Topical oral dosage forms containing bismuth compounds Number:6,902,738 from the United States Patent and Trademark Office (PTO) owispatent Topical oral dosage forms containing bismuth compounds are described, which are useful for treating H. pylori and other bacterial infections that cause gastrointestinal disorders and halitosis, as well as for treating ocular and dermal wounds. Methods of employing topical oral dosage forms for treating bacterial infections that cause gastrointestinal disorders and halitosis, and for treating ocular and dermal wounds, are also described. containing, compounds, Topical, oral, do, 6902738.html, Patent, pto, 6902738

Title: Topical oral dosage forms containing bismuth compounds

Abstract: Topical oral dosage forms containing bismuth compounds are described, which are useful for treating H. pylori and other bacterial infections that cause gastrointestinal disorders and halitosis, as well as for treating ocular and dermal wounds. Methods of employing topical oral dosage forms for treating bacterial infections that cause gastrointestinal disorders and halitosis, and for treating ocular and dermal wounds, are also described.

Patent Number: 6,902,738 Issued on 06/07/2005 to Gubler

Inventors: Gubler; Scott A. (Saint George, UT)

Assignee: Josman Laboratories, Inc. (Irvine, CA)

Appl. No.: 101559

Filed: March 19, 2002

Foreign Application Priority Data

May 02, 1994[JP]

6-93518

Current U.S. Class: 424/440; 424/441; 424/653; 514/900; 514/902

Intern'l Class: A61K 009/20; A61K009/68

Field of Search: 424/439-441,48-58,653 514/900-902

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Primary Examiner: Kishore; Gollamudi S.
Attorney, Agent or Firm: Brinks Hofer Gilson & Lione, Zayia; Gregory H.

Parent Case Text

This application is a continuation-in-part of U.S. application Ser. No. 09/578,824, filed May 24, 2000 now U.S. Pat. No. 6,426,085, which is a continuation of U.S. application Ser. No. 09/363,077, filed Jul. 28, 1999 now abandoned, which is a continuation of U.S. application Ser. No. 09/080,583, filed May 18, 1998 now abandoned, which is a continuation of U.S. application Ser. No. 08/594,148, filed Jan. 31, 1996 now abandoned, which is a continuation-in-part of U.S. application Ser. No. 08/518,971, filed Aug. 24, 1995 now abandoned, which is a continuation-in-part of U.S. application Ser. No. 08/385,060, filed Feb. 7, 1995 now abandoned, which in turn claims priority under 35 U.S.C. §119 to Japanese Application No. 6-93518, filed May 2, 1994. The entire contents of each of the above-identified United States and foreign applications are incorporated herein by reference, except that in the event of any inconsistent disclosure or definition from the present application, the disclosure or definition herein shall be deemed to prevail.

Claims

1. A topical oral dosage form selected from the group consisting of chewing gums, lozenges, troches, and combinations thereof, wherein the topical oral dosage form comprises a pharmaceutically active agent effective against bacteria in an oral cavity which causes halitosis, wherein the pharmaceutically active agent comprises a bismuth compound selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, tripotassium dicitrato bismuthate, bismuth aluminate, bismuth polysulfates, bismuth polyhydroxy compounds, alpha-D-glucopyranoside bismuth complex, beta-D-fructofuranosyl-oktakis (hydrogen sulfate) bismuth complex, L-dihydro ascorbyl-tetrakis (hydrogen sulfate) bismuth complex, bismuth ascorbyl sulfate, bismuth subascorbate, bismuth sucrose sulfate, bismuth cyclodextrin sulfate, and combinations thereof, and wherein the topical oral dosage form provides controlled release of the bismuth compound into saliva in the oral cavity for at least 5 minutes in a concentration in the saliva of at least 2 μg/mL.

2. The topical oral dosage form of claim 1 wherein the bismuth compound is selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth tartrate, bismuth subgallate, tripotassium dicitrato bismuthate, bismuth aluminate, and combinations thereof.

3. The topical oral dosage form of claim 1 wherein the bismuth compound is selected from the group consisting of bismuth polysulfates, bismuth polyhydroxy compounds, alpha-D-glucopyranoside bismuth complex, beta-D-fructofuranosyl-oktakis (hydrogen sulfate) bismuth complex, L-dihydro ascorbyl-tetrakis (hydrogen sulfate) bismuth complex, bismuth ascorbyl sulfate, bismuth subascorbate, bismuth sucrose sulfate, bismuth cyclodextrin sulfate, and combinations thereof.

4. The topical oral dosage form of claim 1 wherein the dosage form is a chewing gum.

5. The topical oral dosage form of claim 1 wherein the dosage form is a lozenge.

6. The topical oral dosage form of claim 1 wherein the dosage form is a troche.

7. The topical dosage form of claim 1 wherein the bismuth compound is colloidal bismuth suboltrate and the topical dosage form is chewing gum.

8. The topical dosage form of claim 7 wherein the chewing gum comprises between about 10 mg and about 200 mg of colloidal bismuth subcitrate.

9. The topical dosage form of claim 7 wherein the chewing gum comprises between about 10 mg and about 100 mg of colloidal bismuth subcitrate.

10. The topical dosage form of claim 7 wherein the chewing gum comprises between about 10 mg and about 50 mg of colloidal bismuth subcitrate.

11. The topical dosage form of claim 1 wherein the controlled release of the bismuth compound in the oral cavity is in an amount of at least ten times the minimum inhibitory concentration for Helicobacter Pylori.

12. The topical dosage form of claim 1 wherein the dosage form is a troche, and wherein the dosage form further comprises a hydrophilic polymer.

13. The topical dosage form of claim 1, further comprising a pharmaceutically effective amount of metronidazole.

14. The topical dosage form of claim 1, further comprising an anti-plaque agent.

15. The topical dosage form of claim 14 wherein said anti-plaque agent is selected from the group consisting of glucanase anhydroglucosidase, glucose oxidase, silicon oil, and sanguinarine.

16. A topical oral dosage form selected from the group consisting of chewing gums, lozenges, troches, and combinations thereof, wherein the topical oral dosage form comprises an effective amount of a pharmaceutically active anti-bacterial agent consisting essentially of a bismuth compound selected from the group consisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuth citrate, bismuth salicylate, bismuth subsalicylate, bismuth subcitrate, bismuth subcarbonate, bismuth tantrate, bismuth subgallate, tripotassium dicitrato bismuthate, bismuth aluminate, bismuth polysulfates, bismuth polyhydroxy compounds, alpha-D-glucopyranoside bismuth complex, beta-D-fructofuranosyl-oktakis (hydrogen sulfate) bismuth complex, L-dihydro ascorbyl-tetrakis (hydrogen sulfate) bismuth complex, bismuth ascorbyl sulfate, bismuth subascorbate, bismuth sucrose sulfate, bismuth cyclodextrin sulfate, and combinations thereof, wherein the topical oral dosage form provides controlled release of the bismuth compound into the saliva in the oral cavity for at least 5 minutes in a concentration in the saliva of at least 2 μg/mL.

17. The topical oral dosage form of claim 16 wherein the bismuth compound is colloidal bismuth subcitrate and the topical dosage form is chewing gum.

18. The topical oral dosage form of clalm 16, further comprising an effective amount of an antibiotic compound.

19. The topical oral dosage form of claim 16 further comprising an antibiotic compound selected from the group consisting of Tetracycline, Amoxicillin, Ampicillin, Doxycycline, Erythromycin, Clarithromycin, Metronidazole, Tinidazole, Ciproflaxacin, Oflaxacin, Norflaxacin, Furazolidine, Nitrofurantoin, and combinations thereof.

Description

BACKGROUND

Until recently, excessive gastric acidity and mental stress were thought to be major pathophysiological reasons for occurrence of peptic ulcers. In the early 1980s, Marshall and Warren (Warren, Lancet, 1:1273-1275, 1983 and Marshall et al., Lancet, 2:1311-1315, 1984) first reported an unidentified curved bacilli in the stomach of patients with gastritis and peptic ulcers. These bacilli, which later were identified as gram negative spiral bacteria and named Helicobacter pylori (Goodwin et al., Int. J. Syst. Bacteriol. 39:397-405, 1989), have been demonstrated to be associated with gastritis and peptic ulcers (Buck et al., J. Infect. Dis. 153:664-669, 1986 and Graham, Gastroenterology 96:615-625, 1989), and are thought to be transmitted by person-to-person contact.

Recent clinical investigations have shown a definitive presence of H. pylori in the dental plaque (Nguyen et al., Journal of Clinical Microbiology 31(4):783-787, 1993; Desai et al., Scandinavian Journal of Gastroenterology 26:1205-1208, 1991; and Lambert et al., Lancet 341(8850):957, 1993), and have also shown that standard oral hygiene practice does not help reduce H. pylori presence in the oral cavity (Nguyen et al., Journal of Clinical Microbiology 31(4):783-787, 1993). As a result of these recent discoveries associating bacterial infection in the causation of peptic ulcer disease, questions regarding the previously established paradigms of ulcer treatment and healing processes have been raised.

H₂ receptor blockers which suppress acid secretion, such as cimetidine (Tagamet®) and ranitidine (Zantac®), have been used to treat and heal duodenal ulcers (Jones et al., Gut. 28:1120-1127, 1987; McIsaac et al., Aliment. Pharmacol. Therap. 1:369-381, 1987; and Boyed et al., Amsterdam:Excerpta Medica, 14-42, 1984). Recently, however, a number of clinical investigations have demonstrated that 70-80% of healed duodenal ulcers reoccur within the next year (Goodwin et al., Int. J. Syst. Bacteriol 39:397-407, 1989), and that these drugs do not reverse the tendency for ulcers to form (Wormsley, British Medical Journal 293:1501, 1986; Gudman et al., British Medical Journal i:1095-1097, 1978; and Bardhan et al., British Medical Journal 284:621-623, 1982).

For many years, bismuth compounds have been used for treating ulcers. Clinical investigations comparing the efficacy of CBS (also known as tripotassium dicitrato bismuthate (TDB)) with placebo (Lambert, Scandinavian Journal of Gastroenterology 26(Supplement 185): 13-21, 1991), cimetidine (Bianchi, et al., Lancet 2:698, 1984), and ranitidine (Bianchi et al., Gut. 25:565, 1984; Lee et al., Lancet 1:1299-1301, 1985; and Dobrilla et al., Gut. 29:181-187, 1988) in initial healing and relapse rates of duodenal ulcers, have shown significantly lower relapse rates in patients treated with CBS. The therapeutic efficacy of CBS (and other bismuth compounds), in healing duodenal ulcers and lowering relapse rates, is attributed to its specific antibacterial activity against H. pylori (McNutty et al., Antimicrobial Agents Chemotherapy 28:837-838, 1985; Lambert et al., Antimicrob. Agents Chemotherapy 3:510-511, 1986; and Goodwin et al., J. of Antimicrobial Agents Chemotherapy 17:309-314, 1986). The minimum inhibitory concentration (MIC) for CBS against H. pylori is reported to be 8 mg/L (Lambert et al., Antimicrob. Agents Chemotherapy 3:510-511) and the range is 4-32 mg/L (Lambert et al., Antimicrob. Agents Chemotherapy 3:510-511).

In addition to its bacteriocidal activity, CBS has been demonstrated to enhance mucus glycoprotein secretion, strengthen viscoelastic gel properties of mucus, cause increased concentration of epithelial growth factor (EGF) in ulcer tissue, and stimulate prostaglandin synthesis in the gastric antral mucosa (Lee, Scandinavian Journal of Gastroenterology 26(Supplement 185): 1-6, 1991). These gastroprotective properties of CBS may contribute to the initial healing of duodenal ulcers and the observed lower rates of relapse by returning the gastric mucosal cells to normal physiologic function. The gastroprotective effects of CBS in prevention of gastric lesions induced by various ulcerogenic agents and the mechanism of ulcer healing have been demonstrated in animal studies (Konturek et al., Digestion 37(Supplement 2):8-15, 1987 and Konturek et al., Scandinavian Journal of Gastroenterology 21 (Supplement 122):6-10, 1986).

Because of the finding that bismuth is an effective antibacterial agent against H. pylori, concomitant dosages of bismuth-containing compounds with other anti-ulcer drugs have been increasingly applied in many clinical cases for treatment of peptic ulcers. The most commonly used regiments include double or triple therapy with bismuth; meanwhile, some recent reports regarding quadruple therapy (wherein a proton pump inhibitor is added to triple therapy) have shown eradication rates of over 90%, but also cause severe side effects such as vomiting and diarrhea.

Additionally, while antibacterial therapy (bismuth and amoxycillin or doxycycline) was shown to be effective in eliminating H. pylori from the gastric mucosa of duodenal ulcer patients, this therapy had no effect on the H. pylori colonies in their dental plaque (Desa