Compositions for the inhibition of exoprotein production...

Cleaning compositions for solid surfaces – auxiliary compositions – Cleaning compositions or processes of preparing – For cleaning a specific substrate or removing a specific...

Reexamination Certificate

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C510S382000, C510S470000, C442S118000, C442S123000, C604S027000, C604S039000

Reexamination Certificate

active

06531435

ABSTRACT:

BACKGROUND
There exists in the female body a complex process which maintains the vagina and physiologically related areas in a healthy state. In a female between the age of menarche and menopause, the normal vagina provides an ecosystem for a variety of microorganisms. Bacteria are the predominant type of microorganism present in the vagina; most women harbor about 10
9
bacteria per gram of vaginal exudate. The bacterial flora of the vagina is comprised of both aerobic and anaerobic bacteria. The more commonly isolated bacteria are Lactobacillus species, corynebacteria,
Gardnerella vaginalis
, Staphylococcus species, Peptococcus species, aerobic and anaerobic Streptococcal species and Bacteroides species. Other microorganisms that have been isolated from the vagina on occasion include yeasts (e.g.,
Candida albicans
), protozoas (e.g.,
Trichomonas vaginalis
), mycoplasmas (e.g.,
Mycoplasma hominis
), chlamydias (e.g.,
Chlamydia trachomatis
) and viruses (e.g.,
Herpes simplex
). These latter organisms are generally associated with vaginitis or venereal disease, although they may be present in low numbers without causing symptoms.
Physiological, social and idiosyncratic factors affect the quantity and species of bacteria present in the vagina. Physiological factors include age, day of the menstrual cycle and pregnancy. For example, vaginal flora present in the vagina throughout the menstrual cycle can include Lactobacillus species, corynebacterium and mycoplasma. Social and idiosyncratic factors include method of birth control, sexual practices, systemic disease (e.g., diabetes) and medication.
Bacterial proteins and metabolic products produced in the vagina can affect other microorganisms and the human host. For example, the vagina between menstrual periods is mildly acidic having a pH ranging from about 3.8 to about 4.5. This pH range is generally considered the most favorable condition for the maintenance of normal flora. At that pH, the vagina normally harbors the numerous species of microorganisms in a balanced ecology, playing a beneficial role in providing protection and resistance to infection and makes the vagina inhospitable to some species of bacteria such as
Staphylococcus aureus
(
S. aureus
). The low pH is a consequence of the growth of lactobacilli and their production of acidic products. Microorganisms in the vagina can also produce antimicrobial compounds such as hydrogen peroxide and bactericides directed at other bacterial species. One example is the lactocins, products of lactobacilli directed against other species of lactobacilli.
Some microbial products may affect the human host. Menstrually occurring toxic shock syndrome (TSS), a severe and sometimes fatal multi-system disease, is associated with colonization by
S. aureus
. This disease has been associated with the use of tampons during menstruation. The disease is caused by Toxic Shock Syndrome Toxin-1 (TSST-1) and other staphylococcal enterotoxins.
S. aureus
can produce and excrete into its environment a variety of exoproteins including enterotoxins, TSST-1, and enzymes such as proteases and lipase.
S. aureus
is found in the vagina of approximately 16% of healthy women of menstrual age. Approximately 25% of the
S. aureus
isolated from the vagina are capable of producing TSST-1.
Symptoms of TSS generally include fever, diarrhea, vomiting and a rapid drop in blood pressure. A characteristic rash is usually present. Systemic vital organ failure occurs in approximately 6% of those who contact the disease.
S. aureus
does not initiate TSS as a result of the invasion of the microorganism into the vaginal cavity. Instead as
S. aureus
grows and multiplies, it can produce TSST-1. Only after entering the bloodstream does the TSST-1 act systemically and produce the symptoms attributed to TSS.
There have been numerous attempts to reduce or eliminate pathogenic microorganisms and menstrually occurring TSS by incorporating into a tampon pledget one or more biostatic, biocidal, and/or detoxifying compounds. For example, L-ascorbic acid has been applied to a catamenial tampon to detoxify toxin found in the vagina of the human female during menstruation.
Others have incorporated monoesters and diesters of polyhydric aliphatic alcohols and a fatty acid containing from 8 to 18 carbon atoms. For example, glycerol monolaurate (GML) has been used to retard the production of
S. aureus
enterotoxins and TSST-1. However, as noted above, esterase is abundantly present in the vaginal epithelium and menstrual fluid. This esterase, in combination with esterase and lipase produced by bacteria can enzymatically degrade the esters into non-effective compounds. Thus, one or more ester compounds may have to be added to the absorbent article, such as a tampon pledget, in such high concentrations that the normal flora present in the vaginal area is disrupted. When the natural condition is altered, overgrowth by pathogens may take place resulting in a condition known as vaginitis. The use of other non-ionic surfactants, such as alkyl ethers, alkyl amine and alkyl amides, has been reported as a means of avoiding the problem of degradation by esterase (see, e.g., U.S. Pat. Nos. 5,685,872; 5,618,554 and 5,612,045).
Many feminine hygiene and internal cleansing products are used by women mainly in liquid form. Many liquid vaginal douches are used to irrigate and cleanse the vagina and prevent vaginal infections, as well as for contraceptive reasons. Vaginal douche compositions may be prepared from a variety of substances. Vinegar is the most common substance used for cleansing the vaginal area. There is, however, insufficient evidence to conclusively establish that vinegar based compositions are effective in altering the vaginal pH for a sufficient length of time to encourage the growth of normal vaginal flora and discourage infections.
It has been reported that where either acidic or alkaline solutions were used daily as a douche, there were no overall changes in vaginal pH or the vaginal mucosa. It has also been reported that during the period of douching, the vaginal pH assumes the pH of the douche solution. Within 30 minutes after douching with an acidic solution, however, the vaginal pH actually becomes alkaline.
Accordingly, there continues to exist a need for agents that will effectively inhibit the production of exoproteins, such as TSST-1, from Gram positive bacteria. The material may be either in the form of an absorbent product that has the agent incorporated therein or in other forms, e.g., coated on a non-absorbent substrate or formulated with a pharmaceutically acceptable carrier. In particular, it would be advantageous to develop new vaginal cleansing compositions that incorporate an agent that will inhibit the production of exoproteins from Gram positive bacteria. Such agents desirably would be substantially unaffected by the enzymes lipase and esterase and, in addition, should not substantially alter the natural flora found in the vaginal area. The selection of compounds to inhibit the production of exoproteins is not so readily apparent, as some surface active compounds, such as block copolymers of propylene oxide and ethylene oxide, can stimulate toxin production by Gram positive bacteria.
SUMMARY
It has been found that alkyl polyglycoside compounds are particularly effective for inhibiting the production of exoprotein(s) of Gram positive bacteria. Exposure to effective amounts of the alkyl polyglycoside can inhibit the production of potentially harmful toxins, such as those produced by Staphylococcus and/or Streptococcal species. For example, the alkyl polyglycoside can be utilized to inhibit the production of TSST-1, alpha toxin and/or enterotoxins A, B and C from
S. aureus
. The alkyl polyglycoside typically has a hydrophilic/lipophilic balance (“HLB”) of at least about 10 and/or an average number of carbon atoms in the alkyl chain of 8 to 12. The alkyl polyglycoside may be used alone or in combination with one or more other surfactants (e.g., myreth-3-myristate, glycerol monolaurate and/or laureth-4) a

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