MXPA00002262A - Vaginal suppository vaccine for urogenital infections - Google Patents

Abstract

This invention is directed to a suppository-based vaccine delivery system for immunizing against urogenital infectious disease in humans and a method for treating same. More particularly, this invention is directed to a suppository-based vaccine delivery system for the prophylaxis against urogenital infectious diseases, such as urinary tract infections. The suppository-based vaccine delivery system is comprised of a vaccine comprised of inactivated bacteria which originate from cultures of 8 to 14 uropathogenic bacteria strains of species:Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptococcus faecalis;and polyethylene glycol suppository base;wherein the suppository is adapted to be inserted into a bodily orifice of a human so as to allow the suppository to be in contact with tissue of the bodily orifice to facilitate transfer of suppository material therethrough.

Description

VACCINATION BASED ON A VAGINAL SUPPOSITORY FOR UROGENITAL INFECTIONS Field of the Invention The present invention relates generally to a system and to a method for treating infections in humans, specifically a prophylactic treatment of urogenital infections in humans. More particularly, the invention relates to an intravaginal vaccine delivery system, based on a suppository for the prophylaxis against urinary tract infections in humans, where the suppository is comprised of a vaccine derived from complete or fractionated pathogenic microorganisms. Even more particularly, the present invention relates to a delivery system based on a suppository for the prophylaxis against recurrent infections of the urinary tract in humans, where the suppository is comprised of a vaccine of complete, inactivated bacteria, which originate from 4 to 20 uropathogenic bacterial strains isolated from the urine of people suffering from urinary tract infections, and which includes a polyethylene glycol suppository base. tr • i Background of the Invention Urinary tract infections are a major problem in medicine. Each part of the urinary tract is affected. The most common forms of the disease are: cystitis, urethral syndrome, pyelitis and pyelonephritis. A tendency for recurrent and chronic progress is the characteristic of urinary tract infections. Diseases are ten times more common in women than in men. This difference must ^ * 10 mainly due to the fact that the particular anatomy of the female urethra favors infections by the body's own bacterial intestinal flora. The main diagnostic criterion for urinary tract infections is bacteriuria, the presence of bacteria in appropriately collected urine samples (medium flow urine). For bacteriuria to be considered significant for diagnosis, it must exceed a concentration of 105 bacteria per milliliter of urine. Bacteria that reach the urinary tract 20 establish the infection either through the blood flow or ascending from the urethra to the bladder and then out through the ureter to the kidneys. Descending infection is the most common mode and explains the most frequent occurrence in women. The position of the urethral ostium and the short urethra in women favor infection. Several bacteria that originate from the fecal flora are always resident in the urethral ostium and in the distal part of the female urethra. Urinary tract infections in women begin when one of the Enterobacteriaceae derived from fecal flora colonizes the vaginal vestibule. The most frequent and most abundant constituent of fecal flora is Escherichia coli, which is also frequently found in urine as the causative organism of urinary tract infections. The Escherichia coli is also usually found in the periurethral region. This bacterium is able to bind to cells of the periurethral epithelium. Bacterial adherence is the precondition for colonization and infection of the urinary tract. Many studies in vi tro have shown that the phenomenon of adherence is due to the possession of pili by Escherichia coli that infects the urinary tract. Escherichia coli bacteria are the most frequent causative agents of urinary tract infections. The urinary tract can also be colonized by other Enterobacteria, such as Proteus and Klebsiella, and gram positive cocci such as Staphylococcus and Streptococcus faecalis (Enterococcus). Other bacteria such as Pseudomonas aeruginesa and Haemophilus infl uenzae can also invade the urinary tract. Any of the bacteria that inhabit the intestinal tract that are eliminated in the faeces can populate the urinary tract. In addition, the human urinary tract can be colonized by mycoplasmas, the L forms of bacteria, chlamydia, fungi, viruses and protozoa. Recurrence and chronic nature are characteristics of urinary tract infections. Recurrence may be due to relapse or reinfection. Despite the great progress in the treatment of other bacterial infections, the morbidity and mortality of urinary tract infections remain unchanged in the last 20 to 25 years. The reasons for this are thousands and depend on the host organism and microbial factors. Recurrence of infections with a strain of a previous infecting organism is rare and can result from the wrong choice of drug, emergence of resistant strains, insufficient treatment duration, insufficient concentration of antibacterial agents, the existence of bacterial L forms, and the survival of organisms in urinary stones. Recurrent urinary tract infections in women are essentially all infections with different organisms and generally with strains that have a greater ability to adhere to the epithelial cells of the vagina and urethra. The reinfectant bacteria originate in the intestinal flora. The composition of the intestinal flora can be altered by the prophylactic and therapeutic use of antibiotics and other antibacterial materials that are used in the treatment and prophylaxis of urinary tract infections. The intestinal flora often develops resistance to antibiotics and the resistant bacteria can then cause a reinfection or primary opportunistic infection of the urinary tract. Such primary infections may be due to opportunistic germs that result from the non-dangerous, normal flora, such as labtobaelli, which are washed away by antibiotics. Other microbes, resistant to antibiotics, can now flourish and become pathogenic. Bacterial resistance to antibiotics caused by plasmids R is not only transferred between the same species of bacteria, but is also transmitted to almost all En terbacteriaceae. Multiresistance is also common. The main cause of recurrent urinary tract infections in women is an immunological effect which facilitates the adhesion of uropathogenic organisms to the periurethral region. Studies have revealed that low levels of secreted urinary IgA (slgA) in the urine indicate a defective local immune response of the urinary tract and favor recurrent urinary tract infections.

• The most important property of the slgA is that it prevents the interaction of the bacterial pili with the specific receptors found on the urinary tract epithelium. The adhesiveness mediated by the pili is an important virulence factor of the bacteria involved. For the defense against infection it is important to reduce the adhesion of the pathogens to the urothelium or to prevent the bacteria from binding to each other. Normally, host organisms form specific local antibodies against the invading bacteria and secrete these antibodies as slgA. In patients with persistent urinary tract infections or who frequently relapse this natural mechanism of local immunological defense against infection • is apparently disturbed. Therefore, the increase of immune defenses is a rationale measure for eliminate the cause of recurrent urinary tract infections. A vaccine that stimulates the production of antibodies to a spectrum of antigens that are present in various types of Escherichia coli and other urinary bacteria commonly found is particularly appropriate.

Previously, vaccines against urinary tract infections have been administered parenterally and have resulted in a greater • resistance against urinary tract infections.

The parenteral administration of SOLCOUROVAC®, a vaccine against urinary tract infections manufactured by Soleo Basel AG, Basel Switzerland and described in the patent No. 4,606,919, the content of which is incorporated herein by reference, decreases infections ^ 10 of the urinary tract after hysterectomy, a reduced frequency of infections in susceptible women, and an increase in slgA. However, some patients suffered from side effects such as malaise, fever and muscle pain. The vaccine oral consisting of immunostimulatory fractions extracted from strains of Escherichia coli decreases bacteriuria, septic episodes, • antibiotics in patients with spinal cord damage, and the incidence of recurrent tract infections urinary in adult women. As with parenteral administration, many patients suffer from adverse reactions. In an attempt to overcome the shortcomings associated with parenteral and oral administrations of the vaccine against urinary tract infections, an intravaginal vaccine against urinary tract infections was proposed. The reason for administering a vaccine against urinary tract infections intravaginally was that there is a mucous immune system where the antigens are adsorbed through the surfaces of the mucous membranes and processed by specialized local lymphoid tissues, after which the antibodies are secreted on the local mucosal surfaces. As discussed above, in the genitourinary tract, temporary or partial deficiencies in vaginal or local urinary antibodies are an important factor in the highlighted susceptibility to urinary tract infections shown in some women. Immunization via mucosal surfaces within the genitourinary tract is preferably by parenteral or oral routes, since it has been found that vaccination via the intravaginal surface creates a secretory immune response in the urogenital tract. In the past, vaccines against urinary tract infections were administered vaginally in the form of a liquid vaccine. Several problems were associated with the intravaginal administration of liquid vaccines against urinary tract infections. The main problem encountered was that the liquid vaccine flowed out of the vagina immediately after insertion. This severely limits the amount of time that the liquid antigens are in contact with the mucosal surface of the vagina, decreasing the • effectiveness of the vaccine. The antigens need sufficient contact with the vaginal mucous membrane to produce a secretory response of immunoglobulin. Patients receiving the vaccine were required to be in the supine or relaxed position for a prolonged period of time after receiving the vaccine. • 10 prevent the vaccine from flowing immediately out of the vagina. However, often the vaccine still accumulated outside the vagina after the period of time in the supine position, limits the effectiveness of the vaccine. 15 In addition, the requirement that patients be in a supine position for a long time after receiving the vaccine is annoying for the patient. Patients can receive several vaccines during the course of treatment and patients should invest a considerable amount of time after each immobile vaccine. Therefore, it is clear that improvements in prophylaxis against urogenital infectious diseases, such as urinary tract infections and vaccines against urinary tract infections.

The object of the invention overcomes the above and other limitations, and teaches a suppository-based vaccine delivery system for prophylaxis against infectious diseases such as the urogenital, the urinary tract infections.

Brief Description of the Invention In accordance with the present invention, a vaccine delivery system based on 9 ^ 10 a suppository administered vaginally for prophylaxis against urogenital infectious diseases, such as urinary tract infections. In addition in accordance with the present invention, a vaccine delivery system based on a suppository for prophylaxis against urogenital infectious diseases, such as urinary tract infections, where the vaccine is in contact with the • vaginal mucous membrane for a sufficient period of time to increase the immune response. Still further in accordance with the present invention, a suppository-based vaccine delivery system is provided for the prophylaxis against urogenital infectious diseases, such as urinary tract infections, where the vaccine is administered easily, does not require that the patient be in the supine position for a prolonged period of time and after receiving the vaccine, and is administered in an adequate manner by the patient for the primary and routine reinforcement requirements. Still more in accordance with the present invention, there is provided a vaccine delivery system based on a suppository for prophylaxis against urogenital infectious diseases, such as snapshots of the urinary tract in humans, the suppository comprising: a vaccine comprised of inactivated bacteria which originate from cultures of 8 to 14 strains of uropathogenic bacteria isolated from the urine of people suffering from urinary tract infection of the species: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis, and are present in an amount of approximately 50 million to approximately 5 billion germs of each strain per suppository, where of. half to three quarters of the strains used belong to species of Escherichia coli; and polyethylene glycol suppository base; wherein the suppository is adapted to be inserted vaginally to allow the suppository to be in contact with the vaginal mucous membrane to facilitate the transfer of the suppository material therethrough.

An advantage of the present invention is that it provides a suppository-based vaccine delivery system for prophylaxis against urogenital infectious diseases, such as urinary tract infections, where the vaccine is in contact with the vaginal mucous membrane for a period of time. enough time to increase the immune response. Another advantage of the present invention is that it provides a vaccine delivery system based on a suppository for prophylaxis against urogenital infectious diseases, such as urinary tract infections, where the vaccine is administered easily, and does not require the patient to be in a supine position for a prolonged period of time after receiving the vaccine. Another advantage of the present invention is that it provides a vaccine delivery system based on a suppository where the vaccine is adequately administered by the patient. Another advantage of the present invention is that it provides a vaccine delivery system based on a suppository, where administration of the vaccine is relatively painless. Another advantage of the present invention is that it provides a vaccine delivery system based on a suppository where slgA - the specific stimulus of mucosal vaccination allows immune responses to specifically prevent bacterial colonization from occurring, instead of fighting the infection a Once colonization has occurred. Yet another advantage of the present invention is that it provides a vaccine delivery system based on a suppository where the patient can periodically self-administer booster vaccines. The other advantages of the invention will become apparent to those skilled in the art upon reading and understanding the following detailed description, the accompanying drawings and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS The invention may take physical form in certain parts and arrangements of parts, a preferred embodiment and a method of which will be described in detail in this specification and illustrated in the accompanying drawings which form part thereof. , and where: Figure 1 is a graph that illustrates the percentage of patients who remained free of infection during the course of the test.

Detailed Description of the Preferred Modality This invention is directed to a vaccine delivery system based on a suppository for immunizing against infectious diseases in humans and a method for treating them. More particularly, this invention is directed to a vaccine delivery system based on a suppository for prophylaxis against urogenital infectious diseases, such as urinary tract infections. The vaccine system is based on a suppository comprised of a vaccine comprised of inactivated bacteria originates from 8 to 14 strains of uropathogenic bacteria of the species: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis, and polyethylene glycol suppository base; wherein the suppository is adapted to be inserted in a human body orifice, to allow the suppository to be in contact with the tissue of the body orifice to facilitate the transfer of the suppository material therethrough. The suppository is comprised of a vaccine comprised of inactivated bacteria which originate from 8 to 14 strains of uropathogenic bacteria of the species: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis. The inactivated bacteria are present in an amount of approximately 50 million to approximately 5 billion germs of each strain per suppository and from half to three quarters of the strains used belong to the species of Escherichia coli. Preferably, the inactive bacteria originate from 6 strains of Escherichia coli species and 1 each of Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis. In a preferred embodiment, the inactive bacteria are present in a total amount of lxlO 9 to about lxlO 10 germs. The suppository is comprised of a vaccine which is prepared according to the method described in U.S. Patent No. 4,606,919, which is incorporated herein by reference in its entirety. The vaccine is prepared by cultivating, on an appropriate nutrient medium, each of the 8 to 14 strains of uropathogenic bacteria mentioned above which have been isolated from the urine of persons suffering from a urinary tract infection, and when conclude the culture, removing the particular biological material formed and inactivating it by known methods, mixing quantities of the bacteria obtained from the individual strains with others and diluting the mixture with a quantity of sterile isotonic solution so that they are present of approximately 50 million 5 trillion germs of each strain per suppository. Urine samples (medium flow urine) were first isolated from people suffering from a urinary tract infection and immediately inoculated on a MacCon ey agar; After inoculation, the agar plates were incubated at 37 ° C for 6 to 19 hours and the colonies formed were then isolated and identified for the determination of their biochemical and biological properties. The colonies identified in this manner were allowed to grow one more on agar plates at 37 ° C during 24 hours and then they were suspended in physiological saline solution, tested to determine their purity by means of Gram stain and lyophilized. To prepare the vaccines, the strains were cultured individually on a solid or liquid nutrient medium; it is preferable to use a solid nutrient medium, for example nutrient agar such as Difco Nutrient Agar. The medium was sterilized at 121 ° C for 15 minutes and had a pH of about 7.2. Roux bottles were used for large-scale preparation, and Petri dishes were used for laboratory preparation. The inoculation was carried out with the inoculum material, a few milliliters of which were uniformly distributed over the entire surface. The Roux bottles were closed with • cotton plugs and the medium was stored with the surface inoculated in the bottom. The inoculated cultures were incubated at 37 ° C for 24 hours. Bacterial turfs were rinsed with a required amount (depending on the growth density of the culture in the container) of buffer of phosphate / saline with gentle agitation, without damaging the agar surface. A smear was obtained from each bottle or each Petri dish, stained by the Gram method and tested to determine its purity. The bottles or Petri dishes that appeared to be contaminated were discarded. The suspensions that originated from a strain and the harvest were poured together through a sterile nylon gauze. Inactivation just like the crop itself, takes place individually for each strain. This can be carried out by heating to a temperature of about 55 ° C to about 60 ° C for about one hour, by treatment with formaldehyde solution by irradiation with? -rays. Due to its simplicity, heat inactivation is required. The quantities obtained by the culture are combined and inactivated in a water bath at 60 ° C for one hour, and phenol is added after inactivation. • The content of the standard vessel 5 (inactivated suspension originating from a strain) is centrifuged at 3,000 rpm for 1 hour and centrifuged in the cold, the supernatant liquid is removed and the bacterial sediment is suspended in saline with a content of 0.01%. thimerosal. The suppository of • The present invention is comprised of any suitable polyethylene glycol suppository base known in the art. More particularly, the polyethylene glycol suppository base is comprised of polyethylene glycol and polysorbate. From Preferably, the polyethylene glycol suppository base is comprised of about 98% by weight of polyethylene glycol and about 2% by weight of • polysorbate. Preferably, the polyethylene glycol has an average molecular weight of about ,000 to 5000. In a more preferred embodiment, the polyethylene glycol suppository base is comprised of approximately 39% by weight of polyethylene glycol having a molecular weight of 8,000 and 59% by weight of polyethylene glycol having a molecular weight of 400 A suitable commercially available polyethylene glycol suppository base is POLIBASE, manufactured by Paddock Laboratories, Inc. The polyethylene glycol suppository base • is present in the vaccine delivery system 5 based on a suppository in any suitable amount to allow the vaccine to be in contact with the vaginal mucous membrane for a sufficient period of time to increase the immune response. Preferably, the polyethylene glycol suppository base • 10 comprises from about 80% to 95% by weight of the suppository. The suppository base of polyethylene glycol confers a degree of miscibility with the surfaces of the mucous membrane of the vagina, where the suspended particles of the vaccine are in contact with such surfaces of the mucous membrane for a sufficient period of time to produce a secretory response of immunoglobin. The polyethylene glycol suppository base has an adjuvant effect that increases the immune response allowing the vaccine to facilitate the time of contact with the membranes of the vaginal mucosa, serving as a deposit that slowly releases antigen, and localizing and releasing antigens to immunocompetent cells. The polyethylene glycol suppository base also functions as a structural need which keeps the suppository in its molded shape.

The suppository is inserted into a laminated suppository liner, which forms a molded body. The suppository is stored in the • coating until it is used. The laminated suppository liner 5 is any coating known in the art suitable for packaging suppositories. The coating of the suppository must be able to withstand temperatures of 60 ° C used in the manufacture of suppositories and temperatures of 4 ° C for the • 10 long-term storage without compromising the integrity of the mold or reacting with the suppository in an unfavorable manner. Preferably, the laminated suppository coating is a coating for suppositories laminated with chloride of polyvinyl-polyethylene. A suitable commercially available laminate suppository liner is a polyvinyl chloride-polyethylene chloride laminate suppository manufactured by Paddoc Laboratories, Inc. 20 'The vaccine system based on a suitable suppository further comprises depolarized gelatin. Depolarized gelatin is any suitable depolarized gelatin known in the art. An example of suitable depolarized gelatin materials is include, but are not limited to Type A or B gelatin of bovine or porcine collagen. Preferably, the depolarized gelatin is Type A gelatin. The depolarized gelatin serves to protect the components during lyophilization. The depolarized gelatin is present in the suppository in any suitable amount. More particularly, the suppository is comprised from about 0.01% to about 0.02% by weight of depolarized gelatin. The vaccine system based on a suppository suitably comprises thimerosal as well. Thimerosal is an antimicrobial preservative. A suitable commercially available thimerosal is available from Sigma Chemical Co. The erosion is present in the suppository in any suitable amount. More particularly, the suppository is comprised from about 0.0005% to about 0.005% by weight of thimerosal. The vaccine delivery system based on a suppository of the present invention is prepared under an aseptically sterile laminar flow hood. The polyethylene glycol suppository base is heated to a temperature of about 80 ° C so that the polyethylene glycol is liquefied. The polyethylene glycol suppository base is heated for about 1 hour. The vaccine comprised of 8 to 14 strains of lyophilized and inactivated uropathogenic bacteria is placed in a flask. A portion of the liquid suppository base is cooled to 60 ° C and poured into 5 individual flasks containing the vaccine. The vaccine and liquid suppository base are agitated for about 10 minutes at a temperature of about 60 ° C forming a homogeneous suspension comprised of the suppository base and the vaccine. The suspension is included in the suppository base and the vaccine is placed in individual laminate suppositories. An additional amount of liquid suppository base is added to the flask containing vaccine residues. The suppository base and vaccine are shaken for about 1 hour at a temperature of 60 ° C to form a homogeneous suspension. This suspension is added to the coating • for laminated suppositories. Pure liquid suppository base is added to the top of the laminated suppository liner until the liner is filled. The suppository is cooled to a temperature of about 24 ° C allowing the base of the suppository to harden. This method ensures that the materials of the active vaccine are located in the bottom of 67% of the suppository where they are protected from cracking or exfoliation that can occur at the tip of the suppository when the coatings are opened for use. • The present invention is further exemplified 5 in the following example. The example illustrates the effectiveness of the vaccine delivery system based on a suppository of the present invention. It should be understood that the example is only illustrative of the preferred embodiments according to the present invention, wherein the claims set forth the scope of the present invention.

EXAMPLE A vaccine release system was prepared based on a suppository comprised of a vaccine comprised of inactivated bacteria which originates from 8 to 14 strains of uropathogenic bacteria • isolated from the urine of people suffering from a urinary tract infection of the species: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis, and are present in an amount of approximately 50 million to approximately 5 billion germs of each strain per suppository, where from half to three quarts of the strains used belong to Escherichia coli species; and polyethylene glycol suppository base. The POLIBASE, a polyethylene glycol suppository base manufactured by Paddock Laboratories, Inc., was heated at a temperature of 80 ° C for about one hour to liquefy the suppository base. A lyophilized SOLCOUROVAC® vaccine manufactured by Soleo Basel AG was aseptically placed in a sterile Erlenmeyer flask, sufficient to manufacture 50 suppositories. Each suppository will have from about lxlO9 to about lx1010 germs. The liquid suppository base was cooled to about 60 ° C and about 100 ml of liquid suppository base were poured into individual flasks containing the vaccine. A sterile magnetic stirrer was placed in the flask, and the vaccine and suppository were shaken for about 10 minutes at about 60 ° C in a temperature controlled water bath to form a homogeneous suspension. The suspension comprised of the suppository base and the vaccine was placed in individual polyvinyl chloride-polyethylene chloride suppositories using a sterile pipette. Approximately 2.0 ml of suspension was placed in each coating.

Approximately 25 ml of liquid suppository base was added to the flask, which contained vaccine residues. The suppository base and vaccine were shaken for about 1 minute at a temperature of about 60 ° C to form a homogeneous suspension. Approximately 0.5 ml of this suspension was added to each coating to fill the coating. The suppository base was cooled and cooled to a temperature of about 24 ° C during ^ r 10 about 30 minutes to harden the suppository base. The suppositories were then stored at 4 ° C. Ninety-one female patients, aged 18 to 82 years, participated in the suppository test.

All patients had more than two urinary tract infections during the last year and all had an evaluation that consisted of excretory urography or renal ultrasound and cystoscopy. They did complete blood count, blood chemistry studies, urinalysis and culture, and specular vaginal examination was performed on the patients before testing the suppository. Patients were advised not to become pregnant during the test and had to have a negative urine pregnancy test before the test.

The 91 patients were divided into three treatment groups. Group 1 received suppositories containing approximately lx109 germs per suppository. Group 2 received suppositories containing approximately 2xl09 germs per suppository. Group 3 received suppositories which did not contain the vaccine. The three groups of patients did not differ in average age, hysterectomy status, sexual activity, or being in antibiotic prophylaxis during weeks 0-4. Of the 91 patients, 44 of those who were on antibiotic prophylaxis at the start of the trial continued to take antibiotics until 2 weeks after the installation of the third suppository. The remaining 47 were out of prophylactic regimens during the test. The characteristics of the patients were compared statistically with the exact two-tailed Fisher test and one-way ANOVA from Kruskal-allis. Such tests are fully explained in the Programs and Systems of Programming SAS / STAT, Changes and Improvements, Ed. 6.07, Cary, SAS Institute, Inc., p. 620, 1993. Most infections were documented by urinary culture and sensitivity, and treated for 3 days with full doses of conventional antibiotics. Episodes of typical bladder irritation symptoms that respond rapidly to antibiotics available at home, but not verified by urine culture, were also counted as recurrent infections and were analyzed in the same manner. Changes in antibody levels during the course were compared by ANOVA of repeated measurements for unbalanced data. The patients did not discontinue the treatment due to adverse reactions. One patient complained of a f 10 episode of dizziness after returning home from the first vaccine, but received the second and third vaccines without eventuality and according to the program. Three other patients reported minor vaginal irritation after insertion of the suppository but were able to complete the regimen of three suppositories without interruption. There were no other reports of episodes of strong vagina discharge, interference with the sexual course, or signs and symptoms of bacterial vaginosis. The analysis of all 91 patients did not show 20 different clinical courses between the placebo and treated groups. This lack of treatment effect was due to the fact that both patients with placebo and with antibiotic prophylaxis vaccine during the first 4 weeks of the study experienced a significant initial delay of time until the first reinfection. There was no significant difference in time to first infection for the low dose and high dose groups, so these data were combined in the vaccine efficacy analysis. Results 5 showed that the number of patients who did not experience infection for 8 weeks was significantly greater in the vaccine-treated groups than in those treated with placebo. In addition, the average time to first infection was delayed from 10 weeks to 8.7 weeks in immunized patients. Figure 1 is a graph that illustrates the percentage of patients who remained free of infection during the test. The patients of Group 1 are represented by line 1. The patients of the Groups 2 and 3 are represented by the solid line. The delivery system based on a suppository according to the present invention allows the vaccine to be in contact with the vaginal mucous membrane for a sufficient period of time for increase the immune response. In addition, the delivery system based on a vaccine according to the present invention is administered appropriately by the patient, pain-free, is sensitive to booster vaccination against urinary tract infections and allows a favorable method for the release of antigen to immunocompetent cells through the mucosa. Although several modalities have been described • a vaccine delivery system based on a suppository to treat urinary tract infections and a method for treating urinary tract infections in humans has been described, it should be understood that those skilled in the art will come up with modifications and adaptations thereof . Other features and aspects of this invention will be appreciated by those skilled in the art upon reading and understanding this description. Such characteristics, aspects and expected variations and modifications of the reported results and the examples are clearly Within the scope of the invention, wherein the invention is limited only by the scope of the following claims. It is noted that in relation to this date, the best method known to the applicant to carry In practice, said invention is the conventional one for the manufacture of the objects to which it refers.

Claims (29)

1. CLAIMS Having described the invention as above, • Property contained in the following 5 claims is claimed as property: 1. A vaccine delivery system based on a suppository for prophylaxis against urogenital infectious diseases, such suppository is characterized ^ P 10 because it comprises: (a) a vaccine comprised of inactivated bacteria which originate from cultures of 8 to 14 strains of bacteria uropathogenic species: Escherichia coli, Klebsiella pneumoniae, Proteus 15 mirabilis, Proteus morganii, and Streptoccus faecalis, and are present in an amount of approximately 50 million to approximately 5 billion germs. • each strain per milliliter, where from -to half to three quarters of the strains used belong to species of 20 Escher? Chia coli; and (b) polyethylene glycol suppository base; where the suppository is adapted to be inserted into a human body orifice to allow the suppository to be in contact with the 25 tissue of the body orifice to facilitate the transfer of the suppository material therethrough.
2. 2. A vaccine delivery system based on a suppository for the prophylaxis against infectious diseases of the urinary tract in humans, the suppository is characterized because it comprises: a vaccine comprised of inactivated bacteria which originate from cultures of 8 to 14 strains of bacteria uropathogens isolated from the urine of people suffering from urinary tract infection of the species: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis, and are present in an amount of approximately 50 million to approximately 5 billion germs of each strain by suppository, where from half to three quarters of the strains used belong to Escherichia coli species; and (b) polyethylene glycol suppository base; wherein the suppository is adapted to be inserted vaginally to allow the suppository to be in contact with the vaginal mucous membrane to facilitate the transfer of the suppository material therethrough.
3. 3. The vaccine delivery system based on a suppository according to claim 2, characterized in that the inactive bacteria originate from 6 strains of Escherichia coli species and 1 each of Klebsiella pneumoniae, Proteus mirabilis, Proteus • morganii, and Streptoccus faecalis.
4. 4. The vaccine delivery system based on a suppository according to claim 2, characterized in that the inactive bacteria are present in a total amount of lxlO 9 up to approximately lxlO 10 germs. • The vaccine delivery system based on a suppository according to claim 2, characterized in that the polyethylene glycol suppository base is comprised of polyethylene glycol and polysorbate. 6. The vaccine delivery system based on a suppository according to claim 5, characterized in that the suppository base of polyethylene glycol is comprised of approximately 98% by weight of polyethylene glycol and approximately 2% by weight of 20 polysorbate. 7. The vaccine delivery system based on a suppository according to claim 5, characterized in that the polyethylene glycol has an average molecular weight of 25 approximately 3000 to 5000. 8. The vaccine delivery system based on a suppository according to claim 5, characterized in that the polyethylene suppository base • glycol comprises from about 80% to 95% by weight of the 5 suppository. 9. The vaccine delivery system based on a suppository according to claim 2, characterized in that the suppository further comprises depolarized gelatin. • 10. The vaccine delivery system based on a suppository according to claim 9, characterized in that the depolarized gelatin is selected from the group consisting of bovine collagen type A gelatin, collagen type A gelatin 15 porcine, bovine collagen type B gelatin, and porcine collagen type A gelatin. 11. The vaccine delivery system based on a suppository according to claim 9, characterized in that the suppository is comprised of 20 about 0.01% to about 0.02% by weight of depolarized gelatin. 12. The vaccine delivery system based on a suppository according to claim 9, characterized in that the suppository is comprised of 25 in addition to thimerosal. 13. The vaccine delivery system based on a suppository according to claim 12, characterized in that the suppository is included • from approximately 0.0005% to approximately 0.005% 5 by weight of thimerosal. 14. A vaccine delivery system based on a suppository for prophylaxis against urinary tract infections in humans, the suppository is characterized in that it comprises: 10 (a) a vaccine comprised of inactivated bacteria which originate from 8 to 14 strains of uropathogenic bacteria isolated from the urine of people suffering from a urinary tract infection of the species: Escheri chia col i, Kl ebsi el la 15 pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecali s, and are present in an amount of approximately 50 million to approximately 5 billion germs of each strain per suppository, where from half to three quarters of The strains used belong to the species of Escheri chia col i, where inactive bacteria originate from 6 strains of Escheri chia coli species and 1 from each of Kl ebsi el la pneumonia e, Pro teus mirabilis, Proteus morganii, and Streptoccus faecalis, and Wherein the inactive bacteria are present in a total amount of lxlO 9 up to about lxlO 10 germs; and (b) polyethylene glycol suppository base, • where the polyethylene suppository base The glycol is comprised of about 98% by weight of polyethylene glycol and about 2% by weight of polysorbate, wherein the polyethylene glycol has an average molecular weight of about 3000 to 5000, and where the suppository base of polyethylene glycol is * 10 comprised from approximately 80% to approximately 95% by weight of the suppository; where the suppository is adapted to be inserted vaginally to allow the suppository to be in contact with the vaginal mucous membrane to facilitate the transfer of the 15 suppository material through it. 15. The vaccine delivery system based on a suppository according to claim 14, characterized in that the suppository is further comprised of depolarized gelatin and thimerosal, wherein the depolarized gelatin is selected from the group consisting of Type A collagen gelatin. bovine, porcine collagen type A gelatin, bovine collagen type B gelatin, and porcine collagen type A gelatin, where the suppository is comprised of from about 0.01% to about 0.02% by weight of depolarized gelatin, and where the suppository is comprised of from about 0.0005% up to about 0.005% by weight of thimerosal. 16. A vaccine delivery system based on a suppository, characterized in that it serves for prophylaxis against urinary tract infections in humans, such suppository results from the mixture of: (a) a vaccine comprised of inactivated bacteria which originate from 8 to 14 strains of uropathogenic bacteria isolated from the urine of persons suffering from a urinary tract infection of the species: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis, and are present in an amount of approximately 50 million to approximately 5 billion germs of each strain per suppository, where from half to three quarters of the strains used belong to the species of Escheri chia coli, where the inactive bacteria originate from 6 strains of Escheri chia coli species and 1 of each of Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis, and where the bacteria inacti are present in a total amount of lxlO9 up to approximately lxlO10 germs; and (b) polyethylene glycol suppository base, where the polyethylene glycol suppository base is comprised of approximately 98% by weight of polyethylene glycol and approximately 2% by weight of polysorbate, where the polyethylene glycol has an average molecular weight from about 3000 to 5000, and wherein the polyethylene glycol suppository base is comprised of from about 80% to about 90% by weight of the suppository; wherein the suppository is adapted to be inserted vaginally to allow the suppository to be in contact with the vaginal mucous membrane to facilitate the transfer of the suppository material therethrough. 17. A method for preventing urogenital disease in humans, the method is characterized in that it comprises the steps of: (a) inserting a suppository-based vaccine delivery system into a human orifice of a human, where such a suppository is comprised of a vaccine comprised of inactivated bacteria which originate from cultures of 8 to 14 strains of uropathogenic bacteria of the species: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis, and are present in an amount of approximately 50 million up to approximately 5 billion germs of each strain per suppository, where from half to three quarters of the strains used belong to species of Escheri chia coli; and the polyethylene glycol suppository base; and (b) contacting the suppository with the tissue of the human orifice to facilitate the transfer of the suppository material therethrough and induce an immune response in the human. 18. A method for preventing urinary tract infections in humans, the method is characterized in that it comprises the steps of: (a) inserting a suppository-based vaccine delivery system into a human vagina, where such a suppository is comprised of a vaccine comprised of inactivated bacteria which originate from cultures of 8 to 14 strains of uropathogenic bacteria of the species: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis, and are present in an amount of approximately 50 million up to approximately 5 billion germs of each strain per suppository, where from half to three quarters of the strains used belong to Escheri chia coli species; and the polyethylene glycol suppository base; and (b) contacting the suppository with the tissue of the human orifice to facilitate the transfer of the suppository material therethrough and induce an immune response in the human. 19. The method according to claim 18, characterized in that the inactive bacteria originate from 6 strains of Escherichia coli species and 1 each of Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, and Streptoccus faecalis. 20. The method according to claim 18, characterized in that the inactive bacteria are present in a total amount of lxlO9 up to about lxlO10 germs. The method according to claim 18, characterized in that the polyethylene glycol suppository base is comprised of polyethylene glycol and polysorbate. The method according to claim 21, characterized in that the polyethylene glycol suppository base is comprised of about 98% by weight of polyethylene glycol and about 2% by weight of polysorbate. 23. The method according to claim 21, characterized in that the polyethylene glycol has an average molecular weight of about 3000 to 5000. 24. The method according to claim 18, characterized in that the polyethylene glycol suppository base comprises from about 80% to 95% by weight of the suppository. 25. The method according to claim 18, characterized in that the suppository further comprises depolarized gelatin. 26. The method according to claim 25, characterized in that the gelatin f & 10 depolarized is selected from the group consisting of Type A gelatin of bovine collagen, porcine collagen type A gelatin, bovine collagen type B gelatin, and porcine collagen type A gelatin. 27. The method according to claim 25, characterized in that the suppository is comprised of from about 0.01% to about 0.02% by weight of depolarized gelatin. • 28. The method according to claim 18, characterized in that the suppository 20 is comprised of in addition to thimerosal. 29. The method according to claim 28, characterized in that the suppository is comprised of from about 0.0005% to about 0.005% by weight of thimerosal.