Title of Invention	“A METHOD FOR DETERMINING A STATE OF INPUT/OUTPUT (I/O) OPERATION AND AN APPARATUS THEREOF”
Abstract	A state of an input/output (I/O) operation in an I/O processing system is determined. A request for performing the I/O operation is received from an I/O operating system at a channel subsystem and forwarded to a control unit controlling an I/O device for executing the I/O operation. After a predetermined amount of time passes without receiving indication from the control unit that the I/O operation is completed, an interrogation request is received at the channel subsystem from the I/O operating system for determining the state of the I/O operation. An interrogation command is sent from the channel subsystem to the control unit. A response is received from the control unit, the response indicates a state of the I/O device executing the I/O operation, a state of the control unit controlling the I/O device executing the I/O operation, and the state of the I/O operation being executed. FIG. 12A

Title of Invention

“A METHOD FOR DETERMINING A STATE OF INPUT/OUTPUT (I/O) OPERATION AND AN APPARATUS THEREOF”

Abstract

A state of an input/output (I/O) operation in an I/O processing system is determined. A request for performing the I/O operation is received from an I/O operating system at a channel subsystem and forwarded to a control unit controlling an I/O device for executing the I/O operation. After a predetermined amount of time passes without receiving indication from the control unit that the I/O operation is completed, an interrogation request is received at the channel subsystem from the I/O operating system for determining the state of the I/O operation. An interrogation command is sent from the channel subsystem to the control unit. A response is received from the control unit, the response indicates a state of the I/O device executing the I/O operation, a state of the control unit controlling the I/O device executing the I/O operation, and the state of the I/O operation being executed. FIG. 12A

Full Text	TECHNICAL FIELD An oral rinse formulation for the treatment or prophylaxis of mucositis or stomatitis comprises one or more of the following components in combination with pharmaceutically acceptable excipients or additives: a) at least one corticosteroid; b) at least one anti-histamine; c) at least one topical anaesthetic; and, d) at least one anti-fungal antibiotic agent. A stable nystatin containing formulation is also provided comprising a buffering agent, a preservative, a chelating agent and an anti-oxidant. BACKGROUND OF THE INVENTION The present invention relates to oral hygiene and in particular, to mouthwashes for the treatment and prophylaxis of mucositis and stomatitis of the oral cavity and to a method of using such a mouthwash. Mouthwashes are typically used as part of an oral hygiene regime which may also include brushing and flossing to maintain a satisfactory level of oral hygiene. Such mouthwashes are generally classified as cosmetic, therapeutic or a combination of the two. Cosmetic rinses are commercial over-the-counter products that help remove oral debris before or after brushing, temporarily suppress bad breath, diminish bacteria in the mouth and refresh the mouth with a pleasant taste. Therapeutic rinses often have the benefits of their cosmetic counterpart, but also contain an added active ingredient, for example chlorhexidine that helps protect against some oral diseases such as gingivitis. Typically, such mouthwashes are alcohol-based. However, available mouthwashes are unsuitable for hospital patients presenting with oral complications as a result of, for example, infection or other lesions as a consequence of chemotherapy or radiotherapy for the treatment of neoplastic disease. Such oral complications may include mucositis or stomatitis. Mucositis or stomatitis presents in approximately 40% of patients with neoplastic disease. Examples of chemotherapeutic drugs that frequently cause mucositis and/or stomatitis include alkylating agents, for example melphalan and busulphan; antimetabolites, for example, cytarabine, floxuridine, 5-fluorouracil, mercaptopurine, methotrexate, and thioguanine and cytotoxic drugs, for example, bleomycin, actinomycin D, daunorubicin, cisplatin, etoposide, mytomycin, vinblastine and vincristine. 3 The terms mucositis and stomatitis are often used interchangeably but may include some general distinctions. Mucositis describes a toxic inflammatory reaction affecting the gastro-intestinal tract, which may result from exposure to chemotherapeutic agents or ionizing radiation. Mucositis typically manifests as an erythematous burn-like lesion, or as random focal-to-diffuse lesions. Stomatitis refers to an inflammatory reaction affecting the oral mucosa, with or without ulceration, that may be caused or intensified by pharmacological, particularly chemotherapeutic treatments or by radiotherapy. Stomatitis can range from mild to severe; a patient presenting with the severe stomatitis is unable to take anything by mouth. Current oral cleaning care in such patients may include gently cleaning the mouth, moisturizing the lips and mouth, and relieving pain and swelling. A soft toothbrush cleans teeth well and gently. Cleansing agents can include “salt and soda” (half a teaspoon of salt and two tablespoons of sodium bicarbonate in 32 ounces of warm water), saline, sterile water or sodium bicarbonate (one teaspoon in 8 ounces of water). Hydrogen peroxide diluted in equal amounts of water or weak salt water can be used in some cases. Mostly, physicians have resorted to these rather limited, temporary relief options. It is therefore extremely important that mucositis and stomatitis be prevented whenever possible or at the very least that they be reduced in their severity and possible complications. Currently there are a number of intervening therapies to choose from. For example, The Joanna Briggs Institute of The Royal Adelaide Hospital has provided some guidance on the treatment of mucositis. However, there is no high quality synthesis of research evidence for these intervention therapies (www.joannabriggs.edu.au/best_practice/bp5.php, 19 February 2004). Of particular interest to the current application are the variety of mouthwashes previously used having mixed actions against mucositis and stomatitis. Such mouthwashes typically include benzydamine hydrochloride, corticosteroids and chamomile (www.joannabriggs.edu.au/best_practise/bp5.php). Formulations such as those disclosed in U.S. 5,635,489; U.S. 4,961,926 and U.S. 5,102,870 describe the use of growth factors and stimulation factors such as granulocyte-macrophage colony stimulating factor and granulocyte-colony stimulating factor. Further attempts at treatment and or prophylaxis of mucositis and stomatitis include the use of nucleoside derivatives which can be formulated into lozenges or mouthwashes and the like to 4 coat the oral cavity or other mucosal areas such as disclosed in U.S. Patent Publication No. 2003/0236217 A1. Other formulations include tetracycline as disclosed in U.S. 6,946,118; hyaluronic acid, glycyrrhetinic acid and polyvinylpyrrolidone in mixture with excipients and adjuvants as disclosed in U.S. 6,828,308; the use of an anti-microbial peptide, preferably protegrin applied topically which has broad spectrum anti-microbial activity, good stability and adheres well to all mucosa as disclosed in U.S. 6,025,326; the use of glutamine as disclosed in U.S. 5,545,668 and the use of triclosan as disclosed in U.S. 5,945,089 Despite the widespread recognition that mucositis is a serious problem, no effective treatment currently exists and, more often than not, any level of patient care is typically palliative. In addition to the lack of effective treatments for mucositis, physicians are unsure of the exact mechanism by which the ulcerations occur in mucositis. It is known that the initial exposure to a chemotherapeutic agent causes a release of cytokines from the epithelial tissues. Subsequently, mitosis is disturbed in the epithelia. Finally, there are alterations in the bacterial flora of the oral cavity. It is unknown which of these occurrences, if any, is responsible for the mucosal damage. Despite the fact that significant quantities or inflammatory mediators are released by the epithelium, conventional anti-inflammatory agents have been unsuccessful in human efficacy studies of the disease. Some of the known and effective treatments for mucositis involves the use of the antibiotics nystatin and amphotericin B. These drugs have been used for the preventive and curative treatment of fungal infections such as oral candidiasis and, in particular, for cancer patients. Due to a lack of commercially available anti-fungal mouthwashes, oral or mouth rinse formulations containing these antifungal agents are commonly prepared in a clinical setting for immediate use. One possible reason for the lack of nystatin and/or amphotericin B mouth rinse formulations is that such formulations are relatively unstable and, therefore, must be used within a short period of time. For example, in one study of mixtures of nystatin and amphotericin B, in combination with sodium bicarbonate, it was determined that the maximum amount of time that such formulations can remain stable is roughly 3 to 4 days (J. Groeschke, et al.; Stability of Amphotericin B and Nystatin in Antifungal Mouthrinses Containing Sodium Hydrogen Carbonate, J. Pharm. and Biomed. Anal., v. 42, 3 (2006), pp. 362-366). 5 Thus, the available mouthwashes are effective at treating only one aspect of mucositis and other oral complications and not treating the complete range of symptoms that present in patients. Further, the effective antifungal mouth rinses have a very limited stability. There exists a need, therefore, for a stable formulation for treating a variety of symptoms and causes of mucositis. STATEMENT OF THE INVENTION Accordingly, the present invention relates to an oral rinse formulation comprising one or more of the following components in combination with pharmaceutically acceptable excipients or additives: a) at least one corticosteroid, b) at least one anti-histamine, c) at least one topical anaesthetic, and d) at least one anti-fungal antibiotic agent; a stable, anti-fungal oral rinse formulation comprising nystatin and a buffering agent, a preservative, a chelating agent and an anti-oxidant; and a stable, anti-fungal oral rinse formulation comprising: an anti-fungal agent; a phosphate buffer; a preservative; a chelating agent; and an antioxidant. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an oral rinse formulation comprising one or more of the following components in combination with pharmaceutically acceptable excipients or additives: a. at least one corticosteroid; b. at least one anti-histamine; c. at least one topical anaesthetic; and d. at least one anti-fungal antibiotic agent. In an embodiment of the present invention, all of components (a) to (d) are included. In another embodiment of the present invention, the formulation further comprising at least one antibiotic agent. In yet another embodiment of the present invention, the formulation has the following composition: - 0.005 to 0.025 mg/ml dexamethasone; - 1 to 2 mg/ml diphenhydramine; - 1 to 20 mg/ ml lidocaine; and - 10,000 to 50,000 iu/ml nystatin. 6 In still another embodiment of the present invention, the additives are chosen from the group consisting of: polysorbate 80, spearmint oil, sorbitol, xanthan gum, sodium benzoate, purified water, aluminium hydroxide, dextrose, sucralose, flavorings and magnesium hydroxide. In still another embodiment of the present invention, the formulation further comprising at least one buffering agent, at least one preservative, at least one chelating agent and at least one antioxidant. In still another embodiment of the present invention, the buffering agent is a phosphate buffer, the preservative is methyl paraben or propyl paraben, the chelating agent is EDTA, and the antioxidant is citric acid or a salt thereof. The present invention relates to use of the formulation as indicated above for the treatment of oral lesions. In an embodiment of the present invention, the use is for the treatment of mucositis or stomatitis. The present invention relates to a stable, anti-fungal oral rinse formulation comprising nystatin and a buffering agent, a preservative, a chelating agent and an anti-oxidant. In an embodiment of the present invention, the buffering agent is a phosphate buffer. In another embodiment of the present invention, the preservative is methyl paraben or propyl paraben. In yet another embodiment of the present invention, the chelating agent is EDTA. In still another embodiment of the present invention, the anti-oxidant is citric acid or a salt thereof. In still another embodiment of the present invention, the nystatin is present in an amount greater than 10,000 iu/ml. The present invention relates to a stable, anti-fungal oral rinse formulation comprising: - an anti-fungal agent; - a phosphate buffer; - a preservative; - a chelating agent; and, - an antioxidant. In an embodiment of the present invention, the anti-fungal agent is selected from nystatin and amphotericin B. 7 In another embodiment of the present invention, the nystatin is present in an amount between 10,000 and 50,000 iu/ml. In yet another embodiment of the present invention, the preservative is chosen from methyl paraben, propyl paraben and mixtures thereof. In still another embodiment of the present invention, the chelating agent is ethylenediamine tetraacetic acid (EDTA). In still another embodiment of the present invention, the antioxidant is citric acid or a salt thereof. In still another embodiment of the present invention, the formulation further comprising: - at least one corticosteroid; - at least one antihistamine; and - at least one topical anaesthetic. In still another embodiment of the present invention, the corticosteroid is dexamethasone and wherein said dexamethasone is present in a concentration of between 0.005 to 0.025 mg/ml. In still another embodiment of the present invention, the antihistamine is diphenhydramine and wherein said diphenhydramine is present in a concentration of between 1 to 2 mg/ml. In still another embodiment of the present invention, the topical anaesthetic is lidocaine and wherein said lidocaine is present in a concentration of between 1 to 20 mg/ml. In one aspect, the present invention provides an oral rinse formulation comprising one or more of the following components in combination with pharmaceutically acceptable excipients or additives: a) at least one corticosteroid; b) at least one anti-histamine; c) at least one topical anaesthetic; d) at least one anti-fungal antibiotic agent. In another aspect, the formulation can include an antibiotic agent. In a further aspect, the invention provides a method of treating or preventing mucositis or stomatitis comprising applying to a patient the above mentioned oral rinse formulation. 8 In another aspect, the invention provides a stable, anti-fungal oral rinse formulation comprising: - an anti-fungal agent; - a phosphate buffer; - a preservative; - a chelating agent; and, - an antioxidant. In one embodiment, the anti-fungal agent is chosen from nystatin and amphotericin B. In a further embodiment, the above formulation comprises: at least one corticosteroid; at least one antihistamine; and at least one topical anaesthetic. Accordingly, the present invention provides, in one embodiment, a mouthwash comprising one or more of the following active ingredients: - at least one corticosteroid; - at least one anti-histamine; - at least one topical anaesthetic; - at least one anti-fungal antibiotic agent. Optionally, the formulation may include an antibiotic agent as well. In another embodiment, the invention provides a mouthwash formulation comprising an antifungal agent, a phosphate buffer, a preservative, a chelating agent and an antioxidant. This formulation preferably also includes at least one corticosteroid, at least one antihistamine, and at least one topical anaesthetic. More preferably, the anti-fungal agent of this formulation comprises nystatin or amphotericin B and, most preferably, nystatin. Preferably, the mouthwash in accordance with the present invention is used in the treatment and/or prophylaxis of oral conditions such as mucositis and/or stomatitis. Although the mouthwash (or mouth rinse) of the present invention includes various components that are known in the art, the inventors note that there is no commercially available formulation that combines the subject components to provide an effective, single formulation that addresses a large variety of symptoms associated with mucositis and/or stomatitis. This is also clearly indicated in the recent article by J. Groeschke, et al. Further, in addition to providing such multipurpose formulation, the inventors have also found an unexpectedly high stability of the 9 formulation, particularly when an anti-fungal is included. More specifically, the formulation described below including nystatin was found to be stable for over 2 months, thereby greatly exceeding the stability expected according to the prior art, such as the article by J. Groeschke, et al. Preferably the mouthwash in accordance with the present invention further comprises water and pharmaceutically acceptable excipients or additives such as: - one or more oils, such as an oil selected from the group comprising anethole, anisole, camphor, methyl salicylate, vanillin, eugenol, furaneol, linalool, menthol, thymol, cinnamaldehyde, citral, methyl butanoate, pentylbutanoate, pentylpentanoate, tea tree oil, peppermint oil, spearmint oil, pineapplemint oil and eucalyptus oil; - sweetening agents, for example sorbitol; - thickening agents, such as xanthan gum, carrageenan, carbomer, or HPMC (hydroxypropyl methyl cellulose); - preservative agents, such as sodium benzoate, methyl paraben, or propyl paraben; - water; - emulsifiers, such as polysorbate 80 (or Tween™ 80); - and/or at least one antacid such as aluminium or magnesium hydroxide. It will be appreciated by persons skilled in the art that the above list of excipients and/or additives is provided merely by way of example and that various other such components may be used in the formulation of the present invention. Oral mucositis results in specific damage that includes the shedding of the mucosal lining of the mouth (desquamation), ulceration and atrophy. Aluminum and magnesium hydroxide antacids coat and protect the oral cavity from damage and provide for re-growth of normal oral tissue. The corticosteroid component provides anti-inflammatory action directly on the oral mucosa and works to limit the inflammatory response associated with mucositis. Preferably, the corticosteroid is dexamethasone. In patients being treated with chemotherapy and radiation, steps may be taken to prevent bacterial infection within the oral cavity. For this reason, in an optional embodiment, the mouthwash formulation of the invention may contain an antibiotic component. Such antibiotic 10 components may be of the macrolide type and may be selected from the group consisting of erythromycin, azithromycin, clarithromycin, dirithromycin, roxithromycin carbomycin A, josamycin, kitasamycin, oleandomycin, spiramycin, troleandomycin, tylosin, cethromycin, ansamycin and telithromycin. In one aspect the antibiotic is erythromycin. Once ulcerations develop inside the mouth, local oral bacteria colonize the wound and release cell wall products into the mucosa, resulting in an amplification of a tissue destructive cycle. The antibiotic component, i.e. Erythromycin, limits such bacterial colonization. As will be understood, limiting the extent of bacterial infection would promote healing of the affected tissues. Alternatively, the antibiotic may be any of the following, alone or in combination: - an aminoglycoside, for example, amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, and tobramycin; - a carbacephem, for example, loracarbef; - a carbapenem, for example, ertapenem, imipenem/cilastatin, and meropenem; - a cephalosporin (first generation), for example, cefadroxil, cefazolin, cephalexin; - a cephalosporin (second generation), for example, cefaclor, cefamandole, cefoxitin, cefprozil, and cefuroxime; - a cephalosporin (third generation), for example, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone; - a cephalosporin (fourth generation), for example, cefepime; - a glycopeptide, for example, teicoplanin, vancomycin; - a penicillin, for example, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin and ticarcillin; - a polypeptide, for example, bacitracin, colistin, and polymyxin B; - a quinolone, for example, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and trovafloxacin; - a sulfonamide, for example, mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole; - a tetracycline, for example, demeclocycline, doxycycline, minocycline, and oxytetracycline, tetracycline, and 11 - another antibiotic, for example, chloramphenicol, clindamycin, ethambutol, fosfomycin, furazolidone, isoniazid, linezolid, metronidazole, nitrofurantoin, pyrazinamide, quinupristin/dalfopristin, rifampin, and spectinomycin. The anti-fungal antibiotic agent may be of the polyene type and may be selected from the group consisting of nystatin, amphotericin B and natamycin. In one aspect, the anti-fungal agent is nystatin or amphotericin B. Patients being treated with chemotherapy and radiation are immuno-compromised. This leads to not only increased risk of bacterial infection but also to an increased risk of fungal infection, thus advancing the risk and degree of oral mucositis. Nystatin and amphotericin B act to prevent and limit the degree of fungal infection. Alternatively, the anti-fungal compound may be selected from an imidazole, for example, miconazole, ketoconazole, clotrimazole, econazole, mebendazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, thiabendazole or tiaconazole; a triazole, for example, fluconazole, itraconazole, ravuconazole, posaconazole or voriconazole; an allylamine, for example, terbenafine, amorolfine, naftifine or butenafine or an echinocandin such as caspofungin or micafungin or any combinations thereof. The topical anaesthetic may be selected from benzocaine, mepivacaine, ropivacaine, bupivacaine, lidocaine, prilocaine, procaine, cloroprocaine or tetracaine. In one aspect the topical anaesthetic is a combination of lidocaine and tetracaine. Pain associated with oral mucositis can be extremely debilitating and lead to poor oral food intake. In extreme cases patients may require feeding tubes if the ulceration continues to advance. Tetracaine and lidocaine act locally to provide relief from pain. Preferably, the anti-histamine may be selected from the group comprising a first generation H1 receptor antagonist, a second generation H1 receptor antagonist, a third generation H1 receptor antagonist, a H2 receptor antagonist, a H3 receptor antagonist and a H4 receptor antagonist. Diphenyhdramine, an antihistamine, helps to sooth soreness, burning, itching (urticaria and pruritis) and inflammation, symptoms that are normally associate with mucositis. The first generation H1 receptor antagonist may be selected from an ethylenediamine, for example, mepyramine or antazoline; an ethanolamine, for example, diphenhydramine, carbinoxamine, doxylamine, clemastine or dimenhydrinate; an alkylamine, for example, 12 pheniramine, chlorphenamine, dexchlorphenamine, brompheniramine or triprolidine; a piperazine, for example, cyclizine, hydroxyzine, meclizine or a tricyclic, for example, promethazine, alimemazine, cyproheptadine or azatadine. In one aspect, the anti-histamine is diphenhydramine. The second generation H1 receptor antagonist may be azelastine, levocabastine or olopatadine. The H3 receptor antagonist may be thioperamide, clobenpropit or impromidine. The H4 receptor antagonist may be thioperamide. Preferably, dexamethasone is used in the range of from 0.005 mg/ml to 0.025 mg/ml, or, more preferably, narrower ranges such as 0.01 mg/ml to 0.02 mg/ml or 0.015 mg/ml to 0.02 mg/ml. In one preferred embodiment, dexamethasone is present in a concentration of 0.016 mg/ml. Preferably, diphenhydramine is used in a range of from 1 mg/ml to 2 mg/ml or, more preferably, in narrower ranges such as 1 mg/ml to 1.5 mg/ml, 1.2 mg/ml to 1.4 mg/ml, or 1.25 mg/ml to 1.3 mg/ml. In one preferred embodiment, dexamethasone is present in a concentration of 1.67 mg/ml. Preferably, lidocaine is used in a range of from 1 mg/ml to 20 mg/ml (i.e. 0.1% to 2%) although narrower ranges may also be used. In one preferred embodiment, lidocaine is present in a concentration of 10 mg/ml. Preferably, nystatin is used in an amount greater than 10,000 iu/ml. More preferably, Nystatin is used in a range of 10,000 iu/ml to 50,000 iu/ml, or 20,000 iu/ml to 40,000 iu/ml, or 30,000 iu/ml to 35,000 iu/ml, or most preferably at a concentration of 33,333 iu/ml. When included in the formulation of the invention, erythromycin is used in a range of from 5 mg/ml to 15 mg/ml, or, more preferably, in narrower ranges such as 10 mg/ml to 15 mg/ml, 12 mg/ml to 15 mg/ml, or 12.5 mg/ml to 15 mg/ml. In a further embodiment, the present invention provides a mouthwash comprising 0.015 mg/ml dexamethasone, 1.25 mg/ml diphenhydramine, 0.5% lidocaine, 20000 iu/ml nystatin, polysorbate 80, spearmint oil, sorbitol, xanthan gum, sodium benzoate, purified water, aluminium hydroxide and magnesium hydroxide. Optionally, the formulation may also include 12.5 mg/ml erythromycin. 13 In a further aspect the present invention provides a method of treating or preventing oral conditions such as mucositis or stomatitis comprising rinsing the oral cavity with the mouthwash of the invention. The present invention also provides, in a further embodiment, a kit for the treatment or prophylaxis of mucositis or stomatitis comprising a container having an amount of mouthwash in accordance with the present invention together with a set of instructions for using the mouthwash. The kit may optionally provide a cup or other container for conveniently dispensing an amount of the mouthwash from the container. Advantageously the cup may also have markings or other indicators for the convenient dispense of a measurement of a therapeutically effective dose of the mouthwash. In a further embodiment, the invention provides a mouthwash or mouth rinse formulation that is exhibits long term stability. The stable formulation of the invention includes nystatin as the antifungal component. In a preferred embodiment, the nystatin containing formulation includes a buffering agent, a preservative, a chelating agent and an anti-oxidant. In another aspect, the invention provides a stable, anti-fungal oral rinse formulation comprising: an anti-fungal agent (chosen from nystatin, amphotericin B and mixtures thereof); a phosphate buffer; a preservative (such as methyl paraben and/or propyl paraben); a chelating agent (such as EDTA); and an antioxidant (such as citric acid or a salt thereof). In a further aspect of the invention, the above formulation also includes at least one corticosteroid; at least one antihistamine; and at least one topical anaesthetic. Examples The following examples are provided to illustrate the invention and are not intended to limit the scope of the invention in any way. Introduction As discussed above, there are currently no mouth rinses available on the market containing Nystatin, Dexamethasone sodium phosphate, Lidocaine HCL and Diphenhydramine HCl available. Moreover, there are no commercially available mouth rinses containing nystatin and 14 this is believed to be mainly due to the poor stability characteristics of formulations containing this drug. For this reason, various mouth rinse (or mouthwash) formulations were prepared to study the stability characteristics. The aim of this project was to develop a stable formulation containing at least nystatin and, preferably the various other treatment agents listed above. As discussed further below, a prototype formulation was developed and its stability was tested at room temperature. The product was found to be stable at room temperature for over three months. Materials and Methods Table 1 below summarises the formulations studied. As shown, nine sample preparations were examined, identified as samples B1 to B9. Where the samples differed in formulation, a notation is included in Table 1. The following procedure was typical of that followed in preparing the formulations of the example. As indicated above, the specific concentrations of the various components for the trials is indicated Table 1. Step 1. Preparation of 1.2% HPMC (hydroxypropyl methyl cellulose) solution for the final volume 1.1) Heat 70 mL DI water to 90°C. 1.2) Slowly add 2.4g HPMC with continuous stirring and heating at 90°C for 1 hour . 1.3) Cool down to room temperature with continuous stirring (about 1 hour). 1.4) Add 130 mL cold DI (de-ionized) water with continuous stirring for 60 minutes. 1.5) Set aside for nystatin suspension preparation in step 3. Step 2. Preparation of water soluble API’s (active pharmaceutical ingredients) and other ingredients 2.1) Dissolve 0.60 g methyl paraben (0.2%) and 60 mg propyl paraben (0.02%) in 15.0 g propylene glycol (5%) and stir at 40°C for 10 min or until completely dissolved. 2.2) Add 3.0g Tween™ 80 (1.0%) then stir for 10 min at 40ºC. 15 2.3) Add 150 mL DI water and cool down to room temperature. 2.4) Add each of the following remaining ingredients and all soluble API’s with continuous stirring until completely dissolved. No heating. 1.5g citric acid 4.3018 g sodium phosphate dibasic 1.5g sucralose 6.444 mg dexamethasone 21-phosphate disodium salt 581.61 mg diphenhydramine HCl 3.741g lidocaine HCl Step 3. Preparation of nystatin suspension 3.1) Slowly add 1.6431g nystatin to 120 mL 1.2 % HPMC solution (from step 1 ) with continuous stirring. The final HPMC concentration in the formulation will therefore be 0.5%. 3.2) Add 0.60 g EDTA (0.2%) and mix well. Step 4. Mix solution from step 2 and nystatin suspension from step 3. Add 1.2 mL NFB mixed berry flavor. Mix well. Step 5. Measure pH. If it is not 6.5±0.5, adjust to pH 6.5±0.5 with 100 mM phosphate buffer (Na2HPO4). Step 6. Adjust final volume to 300 mL with water. Mix well and verify pH again. At the end of Step 6, the formulation (300 ml) will have the composition as listed in the following table. Items marked as * comprise the active drug ingredients. Items marked as ** comprise the alternative components used for a placebo formulation. 16 Note Chemical Name Freebase Concn (mg/mL) Concentration Units Weight of component added Propylene Glycol 5.0 % 15.0g Methyl Paraben 0.20 % 0.6g Propyl Paraben 0.02 % 60mg Tween 80 1.0 % 3.0g Citric Acid 0.50 % 1.5g Sodium Phosphate dibasic 100.0 mM 4.3018g Sucralose 0.50 % 1.5g * Dexamethasone 21- phosphate 0.016 0.02148 mg/mL 6.444mg disodium salt * Diphenhydramine HCl 1.67 1.9387 mg/mL 0.581g * Lidocaine HCl 10 12.47 mg/mL 3.741g HPMC 0.5000 % * Nystatin 33,333IU/mL 5.477 mg/mL 1.6431 EDTA acid calcium disodium 0.20 % 0.6g Mixed NFB Berry Flavor 0.40 % 1.2g Titanium Oxide 5.00 mg/mL 1.5g D&C Yellow No. 10 0.001 % The formulations were stored at room temperature and tested upon formulation (i.e. time = 0) and at 2, 3 and 4 month time points for identity, potency, pH, preservative assay, physical appearance and color. Formulation B8 was used for testing stability and the results of this analysis at the various time points are provided in Tables 2 to 5. Quantification of the respective ingredients was done using high performance liquid chromatography (HPLC). A difference in calculated quantity of less than 5% from the intial formulation (i.e. time = 0) amount was considered a “pass”, that is, indicative of minimal degradation. The relative standard deviation for the HPLC calculations was ≤ 3%. For the re-dispersibility study, the following procedure was followed: - manually shake the sample for 5 seconds. - observe the bottom of the glass bottle. 17 - if settlement or clumping is found, shake for another 5 seconds and observe. - the sample is identified as re-dispersible if no settlement or clumping is found on the bottom of the glass bottle. Conclusions All the samples prepared for the stability study were found to meet the desired criteria. The mouth rinse of the invention was found to be stable, when stored room temperature, for at least up to 4 months. At “accelerated conditions”, that is when stored at 40°C, the formulation was found to remain stable for less than 2 months. These results illustrate an unexpected stability of a nystatin containing formulation particularly when stored at room temperature. The stability of the nystatin containing formulation is believed to be attributable to the presence of the buffering agent (pH control), preservatives (i.e. paraben), the chelating agent (i.e. EDTA), and the antioxidant (i.e. citrate). The data obtained from this study indicates that the formulation of the invention exhibits long term stability and, therefore, provides a unique, single dose formulation that addresses various symptoms associated with mucositis. Although the invention has been described with reference to certain specific embodiments, various modifications thereof will be apparent to those skilled in the art without departing from the purpose and scope of the invention as outlined in the claims appended hereto. Any examples provided herein are included solely for the purpose of illustrating the invention and are not intended to limit the invention in any way. The disclosures of all prior art recited herein are incorporated herein by reference in their entirety. 18 Table 1: Sample formulations prepared for stability study Ingredient Type Active/Excipient Concentration (free base concentration) Grade Other Candidates Notes Corticosteroid Dexamethasone sodium phosphate salt 0.016 mg/mL USP grade H2O soluble Anti-histamine Diphenhydramine HCl 1.67 mg/mL USP grade H2O soluble Anesthetic Lidocaine HCl 10 mg/mL USP grade H2O soluble Anti-fungal Nystatin 33,333 IU/mL (5.477mg/mL) USP grade slightly soluble- 4mg/ml in H2O Anti-oxidant Citric Acid 0.5% w/v USP Chelating agent Calcium disodium EDTA 0.2% (w/v) USP Wetting agent (emulsifier) Polysorbate 80 (Tween™ 80) - 1.0% for B1, B2, B8, B9 - 1.2 % for B3, B4, B5 - 1.5% for B6 USP Polysorbate 20, Poloxamer 407 H2O soluble Sweetening agent Sucralose 0.5 % (w/v) USP H2O soluble Thickener HPMC (Hydroxy Propyl Methyl Cellulose) (from Dow Chemical F4M) - 0.25%(w/v) for B1, B2, B7 - 0.3% for B3, B4 - 0.4% for B5, B6, B8 - 0.5% for B9 USP (Sodium Carboxyl Methyl cellulose) SCMC H2O soluble Preservative Methyl paraben, Propyl paraben - 0.2% Methyl paraben (w/v); - 0.02% Propyl paraben - B2 - no propyl paraben USP parabens are slightly soluble in hot 19 water Tonicity adjusting factor Dextrose used where the osmolality of the formulation is mOsm/kg NaCl H2O soluble Flavour Sensient NFB mixed berry flavor 0.4% v/v Pharma. grade Solvent Purified water >85 % (w/w) Buffer agent Sodium phosphate Dibasic 100 mM USP citrate phosphate buffer H2O soluble 20 Table 2: Sample characteristics upon formulation (time = 0) Test Active/Excipient Specification Limits Method Results Pass/fail Identity Dexamethyasone sodium phosphate; Diphenhydramine HCl; Lidocaine HCl Positive HPLC Conforms Pass Identity Nystatin Positive HPLC Conforms Pass Potency Dexamethasone sodium phosphate 90 to 110% of label claim; less than 5% change in stability sample HPLC 103.2% Pass Potency Diphenhydramine HCl 90 to 110% of label claim; less than 5 % change in stability sample HPLC 100.6% Pass Potency Lidocaine HCl 90 to 110% of label claim; less than 5% change in stability sample HPLC 100.4% Pass Potency Nystatin 90 to 110% of label claim; less than 5% change in stability sample HPLC 108.5% Pass pH 6 to 7 6.37 Pass Preservative assay Methyl paraben, Propyl paraben HPLC Methyl paraben: 100.8% Propyl paraben: 99.1% Pass Physical Appearance Color No significant change in stability sample Light yellow color Visual Light yellow color Pass Re-dispersibility No settlement or clump on the bottom of the product bottle Conforms Pass 21 Table 3: Sample characteristics after 2 months (at room temperature and at 40°C) Test Active/Excipient Specification Limits Method Results Results at room Temp Pass/fail at 40°C Pass/fail Identity Dexamethyasone sodium phosphate; Diphenhydramine HCl; Lidocaine HCl Positive HPLC Conforms Pass Conforms Pass Identity Nystatin Positive HPLC Conforms Pass Conforms Pass Potency Dexamethasone sodium phosphate 90 to 110% of label claim; less than 5% change in stability sample HPLC 98.1% Pass 100.8% Pass Potency Diphenhydramine HCl 90 to 110% of label claim; less than 5% change in stability sample HPLC 100.8% Pass 100.2% Pass Potency Lidocaine HCl 90 to 110% of label claim; less than 5% change in stability sample HPLC 99.7% Pass 98.1% Pass Potency Nystatin 90 to 110% of label claim; less than 5% change in stability sample HPLC 106.8% Pass 98.4% Fail pH 6 to 7 6.3 Pass 6.34 Pass Preservative assay Methyl paraben, Propyl paraben HPLC Methyl paraben: 97.6% Propyl paraben: 99.3% Pass Methyl paraben: 95% Propyl paraben: 99.1% Pass 22 Physical Appearance Color No significant change in stability sample Light yellow color Visual Light yellow color; no significant change Pass Re-dispersibility No settlement or clump on the bottom of the product bottle Conforms Pass 23 Table 4: Sample characteristics after 3 months (at room temperature and at 40°C) Test Active/Excipient Specification Limits Method Results Results at room Temp Pass/fail at 40°C Pass/fail Identity Dexamethyasone sodium phosphate; Diphenhydramine HCl; Lidocaine HCl Positive HPLC Conforms Pass Conforms Pass Identity Nystatin Positive HPLC Conforms Pass Conforms Pass Potency Dexamethasone sodium phosphate 90 to 110% of label claim; less than 5% change in stability sample HPLC 102.7% Pass 97.1% Pass Potency Diphenhydramine HCl 90 to 110% of label claim; less than 5% change in stability sample HPLC 101.85% Pass 101.7% Pass Potency Lidocaine HCl 90 to 110% of label claim; less than 5% change in stability sample HPLC 101.8% Pass 102.15% Pass Potency Nystatin 90 to 110% of label claim; less than 5% change in stability sample HPLC 106% Pass 88.8% Fail pH 6 to 7 6.3 Pass 6.25 Pass Preservative assay Methyl paraben, Propyl paraben HPLC Methyl paraben: 100.1% Propyl paraben: 100.4% Pass Methyl paraben: 95.7% Propyl paraben: 99.4% Pass 24 Physical Appearance Color No significant change in stability sample Light yellow color Visual Light yellow color; no significant change Pass Redispersibility No settlement or clump on the bottom of the product bottle Conforms Pass 25 Table 5: Sample characteristics after 4 months (at room temperature and at 40°C) Test Active/Excipient Specification Limits Method Results Results at room Temp Pass/fail at 40°C Pass/fail Identity Dexamethyasone sodium phosphate; Diphenhydramine HCl; Lidocaine HCl Positive HPLC Conforms Pass Conforms Pass Identity Nystatin Positive HPLC Conforms Pass Conforms Pass Potency Dexamethasone sodium phosphate 90 to 110% of label claim; less than 5% change in stability sample HPLC (not quantified) Pass 102.7 Pass Potency Diphenhydramine HCl 90 to 110% of label claim; less than 5% change in stability sample HPLC (not quantified) Pass 100.1% Pass Potency Lidocaine HCl 90 to 110% of label claim; less than 5% change in stability sample HPLC (not quantified) Pass 102.9% Pass Potency Nystatin 90 to 110% of label claim; less than 5% change in stability sample HPLC 105.3% Pass 92.4% Fail pH 6 to 7 (not quantified) Pass 6.27 Pass Preservative assay Methyl paraben, Propyl paraben HPLC (not quantified) Pass Methyl paraben: 97.1% Propyl paraben: 99.2% Pass 26 Physical Appearance Color No significant change in stability sample Light yellow color Visual (not quantified) Pass Re-dispersibility No settlement or clump on the bottom of the product bottle Conforms Pass 27 WE CLAIM: 1) An oral rinse formulation comprising one or more of the following components in combination with pharmaceutically acceptable excipients or additives: a. at least one corticosteroid; b. at least one anti-histamine; c. at least one topical anaesthetic; and d. at least one anti-fungal antibiotic agent. 2) The formulation of claim 1 wherein all of components (a) to (d) are included. 3) The formulation of claim 1 further comprising at least one antibiotic agent. 4) The formulation of claim 1 having the following composition: - 0.005 to 0.025 mg/ml dexamethasone; - 1 to 2 mg/ml diphenhydramine; - 1 to 20 mg/ ml lidocaine; and - 10,000 to 50,000 iu/ml nystatin. 5) The formulation of claim 4 wherein the additives are chosen from the group consisting of: polysorbate 80, spearmint oil, sorbitol, xanthan gum, sodium benzoate, purified water, aluminium hydroxide, dextrose, sucralose, flavorings and magnesium hydroxide. 6) The formulation of claim 4 further comprising at least one buffering agent, at least one preservative, at least one chelating agent and at least one anti-oxidant. 7) The formulation of claim 6 wherein the buffering agent is a phosphate buffer, the preservative is methyl paraben or propyl paraben, the chelating agent is EDTA, and the anti-oxidant is citric acid or a salt thereof. 8) Use of the formulation of claim 6 for the treatment of oral lesions. 9) The use of claim 8 for the treatment of mucositis or stomatitis. 10) A stable, anti-fungal oral rinse formulation comprising nystatin and a buffering agent, a preservative, a chelating agent and an anti-oxidant. 11) The formulation of claim 10 wherein the buffering agent is a phosphate buffer. 12) The formulation of claim 10 wherein the preservative is methyl paraben or propyl paraben. 13) The formulation of claim 11 wherein the chelating agent is EDTA. 14) The formulation of claim 10 wherein the anti-oxidant is citric acid or a salt thereof. 28 15) The formulation of claim 10 wherein the nystatin is present in an amount greater than 10,000 iu/ml. 16) A stable, anti-fungal oral rinse formulation comprising: - an anti-fungal agent; - a phosphate buffer; - a preservative; - a chelating agent; and, - an antioxidant. 17) The formulation of claim 16 wherein the anti-fungal agent is selected from nystatin and amphotericin B. 18) The formulation of claim 17 wherein the nystatin is present in an amount between 10,000 and 50,000 iu/ml. 19) The formulation of claim 18 wherein the preservative is chosen from methyl paraben, propyl paraben and mixtures thereof. 20) The formulation of claim 19 wherein the chelating agent is ethylenediamine tetraacetic acid (EDTA). 21) The formulation of claim 20 wherein the antioxidant is citric acid or a salt thereof. 22) The formulation of claim 21 further comprising: - at least one corticosteroid; - at least one antihistamine; and - at least one topical anaesthetic. 23) The formulation of claim 22 wherein the corticosteroid is dexamethasone and wherein said dexamethasone is present in a concentration of between 0.005 to 0.025 mg/ml. 24) The formulation of claim 23 wherein the antihistamine is diphenhydramine and wherein said diphenhydramine is present in a concentration of between 1 to 2 mg/ml. 25) The formulation of claim 24 wherein the topical anaesthetic is lidocaine and wherein said lidocaine is present in a concentration of between 1 to 20 mg/ml. Dated this 25th day of March, 2010 To Signature: The Controller of Patent Name: Durgesh Mukharya The Patent Office, at Chennai Of K & S Partners, Agent for the Applicant

Full Text

TECHNICAL FIELD
An oral rinse formulation for the treatment or prophylaxis of mucositis or stomatitis comprises
one or more of the following components in combination with pharmaceutically acceptable
excipients or additives: a) at least one corticosteroid; b) at least one anti-histamine; c) at least one
topical anaesthetic; and, d) at least one anti-fungal antibiotic agent. A stable nystatin containing
formulation is also provided comprising a buffering agent, a preservative, a chelating agent and
an anti-oxidant.
BACKGROUND OF THE INVENTION
The present invention relates to oral hygiene and in particular, to mouthwashes for the treatment
and prophylaxis of mucositis and stomatitis of the oral cavity and to a method of using such a
mouthwash.
Mouthwashes are typically used as part of an oral hygiene regime which may also include
brushing and flossing to maintain a satisfactory level of oral hygiene. Such mouthwashes are
generally classified as cosmetic, therapeutic or a combination of the two. Cosmetic rinses are
commercial over-the-counter products that help remove oral debris before or after brushing,
temporarily suppress bad breath, diminish bacteria in the mouth and refresh the mouth with a
pleasant taste. Therapeutic rinses often have the benefits of their cosmetic counterpart, but also
contain an added active ingredient, for example chlorhexidine that helps protect against some
oral diseases such as gingivitis. Typically, such mouthwashes are alcohol-based.
However, available mouthwashes are unsuitable for hospital patients presenting with oral
complications as a result of, for example, infection or other lesions as a consequence of
chemotherapy or radiotherapy for the treatment of neoplastic disease. Such oral complications
may include mucositis or stomatitis. Mucositis or stomatitis presents in approximately 40% of
patients with neoplastic disease.
Examples of chemotherapeutic drugs that frequently cause mucositis and/or stomatitis include
alkylating agents, for example melphalan and busulphan; antimetabolites, for example,
cytarabine, floxuridine, 5-fluorouracil, mercaptopurine, methotrexate, and thioguanine and
cytotoxic drugs, for example, bleomycin, actinomycin D, daunorubicin, cisplatin, etoposide,
mytomycin, vinblastine and vincristine.
3
The terms mucositis and stomatitis are often used interchangeably but may include some general
distinctions. Mucositis describes a toxic inflammatory reaction affecting the gastro-intestinal
tract, which may result from exposure to chemotherapeutic agents or ionizing radiation.
Mucositis typically manifests as an erythematous burn-like lesion, or as random focal-to-diffuse
lesions. Stomatitis refers to an inflammatory reaction affecting the oral mucosa, with or without
ulceration, that may be caused or intensified by pharmacological, particularly chemotherapeutic
treatments or by radiotherapy. Stomatitis can range from mild to severe; a patient presenting
with the severe stomatitis is unable to take anything by mouth.
Current oral cleaning care in such patients may include gently cleaning the mouth, moisturizing
the lips and mouth, and relieving pain and swelling. A soft toothbrush cleans teeth well and
gently. Cleansing agents can include “salt and soda” (half a teaspoon of salt and two tablespoons
of sodium bicarbonate in 32 ounces of warm water), saline, sterile water or sodium bicarbonate
(one teaspoon in 8 ounces of water). Hydrogen peroxide diluted in equal amounts of water or
weak salt water can be used in some cases. Mostly, physicians have resorted to these rather
limited, temporary relief options.
It is therefore extremely important that mucositis and stomatitis be prevented whenever possible
or at the very least that they be reduced in their severity and possible complications. Currently
there are a number of intervening therapies to choose from. For example, The Joanna Briggs
Institute of The Royal Adelaide Hospital has provided some guidance on the treatment of
mucositis. However, there is no high quality synthesis of research evidence for these
intervention therapies (www.joannabriggs.edu.au/best_practice/bp5.php, 19 February 2004).
Of particular interest to the current application are the variety of mouthwashes previously used
having mixed actions against mucositis and stomatitis. Such mouthwashes typically include
benzydamine hydrochloride, corticosteroids and chamomile
(www.joannabriggs.edu.au/best_practise/bp5.php).
Formulations such as those disclosed in U.S. 5,635,489; U.S. 4,961,926 and U.S. 5,102,870
describe the use of growth factors and stimulation factors such as granulocyte-macrophage
colony stimulating factor and granulocyte-colony stimulating factor.
Further attempts at treatment and or prophylaxis of mucositis and stomatitis include the use of
nucleoside derivatives which can be formulated into lozenges or mouthwashes and the like to
4
coat the oral cavity or other mucosal areas such as disclosed in U.S. Patent Publication No.
2003/0236217 A1.
Other formulations include tetracycline as disclosed in U.S. 6,946,118; hyaluronic acid,
glycyrrhetinic acid and polyvinylpyrrolidone in mixture with excipients and adjuvants as
disclosed in U.S. 6,828,308; the use of an anti-microbial peptide, preferably protegrin applied
topically which has broad spectrum anti-microbial activity, good stability and adheres well to all
mucosa as disclosed in U.S. 6,025,326; the use of glutamine as disclosed in U.S. 5,545,668 and
the use of triclosan as disclosed in U.S. 5,945,089
Despite the widespread recognition that mucositis is a serious problem, no effective treatment
currently exists and, more often than not, any level of patient care is typically palliative. In
addition to the lack of effective treatments for mucositis, physicians are unsure of the exact
mechanism by which the ulcerations occur in mucositis. It is known that the initial exposure to a
chemotherapeutic agent causes a release of cytokines from the epithelial tissues. Subsequently,
mitosis is disturbed in the epithelia. Finally, there are alterations in the bacterial flora of the oral
cavity. It is unknown which of these occurrences, if any, is responsible for the mucosal damage.
Despite the fact that significant quantities or inflammatory mediators are released by the
epithelium, conventional anti-inflammatory agents have been unsuccessful in human efficacy
studies of the disease.
Some of the known and effective treatments for mucositis involves the use of the antibiotics
nystatin and amphotericin B. These drugs have been used for the preventive and curative
treatment of fungal infections such as oral candidiasis and, in particular, for cancer patients. Due
to a lack of commercially available anti-fungal mouthwashes, oral or mouth rinse formulations
containing these antifungal agents are commonly prepared in a clinical setting for immediate use.
One possible reason for the lack of nystatin and/or amphotericin B mouth rinse formulations is
that such formulations are relatively unstable and, therefore, must be used within a short period
of time. For example, in one study of mixtures of nystatin and amphotericin B, in combination
with sodium bicarbonate, it was determined that the maximum amount of time that such
formulations can remain stable is roughly 3 to 4 days (J. Groeschke, et al.; Stability of
Amphotericin B and Nystatin in Antifungal Mouthrinses Containing Sodium Hydrogen
Carbonate, J. Pharm. and Biomed. Anal., v. 42, 3 (2006), pp. 362-366).
5
Thus, the available mouthwashes are effective at treating only one aspect of mucositis and other
oral complications and not treating the complete range of symptoms that present in patients.
Further, the effective antifungal mouth rinses have a very limited stability. There exists a need,
therefore, for a stable formulation for treating a variety of symptoms and causes of mucositis.
STATEMENT OF THE INVENTION
Accordingly, the present invention relates to an oral rinse formulation comprising one or more of
the following components in combination with pharmaceutically acceptable excipients or
additives: a) at least one corticosteroid, b) at least one anti-histamine, c) at least one topical
anaesthetic, and d) at least one anti-fungal antibiotic agent; a stable, anti-fungal oral rinse
formulation comprising nystatin and a buffering agent, a preservative, a chelating agent and an
anti-oxidant; and a stable, anti-fungal oral rinse formulation comprising: an anti-fungal agent; a
phosphate buffer; a preservative; a chelating agent; and an antioxidant.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an oral rinse formulation comprising one or more of the
following components in combination with pharmaceutically acceptable excipients or additives:
a. at least one corticosteroid;
b. at least one anti-histamine;
c. at least one topical anaesthetic; and
d. at least one anti-fungal antibiotic agent.
In an embodiment of the present invention, all of components (a) to (d) are included.
In another embodiment of the present invention, the formulation further comprising at least one
antibiotic agent.
In yet another embodiment of the present invention, the formulation has the following
composition:
- 0.005 to 0.025 mg/ml dexamethasone;
- 1 to 2 mg/ml diphenhydramine;
- 1 to 20 mg/ ml lidocaine; and
- 10,000 to 50,000 iu/ml nystatin.
6
In still another embodiment of the present invention, the additives are chosen from the group
consisting of: polysorbate 80, spearmint oil, sorbitol, xanthan gum, sodium benzoate, purified
water, aluminium hydroxide, dextrose, sucralose, flavorings and magnesium hydroxide.
In still another embodiment of the present invention, the formulation further comprising at least
one buffering agent, at least one preservative, at least one chelating agent and at least one antioxidant.
In still another embodiment of the present invention, the buffering agent is a phosphate buffer,
the preservative is methyl paraben or propyl paraben, the chelating agent is EDTA, and the antioxidant
is citric acid or a salt thereof.
The present invention relates to use of the formulation as indicated above for the treatment of
oral lesions.
In an embodiment of the present invention, the use is for the treatment of mucositis or stomatitis.
The present invention relates to a stable, anti-fungal oral rinse formulation comprising nystatin
and a buffering agent, a preservative, a chelating agent and an anti-oxidant.
In an embodiment of the present invention, the buffering agent is a phosphate buffer.
In another embodiment of the present invention, the preservative is methyl paraben or propyl
paraben.
In yet another embodiment of the present invention, the chelating agent is EDTA.
In still another embodiment of the present invention, the anti-oxidant is citric acid or a salt
thereof.
In still another embodiment of the present invention, the nystatin is present in an amount greater
than 10,000 iu/ml.
The present invention relates to a stable, anti-fungal oral rinse formulation comprising:
- an anti-fungal agent;
- a phosphate buffer;
- a preservative;
- a chelating agent; and,
- an antioxidant.
In an embodiment of the present invention, the anti-fungal agent is selected from nystatin and
amphotericin B.
7
In another embodiment of the present invention, the nystatin is present in an amount between
10,000 and 50,000 iu/ml.
In yet another embodiment of the present invention, the preservative is chosen from methyl
paraben, propyl paraben and mixtures thereof.
In still another embodiment of the present invention, the chelating agent is ethylenediamine
tetraacetic acid (EDTA).
In still another embodiment of the present invention, the antioxidant is citric acid or a salt
thereof.
In still another embodiment of the present invention, the formulation further comprising:
- at least one corticosteroid;
- at least one antihistamine; and
- at least one topical anaesthetic.
In still another embodiment of the present invention, the corticosteroid is dexamethasone and
wherein said dexamethasone is present in a concentration of between 0.005 to 0.025 mg/ml.
In still another embodiment of the present invention, the antihistamine is diphenhydramine and
wherein said diphenhydramine is present in a concentration of between 1 to 2 mg/ml.
In still another embodiment of the present invention, the topical anaesthetic is lidocaine and
wherein said lidocaine is present in a concentration of between 1 to 20 mg/ml.
In one aspect, the present invention provides an oral rinse formulation comprising one or more of
the following components in combination with pharmaceutically acceptable excipients or
additives:
a) at least one corticosteroid;
b) at least one anti-histamine;
c) at least one topical anaesthetic;
d) at least one anti-fungal antibiotic agent.
In another aspect, the formulation can include an antibiotic agent.
In a further aspect, the invention provides a method of treating or preventing mucositis or
stomatitis comprising applying to a patient the above mentioned oral rinse formulation.
8
In another aspect, the invention provides a stable, anti-fungal oral rinse formulation comprising:
- an anti-fungal agent;
- a phosphate buffer;
- a preservative;
- a chelating agent; and,
- an antioxidant.
In one embodiment, the anti-fungal agent is chosen from nystatin and amphotericin B. In a
further embodiment, the above formulation comprises: at least one corticosteroid; at least one
antihistamine; and at least one topical anaesthetic.
Accordingly, the present invention provides, in one embodiment, a mouthwash comprising one
or more of the following active ingredients:
- at least one corticosteroid;
- at least one anti-histamine;
- at least one topical anaesthetic;
- at least one anti-fungal antibiotic agent.
Optionally, the formulation may include an antibiotic agent as well.
In another embodiment, the invention provides a mouthwash formulation comprising an antifungal
agent, a phosphate buffer, a preservative, a chelating agent and an antioxidant. This
formulation preferably also includes at least one corticosteroid, at least one antihistamine, and at
least one topical anaesthetic. More preferably, the anti-fungal agent of this formulation
comprises nystatin or amphotericin B and, most preferably, nystatin.
Preferably, the mouthwash in accordance with the present invention is used in the treatment
and/or prophylaxis of oral conditions such as mucositis and/or stomatitis.
Although the mouthwash (or mouth rinse) of the present invention includes various components
that are known in the art, the inventors note that there is no commercially available formulation
that combines the subject components to provide an effective, single formulation that addresses a
large variety of symptoms associated with mucositis and/or stomatitis. This is also clearly
indicated in the recent article by J. Groeschke, et al. Further, in addition to providing such
multipurpose formulation, the inventors have also found an unexpectedly high stability of the
9
formulation, particularly when an anti-fungal is included. More specifically, the formulation
described below including nystatin was found to be stable for over 2 months, thereby greatly
exceeding the stability expected according to the prior art, such as the article by J. Groeschke, et
al.
Preferably the mouthwash in accordance with the present invention further comprises water and
pharmaceutically acceptable excipients or additives such as:
- one or more oils, such as an oil selected from the group comprising anethole, anisole, camphor,
methyl salicylate, vanillin, eugenol, furaneol, linalool, menthol, thymol, cinnamaldehyde, citral,
methyl butanoate, pentylbutanoate, pentylpentanoate, tea tree oil, peppermint oil, spearmint oil,
pineapplemint oil and eucalyptus oil;
- sweetening agents, for example sorbitol;
- thickening agents, such as xanthan gum, carrageenan, carbomer, or HPMC (hydroxypropyl
methyl cellulose);
- preservative agents, such as sodium benzoate, methyl paraben, or propyl paraben;
- water;
- emulsifiers, such as polysorbate 80 (or Tween™ 80);
- and/or at least one antacid such as aluminium or magnesium hydroxide.
It will be appreciated by persons skilled in the art that the above list of excipients and/or
additives is provided merely by way of example and that various other such components may be
used in the formulation of the present invention.
Oral mucositis results in specific damage that includes the shedding of the mucosal lining of the
mouth (desquamation), ulceration and atrophy. Aluminum and magnesium hydroxide antacids
coat and protect the oral cavity from damage and provide for re-growth of normal oral tissue.
The corticosteroid component provides anti-inflammatory action directly on the oral mucosa and
works to limit the inflammatory response associated with mucositis. Preferably, the
corticosteroid is dexamethasone.
In patients being treated with chemotherapy and radiation, steps may be taken to prevent
bacterial infection within the oral cavity. For this reason, in an optional embodiment, the
mouthwash formulation of the invention may contain an antibiotic component. Such antibiotic
10
components may be of the macrolide type and may be selected from the group consisting of
erythromycin, azithromycin, clarithromycin, dirithromycin, roxithromycin carbomycin A,
josamycin, kitasamycin, oleandomycin, spiramycin, troleandomycin, tylosin, cethromycin,
ansamycin and telithromycin. In one aspect the antibiotic is erythromycin. Once ulcerations
develop inside the mouth, local oral bacteria colonize the wound and release cell wall products
into the mucosa, resulting in an amplification of a tissue destructive cycle. The antibiotic
component, i.e. Erythromycin, limits such bacterial colonization. As will be understood, limiting
the extent of bacterial infection would promote healing of the affected tissues.
Alternatively, the antibiotic may be any of the following, alone or in combination:
- an aminoglycoside, for example, amikacin, gentamicin, kanamycin, neomycin, netilmicin,
streptomycin, and tobramycin;
- a carbacephem, for example, loracarbef;
- a carbapenem, for example, ertapenem, imipenem/cilastatin, and meropenem;
- a cephalosporin (first generation), for example, cefadroxil, cefazolin, cephalexin;
- a cephalosporin (second generation), for example, cefaclor, cefamandole, cefoxitin, cefprozil,
and cefuroxime;
- a cephalosporin (third generation), for example, cefixime, cefdinir, cefditoren, cefoperazone,
cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone;
- a cephalosporin (fourth generation), for example, cefepime;
- a glycopeptide, for example, teicoplanin, vancomycin;
- a penicillin, for example, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin,
dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin and ticarcillin;
- a polypeptide, for example, bacitracin, colistin, and polymyxin B;
- a quinolone, for example, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin,
moxifloxacin, norfloxacin, ofloxacin, and trovafloxacin;
- a sulfonamide, for example, mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide,
sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole;
- a tetracycline, for example, demeclocycline, doxycycline, minocycline, and oxytetracycline,
tetracycline, and
11
- another antibiotic, for example, chloramphenicol, clindamycin, ethambutol, fosfomycin,
furazolidone, isoniazid, linezolid, metronidazole, nitrofurantoin, pyrazinamide,
quinupristin/dalfopristin, rifampin, and spectinomycin.
The anti-fungal antibiotic agent may be of the polyene type and may be selected from the group
consisting of nystatin, amphotericin B and natamycin. In one aspect, the anti-fungal agent is
nystatin or amphotericin B.
Patients being treated with chemotherapy and radiation are immuno-compromised. This leads to
not only increased risk of bacterial infection but also to an increased risk of fungal infection, thus
advancing the risk and degree of oral mucositis. Nystatin and amphotericin B act to prevent and
limit the degree of fungal infection.
Alternatively, the anti-fungal compound may be selected from an imidazole, for example,
miconazole, ketoconazole, clotrimazole, econazole, mebendazole, bifonazole, butoconazole,
fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, thiabendazole or
tiaconazole; a triazole, for example, fluconazole, itraconazole, ravuconazole, posaconazole or
voriconazole; an allylamine, for example, terbenafine, amorolfine, naftifine or butenafine or an
echinocandin such as caspofungin or micafungin or any combinations thereof.
The topical anaesthetic may be selected from benzocaine, mepivacaine, ropivacaine,
bupivacaine, lidocaine, prilocaine, procaine, cloroprocaine or tetracaine. In one aspect the
topical anaesthetic is a combination of lidocaine and tetracaine.
Pain associated with oral mucositis can be extremely debilitating and lead to poor oral food
intake. In extreme cases patients may require feeding tubes if the ulceration continues to
advance. Tetracaine and lidocaine act locally to provide relief from pain.
Preferably, the anti-histamine may be selected from the group comprising a first generation H1
receptor antagonist, a second generation H1 receptor antagonist, a third generation H1 receptor
antagonist, a H2 receptor antagonist, a H3 receptor antagonist and a H4 receptor antagonist.
Diphenyhdramine, an antihistamine, helps to sooth soreness, burning, itching (urticaria and
pruritis) and inflammation, symptoms that are normally associate with mucositis.
The first generation H1 receptor antagonist may be selected from an ethylenediamine, for
example, mepyramine or antazoline; an ethanolamine, for example, diphenhydramine,
carbinoxamine, doxylamine, clemastine or dimenhydrinate; an alkylamine, for example,
12
pheniramine, chlorphenamine, dexchlorphenamine, brompheniramine or triprolidine; a
piperazine, for example, cyclizine, hydroxyzine, meclizine or a tricyclic, for example,
promethazine, alimemazine, cyproheptadine or azatadine. In one aspect, the anti-histamine is
diphenhydramine.
The second generation H1 receptor antagonist may be azelastine, levocabastine or olopatadine.
The H3 receptor antagonist may be thioperamide, clobenpropit or impromidine.
The H4 receptor antagonist may be thioperamide.
Preferably, dexamethasone is used in the range of from 0.005 mg/ml to 0.025 mg/ml, or, more
preferably, narrower ranges such as 0.01 mg/ml to 0.02 mg/ml or 0.015 mg/ml to 0.02 mg/ml. In
one preferred embodiment, dexamethasone is present in a concentration of 0.016 mg/ml.
Preferably, diphenhydramine is used in a range of from 1 mg/ml to 2 mg/ml or, more preferably,
in narrower ranges such as 1 mg/ml to 1.5 mg/ml, 1.2 mg/ml to 1.4 mg/ml, or 1.25 mg/ml to 1.3
mg/ml. In one preferred embodiment, dexamethasone is present in a concentration of 1.67
mg/ml.
Preferably, lidocaine is used in a range of from 1 mg/ml to 20 mg/ml (i.e. 0.1% to 2%) although
narrower ranges may also be used. In one preferred embodiment, lidocaine is present in a
concentration of 10 mg/ml.
Preferably, nystatin is used in an amount greater than 10,000 iu/ml. More preferably, Nystatin is
used in a range of 10,000 iu/ml to 50,000 iu/ml, or 20,000 iu/ml to 40,000 iu/ml, or 30,000 iu/ml
to 35,000 iu/ml, or most preferably at a concentration of 33,333 iu/ml.
When included in the formulation of the invention, erythromycin is used in a range of from 5
mg/ml to 15 mg/ml, or, more preferably, in narrower ranges such as 10 mg/ml to 15 mg/ml, 12
mg/ml to 15 mg/ml, or 12.5 mg/ml to 15 mg/ml.
In a further embodiment, the present invention provides a mouthwash comprising 0.015 mg/ml
dexamethasone, 1.25 mg/ml diphenhydramine, 0.5% lidocaine, 20000 iu/ml nystatin, polysorbate
80, spearmint oil, sorbitol, xanthan gum, sodium benzoate, purified water, aluminium hydroxide
and magnesium hydroxide. Optionally, the formulation may also include 12.5 mg/ml
erythromycin.
13
In a further aspect the present invention provides a method of treating or preventing oral
conditions such as mucositis or stomatitis comprising rinsing the oral cavity with the mouthwash
of the invention.
The present invention also provides, in a further embodiment, a kit for the treatment or
prophylaxis of mucositis or stomatitis comprising a container having an amount of mouthwash in
accordance with the present invention together with a set of instructions for using the
mouthwash. The kit may optionally provide a cup or other container for conveniently dispensing
an amount of the mouthwash from the container. Advantageously the cup may also have
markings or other indicators for the convenient dispense of a measurement of a therapeutically
effective dose of the mouthwash.
In a further embodiment, the invention provides a mouthwash or mouth rinse formulation that is
exhibits long term stability. The stable formulation of the invention includes nystatin as the antifungal
component. In a preferred embodiment, the nystatin containing formulation includes a
buffering agent, a preservative, a chelating agent and an anti-oxidant.
In another aspect, the invention provides a stable, anti-fungal oral rinse formulation comprising:
an anti-fungal agent (chosen from nystatin, amphotericin B and mixtures thereof); a phosphate
buffer; a preservative (such as methyl paraben and/or propyl paraben); a chelating agent (such as
EDTA); and an antioxidant (such as citric acid or a salt thereof).
In a further aspect of the invention, the above formulation also includes at least one
corticosteroid; at least one antihistamine; and at least one topical anaesthetic.
Examples
The following examples are provided to illustrate the invention and are not intended to limit the
scope of the invention in any way.
Introduction
As discussed above, there are currently no mouth rinses available on the market containing
Nystatin, Dexamethasone sodium phosphate, Lidocaine HCL and Diphenhydramine HCl
available. Moreover, there are no commercially available mouth rinses containing nystatin and
14
this is believed to be mainly due to the poor stability characteristics of formulations containing
this drug. For this reason, various mouth rinse (or mouthwash) formulations were prepared to
study the stability characteristics. The aim of this project was to develop a stable formulation
containing at least nystatin and, preferably the various other treatment agents listed above. As
discussed further below, a prototype formulation was developed and its stability was tested at
room temperature. The product was found to be stable at room temperature for over three
months.
Materials and Methods
Table 1 below summarises the formulations studied. As shown, nine sample preparations were
examined, identified as samples B1 to B9. Where the samples differed in formulation, a notation
is included in Table 1.
The following procedure was typical of that followed in preparing the formulations of the
example. As indicated above, the specific concentrations of the various components for the trials
is indicated Table 1.
Step 1. Preparation of 1.2% HPMC (hydroxypropyl methyl cellulose) solution for the final
volume
1.1) Heat 70 mL DI water to 90°C.
1.2) Slowly add 2.4g HPMC with continuous stirring and heating at 90°C for 1 hour .
1.3) Cool down to room temperature with continuous stirring (about 1 hour).
1.4) Add 130 mL cold DI (de-ionized) water with continuous stirring for 60 minutes.
1.5) Set aside for nystatin suspension preparation in step 3.
Step 2. Preparation of water soluble API’s (active pharmaceutical ingredients) and other
ingredients
2.1) Dissolve 0.60 g methyl paraben (0.2%) and 60 mg propyl paraben (0.02%) in 15.0 g
propylene glycol (5%) and stir at 40°C for 10 min or until completely dissolved.
2.2) Add 3.0g Tween™ 80 (1.0%) then stir for 10 min at 40ºC.
15
2.3) Add 150 mL DI water and cool down to room temperature.
2.4) Add each of the following remaining ingredients and all soluble API’s with continuous
stirring until completely dissolved. No heating.
1.5g citric acid
4.3018 g sodium phosphate dibasic
1.5g sucralose
6.444 mg dexamethasone 21-phosphate disodium salt
581.61 mg diphenhydramine HCl
3.741g lidocaine HCl
Step 3. Preparation of nystatin suspension
3.1) Slowly add 1.6431g nystatin to 120 mL 1.2 % HPMC solution (from step 1 ) with
continuous stirring. The final HPMC concentration in the formulation will therefore be 0.5%.
3.2) Add 0.60 g EDTA (0.2%) and mix well.
Step 4. Mix solution from step 2 and nystatin suspension from step 3. Add 1.2 mL NFB mixed
berry flavor. Mix well.
Step 5. Measure pH. If it is not 6.5±0.5, adjust to pH 6.5±0.5 with 100 mM phosphate buffer
(Na2HPO4).
Step 6. Adjust final volume to 300 mL with water. Mix well and verify pH again.
At the end of Step 6, the formulation (300 ml) will have the composition as listed in the
following table. Items marked as * comprise the active drug ingredients. Items marked as **
comprise the alternative components used for a placebo formulation.
16
Note Chemical Name Freebase
Concn
(mg/mL)
Concentration Units Weight of
component
added
Propylene Glycol 5.0 % 15.0g
Methyl Paraben 0.20 % 0.6g
Propyl Paraben 0.02 % 60mg
Tween 80 1.0 % 3.0g
Citric Acid 0.50 % 1.5g
Sodium Phosphate dibasic 100.0 mM 4.3018g
Sucralose 0.50 % 1.5g
* Dexamethasone 21-
phosphate
0.016 0.02148 mg/mL 6.444mg
disodium salt
* Diphenhydramine HCl 1.67 1.9387 mg/mL 0.581g
* Lidocaine HCl 10 12.47 mg/mL 3.741g
HPMC 0.5000 %
* Nystatin 33,333IU/mL 5.477 mg/mL 1.6431
EDTA acid calcium
disodium
0.20 % 0.6g
Mixed NFB Berry Flavor 0.40 % 1.2g
** Titanium Oxide 5.00 mg/mL 1.5g
** D&C Yellow No. 10 0.001 %
The formulations were stored at room temperature and tested upon formulation (i.e. time = 0)
and at 2, 3 and 4 month time points for identity, potency, pH, preservative assay, physical
appearance and color. Formulation B8 was used for testing stability and the results of this
analysis at the various time points are provided in Tables 2 to 5.
Quantification of the respective ingredients was done using high performance liquid
chromatography (HPLC). A difference in calculated quantity of less than 5% from the intial
formulation (i.e. time = 0) amount was considered a “pass”, that is, indicative of minimal
degradation. The relative standard deviation for the HPLC calculations was ≤ 3%.
For the re-dispersibility study, the following procedure was followed:
- manually shake the sample for 5 seconds.
- observe the bottom of the glass bottle.
17
- if settlement or clumping is found, shake for another 5 seconds and observe.
- the sample is identified as re-dispersible if no settlement or clumping is found on the bottom of
the glass bottle.
Conclusions
All the samples prepared for the stability study were found to meet the desired criteria. The
mouth rinse of the invention was found to be stable, when stored room temperature, for at least
up to 4 months. At “accelerated conditions”, that is when stored at 40°C, the formulation was
found to remain stable for less than 2 months. These results illustrate an unexpected stability of
a nystatin containing formulation particularly when stored at room temperature. The stability of
the nystatin containing formulation is believed to be attributable to the presence of the buffering
agent (pH control), preservatives (i.e. paraben), the chelating agent (i.e. EDTA), and the antioxidant
(i.e. citrate). The data obtained from this study indicates that the formulation of the
invention exhibits long term stability and, therefore, provides a unique, single dose formulation
that addresses various symptoms associated with mucositis.
Although the invention has been described with reference to certain specific embodiments,
various modifications thereof will be apparent to those skilled in the art without departing from
the purpose and scope of the invention as outlined in the claims appended hereto. Any examples
provided herein are included solely for the purpose of illustrating the invention and are not
intended to limit the invention in any way. The disclosures of all prior art recited herein are
incorporated herein by reference in their entirety.
18
Table 1: Sample formulations prepared for stability study
Ingredient
Type
Active/Excipient Concentration (free base
concentration)
Grade Other
Candidates
Notes
Corticosteroid Dexamethasone sodium
phosphate salt
0.016 mg/mL USP grade H2O soluble
Anti-histamine Diphenhydramine HCl 1.67 mg/mL USP grade H2O soluble
Anesthetic Lidocaine HCl 10 mg/mL USP grade H2O soluble
Anti-fungal Nystatin 33,333 IU/mL (5.477mg/mL) USP grade slightly
soluble-
4mg/ml in
H2O
Anti-oxidant Citric Acid 0.5% w/v USP
Chelating
agent
Calcium disodium EDTA 0.2% (w/v) USP
Wetting agent
(emulsifier)
Polysorbate 80 (Tween™ 80) - 1.0% for B1, B2, B8, B9
- 1.2 % for B3, B4, B5
- 1.5% for B6
USP Polysorbate 20,
Poloxamer 407
H2O soluble
Sweetening
agent
Sucralose 0.5 % (w/v) USP H2O soluble
Thickener HPMC (Hydroxy Propyl
Methyl Cellulose) (from Dow
Chemical F4M)
- 0.25%(w/v) for B1, B2, B7
- 0.3% for B3, B4
- 0.4% for B5, B6, B8
- 0.5% for B9
USP (Sodium
Carboxyl
Methyl
cellulose)
SCMC
H2O soluble
Preservative Methyl paraben, Propyl
paraben
- 0.2% Methyl paraben (w/v);
- 0.02% Propyl paraben
- B2 - no propyl paraben
USP parabens are
slightly
soluble in hot
19
water
Tonicity
adjusting factor
Dextrose used where the osmolality of
the formulation is mOsm/kg
NaCl H2O soluble
Flavour Sensient NFB mixed berry
flavor
0.4% v/v Pharma.
grade
Solvent Purified water >85 % (w/w)
Buffer agent Sodium phosphate Dibasic 100 mM USP citrate
phosphate
buffer
H2O soluble
20
Table 2: Sample characteristics upon formulation (time = 0)
Test Active/Excipient Specification Limits Method Results Pass/fail
Identity Dexamethyasone sodium phosphate;
Diphenhydramine HCl; Lidocaine
HCl
Positive HPLC Conforms Pass
Identity Nystatin Positive HPLC Conforms Pass
Potency Dexamethasone sodium phosphate 90 to 110% of label claim; less than 5%
change in stability sample
HPLC 103.2% Pass
Potency Diphenhydramine HCl 90 to 110% of label claim; less than 5 %
change in stability sample
HPLC 100.6% Pass
Potency Lidocaine HCl 90 to 110% of label claim; less than 5%
change in stability sample
HPLC 100.4% Pass
Potency Nystatin 90 to 110% of label claim; less than 5%
change in stability sample
HPLC 108.5% Pass
pH 6 to 7 6.37 Pass
Preservative assay Methyl paraben, Propyl paraben HPLC Methyl paraben:
100.8%
Propyl paraben:
99.1%
Pass
Physical
Appearance
Color No significant change in stability sample
Light yellow color
Visual Light yellow
color
Pass
Re-dispersibility No settlement or clump on the bottom of
the product bottle
Conforms Pass
21
Table 3: Sample characteristics after 2 months (at room temperature and at 40°C)
Test Active/Excipient Specification Limits Method Results
Results
at room Temp Pass/fail at 40°C Pass/fail
Identity Dexamethyasone sodium
phosphate;
Diphenhydramine HCl;
Lidocaine HCl
Positive HPLC Conforms Pass Conforms Pass
Identity Nystatin Positive HPLC Conforms Pass Conforms Pass
Potency Dexamethasone sodium
phosphate
90 to 110% of label claim; less
than 5% change in stability
sample
HPLC 98.1% Pass 100.8% Pass
Potency Diphenhydramine HCl 90 to 110% of label claim; less
than 5% change in stability
sample
HPLC 100.8% Pass 100.2% Pass
Potency Lidocaine HCl 90 to 110% of label claim; less
than 5% change in stability
sample
HPLC 99.7% Pass 98.1% Pass
Potency Nystatin 90 to 110% of label claim; less
than 5% change in stability
sample
HPLC 106.8% Pass 98.4% Fail
pH 6 to 7 6.3 Pass 6.34 Pass
Preservative
assay
Methyl paraben, Propyl
paraben
HPLC Methyl
paraben:
97.6%
Propyl
paraben:
99.3%
Pass Methyl
paraben:
95%
Propyl
paraben:
99.1%
Pass
22
Physical
Appearance
Color No significant change in
stability sample
Light yellow color
Visual Light yellow
color; no
significant
change
Pass
Re-dispersibility No settlement or clump on the
bottom of the product bottle
Conforms Pass
23
Table 4: Sample characteristics after 3 months (at room temperature and at 40°C)
Test Active/Excipient Specification Limits Method Results
Results
at room Temp Pass/fail at 40°C Pass/fail
Identity Dexamethyasone sodium
phosphate;
Diphenhydramine HCl;
Lidocaine HCl
Positive HPLC Conforms Pass Conforms Pass
Identity Nystatin Positive HPLC Conforms Pass Conforms Pass
Potency Dexamethasone sodium
phosphate
90 to 110% of label claim; less
than 5% change in stability
sample
HPLC 102.7% Pass 97.1% Pass
Potency Diphenhydramine HCl 90 to 110% of label claim; less
than 5% change in stability
sample
HPLC 101.85% Pass 101.7% Pass
Potency Lidocaine HCl 90 to 110% of label claim; less
than 5% change in stability
sample
HPLC 101.8% Pass 102.15% Pass
Potency Nystatin 90 to 110% of label claim; less
than 5% change in stability
sample
HPLC 106% Pass 88.8% Fail
pH 6 to 7 6.3 Pass 6.25 Pass
Preservative
assay
Methyl paraben, Propyl
paraben
HPLC Methyl paraben:
100.1%
Propyl paraben:
100.4%
Pass Methyl
paraben:
95.7%
Propyl
paraben:
99.4%
Pass
24
Physical
Appearance
Color No significant change in
stability sample
Light yellow color
Visual Light yellow
color; no
significant
change
Pass
Redispersibility
No settlement or clump on the
bottom of the product bottle
Conforms Pass
25
Table 5: Sample characteristics after 4 months (at room temperature and at 40°C)
Test Active/Excipient Specification Limits Method Results
Results
at room Temp Pass/fail at 40°C Pass/fail
Identity Dexamethyasone
sodium phosphate;
Diphenhydramine HCl;
Lidocaine HCl
Positive HPLC Conforms Pass Conforms Pass
Identity Nystatin Positive HPLC Conforms Pass Conforms Pass
Potency Dexamethasone sodium
phosphate
90 to 110% of label claim; less
than 5% change in stability
sample
HPLC (not quantified) Pass 102.7 Pass
Potency Diphenhydramine HCl 90 to 110% of label claim; less
than 5% change in stability
sample
HPLC (not quantified) Pass 100.1% Pass
Potency Lidocaine HCl 90 to 110% of label claim; less
than 5% change in stability
sample
HPLC (not quantified) Pass 102.9% Pass
Potency Nystatin 90 to 110% of label claim; less
than 5% change in stability
sample
HPLC 105.3% Pass 92.4% Fail
pH 6 to 7 (not quantified) Pass 6.27 Pass
Preservative
assay
Methyl paraben, Propyl
paraben
HPLC (not quantified) Pass Methyl
paraben:
97.1%
Propyl
paraben:
99.2%
Pass
26
Physical
Appearance
Color No significant change in
stability sample
Light yellow color
Visual (not quantified) Pass
Re-dispersibility No settlement or clump on the
bottom of the product bottle
Conforms Pass
27
WE CLAIM:
1) An oral rinse formulation comprising one or more of the following components in
combination with pharmaceutically acceptable excipients or additives:
a. at least one corticosteroid;
b. at least one anti-histamine;
c. at least one topical anaesthetic; and
d. at least one anti-fungal antibiotic agent.
2) The formulation of claim 1 wherein all of components (a) to (d) are included.
3) The formulation of claim 1 further comprising at least one antibiotic agent.
4) The formulation of claim 1 having the following composition:
- 0.005 to 0.025 mg/ml dexamethasone;
- 1 to 2 mg/ml diphenhydramine;
- 1 to 20 mg/ ml lidocaine; and
- 10,000 to 50,000 iu/ml nystatin.
5) The formulation of claim 4 wherein the additives are chosen from the group consisting
of: polysorbate 80, spearmint oil, sorbitol, xanthan gum, sodium benzoate, purified water,
aluminium hydroxide, dextrose, sucralose, flavorings and magnesium hydroxide.
6) The formulation of claim 4 further comprising at least one buffering agent, at least one
preservative, at least one chelating agent and at least one anti-oxidant.
7) The formulation of claim 6 wherein the buffering agent is a phosphate buffer, the
preservative is methyl paraben or propyl paraben, the chelating agent is EDTA, and the
anti-oxidant is citric acid or a salt thereof.
8) Use of the formulation of claim 6 for the treatment of oral lesions.
9) The use of claim 8 for the treatment of mucositis or stomatitis.
10) A stable, anti-fungal oral rinse formulation comprising nystatin and a buffering agent, a
preservative, a chelating agent and an anti-oxidant.
11) The formulation of claim 10 wherein the buffering agent is a phosphate buffer.
12) The formulation of claim 10 wherein the preservative is methyl paraben or propyl
paraben.
13) The formulation of claim 11 wherein the chelating agent is EDTA.
14) The formulation of claim 10 wherein the anti-oxidant is citric acid or a salt thereof.
28
15) The formulation of claim 10 wherein the nystatin is present in an amount greater than
10,000 iu/ml.
16) A stable, anti-fungal oral rinse formulation comprising:
- an anti-fungal agent;
- a phosphate buffer;
- a preservative;
- a chelating agent; and,
- an antioxidant.
17) The formulation of claim 16 wherein the anti-fungal agent is selected from nystatin and
amphotericin B.
18) The formulation of claim 17 wherein the nystatin is present in an amount between 10,000
and 50,000 iu/ml.
19) The formulation of claim 18 wherein the preservative is chosen from methyl paraben,
propyl paraben and mixtures thereof.
20) The formulation of claim 19 wherein the chelating agent is ethylenediamine tetraacetic
acid (EDTA).
21) The formulation of claim 20 wherein the antioxidant is citric acid or a salt thereof.
22) The formulation of claim 21 further comprising:
- at least one corticosteroid;
- at least one antihistamine; and
- at least one topical anaesthetic.
23) The formulation of claim 22 wherein the corticosteroid is dexamethasone and wherein
said dexamethasone is present in a concentration of between 0.005 to 0.025 mg/ml.
24) The formulation of claim 23 wherein the antihistamine is diphenhydramine and wherein
said diphenhydramine is present in a concentration of between 1 to 2 mg/ml.
25) The formulation of claim 24 wherein the topical anaesthetic is lidocaine and wherein said
lidocaine is present in a concentration of between 1 to 20 mg/ml.

Dated this 25th day of March, 2010

To Signature:

The Controller of Patent Name: Durgesh Mukharya
The Patent Office, at Chennai
Of K & S Partners,
Agent for the Applicant

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=4pr5aFdfw8SftVzcvRbtgQ==&loc=egcICQiyoj82NGgGrC5ChA==

« Previous Patent

Next Patent »

Patent Number

280021

Indian Patent Application Number

1752/CHENP/2010

PG Journal Number

06/2017

Publication Date

10-Feb-2017

Grant Date

07-Feb-2017

Date of Filing

27-Mar-2010

Name of Patentee

INTERNATIONAL BUSINESS MACHINES CORPORATION

Applicant Address

1, NORTH CASTLE DRIVE, ARMONK, NEW YORK 10504

Inventors:

#	Inventor's Name	Inventor's Address
1	DANIEL CASPER	13 Brett Place, Poughkeepsie, New York 12603, United States of America.
2	SCOTT CARLSON	5150 N. Hidden Valley Road, Tucson, New York 85750, United States of America.
3	JOHN FLANAGAN	15 Slate Hill Drive, Poughkeepsie, New York 12603, United States of America.
4	ROGER HATHORN	5820 East Placita De La Zurencia, Tucson, Arizona 85750, United States of America.
5	CATHERINE HUANG	6 Thornberry Way, Poughkeepsie, New York 12603, United States of America.
6	MATTHEW KALOS	5435 East Heatherwood Way, Tucson, Arizona 85718, United States of America.
7	LOUIS RICCI	5 Spruce Road, Hyde Park, New York 12538, United States of America.
8	DALE RIEDY	6 Oak Bend Road, Poughkeepsie, New York 12603, United States of America.
9	GUSTAV III SITTMANN	422 South Park Avenue, Webster Groves Missouri 63119, United States of America.
10	NJOKU UGOCHUKWU	426 Midland Avenue, Yonkers, New York 10704, United States of America.
11	HARRY YUDENFRIEND	1 Nob Hill Road, Poughkeepsie, New York 12603-5545, United States of America.

PCT International Classification Number

G06F 13/12

PCT International Application Number

PCT/EP2009/051461

PCT International Filing date

2009-02-09

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	12/030,989	2008-02-14	U.S.A.