Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Bacteria or actinomycetales
Reexamination Certificate
1998-11-04
2001-08-21
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
06277370
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to the use of particular species of lactobacilli for preparing pharmaceutical compositions for treatment of vaginal infections, as well as to the pharmaceutical compositions thus prepared, and to methods of treating vaginal infections by administration of said compositions.
Normal vagina and normal uterine neck lodge a variety of bacteria assimilable to those of the gastrointestinal system. These bacteria are frequently involved in non-gonococcus infections of the feminine genital system (such as, for example: vulvovaginal abscesses and abscesses of Bartholin's (or greater vestibular) gland, endometritis, salpingitis, ovary abscesses and pelvic peritonitis).
In the progress of inflammatory pelvic diseases of non-venereal nature, often a mixture of anaerobic and aerobic bacteria is found; such a bacteria range may be responsible of infections after gynecological operations, childbirth, abortion, and has been correlated with use of intrauterine devices for preventing impregnation (IUD).
Bacterial vaginosis is the consequence of a bacterial interaction responsible of substitution at the vagina region of a great number of anaerobic bacteria including Bacteroides, Peptostreptococcus, Peptococcus, Mobiluncus
G. vaginalis,
for lactobacilli. This syndrome is characterized by a smelly although not particularly irritant secretion. There is only a slight itching and dyspareunia is exceptionally uncommon. Bacterial vaginosis is commonly diagnosed among women that have vaginal trouble, although 50% of women responding to diagnosis criteria for bacterial vaginosis are asymptomatic. Bacterial vaginosis is associated with sexual activity and increases as the number of sexual partners increases; however this affection is not considered as an exclusively sexual-transmission disease.
Although bacterial vaginosis is slightly troublesome, it may predispose to development of more serious infections of the genital system, in particular during pregnancy.
A diagnosis of bacterial vaginosis is given when three of the following four symptoms are encountered:
(1) a homogeneous non-inflammatory vaginal secretion, adhering to vagina walls;
(2) a vaginal fluid having pH greater than 4.5;
(3) indicator cells; and
(4) a nauseating smell of the vaginal secretion before or after addition of 10% potassium hydroxide (Whiff's test).
Vaginitis, on the contrary, is characterized by an abnormal vaginal secretion, local irritation and vulvar itch. The above are the symptoms of a local infection due to
T. vaginalis,
or Candida (above all
Candida albicans
). Vaginosis and symptomatic vaginitis are associated with diabetes, parathyroid insufficiency, altered defenses of the host organism, corticosteroid treatment, broad-spectrum antibiotic treatment, oral contraceptive drugs and pregnancy. Itch and secretion are the main symptoms of vaginitis due to Candida. Occasionally dyspareunia occurs. Vulva erythema and vulvovaginal thrush can be noticed. For a diagnosis of vaginitis due to Candida the presence of local symptoms is required because usually women can have Candida in the vagina without showing any trouble.
The results of recent studies have encouraged acknowledgment of the important role accomplished by lactobacilli in keeping a normal bacterial equilibrium within the dynamic ecosystems, such as vagina, and for prevention of genital infections caused by pathogenic organisms.
It is well known that many lactobacilli colonize the vagina of wealthy adult women. They propagate using as an energy source the glycogen secreted from the vaginal mucous membrane and compete with the pathogenic agents from the latter, so as to keep the vaginal lumen defended from the attack of other bacteria. Sulfonamides, antibiotics and disinfectant drugs have been mainly used for treatment of the above mentioned diseases (non-specific vaginitis, vaginosis and vulvar itch, for example). In particular, in the most recent years, with the development of many antibiotics, often antibiotic preparations have been administered to patients. Lactobacilli present in the vagina can succumb to administration of these antibiotics. Unfortunately, pathogenic bacteria (Staphylococcus, for example) can acquire a resistance to antibiotics and thus make it difficult to treat these diseases by administering antibiotics.
In U.S. Pat. No. 5,176,911 use of lactobacilli has been proposed in gynecology for treatment of vaginal infections.
This document refers to the following bacteria:
Lactobacillus casei, Lactobacillus gasseri, Lactobacillus fermentum, Lactobacillus casei
subs. pseudoplantarum and
Lactobacillus crispatus,
and suggests bacteria concentrations of 10
3
to 10
10
CFU/g, preferably of about 10
6
CFU/g.
However, all compositions exemplified in this document contain
Lactobacillus casei
and/or
Lactobacillus fermentum
as the essential components, at concentrations of 1×10
6
CFU/g. Therefore, practically this document teaches that
Lactobacillus casei
and/or
Lactobacillus fermentum
are essential components for preparing pharmaceutical compositions for treatment of vaginal infections and that these compositions are efficient at bacteria concentrations of 1×10
6
CFU/g (abbreviation “CFU” means “colony-forming unit”).
Pharmaceutical compositions of the known art, made in the form of pessaries or tablets for vaginal use, containing lactobacilli, are not sufficiently efficient in re-establishing the vagina colonization. It is further to note that an important proportion of the bacterial cells dies as a result of the physical impact given at the moment of preparation of pessaries and their number is further reduced when they diffuse in the vagina lumen and their propagation should begin.
Therefore, there is a need to dispose of appropriate species of lactobacilli, or mixtures thereof, and of pharmaceutical compositions containing them, which are free of the drawbacks of the known art compositions.
In particular there is need for pharmaceutical compositions for vaginal use having such good qualities that administration of same to a patient is really beneficial.
In addition, the pharmaceutical composition embodiments should be capable of maintaining the number of lactobacilli being propagated constant and ensuring a continuous and constant action in time of said lactobacilli during diffusion of same in the vaginal lumen.
The Applicants have found that lactobacilli-based pharmaceutical compositions greatly efficient for treatment of vaginal infections can be obtained, provided the following features can be met to the highest possible degree:
(a) the selected lactobacillus strain must have a high affinity towards the vaginal epithelium, i.e. a high capability of adhering to the epithelial cells of the vagina, in that this property enables bacteria interaction with the vagina mucosa under both physiological and pathological conditions (thus performing a competitive action with the pathogenic microorganisms in the epithelial receptor sites) and re-establishment of microflora and optimal pH conditions;
(b) at least one selected lactobacillus strain must have a high capability of producing hydrogen peroxide performing an inhibiting action addressed to the pathogenic microorganisms; and
(c) at least one selected lactobacillus strain must be characterized by a high capability of interfering in a competitive manner with adhesion of the
Candida albicans
to HeLa cells.
SUMMARY OF THE INVENTION
Therefore, it is an object of the present invention to provide lactobacilli-based pharmaceutical compositions meeting the above features to the highest possible degree, and therefore adapted to be efficiently employed for treatment of vaginal infections, such as vaginitis and vaginosis, for example. In this connection the Applicants have found that lactobacilli of the
Lactobacillus brevis
and
Lactobacillus salivarius
subs. salicinius species meet the whole of the above three features to a greatly higher degree than other lactobacillus species.
Another object of the present i
Cavaliere Ved. Vesely Renata Maria Anna
De Simone Claudio
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Witz Jean C.
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