Recently, public attention to the area of personal hygiene has increased for a variety of reasons. One reason is the growing awareness that a majority of microbial pathogens (bacteria, fungi, yeast, molds and viruses) that cause disease in the human body gain access through various portals of entry (e.g., eyes, ears, nose, mouth), and that these microorganisms are generally introduced into these portals by the hands. In addition to this, various types of microorganisms that cause infections of the nail and skin are also acquired by direct contact with contaminated surfaces, both organic and inorganic, in the environment. It is therefore logical to conclude that a large number of illnesses may be prevented by the decontamination of the skin and hands, and of the major portal of entry into the body--the mouth.
It has been shown that at least 18% of the world population is afflicted with a microbial infection of the nail plate. Although such infections are more prevalent in third-world countries, there is also a substantial incidence of the infections in developed countries where personal hygiene standards are already high. Research has determined that the factors that constitute a predisposition to contracting such infections include a longer lifespan, increased therapies with antineoplastic agents, and a continually growing population of immunocompromised individuals. Historic treatment of these infections has had limited success; furthermore, physicians are reluctant to treat what has been generally perceived as merely a cosmetic disfiguration with a systemic medication.
Several studies have shown that infections of the nail cause a serious emotional and psychological impact on the affected individual. Patients with onychomycosis have lower ratings for mental and physical health, self esteem, social functioning, and for work-related activities than do their healthy, unafflicted counterparts. The economic impact of nail infections is great: in the 1989 fiscal year, Medicare claims alone totaled greater than 43 million dollars. Lubeck, D. P. Patrick, D. L. McNulty, P, Fifer, S. K., and Birnbaum, J. 1993. "Quality of life of persons with onychomycosis", Quality of Life Research. 2: 341-348.
Microbial infections of the nail are caused by many types of microorganisms. Importantly, nail infections often are the result of a microbial infection of the skin of the hand or foot. Dermal infections, such as body tineas, can spread to cause the much more pernicious conditions of onychia, paronychia, and onychomycosis (nail fungus). Therefore, it has been noted that effective treatments of such infections should also include proper preventative measures, namely, thorough sanitization of the skin of the hands and feet.
Treatment of the nail plate has historically included mechanical avulsion or chemical destruction, followed by application of topical or systemic antifungal agents. Examples of these types of medicaments are listed in Table I.
TABLE I ______________________________________ Antimicrobial Agents for skin and/or nail infections Generic Product Manufacturer ______________________________________ A. Dermatophyte infections Application Topical: Amorolfine Loceryl Roche Econazole-nitrate Spectazole Ortho-McNeill Naftifine Naftin Herbert Labs Oxiconazole Oxistat Glaxo-Wellcome Sulconazole Exelderm Westwood-Squibb Terbinafine Lamisil Novartis Tolnaftate Tinactin Schering-Plough Undecylinic acid Desinex Pharmacraft Gordochrom Gordon Labs Oral: Griseofulvin Fulvicin Schering-Plough Terbinafine Lamisil Novartis B. Yeast infections Application Topical: Nystatin Mycostatin Westwood-Squibb C. Dermatophyte, yeast and bacterial infections Application Topical: Ciclopirox Loprox Hoechst-Roussel olamine Clotrimazole Lotrimin Schering-Plough Econazole-nitrate Spectazole Ortho-McNeill Haloprogin Halotex Westwood-Squibb Miconazole Micatin/ Ortho-McNeill Monistat Derm Fungoid Pedinol Tincture Benzalkonium Mycocide NS Woodward Labs chloride Mone Kenlor Industries D. (Saprophytes) Nondermatophytic filamentous opportunistic infections: cutaneous Application Topical: Amphotericin B Fungizone Bristol-Myers Squibb Ketoconazole Nizoral Janssen Benzalkonium Mycocide NS Woodward Labs chloride Mone Kenlor Industries Oral: Fluconazole Diflucan Roerig-Pfizer Itraconazole Sporanox Janssen E. Deep Mycotic infections: systemic Application Topical: Amphotericin B Fungizone Bristol-Myers Squibb Ketoconazole Nizoral Janssen Oral/IV: Fluconazole Diflucan Roerig-Pfizer Itraconazole Sporanox Janssen Amphotericin B Fungizone Bristol-Myers Squibb Ketoconazole Nizoral Janssen Flucytosine Ancobon Roche F. Actinomycetales Infections Anti- Amikacin Amikin Apothecon bacterial: Ampicillin Omnipen Wyeth-Ayerst Polycillin Apothecon Principen Apothecon Penicillin-G Bicillin Wyeth-Ayerst Wycillin Wyeth-Ayerst Tetracycline Doxycycline Leaderle Trimethoprim Bactrim Roche Sulfamethoxazole Septra Glaxo-Wellcome ______________________________________
Negative aspects associated with oral antifungal therapy for onychomycosis include their limited success rate, contraindications and drug interactions, toxicity, and the high cost of the medication. Furthermore, a general movement has begun in the scientific and medical communities away from the use of systemic antimicrobial therapy because the past indiscriminate and widespread use of broad-spectrum antibiotics has lead to an increase in the number of resistant strains of pathogenic microorganisms.
A variety of microorganisms are also present in the oral cavity. These range from the natural flora of the host to pathogenic species. Among these microorganisms are the gram-positive rods associated with the formation of plaque (a dense, enamel-adherant, microorganism-containing polysaccharide matrix). Even with good oral hygiene, it has been shown that microorganisms (including those responsible for plaque formation) rapidly build up in the oral cavity. Specific areas, including peridontal and subgingival spaces, and interpapillary spaces of the tongue present environments that that harbor bacteria. These species are difficult to reach by toothbrushing, and are only moderately affected by standard mouthwashes. The persistence of these microorganisms in such environments greatly increases the risk of calculus and plaque build up and carie formation, which in turn presents the danger of gingival inflammation and peridontal disease.
Although mouthwashes are standard in oral hygeine, they have generally been used to mask halitosis. Several mouthwashes that have been marketed for the reduction of bacteria and the prevention of plaque build up generally rely on a combination of alcohols (e.g. thymol, eucalyptol, ethanol; such as Listerine), or a combination of alcohols and a quaternary amine (e.g. ethanol, cetylpyridinium chloride; such as Scope) or other oral surfactants (see U.S. Pat. No. 4,657,758), or of alcohol and chlorhexidine digluconate (Peridex from Proctor and Gamble). However, the use of alcohol containing formulations tends to produce unpleasant side effects including pain and stinging of the oral mucosa, foul aftertaste and discoloration of teeth. Prior art attempts to address this issue have included the development of alcohol-free formulations, the active ingredients of which vary. Compositions have included the use of a cetylpyridinium chloride in the presence of an oral surfactant (Lander Alcohol Free Mouthwash from The Lander Company, Inc.) and the use of stabilized chlorine (RetarDent from Rowpar). Because stabilized chlorine molecules are inactivated by interaction with proteins found in the mouth, they are unable to penetrate the occult, non-surface environments inhabited by microorganisms (see above) making these types of alcohol-free formulations of limited efficacy. In addition to this, these formulations sting open sores or cuts in the mouth.
Microbicidal surfactants, such as quaternary ammonium compounds, have certain advantages over other types of microbicides, including a relatively low toxicity against mammalian cells, but high toxicity against a wide spectrum of microbial pathogens when used at relatively low concentrations via the topical route of administration. Quaternary ammonium compounds possess surface-active properties, detergency, and antimicrobial properties including antimicrobial activity against bacteria, fungi, and viruses. The quaternary ammonium compounds possess little, if any, odor and have little or no deleterious effects on synthetic materials, such as rubber, plastics, ceramics, and steel. Furthermore, these biocides are biodegradable, and are less tainting than phenols. They also do not present the tissue-staining problems associated with the use of iodine. These intrinsic properties of cationic surfactants (as represented by quaternary ammonium compounds) have resulted in their inclusion in a variety of applications, and in a high level of popularity among users. The largest areas of application of quaternary ammonium compounds are for sanitization, preservation and disinfection.
The antimicrobial properties and medical uses of formulations containing quaternary ammonium compounds (QACs) in general, and specifically the compounds benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, and cetylpyridinium chloride, have been the subject of lenghty study by several U.S. FDA Panels on Antimicrobials (43 FR 1210, 56 FR 33644). These studies evaluated both the safety and efficacy of the compounds. It has been theorized that the biocidal activity of QACs involves the cationic charge on the amine group. This charge is attracted to negatively-charged protein moieties on the cell membrane of the microorgansim, and facilitates the adhesion of the QACs to the surface of the microorganism. This adhesion to anionic moieties of surface proteins disrupts tertiary and quaternary protein structure, thereby inactivating the protein. Furthermore, the hydrophobic moiety or moities of the QACs are intercalated into the lipid bilayer of the cell membrane causing leakage of the intracellular fluids, eventually killing the microorganisms.
Cationic mineral and organic molecules present in hard water compete with these negatively-charged proteins and greatly limit the ability of QACs to adhere to the cell membrane. In addition to this, the chemical incompatibility of QACs with anionic soaps and anionic detergents has been noted as another limitation to the potential application of QACs. These chemical enviroments thereby reduce the overall antimicrobial efficacy of this class of compounds.
One of the most commonly used QACs is benzalkonium chloride (BAC). It exhibits in vitro and in vivo microbicidal activity across a wide range of concentrations in aqueous solution and in alcoholic solvents. Prior art formulations employ BAC (USP grade) at 0.13% concentration with water as a solvent as a disinfectant for hospital utensils, environmental surfaces, metal instrumentation, catheters, ampules and thermometers (ZEPHIRAN CHLORIDE, Winthrop-Breon Laboratories, New York, N.Y.), and in combination with anti-inflamatories and/or anesthetics, as a topical first aid antiseptic (Bactine, Johnson & Johnson), or at higher concentrations such as 1:250 (w/w; 0.4%) in applications such as disinfectant towelettes, and 1:25 (w/w; 4.0%) for certain surface cleaners.
It is known that the chemical entity known as BAC represents a mixture of N,N-dimethyl alkyl amines, which conform generally to the formula: ##STR1## where R represents an alkyl side chain that can vary from 2 to 22 carbon atoms in length. In particular, the greatest microbicidal activity is believed to reside in the homologs with the n-alkyl side chain length in the range of 10-17 carbons. However, it is necessary to mix homologs together such that the sum of the carbon atoms in the alkyl side chains (R.sub.1 +R.sub.2 +R.sub.3 +. . . R.sub.n).gtoreq.21-22 carbons in order to circumvent the activity-reducing effects of hard (cation containing) water. Accordingly, the United States Pharmacopaeia requires that the composition of commercially available BAC must be within the parameters of : EQU N--C.sub.12 H.sub.25 .gtoreq.40.0% of total EQU N--C.sub.14 H.sub.25 .gtoreq.20.0% of total EQU N--C.sub.12 H.sub.25 +N--C.sub.14 H.sub.25 .gtoreq.70.0% of total
This guideline has remained the industry standard since its inception in 1920-30, most likely due to the lack of development of an alternative system for the delivery of any single homolog as a discrete antimicrobial entity in antimicrobial applications. However, BAC mixtures of these species can contain an undefined set of BAC homologs, which may be present at concentrations as high as 30% of the total benzalkonium chloride species. Furthermore, the current methods of assay of N,N-dimethyl alkyl amines relies on the determination of the average alkyl side chain length of the mixture. Because of this, variation in lot-to-lot composition of BAC mixtures is possible, with the result that the antimicrobial effectiveness of the mixture and any reaction between the patient and the mixture may vary greatly, while the mixture still conforms to the USP specifications. From the above information it is apparent that an improvement over prior art uses of QACs, and BAC in particular, could be achieved if a delivery system could be developed that minimized the adverse effects to the activity of the QAC of hard water, anionic soaps, and anionic detergents, and dermal reactivity of susceptible patients. Likewise, all of the antimicrobial quaternary amine compositions, which, as does BAC, rely on the inclusion of inactive homologs for the preservation of activity in the presence of adverse environmental conditions, would benefit from such an invention.