Treatment of mucosal membranes Number:7,087,249 from the United States Patent and Trademark Office (PTO) owispatent The invention relates to the use of one or more antimicrobial metals preferably selected from silver, gold, platinum, and palladium but most preferably silver, formed with atomic disorder, and preferably in a nanocrystalline form, for reducing inflammation or infection of the mucosal membrane. The antimicrobial metal may be formulated as, or used in the form of, a nanocrystalline coating of one or more antimicrobial or noble metals, a nanocrystalline powder of one or more antimicrobial or noble metals, or a liquid or solution containing dissolved species from a nanocrystalline powder or coating of one or more antimicrobial or noble metals.<H membranes, Treatment, Treatment, of, mu, 7087249.html, Patent, pto, 7087249

Title: Treatment of mucosal membranes

Abstract: The invention relates to the use of one or more antimicrobial metals preferably selected from silver, gold, platinum, and palladium but most preferably silver, formed with atomic disorder, and preferably in a nanocrystalline form, for reducing inflammation or infection of the mucosal membrane. The antimicrobial metal may be formulated as, or used in the form of, a nanocrystalline coating of one or more antimicrobial or noble metals, a nanocrystalline powder of one or more antimicrobial or noble metals, or a liquid or solution containing dissolved species from a nanocrystalline powder or coating of one or more antimicrobial or noble metals.

Patent Number: 7,087,249 Issued on 08/08/2006 to Burrell, et al.

Inventors: Burrell; Robert Edward (Sherwood Park, CA), Naylor; Antony George (Sherwood Park, CA), Moxham; Peter Howard (Sherwood Park, CA)
Assignee: Nucryst Pharmaceuticals Corp. (Alberta, CA)

Appl. No.: 10/131,509

Filed: April 23, 2002

Current U.S. Class: 424/618 ; 424/400; 424/402; 424/404; 424/405; 424/433; 424/434; 424/435; 424/436; 424/443; 424/457; 424/458; 424/468; 424/469; 424/489; 424/490; 424/617; 424/619; 424/646; 424/649; 424/DIG.15; 514/184; 514/492; 514/495; 514/826; 514/849; 514/851; 514/853; 514/882; 514/886; 514/887; 514/900; 514/901; 514/902; 514/912; 514/914; 514/925; 514/931; 514/932; 514/933; 514/934; 514/951; 514/953; 514/954; 514/956; 514/958; 514/964; 514/965; 514/966; 514/967; 514/968; 514/969

Current International Class: A61K 9/00 (20060101); A61K 31/28 (20060101); A61K 31/282 (20060101); A61K 33/24 (20060101); A61K 33/38 (20060101); A61K 9/02 (20060101); A61K 9/14 (20060101); A61K 9/70 (20060101); A61K 9/72 (20060101); A61P 11/00 (20060101)

Field of Search: 424/400,402,404,405,433-436,443,457,458,468,469,489,490,617-619,646,649,DIG.15 514/184,492,495,826,849,851,853,882,886,887,900-902,912,914,925,931-934,951,953,954,956,958,964,965-969,825

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Primary Examiner: Pak; John
Attorney, Agent or Firm: Fish & Richardson P.C.

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part of co-pending U.S. patent application Ser. No. 09/840,637 filed Apr. 23, 2001. This application also claims priority from U.S. Provisional Patent Application No. 60/285,884, filed Apr. 23, 2001. To the extent that they are consistent herewith, the aforementioned applications are incorporated herein by reference.

Claims

We claim:

1. A method of reducing inflammation or infection of a mucosal membrane, comprising: contacting an inflamed or infected problem area of the mucosal membrane with a therapeutically effective amount of one or more antimicrobial metals in nanocrystalline form to provide a localized anti-inflammatory or antimicrobial effect, wherein the one or more antimicrobial metals are selected from the group consisting of silver, gold, platinum and palladium and characterized by sufficient atomic disorder so that the metal, in contact with an alcohol or water-based electrolyte, releases atoms, ions, molecules, or clusters of said metal on a sustainable basis and at a concentration sufficient to provide a localized anti-inflammatory or antimicrobial effect.

2. The method of claim 1, wherein the one or more antimicrobial metals provide a localized antimicrobial effect.

3. The method of claim 2, wherein the mucosal membrane is one or more of the oral cavity, the nasal, bronchial, pulmonary, trachea and pharynx airways, the otic and ophthalmic surfaces, the urogenital system, the reproductive system, and the gastrointestinal tract.

4. The method of claim 2, wherein the mucosal membrane is the oral cavity, the nasal, bronchial, pulmonary, trachea and pharynx airways, the urogenital system, the reproductive system, or the gastrointestinal tract.

5. The method of claim 2, wherein the mucosal membrane is the prostate, the colon or rectal surfaces.

6. The method of claim 1, wherein the antimicrobial metal is nanocrystalline silver.

7. The method of claim 1, wherein the antimicrobial metal is nanocrystalline silver, formed as a composite with oxygen.

8. The method of claim 1, wherein the antimicrobial metal is delivered as a powder, aerosol, spray, mist to the oral cavity, or to an area of the nasal, bronchial, pulmonary, trachea or pharynx airways to a respiratory disorder.

9. The method of claim 8, wherein the antimicrobial metal is nanocrystalline silver delivered as an aerosol, wherein the aerosol has a droplet size which is less than 10 .mu.m, and wherein the concentration of silver in the aerosol is in the range of 40 to 500 .mu.g/ml.

10. The method of claim 9, wherein the aerosol does not contain particulates sized larger than 2 .mu.m.

11. The method of claim 10, wherein the aerosol does not contain particulates sized larger than 1 .mu.m.

12. The method of claim 1, wherein the one or more antimicrobial metals are provided as a coating on, or filler in, a dressing, substrate or patch, or in a pharmaceutical composition with one or more pharmaceutically acceptable carriers suitable for application to the mucosal membrane.

13. The method of claim 12, wherein the pharmaceutical composition includes a nanocrystalline powder of the one or more antimicrobial metals, or a liquid containing dissolved species from a nanocrystalline powder or coating of the one or more antimicrobial metals.

14. The method of claim 13, wherein the pharmaceutical composition is a one or more of a gel, cream, lotion, paste, ointment, foam, suppository, lozenge, gum, tablet, capsule, or wafer containing the antimicrobial metal powder in an amount of 0.01-10% by weight, or one or more of a liquid formulated as a topical solution, aerosol, instillation, infusion, spray, mist, drops, syrup, elixir, mouth wash, or retention enema containing 0.001-10% by weight of the antimicrobial metal.

15. The method of claim 14, wherein the mucosal membrane is contacted to treat a respiratory disorder, a disease or condition of the oral cavity, a gastrointesinal disorder, a nasal disorder, or a disorder of the urogenital or reproductive system.

16. The method of claim 15, wherein the antimicrobial metal is nanocrystalline silver.

17. The method of claim 15, wherein the antimicrobial metal is silver, formed as a composite with oxygen.

18. The method of claim 12, wherein the dressing or pharmaceutical composition is fixed in place or occluded with an occlusive or semi-occlusive layer which maintains the dressing or composition in a moist condition.

19. The method of claim 12, wherein the one or more antimicrobial metals are provided in a hydrated or hydrocolloid-containing dressing, or in a pharmaceutical composition with one or more hydrocolloids.

20. The method of claim 19, wherein the hydrocolloid is one or more of cellulose and derivatives thereof, starch, glycogen, gelatin, pectin, alginate, chitosan, chitin, gum arabic, locust bean gum, karaya gum, gum tragacanth, ghatti gum, agar-agar, carrageenans, carob gum, guar gum, and xanthan gum.

21. The method of claim 20, wherein the hydrocolloid is one or more of carboxymethyl cellulose, alginate, pectin, and glyceryl polymethacrylate.

22. The method of claim 21, wherein the antimicrobial metal is nanocrystalline silver.

23. The method of claim 21, wherein the antimicrobial metal is nanocrystalline silver, formed as a composite with oxygen.

24. The method of claim 1, wherein the antimicrobial metal is in a powder form and is delivered directly to the mucosal membrane.

25. The method of claim 24, wherein the powder is sized with particulates no larger than 2 .mu.m.

26. The method of claim 25, wherein the powder is sized with particulates no larger than 1 .mu.m.

27. The method of claim 26, wherein the antimicrobial metal is nanocrystalline silver.

28. The method of claim 26, wherein the antimicrobial metal is nanocrystalline silver, formed as a composite with oxygen.

Description

FIELD OF THE INVENTION

The invention relates to the use of antimicrobial or noble metals for administration to mucosal membranes.

BACKGROUND OF THE INVENTION

Mucosal membranes are the epithelial membranes which line the oral cavity, the nasal, bronchial, pulmonary, trachea and pharynx airways, the otic and ophthalmic surfaces, the urogenital system, including the prostate, the reproductive system and the gastrointestinal tract including the colon and rectal surfaces. Mucosal membrane includes the surface membranes or cell structures of the mucosal membrane at a subject's targeted site. Mucosal membranes represent the first portal of entry for many diseases. Exemplary of important pathogens of viral (RNA or DNA viruses), bacterial (gram positive and gram negative, whether aerobic, facultative, or anaerobic), fungal, or algal origin (all of which are exemplary of sources of microbial infection of the mucosal membranes) are: Vibrio cholerae, enterotoxigenic Escherichia coli, Rotavirus, Clostridium difficile, Shigella species, Salmonella typhi, parainfluenza virus, influenza virus, Streptococcus pneumoniae, Borellia burgdorferi, HIV, Streptococcus mutans, Plasmodium falciparum, Staphylococcus aureus, Pseudomonas aeruginosa, rabies virus, Epstein-Barr virus, Herpes simplex virus, type I and II.

Mucosal membranes are also the subject of many disorders and diseases which are not strictly microbial in nature, for instance cystic fibrosis, prostatitis and digestive disorders.

Particular problems arise in treating patients suffering from microbial infections, disorders or diseases of the mucosal membrane when the patient is allergic to a form of treatment such as an allergy to all or particular antibiotics.

In general, additional therapies for infections, diseases or disorders of the mucosal membranes are still needed.

SUMMARY OF THE INVENTION

Methods of introducing atomic disorder into antimicrobial metals are taught by Burrell et al, in WO 93/23092, published Nov. 25, 1993, WO 95/13704, published May 26, 1995, and WO 9841095 published Sep. 24, 1998. Through research, the inventors have established that crystalline antimicrobial metals such as silver, formed with atomic disorder, are effective and safe antimicrobial agents against the microbes associated with infections of mucosal membranes. The inventors have further established through clinical observations, and in animal experiments, that antimicrobial or noble metals such as silver, formed with atomic disorder, reduce inflammation of mucosal membranes. This research has resulted in a new therapeutic treatment of mucosal membranes. This new treatment has advantages of fewer side effects, use for patients who cannot be treated with other antibiotics, and less chance of development of resistant bacteria. The antimicrobial metal is preferably formed with atomic disorder at the nanocrystalline level, that is with a very fine, nanocrystalline grain size.

Without being bound by the same, it is believed that the nanocrystalline antimicrobial metals formed with atomic disorder are capable of releasing highly active clusters of the antimicrobial metal (example clusters of Ag.sup.0 or Ag.sup.+/Ag.sup.0), which are responsible for the surprisingly enhanced antimicrobial activity and the surprising presence of the anti-inflammatory activity in the treatment of mucosal membranes, compared with other known antimicrobials such as silver salts (ex. silver nitrate), silver zeolites which release only Ag.sup.+, or silver metal and silver oxide which have only minor solubility. Clusters are known to be small groups of atoms, ions or the like, as described by R. P. Andres et al., "Research Opportunities on Cluster and Cluster-Assembled Materials", J. Mater. Res. Vol 4, No 3, 1989, p. 704. For silver, clusters are believed to contain less than the 14 atoms of a normal face centered cubic crystal lattice form of silver.

The invention thus may be used to deliver nanocrystalline antimicrobial or, more preferably, noble metals formed with atomic disorder across mucosal membranes including without limitation gastrointestinal epithelial tissue, lung epithelial tissue and other mucosal surfaces including oral surfaces, nasal surfaces, sinus surfaces, pharynx surfaces, tracheal surfaces, esophageal surfaces, vaginal surfaces, rectal surfaces, colon surfaces, otic and ophthalmic surfaces,

The invention also provides treatment for respiratory disorders, whether infectious, inflammatory or immunologic in origin, including without limitation emphysema, chronic bronchitis, asthma, pulmonary edema, acute respiratory distress syndrome, bronchopulmonary dysplasia, pulmonary fibrosis, pulmonary atelectasis, tuberculosis, pneumonia and cystic fibrosis, with the use of aerosols, mists or sprays of the nanocrystalline antimicrobial metals.

The invention also provides treatment for other disorders of mucosal membranes, including without limitation, prostatitis, sinusitis, digestive disorders, TENS (toxic epidermal necrolysis syndrome), Stevens Johnstone Syndrome, cystic fibrosis, bronchitis, pneumonia, pharyngitis, common cold, ear infection, sore throat, STD's (sexually transmitted diseases such as syphilis, gonorrhea, herpes, genital warts, HIV, and chlamydia), inflammatory bowel disease, colitis, hemorrhoids, thrush, dental, oral and periodontal disease such as gingivitis, dental caries, periodental inflammation and malodour.

Methods and formulations of this invention have application to both humans and animals.

One particularly preferred embodiment of the invention involves the treatment of respiratory disorders by the administration of the antimicrobial or noble metal as an aerosol, mist or spray, which can be generated by a nebulizer, or by delivering powders or solutions of the metal by inhalers. Another particularly preferred embodiment is the administration of the antimicrobial or noble metal as an instillation for such disorders as inflammatory bowel disease. The antimicrobial or noble metal may be administered alone, or with a carrier such as saline solutions, DMSO, an alcohol or water, most preferably water. An effective daily amount of the antimicrobial or noble metal will vary with the subject, but will be less than is toxic while still providing a therapeutic effect. An exemplary dose is from about 10 .mu.g/kg to about 50 mg/kg of body weight, more preferably 0.5-10 mg/kg.

The inventors have thus discovered that antimicrobial metals, preferably selected from one or more of silver, gold, platinum and palladium, are effective in the treatment of the mucosal membranes. These antimicrobial metals are formed with atomic disorder, such that ions, clusters, atoms or molecules of the metals are released at a concentration sufficient to provide a localized antimicrobial and anti-inflammatory effect. Most preferably, the antimicrobial or noble metals are in a nanocrystalline form, and include sufficient atomic disorder to provide an antimicrobial and anti-inflammatory effect on a sustainable basis.

The crystalline forms of these antimicrobial or noble metals may be used in, or formulated from, any of the following formats: 1. Coatings of the antimicrobial metals on medical grade substrates, for example, dressings, packings, meshes, films, filtering surfaces, filters, infusers, fibres such as dental floss or sutures, containers or vials, from materials composed of, for example, polyethylene, high density polyethylene, polyvinylchloride, latex, silicone, cotton, rayon, polyester, nylon, cellulose, acetate, carboxymethylcellulose, alginate, chitin, chitosan and hydrofibres; 2. Powders, preferably prepared as powders of the antimicrobial or noble metals (i.e., as free standing powders), or as coatings of the antimicrobial or noble metals on biocompatible substrates in powder form, preferably on hydrocolloids, bioabsorbable and/or hygroscopic substrates such as: Synthetic Bioabsorbable Polymers: for example polyesters/polyactones such as polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers, or Naturally Derived Polymers: Proteins: albumin, fibrin, collagen, elastin; Polysaccharides: chitosan, alginates, hyaluronic acid; and Biosynthetic Polyesters: 3-hydroxybutyrate polymers; 3. Occlusions or hydrated dressings, in which the dressing is impregnated with a powder or solution of the antimicrobial metals, or is used with a topical formulation of the antimicrobial metals, with such dressings for example as hydrocolloids, hydrogels, polyethylene, polyurethane, polvinylidine, siloxane or silicone dressings 4. Gels, formulated with powders or solutions of the antimicrobial or noble metals with such materials as hydrocolloid powders such as carboxymethylcellulose, alginate, chitin, chitosan and hydrofibres, together with such ingredients as preservatives, pectin and viscosity enhancers; 5. Creams, lotions, pastes, foams and ointments formulated with powders or solutions of the antimicrobial or noble metals, for example as emulsions or with drying emollients; 6. Liquids, formulated as solutions, dispersions, or suspensions, by dissolving coatings or powders of the antimicrobial or noble metals, for example as topical solutions, aerosols, mists, sprays, drops, infusions and instillation solutions for body cavities and tubes such as the bladder, prostate, perintheal, pericharcliar, pleural, intestinal and ailimentary canal; 7. Formulations suitable for administration to the nasal membranes, the oral cavity or to the gastrointestinal tract, formulated with powders or liquids of the antimicrobial or noble metal in such forms as lozenges, toothpastes, gels, powders, coated dental implants, dental floss or tape, chewing gum, wafers, mouth washes or rinses, drops, sprays, elixirs, syrups, tablets, or capsules; 8. Formulations suitable for vaginal or rectal administration formulated with powders or liquids of the antimicrobial or noble metal in such forms as suppositories, dressings, packings, tampons, creams, gels, ointments, pastes, foams, sprays, and solutions for retention enemas or instillations.

Solutions of the antimicrobial or noble metals may lose some activity with aging and are thus either stabilized or generated fresh for administration. Alternatively, the antimicrobial or noble metals may be packaged for convenient solution generation, for instance in a pervious membrane such as a tea bag-type infusers. Other two part systems or two phase may be used in which the metal coating or powder is separated from any liquid carrier or hydrating agents, for example packaging the components in kit form, with the antimicrobial metal being provided in dissolving capsules, as a coating on the inside of vials or containers, on substrates such as dressings, separated by a membrane which can be perforated, or in a separate container from the carrier etc.

In the above formats, the antimicrobial or noble metals are thus formulated from coatings or powders of the antimicrobial or noble metals, or from solutions prepared by dissolving the coatings or powders therein. The formulations include a therapeutically effective amount of the coatings or powders, and most preferably, the following amounts:

TABLE-US-00001 For coatings: 150-30