nella Tabella 1 di seguito. As shown in Figure 2, the protein concentration was 10 mg/mL in PBS buffer pH 7.4. Kinetic data points were acquired by UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?) 25 ?C; (?) 35?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section. The values are summarized in Table 1 below.
Come mostrato nella figura 3, la concentrazione di proteina era 10 mg/mL in tampone PBS pH 7,4. I punti dati cinetici sono stati acquisiti tramite spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?) 25 ?C; (?) 35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. I valori sono riassunti nella Tabella 1 di seguito. As shown in Figure 3, the protein concentration was 10 mg/mL in PBS buffer pH 7.4. Kinetic data points were acquired via UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?) 25 ?C; (?) 35?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section. The values are summarized in Table 1 below.
Come mostrato nella figura 4, la concentrazione di proteina era 10 mg/mL in tampone PBS pH 7,4 e carbossimetilglucano all?1 %. I punti dati cinetici sono stati acquisiti mediante spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?) 25 ?C; (?) 35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. I valori sono riassunti nella Tabella 1. As shown in Figure 4 , the protein concentration was 10 mg/mL in PBS buffer pH 7.4 and 1% carboxymethylglucan. Kinetic data points were acquired by UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?) 25 ?C; (?) 35?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section. The values are summarized in Table 1.
Come mostrato nella figura 5, la concentrazione di proteina era 10 mg/mL in tampone PBS pH 7,4 contenente acido sialico (1%) e carbossimetilglucano (1%). I punti dati cinetici sono stati acquisiti mediante spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?) 25 ?C; (?) 35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. I valori sono riassunti nella Tabella 1. As shown in Figure 5 , the protein concentration was 10 mg/mL in PBS buffer pH 7.4 containing sialic acid (1%) and carboxymethylglucan (1%). Kinetic data points were acquired by UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?) 25 ?C; (?) 35?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section. The values are summarized in Table 1.
Come mostrato nella figura 6 la concentrazione di proteina era 10 mg/mL in tampone PBS pH 7,4 contenente acido sialico (1%) e carbossimetilglucano (5%). I punti dati cinetici sono stati acquisiti mediante spettroscopia UV-CD considerando quindi la perdita progressiva della struttura secondaria. Le temperature sono state: (?)25 ?C; (?)35 ?C; e (?) 45 ?C. Le linee continue sono state ottenute mediante adattamento dei minimi quadrati dei dati al decadimento esponenziale semplice descritto nella sezione dei materiali. I valori sono riassunti nella Tabella 1. As shown in Figure 6 the protein concentration was 10 mg/mL in PBS buffer pH 7.4 containing sialic acid (1%) and carboxymethylglucan (5%). Kinetic data points were acquired by UV-CD spectroscopy thus considering the progressive loss of secondary structure. The temperatures were: (?)25 ?C; (?)35 ?C; and (?) 45 ?C. The solid lines were obtained by least squares fitting of the data to the simple exponential decay described in the materials section. The values are summarized in Table 1.
TABELLA 1 TABLE 1
Risultati di adattamento dei dati rispetto alle Figg.2-6. Data fitting results compared to Figs.2-6.
La costante cinetica k pu? essere ottenuta in giorni<-1 >dalla relazione k = ln(2) / t1/2 The kinetic constant k can? be obtained in days<-1 > from the relation k = ln(2) / t1/2
Come evidente dai dati ottenuti, l?associazione dell?invenzione aumenta fortemente la stabilit? della lattoferrina a temperature da 25 a 45? C. In particolare, si osserva un aumento di 6-8 volte della stabilit? termica della lattoferrina in presenza di almeno l?1 % di carbossimetilglucano, con un modesto aumento della stabilit? fino al 5% di carbossimetilglucano. L?acido sialico alla concentrazione dell?1% produce un aumento di 2-3 volte nella stabilit? ma la sua concentrazione non pu? essere aumentata a causa del rilascio di ammonio a temperature pi? elevate. La miscelazione dell?acido sialico con il carbossimetilglucano fornisce valori di t1/2 che sono paragonabili, o leggermente superiori, a quelli osservati in presenza del solo carbossimetilglucano. In conclusione, gli effetti del carbossimetilglucano e dell?acido sialico sulla stabilit? termica della lattoferrina sono sinergici sebbene non additivi, e l?aumento della concentrazione di carbossimetilglucano superiore all?1% ha solo effetti modesti sulla stabilit? complessiva della lattoferrina. As evident from the data obtained, the association of the invention strongly increases the stability? of lactoferrin at temperatures from 25 to 45? C. In particular, is there a 6-8-fold increase in stability? temperature of lactoferrin in the presence of at least l? 1% of carboxymethylglucan, with a modest increase in the stability? up to 5% carboxymethylglucan. Sialic acid at a concentration of 1% produces a 2-3 fold increase in stability? but his concentration can not? be increased due to the release of ammonium at temperatures pi? elevated. Mixing sialic acid with carboxymethylglucan gives t1/2 values that are comparable to, or slightly higher than, those observed in the presence of carboxymethylglucan alone. In conclusion, the effects of carboxymethylglucan and sialic acid on the stability thermal stability of lactoferrin are synergistic although not additive, and increasing the concentration of carboxymethyl glucan above 1% has only modest effects on stability? total lactoferrin.
Claims (23)
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