IT202000005026A1 - Lactoferrin for inhalation use with antiviral action - Google Patents
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- IT202000005026A1 IT202000005026A1 IT102020000005026A IT202000005026A IT202000005026A1 IT 202000005026 A1 IT202000005026 A1 IT 202000005026A1 IT 102020000005026 A IT102020000005026 A IT 102020000005026A IT 202000005026 A IT202000005026 A IT 202000005026A IT 202000005026 A1 IT202000005026 A1 IT 202000005026A1
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Classifications
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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- A61M15/00—Inhalators
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Description
DESCRIZIONE dell?invenzione avente per titolo: ?Lattoferrina per uso inalatorio ad azione antivirale? DESCRIPTION of the invention entitled:? Lactoferrin for inhalation use with antiviral action?
La presente invenzione si riferisce a una composizione comprendente lattoferrina per uso inalatorio come antivirale, preferibilmente per uso nel trattamento di infezioni virali dell?apparato respiratorio e di sintomi o disturbi derivanti da o connessi a dette infezioni virali, preferibilmente infezioni virali da un SARS-coronavirus (e.g. COVID-19). In aggiunta, la presente invenzione si riferisce a un dispositivo per la somministrazione per via inalatoria di detta composizione comprendente lattoferrina e al suo uso in detti metodi di trattamento di infezioni virali. The present invention relates to a composition comprising lactoferrin for inhalation use as antiviral, preferably for use in the treatment of viral infections of the respiratory system and symptoms or disorders deriving from or connected to said viral infections, preferably viral infections from a SARS-coronavirus (e.g. COVID-19). In addition, the present invention relates to a device for the inhalation administration of said composition comprising lactoferrin and to its use in said methods of treating viral infections.
Le infezioni virali delle vie respiratorie, come dice il nome stesso, sono le malattie infettive causate da virus che colpiscono gli organi dell'apparato respiratorio superiore e/o inferiore (naso, trachea, bronchi e polmoni). Viral respiratory tract infections, as the name implies, are infectious diseases caused by viruses that affect the upper and / or lower respiratory organs (nose, trachea, bronchi and lungs).
Preferibilmente, la presente invenzione si riferisce a infezioni virali causate da almeno un virus della specie coronavirus da sindrome respiratoria acuta grave, abbreviato come SARS-CoV (dall'inglese Severe acute respiratory syndrome-coronavirus). Detti virus della specie SARS-CoV sono virus a RNA monocatenari di polarit? positiva (gruppo IV della classificazione di Baltimore), appartenenti al genere dei Betacoronavirus. Preferably, the present invention refers to viral infections caused by at least one virus of the severe acute respiratory syndrome coronavirus species, abbreviated as SARS-CoV (Severe acute respiratory syndrome-coronavirus). Said viruses of the SARS-CoV species are monocathenary RNA viruses of polarity. positive (group IV of the Baltimore classification), belonging to the genus of Betacoronavirus.
Un virus della specie coronavirus da sindrome respiratoria acuta grave ? il virus all'origine dell'epidemia di SARS del 2002-2003 in Cina, denominato ceppo SARS-CoV. A virus of the severe acute respiratory syndrome coronavirus species? the virus behind the 2002-2003 SARS outbreak in China, known as the SARS-CoV strain.
Fu scoperto per la prima volta nel novembre 2002 nella provincia cinese di Guangdong. Dal 1? novembre 2002 al 31 agosto 2003, il virus contagi? 8.096 persone in una trentina di Paesi, causando 774 decessi, prevalentemente in Cina, Hong Kong, Taiwan e tutto il sud-est asiatico. Verso la fine del 2019 un secondo virus della specie coronavirus da sindrome respiratoria acuta grave, denominato ceppo SARS-CoV-2 o, alternativamente, COVID-19, ha causato una nuova epidemia di SARS in Cina e nel resto del mondo. It was first discovered in November 2002 in China's Guangdong province. From 1? November 2002 to August 31, 2003, is the virus contagious? 8,096 people in thirty countries, causing 774 deaths, mainly in China, Hong Kong, Taiwan and all of Southeast Asia. In late 2019, a second virus of the severe acute respiratory syndrome coronavirus species, called the SARS-CoV-2 strain or, alternatively, COVID-19, caused a new SARS outbreak in China and the rest of the world.
La Richiedente affronta e risolve il problema del trattamento di infezioni virali, preferibilmente infezioni virali delle vie respiratorie (alte e basse vie respiratorie), in particolare di infezioni virali delle vie respiratorie causate da almeno un virus della specie coronavirus da sindrome respiratoria acuta grave (quale ceppo SARS-CoV, SARS-CoV-2/COVID-19 o SARS-CoV-like), fornendo composizioni per uso inalatorio comprendenti lattoferrina o un suo derivato e, opzionalmente, N-acetilcisteina e/o un acido ialuronico o un loro sale, per uso in metodi di trattamento di dette infezioni virali o sintomi o disturbi ad esse connessi. The Applicant addresses and solves the problem of treating viral infections, preferably viral infections of the respiratory tract (upper and lower respiratory tract), in particular of viral infections of the respiratory tract caused by at least one virus of the severe acute respiratory syndrome coronavirus species (such as strain SARS-CoV, SARS-CoV-2 / COVID-19 or SARS-CoV-like), providing compositions for inhalation use comprising lactoferrin or a derivative thereof and, optionally, N-acetylcysteine and / or a hyaluronic acid or a salt thereof , for use in methods of treating said viral infections or related symptoms or disorders.
La lattoferrina, conosciuta anche come lattotransferrina, ? una proteina globulare multifunzionale. La lattoferrina appartiene alla famiglia delle transferrine e possiede una massa molecolare di circa 80 KDa, con due siti di legame per lo ione ferrico (Fe<3+>), similmente alla stessa transferrina. La lattoferrina non ? mai satura di ferro e il suo contenuto ferrico varia. La lattoferrina ha attivit? antimicrobica, sia battericida sia fungicida sia verso vari virus. ? ipotizzato che l'attivit? antimicrobica della lattoferrina sia correlata alla sua affinit? per il Fe<3+>, quindi alla sua elevata capacit? di competere allo stato libero con i microrganismi ferrodipendenti, e ad un'azione diretta sulla membrana esterna dei batteri Gram negativi. La combinazione della lattoferrina con lo ione ferrico nelle secrezioni delle mucose modula l'attivit? e le capacit? aggregative dei batteri e dei virus verso le membrane cellulari. Questo ? dovuto al fatto che alcuni batteri e virus richiedono ferro per poter effettuare la replicazione cellulare e la lattoferrina, al contrario, lo sottrae dall'ambiente circostante, impedendo la proliferazione di detti batteri e virus. Lactoferrin, also known as lactotransferrin,? a multifunctional globular protein. Lactoferrin belongs to the transferrin family and has a molecular mass of about 80 KDa, with two binding sites for the ferric ion (Fe <3+>), similar to the transferrin itself. Lactoferrin not? never saturated with iron and its ferric content varies. Does lactoferrin have activity? antimicrobial, both bactericidal and fungicidal and against various viruses. ? hypothesized that the activity? antimicrobial of lactoferrin is related to its affinity? for the Fe <3+>, therefore to its high capacity? to compete in the free state with the iron-dependent microorganisms, and to a direct action on the outer membrane of Gram negative bacteria. The combination of lactoferrin with ferric ion in mucosal secretions modulates the activity? and the capacities? aggregative of bacteria and viruses towards cell membranes. This ? due to the fact that some bacteria and viruses require iron in order to carry out cell replication and lactoferrin, on the contrary, removes it from the surrounding environment, preventing the proliferation of said bacteria and viruses.
La lattoferrina mostra attivit? antivirale contro i virus del DNA e dell'RNA, inclusi rotavirus, virus respiratorio sinciziale, herpes virus e HIV. L'effetto antivirale dell'LF risiede nella fase iniziale dell'infezione. La lattoferrina impedisce l'ingresso del virus nella cellula ospite, bloccando i recettori cellulari o legandosi direttamente alle particelle del virus. L'effetto antivirale della lattoferrina ? dovuto principalmente alla sua capacit? di legarsi ai glicosamminoglicani della membrana plasmatica. Inoltre, ? noto in letteratura che la lattoferrina partecipa alla risposta immunitaria dell'ospite contro l'invasione acuta da coronavirus della sindrome respiratoria acuta (SARS-CoV) migliorando l'attivit? delle cellule NK e stimolando l'aggregazione e l'adesione dei neutrofili. Inoltre, ? stato ipotizzato che la lattoferrina possa svolgere un ruolo protettivo nella difesa dell'ospite contro l'infezione da SARS-CoV attraverso il legame con gli HSPG (HSPG, proteoglicani eparan solfato di superficie cellulare, ampiamente distribuiti) e bloccando l'interazione preliminare tra SARS-CoV e cellule ospiti, in quanto gli HSPG sono molecole essenziali della superficie cellulare coinvolte nell'ingresso delle cellule SARS-CoV. Does lactoferrin show activity? antiviral against DNA and RNA viruses, including rotavirus, respiratory syncytial virus, herpes virus and HIV. The antiviral effect of LF lies in the initial stage of infection. Lactoferrin prevents the virus from entering the host cell by blocking cell receptors or by binding directly to virus particles. The antiviral effect of lactoferrin? mainly due to its ability? to bind to plasma membrane glycosaminoglycans. Furthermore, ? known in the literature that lactoferrin participates in the host immune response against the acute coronavirus invasion of acute respiratory syndrome (SARS-CoV) by improving activity? of NK cells and stimulating the aggregation and adhesion of neutrophils. Furthermore, ? It has been hypothesized that lactoferrin may play a protective role in host defense against SARS-CoV infection by binding to HSPGs (HSPGs, widely distributed cell surface heparan sulfate proteoglycans) and by blocking the preliminary interaction between SARS -CoV and host cells, as HSPGs are essential cell surface molecules involved in the entry of SARS-CoV cells.
Nel contesto della presente invenzione, per derivati della lattoferrina ? inteso qualunque peptide o proteina globulare multifunzionale derivante dalla lattoferrina che dimostra analoghi effetti antivirali, ad esempio apolattoferrina o lattoferricina. La lattoferricina ? un derivato della lattoferrina con nota attivit? antibatterica. l?apolattoferrina ? la lattoferrina in cui il lobo N-terminale (o apolattoferrina) assume una conformazione aperta. In the context of the present invention, for lactoferrin derivatives? meaning any peptide or multifunctional globular protein derived from lactoferrin that demonstrates similar antiviral effects, for example apolactoferrin or lactoferricin. Lactoferricin? a derivative of lactoferrin with known activity? antibacterial. l? apolactoferrin? lactoferrin in which the N-terminal lobe (or apolactoferrin) takes on an open conformation.
Le composizioni dell?invenzione, a base di lattoferrina o di un suo derivato e, opzionalmente, N-acetilcisteina o un suo sale e/o acido ialuronico o un suo sale, formulate per uso inalatorio, preferibilmente in forma di polveri secche per inalazione, risultano efficaci come antivirali, in particolare nel trattamento di infezioni virali delle vie respiratorie e dei sintomi o disturbi ad esse connessi, in particolare infezioni causate da almeno un virus della specie coronavirus da sindrome respiratoria acuta grave (quale ceppo SARS-CoV, SARS-CoV-2 o SARS-CoV-like). The compositions of the invention, based on lactoferrin or one of its derivatives and, optionally, N-acetylcysteine or one of its salt and / or hyaluronic acid or one of its salt, formulated for inhalation use, preferably in the form of dry powders for inhalation, they are effective as antivirals, in particular in the treatment of viral infections of the respiratory tract and associated symptoms or disorders, in particular infections caused by at least one virus of the severe acute respiratory syndrome coronavirus species (such as SARS-CoV, SARS-CoV strain -2 or SARS-CoV-like).
Le composizioni dell?invenzione, a base di lattoferrina o di un suo derivato e, opzionalmente, acido ialuronico o un suo sale, possono essere formulate, mediante l?aggiunta di specifici eccipienti ed additivi, come soluzioni o emulsioni o dispersioni adatte per essere nebulizzate e somministrate con un dispositivo spray o simili nel naso, nella gola e in bocca per uso inalatorio, orale o nasale. Dette composizioni sprayzzabili risultano efficaci come antivirali, in particolare nel trattamento di infezioni virali delle vie respiratorie e dei sintomi o disturbi ad esse connessi, in particolare infezioni causate da almeno un virus della specie coronavirus da sindrome respiratoria acuta grave (quale ceppo SARS-CoV, SARS-CoV-2 o SARS-CoV-like). The compositions of the invention, based on lactoferrin or a derivative thereof and, optionally, hyaluronic acid or one of its salt, can be formulated, by adding specific excipients and additives, as solutions or emulsions or dispersions suitable for nebulization. and administered with a spray device or similar into the nose, throat and mouth for inhalation, oral or nasal use. Said spray compositions are effective as antivirals, in particular in the treatment of viral infections of the respiratory tract and associated symptoms or disorders, in particular infections caused by at least one virus of the severe acute respiratory syndrome coronavirus species (such as SARS-CoV strain, SARS-CoV-2 or SARS-CoV-like).
Le composizioni dell?invenzione, a base di lattoferrina o di un suo derivato e, opzionalmente, N-acetilcisteina o un suo sale e/o acido ialuronico o un suo sale, non presentano effetti collaterali rilevanti e possono essere somministrate a tutte le categorie di soggetti aventi bisogno, compresi anziani, donne in gravidanza o allattamento, soggetti pediatrici (0-12 anni), soggetti con complicazioni respiratorie o diabete. The compositions of the invention, based on lactoferrin or one of its derivatives and, optionally, N-acetylcysteine or one of its salt and / or hyaluronic acid or one of its salt, have no significant side effects and can be administered to all categories of subjects in need, including the elderly, pregnant or breastfeeding women, pediatric subjects (0-12 years), subjects with respiratory complications or diabetes.
Inoltre, le composizioni dell?invenzione, a base di lattoferrina e, opzionalmente, N-acetilcisteina e/o acido ialuronico, sono di facile preparazione ed economicamente vantaggiose. Furthermore, the compositions of the invention, based on lactoferrin and, optionally, N-acetylcysteine and / or hyaluronic acid, are easy to prepare and economically advantageous.
? noto che la somministrazione per via inalatoria di un farmaco permette un rapido onset (assenza di first pass dallo stomaco e dal fegato) e assenza di effetti collaterali di danneggiamento dello stomaco (ad esempio, dolore, sanguinamento, ulcere e/o indigestione) potenzialmente presenti nella somministrazione orale (gastro-enterale) del farmaco. ? It is known that the inhaled administration of a drug allows a rapid onset (absence of first pass from the stomach and liver) and the absence of potentially present side effects of stomach damage (for example, pain, bleeding, ulcers and / or indigestion) in oral (gastro-enteral) administration of the drug.
Quindi, la somministrazione per via inalatoria di lattoferrina e, opzionalmente, N-acetilcisteina e/o acido ialuronico pu? risultare vantaggiosa rispetto alla classica somministrazione orale in compresse e di alto interesse per pazienti con disturbi connessi a dette infezioni virali. In particolare, il soggetto pu? autosomministrarsi la dose necessaria di lattoferrina e, opzionalmente, N-acetilcisteina e/o acido ialuronico per via inalatoria, che porta ad una pressoch? immediata biodisponibilit? ematica di lattoferrina e, opzionalmente, N-acetilcisteina e/o acido ialuronico nel soggetto. Infatti, la somministrazione per via inalatoria di sostanze attive porta dette sostanze nei polmoni e, quindi, al loro assorbimento nel flusso sanguigno in modo significativamente pi? veloce rispetto ad una somministrazione orale gastro-enterica (e.g. una compressa orale). Therefore, the inhaled administration of lactoferrin and, optionally, N-acetylcysteine and / or hyaluronic acid can? be advantageous compared to the classic oral administration in tablets and of high interest for patients with disorders related to said viral infections. In particular, the subject can? self-administer the necessary dose of lactoferrin and, optionally, N-acetylcysteine and / or hyaluronic acid by inhalation, which leads to an almost? immediate bioavailability lactoferrin and, optionally, N-acetylcysteine and / or hyaluronic acid in the subject. In fact, the inhaled administration of active substances leads these substances into the lungs and, therefore, to their absorption in the bloodstream in a significantly more? faster than a gastrointestinal oral administration (e.g. an oral tablet).
Tuttavia, la somministrazione di farmaci in polvere per via inalatoria pu? comportare problemi di tosse nel soggetto somministrato, di bassi dosaggi dovuti a limitate capacit? di emissione degli inalatori, inconvenienti di impacchettamento delle polveri, inconvenienti di raggiungimento delle vie polmonari solo di una bassa porzione del principio attivo somministrato, difficolt? da parte del soggetto di utilizzare gli inalatori, difficolt? di regolare il dosaggio da parte del soggetto in caso di inalatori multidose, problemi di sterilit? batterica in caso di inalatori multiuso. However, the administration of inhaled powder medications can be used. lead to cough problems in the subject administered, of low dosages due to limited capacity? of emission of the inhalers, drawbacks of packing the powders, drawbacks of reaching the pulmonary pathways of only a low portion of the administered active ingredient, difficulty? on the part of the subject to use the inhalers, difficulty? to adjust the dosage by the subject in case of multidose inhalers, sterility problems? bacterial in case of multipurpose inhalers.
Per superare i suddetti inconvenienti, la Richiedente ha sviluppato un dispositivo (in breve, dispositivo dell?invenzione) comprendente un inalatore monodose, preferibilmente un inalatore monodose monouso, accoppiato con un contenitore monodose comprendente la composizione dell?invenzione che risulta efficace per la somministrazione per via inalatoria di lattoferrina e, opzionalmente, N-acetilcisteina e/o acido ialuronico in forma di polvere ad un soggetto avente bisogno. To overcome the aforementioned drawbacks, the Applicant has developed a device (in short, device of the invention) comprising a single-dose inhaler, preferably a single-dose single-use inhaler, coupled with a single-dose container comprising the composition of the invention which is effective for administration by inhalation route of lactoferrin and, optionally, N-acetylcysteine and / or hyaluronic acid in powder form to a subject in need.
Il dispositivo dell?invenzione risulta di semplice costruzione ed economico. Inoltre, il dispositivo dell?invenzione risulta di semplice utilizzo da parte di qualunque tipo di soggetto, compresi soggetti con difficolt? respiratorie, ad esempio soggetti asmatici, bambini e anziani. Il facile utilizzo del dispositivo dell?invenzione permette di migliorare l'aderenza del soggetto alla terapia. Inoltre, quando il dispositivo dell?invenzione ? monouso risulta esente da problemi di sterilit? batterica. Infine, se l?inserimento della capsula/contenitore comprendente il principio attivo (i.e. lattoferrina e, opzionalmente, N-acetil cisteina e/o acido ialuronico) nell?inalatore avviene da parte del costruttore del dispositivo della presente invenzione, invece che da parte del soggetto utilizzatore, l?utilizza del dispositivo dell?invenzione risulta ancora pi? semplice ed immediato per il soggetto in stato di bisogno. The device of the invention is simple in construction and inexpensive. Furthermore, the device of the invention is easy to use by any type of subject, including subjects with difficulties. respiratory diseases, for example asthmatics, children and the elderly. The easy use of the device of the invention allows to improve the subject's adherence to the therapy. Also, when is the device of the invention? disposable is free from sterility problems? bacterial. Finally, if the insertion of the capsule / container comprising the active ingredient (i.e. lactoferrin and, optionally, N-acetyl cysteine and / or hyaluronic acid) in the inhaler takes place by the manufacturer of the device of the present invention, instead of by the subject user, the use of the device of the invention is even more? simple and immediate for the person in need.
Questi scopi ed altri ancora, che risulteranno chiari dalla descrizione dettagliata che segue, sono raggiunti dalle composizioni, dalle miscele, dal dispositivo e dall?inalatore della presente invenzione grazie alle caratteristiche tecniche rivendicate nelle unite rivendicazioni. These objects and others besides, which will become clear from the detailed description that follows, are achieved by the compositions, mixtures, device and inhaler of the present invention thanks to the technical characteristics claimed in the appended claims.
FIGURE FIGURES
La Fig.1 ? una vista prospettica superiore dell?inalatore visto dalla sua estremit? distale; Fig. 1? a superior perspective view of the inhaler seen from its end distal;
la Fig.2 ? una vista prospettica inferiore dell?inalatore visto dalla sua estremit? distale; Fig.2? a lower perspective view of the inhaler seen from its end distal;
la Fig.3 ? una vista in pianta dall?alto dell?inalatore; la Fig.4 ? una vista analoga alla precedente con la cartuccia montata sull?inalatore; Fig.3? a top plan view of the inhaler; Fig. 4? a view similar to the previous one with the cartridge mounted on the inhaler;
la Fig.5 ? una vista in sezione dell?inalatore lungo il suo piano longitudinale di mezzeria, con la cartuccia montata su di esso; Fig. 5? a sectional view of the inhaler along its longitudinal center plane, with the cartridge mounted thereon;
la Fig.6 ? una vista analoga alla precedente con la cartuccia aperta per l?erogazione della polvere comprendente la composizione dell?invenzione. Fig. 6? a view similar to the previous one with the cartridge open for dispensing the powder comprising the composition of the invention.
DESCRIZIONE DETTAGLIATA DELL?INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Forma oggetto della presente invenzione una composizione per uso inalatorio (in breve, composizione dell?invenzione) per uso come antivirale in un soggetto avente bisogno, preferibilmente per uso in un metodo di trattamento di infezioni virali dell?apparato respiratorio e di sintomi o disturbi derivanti da o connessi a detta infezione virale, in cui detta composizione comprende: The subject of the present invention is a composition for inhalation use (in short, composition of the invention) for use as an antiviral in a subject in need, preferably for use in a method of treating viral infections of the respiratory system and resulting symptoms or disorders. from or related to said viral infection, wherein said composition comprises:
(i) una miscela M (in breve, miscela M dell?invenzione) comprendente o, alternativamente, consistente di lattoferrina o un suo derivato di grado farmaceutico accettabile; e, opzionalmente, (i) a blend M (briefly, blend M of the invention) comprising or, alternatively, consisting of lactoferrin or a derivative thereof of acceptable pharmaceutical grade; and, optionally,
(ii) almeno un additivo e/o eccipiente di grado farmaceutico accettabile. (ii) at least one additive and / or excipient of acceptable pharmaceutical grade.
In una forma di realizzazione, la composizione dell?invenzione comprende detta miscela M dell?invenzione che comprende lattoferrina o un suo derivato e, inoltre, N-acetilcisteina (NAC) o un suo sale di grado farmaceutico accettabile. In one embodiment, the composition of the invention comprises said mixture M of the invention which comprises lactoferrin or a derivative thereof and, in addition, N-acetylcysteine (NAC) or an acceptable pharmaceutical grade salt thereof.
Nel contesto della presente invenzione, quale sale di grado farmaceutico accettabile di N-acetil cisteina (NAC) sono intesi tutti i sali noti nell?arte e/o al tecnico del ramo e idonei all?uso della presente invenzione. Un esempio preferito di sale di N-acetilcisteina di grado farmaceutico accettabile ? il sale di L-lisina di N-acetilcisteina (NAL). In the context of the present invention, as acceptable pharmaceutical grade salt of N-acetyl cysteine (NAC) are meant all the salts known in the art and / or to the person skilled in the art and suitable for the use of the present invention. A preferred example of acceptable pharmaceutical grade N-acetylcysteine salt? the L-lysine salt of N-acetylcysteine (NAL).
L?N-acetilcisteina ? la sostanza identificata con nome IUPAC acido 2R-acetammido-3-sulfanilpropanoico, esempio di CAS: 616-91-1. L?N-acetilcisteina ? un derivato N-acetilato dell'amminoacido cisteina che presenta attivit? antiossidante e mucolitica. Gli antiossidanti sono sostanze che rallentano o prevengono l'ossidazione di altre sostanze. I mucolitici sono sostanze che rendono il muco secreto dall?apparato respiratorio pi? fluido e facilitano il lavoro di espulsione del muco stesso da parte di bronchi e trachea. ? noto che i maggiori determinanti della viscosit? ed elasticit? delle secrezioni dell?apparato respiratorio sono le fucomucine e le immunoglobuline IgG. L?N-acetilcisteina, in particolare, ? caratterizzata dalla capacit? di scindere i ponti di solfuro delle proteine: nel caso del muco, l?N-acetilcisteina depolimerizza i complessi mucoproteici (agglomerati di glicoproteine) in unit? pi? piccole, dotate di minore viscosit?, ed esercita un importante effetto mucolitico e fluidificante sulle secrezioni mucosali e mucopurulente. L? N-acetylcysteine? the substance identified with IUPAC name 2R-acetamido-3-sulfonylpropanoic acid, example of CAS: 616-91-1. L? N-acetylcysteine? an N-acetylated derivative of the amino acid cysteine which exhibits activity? antioxidant and mucolytic. Antioxidants are substances that slow down or prevent the oxidation of other substances. The mucolytics are substances that make the mucus secreted by the respiratory system more? fluid and facilitate the work of expelling the mucus itself from the bronchi and trachea. ? known that the major determinants of viscosity? and elasticity? of the secretions of the respiratory system are fucomucins and IgG immunoglobulins. L? N-acetylcysteine, in particular,? characterized by the ability? to break down the sulphide bridges of proteins: in the case of mucus, N-acetylcysteine depolymerizes the mucoprotein complexes (agglomerates of glycoproteins) in units? pi? small, with lower viscosity, and exerts an important mucolytic and fluidifying effect on mucosal and mucopurulent secretions.
In una forma di realizzazione, la miscela M della composizione dell?invenzione, oltre a lattoferrina o un suo derivato e, opzionalmente, N-acetilcisteina (NAC) o un suo sale, comprende inoltre acido ialuronico (HA) o un suo sale di grado farmaceutico accettabile. In one embodiment, the mixture M of the composition of the invention, in addition to lactoferrin or a derivative thereof and, optionally, N-acetylcysteine (NAC) or a salt thereof, further comprises hyaluronic acid (HA) or a grade salt thereof. pharmaceutical acceptable.
Ad esempio, la miscela M della composizione dell?invenzione comprende o, alternativamente, consiste di lattoferrina, o un suo derivato, e acido ialuronico, o un loro sale di grado farmaceutico accettabile. For example, the mixture M of the composition of the invention comprises or, alternatively, consists of lactoferrin, or a derivative thereof, and hyaluronic acid, or an acceptable pharmaceutical grade salt thereof.
Alternativamente, la miscela M della composizione dell?invenzione comprende, alternativamente, consiste di lattoferrina, o un suo derivato, N-acetilcisteina e acido ialuronico, o un loro sale di grado farmaceutico accettabile. Alternatively, the mixture M of the composition of the invention comprises, alternatively, consists of lactoferrin, or a derivative thereof, N-acetylcysteine and hyaluronic acid, or an acceptable pharmaceutical grade salt thereof.
L?acido ialuronico (ad esempio CAS 9004-61-9) ? un glicosamminoglicano non solforato e privo di core proteico. L?acido ialuronico e i suoi sali sono macromolecole. In particolare, l?acido ialuronico o il suo sale, preferibilmente sodio ialuronato, nel contesto della presente invenzione ha preferibilmente un peso molecolare medio compreso da 20 kDa a 4000 kDa, preferibilmente compreso da 50 kDa a 1500 kDa, ancor pi? preferibilmente compreso da 150 kDa a 1000 kDa. Hyaluronic acid (e.g. CAS 9004-61-9)? a non-sulphured glycosaminoglycan with no core protein. Hyaluronic acid and its salts are macromolecules. In particular, hyaluronic acid or its salt, preferably sodium hyaluronate, in the context of the present invention preferably has an average molecular weight ranging from 20 kDa to 4000 kDa, preferably ranging from 50 kDa to 1500 kDa, even more? preferably comprised from 150 kDa to 1000 kDa.
Nel contesto della presente invenzione per sale dell?acido ialuronico, ? inteso preferibilmente un sale di un metallo alcalino o alcalino terroso, come per esempio sodio, potassio, magnesio o calcio; preferibilmente il sale dell?acido ialuronico ? il sale sodico (sodio ialuronato). In the context of the present invention for hyaluronic acid salt,? preferably a salt of an alkaline or alkaline earth metal, such as for example sodium, potassium, magnesium or calcium; preferably the salt of hyaluronic acid? the sodium salt (sodium hyaluronate).
La presenza di acido ialuronico nella composizione dell?invenzione in combinazione N-acetilcisteina o un suo sale potenzia l?efficacia mucolitica dell?N-acetilcisteina (riduzione di viscosit? del muco e facilit? di espettorare/eliminare il muco per il soggetto affetto da iper-produzione di muco). The presence of hyaluronic acid in the composition of the invention in combination N-acetylcysteine or one of its salt enhances the mucolytic efficacy of N-acetylcysteine (reduction of mucus viscosity and ease of expectoration / elimination of mucus for the subject affected by hyper-production of mucus).
Preferibilmente, l?infezione virale trattata mediante la composizione dell?invenzione ? una infezione causata da un virus della famiglia Coronaviridae, subfamiglia: Coronavirinae, genere: Betacoronavirus, specie: coronavirus da sindrome respiratoria acuta grave o severe acute respiratory syndrome-related coronavirus (in breve, SARSr-CoV o SARS-coronavirus); scelto tra i seguenti ceppi: (I) coronavirus da sindrome respiratoria acuta grave (SARS-CoV o SARS) (II) coronavirus-2 da sindrome respiratoria acuta grave (SARS-CoV-2 o COVID-19 o 2019-nCoV), e (III) coronavirus-like da sindrome respiratoria acuta grave (SARS-CoV-like o SL-CoV); preferibilmente COVID-19. Preferably, the viral infection treated by the composition of the invention? an infection caused by a virus of the family Coronaviridae, subfamily: Coronavirinae, genus: Betacoronavirus, species: severe acute respiratory syndrome coronavirus or severe acute respiratory syndrome-related coronavirus (for short, SARSr-CoV or SARS-coronavirus); selected from the following strains: (I) severe acute respiratory syndrome coronavirus (SARS-CoV or SARS) (II) severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or COVID-19 or 2019-nCoV), and (III) coronavirus-like severe acute respiratory syndrome (SARS-CoV-like or SL-CoV); preferably COVID-19.
In breve, nel contesto della presente invenzione questi virus (e.g. (I), (II) e (III)) sono denominati ?virus della specie SARS-coronavirus? o, semplicemente, ?SARS-coronavirus?. Briefly, in the context of the present invention these viruses (e.g. (I), (II) and (III)) are referred to as? Virus of the SARS-coronavirus species? or, simply,? SARS-coronavirus ?.
I sintomi o disturbi derivanti o connessi a detta infezione virale delle vie respiratorie, preferibilmente infezione da coronavirus come sopra definiti (e.g. SARSr-CoV, SARSr-CoV-2, SARSr-CoV-like) possono essere: sindrome respiratoria acuta (SARS), complicazioni respiratorie, asma, bronco pneumopatia cronica ostruttiva (BPCO), bronchite, enfisema, fibrosi cistica, tosse, pertosse, polmonite, pleurite, bronchiolite, raffreddore, sinusite, rinite, tracheite, faringite, laringite, laringotracheobronchite acuta, epiglottite e bronchiectasia. Symptoms or disorders deriving from or related to said viral respiratory tract infection, preferably coronavirus infection as defined above (e.g. SARSr-CoV, SARSr-CoV-2, SARSr-CoV-like) can be: acute respiratory syndrome (SARS), respiratory complications, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, cough, whooping cough, pneumonia, pleurisy, bronchiolitis, colds, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, acute laryngotracheobronchitis, epiglottitis and bronchiectasis.
Le composizioni dell?invenzione secondo una qualunque delle forme di realizzazione descritte possono essere per uso come coadiuvanti di ulteriori approcci terapeutici antivirali. The compositions of the invention according to any of the disclosed embodiments can be for use as adjuvants of further antiviral therapeutic approaches.
La composizione della presente invenzione, comprendente lattoferrina o un suo derivato e, opzionalmente, N-acetilcisteina o un suo sale e/o acido ialuronico o un suo sale, ? formulata per uso inalatorio, preferibilmente in forma di polvere secca per inalazione per bocca. The composition of the present invention, comprising lactoferrin or a derivative thereof and, optionally, N-acetylcysteine or a salt thereof and / or hyaluronic acid or a salt thereof,? formulated for inhalation use, preferably in dry powder form for inhalation by mouth.
La composizione dell?invenzione formulata per uso inalatorio pu? comprendere almeno un additivo e/o eccipiente di grado farmaceutico accettabile idoneo a detta formulazione della composizione in forma di polvere secca per inalazione per bocca e nota al tecnico del ramo, in cui detto almeno un additivo e/o eccipiente pu? comprendere almeno un primo carrier e/o un almeno un secondo carrier e/o almeno un ulteriore additivo e/o eccipiente diverso da detti primo e secondo carrier, secondo quanto di seguito definito. The composition of the invention formulated for inhalation use can? comprise at least one additive and / or excipient of acceptable pharmaceutical grade suitable for said formulation of the composition in the form of dry powder for inhalation by mouth and known to the person skilled in the art, in which said at least one additive and / or excipient can be used in the art. comprise at least one first carrier and / or at least one second carrier and / or at least one further additive and / or excipient other than said first and second carriers, as defined below.
Detto primo carrier ? scelto tra: lattosio, mannosio, un destrano e loro miscele. Said first carrier? chosen from: lactose, mannose, a dextran and their mixtures.
La composizione dell?invenzione in forma di polvere secca per inalazione pu? comprendere: (i) la miscela M che comprende o, alternativamente, consiste di lattoferrina o un suo derivato; (ii) quale additivo e/o eccipiente, detto almeno un primo carrier scelto tra lattosio, un destrano, mannitolo e loro miscele (preferibilmente lattosio). Preferibilmente, la composizione dell?invenzione comprende lattoferrina e lattosio. The composition of the invention in the form of dry powder for inhalation can? comprising: (i) the mixture M which comprises or, alternatively, consists of lactoferrin or a derivative thereof; (ii) as additive and / or excipient, said at least a first carrier selected from lactose, a dextran, mannitol and their mixtures (preferably lactose). Preferably, the composition of the invention comprises lactoferrin and lactose.
Alternativamente, la composizione dell?invenzione in forma di polvere secca per inalazione pu? comprendere: (i) la miscela M che comprende o, alternativamente, consiste di lattoferrina, o un suo derivato, e N-acetilcisteina, o un suo sale; (ii) quale additivo e/o eccipiente, detto almeno un primo carrier scelto tra lattosio, un destrano, mannitolo e loro miscele (preferibilmente lattosio). Preferibilmente, la composizione dell?invenzione comprende lattoferrina, N-acetilcisteina o un suo sale, lattosio. Alternatively, the composition of the invention in the form of a dry powder for inhalation can be used. comprising: (i) the mixture M comprising or, alternatively, consisting of lactoferrin, or a derivative thereof, and N-acetylcysteine, or a salt thereof; (ii) as additive and / or excipient, said at least a first carrier selected from lactose, a dextran, mannitol and their mixtures (preferably lactose). Preferably, the composition of the invention comprises lactoferrin, N-acetylcysteine or a salt thereof, lactose.
Detto almeno un primo carrier, ad esempio lattosio, pu? essere presente nella composizione dell?invenzione in una % in peso da 1% a 80% rispetto al peso totale della miscela M o della composizione, preferibilmente da 5% a 50%, pi? preferibilmente da 10% a 40%. Said at least a first carrier, for example lactose, can? be present in the composition of the invention in a% by weight of from 1% to 80% with respect to the total weight of the mixture M or of the composition, preferably from 5% to 50%, plus? preferably from 10% to 40%.
In una forma di realizzazione il rapporto in peso miscela M (lattoferrina o un suo derivato e, opzionalmente, N-acetilcisteina o un suo sale): detto almeno un primo carrier (e.g. lattosio) ? compreso nell?intervallo da 10:1 a 1:10, preferibilmente da 5:1 a 1:5, pi? preferibilmente da 2:1 a 1:2. In one embodiment, the mixture weight ratio M (lactoferrin or a derivative thereof and, optionally, N-acetylcysteine or a salt thereof): said at least a first carrier (e.g. lactose)? included in the range from 10: 1 to 1:10, preferably from 5: 1 to 1: 5, plus? preferably from 2: 1 to 1: 2.
Il lattosio (nome IUPAC ?-D-galattopiranosil-(1?4)-D-glucopiranosio, CAS 63-42-3) ? un disaccaride e uno zucchero riducente destrogiro. La molecola del lattosio ? costituita da una molecola di D-galattosio e da una di D-glucosio unite da un legame glicosidico (acetalico) ?(1?4). Il gruppo aldeidico dell'unit? del glucosio ? responsabile delle propriet? riducenti del lattosio. Il lattosio viene aggiunto nelle polveri per inalazione della presente invenzione per migliorare sia l'efficienza con cui si svuota il DPI dopo l'attivazione respiratoria, sia la turbolenza e la dispersione del principio attivo (lattoferrina e, opzionalmente, N-acetilcisteina) all'interno delle piccole vie aeree, sia per evitare l?aggregazione delle particelle della polvere da inalare. Le particelle di lattosio hanno un diametro particellare tale per cui non possono penetrare nelle parti profonde dell'apparato respiratorio, pertanto la maggior parte del lattosio si deposita nell'orofaringe per poi passare nello stomaco dopo essere stata inghiottita. Lactose (IUPAC name? -D-galactopyranosyl- (1? 4) -D-glucopyranose, CAS 63-42-3)? a disaccharide and a dextrorotatory reducing sugar. The lactose molecule? consisting of a molecule of D-galactose and one of D-glucose joined by a glycosidic (acetal) bond? (1? 4). The aldehyde group of the unit? of glucose? property manager lactose reducing agents. Lactose is added in the inhalation powders of the present invention to improve both the efficiency with which the PPE is emptied after respiratory activation, and the turbulence and dispersion of the active ingredient (lactoferrin and, optionally, N-acetylcysteine) to the inside the small airways, both to avoid the aggregation of dust particles to be inhaled. The lactose particles have a particle diameter such that they cannot penetrate the deep parts of the respiratory system, therefore most of the lactose is deposited in the oropharynx and then passes into the stomach after being swallowed.
Detto secondo carrier ? uno stearato scelto nel gruppo comprendente o alternativamente, consistente di: stearato di magnesio, stearato di zinco, stearato di calcio, stearato di sodio, stearato di litio, stearil fumarato di sodio, stearoil lattilato di sodio e loro miscele; pi? preferibilmente stearato di magnesio (o magnesio stearato). Said second carrier? a stearate selected from the group comprising or alternatively, consisting of: magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof; pi? preferably magnesium stearate (or magnesium stearate).
La composizione dell?invenzione in forma di polvere secca per inalazione pu? comprendere: (i) la miscela M che comprende o, alternativamente, consiste di lattoferrina o un suo derivato; (ii) quale additivo e/o eccipiente, detto almeno un secondo carrier scelto tra stearato di magnesio, stearato di zinco, stearato di calcio, stearato di sodio, stearato di litio, stearil fumarato di sodio, stearoil lattilato di sodio e loro miscele (preferibilmente stearato di magnesio). The composition of the invention in the form of dry powder for inhalation can? comprising: (i) the mixture M which comprises or, alternatively, consists of lactoferrin or a derivative thereof; (ii) as additive and / or excipient, said at least a second carrier selected from magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and their mixtures ( preferably magnesium stearate).
Alternativamente, la composizione dell?invenzione in forma di polvere secca per inalazione pu? comprendere: (i) la miscela M che comprende o, alternativamente, consiste di lattoferrina o un suo derivato; (ii) quale additivo e/o eccipiente, detto almeno un primo carrier scelto tra lattosio, un destrano, mannitolo e loro miscele (preferibilmente lattosio) e inoltre detto almeno un secondo carrier scelto tra stearato di magnesio, stearato di zinco, stearato di calcio, stearato di sodio, stearato di litio, stearil fumarato di sodio, stearoil lattilato di sodio e loro miscele (preferibilmente stearato di magnesio). Preferibilmente, la composizione dell?invenzione comprende lattoferrina, lattosio e stearato di magnesio. Alternatively, the composition of the invention in the form of a dry powder for inhalation can be used. comprising: (i) the mixture M which comprises or, alternatively, consists of lactoferrin or a derivative thereof; (ii) as additive and / or excipient, said at least one first carrier selected from lactose, a dextran, mannitol and their mixtures (preferably lactose) and also said at least a second carrier selected from magnesium stearate, zinc stearate, calcium stearate , sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and their mixtures (preferably magnesium stearate). Preferably, the composition of the invention comprises lactoferrin, lactose and magnesium stearate.
Inoltre, la composizione dell?invenzione in forma di polvere secca per inalazione pu? comprendere: (i) la miscela M che comprende o, alternativamente, consiste di lattoferrina, o un suo derivato, e N-acetilcisteina, o un suo sale; (ii) quale additivo e/o eccipiente, detto almeno un secondo carrier scelto tra stearato di magnesio, stearato di zinco, stearato di calcio, stearato di sodio, stearato di litio, stearil fumarato di sodio, stearoil lattilato di sodio e loro miscele (preferibilmente stearato di magnesio). Preferibilmente, la composizione dell?invenzione comprende lattoferrina, N-acetilcisteina, o un suo sale, e stearato di magnesio. Furthermore, the composition of the invention in the form of dry powder for inhalation can be used. comprising: (i) the mixture M comprising or, alternatively, consisting of lactoferrin, or a derivative thereof, and N-acetylcysteine, or a salt thereof; (ii) as additive and / or excipient, said at least a second carrier selected from magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and their mixtures ( preferably magnesium stearate). Preferably, the composition of the invention comprises lactoferrin, N-acetylcysteine, or a salt thereof, and magnesium stearate.
Alternativamente, la composizione dell?invenzione in forma di polvere secca per inalazione pu? comprendere: (i) la miscela M che comprende o, alternativamente, consiste di lattoferrina, o un suo derivato, e N-acetilcisteina, o un suo sale; (ii) quale additivo e/o eccipiente, detto almeno un primo carrier scelto tra lattosio, un destrano, mannitolo e loro miscele (preferibilmente lattosio) e inoltre detto almeno un secondo carrier scelto tra stearato di magnesio, stearato di zinco, stearato di calcio, stearato di sodio, stearato di litio, stearil fumarato di sodio, stearoil lattilato di sodio e loro miscele (preferibilmente stearato di magnesio). Preferibilmente, la composizione dell?invenzione comprende lattoferrina, N-acetilcisteina o un suo sale, lattosio e stearato di magnesio. Alternatively, the composition of the invention in the form of a dry powder for inhalation can be used. comprising: (i) the mixture M comprising or, alternatively, consisting of lactoferrin, or a derivative thereof, and N-acetylcysteine, or a salt thereof; (ii) as additive and / or excipient, said at least one first carrier selected from lactose, a dextran, mannitol and their mixtures (preferably lactose) and also said at least a second carrier selected from magnesium stearate, zinc stearate, calcium stearate , sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and their mixtures (preferably magnesium stearate). Preferably, the composition of the invention comprises lactoferrin, N-acetylcysteine or a salt thereof, lactose and magnesium stearate.
Quindi, la composizione in forma di polvere secca per inalazione della presente invenzione pu? comprendere, quale almeno un additivo e/o eccipiente, detto almeno un secondo carrier (e.g. uno stearato, preferibilmente magnesio stearato) in alternativa a detto primo carrier oppure in aggiunta a detto almeno un primo carrier (e.g. lattosio). Hence, the dry powder composition for inhalation of the present invention can be used. comprising, as at least one additive and / or excipient, said at least a second carrier (e.g. a stearate, preferably magnesium stearate) as an alternative to said first carrier or in addition to said at least one first carrier (e.g. lactose).
Detto almeno un secondo carrier, ad esempio magnesio stearato, pu? essere presente nella miscela M o nella composizione dell?invenzione in una % in peso da 0,05% a 60% rispetto al peso totale della miscela M o della composizione, preferibilmente da 0,1% a 30%, pi? preferibilmente da 0,1% a 10%. Said at least a second carrier, for example magnesium stearate, can? be present in the mixture M or in the composition of the invention in a% by weight of from 0.05% to 60% with respect to the total weight of the mixture M or of the composition, preferably from 0.1% to 30%, plus preferably from 0.1% to 10%.
Quando la composizione dell?invenzione in forma di polvere secca per inalazione comprende sia detto almeno un secondo carrier (e.g. magnesio stearato) sia detto almeno un primo carrier (e.g. lattosio), la somma di detto almeno un primo e un secondo carrier pu? essere presente nella miscela M o nella composizione dell?invenzione in una % in peso da 1% a 80% rispetto al peso totale della miscela M o della composizione, preferibilmente da 5% a 50%, pi? preferibilmente da 10% a 40%. When the composition of the invention in the form of dry powder for inhalation comprises both said at least one second carrier (e.g. magnesium stearate) and said at least one first carrier (e.g. lactose), the sum of said at least one first and a second carrier can be present in the mixture M or in the composition of the invention in a% by weight of from 1% to 80% with respect to the total weight of the mixture M or of the composition, preferably from 5% to 50%, plus preferably from 10% to 40%.
Detto almeno un ulteriore additivo e/o eccipiente di grado farmaceutico accettabile diverso da detti almeno un primo e un secondo carrier, se presente nella composizione dell?invenzione in forma di polvere secca per inalazione, ? scelto nel gruppo comprendente o, alternativamente, consistente di: maltodestrina, leucina, sodio citrato e loro miscele, oppure qualunque altro additivo e/o eccipiente noto al tecnico del ramo. Said at least one further additive and / or excipient of acceptable pharmaceutical grade other than said at least a first and a second carrier, if present in the composition of the invention in the form of dry powder for inhalation,? selected from the group comprising or, alternatively, consisting of: maltodextrin, leucine, sodium citrate and their mixtures, or any other additive and / or excipient known to those skilled in the art.
Preferibilmente, la composizione dell?invenzione o la miscela M dell?invenzione in forma di polvere secca idonea all?inalazione per via orale ha un diametro di particella medio o un diametro medio geometrico di volume (volume median geometric diameter, in breve VMGD) compreso nell?intervallo da 0,5 ?m a 50 ?m, preferibilmente da 0,5 ?m a 20 ?m, pi? preferibilmente da 0.5 ?m a 5 ?m o da 1 ?m a 5 ?m o da 0.5 ?m a 3 ?m o da 1 ?m a 3 ?m, ad esempio circa 0.5 ?m, 1 ?m, 2 ?m, 3 ?m, 4 ?m, 5 ?m (+0,5 ?m). Preferably, the composition of the invention or the mixture M of the invention in the form of dry powder suitable for oral inhalation has an average particle diameter or a geometric mean volume diameter (volume median geometric diameter, VMGD for short) including in the range from 0.5? m to 50? m, preferably from 0.5? m to 20? m, plus preferably 0.5? m to 5? m or 1? m to 5? m or 0.5? m to 3? m or 1? m to 3? m, for example about 0.5? m, 1? m, 2? m, 3? m, 4 ? m, 5? m (+0.5? m).
Il diametro di particella medio o il diametro medio geometrico di volume (volume median geometric diameter, in breve VMGD) della polvere secca della composizione o miscela M della presente invenzione formulata per inalazione sono misurati secondo metodologie standard note al tecnico del ramo, in particolare secondo tecnologie note nel settore delle polveri per inalazione per via orale. The mean particle diameter or the geometric mean volume diameter (volume median geometric diameter, VMGD for short) of the dry powder of the composition or mixture M of the present invention formulated for inhalation are measured according to standard methods known to the skilled in the art, in particular according to technologies known in the field of oral inhalation powders.
La composizione dell?invenzione o la miscela M dell?invenzione, comprendete lattoferrina o un suo derivato e, opzionalmente, N-acetilcisteina o un suo sale e/o acido ialuronico o un suo sale, e, opzionalmente, detto almeno un primo carrier e/o detto almeno un secondo carrier (ad esempio lattosio e/o stearato di magnesio), pu? essere in forma di polvere secca micronizzata. The composition of the invention or the mixture M of the invention, comprise lactoferrin or a derivative thereof and, optionally, N-acetylcysteine or a salt thereof and / or hyaluronic acid or a salt thereof, and, optionally, said at least a first carrier and / or said at least a second carrier (for example lactose and / or magnesium stearate), can? be in the form of micronized dry powder.
Nel contesto della presente invenzione, con il termine ?polvere secca? viene inteso una polvere avente un basso contenuto di umidit?, ad esempio una polvere avente un contenuto compreso nell?intervallo da 0,01% a 15% in peso rispetto al peso totale della polvere, preferibilmente da 0,1% a 10%, pi? preferibilmente da 0,5% a 5%. In the context of the present invention, with the term? Dry powder? a powder having a low moisture content is meant, for example a powder having a content in the range from 0.01% to 15% by weight with respect to the total weight of the powder, preferably from 0.1% to 10%, pi? preferably from 0.5% to 5%.
La composizione dell?invenzione e/o la miscela M dell?invenzione sono prodotte in forma idonea all?inalazione, preferibilmente polvere secca per inalazione, mediante procedimenti noti al tecnico del ramo nel settore dei farmaci o prodotti inalabili. Ad esempio, la composizione dell?invenzione pu? essere preparata mediante un procedimento di miscelazione meccanica dei singoli componenti. Inoltre o in alternativa, la composizione dell?invenzione pu? essere preparata mediante un procedimento di spray-drying. The composition of the invention and / or the mixture M of the invention are produced in a form suitable for inhalation, preferably dry powder for inhalation, by means of processes known to those skilled in the art in the field of drugs or inhalable products. For example, the composition of the invention can? be prepared by means of a mechanical mixing process of the individual components. Furthermore or alternatively, the composition of the invention can? be prepared by a spray-drying process.
La composizione dell?invenzione per uso inalatorio, preferibilmente in forma di polvere secca per inalazione per bocca, risulta efficace come antivirale, in particolare nel trattamento di infezioni delle vie respiratorie causate da un virus SARS-coronavirus, preferibilmente SARS-CoV o COVID-19, in dosaggi giornalieri di lattoferrina compresi nell?intervallo da 5 mg a 1000 mg o da 5 mg a 500 mg, preferibilmente da 10 mg a 300 mg, pi? preferibilmente da 10 mg a 200 mg, ad esempio da 10 mg a 100 mg, da 10 mg a 90 mg, da 10 mg a 80 mg, da 10 mg a 70 mg, da 10 mg a 60 mg, da 10 mg a 50 mg, da 10 mg a 180 mg, da 10 mg a 160 mg, da 10 mg a 140 mg, da 10 mg a 120 mg. The composition of the invention for inhalation use, preferably in the form of dry powder for inhalation by mouth, is effective as antiviral, in particular in the treatment of respiratory tract infections caused by a SARS-coronavirus virus, preferably SARS-CoV or COVID-19 , in daily dosages of lactoferrin included in the range from 5 mg to 1000 mg or from 5 mg to 500 mg, preferably from 10 mg to 300 mg, plus? preferably from 10 mg to 200 mg, for example from 10 mg to 100 mg, from 10 mg to 90 mg, from 10 mg to 80 mg, from 10 mg to 70 mg, from 10 mg to 60 mg, from 10 mg to 50 mg, 10 mg to 180 mg, 10 mg to 160 mg, 10 mg to 140 mg, 10 mg to 120 mg.
I suddetti dosaggi giornalieri possono essere somministrati al soggetto in stato di bisogno in un'unica dose (dose singola) o in dosi ripetute, ad esempio due, tre o 4 dosi giornaliere. The above daily dosages can be administered to the subject in need in a single dose (single dose) or in repeated doses, for example two, three or 4 doses per day.
La composizione dell?invenzione pu? essere somministrata mediante un inalatore adatto all?inalazione di polvere secca noto nell?arte (DPI, dispositivi per inalazione), quale inalatore monodose o multidose, monouso o riutilizzabile dopo ogni dosaggio. The composition of the invention can? be administered via an inhaler suitable for inhaling dry powder known in the art (PPE, inhalation devices), such as single-dose or multi-dose inhaler, disposable or reusable after each dosage.
Forma oggetto della presente invenzione un dispositivo di rilascio di una composizione per via inalatoria (in breve, dispositivo della presente invenzione, quale inalatore pi? composizione) in cui detto dispositivo comprende: The present invention relates to a device for delivering a composition by inhalation (in short, device of the present invention, such as inhaler plus composition) in which said device comprises:
- un inalatore per polvere secca (in breve, inalatore della presente invenzione) avente le caratteristiche riportate di seguito e nel documento brevettuale EP3386575B1 incorporato per riferimento nella presente descrizione nelle parti descriventi l?inalatore, quali da [0024] a [0041] e da Figura 1 a Figura 8; e - an inhaler for dry powder (in short, inhaler of the present invention) having the characteristics indicated below and in patent document EP3386575B1 incorporated by reference in the present description in the parts describing the inhaler, such as from [0024] to [0041] and from Figure 1 to Figure 8; And
- la composizione dell?invenzione secondo una qualsiasi delle forme di realizzazione descritte nella presente invenzione compresa nella cartuccia (C) alloggiata o da alloggiare in detto inalatore, in cui detta composizione comprende: (i) la miscela M comprendente o, alternativamente, consistente di lattoferrina o un suo derivato e, opzionalmente, N-acetilcisteina o un suo sale di grado farmaceutico accettabile e/o acido ialuronico o un suo sale di grado farmaceutico accettabile; e, opzionalmente, detta composizione comprende inoltre (ii) almeno un additivo e/o eccipiente di grado farmaceutico accettabile (i.e. un primo carrier e/o un secondo carrier e/o un ulteriore additivo diverso da detti primo e secondo carrier), in cui detta composizione ? in forma di polvere secca per somministrazione per inalazione avente le caratteristiche definite nella presente invenzione, quali diametro medio geometrico di volume (VMGD), % in peso, rapporti in peso etc. - the composition of the invention according to any one of the embodiments described in the present invention comprised in the cartridge (C) housed or to be housed in said inhaler, wherein said composition comprises: (i) the mixture M comprising or, alternatively, consisting of lactoferrin or a derivative thereof and, optionally, N-acetylcysteine or an acceptable pharmaceutical grade salt thereof and / or hyaluronic acid or an acceptable pharmaceutical grade salt thereof; and, optionally, said composition further comprises (ii) at least one additive and / or excipient of acceptable pharmaceutical grade (i.e. a first carrier and / or a second carrier and / or a further additive other than said first and second carriers), in which said composition? in the form of dry powder for administration by inhalation having the characteristics defined in the present invention, such as geometric mean volume diameter (VMGD),% by weight, weight ratios etc.
Detta composizione dell?invenzione per inalazione, preferibilmente in forma di polvere secca, comprendente lattoferrina o un suo derivato e, opzionalmente N-acetil cisteina e/o acido ialuronico e/o additivi, ? compresa in una cartuccia (C) alloggiata, in modo temporaneo al momento dell?utilizzo o in modo fisso, in detto inalatore della presente invenzione a dare il dispositivo della presente invenzione. Said composition of the invention for inhalation, preferably in the form of a dry powder, comprising lactoferrin or a derivative thereof and, optionally N-acetyl cysteine and / or hyaluronic acid and / or additives,? comprised in a cartridge (C) housed, temporarily at the time of use or in a fixed manner, in said inhaler of the present invention to give the device of the present invention.
L?inalatore monodose dell?invenzione pu? essere un inalatore monodose monouso (a perdere). L?inalatore monodose dell?invenzione ? azionato dal soggetto mediante aspirazione per bocca. The single-dose inhaler of the invention can be a single-use (disposable) single-dose inhaler. The single-dose inhaler of the invention? operated by the subject by mouth suction.
Forme di realizzazione (FRn) dell?inalatore monodose, preferibilmente monodose monouso, della presente invenzione sono le seguenti: Embodiments (FRn) of the single-dose inhaler, preferably single-use single-dose, of the present invention are as follows:
FR1. Inalatore per medicinali in polvere (composizioni in polvere secca per inalazione) costituito da un corpo cavo sagomato sostanzialmente a pipa che presenta una prima porzione (1), per alloggiare una cartuccia (C) di medicinale in polvere, ed una seconda porzione (2) collegata sostanzialmente perpendicolarmente a detta prima porzione (1) per l'erogazione del medicinale mediante un flusso d'aria primario (FP) che porta la polvere da una zona interna di caduta (5), situata sul fondo di detta prima porzione (1), lungo un condotto di erogazione (3) la cui estremit? ? atta ad essere posta nella bocca del paziente, detto condotto di erogazione (3) essendo diviso orizzontalmente da un setto separatore (4) in un condotto superiore (3a) che eroga detto flusso d?aria primario (FP) ed un condotto inferiore (3b) che eroga un flusso d?aria secondario (FS) privo di polvere, l?aspirazione dell?aria che forma il flusso primario (FP) essendo realizzata attraverso almeno tre prese d?aria (7) formate nella prima porzione (1) che sono preferibilmente disposte simmetricamente rispetto al piano di mezzeria longitudinale dell?inalatore, l?aspirazione dell?aria che forma il flusso secondario (FS) essendo realizzata attraverso una presa d?aria (8) ricavata alla estremit? distale di detto condotto inferiore (3b), FR1. Inhaler for powdered medicines (dry powder compositions for inhalation) consisting of a substantially pipe-shaped hollow body which has a first portion (1), to house a cartridge (C) of powdered medicine, and a second portion (2) substantially perpendicularly connected to said first portion (1) for dispensing the medicine by means of a primary air flow (FP) which carries the powder from an internal drop zone (5), located on the bottom of said first portion (1) , along a delivery duct (3) whose end? ? adapted to be placed in the patient's mouth, said delivery duct (3) being divided horizontally by a separator septum (4) into an upper duct (3a) which delivers said primary air flow (FP) and a lower duct (3b ) which delivers a dust-free secondary air flow (FS), the suction of the air that forms the primary flow (FP) being achieved through at least three air intakes (7) formed in the first portion (1) which they are preferably arranged symmetrically with respect to the longitudinal central plane of the inhaler, the aspiration of the air that forms the secondary flow (FS) being realized through an air intake (8) obtained at the end? distal of said lower duct (3b),
l?inalatore essendo caratterizzato dal fatto che detta base di supporto per la cartuccia (C) include una pluralit? di superfici di supporto orizzontali (9) sporgenti all'interno della prima porzione (1), canali di flusso orientati (11) formati nella base di supporto che si estendono tra dette almeno tre prese d'aria (7) e la regione interna di caduta della polvere (5). the inhaler being characterized in that said support base for the cartridge (C) includes a plurality of of horizontal support surfaces (9) projecting inside the first portion (1), oriented flow channels (11) formed in the support base which extend between said at least three air inlets (7) and the internal region of dust fall (5).
FR2. Inalatore secondo la FR1, caratterizzato dal fatto che gli assi longitudinali dei canali (11) che si estendono da prese d?aria (7) laterali formano un angolo (?) con il piano di mezzeria di 55??20%. FR2. Inhaler according to FR1, characterized by the fact that the longitudinal axes of the channels (11) that extend from the lateral air intakes (7) form an angle (?) With the center plane of 55-20%.
FR3. Inalatore secondo una delle FR precedenti, caratterizzato dal fatto che dette superfici di appoggio orizzontali (9) sporgenti all'interno della prima porzione (1) sono formate su un piano corrispondente alla sommit? del condotto superiore (3a) cosicch? anche una porzione distale (9?) di quest?ultima faccia parte della base di supporto. FR3. Inhaler according to one of the previous FRs, characterized in that said horizontal support surfaces (9) projecting inside the first portion (1) are formed on a plane corresponding to the top? of the upper duct (3a) so that? a distal portion (9?) of the latter is also part of the support base.
FR4. Inalatore secondo una delle FR precedenti, caratterizzato dal fatto che il collegamento tra la zona interna (5) di caduta della polvere ed il condotto superiore (3a) ? realizzato attraverso una griglia (6). FR4. Inhaler according to one of the previous FRs, characterized in that the connection between the internal area (5) where the powder falls and the upper duct (3a)? made through a grid (6).
FR5. Inalatore secondo una delle FR precedenti, caratterizzato dal fatto di comprendere inoltre tre setti verticali (14) che si estendono per tutta l?altezza della griglia (6) e la dividono in quattro zone di ingresso dell?aria, detti setti verticali (14) essendo preferibilmente disposti in modo che dette zone di ingresso abbiano la stessa larghezza. FR5. Inhaler according to one of the previous FRs, characterized by the fact that it also comprises three vertical septa (14) which extend for the entire height of the grille (6) and divide it into four air inlet areas, called vertical septa (14) being preferably arranged so that said inlet areas have the same width.
FR6. Inalatore secondo una delle FR precedenti, caratterizzato dal fatto che il setto separatore (4) ? pi? corto del condotto di erogazione (3), preferibilmente di una distanza (d) compresa tra 4 e 7 mm. FR6. Inhaler according to one of the previous FRs, characterized by the fact that the separating septum (4)? pi? short of the delivery duct (3), preferably with a distance (d) comprised between 4 and 7 mm.
FR7. Inalatore secondo una delle FR precedenti, caratterizzato dal fatto che la prima porzione (1) comprende una parete perimetrale (12) che si estende al di sopra della base di supporto ed ? provvista di mezzi di accoppiamento per il bloccaggio della cartuccia (C) sull?inalatore. FR7. Inhaler according to one of the preceding FRs, characterized in that the first portion (1) comprises a perimeter wall (12) which extends above the support base and? provided with coupling means for locking the cartridge (C) on the inhaler.
FR8. Inalatore secondo una delle FR precedenti, caratterizzato dal fatto che, in corrispondenza di ciascuna superficie di appoggio (9), la parete perimetrale (12) ha una zona elastica (12a) di spessore ridotto con un dente triangolare centrale (12b) che sporge all?interno, detto dente (12b) essendo ricavato con una superficie inclinata che si estende dalla sommit? della parete (12) verso la base di supporto e con una base orizzontale inferiore in modo da formare un invito per l?inserimento dall?alto della cartuccia (C) ed un sottosquadro per il suo bloccaggio sulla base di supporto. FR8. Inhaler according to one of the previous FRs, characterized by the fact that, in correspondence with each support surface (9), the perimeter wall (12) has an elastic zone (12a) of reduced thickness with a central triangular tooth (12b) that protrudes all the way ? internal, said tooth (12b) being obtained with an inclined surface that extends from the top? of the wall (12) towards the support base and with a lower horizontal base so as to form an opening for the insertion of the cartridge from the top (C) and an undercut for its locking on the support base.
FR9. Inalatore secondo una delle FR precedenti, caratterizzato dal fatto che la presa d?aria (8) del condotto inferiore (3b) ? divisa in una pluralit? di zone di ingresso dell?aria, preferibilmente aventi la stessa larghezza, da uno o pi? setti allungati (15), preferibilmente non pi? di sette, che si estendono al di sotto della zona (5) di caduta della polvere. FR9. Inhaler according to one of the previous FRs, characterized in that the air intake (8) of the lower duct (3b)? divided into a plurality? of air inlet areas, preferably having the same width, from one or more? elongated septa (15), preferably no more? of seven, which extend below the dust fall zone (5).
FR10. Inalatore secondo una delle FR precedenti, caratterizzato dal fatto che la sezione minima di ingresso del condotto superiore (3a) ? di 25,6 mm??20%, la sezione minima di ingresso del condotto inferiore (3b) ? di 14,3 mm??20%, ed il rapporto tra dette sezioni pu? variare nell?intervallo da 1:1 a 9:1. FR10. Inhaler according to one of the previous FRs, characterized in that the minimum inlet section of the upper duct (3a)? 25.6 mm ?? 20%, the minimum inlet section of the lower duct (3b)? of 14.3 mm ?? 20%, and the ratio between these sections pu? vary in the range from 1: 1 to 9: 1.
FR11. Inalatore secondo una delle FR precedenti, caratterizzato dal fatto che le prese d?aria (7) per il flusso d?aria primario (FP) consistono in sporgenze, preferibilmente semicircolari, ricavate nella parete inferiore della prima porzione (1) al di sotto della base di supporto. FR11. Inhaler according to one of the previous FRs, characterized by the fact that the air intakes (7) for the primary air flow (FP) consist of projections, preferably semicircular, obtained in the lower wall of the first portion (1) below the support base.
FR12. Dispositivo monodose a perdere (monouso) per l?inalazione di lattoferrina o un suo derivato e, opzionalmente, N-acetilcisteina o un suo sale e/o acido ialuronico o un suo sale in polvere, caratterizzato dal fatto di comprendere un inalatore secondo una delle rivendicazioni da 9 a 11 ed una cartuccia auto-forante comprendente la composizione in polvere secca dell?invenzione bloccata sulla base di supporto di detto inalatore, detta cartuccia (C) avente una forma a pianta longitudinale simmetrica sostanzialmente corrispondente alla forma di detta base di supporto e una regione (P) progettata per ricevere la pressione delle dita di un paziente per aprire la cartuccia (C), detta regione (P) essendo centrata sul piano di simmetria longitudinale della cartuccia (C). FR12. Disposable single-dose device (disposable) for the inhalation of lactoferrin or one of its derivatives and, optionally, N-acetylcysteine or one of its salt and / or hyaluronic acid or one of its salt in powder form, characterized in that it comprises an inhaler according to one of the claims 9 to 11 and a self-piercing cartridge comprising the dry powder composition of the invention blocked on the support base of said inhaler, said cartridge (C) having a longitudinal symmetrical plan shape substantially corresponding to the shape of said support base and a region (P) designed to receive the pressure of a patient's fingers to open the cartridge (C), said region (P) being centered on the longitudinal plane of symmetry of the cartridge (C).
La somministrazione delle composizioni dell?invenzione, comprendenti lattoferrina o un suo derivato e, opzionalmente, N-acetilcisteina o un suo sale e/o acido ialuronico o un suo sale, in forma di polvere secca per inalazione mediante il dispositivo di rilascio dell?invenzione, azionato dall?aspirazione del soggetto avente bisogno, ? tale da rendere effettiva la somministrazione della dose efficace e massima l?efficacia intrinseca delle composizioni dell?invenzione stessa. The administration of the compositions of the invention, comprising lactoferrin or a derivative thereof and, optionally, N-acetylcysteine or a salt thereof and / or hyaluronic acid or a salt thereof, in the form of dry powder for inhalation by means of the release device of the invention , activated by the aspiration of the subject in need,? such as to make effective the administration of the effective dose and maximum the intrinsic efficacy of the compositions of the invention itself.
La composizione dell?invenzione in forma di polvere secca per inalazione, secondo una qualsiasi delle forme di realizzazione definite nella presente invenzione, mostra una buona scorrevolezza, una buona uniformit? di distribuzione del principio attivo e un'adeguata stabilit? chimica e fisica prima dell'uso. The composition of the invention in dry powder form for inhalation, according to any of the embodiments defined in the present invention, exhibits good flowability, good uniformity. distribution of the active ingredient and adequate stability? chemistry and physics before use.
Inoltre, la composizione dell?invenzione in forma di polvere secca per inalazione, quando inalata per mezzo dell?inalatore dell?invenzione attivato mediante singola azione di aspirazione da parte del soggetto a cui ? somministrata la composizione, d? origine a una buona frazione respirabile e a una dose terapeuticamente attiva accurata del principio attivo. Furthermore, the composition of the invention in the form of a dry powder for inhalation, when inhaled by means of the inhaler of the invention activated by a single suction action by the subject to whom? given the composition, d? originate a good respirable fraction and an accurate therapeutically active dose of the active ingredient.
Il termine "buona scorrevolezza" si riferisce a una composizione che pu? essere facilmente gestita durante il procedimento di preparazione ed ? in grado di garantire una somministrazione accurata e riproducibile della dose terapeuticamente efficace quando somministrata con il dispositivo dell?invenzione mediante azione di aspirazione del soggetto. Le caratteristiche del flusso possono essere valutate misurando l'indice di Carr; un indice di Carr inferiore a 25 ? di solito preso per indicare buone caratteristiche di flusso. The term "good smoothness" refers to a composition that can? be easily managed during the preparation process and d? capable of ensuring accurate and reproducible administration of the therapeutically effective dose when administered with the device of the invention by aspirating the subject. The characteristics of the flow can be evaluated by measuring the Carr index; a Carr index below 25? usually taken to indicate good flow characteristics.
L'espressione ?uniformit? di distribuzione? si riferisce a una composizione in cui, al momento della miscelazione, l'uniformit? del contenuto del principio attivo, espressa come deviazione standard relativa (RSD), ? inferiore al 5%. The expression? Uniformity? distribution? refers to a composition in which, at the time of mixing, the uniformity? of the content of the active substance, expressed as relative standard deviation (RSD),? less than 5%.
L'espressione "chimicamente stabile" si riferisce a una formulazione che soddisfa i requisiti della linea guida ICH Q1A riferita a "Test di stabilit? di nuove sostanze attive (e medicinali)". The term "chemically stable" refers to a formulation that meets the requirements of the ICH Q1A guideline referring to "Stability test of new active substances (and medicinal products)".
L'espressione "fisicamente stabile? si riferisce a una formulazione in cui se presenti pi? componenti delle particelle di polvere secca della composizione dell?invenzione, queste componenti non si separano sostanzialmente durante il procedimento di preparazione della polvere secca e/o durante il tempo compreso tra la preparazione e l?uso della composizione. The term "physically stable" refers to a formulation in which if multiple components of the dry powder particles of the composition of the invention are present, these components do not substantially separate during the dry powder preparation process and / or over time. between the preparation and the use of the composition.
La tendenza a separare pu? essere valutata secondo Staniforth et al., J. Pharm. Pharmacol., 34.700-706, 1982, che ? qui incorporato come riferimento nella sua interezza, ed ? considerato accettabile se la distribuzione del principio attivo nella composizione in polvere secca dopo il test, espressa come deviazione standard relativa (RSD), non cambia in modo significativo rispetto a quello della composizione prima del test. The tendency to separate can? be evaluated according to Staniforth et al., J. Pharm. Pharmacol., 34.700-706, 1982, what? incorporated herein as a reference in its entirety, and d? considered acceptable if the distribution of the active substance in the dry powder composition after the test, expressed as relative standard deviation (RSD), does not change significantly compared to that of the composition before the test.
L'espressione "frazione respirabile" si riferisce a un indice della percentuale di particelle di ingrediente attivo che raggiunge i polmoni (zona profonda) in un soggetto. La frazione respirabile, definita anche frazione di particelle fini (FPF, fine particle fraction), viene valutata utilizzando idonei apparati in vitro come Multistage Cascade Impactor o Multi Stage Liquid Impinger (MLSI) secondo le procedure riportate nelle comuni farmacopee. La FPF viene calcolata dal rapporto tra la dose erogata e la massa di particelle fini (o dose di particelle fini, in breve FPD, fine particle dose). Una frazione respirabile superiore al 30% ? un indice di buone prestazioni inalatorie. The term "respirable fraction" refers to an index of the percentage of active ingredient particles that reach the lungs (deep area) in an individual. The respirable fraction, also called fine particle fraction (FPF), is evaluated using suitable in vitro apparatuses such as Multistage Cascade Impactor or Multi Stage Liquid Impinger (MLSI) according to the procedures reported in the common pharmacopoeias. FPF is calculated from the ratio between the delivered dose and the mass of fine particles (or fine particle dose, FPD for short, fine particle dose). A breathable fraction greater than 30%? an index of good inhalation performance.
L'espressione "dose terapeuticamente attiva accurata del principio attivo" si riferisce a una composizione in cui la variazione tra la dose giornaliera media erogata e la dose media emessa ? pari o inferiore al 15%, preferibilmente inferiore al 10%. The term "accurate therapeutically active dose of active ingredient" refers to a composition in which the variation between the average daily delivered dose and the average emitted dose? equal to or less than 15%, preferably less than 10%.
Nel contesto della presente invenzione, i termini ?agente attivo?, ?principio attivo? e ?ingrediente attivo? sono sinonimi e fanno riferimento alla lattoferrina o un suo derivato e, opzionalmente, all? N-acetilcisteina e suoi sali di grado farmaceutico o alimentare accettabili e/o acido ialuronico e suoi sali di grado farmaceutico o alimentare accettabili. In the context of the present invention, the terms? Active agent ?,? Active ingredient? and? active ingredient? are synonyms and refer to lactoferrin or its derivative and, optionally, to all? N-acetylcysteine and its acceptable pharmaceutical or food grade salts and / or hyaluronic acid and its acceptable pharmaceutical or food grade salts.
Se non diversamente specificato, l?espressione composizione o miscela o altro che comprende un componente in una quantit? ?compresa in un intervallo da x a y? intende che detta componente pu? essere presente nella composizione o miscela o altro in tutte le quantit? presenti in detto intervallo, anche se non esplicitate, estremi dell?intervallo compresi. Unless otherwise specified, the expression composition or mixture or other that includes a component in a quantity? is in a range from x to y? do you mean that this component can? be present in the composition or mixture or other in all quantities? present in said interval, even if not explicit, extremes of the interval included.
Se non diversamente specificato, l?indicazione che una composizione o miscela ?comprende? uno o pi? componenti o sostanze significa che altri componenti o sostanze possono essere presenti oltre a quello, o quelli, specificamente indicati. Unless otherwise specified, an indication that a composition or mixture? Includes? one or more? components or substances means that other components or substances may be present in addition to that, or those, specifically indicated.
Per ?metodo di trattamento? nell?ambito della presente invenzione si intende un intervento su un soggetto avente bisogno, comprendente la somministrazione di una composizione o miscela di sostanze, avente come finalit? l?eliminazione, la riduzione/diminuzione o la prevenzione di una patologia o malattia e dei suoi sintomi o disturbi. By? Method of treatment? in the ambit of the present invention it is meant an intervention on a subject in need, comprising the administration of a composition or mixture of substances, having as final aim? the elimination, reduction / reduction or prevention of a disease or disease and its symptoms or disorders.
Con il termine ?soggetto/i? nell?ambito della presente invenzione vengono indicati soggetti umani o soggetti animali, preferibilmente mammiferi (e.g. animali da compagnia come cani, gatti, cavalli, pecore o bovini). With the term? Subject (s)? within the scope of the present invention, human subjects or animal subjects are indicated, preferably mammals (e.g. companion animals such as dogs, cats, horses, sheep or cattle).
Preferibilmente, le composizioni dell?invenzione sono per uso in metodi di trattamento su soggetti umani. Preferably, the compositions of the invention are for use in treatment methods on human subjects.
Claims (10)
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IT102020000005026A IT202000005026A1 (en) | 2020-03-09 | 2020-03-09 | Lactoferrin for inhalation use with antiviral action |
EP21717209.7A EP4117712A1 (en) | 2020-03-09 | 2021-03-09 | Lactoferrin for oral inhalation use for the treatment of a disease caused by a sars-corona virus |
PCT/IB2021/051941 WO2021181261A1 (en) | 2020-03-09 | 2021-03-09 | Lactoferrin for oral inhalation use for the treatment of a disease caused by a sars-corona virus |
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IT102020000005026A IT202000005026A1 (en) | 2020-03-09 | 2020-03-09 | Lactoferrin for inhalation use with antiviral action |
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WO2023230057A1 (en) * | 2022-05-23 | 2023-11-30 | Tygrus, LLC | Therapeutic useful against antimicrobial resistant agents |
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