CA2701583A1 - Mouthwash and method of using same for the treatment of mucositis or stomatitis - Google Patents
Mouthwash and method of using same for the treatment of mucositis or stomatitis Download PDFInfo
- Publication number
- CA2701583A1 CA2701583A1 CA2701583A CA2701583A CA2701583A1 CA 2701583 A1 CA2701583 A1 CA 2701583A1 CA 2701583 A CA2701583 A CA 2701583A CA 2701583 A CA2701583 A CA 2701583A CA 2701583 A1 CA2701583 A1 CA 2701583A1
- Authority
- CA
- Canada
- Prior art keywords
- formulation
- agent
- nystatin
- fungal
- preservative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 206010028116 Mucosal inflammation Diseases 0.000 title claims abstract description 28
- 201000010927 Mucositis Diseases 0.000 title claims abstract description 28
- 229940051866 mouthwash Drugs 0.000 title claims abstract description 24
- 208000003265 stomatitis Diseases 0.000 title claims abstract description 22
- 238000011282 treatment Methods 0.000 title claims abstract description 15
- 239000002324 mouth wash Substances 0.000 title description 36
- 238000000034 method Methods 0.000 title description 7
- 239000000203 mixture Substances 0.000 claims abstract description 85
- 238000009472 formulation Methods 0.000 claims abstract description 75
- 229960000988 nystatin Drugs 0.000 claims abstract description 33
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 claims abstract description 33
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 15
- 239000003755 preservative agent Substances 0.000 claims abstract description 14
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000001387 anti-histamine Effects 0.000 claims abstract description 12
- 239000000739 antihistaminic agent Substances 0.000 claims abstract description 12
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 12
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 12
- 235000006708 antioxidants Nutrition 0.000 claims abstract description 12
- 239000003246 corticosteroid Substances 0.000 claims abstract description 12
- 230000002335 preservative effect Effects 0.000 claims abstract description 12
- 230000003444 anaesthetic effect Effects 0.000 claims abstract description 11
- 239000002738 chelating agent Substances 0.000 claims abstract description 11
- 230000000699 topical effect Effects 0.000 claims abstract description 11
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 10
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 9
- 239000006172 buffering agent Substances 0.000 claims abstract description 7
- 239000000654 additive Substances 0.000 claims abstract description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical group COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 14
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 11
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 claims description 10
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 10
- 229960003942 amphotericin b Drugs 0.000 claims description 10
- 229940121375 antifungal agent Drugs 0.000 claims description 10
- 229960000520 diphenhydramine Drugs 0.000 claims description 10
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 10
- 229960004194 lidocaine Drugs 0.000 claims description 10
- 229960003957 dexamethasone Drugs 0.000 claims description 9
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 9
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003429 antifungal agent Substances 0.000 claims description 8
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 7
- 229960002216 methylparaben Drugs 0.000 claims description 7
- 239000008363 phosphate buffer Substances 0.000 claims description 7
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 7
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 7
- 229960003415 propylparaben Drugs 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- 239000004376 Sucralose Substances 0.000 claims description 3
- 229910021502 aluminium hydroxide Inorganic materials 0.000 claims description 3
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 3
- 239000000347 magnesium hydroxide Substances 0.000 claims description 3
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 3
- 239000001683 mentha spicata herb oil Substances 0.000 claims description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 3
- 229940068968 polysorbate 80 Drugs 0.000 claims description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 3
- 235000010234 sodium benzoate Nutrition 0.000 claims description 3
- 239000004299 sodium benzoate Substances 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 235000019721 spearmint oil Nutrition 0.000 claims description 3
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 3
- 235000019408 sucralose Nutrition 0.000 claims description 3
- 239000000230 xanthan gum Substances 0.000 claims description 3
- 235000010493 xanthan gum Nutrition 0.000 claims description 3
- 229920001285 xanthan gum Polymers 0.000 claims description 3
- 229940082509 xanthan gum Drugs 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 208000025157 Oral disease Diseases 0.000 claims description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims 1
- 239000008121 dextrose Substances 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 description 16
- -1 for 28 example Chemical compound 0.000 description 13
- 210000000214 mouth Anatomy 0.000 description 13
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 6
- 208000025865 Ulcer Diseases 0.000 description 5
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- 239000000938 histamine H1 antagonist Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
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- 229930186147 Cephalosporin Natural products 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 description 3
- 235000019800 disodium phosphate Nutrition 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
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- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
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Landscapes
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- Oral & Maxillofacial Surgery (AREA)
- Oncology (AREA)
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Abstract
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.
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.
Description
Agent ref. 70780/00007 4 [0001] This application is a continuation in part of US application number 11/692,737, filed on March 28, 2007, which claims priority from US provisional application number 60/786,376, 6 filed on March 28, 2006. The entire contents of both applications are incorporated herein by 7 reference.
9 [0002] 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 11 using such a mouthwash.
12 [0003] Mouthwashes are typically used as part of an oral hygiene regime which may also 13 include brushing and flossing to maintain a satisfactory level of oral hygiene. Such 14 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 16 or after brushing, temporarily suppress bad breath, diminish bacteria in the mouth and refresh 17 the mouth with a pleasant taste. Therapeutic rinses often have the benefits of their cosmetic 18 counterpart, but also contain an added active ingredient, for example chlorhexidine that helps 19 protect against some oral diseases such as gingivitis. Typically, such mouthwashes are alcohol-based.
21 [0004] However, available mouthwashes are unsuitable for hospital patients presenting with 22 oral complications as a result of, for example, infection or other lesions as a consequence of 23 chemotherapy or radiotherapy for the treatment of neoplastic disease. Such oral complications 24 may include mucositis or stomatitis. Mucositis or stomatitis presents in approximately 40% of patients with neoplastic disease.
26 [0005] Examples of chemotherapeutic drugs that frequently cause mucositis and/or 27 stomatitis include alkylating agents, for example melphalan and busulphan;
antimetabolites, for 28 example, cytarabine, floxuridine, 5-fluorouracil, mercaptopurine, methotrexate, and thioguanine 29 and cytotoxic drugs, for example, bleomycin, actinomycin D, daunorubicin, cisplatin, etoposide, mytomycin, vinblastine and vincristine.
31 [0006] The terms mucositis and stomatitis are often used interchangeably but may include 32 some general distinctions. Mucositis describes a toxic inflammatory reaction affecting the 21978530.1 1 Agent ref. 70780/00007 1 gastro-intestinal tract, which may result from exposure to chemotherapeutic agents or ionizing 2 radiation. Mucositis typically manifests as an erythematous burn-like lesion, or as random focal-3 to-diffuse lesions. Stomatitis refers to an inflammatory reaction affecting the oral mucosa, with 4 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 6 patient presenting with the severe stomatitis is unable to take anything by mouth.
7 [0007] Current oral cleaning care in such patients may include gently cleaning the mouth, 8 moisturizing the lips and mouth, and relieving pain and swelling. A soft toothbrush cleans teeth 9 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 11 bicarbonate (one teaspoon in 8 ounces of water). Hydrogen peroxide diluted in equal amounts 12 of water or weak salt water can be used in some cases. Mostly, physicians have resorted to 13 these rather limited, temporary relief options.
14 [0008] 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 16 complications. Currently there are a number of intervening therapies to choose from. For 17 example, The Joanna Briggs Institute of The Royal Adelaide Hospital has provided some 18 guidance on the treatment of mucositis. However, there is no high quality synthesis of research 19 evidence for these intervention therapies (www.joannabriggs.edu.au/best_practice/bp5.php, 19 February 2004).
21 [0009] Of particular interest to the current application are the variety of mouthwashes 22 previously used having mixed actions against mucositis and stomatitis. Such mouthwashes 23 typically include benzydamine hydrochloride, corticosteroids and chamomile 24 (www.joannabriggs.edu.au/best_practise/bp5.php).
[0010] Formulations such as those disclosed in U.S. 5,635,489; U.S. 4,961,926 and U.S.
26 5,102,870 describe the use of growth factors and stimulation factors such as granulocyte-27 macrophage colony stimulating factor and granulocyte-colony stimulating factor.
28 [0011] Further attempts at treatment and or prophylaxis of mucositis and stomatitis include 29 the use of nucleoside derivatives which can be formulated into lozenges or mouthwashes and the like to coat the oral cavity or other mucosal areas such as disclosed in U.S. Patent 31 Publication No. 2003/0236217 Al.
32 [0012] Other formulations include tetracycline as disclosed in U.S.
6,946,118; hyaluronic 33 acid, glycyrrhetinic acid and polyvinylpyrrolidone in mixture with excipients and adjuvants as 21978530.1 2 Agent ref. 70780/00007 1 disclosed in U.S. 6,828,308; the use of an anti-microbial peptide, preferably protegrin applied 2 topically which has broad spectrum anti-microbial activity, good stability and adheres well to all 3 mucosa as disclosed in U.S. 6,025,326; the use of glutamine as disclosed in U.S. 5,545,668 4 and the use of triclosan as disclosed in U.S. 5,945,089 [0013] Despite the widespread recognition that mucositis is a serious problem, no effective 6 treatment currently exists and, more often than not, any level of patient care is typically 7 palliative. In addition to the lack of effective treatments for mucositis, physicians are unsure of 8 the exact mechanism by which the ulcerations occur in mucositis. It is known that the initial 9 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 11 flora of the oral cavity. It is unknown which of these occurrences, if any, is responsible for the 12 mucosal damage. Despite the fact that significant quantities or inflammatory mediators are 13 released by the epithelium, conventional anti-inflammatory agents have been unsuccessful in 14 human efficacy studies of the disease.
[0014] Some of the known and effective treatments for mucositis involves the use of the 16 antibiotics nystatin and amphotericin B. These drugs have been used for the preventive and 17 curative treatment of fungal infections such as oral candidiasis and, in particular, for cancer 18 patients. Due to a lack of commercially available anti-fungal mouthwashes, oral or mouth rinse 19 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 21 formulations is that such formulations are relatively unstable and, therefore, must be used within 22 a short period of time. For example, in one study of mixtures of nystatin and amphotericin B, in 23 combination with sodium bicarbonate, it was determined that the maximum amount of time that 24 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 26 Carbonate, J. Pharm. and Biomed. Anal., v. 42, 3 (2006), pp. 362-366).
27 [0015] Thus, the available mouthwashes are effective at treating only one aspect of 28 mucositis and other oral complications and not treating the complete range of symptoms that 29 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 31 causes of mucositis.
21978530.1 3 Agent ref. 70780/00007 2 [0016] In one aspect, the present invention provides an oral rinse formulation comprising 3 one or more of the following components in combination with pharmaceutically acceptable 4 excipients or additives:
a) at least one corticosteroid;
6 b) at least one anti-histamine;
7 c) at least one topical anaesthetic;
8 d) at least one anti-fungal antibiotic agent.
9 [0017] In another aspect, the formulation can include an antibiotic agent.
[0018] In a further aspect, the invention provides a method of treating or preventing 11 mucositis or stomatitis comprising applying to a patient the above mentioned oral rinse 12 formulation.
13 [0019] In another aspect, the invention provides a stable, anti-fungal oral rinse formulation 14 comprising:
- an anti-fungal agent;
'16 - a phosphate buffer;
17 - a preservative;
18 - a chelating agent; and, 19 - an antioxidant.
[0020] In one embodiment, the anti-fungal agent is chosen from nystatin and amphotericin 21 B. In a further embodiment, the above formulation comprises: at least one corticosteroid; at 22 least one antihistamine; and at least one topical anaesthetic.
24 [0021] Accordingly, the present invention provides, in one embodiment, a mouthwash comprising one or more of the following active ingredients:
26 - at least one corticosteroid;
27 - at least one anti-histamine;
28 - at least one topical anaesthetic;
29 - at least one anti-fungal antibiotic agent.
[0022] Optionally, the formulation may include an antibiotic agent as well.
21978530.1 4 Agent ref. 70780/00007 1 [0023] In another embodiment, the invention provides a mouthwash formulation comprising 2 an anti-fungal agent, a phosphate buffer, a preservative, a chelating agent and an antioxidant.
3 This formulation preferably also includes at least one corticosteroid, at least one antihistamine, 4 and at least one topical anaesthetic. More preferably, the anti-fungal agent of this formulation comprises nystatin or amphotericin B and, most preferably, nystatin.
6 [0024] Preferably, the mouthwash in accordance with the present invention is used in the 7 treatment and/or prophylaxis of oral conditions such as mucositis and/or stomatitis.
8 [0025] Although the mouthwash (or mouth rinse) of the present invention includes various 9 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 11 that addresses a large variety of symptoms associated with mucositis and/or stomatitis. This is 12 also clearly indicated in the recent article by J. Groeschke, et al.
Further, in addition to 13 providing such multipurpose formulation, the inventors have also found an unexpectedly high 14 stability of the 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, 16 thereby greatly exceeding the stability expected according to the prior art, such as the article by 17 J. Groeschke, et al.
18 [0026] Preferably the mouthwash in accordance with the present invention further 19 comprises water and pharmaceutically acceptable excipients or additives such as:
- one or more oils, such as an oil selected from the group comprising anethole, 21 anisole, camphor, methyl salicylate, vanillin, eugenol, furaneol, linalool, menthol, thymol, 22 cinnamaldehyde, citral, methyl butanoate, pentylbutanoate, pentylpentanoate, tea tree oil, 23 peppermint oil, spearmint oil, pineapplemint oil and eucalyptus oil;
24 - sweetening agents, for example sorbitol;
- thickening agents, such as xanthan gum, carrageenan, carbomer, or HPMC
26 (hydroxypropyl methyl cellulose);
27 - preservative agents, such as sodium benzoate, methyl paraben, or propyl paraben;
28 - water;
29 - emulsifiers, such as polysorbate 80 (or TweenTM 80);
- and/or at least one antacid such as aluminium or magnesium hydroxide.
21978530.1 5 Agent ref. 70780/00007 1 [0027] It will be appreciated by persons skilled in the art that the above list of excipients 2 and/or additives is provided merely by way of example and that various other such components 3 may be used in the formulation of the present invention.
4 [0028] Oral mucositis results in specific damage that includes the shedding of the mucosal lining of the mouth (desquamation), ulceration and atrophy. Aluminum and magnesium 6 hydroxide antacids coat and protect the oral cavity from damage and provide for re-growth of 7 normal oral tissue.
8 [0029] The corticosteroid component provides anti-inflammatory action directly on the oral 9 mucosa and works to limit the inflammatory response associated with mucositis. Preferably, the corticosteroid is dexamethasone.
11 [0030] In patients being treated with chemotherapy and radiation, steps may be taken to 12 prevent bacterial infection within the oral cavity. For this reason, in an optional embodiment, the 13 mouthwash formulation of the invention may contain an antibiotic component.
Such antibiotic 14 components may be of the macrolide type and may be selected from the group consisting of erythromycin, azithromycin, clarithromycin, dirithromycin, roxithromycin carbomycin A, 16 josamycin, kitasamycin, oleandomycin, spiramycin, troleandomycin, tylosin, cethromycin, 17 ansamycin and telithromycin. In one aspect the antibiotic is erythromycin.
Once ulcerations 18 develop inside the mouth, local oral bacteria colonize the wound and release cell wall products 19 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 21 the extent of bacterial infection would promote healing of the affected tissues.
22 [0031] Alternatively, the antibiotic may be any of the following, alone or in combination:
23 - an aminoglycoside, for example, amikacin, gentamicin, kanamycin, neomycin, 24 netilmicin, streptomycin, and tobramycin;
- a carbacephem, for example, loracarbef;
26 - a carbapenem, for example, ertapenem, imipenem/cilastatin, and meropenem;
27 - a cephalosporin (first generation), for example, cefadroxil, cefazolin, cephalexin;
28 - a cephalosporin (second generation), for example, cefaclor, cefamandole, cefoxitin, 29 cefprozil, and cefuroxime;
- a cephalosporin (third generation), for example, cefixime, cefdinir, cefditoren, 31 cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone;
32 - a cephalosporin (fourth generation), for example, cefepime;
21978530.1 6 Agent ref. 70780/00007 1 - a glycopeptide, for example, teicoplanin, vancomycin;
2 - a penicillin, for example, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, 3 dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin and ticarcillin;
4 - a polypeptide, for example, bacitracin, colistin, and polymyxin B;
- a quinolone, for example, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, 6 lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and trovafloxacin;
7 - a sulfonamide, for example, mafenide, prontosil, sulfacetamide, sulfamethizole, 8 sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole;
9 - a tetracycline, for example, demeclocycline, doxycycline, minocycline, and oxytetracycline, tetracycline, and 11 - another antibiotic, for example, chloramphenicol, clindamycin, ethambutol, 12 fosfomycin, furazolidone, isoniazid, linezolid, metronidazole, nitrofurantoin, pyrazinamide, 13 quinupristin/dalfopristin, rifampin, and spectinomycin.
14 [0032] 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-16 fungal agent is nystatin or amphotericin B.
17 [0033] Patients being treated with chemotherapy and radiation are immuno-compromised.
18 This leads to not only increased risk of bacterial infection but also to an increased risk of fungal 19 infection, thus advancing the risk and degree of oral mucositis. Nystatin and amphotericin B act to prevent and limit the degree of fungal infection.
21 [0034] Alternatively, the anti-fungal compound may be selected from an imidazole, for 22 example, miconazole, ketoconazole, clotrimazole, econazole, mebendazole, bifonazole, 23 butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, 24 thiabendazole or tiaconazole; a triazole, for example, fluconazole, itraconazole, ravuconazole, posaconazole or voriconazole; an allylamine, for example, terbenafine, amorolfine, naftifine or 26 butenafine or an echinocandin such as caspofungin or micafungin or any combinations thereof.
27 [0035] The topical anaesthetic may be selected from benzocaine, mepivacaine, ropivacaine, 28 bupivacaine, lidocaine, prilocaine, procaine, cloroprocaine or tetracaine.
In one aspect the 29 topical anaesthetic is a combination of lidocaine and tetracaine.
[0036] Pain associated with oral mucositis can be extremely debilitating and lead to poor 31 oral food intake. In extreme cases patients may require feeding tubes if the ulceration continues 32 to advance. Tetracaine and lidocaine act locally to provide relief from pain.
21978530.1 7 Agent ref. 70780/00007 1 [0037] Preferably, the anti-histamine may be selected from the group comprising a first 2 generation H1 receptor antagonist, a second generation H1 receptor antagonist, a third 3 generation H1 receptor antagonist, a H2 receptor antagonist, a H3 receptor antagonist and a H4 4 receptor antagonist.
[0038] Diphenyhdramine, an antihistamine, helps to sooth soreness, burning, itching 6 (urticaria and pruritis) and inflammation, symptoms that are normally associate with mucositis.
7 [0039] The first generation H1 receptor antagonist may be selected from an 8 ethylenediamine, for example, mepyramine or antazoline; an ethanolamine, for example, 9 diphenhydramine, carbinoxamine, doxylamine, clemastine or dimenhydrinate; an alkylamine, for example, pheniramine, chlorphenamine, dexchlorphenamine, brompheniramine or triprolidine; a 11 piperazine, for example, cyclizine, hydroxyzine, meclizine or a tricyclic, for example, 12 promethazine, alimemazine, cyproheptadine or azatadine. In one aspect, the anti-histamine is 13 diphenhydramine.
14 [0040] The second generation H1 receptor antagonist may be azelastine, levocabastine or olopatadine.
16 [0041] The H3 receptor antagonist may be thioperamide, clobenpropit or impromidine.
17 [0042] The H4 receptor antagonist may be thioperamide.
18 [0043] Preferably, dexamethasone is used in the range of from 0.005 mg/ml to 0.025 mg/ml, 19 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 21 mg/ml.
22 [0044] Preferably, diphenhydramine is used in a range of from 1 mg/ml to 2 mg/ml or, more 23 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 24 mg/ml to 1.3 mg/ml. In one preferred embodiment, dexamethasone is present in a concentration of 1.67 mg/ml.
26 [0045] Preferably, lidocaine is used in a range of from 1 mg/ml to 20 mg/ml (i.e. 0.1 % to 2%) 27 although narrower ranges may also be used. In one preferred embodiment, lidocaine is present 28 in a concentration of 10 mg/ml.
29 [0046] 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 31 30,000 iu/ml to 35,000 iu/ml, or most preferably at a concentration of 33,333 iu/ml.
21978530.1 8 Agent ref. 70780/00007 1 [0047] When included in the formulation of the invention, erythromycin is used in a range of 2 from 5 mg/ml to 15 mg/ml, or, more preferably, in narrower ranges such as 10 mg/ml to 15 3 mg/ml, 12 mg/ml to 15 mg/ml, or 12.5 mg/ml to 15 mg/ml.
4 [0048] 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 6 nystatin, polysorbate 80, spearmint oil, sorbitol, xanthan gum, sodium benzoate, purified water, 7 aluminium hydroxide and magnesium hydroxide. Optionally, the formulation may also include 8 12.5 mg/ml erythromycin.
9 [0049] 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 11 mouthwash of the invention.
12 [0050] The present invention also provides, in a further embodiment, a kit for the treatment 13 or prophylaxis of mucositis or stomatitis comprising a container having an amount of mouthwash 14 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 16 an amount of the mouthwash from the container. Advantageously the cup may also have 17 markings or other indicators for the convenient dispense of a measurement of a therapeutically 18 effective dose of the mouthwash.
19 [0051] 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 21 nystatin as the anti-fungal component. In a preferred embodiment, the nystatin containing 22 formulation includes a buffering agent, a preservative, a chelating agent and an anti-oxidant.
23 [0052] In another aspect, the invention provides a stable, anti-fungal oral rinse formulation 24 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 26 agent (such as EDTA); and an antioxidant (such as citric acid or a salt thereof).
27 [0053] In a further aspect of the invention, the above formulation also includes at least one 28 corticosteroid; at least one antihistamine; and at least one topical anaesthetic.
29 [0054] Examples [0055] The following examples are provided to illustrate the invention and are not intended 31 to limit the scope of the invention in any way.
21978530.1 9 Agent ref. 70780/00007 1 [0056] Introduction 2 [0057] As discussed above, there are currently no mouth rinses available on the market 3 containing Nystatin, Dexamethasone sodium phosphate, Lidocaine HCL and Diphenhydramine 4 HCI available. Moreover, there are no commercially available mouth rinses containing nystatin and this is believed to be mainly due to the poor stability characteristics of formulations 6 containing this drug. For this reason, various mouth rinse (or mouthwash) formulations were 7 prepared to study the stability characteristics. The aim of this project was to develop a stable 8 formulation containing at least nystatin and, preferably the various other treatment agents listed 9 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 11 three months.
12 [0058] Materials and Methods 13 [0059] Table 1 below summarises the formulations studied. As shown, nine sample 14 preparations were examined, identified as samples 131 to B9. Where the samples differed in formulation, a notation is included in Table 1.
16 [0060] The following procedure was typical of that followed in preparing the formulations of 17 the example. As indicated above, the specific concentrations of the various components for the 18 trials is indicated Table 1.
19 [0061] Step 1. Preparation of 1.2% HPMC (hydroxypropyl methyl cellulose) solution for the final volume 21 1.1) Heat 70 mL DI water to 90CC.
22 1.2) Slowly add 2.4g HPMC with continuous stirring and heating at 90 C for 23 hour.
24 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 26 minutes.
27 1.5) Set aside for nystatin suspension preparation in step 3.
21978530.1 10 Agent ref. 70780/00007 1 [0062] Step 2. Preparation of water soluble API's (active pharmaceutical ingredients) 2 and other ingredients 3 2.1) Dissolve 0.60 g methyl paraben (0.2%) and 60 mg propyl paraben (0.02%) 4 in 15.0 g propylene glycol (5%) and stir at 40 C for 10 min or until completely dissolved.
6 2.2) Add 3.Og TweenTM 80 (1.0%) then stir for 10 min at 40 C.
7 2.3) Add 150 mL DI water and cool down to room temperature.
8 2.4) Add each of the following remaining ingredients and all soluble API's with 9 continuous stirring until completely dissolved. No heating.
i. 1.5g citric acid 11 ii. 4.3018 g sodium phosphate dibasic 12 iii. 1.5g sucralose 13 iv. 6.444 mg dexamethasone 21-phosphate disodium salt 14 v. 581.61 mg diphenhydramine HCI
vi. 3.741g lidocaine HCI
16 [0063] Step 3. Preparation of nystatin suspension 17 3.1) Slowly add 1.6431g nystatin to 120 mL 1.2 % HPMC solution (from step 1 ) 18 with continuous stirring. The final HPMC concentration in the formulation will 19 therefore be 0.5%.
3.2) Add 0.60 g EDTA (0.2%) and mix well.
21 [0064] Step 4. Mix solution from step 2 and nystatin suspension from step 3. Add 1.2 22 mL NFB mixed berry flavor. Mix well.
23 [0065] Step 5. Measure pH. If it is not 6.5 0.5, adjust to pH 6.5 0.5 with 100 mM
24 phosphate buffer (Na2HPO4).
[0066] Step 6. Adjust final volume to 300 mL with water. Mix well and verify pH again.
26 [0067] At the end of Step 6, the formulation (300 ml) will have the composition as listed in 27 the following table. Items marked as * comprise the active drug ingredients. Items marked as **
28 comprise the alternative components used for a placebo formulation.
21978530.1 11 Agent ref. 70780/00007 Note Chemical Name Freebase Concentration Units Weight of Concn component (m /mL) added Propylene Glycol 5.0 % 15.Og Methyl Paraben 0.20 % 0.6g Propyl Paraben 0.02 % 60mg Tween 80 1.0 % 3.Og Citric Acid 0.50 % 1.5g Sodium Phosphate dibasic 100.0 mm 4.3018g Sucralose 0.50 % 1.5g Dexamethasone 21- 0.016 0.02148 mg/mL 6.444mg phosphate disodium salt Diphenhydramine HCI 1.67 1.9387 mg/mL 0.581g Lidocaine HCI 10 12.47 mg/mL 3.741g HPMC 0.5000 %
Nystatin 33,3331U/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 %
3 [0068] The formulations were stored at room temperature and tested upon formulation (i.e.
4 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 6 this analysis at the various time points are provided in Tables 2 to 5.
7 [0069] Quantification of the respective ingredients was done using high performance liquid 8 chromatography (HPLC). A difference in calculated quantity of less than 5%
from the intial 9 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%.
11 [0070] For the re-dispersibility study, the following procedure was followed:
12 - manually shake the sample for 5 seconds.
13 - observe the bottom of the glass bottle.
14 - 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 16 bottom of the glass bottle.
21978530.1 12 Agent ref. 70780/00007 1 [0071] Conclusions 2 [0072] All the samples prepared for the stability study were found to meet the desired 3 criteria. The mouth rinse of the invention was found to be stable, when stored room 4 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 6 illustrate an unexpected stability of a nystatin containing formulation particularly when stored at 7 room temperature. The stability of the nystatin containing formulation is believed to be 8 attributable to the presence of the buffering agent (pH control), preservatives (i.e. paraben), the 9 chelating agent (i.e. EDTA), and the anti-oxidant (i.e. citrate). The data obtained from this study indicates that the formulation of the invention exhibits long term stability and, therefore, provides 11 a unique, single dose formulation that addresses various symptoms associated with mucositis.
13 [0073] Although the invention has been described with reference to certain specific 14 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 16 hereto. Any examples provided herein are included solely for the purpose of illustrating the 17 invention and are not intended to limit the invention in any way. The disclosures of all prior art 18 recited herein are incorporated herein by reference in their entirety.
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9 [0002] 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 11 using such a mouthwash.
12 [0003] Mouthwashes are typically used as part of an oral hygiene regime which may also 13 include brushing and flossing to maintain a satisfactory level of oral hygiene. Such 14 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 16 or after brushing, temporarily suppress bad breath, diminish bacteria in the mouth and refresh 17 the mouth with a pleasant taste. Therapeutic rinses often have the benefits of their cosmetic 18 counterpart, but also contain an added active ingredient, for example chlorhexidine that helps 19 protect against some oral diseases such as gingivitis. Typically, such mouthwashes are alcohol-based.
21 [0004] However, available mouthwashes are unsuitable for hospital patients presenting with 22 oral complications as a result of, for example, infection or other lesions as a consequence of 23 chemotherapy or radiotherapy for the treatment of neoplastic disease. Such oral complications 24 may include mucositis or stomatitis. Mucositis or stomatitis presents in approximately 40% of patients with neoplastic disease.
26 [0005] Examples of chemotherapeutic drugs that frequently cause mucositis and/or 27 stomatitis include alkylating agents, for example melphalan and busulphan;
antimetabolites, for 28 example, cytarabine, floxuridine, 5-fluorouracil, mercaptopurine, methotrexate, and thioguanine 29 and cytotoxic drugs, for example, bleomycin, actinomycin D, daunorubicin, cisplatin, etoposide, mytomycin, vinblastine and vincristine.
31 [0006] The terms mucositis and stomatitis are often used interchangeably but may include 32 some general distinctions. Mucositis describes a toxic inflammatory reaction affecting the 21978530.1 1 Agent ref. 70780/00007 1 gastro-intestinal tract, which may result from exposure to chemotherapeutic agents or ionizing 2 radiation. Mucositis typically manifests as an erythematous burn-like lesion, or as random focal-3 to-diffuse lesions. Stomatitis refers to an inflammatory reaction affecting the oral mucosa, with 4 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 6 patient presenting with the severe stomatitis is unable to take anything by mouth.
7 [0007] Current oral cleaning care in such patients may include gently cleaning the mouth, 8 moisturizing the lips and mouth, and relieving pain and swelling. A soft toothbrush cleans teeth 9 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 11 bicarbonate (one teaspoon in 8 ounces of water). Hydrogen peroxide diluted in equal amounts 12 of water or weak salt water can be used in some cases. Mostly, physicians have resorted to 13 these rather limited, temporary relief options.
14 [0008] 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 16 complications. Currently there are a number of intervening therapies to choose from. For 17 example, The Joanna Briggs Institute of The Royal Adelaide Hospital has provided some 18 guidance on the treatment of mucositis. However, there is no high quality synthesis of research 19 evidence for these intervention therapies (www.joannabriggs.edu.au/best_practice/bp5.php, 19 February 2004).
21 [0009] Of particular interest to the current application are the variety of mouthwashes 22 previously used having mixed actions against mucositis and stomatitis. Such mouthwashes 23 typically include benzydamine hydrochloride, corticosteroids and chamomile 24 (www.joannabriggs.edu.au/best_practise/bp5.php).
[0010] Formulations such as those disclosed in U.S. 5,635,489; U.S. 4,961,926 and U.S.
26 5,102,870 describe the use of growth factors and stimulation factors such as granulocyte-27 macrophage colony stimulating factor and granulocyte-colony stimulating factor.
28 [0011] Further attempts at treatment and or prophylaxis of mucositis and stomatitis include 29 the use of nucleoside derivatives which can be formulated into lozenges or mouthwashes and the like to coat the oral cavity or other mucosal areas such as disclosed in U.S. Patent 31 Publication No. 2003/0236217 Al.
32 [0012] Other formulations include tetracycline as disclosed in U.S.
6,946,118; hyaluronic 33 acid, glycyrrhetinic acid and polyvinylpyrrolidone in mixture with excipients and adjuvants as 21978530.1 2 Agent ref. 70780/00007 1 disclosed in U.S. 6,828,308; the use of an anti-microbial peptide, preferably protegrin applied 2 topically which has broad spectrum anti-microbial activity, good stability and adheres well to all 3 mucosa as disclosed in U.S. 6,025,326; the use of glutamine as disclosed in U.S. 5,545,668 4 and the use of triclosan as disclosed in U.S. 5,945,089 [0013] Despite the widespread recognition that mucositis is a serious problem, no effective 6 treatment currently exists and, more often than not, any level of patient care is typically 7 palliative. In addition to the lack of effective treatments for mucositis, physicians are unsure of 8 the exact mechanism by which the ulcerations occur in mucositis. It is known that the initial 9 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 11 flora of the oral cavity. It is unknown which of these occurrences, if any, is responsible for the 12 mucosal damage. Despite the fact that significant quantities or inflammatory mediators are 13 released by the epithelium, conventional anti-inflammatory agents have been unsuccessful in 14 human efficacy studies of the disease.
[0014] Some of the known and effective treatments for mucositis involves the use of the 16 antibiotics nystatin and amphotericin B. These drugs have been used for the preventive and 17 curative treatment of fungal infections such as oral candidiasis and, in particular, for cancer 18 patients. Due to a lack of commercially available anti-fungal mouthwashes, oral or mouth rinse 19 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 21 formulations is that such formulations are relatively unstable and, therefore, must be used within 22 a short period of time. For example, in one study of mixtures of nystatin and amphotericin B, in 23 combination with sodium bicarbonate, it was determined that the maximum amount of time that 24 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 26 Carbonate, J. Pharm. and Biomed. Anal., v. 42, 3 (2006), pp. 362-366).
27 [0015] Thus, the available mouthwashes are effective at treating only one aspect of 28 mucositis and other oral complications and not treating the complete range of symptoms that 29 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 31 causes of mucositis.
21978530.1 3 Agent ref. 70780/00007 2 [0016] In one aspect, the present invention provides an oral rinse formulation comprising 3 one or more of the following components in combination with pharmaceutically acceptable 4 excipients or additives:
a) at least one corticosteroid;
6 b) at least one anti-histamine;
7 c) at least one topical anaesthetic;
8 d) at least one anti-fungal antibiotic agent.
9 [0017] In another aspect, the formulation can include an antibiotic agent.
[0018] In a further aspect, the invention provides a method of treating or preventing 11 mucositis or stomatitis comprising applying to a patient the above mentioned oral rinse 12 formulation.
13 [0019] In another aspect, the invention provides a stable, anti-fungal oral rinse formulation 14 comprising:
- an anti-fungal agent;
'16 - a phosphate buffer;
17 - a preservative;
18 - a chelating agent; and, 19 - an antioxidant.
[0020] In one embodiment, the anti-fungal agent is chosen from nystatin and amphotericin 21 B. In a further embodiment, the above formulation comprises: at least one corticosteroid; at 22 least one antihistamine; and at least one topical anaesthetic.
24 [0021] Accordingly, the present invention provides, in one embodiment, a mouthwash comprising one or more of the following active ingredients:
26 - at least one corticosteroid;
27 - at least one anti-histamine;
28 - at least one topical anaesthetic;
29 - at least one anti-fungal antibiotic agent.
[0022] Optionally, the formulation may include an antibiotic agent as well.
21978530.1 4 Agent ref. 70780/00007 1 [0023] In another embodiment, the invention provides a mouthwash formulation comprising 2 an anti-fungal agent, a phosphate buffer, a preservative, a chelating agent and an antioxidant.
3 This formulation preferably also includes at least one corticosteroid, at least one antihistamine, 4 and at least one topical anaesthetic. More preferably, the anti-fungal agent of this formulation comprises nystatin or amphotericin B and, most preferably, nystatin.
6 [0024] Preferably, the mouthwash in accordance with the present invention is used in the 7 treatment and/or prophylaxis of oral conditions such as mucositis and/or stomatitis.
8 [0025] Although the mouthwash (or mouth rinse) of the present invention includes various 9 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 11 that addresses a large variety of symptoms associated with mucositis and/or stomatitis. This is 12 also clearly indicated in the recent article by J. Groeschke, et al.
Further, in addition to 13 providing such multipurpose formulation, the inventors have also found an unexpectedly high 14 stability of the 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, 16 thereby greatly exceeding the stability expected according to the prior art, such as the article by 17 J. Groeschke, et al.
18 [0026] Preferably the mouthwash in accordance with the present invention further 19 comprises water and pharmaceutically acceptable excipients or additives such as:
- one or more oils, such as an oil selected from the group comprising anethole, 21 anisole, camphor, methyl salicylate, vanillin, eugenol, furaneol, linalool, menthol, thymol, 22 cinnamaldehyde, citral, methyl butanoate, pentylbutanoate, pentylpentanoate, tea tree oil, 23 peppermint oil, spearmint oil, pineapplemint oil and eucalyptus oil;
24 - sweetening agents, for example sorbitol;
- thickening agents, such as xanthan gum, carrageenan, carbomer, or HPMC
26 (hydroxypropyl methyl cellulose);
27 - preservative agents, such as sodium benzoate, methyl paraben, or propyl paraben;
28 - water;
29 - emulsifiers, such as polysorbate 80 (or TweenTM 80);
- and/or at least one antacid such as aluminium or magnesium hydroxide.
21978530.1 5 Agent ref. 70780/00007 1 [0027] It will be appreciated by persons skilled in the art that the above list of excipients 2 and/or additives is provided merely by way of example and that various other such components 3 may be used in the formulation of the present invention.
4 [0028] Oral mucositis results in specific damage that includes the shedding of the mucosal lining of the mouth (desquamation), ulceration and atrophy. Aluminum and magnesium 6 hydroxide antacids coat and protect the oral cavity from damage and provide for re-growth of 7 normal oral tissue.
8 [0029] The corticosteroid component provides anti-inflammatory action directly on the oral 9 mucosa and works to limit the inflammatory response associated with mucositis. Preferably, the corticosteroid is dexamethasone.
11 [0030] In patients being treated with chemotherapy and radiation, steps may be taken to 12 prevent bacterial infection within the oral cavity. For this reason, in an optional embodiment, the 13 mouthwash formulation of the invention may contain an antibiotic component.
Such antibiotic 14 components may be of the macrolide type and may be selected from the group consisting of erythromycin, azithromycin, clarithromycin, dirithromycin, roxithromycin carbomycin A, 16 josamycin, kitasamycin, oleandomycin, spiramycin, troleandomycin, tylosin, cethromycin, 17 ansamycin and telithromycin. In one aspect the antibiotic is erythromycin.
Once ulcerations 18 develop inside the mouth, local oral bacteria colonize the wound and release cell wall products 19 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 21 the extent of bacterial infection would promote healing of the affected tissues.
22 [0031] Alternatively, the antibiotic may be any of the following, alone or in combination:
23 - an aminoglycoside, for example, amikacin, gentamicin, kanamycin, neomycin, 24 netilmicin, streptomycin, and tobramycin;
- a carbacephem, for example, loracarbef;
26 - a carbapenem, for example, ertapenem, imipenem/cilastatin, and meropenem;
27 - a cephalosporin (first generation), for example, cefadroxil, cefazolin, cephalexin;
28 - a cephalosporin (second generation), for example, cefaclor, cefamandole, cefoxitin, 29 cefprozil, and cefuroxime;
- a cephalosporin (third generation), for example, cefixime, cefdinir, cefditoren, 31 cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone;
32 - a cephalosporin (fourth generation), for example, cefepime;
21978530.1 6 Agent ref. 70780/00007 1 - a glycopeptide, for example, teicoplanin, vancomycin;
2 - a penicillin, for example, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, 3 dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin and ticarcillin;
4 - a polypeptide, for example, bacitracin, colistin, and polymyxin B;
- a quinolone, for example, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, 6 lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and trovafloxacin;
7 - a sulfonamide, for example, mafenide, prontosil, sulfacetamide, sulfamethizole, 8 sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole;
9 - a tetracycline, for example, demeclocycline, doxycycline, minocycline, and oxytetracycline, tetracycline, and 11 - another antibiotic, for example, chloramphenicol, clindamycin, ethambutol, 12 fosfomycin, furazolidone, isoniazid, linezolid, metronidazole, nitrofurantoin, pyrazinamide, 13 quinupristin/dalfopristin, rifampin, and spectinomycin.
14 [0032] 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-16 fungal agent is nystatin or amphotericin B.
17 [0033] Patients being treated with chemotherapy and radiation are immuno-compromised.
18 This leads to not only increased risk of bacterial infection but also to an increased risk of fungal 19 infection, thus advancing the risk and degree of oral mucositis. Nystatin and amphotericin B act to prevent and limit the degree of fungal infection.
21 [0034] Alternatively, the anti-fungal compound may be selected from an imidazole, for 22 example, miconazole, ketoconazole, clotrimazole, econazole, mebendazole, bifonazole, 23 butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, 24 thiabendazole or tiaconazole; a triazole, for example, fluconazole, itraconazole, ravuconazole, posaconazole or voriconazole; an allylamine, for example, terbenafine, amorolfine, naftifine or 26 butenafine or an echinocandin such as caspofungin or micafungin or any combinations thereof.
27 [0035] The topical anaesthetic may be selected from benzocaine, mepivacaine, ropivacaine, 28 bupivacaine, lidocaine, prilocaine, procaine, cloroprocaine or tetracaine.
In one aspect the 29 topical anaesthetic is a combination of lidocaine and tetracaine.
[0036] Pain associated with oral mucositis can be extremely debilitating and lead to poor 31 oral food intake. In extreme cases patients may require feeding tubes if the ulceration continues 32 to advance. Tetracaine and lidocaine act locally to provide relief from pain.
21978530.1 7 Agent ref. 70780/00007 1 [0037] Preferably, the anti-histamine may be selected from the group comprising a first 2 generation H1 receptor antagonist, a second generation H1 receptor antagonist, a third 3 generation H1 receptor antagonist, a H2 receptor antagonist, a H3 receptor antagonist and a H4 4 receptor antagonist.
[0038] Diphenyhdramine, an antihistamine, helps to sooth soreness, burning, itching 6 (urticaria and pruritis) and inflammation, symptoms that are normally associate with mucositis.
7 [0039] The first generation H1 receptor antagonist may be selected from an 8 ethylenediamine, for example, mepyramine or antazoline; an ethanolamine, for example, 9 diphenhydramine, carbinoxamine, doxylamine, clemastine or dimenhydrinate; an alkylamine, for example, pheniramine, chlorphenamine, dexchlorphenamine, brompheniramine or triprolidine; a 11 piperazine, for example, cyclizine, hydroxyzine, meclizine or a tricyclic, for example, 12 promethazine, alimemazine, cyproheptadine or azatadine. In one aspect, the anti-histamine is 13 diphenhydramine.
14 [0040] The second generation H1 receptor antagonist may be azelastine, levocabastine or olopatadine.
16 [0041] The H3 receptor antagonist may be thioperamide, clobenpropit or impromidine.
17 [0042] The H4 receptor antagonist may be thioperamide.
18 [0043] Preferably, dexamethasone is used in the range of from 0.005 mg/ml to 0.025 mg/ml, 19 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 21 mg/ml.
22 [0044] Preferably, diphenhydramine is used in a range of from 1 mg/ml to 2 mg/ml or, more 23 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 24 mg/ml to 1.3 mg/ml. In one preferred embodiment, dexamethasone is present in a concentration of 1.67 mg/ml.
26 [0045] Preferably, lidocaine is used in a range of from 1 mg/ml to 20 mg/ml (i.e. 0.1 % to 2%) 27 although narrower ranges may also be used. In one preferred embodiment, lidocaine is present 28 in a concentration of 10 mg/ml.
29 [0046] 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 31 30,000 iu/ml to 35,000 iu/ml, or most preferably at a concentration of 33,333 iu/ml.
21978530.1 8 Agent ref. 70780/00007 1 [0047] When included in the formulation of the invention, erythromycin is used in a range of 2 from 5 mg/ml to 15 mg/ml, or, more preferably, in narrower ranges such as 10 mg/ml to 15 3 mg/ml, 12 mg/ml to 15 mg/ml, or 12.5 mg/ml to 15 mg/ml.
4 [0048] 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 6 nystatin, polysorbate 80, spearmint oil, sorbitol, xanthan gum, sodium benzoate, purified water, 7 aluminium hydroxide and magnesium hydroxide. Optionally, the formulation may also include 8 12.5 mg/ml erythromycin.
9 [0049] 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 11 mouthwash of the invention.
12 [0050] The present invention also provides, in a further embodiment, a kit for the treatment 13 or prophylaxis of mucositis or stomatitis comprising a container having an amount of mouthwash 14 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 16 an amount of the mouthwash from the container. Advantageously the cup may also have 17 markings or other indicators for the convenient dispense of a measurement of a therapeutically 18 effective dose of the mouthwash.
19 [0051] 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 21 nystatin as the anti-fungal component. In a preferred embodiment, the nystatin containing 22 formulation includes a buffering agent, a preservative, a chelating agent and an anti-oxidant.
23 [0052] In another aspect, the invention provides a stable, anti-fungal oral rinse formulation 24 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 26 agent (such as EDTA); and an antioxidant (such as citric acid or a salt thereof).
27 [0053] In a further aspect of the invention, the above formulation also includes at least one 28 corticosteroid; at least one antihistamine; and at least one topical anaesthetic.
29 [0054] Examples [0055] The following examples are provided to illustrate the invention and are not intended 31 to limit the scope of the invention in any way.
21978530.1 9 Agent ref. 70780/00007 1 [0056] Introduction 2 [0057] As discussed above, there are currently no mouth rinses available on the market 3 containing Nystatin, Dexamethasone sodium phosphate, Lidocaine HCL and Diphenhydramine 4 HCI available. Moreover, there are no commercially available mouth rinses containing nystatin and this is believed to be mainly due to the poor stability characteristics of formulations 6 containing this drug. For this reason, various mouth rinse (or mouthwash) formulations were 7 prepared to study the stability characteristics. The aim of this project was to develop a stable 8 formulation containing at least nystatin and, preferably the various other treatment agents listed 9 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 11 three months.
12 [0058] Materials and Methods 13 [0059] Table 1 below summarises the formulations studied. As shown, nine sample 14 preparations were examined, identified as samples 131 to B9. Where the samples differed in formulation, a notation is included in Table 1.
16 [0060] The following procedure was typical of that followed in preparing the formulations of 17 the example. As indicated above, the specific concentrations of the various components for the 18 trials is indicated Table 1.
19 [0061] Step 1. Preparation of 1.2% HPMC (hydroxypropyl methyl cellulose) solution for the final volume 21 1.1) Heat 70 mL DI water to 90CC.
22 1.2) Slowly add 2.4g HPMC with continuous stirring and heating at 90 C for 23 hour.
24 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 26 minutes.
27 1.5) Set aside for nystatin suspension preparation in step 3.
21978530.1 10 Agent ref. 70780/00007 1 [0062] Step 2. Preparation of water soluble API's (active pharmaceutical ingredients) 2 and other ingredients 3 2.1) Dissolve 0.60 g methyl paraben (0.2%) and 60 mg propyl paraben (0.02%) 4 in 15.0 g propylene glycol (5%) and stir at 40 C for 10 min or until completely dissolved.
6 2.2) Add 3.Og TweenTM 80 (1.0%) then stir for 10 min at 40 C.
7 2.3) Add 150 mL DI water and cool down to room temperature.
8 2.4) Add each of the following remaining ingredients and all soluble API's with 9 continuous stirring until completely dissolved. No heating.
i. 1.5g citric acid 11 ii. 4.3018 g sodium phosphate dibasic 12 iii. 1.5g sucralose 13 iv. 6.444 mg dexamethasone 21-phosphate disodium salt 14 v. 581.61 mg diphenhydramine HCI
vi. 3.741g lidocaine HCI
16 [0063] Step 3. Preparation of nystatin suspension 17 3.1) Slowly add 1.6431g nystatin to 120 mL 1.2 % HPMC solution (from step 1 ) 18 with continuous stirring. The final HPMC concentration in the formulation will 19 therefore be 0.5%.
3.2) Add 0.60 g EDTA (0.2%) and mix well.
21 [0064] Step 4. Mix solution from step 2 and nystatin suspension from step 3. Add 1.2 22 mL NFB mixed berry flavor. Mix well.
23 [0065] Step 5. Measure pH. If it is not 6.5 0.5, adjust to pH 6.5 0.5 with 100 mM
24 phosphate buffer (Na2HPO4).
[0066] Step 6. Adjust final volume to 300 mL with water. Mix well and verify pH again.
26 [0067] At the end of Step 6, the formulation (300 ml) will have the composition as listed in 27 the following table. Items marked as * comprise the active drug ingredients. Items marked as **
28 comprise the alternative components used for a placebo formulation.
21978530.1 11 Agent ref. 70780/00007 Note Chemical Name Freebase Concentration Units Weight of Concn component (m /mL) added Propylene Glycol 5.0 % 15.Og Methyl Paraben 0.20 % 0.6g Propyl Paraben 0.02 % 60mg Tween 80 1.0 % 3.Og Citric Acid 0.50 % 1.5g Sodium Phosphate dibasic 100.0 mm 4.3018g Sucralose 0.50 % 1.5g Dexamethasone 21- 0.016 0.02148 mg/mL 6.444mg phosphate disodium salt Diphenhydramine HCI 1.67 1.9387 mg/mL 0.581g Lidocaine HCI 10 12.47 mg/mL 3.741g HPMC 0.5000 %
Nystatin 33,3331U/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 %
3 [0068] The formulations were stored at room temperature and tested upon formulation (i.e.
4 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 6 this analysis at the various time points are provided in Tables 2 to 5.
7 [0069] Quantification of the respective ingredients was done using high performance liquid 8 chromatography (HPLC). A difference in calculated quantity of less than 5%
from the intial 9 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%.
11 [0070] For the re-dispersibility study, the following procedure was followed:
12 - manually shake the sample for 5 seconds.
13 - observe the bottom of the glass bottle.
14 - 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 16 bottom of the glass bottle.
21978530.1 12 Agent ref. 70780/00007 1 [0071] Conclusions 2 [0072] All the samples prepared for the stability study were found to meet the desired 3 criteria. The mouth rinse of the invention was found to be stable, when stored room 4 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 6 illustrate an unexpected stability of a nystatin containing formulation particularly when stored at 7 room temperature. The stability of the nystatin containing formulation is believed to be 8 attributable to the presence of the buffering agent (pH control), preservatives (i.e. paraben), the 9 chelating agent (i.e. EDTA), and the anti-oxidant (i.e. citrate). The data obtained from this study indicates that the formulation of the invention exhibits long term stability and, therefore, provides 11 a unique, single dose formulation that addresses various symptoms associated with mucositis.
13 [0073] Although the invention has been described with reference to certain specific 14 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 16 hereto. Any examples provided herein are included solely for the purpose of illustrating the 17 invention and are not intended to limit the invention in any way. The disclosures of all prior art 18 recited herein are incorporated herein by reference in their entirety.
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Claims (25)
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.
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.
- 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.
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.
- 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.
- 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.
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PCT/CA2007/001743 WO2009043134A1 (en) | 2007-10-03 | 2007-10-03 | Mouthwash and method of using same for the treatment of mucositis or stomatitis |
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CA (1) | CA2701583A1 (en) |
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PL2701681T3 (en) | 2011-04-29 | 2017-03-31 | Moberg Pharma Ab | Pharmaceutical compositions comprising a local anaesthetic such as bupivacaine for local administration to the mouth or throat |
MX354123B (en) * | 2013-02-07 | 2018-02-14 | Galvan Gonzalez Tomas Bernardo | Oral antiseptic composition for treating oral mucositis. |
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US5945089A (en) | 1998-11-05 | 1999-08-31 | I-Dent International Corporation | Method of treating mucositis |
US6946118B1 (en) | 1999-09-14 | 2005-09-20 | Orapharma, Inc. | Formulations for treating or preventing mucositis |
US6828308B2 (en) | 2000-07-28 | 2004-12-07 | Sinclair Pharmaceuticals, Ltd. | Compositions and methods for the treatment or prevention of inflammation |
WO2002041837A2 (en) * | 2000-11-22 | 2002-05-30 | Rxkinetix, Inc. | Treatment of mucositis |
EP1383527A4 (en) * | 2001-04-24 | 2004-07-14 | Gen Hospital Corp | Methods and compositions for treating oral and esophageal lesions |
EP1509234B1 (en) | 2002-05-21 | 2008-12-17 | Abbott Laboratories | Treatment of mucositis |
US20070231274A1 (en) * | 2006-03-28 | 2007-10-04 | Myrex Pharmaceuticals Inc. | Mouthwash and Method of Using Same for the Treatment of Mucositis or Stomatitis |
-
2007
- 2007-10-03 CA CA2701583A patent/CA2701583A1/en not_active Abandoned
- 2007-10-03 WO PCT/CA2007/001743 patent/WO2009043134A1/en active Application Filing
- 2007-10-03 EP EP07866180A patent/EP2203152A4/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
EP2203152A1 (en) | 2010-07-07 |
EP2203152A4 (en) | 2011-05-25 |
WO2009043134A1 (en) | 2009-04-09 |
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