IT202000016984A1 - SANITIZING AND ANTIINFECTIVE COMPOSITIONS FOR ORAL MUCOSA - Google Patents
SANITIZING AND ANTIINFECTIVE COMPOSITIONS FOR ORAL MUCOSA Download PDFInfo
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- IT202000016984A1 IT202000016984A1 IT102020000016984A IT202000016984A IT202000016984A1 IT 202000016984 A1 IT202000016984 A1 IT 202000016984A1 IT 102020000016984 A IT102020000016984 A IT 102020000016984A IT 202000016984 A IT202000016984 A IT 202000016984A IT 202000016984 A1 IT202000016984 A1 IT 202000016984A1
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- hyaluronic acid
- hydrogen peroxide
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- 238000011012 sanitization Methods 0.000 title description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 24
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 18
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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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
- A61K9/0058—Chewing gums
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- 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
- A61K33/40—Peroxides
-
- 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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/0043—Nose
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Inorganic Chemistry (AREA)
- Otolaryngology (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for an industrial invention entitled:
?COMPOSIZIONI IGIENIZZANTI E ANTIINFETTIVE PER LE MUCOSE ORALI? ? SANITIZING AND ANTIINFECTIVE COMPOSITIONS FOR ORAL MUCOSA?
La presente invenzione ha per oggetto composizioni per la somministrazione locale nelle vie respiratorie, in particolare nelle cavit? nasali e oro-faringee, comprendenti acido ialuronico, suoi sali o derivati e perossido di idrogeno in associazione con opportuni veicoli ed eccipienti. The present invention relates to compositions for local administration in the respiratory tract, in particular in the cavities nasal and oropharyngeal, comprising hyaluronic acid, its salts or derivatives and hydrogen peroxide in association with suitable vehicles and excipients.
Stato della tecnica State of the art
L?apparato respiratorio viene comunemente diviso in due distinti distretti, le alte vie e le basse vie respiratorie. Queste ultime includono naso e seni paranasali, cavit? orale, rino-orofaringe e trachea. La microfiltrazione e l?umidificazione dell?aria attraverso la mucosa nasale e lo scambio di calore attraverso i turbinati sono fondamentali per regolare l?umidit? e per garantire lo scambio ematosico a livello polmonare. The respiratory system is commonly divided into two distinct districts, the upper respiratory tract and the lower respiratory tract. These include the nose and sinuses, cavities oral, nasopharynx and trachea. The microfiltration and humidification of the air through the nasal mucosa and the heat exchange through the turbinates are essential for regulating the humidity in the nose. and to ensure blood exchange in the lungs.
La mucosa nasale ha la funzione di inglobare agenti esterni (polvere, inquinanti, microorganismi) nel muco prodotto dalle cellule mucipare e trasportarli verso la rinofaringe grazie al meccanismo della ?clearance muco ciliare?. The nasal mucosa has the function of incorporating external agents (dust, pollutants, microorganisms) into the mucus produced by the mucus cells and transporting them towards the nasopharynx thanks to the mechanism of ?mucociliary clearance?.
Allo scopo di trattare e prevenire infezioni e di impedire la colonizzazione di agenti patogeni quali virus e batteri responsabili di infezioni respiratorie sono stati proposti spray nasali a base di antibiotici e spray a base di soluzioni saline per la detersione ed il trattamento delle cavit? nasali. La soluzione salina o leggermente ipertonica esercita un effetto decongestionante sulla mucosa nasale ed un effetto meccanico di lavaggio delle sostanze e dei batteri depositati e accumulati nelle cavit? nasali. In order to treat and prevent infections and to prevent the colonization of pathogens such as viruses and bacteria responsible for respiratory infections, nasal sprays based on antibiotics and sprays based on saline solutions have been proposed for cleansing and treating cavities. nasals. The saline or slightly hypertonic solution exerts a decongestant effect on the nasal mucosa and a mechanical washing effect of the substances and bacteria deposited and accumulated in the cavities. nasals.
Per la detersione e igienizzazione delle alte vie respiratorie si utilizzano altres? docce o irrigazioni nasali che prevedono l?instillazione di volumi molto maggiori di quello erogati dagli spray. La soluzione fisiologica o ipertonica viene fatta passare attraverso una narice e fatta fuoriuscire dall?altra in modo da determinare un lavaggio capace di rimuovere anche agenti esterni e patogeni non facilmente raggiungibili con gli spray in quanto localizzati pi? in profondit?. E? infatti noto come i batteri siano in grado di organizzarsi per resistere sia alla terapia antibiotica locale sia alle soluzioni saline ed ai lavaggi nasali formando colonie che aderiscono stabilmente alla mucosa producendo un biofilm costituito prevalentemente da proteine, glicoproteine ed acidi nucleici all?interno del quale possono annidarsi gli stessi batteri altri agenti patogeni. For the cleansing and sanitation of the upper respiratory tract are also used? showers or nasal irrigations which require the instillation of much larger volumes than that supplied by the sprays. The saline or hypertonic solution is passed through one nostril and released from the other in order to determine a washing capable of also removing external agents and pathogens that are not easily reachable with sprays as they are located more? in depth. AND? in fact, it is known that bacteria are able to organize themselves to resist both local antibiotic therapy and saline solutions and nasal washings, forming colonies that adhere stably to the mucosa, producing a biofilm mainly made up of proteins, glycoproteins and nucleic acids, within which they can nest the same bacteria other pathogens.
Contrastare lo sviluppo e possibilmente eliminare le colonie batteriche ? quindi un obiettivo prioritario della terapia delle infezioni respiratorie in genere ed in particolare di quelle rinosinusali. Contrast the development and possibly eliminate the bacterial colonies? therefore a priority objective of the treatment of respiratory infections in general and of rhinosinusal ones in particular.
EP 1847256 descrive formulazioni inalatorie di antibiotici associati ad acido ialuronico. EP 1847256 describes inhalation formulations of antibiotics associated with hyaluronic acid.
EP 211855 descrive formulazioni inalatorie comprendenti acido ialuronico e soluzioni ipertoniche di NaCl utili per idratare le secrezioni viscose in pazienti affetti da fibrosi cistica. EP 211855 describes inhalation formulations comprising hyaluronic acid and hypertonic solutions of NaCl useful for hydrating viscous secretions in patients affected by cystic fibrosis.
La nebulizzazione di acido ialuronico nelle alte vie respiratorie ? stata descritta inoltre in EP 1407776. The nebulization of hyaluronic acid in the upper respiratory tract? has also been described in EP 1407776.
EP 1948200 descrive composizioni topiche cicatrizzanti in forma di gel comprendenti acido ialuronico e acqua ossigenata. Dette composizioni sono impiegate come medicamenti o presidi favorenti la cicatrizzazione e la guarigione di ferite traumatiche e post-chirurgiche, ulcere post-traumatiche e diabetiche, piaghe da decubito, follicoliti, impetigine, peronissi. EP 1948200 describes topical healing compositions in gel form comprising hyaluronic acid and hydrogen peroxide. Said compositions are used as medicaments or aids promoting the healing and healing of traumatic and post-surgical wounds, post-traumatic and diabetic ulcers, bedsores, folliculitis, impetigo, peronyxis.
L?acido ialuronico, un polisaccaride della matrice extracellulare secreto dai fibroblasti, ha un ruolo fondamentale, tra gli altri, nei meccanismi di riparazione tessutale grazie alle sue propriet? fisico-chimiche (igroscopiche, reologiche e viscoelastiche) e biologiche. ? un elemento fondamentale per il ripristino e il mantenimento dell?omeostasi cutanea e delle mucose. Hyaluronic acid, a polysaccharide of the extracellular matrix secreted by fibroblasts, has a fundamental role, among others, in tissue repair mechanisms thanks to its properties? physical-chemical (hygroscopic, rheological and viscoelastic) and biological. ? a fundamental element for the restoration and maintenance of skin and mucous membranes homeostasis.
Il perossido di idrogeno ? un potente agente ossidante con potere antibatterico, antivirale e fungicida. Il perossido di idrogeno ? anche un metabolita del sistema immunitario, prodotto dai granulociti neutrofili come prima risposta all?insulto di tossine, parassiti, batteri, virus e lieviti. La sua attivit? e limitata su mucose perch?, alle concentrazioni utili per agire da antibatterico, antivirale, emostatico, antiinfiammatorio e fungicida, risulta dannoso anche per le cellule che costituiscono le mucose. Hydrogen peroxide? a powerful oxidizing agent with antibacterial, antiviral and fungicidal power. Hydrogen peroxide? also a metabolite of the immune system, produced by neutrophil granulocytes as a first response to the insult of toxins, parasites, bacteria, viruses and yeasts. His activity? and limited on mucous membranes because, at concentrations useful for acting as an antibacterial, antiviral, hemostatic, anti-inflammatory and fungicidal, it is also harmful to the cells that make up the mucous membranes.
Altri agenti ossidanti e/o fonti di ossigeno utilizzati come antiossidanti/antisettici comprendono perborati di sodio, percarbonati di sodio, carbamilperossido, permanganati e persali in genere, con limitazioni e controindicazioni analoghe all?acqua ossigenata. Other oxidizing agents and/or sources of oxygen used as antioxidants/antiseptics include sodium perborates, sodium percarbonates, carbamyl peroxide, permanganates and persalts in general, with similar limitations and contraindications to hydrogen peroxide.
DESCRIZIONE DELL?INVENZIONE DESCRIPTION OF THE INVENTION
Si ? ora trovato che l?associazione di acqua ossigenata con acido ialuronico, applicata localmente, permette di disinfettare efficacemente e senza effetti collaterali la cavit? rinofaringea, sorprendentemente senza effetti irritativi sulla mucosa anche a concentrazioni che normalmente provocano irritazione, grazie ad un?inaspettata attivit? sinergica con l?acido ialuronico che funge, in particolare, da idratante e lenitivo per la mucosa. Yes ? It has now been found that the association of hydrogen peroxide with hyaluronic acid, applied topically, allows the cavity to be disinfected effectively and without side effects. nasopharyngeal, surprisingly without irritating effects on the mucosa even at concentrations that normally cause irritation, thanks to an unexpected activity synergistic with hyaluronic acid which acts, in particular, as a moisturizer and soothing for the mucosa.
L?invenzione fornisce pertanto formulazioni per la somministrazione nelle cavit? nasale od orale contenenti acido ialuronico, suoi sali e derivati, acqua ossigenata in associazione con opportuni veicoli ed eccipienti. The invention therefore provides formulations for administration into cavities. nasal or oral containing hyaluronic acid, its salts and derivatives, hydrogen peroxide in association with suitable vehicles and excipients.
Le composizioni dell?invenzione sono in forma di gel acquosi, collutorio, spray nasale, gocce, soluzioni inalabili mediante adatti erogatori. Preferibilmente, l?acido ialuronico ? presente come ialuronato di sodio in percentuali in peso da 0,01 a 5%, preferibilmente da 0,1 a 1% e l?acqua ossigenata (130 Vol., corrispondenti ad una soluzione al 35% in peso) da 0,1 a 3%, preferibilmente da 1 a 2%. Il peso molecolare dell?acido ialuronico pu? variare entro ampi limiti, ad esempio da 10<3 >a 10<7 >Da, preferibilmente da 10<5 >a 10<7 >Da. In alternativa all?acido ialuronico o agli ialuronati, tipicamente ialuronati di sodio, si possono impiegare derivati di acido ialuronico, in particolari gli esteri lipoati descritti in EP 2 222 712, gli esteri butirrici descritti in EP 941253, e gli esteri misti butirrici-formici descritti in WO 2009 68215. E? preferito acido ialuronico in forma di sodio ialuronato di origine biotecnologica ad alto peso molecolare (10<6 >Da o maggiore), disponibile in commercio da pi? fonti. The compositions of the invention are in the form of aqueous gels, mouthwash, nasal spray, drops, inhalable solutions using suitable dispensers. Preferably, the hyaluronic acid? present as sodium hyaluronate in percentages by weight from 0.01 to 5%, preferably from 0.1 to 1% and hydrogen peroxide (130 Vol., corresponding to a 35% solution by weight) from 0.1 to 3 %, preferably from 1 to 2%. The molecular weight of hyaluronic acid can? vary within broad limits, for example from 10<3 > to 10<7 >Da, preferably from 10<5 > to 10<7 >Da. As an alternative to hyaluronic acid or hyaluronates, typically sodium hyaluronates, hyaluronic acid derivatives can be used, in particular the lipoate esters described in EP 2 222 712, the butyric esters described in EP 941253, and the mixed butyric-formic esters described in WO 2009 68215 . And? preferred hyaluronic acid in the form of sodium hyaluronate of biotechnological origin with high molecular weight (10<6>Da or greater), commercially available for more than sources.
Le composizioni dell?invenzione sono preferibilmente esenti da alcol e da preservanti ma possono contenere altri ingredienti quali glicina, altri agenti antisettici (sali di argento, sali ammonici quaternari, clorexidina, urea perossido, ossichinolina solfato), agenti emollienti, anti-irritanti, anti-infiammatori e antiedemigeni, estratti vegetali quali estratti di Glycyrrhiza glabra, Berberis aristata, Aloe vera, Sisymbrium officinale, Elicriso, camomilla, altea, arnica, menta, melissa. The compositions of the invention are preferably free from alcohol and preservatives but may contain other ingredients such as glycine, other antiseptic agents (silver salts, quaternary ammonium salts, chlorhexidine, urea peroxide, oxyquinoline sulphate), emollient, anti-irritant, anti -inflammatory and anti-edema, plant extracts such as extracts of Glycyrrhiza glabra, Berberis aristata, Aloe vera, Sisymbrium officinale, Helichrysum, chamomile, marshmallow, arnica, mint, lemon balm.
Le composizioni dell?invenzione a base acquosa contengono inoltre aromi, dolcificanti, agenti viscosizzanti, gelificanti, surfattanti ed altri eccipienti di uso convenzionale per collutori e spray nasali. The water-based compositions of the invention also contain flavourings, sweeteners, viscosifying agents, gelling agents, surfactants and other excipients of conventional use for mouthwashes and nasal sprays.
La soluzione disinfettante potr? raggiungere il rinofaringe sia mediante aerosolizzazione con particelle di grandezza maggiore di circa 15 ?m sia mediante altri sistemi quali diffusori, siringhe e soffietti. Il volume di somministrazione pu? variare generalmente da 2 a 10 ml, con frequenza di trattamento da una fino a 4-5 volte al giorno. L?acido ialuronico aderisce alla mucosa nasale proteggendola dagli agenti esterni mentre l?acqua ossigenata esplica una potente azione antibatterica ed antivirale, anche nei confronti di virus respiratori responsabili delle recenti pandemie. The disinfectant solution can reach the nasopharynx both by aerosolization with particles larger than about 15 µm and by other systems such as diffusers, syringes and bellows. The volume of administration can generally vary from 2 to 10 ml, with a treatment frequency of one to 4-5 times a day. Hyaluronic acid adheres to the nasal mucosa protecting it from external agents while hydrogen peroxide has a powerful antibacterial and antiviral action, even against respiratory viruses responsible for recent pandemics.
Le composizioni dell?invenzione sono preparate sciogliendo in una prima fase l?acido ialuronico, un suo derivato o un suo sale ed eventualmente glicina in acqua deionizzata. Alla soluzione omogenea ottenuta si aggiunge quindi l?eventuale polimero addensante e quindi una soluzione acquosa di eventuali altri componenti. L?acqua ossigenata viene quindi aggiunta lentamente sotto continua agitazione fino ad ottenere una dispersione omogenea. The compositions of the invention are prepared by dissolving hyaluronic acid, a derivative thereof or a salt thereof and optionally glycine in deionized water in a first phase. The thickening polymer, if any, and then an aqueous solution of any other components are then added to the homogeneous solution obtained. The hydrogen peroxide is then added slowly with continuous stirring until a homogeneous dispersion is obtained.
I seguenti esempi illustrano ulteriormente l?invenzione. The following examples further illustrate the invention.
Esempio 1- Collutorio Example 1- Mouthwash
Esempio 2 - Collutorio Example 2 - Mouthwash
Esempio 3 - Gel Example 3 - Gel
Esempio 4 - Prove cliniche Example 4 - Clinical trials
La composizione dell?esempio 1 ? stata sottoposta a una valutazione clinica in tre diversi gruppi di pazienti: 25 pazienti affetti da gengiviti, 25 pazienti con tasche periodontali e 19 pazienti dopo estrazione del dente del giudizio. Lo studio ? stato effettuato in confronto al placebo per i primi due gruppi (21 e 25 pazienti, rispettivamente) e in confronto a placebo (17 pazienti) e a un collutorio a base di clorexidina (18 pazienti) per il terzo. The composition of example 1 ? was subjected to a clinical evaluation in three different groups of patients: 25 patients with gingivitis, 25 patients with periodontal pockets and 19 patients after wisdom tooth extraction. I study ? was carried out in comparison with placebo for the first two groups (21 and 25 patients, respectively) and in comparison with placebo (17 patients) and a chlorhexidine-based mouthwash (18 patients) for the third.
I parametri considerati sono stati il dolore acuto e cronico, misurati con punteggio VAS, l?indice di placca secondo Silness e Loe (1964), l?indice di sanguinamento secondo Mombelli (1987) e i cambiamenti soggettivi nel gusto ed olfatto. Per l?estrazione del dente del giudizio venivano anche considerati la presenza di tessuto di granulazione, suppurazione, arrossamento, gonfiore, ri-epitelizzazione, dolore alla palpazione. La durata della valutazione ? stata di 21 giorni per la gengivite, 9 giorni per l?estrazione e 7 giorni per le tasche periodontali. Il trattamento prevedeva due somministrazioni al giorno di 5-10 ml del collutorio. I risultati, sottoposti ad analisi statistica, hanno confermato la maggiore efficacia rispetto al placebo e al collutorio di controllo, in particolare per quanto riguarda l?indice di sanguinamento, l?indice di placca e il sollievo dal dolore. The parameters considered were acute and chronic pain, measured with VAS score, plaque index according to Silness and Loe (1964), bleeding index according to Mombelli (1987) and subjective changes in taste and smell. For wisdom tooth extraction, the presence of granulation tissue, suppuration, redness, swelling, re-epithelialization, pain on palpation were also considered. The duration of the evaluation? was 21 days for gingivitis, 9 days for extraction and 7 days for periodontal pockets. The treatment involved two daily administrations of 5-10 ml of the mouthwash. The results, subjected to statistical analysis, confirmed the greater efficacy compared to the placebo and the control mouthwash, in particular as regards the bleeding index, the plaque index and the pain relief.
Claims (8)
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| EP0211855A1 (en) | 1985-02-13 | 1987-03-04 | Secr Defence Brit | Optical components. |
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| EP1407776A1 (en) | 2002-10-10 | 2004-04-14 | Giuseppe Petrigni | A pharmaceutical colloidal preparation comprising hyaluronic acid biopolymers useful in the treatment of respiratory diseases |
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| WO2009068215A1 (en) | 2007-11-27 | 2009-06-04 | Sigea S.R.L. | Mixed butyric-formic esters of acid polysaccharides, and their preparation and use as skin cosmetics |
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| WO2011006263A1 (en) * | 2009-07-17 | 2011-01-20 | Klox Technologies Inc. | Antibacterial oral composition |
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