Drug – bio-affecting and body treating compositions – Dentifrices
Reexamination Certificate
2001-11-21
2004-02-03
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Dentifrices
Reexamination Certificate
active
06685917
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a therapeutic composition useful for treatment of mucositis and methods for using the therapeutic composition.
BACKGROUND OF THE INVENTION
Mucositis is a serious and often very painful disorder involving inflammation of the mucous membrane, with the inflammation often accompanied by infection and/or ulceration. Mucositis can occur at any of the different mucosal sites in the body. A nonlimiting list of examples of locations where mucositis can occur include mucosal sites in the oral cavity, esophagus, gastrointestinal tract, bladder, vagina, rectum, lung, nasal cavity, ear and orbita. Mucositis often develops as a side effect of cancer therapy, and especially as a side effect of chemotherapy and radiation therapy for the treatment of cancer. While cancerous cells are the primary targets of cancer therapies, other cell types can be damaged as well. Exposure to radiation and/or chemotherapeutics often results in significant disruption of cellular integrity in mucosal epithelium, leading to inflammation, infection and/or ulceration at mucosal sites.
As one example, oral mucositis (OM) is a painful and costly complication of some cancer therapies. The oral cavity is lined with mucosal epithelium, and exposure to radiation and/or chemotherapeutics results in the disruption of cellular integrity leading to the development of ulcerative lesions commonly referred to as oral mucositis. Oral mucositis is most prevalent in patient populations with head and neck malignancies being treated with radiation therapy. Oral mucositis usually occurs after the second week of radiation therapy, with severe symptoms usually resolving within six weeks following completion of therapy. It has been reported that this condition also affects approximately forty percent of patients undergoing chemotherapy, bone marrow transplantation or combinations thereof. Chemotherapeutic agents likely to cause oral mucositis include bleomycin, dactinomycin, doxorubicin, etoposide, floxuridine, 5-fluorouracil, hydroxyurea, methotrexate, mitomycin, vinblastine, vincristine, and vinorelbine. The risk of developing mucositis is markedly exacerbated when chemotherapeutic agents that typically produce mucosal toxicity are given in high doses, in frequent repetitive schedules, or in combination with ionizing irradiation (e.g., conditioning regimens prior to bone marrow transplant). The lesions induced by chemotherapeutic agents are clinically significant by about a week after treatment and the severity progresses to about day ten through twelve and begins to subside by day fourteen.
Oral mucositis appears to be a four-phase process: the primary phase is inflammatory/vascular in nature resulting in a cytokine release from the epithelium brought on by damage caused by radiation and/or chemotherapy. The second phase, referred to as the epithelial phase, is signaled by atrophy and ulceration of the mucosal epithelium. The third phase is defined as the ulcerative/bacterial phase represented by ulcerative lesions that are prone to bacterial infection further compromising the patients' immune system. These painful lesions often limit a patient's ability to eat and drink and in some cases require hospitalization. The presence of these lesions can also interrupt scheduled chemotherapy and/or radiation treatments. The last phase, the healing phase, is characterized by a proliferation and differentiation of epithelium as well as bacterial control.
Routine oral hygiene is extremely important in reducing the incidence and severity of mucositis. Oral hygiene methods include rinsing/irrigation and mechanical plaque removal. Although not entirely supported by controlled clinical trials, allopurinol mouthwash and vitamin E have been cited as agents that may decrease the severity of mucositis. Prophylaxis against fungal infections is commonly employed in an effort to treat oral mucositis and includes use of topical antifungal agents such as nystatin-containing mouthwashes and clotrimazole troches. Although topical antifungal prophylaxis and treatment may clear superficial oropharyngeal infections, topical agents tend not to be well absorbed and have not been demonstrated to be effective against more deeply invasive fungal infections, which typically involve the esophagus and lower gastrointestinal tract. For this reason, systemic agents are indicated for treating all except superficial fungal infections in the oral cavity.
Many different compounds have been evaluated for use as a prophylaxis and treatment of oral mucositis. Current therapies include cryotherapy (ice chips) to reduce pain and inflammation, analgesics to manage pain, and antibiotic therapy to control the opportunistic infection. Analgesics such as lidocaine mouthwashes are effective for short periods of time but within hours the pain and discomfort usually returns.
Chlorhexidine is a broad spectrum antimicrobial with activity against gram-positive and gram-negative organisms, yeast, and other fungal organisms. It also has the desirable properties of sustained binding to oral surfaces and minimal gastrointestinal (GI) absorption, thereby limiting adverse systemic effects. Its use in the prophylaxis of oral infections shows promise in reducing inflammation and ulceration, as well as in reducing oral microorganisms in high-risk patient groups. Other agents, such as allopurinol, leucovorin, vitamins, and growth factors, have been tried for the prevention of chemotherapy-induced mucositis. Use of a capsaicin-containing candy has also been advocated to desensitize pain receptors in the mouth. Also, studies utilizing nonsteroidal agents and coating agents, such as sucralfate (Carafate), have had conflicting results. Finally, claims that chlorhexidine (Peridex) reduces mucositis in both irradiated patients and leukemia patients receiving bone marrow transplants have not been verified. To date, none of these approaches has shown a significant impact.
Occurrence of mucositis at mucosal sites other than in the oral cavity in association with chemotherapy or radiation therapy are mechanistically similar to the occurrence of oral mucositis. For example, patients undergoing radiation therapy treatment for non-small cell lung cancer frequently develop esophagitis as a side effect of treatment. Esophagitis in this patient population can impede the progress of cancer treatment.
Given that a large number of patients suffer mucositis annually and patients undergoing cancer therapy often receive multiple cycles of chemotherapy and/or radiation therapy, there is a significant need for improved treatment of mucositis. The present invention is directed to this need.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a therapeutic composition for the treatment of mucositis. By treatment of mucositis, it is meant that the therapeutic composition is effective to prevent or reduce the incidence, severity and/or duration of the disease. The therapeutic composition comprises at least one pharmaceutical substance that, as formulated in the therapeutic composition, presents therapeutic effect in mammalian hosts, typically human hosts, for the treatment of mucositis, together with at least one biocompatible polymer that aids delivery of the pharmaceutical substance to the targeted mucosal site. One preferred embodiment of the therapeutic composition includes N-acetylcysteine as the pharmaceutical substance and a polyoxyalkylene block copolymer as the biocompatible polymer.
The therapeutic composition can be made with or without reverse-thermal viscosity behavior. For many applications, reverse-thermal viscosity behavior is beneficial to permit administration in a lower viscosity fluid form that tends to convert to a higher viscosity form following administration as the temperature of the therapeutic composition increases in the body. This also facilitates administration at a refrigerated temperature, which is soothing and refreshing to the host in a number of situations, such as for the treatment of mucosal surfaces in the oral cav
Etter Jeffrey B.
Rodell Timothy C.
Rosenthal Gary J.
Samaniego Adrian
Schauer Wren H.
Marsh & Fischmann & Breyfogle LLP
Rose Shep K.
RxKinetix, Inc.
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