Treatment of mucositis using N-acetylcysteine

Abstract

This present invention provides a therapeutic composition for use in the treatment of mucositis and a method for using such a therapeutic composition. The therapeutic composition includes a pharmaceutical substance effective for treating mucositis formulated with a biocompatible polymer, such as a biocompatible reverse-thermal gelation polymer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is divisional of U.S. patent application Ser. No. 10 / 728,277 filed Dec. 4, 2003, which is a continuation of U.S. patent application Ser. No. 09 / 993,383 filed Nov. 21, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 721,516 filed Nov. 22, 2000, the entire contents, and each portion thereof, of each and every one of these referenced applications are incorporated herein by reference as if set forth herein in full.FIELD OF THE INVENTION [0002] This invention relates to a therapeutic composition useful for treatment of mucositis and methods for using the therapeutic composition. BACKGROUND OF THE INVENTION [0003] 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...

AI Technical Summary

Benefits of technology

[0011] 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.

[0012] 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 cavity or esophagus. The biocompatible polymer will often be a reverse-thermal gelation polymer capable of imparting the desired reverse-thermal viscosity behavior to the therapeutic composition. Also, the therapeutic composition can be made in a variety of product forms, with different product forms being more desirable for targeting treatment to different mucosal sites. Also, in some applications it is desirable that the reverse-thermal viscosity behavior can include reverse-thermal gelation, in which case the therapeutic composition converts to a gel form as the temperature of the composition is increased from below to above a reverse-thermal gel transition temperature. When the therapeutic composition has reverse-thermal gelation properties, the therapeutic composition will preferably have a reverse-thermal gel transition temperature that is no higher than, and even more preferably lower than, the physiological temperature of the host. Depending upon the specific application, the therapeutic composition could be administered to the host at a cold temperature at which the therapeutic composition is in the form of a flowable medium, or at a temperature at which the therapeutic composition is in the form of a gel. When administered in the form of a gel, the therapeutic composition will often have a thick, pudding-like texture. Inside the body, the gel tends to break down as biological fluids dilute the therapeutic composition. But even with breakdown of the gel, significant amounts of the biocompatible polymer and pharmaceutical substance tend to adhere to mucosal surfaces to promote effective delivery of the pharmaceutical substance to treat the targeted mucosal site.

[0020] For enhanced performance of the therapeutic composition, it is important that one or more of the components of the therapeutic composition are sufficiently bioadhesive to promote ready adhesion to mucosal surfaces, thereby promoting retention of the pharmaceutical substance adjacent the mucosal surface for effective delivery to the targeted mucosal site. In one preferred embodiment, the biocompatible polymer is bioadhesive, so that when the therapeutic composition is contacted with a mucosal surface, at least a portion of the biocompatible polymer readily adheres to the surface. Preferably, the biocompatible polymer and the pharmaceutical substance are closely associated with each other in the therapeutic composition such that when the biocompatible polymer adheres to a surface inside the oral cavity, the pharmaceutical substance also adheres to the surface along with the biocompatible polymer. This will often be the case when the carrier liquid is water and the biocompatible polymer has surfactant properties. In a preferred embodiment the surfactant properties of the biocompatible polymer enhance solubility of the pharmaceutical substance in the carrier liquid. In one embodiment, the therapeutic composition includes, in addition to the biocompatible polymer, a separate bioadhesive agent that enhances the bioadhesive properties of the therapeutic composition. The bioadhesive agent is frequently a second polymer having even greater bioadhesive properties.

[0021] In a further enhancement, the therapeutic composition may include a penetration enhancer, which aids rapid transport of the pharmaceutical substance across the mucosal epithelium. The therapeutic composition can also include other components that are compatible with the pharmaceutical substance and the biocompatible polymer.

Problems solved by technology

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.

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.

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).

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.

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.

Analgesics such as lidocaine mouthwashes are effective for short periods of time but within hours the pain and discomfort usually returns.

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.

Esophagitis in this patient population can impede the progress of cancer treatment.

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