Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
Reexamination Certificate
2001-03-23
2004-01-27
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
C424S464000, C424S439000, C424S484000, C424S450000, C424S451000, C514S901000
Reexamination Certificate
active
06683067
ABSTRACT:
FIELD OF THE INVENTION
The present application relates generally to formulations containing a tetracycline that are useful for treating or preventing mucositis.
BACKGROUND OF THE INVENTION
Mucositis is a dose-limiting side effect of cancer therapy and bone marrow transplantation and is not adequately managed by current treatment (Sonis, 1993a, “Oral Complications,” in:
Cancer Medicine, pp.
2381-2388, Holand et al.; Eds., Lea and Febiger, Philadelphia; Sonis, 1993b, “Oral Complications in Cancer Therapy,” In:
Principles and Practice of Oncology
, pp. 2385-2394, De Vitta et al., Eds., J. B. Lippincott, Philadelphia). Oral mucositis is found in almost 100% of patients receiving radiotherapy for head and neck tumors, in about 40% of patients receiving chemotherapy, and in about 90% of children with leukemia (Sonis, 1993b, supra). Complications related to oral mucositis, though varying in the different patient populations, generally include pain, poor oral intake with consequent dehydration and weight loss, and systemic infection with organisms originating in the oral cavity leading to septicemia (Sonis, 1993b; U.S. Pat. No. 6,025,326 to Steinberg et al.). In addition to the oral cavity, mucositis may also affect other parts of the gastro-intestinal tract.
A variety of approaches to the treatment of oral mucositis and associated oral infections have been tested with limited success. For example, the use of an allopurinol mouthwash, an oral sucralfate slurry, and pentoxifyline were reported in preliminary studies to result in a decrease in mucositis. Subsequent randomized and controlled studies, however, have failed to demonstrate any benefit from treatment with these agents (Loprinzi et al., 1995,
Sem. Oncol.
22 Suppl. 3): 95-97; Epstein & Wong, 1994,
Int. J. Radiation Oncology Biol. Phys.
28:693-698; Verdi et al., 1995,
Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod.
80:36-42).
Other therapies have been directed at decreasing oral flora and the extent of oral infections. Systemic treatment with G- and GM-CSF has been shown to result in a decreased incidence of oral mucositis, presumably by allowing for more rapid neutrophil recovery and thus an improved ability to combat infection, although it has been postulated that the CSFs may have a more direct effect on the oral mucosa (Chi et al., 1995,
J. Clin. Oncol.
13:2620-2628). Nonetheless, in one study, GM-CSF was reported to exacerbate mucositis (Cartee et al., 1994,
Cytokine
7:741-477). Benzydamine hydrochloride, a nonsteroidal drug with analgesic and antimicrobial properties, has been studied both in patients undergoing radiation therapy and in patients receiving intra-arterial chemotherapy (Epstein et al., 1986,
Oral Surg. Oral Med. Oral Pathol.
62:145-148; Epstein et al., 1989,
Int. J. Radiation Oncology Biol. Phys.
16:1571-1575) but without much success.
Chlorhexidine, an antimicrobial mouth rinse, has also been used extensively in the treatment and prevention of oral mucositis (Ferretti et al., 1990,
Bone Marrow Transplan.
3:483-493; Weisdorf et al., 1989,
Bone Marrow Transplan.
4:89-95). It has been noted, however, that the efficacy of chlorhexidine is significantly decreased in saliva, and that this compound is relatively ineffective against the Gram negative bacteria that tend to colonize the oral cavity in patients undergoing radiation therapy (Spijkervet et al., 1990,
Oral Surg. Oral Med. Oral Pathol.
69:444-449). In addition, at least one study has shown that the use of chlorhexidine may be detrimental and result in a higher incidence of mucositis (Foote et al., 1994,
J. Clin Oncol.
12:2630-2633).
Several studies have shown that the use of a vancomycin paste and antibiotic lozenges containing polymixin B, tobramycin and amphotericin B in patients undergoing myelosuppresive chemotherapy or radiation therapy can result in a decrease in oral mucositis and in the incidence of sepsis due to alpha hemolytic streptococci (Barker et al., 1995,
J. Ped. Hem. Oncol.
17:151-155; Spijkervet et al., 1991, In:
Irradiation Mucositis
, Munksgaard Press, pp. 43-50).
Other methods of treating or preventing mucositis using a variety of formulations have been reported. U.S. Pat. No. 5,545,668 to Skubitz et al. describes formulations containing glutamine. U.S. Pat. No. 5,635,489 to Haley, U.S. Pat. No. 4,961,926 to Gabrilove, and U.S. Pat. No. 5,102,870 to Florine et al., describe treatments using formulations containing growth factors or stimulating factors. Formulations contain antimicrobial peptides such as protegrin as the effective ingredient have also been described by U.S. Pat. No. 6,025,326 to Steinberg et. al. A triclosan formulation for treating mucositis was reported in U.S. Pat. No. 5,945,089 to Libin.
Despite the clear need for therapeutic agents to treat oral mucositis, none of the treatments provide significant long-term relief or decrease the severity or duration of mucositis. As a result, there is no standard treatment for oral mucositis.
Rothwell and Spektor (Special Care in Dentistry, January-February 1990, pages 21-25) have shown that patients to whom an oral rinse containing tetracycline, diphenhydramine, nystatin, and hydrocortisone was administered developed less severe mucositis than patients receiving a control rinse. The concentrations of the active ingredients in this study were tetracycline, 500 mg; nystatin, 1,200,000 U; hydrocortisone, 100 mg; and diphenhydramine elixir, 10 ml made up to a total volume of 250 ml. The tetracycline was unstable in solution with the other ingredients and was therefore administered in a separate solution.
WO 99/45910 by Sonis and Fey describes a method for treating and preventing mucositis by administering a non-steroidal anti-inflammatory (NSAID), an inflammatory cytokine inhibitor, or a mast cell inhibitor and second different therapeutic agent which is an NSAID, an inflammatory cytokine inhibitor, a mast cell inhibitor, a matrix metalloproteinase (MMP) inhibitor or a nitric oxide inhibitor. There are further claims where the MMP inhibitor is a tetracycline. These complex mixtures appear to reduce mucositis in animal models but the relative efficacies of the different active agents and effective dosages are unclear. Most of the active ingredients have side effects if absorbed systemically at effective dosages. Only the compositions containing the tetracyclines appear to significantly reduce the symptoms of the mucositis.
It is therefore an object of the present invention to provide a method and composition to decrease the duration and/or severity of mucositis by administering a composition containing a tetracycline as the active ingredient which is not absorbed systemically.
It is a further object of the present invention to provide a treatment that is safe, efficacious and easy for the patient to use.
SUMMARY OF THE INVENTION
Mucositis is treated and/or prevented by administrating to a patient a formulation comprising a tetracycline that is poorly absorbed from the gastro-intestinal tract. The tetracycline may be in the form of a pharmaceutically acceptable salt or a base. The formulations may optionally also contain an antifungal agent to prevent fungal overgrowth due to reduction in the normal oral flora by the tetracycline. Such compositions have the advantage of treating the entire gastrointestinal tract since the active ingredient is not removed from the tract via absorption. Further, such compositions minimize systemic exposure and accompanying side effects.
DETAILED DESCRIPTION OF THE INVENTION
I. Topical Tetracycline Formulations
Topical formulations for treating mucositis have been developed. These include as the active ingredient to treat the mucositis a tetracycline type compound that is poorly absorbed when administered orally or topically to the mucosa, a carrier which may be a solvent or suspending agent and include excipients modifying the viscosity, taste, stability, adherence or release properties, and optionally an anti-fungal agent.
A. Tetracyclines
As used herein, tetracyclines include compounds that may or may not have antibi
Comiskey Stephen J.
Lawter James Ronald
Holland & Knight LLP
OraPharma, Inc.
Webman Edward J.
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