Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Bacteria or actinomycetales
Reexamination Certificate
1998-07-09
2001-01-30
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Bacteria or actinomycetales
Reexamination Certificate
active
06180100
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to bacterial compositions and methods employing said compositions for treating or preventing urinary tract infections. More particularly, this invention relates to the ability of strains of lactobacilli to adhere to uroepithelial or vaginal epithelial cells and associated mucous and to produce an inhibitor against the growth of pathogenic bacteria.
It is well known that indigenous, non-pathogenic bacteria predominate on epithelial cells and associated mucus in the healthy state, and that pathogenic organisms predominate in the stages leading to and during infections. The possibility that indigenous bacteria have a role in preventing infection has been postulated for many years, but few studies have been carried out to identify specific bacteria and their properties required for such an effect.
Urinary tract infections (UTI) are a common cause of illness in both pre- and post-menopausal women. In fact, researchers have estimated that between 10 and 20% of females will develop a UTI during life. In the great majority of these women the infecting organisms originate in the bowel and colonize the perineum, vagina, urethra and bladder in a sequential manner. The majority of infections are caused by
Escherichia coli.
The remaining infections are caused by a variety of bacteria are caused by a variety of bacteria, including
Staphylococcus saprophyticus, Proteus mirabilis,
Klebsiella spp.,
Pseudomonas aeruginosa,
enterococci and Staphylococcus
For the treatment of many lower urinary tract infections, antibiotic therapy is prescribed. It is recognized, however, that the balance of normal microflora in the urogenital tract, which is disrupted by infection, is further upset by the prolonged use of antimicrobial compounds. (Ohashi H. 1982
Kansenshogaku Zasshi,
56:647-654). Accordingly an alternate treatment for urinary tract infections is desirable.
U.S. Pat. No. 4,314,995 to Hata et al. investigated anaerobic, lactobacilli-like organisms as a means of treating a number of infectious diseases, but no consideration was given to the combined importance of bacterial adherence, competitive exclusion and inhibitor activity, and no discussion was included of the treatment of urinary tract infections.
U.S. Pat. No. 4,347,240 to Mutai et al. discloses a composition and method employing a specific strain of lactobacilli to inhibit tumor growth.
SUMMARY OF THE INVENTION
The present invention provides a method for the treatment or prevention of urinary tract infections of mammals including humans which comprises administering a safe and effective amount of one or more lactobacillus viable whole cells, non-viable whole cells, cell wall fragments or inhibitory substances. The lactobacillus is of one or more species of lactobacillus which adheres to uroepithelial or vaginal epithelial cells.
The preferred strains of lactobacilli within the scope of this invention are aerobic and microaerophilic isolates which particularly after growth in urine and in brain heart infusion yeast extract medium:
a) adhere to uroepithelial or vaginal epithelial cells,
b) competitively exclude pathogenic bacteria from adhering to uroepithelial or vaginal epithelial cells,
c) produce an inhibitor activity against the growth of pathogenic bacteria.
Also defined within the present invention are compositions suitable for treating or preventing urinary tract infections of mammals including humans which comprise one or more lactobacillus viable whole cells, non-viable whole cells, cell wall fragments or inhibitory substances and a pharmaceutically acceptable carrier, wherein the lactobacillus is of one or more species of lactobacillus which adheres to uroepithelial or vaginal epithelial cells.
PREFERRED EMBODIMENTS
In a preferred aspect, the lactobacillus is aerobically or microaerophilically grown and may be selected from the group consisting of
Lactobacillus casei, L. acidophilus, L. plantarum, L. fermentum, L. brevis, L. jensenii
and
L. crispatus.
More specifically, the lactobacillus may be aerobically grown and is selected from the group consisting of
Lactobacillus casei
var
rhamnosus
GR-1 (ATCC. 55826),
L. casei
var
rhamnosus
GR-2 (ATCC. 55915)
L. casei
var
rhamnosus
GR-3 (ATCC. 55917),
L. casei
var
rhamnosus
GR-4 (ATCC. 55916),
L. casei
var
rhamnosus
RC-9,
L. casei
var
rhamnosus
RC-17 (ATCC. 55825),
L. casei
var
alactosus
RC-21,
L. casei
NRC 430 and
L. casei
ATCC 7469.
Alternatively, the lactobacillus may be microaerophilically grown and selected from the group consisting of
L. rhamnosus
RC-12(ATCC 55895),
L. acidophilus
RC-25,
L. plantarum
RC-19,
L. jensenii
RC-11 (ATCC. 55920),
L. acidophilus
ATCC 4357,
L. plantarum
ATCC 8014,
L. fermentum
A-60, and
L. fermentum
B-54 (ATCC. 55884).
In a preferred form of the present invention, the lactobacillus is selected to be substantially resistant to spermicide. Details are provided hereinbelow.
In another aspect of this invention, a pharmaceutical composition is provided for treating or preventing urinary tract infections in humans and lower animals which comprises a safe and effective amount of one or more of the said aforementioned lactobacilli, cell wall fragments or inhibitory substances with a pharmaceutically acceptable carrier.
Although this invention is not intended to be limited to any particular mode of application, intravaginal, intraurethral or periurethral installation of the compositions are preferred. The compositions may be installed in the form of a cream, liquid, paste, gel or suppository as desired. One preferred form is a cream formulation comprising one or more lactobacillus viable whole cells, non-viable whole cells, cell wall fragments or inhibitory substances in a jelly base, preferably a K-jelly base. Another preferred form of application involves the preparation of a freeze-dried capsule comprising the composition of the present invention. It has been found that a capsule comprising 10
9
organisms is suitable.
By “safe and effective amount” as used herein is meant an amount of lactobacillus high enough to significantly-positively modify the condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of lactobacillus will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, and the specific lactobacillus employed. We have found that at least 10 lactobacilli, and preferably 20 to 30, and more preferably more than 40 said bacteria adhered to epithelial cells are desired. The effective amount of lactobacillus will thus be the minimum amount which will provide the desired attachment to epithelial cells. The presence of 5×10
9
bacteria, as viable or non-viable whole cells, in 0.05 ml. solution of phosphate buffered saline solution, or in 0.05 ml. of suspension of agar, or the dry weight equivalent of cell wall fragments, has been found effective when administered in quantities of from about 0.05 ml. to about 20 ml.
By “pharmaceutically-acceptable carrier” as used herein is meant one or more compatible solid or liquid filler diluents, or encapsulating substances. By “compatible” as used herein is meant that the components of the composition are capable of being comingled without interacting in a manner which would substantially decrease the pharmaceutical efficacy of the total composition under ordinary use situations.
Some examples of substances which can serve as pharmaceutical carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethycellulose, ethylcellulose and cellulose acetates; powdered tragancanth; malt; gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil, sesame oil, olive oil, corn oil and oil of theo
Bruce Andrew W.
Reid Gregor
Scully Scott Murphy & Presser
Urex Biotech., Inc.
Witz Jean C.
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