IT202000028082A1 - COMPOSITION, PREPARATION AND USE OF A BROME-BASED MIXTURE FOR PERIOCULAR HYGIENE, TREATMENT AND PREVENTION OF BLEPHARITIS - Google Patents
COMPOSITION, PREPARATION AND USE OF A BROME-BASED MIXTURE FOR PERIOCULAR HYGIENE, TREATMENT AND PREVENTION OF BLEPHARITIS Download PDFInfo
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- IT202000028082A1 IT202000028082A1 IT102020000028082A IT202000028082A IT202000028082A1 IT 202000028082 A1 IT202000028082 A1 IT 202000028082A1 IT 102020000028082 A IT102020000028082 A IT 102020000028082A IT 202000028082 A IT202000028082 A IT 202000028082A IT 202000028082 A1 IT202000028082 A1 IT 202000028082A1
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- atcc
- blepharitis
- solution
- concentration
- prevention
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- 208000010217 blepharitis Diseases 0.000 title claims description 32
- 238000011282 treatment Methods 0.000 title claims description 19
- 239000000203 mixture Substances 0.000 title claims description 15
- 230000002265 prevention Effects 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title description 4
- 239000000243 solution Substances 0.000 claims description 45
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 30
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 28
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 26
- 229910052794 bromium Inorganic materials 0.000 claims description 25
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 15
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 14
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- 239000005708 Sodium hypochlorite Substances 0.000 claims description 11
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- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 claims description 9
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- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 3
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- 238000012360 testing method Methods 0.000 description 34
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
Descrizione dell?invenzione industriale dal titolo: ?COMPOSIZIONE, PREPARAZIONE ED IMPIEGO DI UNA MISCELA A BASE DI BROMO PER L?IGIENE PERIOCULARE, IL TRATTAMENTO E LA PREVENZIONE DELLE BLEFARITI?, Description of the industrial invention entitled: ?COMPOSITION, PREPARATION AND USE OF A BROME-BASED BLEND FOR PERIOCULAR HYGIENE, TREATMENT AND PREVENTION OF BLEPHARITIS?,
DESCRIZIONE DESCRIPTION
Sommario dell?invenzione Summary of the invention
La presente invenzione riguarda il settore medico-farmaceutico e, pi? precisamente, dei preparati ad uso topico esterno (soluzioni), in particolare una soluzione acquosa per uso esterno comprendente Bromuro di Potassio (KBr), Ipoclorito di Sodio (NaClO) ed Acido Fosforico (H3PO4). La soluzione, cos? stabilizzata, ed a pH neutro, sviluppa Ipobromito di Sodio, che svolge elevata attivit? battericida cos? da poter utilizzare il prodotto nel mantenimento dell?igiene della zona perioculare, delle ciglia e delle palpebre, con buona tollerabilit? locale, nel trattamento e nella e prevenzione delle blefariti. The present invention relates to the medical-pharmaceutical sector and, more precisely, preparations for external topical use (solutions), in particular an aqueous solution for external use comprising Potassium Bromide (KBr), Sodium Hypochlorite (NaClO) and Phosphoric Acid (H3PO4). The solution, what? stabilized, and at neutral pH, it develops sodium hypobromite, which carries out high activity? bactericide what? to be able to use the product in maintaining the hygiene of the eye area, eyelashes and eyelids, with good tolerability? local, in the treatment and prevention of blepharitis.
Ambito dell?invenzione Scope of the invention
La blefarite ? una infiammazione cronica delle palpebre, la quale pu? coinvolgere altre strutture oculari come la ghiandola di Meibomio (Wolffsohn et al. 2017) che provoca, a sua volta, secchezza oculare evaporativa ed infiammazione. Blepharitis? a chronic inflammation of the eyelids, which pu? involve other ocular structures such as the meibomian gland (Wolffsohn et al. 2017) which, in turn, causes evaporative dry eye and inflammation.
La ghiandola di Meibomio ? situata nella parte tarsale della palpebra superiore ed inferiore. Essa ha la funzione di secernere lo strato lipidico che rappresenta lo strato pi? esterno del film lacrimale, con funzione di difesa dell'epitelio corneale, di controllo dell'evaporazione dello strato acquoso della lacrima, mantenendo il corretto livello di idratazione della cornea. The meibomian gland ? located in the tarsal part of the upper and lower eyelids. It has the function of secreting the lipid layer which represents the lowest layer. outside of the tear film, with the function of defending the corneal epithelium, controlling the evaporation of the aqueous layer of the tear, maintaining the correct level of hydration of the cornea.
Le ghiandole, il cui numero ? di oltre 50, sono posizionate in verticale l'una accanto all'altra nelle due palpebre, e riversano il loro secreto lungo la rima palpebrale attraverso dei forellini denominati dotti escretori. The glands, whose number ? more than 50, are positioned vertically next to each other in the two eyelids, and pour their secretion along the palpebral fissure through small holes called excretory ducts.
I dotti delle ghiandole di Meibomio sono tortuosi ed i detriti cellulari presenti sul bordo palpebrale, vi penetrano, non riescono a fuoriuscire e procurano cos?, la cronicizzazione dell?infiammazione e la formazione di frequenti Orzaioli e Calazi. The ducts of the meibomian glands are tortuous and the cellular debris present on the edge of the eyelid penetrate them, they are unable to escape and thus cause the inflammation to become chronic and the formation of frequent styes and chalazi.
La blefarite ? una delle pi? comuni patologie oculari; ? stato riportato in letteratura come rilevabile dal 37% al 47% dei pazienti sottoposti a valutazione oftalmologica ed optometrica di routine (Lemp et al. 2009). Blepharitis? one of the most common eye diseases; ? It has been reported in the literature as detectable in 37% to 47% of patients undergoing routine ophthalmologic and optometric evaluation (Lemp et al. 2009).
La blefarite coinvolge in maniera predominante la pelle, le ciglia e le palpebre e tende ad essere di natura stafilococcica o seborroica, mentre un coinvolgimento delle ghiandole meibomiane potrebbe essere seborroico, ostruttivo od una loro combinazione. La fisiopatologia della blefarite ? una complessa interazione di diversi fattori, tra cui secrezioni anormali del margine palpebrale, organismi microbici e anormalit? del film lacrimale (Jackson et al. 2008). Blepharitis predominantly involves the skin, eyelashes, and eyelids and tends to be staphylococcal or seborrheic in nature, whereas meibomian gland involvement could be seborrheic, obstructive, or a combination. The pathophysiology of blepharitis? a complex interaction of several factors, including abnormal lid margin secretions, microbial organisms, and abnormalities of the tear film (Jackson et al. 2008).
La blefarite ? caratterizzata da prurito oculare, bruciore, secchezza, irritazione o lacrimazione; il soggetto che ne ? affetto pu? anche riportare visione offuscata o sensazione di pesantezza palpebrale (Amescua et al. 2019, Cheng et al. 2015, Lemp et al. 2009). Blepharitis? characterized by eye itching, burning, dryness, irritation, or watery eyes; what about the subject? affection can also report blurred vision or feeling of lid heaviness (Amescua et al. 2019, Cheng et al. 2015, Lemp et al. 2009).
Nella disfunzione della ghiandola di Meibomio, la pi? comune forma di blefarite posteriore, gioca un ruolo importante il microbioma, per questo gli antibiotici topici possono essere utilizzati per ridurre la carica batterica e provvedere ad un sollievo dei sintomi (Miller et al. 2009; Lindsley et al. 2012). In meibomian gland dysfunction, the most? common form of posterior blepharitis, the microbiome plays an important role, therefore topical antibiotics can be used to reduce the bacterial load and provide relief of symptoms (Miller et al. 2009; Lindsley et al. 2012).
Il Demodex folliculorum ed il Demodex brevis, sono parassiti saprofiti delle ciglia, sono principalmente responsabili di molte blefariti anteriori e posteriori e sono stati ritrovati nel 29-100% dei pazienti (Basta-Juzbasic et al. 2002; Cheng et al. 2015; Liu et al. 2010). Demodex folliculorum and Demodex brevis, are saprophytic parasites of the eyelashes, are mainly responsible for many anterior and posterior blepharitis and have been found in 29-100% of patients (Basta-Juzbasic et al. 2002; Cheng et al. 2015; Liu et al. 2010).
Il Demodex pu? essere anche un vettore per molti batteri che possono associarsi al parassita, mentre i batteri che stazionano nella zona perioculare possono o meno dare inizio ad una blefarite. The Demodex can? also be a vector for many bacteria that can associate with the parasite, while the bacteria stationed in the periocular area may or may not initiate blepharitis.
In ogni caso i margini palpebrali dei pazienti con blefarite, sono spesso colonizzati da batteri, principalmente Gram-positivi, comprendenti varie specie di Stafilococco, Proponibacterium e specie del Corynebacterium (Dougherty et al. 1984; McCulley et al. 1986; Groden et al. 1991). In any case, the lid margins of patients with blepharitis are often colonized by bacteria, mainly Gram-positive, including various species of Staphylococcus, Proponibacterium and Corynebacterium species (Dougherty et al. 1984; McCulley et al. 1986; Groden et al. 1991).
Il trattamento di routine comprende la pulizia delle palpebre, l?impiego di compresse calde e spesso l?utilizzo di antibiotici (Lindsley et al. 2012); tuttavia, molti soggetti con blefarite, possono richiedere una terapia anche a lungo termine perch? la blefarite pu? essere cronica ed il sollievo dai sintomi pu? risultare soltanto temporaneo. Routine treatment includes eyelid cleansing, the use of warm compresses and often the use of antibiotics (Lindsley et al. 2012); however, many subjects with blepharitis may also require long-term therapy because can blepharitis be chronic and symptom relief can? be only temporary.
Al fine di prevenire l?insorgere ed il peggioramento della blefarite, specie nei soggetti pi? predisposti o con una storia pregressa di blefarite, ? quindi intuitiva la necessit? di dover eseguire una frequente igiene della zona perioculare, delle ciglia e delle palpebre, con l?obiettivo di mantenere tale area libera da batteri o parassiti ed in ogni caso abbattere la carica batterica del microbioma presente. In order to prevent the onset and worsening of blepharitis, especially in older subjects. predisposed or with a previous history of blepharitis, ? therefore intuitive the need? having to perform frequent hygiene of the eye area, eyelashes and eyelids, with the aim of keeping this area free from bacteria or parasites and in any case reducing the bacterial load of the microbiome present.
Stato dell?arte State of art
Lo sviluppo e l?impiego degli antibiotici, a partire dalla seconda met? del XX secolo, ha rivoluzionato l?approccio al trattamento ed alla prevenzione delle malattie infettive e delle infezioni permettendo l?evoluzione della medicina moderna. Tuttavia, la comparsa di resistenza agli antibiotici rischia di rendere vane queste conquiste. The development and? Use of antibiotics, starting from the second half? of the 20th century, revolutionized the approach to the treatment and prevention of infectious diseases and infections allowing the evolution of modern medicine. However, the emergence of antibiotic resistance risks rendering these achievements in vain.
Negli ultimi anni, il fenomeno dell?antibioticoresistenza ? aumentato notevolmente, la resistenza agli antibiotici ? una minaccia sempre pi? grave per la salute pubblica globale e richiede l?intervento di tutti i settori governativi e della societ? in generale (Cassini et al. 2018). In recent years, the phenomenon of antibiotic resistance? significantly increased, the resistance to antibiotics ? an increasingly threat? serious for global public health and requires action from all sectors of government and society in general (Cassini et al. 2018).
Il problema dell?antibiotico-resistenza, riguarda anche il settore dell?oftalmologia: in particolare, i pazienti che devono effettuare una chirurgia per la cataratta, qualora affetti da blefarite ed infezione delle palpebre, devono prima fare obbligatoriamente un trattamento antibiotico (linee guida ESCRS) per cui, una corretta prevenzione della blefarite attraverso una accurata detergenza, pu? evitare l?abuso di terapia antibiotica preoperatoria in questi soggetti. The problem of antibiotic resistance also concerns the ophthalmology sector: in particular, patients who have to undergo cataract surgery, if suffering from blepharitis and eyelid infection, must first undergo mandatory antibiotic treatment (ESCRS guidelines ) for which, a correct prevention of blepharitis through an accurate cleansing, pu? avoid the abuse of preoperative antibiotic therapy in these subjects.
Per la prevenzione della blefarite, molti rimedi naturali hanno incrementato la loro popolarit? negli ultimi decenni. Uno di questi prodotti ? il Tea Tree Oil (TTO), un olio volatile essenziale estratto principalmente dalla pianta australiana della melaleuca alternifolia. Questo componente ? particolarmente impiegato per le sue propriet? antimicrobiche ed ? incorporato come ingrediente attivo in molte formulazioni topiche utilizzate per trattare le infezioni cutanee (Carson et al. 2006), in particolare, schiume e salviette imbevute con tale agente. L?attivit? del TTO ? stata testata, oltre che sul Demodex, anche contro diverse specie batteriche, la maggior parte suscettibili a MIC di TTO comprese tra lo 0.025% e l?1.25%. Una recente review della Cochrane (Savla et al. 2020) suggerisce una certa incertezza sull?efficacia di questo trattamento alla concentrazione tra il 5% ed il 50%; inoltre per evitare fenomeni di irritazione e di compliance, sarebbe opportuno utilizzare basse concentrazioni. La ridotta compliance del paziente ? stata associata con l?efficacia effettiva del trattamento (Koo et al. For the prevention of blepharitis, many natural remedies have increased their popularity. in the last decades. One of these products? Tea Tree Oil (TTO), a volatile essential oil extracted mainly from the Australian melaleuca alternifolia plant. This component? particularly used for its properties? antimicrobial and incorporated as an active ingredient in many topical formulations used to treat skin infections (Carson et al. 2006), in particular, foams and wipes soaked with this agent. The activity of the TTO? In addition to Demodex, it has also been tested against various bacterial species, most of which are susceptible to TTO MICs between 0.025% and 1.25%. A recent Cochrane review (Savla et al. 2020) suggests some uncertainty about the efficacy of this treatment at a concentration between 5% and 50%; moreover, to avoid irritation and compliance phenomena, it would be advisable to use low concentrations. Reduced patient compliance? been associated with actual treatment efficacy (Koo et al.
2012). 2012).
Un altro agente usato per l?igiene oculare e la prevenzione di blefarite, sono le salviette oftalmiche a base di argento colloidale. La letteratura a supporto dell?efficacia dell?argento colloidale ? molto controversa e poco chiara sulla reale efficacia nei confronti di batteri, funghi e Demodex (Van Hasselt et al. 2004). Tra gli effetti collaterali dell?utilizzo cronico dell?argento colloidale poi, c?? l?argiria, una malattia irreversibile che si manifesta con una decolorazione blu-grigia che pu? colpire la pelle, gli occhi e gli organi interni (Okan et al. 2007). Another agent used for eye hygiene and the prevention of blepharitis are colloidal silver-based ophthalmic wipes. The literature supporting the efficacy of colloidal silver? very controversial and unclear on the real efficacy against bacteria, fungi and Demodex (Van Hasselt et al. 2004). Among the side effects of the chronic use of colloidal silver then, c?? argyria, a life-threatening disease that manifests itself as a blue-gray discoloration that can affect the skin, eyes and internal organs (Okan et al. 2007).
La Taurina ? un aminoacido che gioca un ruolo importante nei diversi processi biologici e potrebbe giocare un ruolo importante nell?infiammazione associata agli stress ossidativi. La taurina reagisce con l?acido ipocloroso generato dal sistema mieloperossidasi, questa reazione provoca la formazione di cloramina taurina, meno tossica. Le aloamine, taurina cloramina (TauCl) e la taurina bromamina (TauBr), esercitano propriet? antimicrobiche (Marcinkiewicz et al. 2014). The Taurine? an amino acid that plays an important role in different biological processes and could play an important role in inflammation associated with oxidative stress. Taurine reacts with hypochlorous acid generated by the myeloperoxidase system, this reaction causes the formation of the less toxic chloramine taurine. The aloamines, taurine chloramine (TauCl) and taurine bromamine (TauBr), have properties antimicrobial (Marcinkiewicz et al. 2014).
Il documento brevettuale WO 02/058692 A2 descrive l?invenzione di composizioni farmaceutiche comprendenti (i) almeno una composizione alogenata ed (ii) almeno un derivato N-alogenato di almeno un composto scelto tra zwitterione e/o composti amminoacidici. La composizione alogenata ? vantaggiosamente un ipoclorito di metallo alcalino, preferibilmente ipoclorito di sodio, ed il derivato N-alogenato ? preferibilmente un derivato della taurina N-alogenato ed in particolare un derivato della N-aloammina taurina e pi? preferibilmente ancora N-clorammina taurina. L'invenzione riguarda anche la preparazione di dette composizioni ed il loro utilizzo come antisettico, antinfiammatorio ad ampio spettro e come modulatore dell'immunit?, senza per questo, stimolare l'attivit? della mieloperossidasi. In particolare, il documento, pur prendendo in considerazione N-cloramina taurina che basa la sua attivit? antimicrobica sull?ipoclorito di sodio, non prende in considerazione i derivati del bromo e non si rivolge alla prevenzione delle blefariti. The patent document WO 02/058692 A2 describes the invention of pharmaceutical compositions comprising (i) at least one halogenated composition and (ii) at least one N-halogenated derivative of at least one compound selected from zwitterion and/or amino acid compounds. The halogenated composition? advantageously an alkali metal hypochlorite, preferably sodium hypochlorite, and the N-halogenated derivative ? preferably a derivative of N-halogenated taurine and in particular a derivative of N-haloamine taurine and more? preferably still N-chloramine taurine. The invention also relates to the preparation of said compositions and their use as an antiseptic, broad-spectrum anti-inflammatory and as an immunity modulator, without thereby stimulating the activity of the skin. of myeloperoxidase. In particular, the document, while taking into consideration N-chloramine taurine which bases its activity? antimicrobial on sodium hypochlorite, does not take bromine derivatives into consideration and is not aimed at the prevention of blepharitis.
Prodotti a base di Ipoclorito di sodio in soluzione a bassa concentrazione (0.01%), sono in grado di liberare acido ipocloroso HClO con propriet? antibatteriche ed antisettiche. Uno studio effettuato per misurare la capacit? di questa soluzione nel ridurre la carica batterica nella zona perioculare, ha valutato la conta batterica prima e dopo 20 minuti dall?applicazione (Stroman et al. 2017), dimostrando il 99% di riduzione nella carica batterica dello stafilococco epidermidis e di altre specie batteriche. Il problema tuttavia dell?acido ipocloroso, risiede nella sua tossicit? come causa di dermatite da contatto, prurito e psoriasi, con un grado di irritazione che dipende dall?esposizione cutanea. Tale capacit? irritante risulta strettamente correlato al range di pH in cui la soluzione contenente HClO risulta stabile (pH 3.5-5.5), quando il pH viene aumentato al di sopra di 5.5 (pi? compatibile con la pelle), HClO viene deprotonato in anione ClO-, meno reattivo e meno efficace come attivit? antimicrobica (Pelgrift & Friedman, 2013). E? stato infine dimostrato che l?acido ipocloroso in soluzione allo 0.01%, pur esercitando attivit? antibatterica nel biofilm, non ? in grado di distruggere il biofilm a livello strutturale (Romanowski et al. 2018). Products based on sodium hypochlorite in a low concentration solution (0.01%), are able to release hypochlorous acid HClO with properties? antibacterial and antiseptic. A study carried out to measure the ability? of this solution in reducing the bacterial load in the periocular area, evaluated the bacterial count before and 20 minutes after application (Stroman et al. 2017), demonstrating a 99% reduction in the bacterial load of staphylococcus epidermidis and other bacterial species . However, the problem of hypochlorous acid lies in its toxicity? as a cause of contact dermatitis, pruritus and psoriasis, with the degree of irritation depending on dermal exposure. This ability? irritant is closely related to the pH range in which the HClO-containing solution is stable (pH 3.5-5.5), when the pH is increased above 5.5 (more compatible with the skin), HClO is deprotonated into ClO- anion, less reactive and less effective as an activity? antimicrobial (Pelgrift & Friedman, 2013). AND? Finally, it has been demonstrated that hypochlorous acid in a 0.01% solution, while exerting activity? antibacterial in the biofilm, not ? able to destroy the biofilm at a structural level (Romanowski et al. 2018).
Il documento brevettuale WO 2016/183090 A1, descrive un metodo in vitro per l?inattivazione di esotossine batteriche utilizzando un sale di ipoclorito od acido ipocloroso, con riferimento a tessuti oculari ed alle zone perioculari, con l?obiettivo di trattare pazienti con blefarite, anche in presenza di un?infezione oculare. The patent document WO 2016/183090 A1 , describes an in vitro method for the inactivation of bacterial exotoxins using a hypochlorite salt or hypochlorous acid, with reference to ocular tissues and periocular areas, with the aim of treating patients with blepharitis, even in the presence of an eye infection.
Il documento brevettuale WO 2016/196330 A1, descrive un metodo in vitro per l?inattivazione della lipasi batterica utilizzando miscele di acido ipocloroso e sale ipoclorito in una soluzione acquosa di concentrazioni tra 0.005% e 0.05%, tale soluzione ? proposta come trattamento o prevenzione di blefariti, disfunzione delle ghiandole di Meibomio o occhio secco associate con lipasi, al fine di inattivare quest?ultima. The patent document WO 2016/196330 A1, describes an in vitro method for the inactivation of bacterial lipase using mixtures of hypochlorous acid and hypochlorite salt in an aqueous solution of concentrations between 0.005% and 0.05%, such a solution ? proposed as treatment or prevention of blepharitis, meibomian gland dysfunction or dry eye associated with lipase, in order to inactivate the latter.
In entrambe queste due ultime applicazioni, i risultati sono comunque dipendenti da: elevati tempi di incubazione utilizzati, dalle concentrazioni di HClO e, soprattutto, dal range di pH. In both of these last two applications, the results are however dependent on: high incubation times used, the concentrations of HClO and, above all, the pH range.
Nel documento brevettuale US 2018/0206502 A1 viene divulgata una soluzione antimicrobica costituita essenzialmente da (a) acido ipocloroso, (b) un catione bivalente, selezionato fra calcio, magnesio ed una combinazione di questi, (c) anione fosfato e (d) acqua, nonch? un processo per la sua produzione, dove la soluzione pu? essere stabilizzata in un range di pH compreso tra 3 e 7 con l?aggiunta di un agente che stabilizza il pH. Viene anche divulgato un metodo per trattare o prevenire l'infezione associata alla chirurgia addominale su un mammifero, comprendente l'uso della detta soluzione antimicrobica. Anche in questo caso si deve osservare che la stabilizzazione viene fatta ad un range di pH molto ampio, che se risulta accettabile per un uso su ferite addominali, non garantisce l?assoluta tolleranza del prodotto nella zona perioculare. In the patent document US 2018/0206502 A1 an antimicrobial solution is disclosed essentially consisting of (a) hypochlorous acid, (b) a divalent cation, selected from calcium, magnesium and a combination thereof, (c) phosphate anion and (d) water , as well as a process for its production, where the solution can? be stabilized in the pH range of 3 to 7 by the addition of a pH stabilizing agent. Also disclosed is a method of treating or preventing infection associated with abdominal surgery on a mammal, comprising the use of said antimicrobial solution. Also in this case it must be noted that the stabilization is carried out at a very wide pH range, which, if it is acceptable for use on abdominal wounds, does not guarantee absolute tolerance of the product in the periocular area.
Nell?ambito di una ricerca finalizzata al trattamento ed alla prevenzione della blefarite, la Richiedente ha riscontrato che nella pratica medica, i pi? deboli composti clorurati come le cloramine, possono avere un buona efficacia antiinfettiva in presenza di materiale proteico (membrane mucose, ferite aperte) mentre i composti a base di bromo, hanno la loro migliore applicazione in regioni meno sensibili del corpo, con minore materiale organico, come ad esempio la superficie intatta della pelle (Gottardi et al. 2014), tanto da averli presi in considerazione come trattamento efficace nell?acne (Marcinkiewicz et al. 2006). As part of a research aimed at the treatment and prevention of blepharitis, the Applicant has found that in medical practice, the most weak chlorinated compounds such as chloramines, can have a good anti-infective efficacy in the presence of protein material (mucous membranes, open wounds) while bromine-based compounds, have their best application in less sensitive regions of the body, with less organic material, such as the intact surface of the skin (Gottardi et al. 2014), so much so that they have been considered as an effective treatment in acne (Marcinkiewicz et al. 2006).
Nessuno dei trattamenti sopra menzionati peraltro ha preso in considerazione prodotti a base di bromo, nel trattamento e nella prevenzione delle blefariti. However, none of the treatments mentioned above took bromine-based products into consideration in the treatment and prevention of blepharitis.
Nella presente invenzione viene proposto per la prima volta l?impiego di una soluzione acquosa per uso esterno comprendente Bromuro di Potassio (KBr), Ipoclorito di Sodio (NaClO) ed Acido Fosforico (H3PO4). La soluzione, cos? stabilizzata, ed a pH neutro, sviluppa Ipobromito di Sodio, che svolge elevata attivit? battericida cos? da poter utilizzare il prodotto nel mantenimento dell?igiene della zona perioculare, delle ciglia e delle palpebre, con buona tollerabilit? locale nel trattamento e nella prevenzione delle blefariti. The present invention proposes for the first time the use of an aqueous solution for external use comprising Potassium Bromide (KBr), Sodium Hypochlorite (NaClO) and Phosphoric Acid (H3PO4). The solution, what? stabilized, and at neutral pH, it develops sodium hypobromite, which carries out high activity? bactericide what? to be able to use the product in maintaining the hygiene of the eye area, eyelashes and eyelids, with good tolerability? local in the treatment and prevention of blepharitis.
Compito dell?invenzione Task of the invention
La presente invenzione riguarda il settore medico-farmaceutico e, pi? precisamente, una soluzione a base di bromo utilizzata in maniera innovativa per il trattamento e la prevenzione della blefarite e per la quotidiana detergenza e pulizia della zona perioculare. The present invention relates to the medical-pharmaceutical sector and, more precisely, a bromine-based solution used in an innovative way for the treatment and prevention of blepharitis and for the daily cleaning and cleansing of the eye area.
L?idea ? quella di utilizzare il bromo come sostitutivo del cloro, il quale ? spesso utilizzato in prodotti analoghi per la detergenza e la pulizia delle palpebre e dell?area perioculare. The idea? to use bromine as a substitute for chlorine, which ? often used in similar products for cleansing and cleaning the eyelids and the eye area.
Utilizzare per la detergenza e la pulizia perioculare un prodotto a base di bromo ha molti vantaggi rispetto ai comuni prodotti a base di cloro: Using a bromine-based product for cleansing and cleaning around the eyes has many advantages over common chlorine-based products:
? il bromo e l?acido ipobromoso sono pi? stabili delle corrispettive specie di cloro a pH neutro (Figura 1) e dunque pi? compatibile con il pH fisiologico, ? bromine and? hypobromous acid are more? stable of the corresponding species of chlorine at neutral pH (Figure 1) and therefore more? compatible with the physiological pH,
? il bromo ? meno tossico del cloro (Withers and Lees, 1986), ? the bromine ? less toxic than chlorine (Withers and Lees, 1986),
? il bromo ? meno volatile del cloro a temperatura ambiente e dunque pi? stabile, ? the bromine ? less volatile than chlorine at room temperature and therefore more? stable,
? il bromo ha una maggiore efficacia battericida su pelle integra o pelle con acne rispetto al cloro (Marcinkiewicz et al. 2006, 2008; ? bromine has a greater bactericidal efficacy on intact skin or skin with acne than chlorine (Marcinkiewicz et al. 2006, 2008;
Marcinkiewicz 2010; Gottardi et al., 2014). Marcinkiewicz 2010; Gottardi et al., 2014).
Le soluzioni a base di bromo sono da tempo conosciute ed utilizzate come disinfettanti alternativi al cloro soprattutto per piscine. L?originalit? alla base del presente brevetto ? nell?utilizzo innovativo della soluzione a base di bromo come disinfettante per la pulizia perioculare. Descrizione dettagliata dell?invenzione Bromine-based solutions have long been known and used as alternative disinfectants to chlorine especially for swimming pools. The originality the basis of this patent? in the innovative use of the bromine-based solution as a disinfectant for cleaning around the eyes. Detailed description of the invention
La presente soluzione ? stata ottenuta aggiungendo KBr (aq), ClO<- >e H3PO4 in acqua; si ottiene cos? una soluzione di Br2, HBrO/BrO-, Br <- >e Cl-. This solution? was obtained by adding KBr (aq), ClO<- > and H3PO4 in water; is obtained cos? a solution of Br2, HBrO/BrO-, Br <- > and Cl-.
Gli equilibri presenti in soluzione sono riportati di seguito The equilibria present in solution are shown below
Per l?ottenimento della presente soluzione il primo step ? quello di mettere Bromuro di Potassio (KBr) in soluzione acquosa. Il KBr si dissocia completamente in soluzione acquosa, si ottiene cos? una soluzione di Br<- >e K<+ >(reazione 1). Viene quindi aggiunta una soluzione di ipoclorito di sodio alla quale viene aggiunto un acido, in questo caso acido fosforico (H3PO4), che in soluzione si dissocia liberando ioni H3O<+>. In ambiente acido si ha formazione di cloro (Cl2). Successivamente, il cloro reagisce con il bromuro in soluzione formando quantitativamente bromo (Br2) e cloruro (reazione 4). Il Bromo in soluzione disproporziona formando acido ipobromoso e bromuro secondo l?equilibrio del bromo attivo libero (Br2, HBrO/BrO-) (reazione 5). Il bromuro contribuisce a stabilizzare il bromo e l?acido ipobromoso, in parte dissociato in ipobromito. To obtain this solution, the first step is that of putting Potassium Bromide (KBr) in aqueous solution. The KBr completely dissociates in aqueous solution, so you get? a solution of Br<- >and K<+ >(reaction 1). A sodium hypochlorite solution is then added to which an acid is added, in this case phosphoric acid (H3PO4), which dissociates in solution, releasing H3O<+> ions. In an acid environment, chlorine (Cl2) is formed. Subsequently, the chlorine reacts with the bromide in solution to quantitatively form bromine (Br2) and chloride (reaction 4). Bromine in solution disproportionates forming hypobromous acid and bromide according to the balance of free active bromine (Br2, HBrO/BrO-) (reaction 5). Bromide helps stabilize bromine and hypobromous acid, which is partially dissociated into hypobromite.
Si ottiene dunque una soluzione acquosa ricca di bromo e acido ipobromoso in forma stabile con azione biocida. La soluzione cos? ottenuta viene indicata per brevit? nel proseguo con la sigla MDI-102 che e viene testata per la prima volta come soluzione disinfettante contro i batteri presenti nell?area perioculare. L?innovazione alla base del presente brevetto sta nell?utilizzo di una soluzione a base di bromo come disinfettante e biocida per il trattamento della blefarite come verr? descritto dettagliatamente nei seguenti paragrafi. An aqueous solution rich in bromine and hypobromous acid in a stable form with biocidal action is thus obtained. What is the solution? obtained is indicated for brevity? in continuation with the acronym MDI-102 which is tested for the first time as a disinfectant solution against the bacteria present in the periocular area. The innovation at the basis of this patent lies in the use of a bromine-based solution as a disinfectant and biocide for the treatment of blepharitis as it will come? described in detail in the following paragraphs.
Ulteriori caratteristiche e vantaggi della presente invenzione risulteranno evidenti dalle prove sperimentali che seguono facendo riferimento alle allegate tavole di disegno in cui: Further characteristics and advantages of the present invention will become evident from the following experimental tests with reference to the enclosed drawings in which:
la fig. 1 mostra la stabilit? di HClO/CLO<- >e di HBrO<- >in funzione del pH; the fig. 1 shows the stability? of HClO/CLO<- >and of HBrO<- >as a function of pH;
le figg. 2a- 2g mostrano i risultati dei test cinetici condotti con MDI-102 (500 ppm) rispettivamente sui seguenti microorganismi: (a) Enterococcus hirae 10541; (b) Escheria coli ATCC<.8739; (c) Pseudomonas aeruginosa ATCC:9027, (d) Pseudomonas aeruginosa ATCC:15442; (e) Staphylococcus aureus ATCC:6538; (f) Staphylococcus epidermis ATCC:12228, (g) Serratia marcescens ATCC:13880 figs. 2a-2g show the results of the kinetic tests conducted with MDI-102 (500 ppm) respectively on the following microorganisms: (a) Enterococcus hirae 10541; (b) Escheria coli ATCC<.8739; (c) Pseudomonas aeruginosa ATCC:9027, (d) Pseudomonas aeruginosa ATCC:15442; (e) Staphylococcus aureus ATCC:6538; (f) Staphylococcus epidermis ATCC:12228, (g) Serratia marcescens ATCC:13880
le figg.3a-3g mostrano i risultati dei test cinetici condotti con con MDI-102 (80 ppm) sugli stessi microorganismi della fig. 2; figs.3a-3g show the results of the kinetic tests conducted with MDI-102 (80 ppm) on the same microorganisms of fig. 2;
le figg.4a-4g, mostrano i risultati dei test cinetici condotti con MDI-102 (80ppm)+albumina 3 g <L-1 >sugli stessi microorganismi delle fig. precedenti. Parte sperimentale figs.4a-4g show the results of the kinetic tests conducted with MDI-102 (80ppm)+albumin 3 g <L-1> on the same microorganisms of figs. previous. Experimental part
Materiali e reagenti Materials and reagents
La soluzione oggetto della presente invenzione ha una concentrazione di bromo attivo libero (Br2, HBrO/BrO-) che pu? variare dai 50 ai 550 ppm; ed ? ottenibile mescolando bromuro di potassio (KBr) ad una concentrazione compresa tra 0.1 e 1%, acido fosforico (H3PO4 85%) a concentrazione compresa tra 0.05 e 0.5%, soluzione di ipoclorito di sodio (NaClO al 3%) a concentrazione compresa tra lo 0.005 e lo 0.05% in acqua ultra pura (q.b. 90-99%). The solution object of the present invention has a concentration of free active bromine (Br2, HBrO/BrO-) which can vary from 50 to 550 ppm; and ? obtainable by mixing potassium bromide (KBr) at a concentration between 0.1 and 1%, phosphoric acid (H3PO4 85%) at a concentration between 0.05 and 0.5%, sodium hypochlorite solution (3% NaClO) at a concentration between 0.005 and 0.05% in ultra pure water (to taste 90-99%).
Il KBr ? stato acquistato da CARLO ERBA Reagents, mentre l?acido fosforico ? stato acquistato da Merck-Sigma Aldrich, l?ipoclorito di sodio utilizzato ? di tipo per acqua potabile conforme UNI EN 901:2013. The KBr? been purchased from CARLO ERBA Reagents, while the? phosphoric acid ? been purchased from Merck-Sigma Aldrich, the? sodium hypochlorite used? of the type for drinking water compliant with UNI EN 901:2013.
L?albumina utilizzata per i test dirty (come verr? spiegato in dettaglio in seguito) ? stata acquistata da VWR. The albumin used for the dirty tests (as will be explained in detail later) ? was purchased by VWR.
A causa della bassa stabilit? dell?ipoclorito di sodio, il titolo del cloro viene controllato prima di preparare la soluzione. Due to the low stability? of sodium hypochlorite, the chlorine titer is checked before preparing the solution.
La concentrazione di alogeno libero ? misurata utilizzando un kit di Hach Lange. Il principio del metodo si basa sul fatto che l?alogeno libero, a pH compreso fra 6.2 e 6.5, ossida l? N,N-dietil-pfenilendiammina (DPD) contenuto nel kit, con formazione di un composto rosa-rosso (assorbanza 510 nm). La concentrazione del composto ? misurata tramite l?utilizzo di uno spettrofotometro Hach DR6000 e cuvette con cammino ottico da 2,5 cm. The concentration of free halogen ? measured using a Hach Lange kit. The principle of the method is based on the fact that the free halogen, at a pH between 6.2 and 6.5, oxidizes the? N,N-diethyl-pphenylenediamine (DPD) contained in the kit, forming a pink-red compound (absorbance 510 nm). The concentration of the compound? measured using a Hach DR6000 spectrophotometer and 2.5cm pathlength cuvettes.
Piano sperimentale e test cinetici Experimental plan and kinetic tests
Per testare l?efficacia battericida della presente soluzione sono stati utilizzati come ceppi batterici quelli riportati in: To test the bactericidal efficacy of this solution, the bacterial strains reported in the following were used:
? norma UNI EN ISO 11930:2019 relativa al Challenge test e alla contaminazione microbica nei cosmetici, ? UNI EN ISO 11930:2019 standard relating to the Challenge test and microbial contamination in cosmetics,
? norma UNI EN 1276:2019 relativa ai metodi di prova e ai requisiti minimi per l?attivit? battericida di prodotti antisettici e chimici disinfettanti, ? UNI EN 1276:2019 standard relating to test methods and minimum requirements for the activity bactericide of antiseptic and chemical disinfectant products,
? la norma UNI EN ISO 14729:2010 relativa ai prodotti per la cura delle lenti a contatto e dei requisiti microbiologici di questi prodotti, ? in articoli di letteratura relativi a prodotti per il trattamento della blefarite (Stroman et al 2017). ? the UNI EN ISO 14729:2010 standard relating to products for the care of contact lenses and the microbiological requirements of these products, ? in literature articles related to products for the treatment of blepharitis (Strman et al 2017).
I microrganismi utilizzati sono riportati di seguito: The microorganisms used are listed below:
? (a) Pseudomonas aeruginosa ATCC: 9027 (UNI EN ISO 11930:2019), ? (a) Pseudomonas aeruginosa ATCC: 9027 (UNI EN ISO 11930:2019),
? (b) Enterococcus hirae ATCC: 10541 (UNI EN 1276:2019), ? (b) Enterococcus hirae ATCC: 10541 (UNI EN 1276:2019),
? ( c) Serratia marcescens ATCC: 13880 (UNI EN ISO 14729:2010), ? (c) Serratia marcescens ATCC: 13880 (UNI EN ISO 14729:2010),
? (d) Staphylococcus aureus ATCC: 6538 (UNI EN 1276:2019), ? (d) Staphylococcus aureus ATCC: 6538 (UNI EN 1276:2019),
(e ) Pseudomonas aeruginosa ATCC: 15442 (UNI EN 1276:2019), (e ) Pseudomonas aeruginosa ATCC: 15442 (UNI EN 1276:2019),
(f) Escherichia coli ATCC: 8739 (UNI EN ISO 11930:2019), (f) Escherichia coli ATCC: 8739 (UNI EN ISO 11930:2019),
(g) Staphylococcus epidermidis ATCC:12228 (Stroman et al. 2017 DOI:10.214/OPTH.5132851). (g) Staphylococcus epidermidis ATCC:12228 (Stroman et al. 2017 DOI:10.214/OPTH.5132851).
L?efficacia del MDI-102 ? stata testata a due concentrazioni: 500 ppm (figg 2 a- 2g) e 80 ppm (3 a- 3g) di bromo attivo libero. L?efficacia di MDI-102 ? stata testata su inoculi di microrganismi a concentrazione compresa tra 2x10<5 >e 3x10<7 >unit? formanti colonia (UFC) mL<-1 >(Stroman et al. 2017). La concentrazione di microrganismi ? stata monitorata a diversi tempi, rispettivamente 0.5, 1, 2, 5, 20, 30 minuti dopo l?aggiunta di MDI-102 alla soluzione. Per ogni soluzione ? stato condotto un bianco (control) senza MDI-102 in modo da controllare l?andamento della concentrazione microbica in assenza di disinfettante. I test sono stati condotti a 25? ?1? ?C. Dopo il tempo prestabilito un?aliquota di campione ? stata piastrata ed incubata per 48 h a 36? ?1??C. The effectiveness of MDI-102 ? was tested at two concentrations: 500 ppm (figs 2 a- 2g) and 80 ppm (3 a- 3g) of free active bromine. The effectiveness of MDI-102 ? been tested on inoculums of microorganisms at a concentration between 2x10<5> and 3x10<7>unit? colony forming agents (CFU) mL<-1 >(Stroman et al. 2017). The concentration of microorganisms ? was monitored at different times, respectively 0.5, 1, 2, 5, 20, 30 minutes after the addition of MDI-102 to the solution. For each solution ? A blank (control) was conducted without MDI-102 in order to check the trend of the microbial concentration in the absence of disinfectant. Tests were conducted at 25? ?1? ?C. After the pre-established time, a sample aliquot ? been plated and incubated for 48 h at 36? ?1??C.
I test cinetici sono successivamente stati ripetuti in condizione dirty, (figg. 4a ? 4g) ovvero con aggiunta di albumina 3 g L<-1 >come interferente proteico (UNI EN 1276:2019). Questi test sono stati condotti al fine di testare l?efficacia del MDI-102 non solo in assenza di interferente proteico ma anche in condizioni maggiormente rappresentative di quella che ? la situazione reale in cui la superficie perioculare pu? non essere completamente pulita (condizioni dirty). I test sono stati condotti con le stesse modalit?, microrganismi, concentrazione dell?inoculo, temperatura e tempi dei test precedentemente esposti con la sola differenza dell?aggiunta di albumina (3 g L<-1>). The kinetic tests were subsequently repeated in a dirty condition, (figs. 4a ? 4g) or with the addition of albumin 3 g L<-1 > as a protein interferent (UNI EN 1276:2019). These tests were conducted in order to test the effectiveness of MDI-102 not only in the absence of protein interferent but also in conditions more representative of what? the real situation in which the periocular surface pu? not be completely clean (dirty condition). The tests were conducted with the same methods, microorganisms, concentration of the inoculum, temperature and times of the tests previously described with the only difference of the addition of albumin (3 g L<-1>).
I test dirty sono stati condotti con la sola soluzione a 80 ppm in quanto, qualora il test risulti efficace a questa concentrazione si pu? considerare conseguentemente efficace anche per la soluzione di MDI-102 a 500 ppm. The dirty tests were conducted with only the 80 ppm solution because, if the test is effective at this concentration, it can be consequently consider effective also for the MDI-102 solution at 500 ppm.
Caratterizzazione e tollerabilit? dermatologica Characterization and tolerability dermatological
Al fine di valutare se la formulazione pu? provocare un?infiammazione allergica della cute, ? stato condotto un test allergologico denominato Patch test. Il test ? stato condotto sulla soluzione di MDI-102 a 500 ppm essendo questa la soluzione a maggiore concentrazione di bromo attivo libero. Il patch test ? stato condotto su 20 volontari scelti in base ai seguenti criteri: In order to evaluate whether the formulation pu? cause allergic inflammation of the skin, ? an allergy test called patch test was conducted. The test ? was carried out on the MDI-102 solution at 500 ppm, this being the solution with the highest concentration of free active bromine. The patch test ? was conducted on 20 volunteers selected on the basis of the following criteria:
? Criteri di inclusione ? Inclusion criteria
Soggetti di sesso maschile e femminile, Male and female subjects,
Et? compresa tra i 18 ed i 70 anni, Age? between 18 and 70 years old,
Soggetti sani, healthy subjects,
Soggetti informati sulla finalit? dello studio, ? Criteri di non inclusione Subjects informed about the purpose? of study, ? Non-inclusion criteria
Soggetti che non soddisfano i criteri di inclusione, Individuals who do not meet the inclusion criteria,
Donne incinte o in allattamento, Pregnant or breastfeeding women,
Soggetti con macchie o segni (ad esempio tatuaggi, cicatrici, scottature) nell?area cutanea scelta per il test che possano interferire con le valutazioni cliniche, Subjects with spots or marks (e.g. tattoos, scars, sunburn) in the skin area chosen for testing that could interfere with clinical evaluations,
Soggetti con problemi dermatologici nell?area del test, Subjects with dermatological problems in the test area,
Soggetti con medicazioni che possono interferire con la risposta cutanea al patch test, Individuals with medications that may interfere with skin response to patch testing,
Soggetti in terapia farmacologica sia locale che sistemica, Subjects on both local and systemic pharmacological therapy,
Soggetti con storia clinica pregressa per dermatite da contatto, Subjects with a previous medical history of contact dermatitis,
Anamnesi positiva per atopia. History of atopy.
Il prodotto viene applicato tal quale utilizzando la Finn Chamber, un dischetto di alluminio di 8 mm di diametro contenente un dischetto di carta assorbente. La Finn Chamber viene fissata alla cute mediante un cerotto gi? testato per la sua innocuit? e garantisce l?applicazione in occlusione della sostanza interessata. La quantit? di prodotto applicata ? sufficiente a saturare il dischetto di carta senza che il prodotto fuoriesca dalla celletta una volta applicata sulla cute. L?applicazione del prodotto sulla cute ha una durata di 48 ore. Le reazioni cutanee sono valutate clinicamente 15 minuti, 1 e 24 ore dopo la rimozione della Finn Chamber. Una Finn Chamber contenente un dischetto di carta assorbente saturato con acqua demineralizzata costituisce il controllo negativo. The product is applied as it is using the Finn Chamber, an 8 mm diameter aluminum disk containing an absorbent paper disk. The Finn Chamber is fixed to the skin using a plaster already? tested for its harmlessness? and guarantees the application in occlusion of the substance concerned. The quantity? of product applied ? enough to saturate the paper disk without the product coming out of the cell once applied to the skin. The application of the product on the skin lasts 48 hours. Skin reactions are clinically evaluated 15 minutes, 1 and 24 hours after removal of the Finn Chamber. A Finn Chamber containing a blotting paper disk saturated with demineralized water constitutes the negative control.
Dopo la rimozione della Finn Chambers, i volontari vengono sottoposti all?analisi clinica che rileva l?eventuale presenza di reazioni eritematose e/o edematose. L?analisi clinica viene effettuata a distanza di 15 minuti, 1 ora e 24 ore dalla rimozione del patch test. Le reazioni cutanee vengono valutate in base al punteggio riportato in Tabella 1 che descrive la gravit? dell?eritema dell?edema o di altre lesioni cutanee indicative di un?irritazione. I risultati vengono raccolti in una tabella e rappresentati graficamente. Per ogni tempo sperimentale viene calcolato l?Indice di Irritazione medio (IIM), rappresentato dalla somma del valore medio di eritema e del valore medio di edema registrati, in base al quale ? possibile classificare il prodotto, come riportato in Tabella 2. After the removal of the Finn Chambers, the volunteers are subjected to clinical analysis which detects the possible presence of erythematous and/or oedematous reactions. The clinical analysis is performed 15 minutes, 1 hour and 24 hours after removal of the patch test. Skin reactions are evaluated based on the score reported in Table 1 which describes the severity of oedematous erythema or other skin lesions indicative of irritation. The results are compiled in a table and graphically represented. For each experimental time, the average Irritation Index (IIM) is calculated, represented by the sum of the average value of erythema and the average value of edema recorded, on the basis of which ? possible to classify the product, as shown in Table 2.
Tabella 1. Patch Test su 20 volontari: scala di valutazione delle reazioni cutanee. Table 1. Patch Test on 20 volunteers: evaluation scale of skin reactions.
Tabella 2. Classificazione dell?indice di irritazione medio. Table 2. Classification of average irritation index.
In Tabella 3 vengono riportati i risultati del Patch Test (reazioni edematose ed eritematose) del MDI-102 a 500 ppm effettuato su 20 volontari. I valori medi di edema ed eritema ritrovati su 20 volontari sono riportati in Tabella 4. L?indice di irritazione medio eritematoso su 20 pazienti ? 0.1 dopo rispettivamente 15 minuti, 1 ora e 24 ore; mentre l?indice di irritazione edematoso ? 0 rispettivamente dopo 15 minuti, 1 ora e 24 ore. In base ai risultati ottenuti, e ai valori di riferimento in Tabella 2, il prodotto MDI-102 (500 ppm) ha un indice di irritazione medio inferiore a 0.5; dopo essere stato dermatologicamente testato pu? quindi essere considerato non irritante (Tabella 2). Table 3 shows the results of the Patch Test (edematous and erythematous reactions) of MDI-102 at 500 ppm carried out on 20 volunteers. The average values of edema and erythema found on 20 volunteers are shown in Table 4. The average erythematous irritation index on 20 patients? 0.1 after 15 minutes, 1 hour and 24 hours respectively; while the index of edematous irritation? 0 after 15 minutes, 1 hour and 24 hours respectively. Based on the results obtained, and on the reference values in Table 2, the MDI-102 product (500 ppm) has an average irritation index lower than 0.5; after being dermatologically tested can? hence be considered non-irritating (Table 2).
Tabella 3. Risultati dei Patch Test su 20 Table 3. Patch Test Results of 20
volontari: reazioni edematose ed eritematose. volunteers: oedematous and erythematous reactions.
Tabella 4. Valori medi di edema ed eritema ritrovati. Table 4. Mean values of edema and erythema found.
Discussione e conclusioni Discussion and conclusions
I test cinetici sono stati condotti per valutare l?efficacia di MDI-102 sui microrganismi possibilmente presenti sulla superficie perioculare ma soprattutto al fine di valutare dopo quanto tempo la presente soluzione biocida fosse efficace contro suddetti microrganismi. The kinetic tests were conducted to evaluate the effectiveness of MDI-102 on the microorganisms possibly present on the periocular surface but above all in order to evaluate after how long the present biocidal solution was effective against the aforementioned microorganisms.
I test cinetici effettuati su MDI-102 (500 ppm) sono riportati nelle Figure 2 a-g per i seguenti microrganismi: (a) Enterococcus hirae ATCC: 10541, (b) Escherichia coli ATCC: 8739, (c) Pseudomonas aeruginosa ATCC: 9027, (d) Pseudomonas aeruginosa ATCC: 15442, (e) Staphylococcus aureus ATCC: 6538, (f) Staphylococcus epidermidis ATCC:12228, (g) Serratia marcescens ATCC: 13880. The kinetic tests performed on MDI-102 (500 ppm) are reported in Figures 2 a-g for the following microorganisms: (a) Enterococcus hirae ATCC: 10541, (b) Escherichia coli ATCC: 8739, (c) Pseudomonas aeruginosa ATCC: 9027, (d) Pseudomonas aeruginosa ATCC: 15442, (e) Staphylococcus aureus ATCC: 6538, (f) Staphylococcus epidermidis ATCC: 12228, (g) Serratia marcescens ATCC: 13880.
In Bianco (linea tratteggiata) il controllo ovvero l?andamento della concentrazione dei microrganismi senza aggiunta di MDI-102 funzione del tempo. In nero la concentrazione microbica in funzione del tempo in presenza di MDI-102 a 500 ppm (concentrazione di Bromo attivo libero). In verde l?andamento dell?azione antibatterica nel tempo di MDI-102 500 ppm. In White (dashed line) the control or the trend of the concentration of microorganisms without the addition of MDI-102 as a function of time. In black the microbial concentration as a function of time in the presence of MDI-102 at 500 ppm (concentration of free active bromine). In green the trend of the antibacterial action of MDI-102 500 ppm over time.
Come si evince da Figura 2 (a-g) il MDI-102 (500 ppm) ? in grado di rimuovere tutta la concentrazione di microrganismi dell?inoculo (concentrazione compresa tra 10<5 >e 10<7 >UFC mL<-1>) dopo appena 30 secondi di contatto (100% di rimozione) tra inoculo e soluzione di biocida. La conta microbica risulta infatti essere pari 0 UFC per tutti i microrganismi testati al primo tempo (30 secondi). As can be seen from Figure 2 (a-g) the MDI-102 (500 ppm) ? capable of removing all the concentration of microorganisms from the inoculum (concentration between 10<5 > and 10<7 >CFU mL<-1>) after just 30 seconds of contact (100% removal) between inoculum and biocide solution . The microbial count is in fact equal to 0 CFU for all the microorganisms tested in the first time (30 seconds).
Lo stesso risultato si ottiene con la soluzione di MDI-102 80 ppm, come riportato in Figura 3 (a-g). The same result is obtained with the 80 ppm MDI-102 solution, as shown in Figure 3 (a-g).
In Bianco (linea tratteggiata gialla) il controllo ovvero l?andamento della concentrazione dei microrganismi senza aggiunta di MDI-102 funzione del tempo. In nero la concentrazione microbica in funzione del tempo in presenza di MDI-102 a 80 ppm (concentrazione di Bromo attivo libero). In verde l?andamento dell?azione antibatterica nel tempo di MDI-102 80 ppm. In White (yellow dashed line) the control or the trend of the concentration of microorganisms without the addition of MDI-102 as a function of time. In black the microbial concentration as a function of time in the presence of MDI-102 at 80 ppm (concentration of free active Bromine). In green the trend of the antibacterial action of MDI-102 80 ppm over time.
Come si evince da Figura 3 (a-g) la concentrazione ? pari a zero dopo appena 30 secondi per tutti i microrganismi testati (rimozione del 100% dopo 30 secondi) tranne che per lo Pseudomonas aeruginosa (ATCC: 9027) la cui concentrazione dopo 30 secondi ? pari a 5 UFC mL<-1>. Considerando una concentrazione iniziale di pari a 2*10<5 >UFC mL<-1 >di Pseudomonas aeruginosa (ATCC: 9027), si ottiene una rimozione pari a 99.998% dopo appena 30 secondi. Si pu? dunque affermare che la soluzione di MDI-102 a 80 ppm ? efficace come quella di MDI-102 a 500 ppm. How can the concentration be seen from Figure 3 (a-g)? equal to zero after just 30 seconds for all tested microorganisms (100% removal after 30 seconds) except for Pseudomonas aeruginosa (ATCC: 9027) whose concentration after 30 seconds? equal to 5 CFU mL<-1>. Considering an initial concentration of 2*10<5 >CFU mL<-1 > of Pseudomonas aeruginosa (ATCC: 9027), a removal of 99.998% is obtained after just 30 seconds. Can you? therefore to affirm that the solution of MDI-102 to 80 ppm ? as effective as that of MDI-102 at 500 ppm.
I risultati ottenuti sono stati messi a confronto con quelli trovati in letteratura per Avenova<? >(NovaBay Pharmaceuticals, Inc., Emeryville, CA), una soluzione a base di HClO (0.01%) utilizzata per l?igiene della zona perioculare. I test condotti da Stroman et al. (2017) su Avenova<? >messo a contatto con diversi microrganismi presenti sulla superficie perioculare a concentrazione compresa tra 10<5>-10<7 >UFC mL<-1 >(stesso intervallo di concentrazione del presente studio) hanno riportato i seguenti risultati. Avenova<? >(100 ppm di HClO) ? in grado di rimuovere quantitativamente una concentrazione maggiore del 99% degli Stafilococchi testati dopo 20 minuti e, nel dettaglio, una concentrazione maggiore del 99.5% di Staphylococcus epidermidis. MDI-102, ad una concentrazione di 80 ppm di Bromo attivo libero (inferiore di 20 ppm alla rispettiva concentrazione di alogeno di Avenova<?>), ? in grado di rimuove, dopo appena 30 secondi (un intervallo di tempo minore del 97.5% rispetto a quello testato da Stroman et al. (2017)) il 99.9996% della concentrazione dei microrganismi testati (media calcolata sulla rimozione di tutti i microrganismi) e di ridurre la concentrazione Staphylococcus epidermidis del 99.9975%. The results obtained were compared with those found in the literature for Avenova<? >(NovaBay Pharmaceuticals, Inc., Emeryville, CA), a solution based on HClO (0.01%) used for the hygiene of the eye area. Tests conducted by Stroman et al. (2017) about Avenova<? >put in contact with various microorganisms present on the periocular surface at concentrations between 10<5>-10<7 >CFU mL<-1 >(same concentration range as in the present study) reported the following results. Avenova<? >(100ppm HClO) ? capable of quantitatively removing a concentration greater than 99% of the Staphylococci tested after 20 minutes and, in detail, a concentration greater than 99.5% of Staphylococcus epidermidis. MDI-102, at a concentration of 80 ppm of free active bromine (20 ppm lower than the respective halogen concentration of Avenova<?>), ? able to remove, after just 30 seconds (a time interval 97.5% less than that tested by Stroman et al. (2017)) 99.9996% of the concentration of the tested microorganisms (average calculated on the removal of all microorganisms) and to reduce Staphylococcus epidermidis concentration by 99.9975%.
Come precedentemente accennato, i test di efficacia battericida sono stati condotti anche in dirty condition. I microrganismi selezionati (come specificato nella sezione ?Parte sperimentale?) sono stati messi a contatto con una soluzione di MDI-102 (concentrazione finale 80 ppm) e 3 g L<-1 >di albumina utilizzato come interferente. L?efficacia di biocidi alogenati ? infatti spesso testata anche in presenza di peptoni (Gottardi et al. 2014). As previously mentioned, the bactericidal efficacy tests were also conducted in dirty conditions. The selected microorganisms (as specified in the section ?Experimental part?) were put in contact with a solution of MDI-102 (final concentration 80 ppm) and 3 g L<-1 > of albumin used as interferent. The effectiveness of halogenated biocides? in fact often tested also in the presence of peptones (Gottardi et al. 2014).
In Figura 4 (a-g) vengono riportati i test in presenza di albumina: Figure 4 (a-g) shows the tests in the presence of albumin:
I test cinetici sono condotti con MDI-102 (80 ppm) albumina 3 g L<-1 >sui seguenti microrganismi: (a) Enterococcus hirae ATCC: 10541, (b) Escherichia coli ATCC: 8739, (c) Pseudomonas aeruginosa ATCC: 9027, (d) Pseudomonas aeruginosa ATCC: 15442, (e) Staphylococcus aureus ATCC: 6538, (f) Staphylococcus epidermidis ATCC:12228, (g) Serratia marcescens ATCC: 13880. Kinetic tests are conducted with MDI-102 (80 ppm) albumin 3 g L<-1 > on the following microorganisms: (a) Enterococcus hirae ATCC: 10541, (b) Escherichia coli ATCC: 8739, (c) Pseudomonas aeruginosa ATCC: 9027, (d) Pseudomonas aeruginosa ATCC: 15442, (e) Staphylococcus aureus ATCC: 6538, (f) Staphylococcus epidermidis ATCC: 12228, (g) Serratia marcescens ATCC: 13880.
In Bianco (linea tratteggiata gialla) il controllo ovvero l?andamento della concentrazione dei microrganismi senza aggiunta di MDI-102 funzione del tempo. In nero la concentrazione microbica in funzione del tempo in presenza di MDI-102 a 80 ppm (concentrazione di Bromo attivo libero). In verde l?andamento dell?azione antibatterica nel tempo di MDI-102 80 ppm in dirty condition. In White (yellow dashed line) the control or the trend of the concentration of microorganisms without the addition of MDI-102 as a function of time. In black the microbial concentration as a function of time in the presence of MDI-102 at 80 ppm (concentration of free active Bromine). In green the trend of the antibacterial action of MDI-102 80 ppm in dirty condition over time.
I test condotti in dirty condition (Fig. 4 a-g) hanno confermato i risultati ottenuti in assenza di interferente. L?utilizzo di MDI-102 80 ppm ? in grado di rimuovere dopo appena 30 secondi una percentuale di microrganismi (Enterococcus hirae ATCC: 10541, Escherichia coli ATCC: 8739, Pseudomonas aeruginosa ATCC: 9027, Pseudomonas aeruginosa ATCC: 15442, Staphylococcus aureus ATCC: 6538, Staphylococcus epidermidis ATCC:12228, Serratia marcescens) ? 99,98% anche su superfici non pulite (3 g L<-1 >di albumina). The tests conducted in dirty conditions (Fig. 4 a-g) confirmed the results obtained in the absence of interferent. The use of MDI-102 80ppm ? capable of removing a percentage of microorganisms after just 30 seconds (Enterococcus hirae ATCC: 10541, Escherichia coli ATCC: 8739, Pseudomonas aeruginosa ATCC: 9027, Pseudomonas aeruginosa ATCC: 15442, Staphylococcus aureus ATCC: 6538, Staphylococcus epidermidis ATCC: 12228, Serratia marcescens) ? 99.98% even on unclean surfaces (3 g L<-1 >of albumin).
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