Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2001-10-02
2003-03-18
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C514S967000
Reexamination Certificate
active
06534548
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the inhibition of exoprotein production from Gram positive bacteria. More particularly, the present invention relates to compositions comprising isoprenoid compounds and the effects of these compounds on Gram positive bacteria. The present invention also relates to methods of using these isoprenoid containing compositions.
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 fluid. 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 Streptococcus species, and Bacteroides species. Other microorganisms that have been isolated from the vagina on occasion include yeast (
Candida albicans
), protozoa (
Trichomonas vaginalis
), mycoplasma (
Mycoplasma hominis
), chlamydia (
Chlamydia trachomatis
), and viruses (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 effect 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 lactobacilli, corynebacterium, ureaplasma, and mycoplasma. Social and idiosyncratic factors include method of birth control, sexual practices, systemic disease (e.g., diabetes), and medications.
Bacterial proteins and metabolic products produced in the vagina can effect 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, bacteriocin-like products of lactobacilli directed against other species of lactobacilli.
Some microbial products produced in the vagina may negatively affect the human host. For example,
S. aureus
can produce and excrete into its environment a variety of exoproteins including enterotoxins, Toxic Shock Syndrome Toxin-1 (TSST-1), and enzymes such as proteases and lipase. When absorbed into the bloodstream of the host, TSST-1 may produce Toxic Shock Syndrome (TSS) in non-immune humans.
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 found to produce TSST-1. TSST-1 and some of the staphylococcal enterotoxins have been identified as causing TSS in humans.
Symptoms of Toxic Shock Syndrome generally include fever, diarrhea, vomiting and a rash followed by a rapid drop in blood pressure. Multiple organ failure occurs in approximately 6% of those who contract the disease.
S. aureus
does not initiate Toxic Shock Syndrome 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 TSST-1 toxin act systemically and produce the symptoms attributed to Toxic Shock Syndrome.
Menstrual fluid has a pH of about 7.3. During menses, the pH of the vagina moves toward neutral and can become slightly alkaline. This change permits microorganisms whose growth is inhibited by an acidic environment the opportunity to proliferate. For example,
S. aureus
is more frequently isolated from vaginal swabs during menstruation than from swabs collected between menstrual periods.
When
S. aureus
is present in an area of the human body that harbors a normal microbial population such as the vagina, it may be difficult to eradicate the
S. aureus
bacterium without harming members of the normal microbial flora required for a healthy vagina. Typically, antibiotics that kill
S. aureus
are not an option for use in catamenial products because of their effect on the normal vaginal microbial flora and their propensity to stimulate toxin production if all of the
S. aureus
are not killed. An alternative to eradication is technology designed to prevent or substantially reduce the bacterium's ability to produce toxins.
There have been numerous attempts to reduce or eliminate pathogenic microorganisms and menstrually occurring Toxic Shock Syndrome 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 menstrual tampon to detoxify toxin found in the vagina. Others have incorporated monoesters and diesters of polyhydric aliphatic alcohols, such as glycerol monolaurate, as biocidal compounds (see, e.g., U.S. Pat. No. 5,679,369). Still others have introduced other non-ionic surfactants, such as alkyl ethers, alkyl amines, and alkyl amides as detoxifying compounds (see, e.g., U.S. Pat. Nos. 5,685,872, 5,618,554, and 5,612,045).
Despite the aforementioned art, there continues to be a need for compositions and methods for using the compositions that will effectively inhibit the production of exoproteins, such as TSST-1, from Gram positive bacteria, and maintain activity even in the presence of the enzymes lipase and esterase which can have adverse effects on potency and which may also be present in the vagina. Further, it is desirable that the compositions useful in the inhibition of the production of exoproteins be substantially non-harmful to the natural flora found in the vaginal area.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that isoprenoid compounds, such as a terpene compound or terpenoid compound, are particularly effective for inhibiting the production of exoprotein(s) of Gram positive bacteria. The present invention relates to compositions incorporating these isoprenoid compounds and methods for using these isoprenoid-containing compositions to inhibiting the production of exoproteins from Gram positive bacteria.
It is a general object of the present invention to provide a composition for use in inhibiting the production of exoproteins from Gram positive bacteria. The compositions of the present invention are particularly useful for inhibiting the production of TSST-1, Enterotoxin B and alpha hemolysin from
S. aureus
bacteria. The compositions, which comprise one or more isoprenoid compounds as described herein and a pharmaceutically acceptable carrier, can be prepared and applied to a substrate or product in a variety of suitable forms, including without limitation, aqueous solutions, lotions, balms, gels, salves, ointments, boluses, suppositories, and the like. In one embodiment, the active isoprenoid compound of the composition can be formulated into a variety of vaginal cleaning formulations, such as those employed in current commercial douche formulations, or in higher viscosity douches.
Another object of the present invention is to provide methods for using the isoprenoid containing compositions of the present invention. The methods as described herein comprise exposing Gram positive bacteria to an effective amount of an iso
Proctor Richard A.
Syverson Rae Ellen
Kimberly--Clark Worldwide, Inc.
Weddington Kevin E.
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