WO2004060379A2 - Pharmaceutical compositions comprising an antibacterial agent nd antifungal agent and a nitroimidazole for the treatment and prevention of genitourinary infections and their extragenital complications - Google Patents
Pharmaceutical compositions comprising an antibacterial agent nd antifungal agent and a nitroimidazole for the treatment and prevention of genitourinary infections and their extragenital complications Download PDFInfo
- Publication number
- WO2004060379A2 WO2004060379A2 PCT/HU2003/000110 HU0300110W WO2004060379A2 WO 2004060379 A2 WO2004060379 A2 WO 2004060379A2 HU 0300110 W HU0300110 W HU 0300110W WO 2004060379 A2 WO2004060379 A2 WO 2004060379A2
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- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- nitroimidazole
- sulfonamide
- treatment
- antibacterial
- Prior art date
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- 238000011282 treatment Methods 0.000 title claims abstract description 72
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 30
- 239000003429 antifungal agent Substances 0.000 title claims abstract description 29
- 208000015181 infectious disease Diseases 0.000 title claims abstract description 18
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Definitions
- This invention relates to novel compositions and their uses in treatments as suppositories, especially vaginal suppositories, ointments, vaginal drops and talc powders, and painting solutions, or any form of the compositions useful for systemic treatment. Substitution of a nitroimidazole
- vaginal suppositories are currently commercially available for the treatment of various maladies.
- the attending physician ordinarily decides which composition is best suited to the patient's needs following physical examination.
- Canesten active ingredient is clotrimazol; bis-phenyl-(2-chlorophenyl)- l-(imidazolyl)- methane; and Pimafucin (the active ingredient is natamycin-primaricin) are most commonly used.
- Klion D the active ingredient is metronidazole; l-(2'-hydroxiethyl)-2-methyl-5-nitroimidazol and myconasol-nitrate
- Klion vaginal suppository active ingredient is metronidazole
- compositions exert their effects through the disinfective action of iodine.
- Betadine iodine is released from the carrier.
- Other vaginal suppositories feed the natural flora of the vagina. These include Genia 92 nutrients, e.g.:folic acid, lactic acid, lactose, and lactamine.
- a common disadvantage of the above compositions is that none of them makes possible the combination of the effects of (i) bactericide (for aerobe and anaerobe bacteria), involving anti-Mobiluncus and anti- Gardnerella, (ii) fungicide, and (iii) anti protozoa simultaneously. Moreover, they have no antiviral effect at all.
- the composition of the present invention includes an antibacterial agent, an antifungal agent effective against a Candida species, and a nitroimidazole, wherein the antibacterial agent, the antifungal agent, and the nitroimidazole are present in the composition in synergistic effective amounts.
- the composition of the present invention further includes a pharmaceutically acceptable carrier.
- the basis of the discovery according to the invention is that the effect of the antibacterial agent ingredient is unexpectedly intensified by the other active components of the present composition.
- the antibacterial effect particularly of chloramphenicol and sulfonamide, against Chlamydia trachomatis is greatly increased by the present compositions.
- an increased inhibitory effect of the antibacterial agent, particularly chloramphenicol and nitroimidazole, particularly metronidazole, components against anaerobe pathogens e.g. B. fragilis
- the antibacterial effect of the sulfonamide and/ or nitroimidazole also unexpectedly potantiated antibiotics generally against each pathogenic bacterium, in the antifungal protection provided by the antifungal agent.
- the antifungal agent or agents play a minor role in the synergistic effect.
- a further aspect and embodiment of the present invention provides for the inclusion of a sulfonamide in addition to another antibacterial agent, the antifungal agent, and the nitroimidazole, when present in a composition in synergistic effective amounts.
- another embodiment of the present invention comprises an antibacterial agent, a sulfonamide, an antifungal agent effective against a Candida species, and a nitroimidazole, wherein each of these components are present in a composition in synergistic effective amounts.
- the composition further includes a pharmaceutically acceptable carrier for obtaining a suitably deliverable medication to a patient. It has been observed through experimental data that the antibacterial effect of sulfonamide standing alone is greatly enhanced when coupled with the other ingredients of the present compositions. Therefore, such an unexpected increased effectiveness of sulfonamide when incorporated into
- compositions of the present invention forms an additional embodiment and aspect of the present invention.
- An additional aspect and embodiment of the present invention further supports the unexpected increased effectiveness of sulfonamide when combined with other active ingredients.
- the treatment spectrum is broader and the effect of the combination is much stronger than would be expected from its individual components, while simultaneously decreasing the necessary dosage for
- nitroimidazole and/ or sulfonamide component(s) probably causing apoptosis of the involved eukaryotic cells and by killing most of the prokaryotic cells. (Apoptosis-like additional effect ).
- the level of the mechanism of action is the same in the case of a nitroimidazole or a sulfonamide. Both of them act on transcriptional level.
- the present invention relates to novel compositions having synergistic effective amounts of one or more antibacterial agents, a nitroimidazole, and an antifungal agent effective against a Candida species.
- the antibacterial agents used in the present invention are also commonly referred to as antibiotics.
- the present invention contemplates the use of any antibiotic as defined by Martindale - The Extra Pharmacopoeia, 29 th Ed, London, The Pharmaceutical Press, 1989 (hereinafter "MARTINDALE").
- MARTINDALE Martindale - The Extra Pharmacopoeia, 29 th Ed, London, The Pharmaceutical Press, 1989
- the aminoglycosides, cephalosporins, penicillins, and polymyxins are generally bactericidal by this criterium whereas chloramphenicol, erythromycin, the sulfonamide s, and the tetracyclines are usually bacteriostatic.
- chloramphenicol, erythromycin, the sulfonamide s, and the tetracyclines are usually bacteriostatic.
- an antibiotic which is bactericidal in a certain concentration may become bacteriostatic at lower concentrations.
- antibiotics are classified into five classes based on chemical structure and mechanism of action in Chapter 43 of Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9 th Ed. (McGraw- Hill, 1996) (hereinafter "GOODMAN-GILMAN”). Such classes are set forth in Chapter 43,pages 1029- 1030 of GOODMAN-GILMAN. As described therein, the individual members of each class are interchangeable with one another since they act on the target microorganism in the same way, and in most cases are also chemically interrelated with one another.
- a sulfonamide for the particularly desirable antibiotic effect thereof when used in combination with the other components of the composition of the present invention.
- Any sulfonamide may be utilized in the composition of the present invention as all sulfonamides are structural analogs and competitive antagonists of para-aminobenzoic acid (see GOODMAN-GILMAN page 1058). Though all sulfonamides are interchangeable as applied to the composition of the present invention, a particularly preferred sulfonamide is sulfadimidin. In applications where a patient has an allergy to sulfonamides, it is preferred to formulate the composition of the present invention without inclusion of a sulfonamide.
- the antifungal agents utilized in the compositions of the present invention are preferably effective against Candida species (Candida albicans, Candida stelloidea, etc). Antifungal agents are divided into groups in GOODMAN-GILMAN, Chapter 49, pages 1 175- 1190,def ⁇ ning antifungal agents effective against Candida species which act only topically, and those agents effective against Candida species both systemically and topically.
- the antifungal agents effective against Candida species which act both systemically and topically are divided into the following subclasses: polyenes, azoles, and pyrimidines. According to GOODMAN-GILMAN, Chapter 49, members of each subclass are interchangeable, in that each member of a respective subclass exhibits similar chemical properties and functionalities. Characteristic representatives of the polyenes are natamycin and nystatin. A characteristic representative of the azole subclass is clotrimazole. A characteristic representative of the pyrimidine subclass is flucitozine.
- antifungal agents effective against Candida species are those antifungal agents which act only topically. Characteristic representatives of this subclass are ciclopirox olamine, naftifine, terbinafine, and haloprogin. Though the antifungal agents selected for use in the compositions of the present invention are preferably effective against Candida species, it is not necessary that such antifungal agents be effective solely against such Candida species. For example, particular selected antifungal agents of the present invention may be effective against a multiplicity of fungi.
- the nitroimidazole component of the compositions of the present invention further contribute to the unexpected increased efficacy of each component of the compositions.
- the mechanism of action of the nitroimidazoles is set forth in GOODMAN-GILMAN, page 996 as reflecting a selective toxicity to anaerobic or microaerophilic microorganisms.
- the members of the nitroimidazole group share a common functionality and are so closely related in structure so as to be interchangeable (see GOODMAN-GILMAN).
- Characteristic representatives of the nitroimidazole group are metronidazole and tinidazole.
- composition of the present invention includes:
- compositions of the present invention are polyethylene-glycol, but other suitable carriers may also be employed.
- the amount of polyaethylene-glycol supplements the combination of the active ingredients to the necessary amount in case of a 10 unit package.
- the essence of the present invention is the unexpected increased efficacy of the presently disclosed components when utilized in the compositions of the present invention, as contrasted with the minimal effectiveness of such components standing alone.
- compositions of the present invention are more effective and qualitatively different from the separate administration of the individual components.
- Such compositions are preferably contained and administered in the form of vaginal suppositories, ointments, vaginal drops, talc powders, and painting solutions.
- Administration of the present compositions has resulted in complete recovery in cases when recovery could not be reached by the separate administration of the components.
- compositions are useful in a variety of applications and treatments, including the following: Prophylactic Use.
- Use of the present compositions prevent infection from infected swimming-pool water or sexual activity.
- the compositions are indispensable prior to gynecological operations (especially utero-vaginal interventions) as a prophylactic suppository.
- Treatment of infection For infections, use of a preparation containing a composition of the present invention results in absolute recovery in 90% of the cases. Since systemic treatment is not needed, a smaller dose is administered. Cessation of treatment results in side effects disappearing (for local treatments there were no side effects observed). Resistance of the pathogens against the components used is also obviated because in local treatment the relatively small amount of preparation applied absolutely kills the pathogens.
- compositions of the present invention promote the spontaneous healing of the bleeding, inflamed portion of the uterus. As a result, the above -de scribed invasive conventional treatments become unnecessary. Constant inflammation plays a decisive role in the formation of cancer of the cervix of the uterus.
- Application of the compositions according to the invention greatly diminishes the risk of the formation of the cancer of the cervix of the uterus, by stopping the inflammation.
- Nitroimidazole has certain anticancer effects, which are observed during the radiation treatment of the tumors, where it increases the efficacy of the radiation treatment.
- sulfonamides display anti-tumor characteristics as well(see Supuran CT et al. Carbonic Anhidrase Inhibitors: Sulfonamides as Antitumor Agents? Biorg .Med.Chem., March, 2001, 9(13):703-714).
- Ascending infections such as Cystitis, PID, etc.
- Ascending infections are typically caused by the same microbes as are in the vagina.
- the systemic application of the present combinations unexpectedly shorten the usual duration of treatment.
- complications of the inflammation can be vascular damage anywhere in the body (e.g. atherosclerosis and the connected diseases(see Ross, R. Mechanism of disease: Atherosclerosis - an inflammatory disease. N.Engl.J.Med.1999, 2: 115- 126.), neovascularisation, etc..
- L5 Chronic inflammation has been shown to be an important risk factor for a variety of epithelial cancers, including those of the esophagus, stomach, pancreas, liver, biliary tract, colon, vulva and bladder (see Stephen E.Hawes, Nancy B.Kiviat. (editorials) Are Genital Infections and Inflammation Cofactors in the Pathogenesis of Invasive Cervical Cancer?, Journal of the »0 National Cancer Institute 2002, 94: 1592-1593).
- the present combination acts against viral infections, possibly by killing all non viral pathogens, enhancing the immunocapacity of the body against the viruses.
- the preparation according to the invention can also be administered to pregnant women to prevent adverse pregnancy outcome (and probably toxaemias of pregnancy too ).
- erythromycin is the preferred antibacterial agent component.
- compositions according to the invention were tested on 300-400 cases, with 300-400 controls. In all cases, the full microbiological examination included Chlamydia trachomatis and the Mycoplasmas.
- compositions according to the invention can be carried out by methods known in the art for the preparation of such compositions.
- the following experimental results demonstrate the unexpected efficacy of the compositions of the present invention, and set forth examplary compositions indicative of the many possible species combinations useful in the treatment of various maladies.
- the examples will serve to further typify the nature of the invention, but should not be construed as a limitation on the scope thereof, which is defined solely by the appended claims.
- Ciprofloxacin 0.04g
- Neomycin 0.1 Og
- Clotrimazole 0.10g
- Ciprofloxacin 750 mg/day (500mg + 250mg)
- Ketoconazole 400 mg/day (200mg + 200mg)
- Tinidazole 1000 mg/day (500mg + 500mg)
- Ciprofloxacin 750 mg/day (500mg + 250mg)
- Ketoconazole 400 mg/day (200mg + 200mg)
- Tinidazole 1000 mg/day (500mg + 500mg)
- Completely treated 8 Remained the same : 1
- compositions demonstrate significantly reduced treatment periods compared to application of these components separately. Previous treatment of the patients comprising the above test groups had failed with standard local administration of :
- the sulfonamides or nitroimidazoles are unexpectedly strongly effective against most of the prokaryotic cells and the unhealthy mammalian (eukaryotic) cells too by causing their early death.
- Unhealthy means infected cells and tumor cells.
- the TP 53 gene encodes p53.
- One of its guardian funtions is to stop cells replicating damaged DNA. Normal cells with damaged DNA arrest at a checkpoint at the Gl/S stage of the cell cycle until the damage is repaired, but unhealthy cells do not.
- Probably related to not normal "unhealthy cells” is a crucial role of p53 in programmed cell death (apoptosis).
- compositions of the present invention the a.) nitroimidazoles (mutagenic effects) and b.) sulfonamides (antifolates- teratogen effects) caused damage in DNA respectively, and so unexpectedly increased the effectiveness of the other ingredient or ingredients.
- metronidazole inhibits DNA synthesis in T.vaginalis and Clostridium bifermentans and causes degradation of existing DNA in the latter microorganism.
- Sulfonamides are structural analogs and competitive antagonists of para- aminobenzoic acid (PABA) and thus prevent normal utilization of PABA for the synthesis of folic acid.
- PABA para- aminobenzoic acid
- One of the most active antibacterial agent that exerts a synergistic effect when used with a sulfonamide is trimethoprim. The simultaneous administration of them thus introduces sequential blocks in the pathway of the synthesis of tetrahydrofolate from precursor molecules. (see GOODMAN-GILMAN page 1058.).
- Sulfonamides do not effect healthy mammalian cells. Antifolates occupy a special place in antineoplastic chemotherapy, e.g.Methotrexate - its toxicity includes teratogenesis.
- Examples in the present application supporting a.) and b.) are as follows: l .Precancerous cells died: Following the treatment with the present compositions the cytological findings of Papanicolau smears improved from P3 to P 2 or Pi. The two cases of P improved to P2 and Pi respectively. The precancerous or cancerous cells disappeared. They died because the mutagenic effect can damage the DNA of the cells but can not repair DNA and so cure the cells. 2. Infected cells of Condyloma acuminatum died. (The infection caused by the human papilloma virus.): Probably because of the early death of the host cells the formation of mature infectious progeny virus is not possible, perhaps the steps of the viral replicative cycle could not be successfully completed.
- Sulfonamides are structural analogs and so competitive antagonists of para-aminobenzoic acid (PABA) :H 2 N-t ⁇ -COOH .They prevent the synthesis of folic acid and this prevention results in folic acid antagonist effect.
- PABA para-aminobenzoic acid
- sulfonamide is employed herein as a generic name for derivates of para- aminobenzenesul -SO2N 1 H2 ( E.g. sulfamethoxazole
- the minimal structural prerequisites for antibacterial action are all embodied in sulfanilamide itself.
- The-SO2NH2 group is not essential as such, but the important feature is that the sulfur is directly linked to the benzene ring.
- the para-NH2 group(the N of which has been designated as N 4 ) is essential and can be replaced only by such radicals as can be converted in vivo to a free amino group.
- Substitutions made in the amide NH2 group (the of N which has been designated as N 1 ) have variable effects on antibacterial activity of the molecule.
- An additional aspect and embodiment of the present invention is nitroimidazole substitution made in the amide NH2 group of sulfanilamid or the same substitution(s) made in the single ring of the lipid soluble antifolate trimetrexate.
- the examples above serve to further typify the nature of the invention but should not be construed as a limitation.
- the enhanced antimicrobial activity provided by the combined treatment cures the infection quickly and so the immun stimulus shortens and it results in a weaker immune response.
- Vaccination against pathogen microbes of the vagina by vaccines prepared and applied by known techniques, improves the immune response and resistance of the body after the antimicrobial treatment.
- the combined treatment and vaccination together is especially important for the treatment of infertility (of infectious origin) and dental diseases.
- vaginal bacterial samples were taken with cotton swabs (for culture and gram stain) .
- the most common microorganisms found were E.coli, Enterococcus faecalis, B-group streptococci, Candida albicans, Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella, Trichomonas vaginalis, Chlamydia trachomatis, and, to a lesser extent, Staphylococci, Proteus, Klebsiella, Haemophylus, etc. Antibiotic sensitivity was examined as well. After taking samples, patients were treated with the above-listed combinations of the present invention.
- a significantly lower amount of each active ingredient is needed in the present invention as compared to typical monotherapy formulations.
- the effective treatment of bacterial vaginosis is especially important because of its serious clinical implications and morbidity such as post- hysterectomy vaginal cuff cellulitis, plasmacell endometritis.
- clinical implications include amniotic fluid infection, clinical chorioamnionitis, postpartum endometritis, premature rupture of the membranes, pre-term delivery, and low birth weight.
- compositions of the present invention further displayed unexpected anti-viral activity.
- treatment using the compositions of the present invention along with local Podophyllin treatment proved to be permanently successful in 66% of the cases treated.
- patients with frequently recurring herpes genitalis became permanently free of symptoms following treatment with the preparations of the present invention in 75% of the cases tested.
- the present combination can be used in applications such as suppositories, ointments, talc powder, solution, painting solutions, vaginal drops, or impregnated tampons.
- the preparations contain the combination of the active ingredients in the same ratio as described above for localized treatment.
- Ointment preparations contain the combination of the active ingredients in the same ratio as in the vaginal suppository,together with ointment base, with yellow Vaseline and other components known per se, if required. This preparation is especially effective in case of tissue damage
- the talc powder preparation contains the active ingredient combination in solid form, with carriers such as talc, etc.
- the painting solutions and vaginal drops are prepared with an appropriate organic solvent.
- the vaginal drop solutions are useful in pediatric gynecology; but can also be used for adults in adequate doses.
- compositions can also optionally contain borax (NA2B4O7.4H2O ).
- compositions mentioned above can be prepared by known techniques used in the preparation of the pharmaceutical compositions.
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Gynecology & Obstetrics (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compositions having synergistic effective amounts of one or more antibacterial a gents, a nitroimidazole, and/or a sulfonamide with or without an antifungal agent effective against a candida species. The compositions are particularly useful in the treatment of genitourinary infections and their extragenital complications. Vaccination against pathogen microbes of the vagina provides a stronger and longer immune response, than the infection.
Description
PHARMACEUTICAL COMPOSITIONS PRIMARILY FOR THE
TREATMENT AND PREVENTION OF GENITOURINARY INFECTIONS
AND THEIR EXTRAGENITAL COMPLICATIONS.
Cross-reference to Related Applications
This application is based on a continuation-in-part(CIP) of co-pending application Serial No. 08/776,273, filed January 22, 1997,the contents of which are herein incorporated by reference. The present application comprises some new material-mainly deeper explanations-so it needs a new priority date.
Field of the invention
This invention relates to novel compositions and their uses in treatments as suppositories, especially vaginal suppositories, ointments, vaginal drops and talc powders, and painting solutions, or any form of the compositions useful for systemic treatment. Substitution of a nitroimidazole
(made in the amide NH2 group of Sulfanilamide, or in molecules or compounds having antifolic acid effectiveness) yields new compounds having combined effectiveness. Vaccination can provide stronger and longer immune response than the natural one (polyvalent serum).
Background of the invention
A variety of vaginal suppositories are currently commercially available for the treatment of various maladies. The attending physician ordinarily decides which composition is best suited to the patient's needs following physical examination.
For example, for the treatment of vaginal mycosis, Canesten (active ingredient is clotrimazol; bis-phenyl-(2-chlorophenyl)- l-(imidazolyl)- methane; and Pimafucin (the active ingredient is natamycin-primaricin) are most commonly used. For fungal and protozoan infection, Klion D (the active ingredient is metronidazole; l-(2'-hydroxiethyl)-2-methyl-5-nitroimidazol and myconasol-nitrate ) is used. For protozoan infection, Klion vaginal suppository (active ingredient is metronidazole) is commonly used. Certain compositions exert their effects through the disinfective action of iodine. These include Betadine (iodine is released from the carrier). Other vaginal suppositories feed the natural flora of the vagina. These include Genia 92 nutrients, e.g.:folic acid, lactic acid, lactose, and lactamine.
A common disadvantage of the above compositions is that none of them makes possible the combination of the effects of (i) bactericide (for aerobe and anaerobe bacteria), involving anti-Mobiluncus and anti- Gardnerella, (ii) fungicide, and (iii) anti protozoa simultaneously. Moreover, they have no antiviral effect at all.
Summary of the invention
The invention relates to compositions which make possible the attack of pathogens from different directions, which simultaneously aid in the body's antiviral struggle. The invention facilitates rapid and simple selection of the safest and most useful compositions.
The basis of the invention is the discovery that a unique combination of active ingredients has numerous advantages over the art. In a preferred embodiment, the composition of the present invention includes an antibacterial agent, an antifungal agent effective against a Candida species, and a nitroimidazole, wherein the antibacterial agent, the antifungal agent, and the nitroimidazole are present in the composition in synergistic effective amounts. Preferably, the composition of the present invention further includes a pharmaceutically acceptable carrier.
The basis of the discovery according to the invention is that the effect of the antibacterial agent ingredient is unexpectedly intensified by the other active components of the present composition. For example, the antibacterial effect, particularly of chloramphenicol and sulfonamide, against Chlamydia trachomatis is greatly increased by the present compositions. Additionally, an increased inhibitory effect of the antibacterial agent, particularly chloramphenicol and nitroimidazole, particularly metronidazole, components against anaerobe pathogens ( e.g. B. fragilis) was observed when utilized in compositions of the present invention. The antibacterial effect of the sulfonamide and/ or nitroimidazole also unexpectedly potantiated antibiotics generally against each pathogenic bacterium, in the antifungal protection provided by the antifungal agent. The antifungal agent or agents play a minor role in the synergistic effect.
The unexpected increased effectiveness of the components of the present composition when present in synergistic effective amounts has been observed when utilizing the three ingredients listed above. A further aspect and embodiment of the present invention provides for the inclusion of a sulfonamide in addition to another antibacterial agent, the antifungal agent, and the nitroimidazole, when present in a composition in synergistic effective amounts. As such, another embodiment of the present invention comprises an antibacterial agent, a sulfonamide, an antifungal agent effective against a Candida species, and a nitroimidazole, wherein each of these components are present in a composition in synergistic effective amounts. Preferably, the composition further includes a pharmaceutically acceptable carrier for obtaining a suitably deliverable medication to a patient.
It has been observed through experimental data that the antibacterial effect of sulfonamide standing alone is greatly enhanced when coupled with the other ingredients of the present compositions. Therefore, such an unexpected increased effectiveness of sulfonamide when incorporated into
5 the compositions of the present invention forms an additional embodiment and aspect of the present invention.
An additional aspect and embodiment of the present invention further supports the unexpected increased effectiveness of sulfonamide when combined with other active ingredients. A particular example which has
0 proven unexpectedly effective against bacterial vaginosis is the combination of a sulfonamide and a nitroimidazole.
Thus, the treatment spectrum is broader and the effect of the combination is much stronger than would be expected from its individual components, while simultaneously decreasing the necessary dosage for
[5 treatment compared to the individual active ingredients. This results in a decrease of the possible side effects while using the present combination of elements. Another significant advantage of the solution according to the invention is that drug resistance does not occur. The main role in the synergistic effect is played in the compositions of the invention by the
»0 nitroimidazole and/ or sulfonamide component(s), probably causing apoptosis of the involved eukaryotic cells and by killing most of the prokaryotic cells. (Apoptosis-like additional effect ).The level of the mechanism of action is the same in the case of a nitroimidazole or a sulfonamide. Both of them act on transcriptional level.
25
Detailed Description of the Invention
30 The present invention relates to novel compositions having synergistic effective amounts of one or more antibacterial agents, a nitroimidazole, and an antifungal agent effective against a Candida species. The antibacterial agents used in the present invention are also commonly referred to as
antibiotics. The present invention contemplates the use of any antibiotic as defined by Martindale - The Extra Pharmacopoeia, 29th Ed, London, The Pharmaceutical Press, 1989 (hereinafter "MARTINDALE"). As stated in MATINDALE, page 94: Antibiotics have traditionally been divided into bacteriostatic antibiotics which reversibly inhibit the growth of susceptible microorganisms and bactericidal antibiotics which kill the organisms in vitro. Given in high therapeutic doses, the aminoglycosides, cephalosporins, penicillins, and polymyxins are generally bactericidal by this criterium whereas chloramphenicol, erythromycin, the sulfonamide s, and the tetracyclines are usually bacteriostatic. However, an antibiotic which is bactericidal in a certain concentration may become bacteriostatic at lower concentrations.
In addition, antibiotics are classified into five classes based on chemical structure and mechanism of action in Chapter 43 of Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed. (McGraw- Hill, 1996) (hereinafter "GOODMAN-GILMAN"). Such classes are set forth in Chapter 43,pages 1029- 1030 of GOODMAN-GILMAN. As described therein, the individual members of each class are interchangeable with one another since they act on the target microorganism in the same way, and in most cases are also chemically interrelated with one another.
Experimental data set forth in the examples detailed below indicate that antibiotics belonging to each of the five classes defined in Chapters 43- 48 of GOODMAN-GILMAN are effective and preferred for use in compositions of the present invention. In some embodiments of the present invention, it is desired to utilize a sulfonamide for the particularly desirable antibiotic effect thereof when used in combination with the other components of the composition of the present invention. Any sulfonamide may be utilized in the composition of the present invention as all sulfonamides are structural analogs and competitive antagonists of para-aminobenzoic acid (see GOODMAN-GILMAN page 1058). Though all sulfonamides are interchangeable as applied to the composition of the present invention, a particularly preferred sulfonamide is sulfadimidin. In applications where a patient has an allergy to sulfonamides,
it is preferred to formulate the composition of the present invention without inclusion of a sulfonamide.
The antifungal agents utilized in the compositions of the present invention are preferably effective against Candida species (Candida albicans, Candida stelloidea, etc). Antifungal agents are divided into groups in GOODMAN-GILMAN, Chapter 49, pages 1 175- 1190,defιning antifungal agents effective against Candida species which act only topically, and those agents effective against Candida species both systemically and topically. The antifungal agents effective against Candida species which act both systemically and topically are divided into the following subclasses: polyenes, azoles, and pyrimidines. According to GOODMAN-GILMAN, Chapter 49, members of each subclass are interchangeable, in that each member of a respective subclass exhibits similar chemical properties and functionalities. Characteristic representatives of the polyenes are natamycin and nystatin. A characteristic representative of the azole subclass is clotrimazole. A characteristic representative of the pyrimidine subclass is flucitozine.
Another subclass of antifungal agents effective against Candida species are those antifungal agents which act only topically. Characteristic representatives of this subclass are ciclopirox olamine, naftifine, terbinafine, and haloprogin. Though the antifungal agents selected for use in the compositions of the present invention are preferably effective against Candida species, it is not necessary that such antifungal agents be effective solely against such Candida species. For example, particular selected antifungal agents of the present invention may be effective against a multiplicity of fungi.
The nitroimidazole component of the compositions of the present invention further contribute to the unexpected increased efficacy of each component of the compositions. The mechanism of action of the nitroimidazoles is set forth in GOODMAN-GILMAN, page 996 as reflecting a selective toxicity to anaerobic or microaerophilic microorganisms. As such, the members of the nitroimidazole group share a common functionality and are so closely related in structure so as to be interchangeable (see
GOODMAN-GILMAN). Characteristic representatives of the nitroimidazole group are metronidazole and tinidazole.
In a preferred embodiment, the composition of the present invention includes:
Component Amount a.) Antibacterial Agent 0.04-0.30 g b.) Antifungal Agent 0.025-0.30 g c.) Nitroimidazole 0.10-0.45 g A preferred pharmaceutically acceptable carrier for the compositions of the present invention is polyethylene-glycol, but other suitable carriers may also be employed. The amount of polyaethylene-glycol supplements the combination of the active ingredients to the necessary amount in case of a 10 unit package. The essence of the present invention is the unexpected increased efficacy of the presently disclosed components when utilized in the compositions of the present invention, as contrasted with the minimal effectiveness of such components standing alone. Commercially available medications containing only one component of the compositions of the present invention have been found to be ineffective, even after extended treatment periods or administration of hudge doses. Monotherapy, which is the treatment with a single active ingredient, is ineffective, in that a relapse rate of vaginal bacterial vaginosis is about 80% if the patients receiving such monotherapy, even over a treatment duration of up to 20 days. Through clinical trials, Applicant has discovered an unexpected synergy of effectiveness in compositions consisting of the three active ingredients referred to above.
The combination of elements used in the compositions of the present invention are more effective and qualitatively different from the separate administration of the individual components. Such compositions are preferably contained and administered in the form of vaginal suppositories, ointments, vaginal drops, talc powders, and painting solutions. Administration of the present compositions has resulted in complete
recovery in cases when recovery could not be reached by the separate administration of the components.
The compositions are useful in a variety of applications and treatments, including the following: Prophylactic Use. Use of the present compositions prevent infection from infected swimming-pool water or sexual activity. The compositions are indispensable prior to gynecological operations (especially utero-vaginal interventions) as a prophylactic suppository.
Treatment of infection. For infections, use of a preparation containing a composition of the present invention results in absolute recovery in 90% of the cases. Since systemic treatment is not needed, a smaller dose is administered. Cessation of treatment results in side effects disappearing (for local treatments there were no side effects observed). Resistance of the pathogens against the components used is also obviated because in local treatment the relatively small amount of preparation applied absolutely kills the pathogens.
Treatment of Chronic Vaginitis. Presently, techniques such as laser surgery, conventional surgery, cryocoagulation or electro-cauterisation are used for the treatment of the cervicalization (ectopium), or the (slightly) positive epithelial differences(such as the slightly acetic acid positive epithelium, or the decrease of the iodine positivity ),or slightly pathological epithelium and P3 cytological findings respectively.
The compositions of the present invention promote the spontaneous healing of the bleeding, inflamed portion of the uterus. As a result, the above -de scribed invasive conventional treatments become unnecessary. Constant inflammation plays a decisive role in the formation of cancer of the cervix of the uterus. Application of the compositions according to the invention greatly diminishes the risk of the formation of the cancer of the cervix of the uterus, by stopping the inflammation. Nitroimidazole has certain anticancer effects, which are observed during the radiation treatment of the tumors, where it increases the efficacy of the radiation treatment. In addition, it has been postulated that sulfonamides display anti-tumor characteristics as well(see Supuran CT et al. Carbonic Anhidrase Inhibitors:
Sulfonamides as Antitumor Agents? Biorg .Med.Chem., March, 2001, 9(13):703-714).
Following the treatment with the present compositions, the laboratory findings improved from P3 cyto logical results to P2 or Pi without exception
5 and the epithelium became normal kolposcopically.
Treatment of complications of ascending infections. Ascending infections such as Cystitis, PID, etc., are typically caused by the same microbes as are in the vagina. The systemic application of the present combinations unexpectedly shorten the usual duration of treatment. 0 Later complications of the inflammation (infection) can be vascular damage anywhere in the body (e.g. atherosclerosis and the connected diseases(see Ross, R. Mechanism of disease: Atherosclerosis - an inflammatory disease. N.Engl.J.Med.1999, 2: 115- 126.), neovascularisation, etc.. L5 Chronic inflammation has been shown to be an important risk factor for a variety of epithelial cancers, including those of the esophagus, stomach, pancreas, liver, biliary tract, colon, vulva and bladder (see Stephen E.Hawes, Nancy B.Kiviat. (editorials) Are Genital Infections and Inflammation Cofactors in the Pathogenesis of Invasive Cervical Cancer?, Journal of the »0 National Cancer Institute 2002, 94: 1592-1593).
Antiviral effect. The present combination acts against viral infections, possibly by killing all non viral pathogens, enhancing the immunocapacity of the body against the viruses.
In those cases when, because of inflammation and vaginal discharge, 25 the treatment of the Condyloma acuminatum (caused by the human papilloma virus) failed, local treatment using the present composition proved to be permanently successful.
Moreover, it was observed that patients with frequently reoccuring herpes genitalis, became permanently free of symptoms following the 30 treatment with the preparation of the present invention.
The preparation according to the invention can also be administered to pregnant women to prevent adverse pregnancy outcome (and probably
toxaemias of pregnancy too ).In such applications, erythromycin is the preferred antibacterial agent component.
Application in the veterinary medicine .The treatment of kolpitis in female dogs by the present combinations proved similarly effective as compared to human treatment.
Treatment of the inflamed glandula Bartholini by drainage and injected solution of a composition of the invention instead of simple incision or marsupialization.
Other similar applications are also possible inside the body. Combined (local and systemic) treatment .
(a) In pregnancy to prevent intrauterine Chlamydia trachomatis infection causing pneumonia or perhaps blindness. (see Milankovits Marton: The possible role of non trachoma Chlamydia trachomatis serovars in intrauterine blindness. ^111 Congress of the European Association of Gynaecologists 85 Obstetricians, 25th-28th June, 1997, Trinity College, Dublin, Ireland.)
(b) In cases of infections of sportswomen (mainly carriers)to improve their physical abilities and fitness.
The compositions according to the invention were tested on 300-400 cases, with 300-400 controls. In all cases, the full microbiological examination included Chlamydia trachomatis and the Mycoplasmas.
Preparations of the compositions according to the invention can be carried out by methods known in the art for the preparation of such compositions. The following experimental results demonstrate the unexpected efficacy of the compositions of the present invention, and set forth examplary compositions indicative of the many possible species combinations useful in the treatment of various maladies. The examples will serve to further typify the nature of the invention, but should not be construed as a limitation on the scope thereof, which is defined solely by the appended claims.
Example 1
309 Patients
Seven days treatment
Chloramphenicol : 0.10 g
Sulfadimidin : 0.10 g
Nystatin : 0.10g
Metronidazole : 0.40g
Massa Polyoxaethenum : 2.00g
Completely treated : 306
Remained the same: 3
Worsened : 0
Example 2
90 Patients
Seven days treatment
Ciprofloxacin: 0.04g
Sulfadimidin 0.10g
Nystatin : 0.10g
Metronidazole: 0.40g
Massa
Polyoxaethenum 2.00g
Completely treated : 89
Remained the same : 1
Worsened : 0
Example 3
77 Patients
Seven days treatment
Ampicillin: 0.20g
Sulfadimidin 0.10g
Nystatin : 0.10g
Metronidazole: 0.40g
Massa
Polyoxaethenum: 2.00g
Completely treated : 75
Remained the same : 2 Worsened : 0
Example 4
60 Patients
Seven days treatment Sulfadimidin : 0.1 Og
Nystatin : 0.1 Og
Metronidazole: 0.40g
Massa
Polyoxaethenum : 2.00g Completely treated : 52
Remained the same : 8
Worsened : 0
Example 5 19 Patients
Seven days treatment
Neomycin : 0.1 Og
Sulfadimidin : 0.1 Og
Nystatin : 0.1 Og Metronidazole : 0.40g
Massa
Polyoxaethenum : 2.00g
Completely treated : 18
Remained the same : 1 Worsened : 0
Example 6
10 Patients
Seven days treatment
Polymixin : 0.05g
Sulfadimidin : 0.10g
Nystatin : 0.10g
Metronidazole : 0.40g
Massa
Polyoxaethenum : 2.00g
Completely treated : 9
Remained the same : 1
Worsened : 0
Example 7
12 Patients
Seven days treatment
Semicillin : 0.20g
Sulfadimidin : 0.10g
Nystatin : 0.10g
Tinidazole : 0.40g
Massa
Polyoxaethenum : 2.00g
Completely treated : 1 1
Remained the same : 1
Worsened : 0
Example 8
10 Patients
Seven days treatment
Semicillin : 0.20g
Sulfadimidin : 0.10g
Clotrimazole : 0.10g
Metronidazole : 0.40g
Massa
Polyoxaethenum : 2.00g
Completely treated : 9
Remained the same : 1
5 Worsened : 0
Example 9
10 Patients
Seven days treatment
0 Semicillin : 0.20g
Sulfadimidin : 0.1 Og
Natamycin : 0.30g
Metronidazole : 0.40g
Massa
[5 Polyoxaethenum : 2.00g
Completely treated : 9
Remained the same : 1
Worsened : 0
>0 Example 10
10 Patients
Seven days treatment
Chloramphenicol : 0.1 Og
Nystatin : 0.1 Og
>5 Metronidazole : 0.40g
Massa
Polyoxaethenum : 2.00g
Completely treated : 8
Remained the same : 2
30 Worsened : 0
Example 11
10 Patients
Seven days treatment
Semicillin : 0.20g
Natamycin : 0.30g
Metronidazole : 0.40g
Massa
Polyoxaethenum : 2.00g
Completely treated : 7
Remained the same : 3
Worsened : 0
Example 12
8 Patients
Seven days treatment
Chloramphenicol : 0.10g
Sulfadimidin : 0.10g
Nystatin : 0.10g
Metronidazole : 0.10g
Massa
Polyoxaethenum : 2.00g
Completely treated : 7
Remained the same : 1
Worsened : 0
Example 13
Systemic administration (per os) 9 Patients
Seven days treatment Ciprofloxacin : 750 mg/day (500mg + 250mg) Ketoconazole : 400 mg/day (200mg + 200mg) Tinidazole : 1000 mg/day (500mg + 500mg) Completely treated : 8
Remained the same : 1
Worsened : 0
The above examples demonstrate the interchangeability of specific species within the respective genera antibacterial agent, nitroimidazole, and antifungal agent effective against a Candida species, while maintaining the efficacy of the various compositions of the present invention. Examples 10 and 11 illustrate the high level of effectiveness of even three component compositions of the present invention. Such effective experimental results are particularly unexpected when contrasted with the treatment efficacy using a single active ingredient. Such monotherapy treatments result in less than 20% complete recovery. (e.g. for bacterial vaginosis)
The compositions demonstrate significantly reduced treatment periods compared to application of these components separately. Previous treatment of the patients comprising the above test groups had failed with standard local administration of :
The Agent The Duration of Treatment
Klion (metronidazole) 10 days Klion D 10 days
Pimafucin (natamycin) 20 days
Canesten (clotrimazol) 8- 10 days
For example, it has been found that no benefit is realized through repeated 2000 mg doses of metronidazole administered alone (see Carey JC, Klebanoff MA, et all. Metronidazole to Prevent Pre-term Delivery in Pregnant Women with Asymptomatic Bacterial Vaginosis, New England Journal of Medicine 2000; 342:534-40). In a further aspect of the present invention, it has been found that the respective effectiveness of a nitroimidazole and a sulfonamide when utilized alone is enhanced when combined. As such, an unexpected success rate of over 60% against bacterial vaginosis is achieved through the combination of a sulfonamide and a nitroimidazole. In the compositions of the invention the sulfonamides or nitroimidazoles are unexpectedly strongly
effective against most of the prokaryotic cells and the unhealthy mammalian (eukaryotic) cells too by causing their early death. (Unhealthy means infected cells and tumor cells. )The TP 53 gene encodes p53.One of its guardian funtions is to stop cells replicating damaged DNA. Normal cells with damaged DNA arrest at a checkpoint at the Gl/S stage of the cell cycle until the damage is repaired, but unhealthy cells do not. Probably related to not normal "unhealthy cells" is a crucial role of p53 in programmed cell death (apoptosis). In the compositions of the present invention the a.) nitroimidazoles (mutagenic effects) and b.) sulfonamides (antifolates- teratogen effects) caused damage in DNA respectively, and so unexpectedly increased the effectiveness of the other ingredient or ingredients. (a)Early work established that metronidazole inhibits DNA synthesis in T.vaginalis and Clostridium bifermentans and causes degradation of existing DNA in the latter microorganism. These findings are consistent with the antimicrobial and mutagenic effects of metronidazole. Once the drug has diffused into the cells, the nitro group accepts electrons from electron- transport proteins with sufficiently low negative redox potentials, e.g. flavoprotein in mammalian cells and ferredoxins or their equivalent in protozoa and bacteria, (see GOODMAN-GILMAN page 996.) (b) Sulfonamides are structural analogs and competitive antagonists of para- aminobenzoic acid (PABA) and thus prevent normal utilization of PABA for the synthesis of folic acid. One of the most active antibacterial agent that exerts a synergistic effect when used with a sulfonamide is trimethoprim. The simultaneous administration of them thus introduces sequential blocks in the pathway of the synthesis of tetrahydrofolate from precursor molecules. (see GOODMAN-GILMAN page 1058.). Sulfonamides do not effect healthy mammalian cells. Antifolates occupy a special place in antineoplastic chemotherapy, e.g.Methotrexate - its toxicity includes teratogenesis.
Examples in the present application supporting a.) and b.) are as follows: l .Precancerous cells died: Following the treatment with the present compositions the cytological findings of Papanicolau smears improved from P3 to P2 or Pi. The two cases of P improved to P2 and Pi respectively. The
precancerous or cancerous cells disappeared. They died because the mutagenic effect can damage the DNA of the cells but can not repair DNA and so cure the cells. 2. Infected cells of Condyloma acuminatum died. (The infection caused by the human papilloma virus.): Probably because of the early death of the host cells the formation of mature infectious progeny virus is not possible, perhaps the steps of the viral replicative cycle could not be successfully completed.
It has been observed through experimental data, that the antibacterial or antitumor effect of sulfonamide or nitroimidazole standing alone is greatly enhanced when coupled with the other antibacterial ingredient or ingredients of the present compositions. Therefore, such an unexpected increased effectiveness of sulfonamide or nitroimidazole when incorporated into the compositions of the present invention forms an additional embodiment and aspect of the present invention. Sulfonamides are structural analogs and so competitive antagonists of para-aminobenzoic acid (PABA) :H2N-t ^-COOH .They prevent the synthesis of folic acid and this prevention results in folic acid antagonist effect. The term sulfonamide is employed herein as a generic name for derivates of para- aminobenzenesul -SO2N1H2 ( E.g. sulfamethoxazole
The minimal structural prerequisites for antibacterial action are all embodied in sulfanilamide itself. The-SO2NH2 group is not essential as such, but the important feature is that the sulfur is directly linked to the benzene ring. The para-NH2 group(the N of which has been designated as N4 ) is essential and can be replaced only by such radicals as can be converted in vivo to a free amino group. Substitutions made in the amide NH2 group (the of N which has been designated as N1) have variable effects on antibacterial activity of the molecule. Substitution of heterocyclic aromatic nuclei at N yealds highly potent compounds, (e.g. sulfamethoxazole).
An additional aspect and embodiment of the present invention is nitroimidazole substitution made in the amide NH2 group of sulfanilamid or the same substitution(s) made in the single ring of the lipid soluble antifolate
trimetrexate. The examples above serve to further typify the nature of the invention but should not be construed as a limitation.
The enhanced antimicrobial activity provided by the combined treatment cures the infection quickly and so the immun stimulus shortens and it results in a weaker immune response. Vaccination against pathogen microbes of the vagina, by vaccines prepared and applied by known techniques, improves the immune response and resistance of the body after the antimicrobial treatment. The combined treatment and vaccination together is especially important for the treatment of infertility (of infectious origin) and dental diseases.
The following examples demonstrate the effectiveness of a pharmaceutical composition containing a sulfonamide and/ or a nitroimidazole with and without trimethoprim or clindamycin.
Example 14
1 1 Patients
Seven days treatment
Sulfadimidin : 0.10g
Metronidazole : 0.40g
Massa
Polyoxaethenum : 2.00g
Completely treated : 7
Remained the same : 4
Worsened : 0
Example 15
12 Patients
Seven days treatment
Sulfadimidin : 0.10g
Metronidazole : 0.40g
Natrium
Tetraboratum : 0.05g
Massa
Polyoxaethenum : 2.00g
Completely treated : 8
Remained the same : 4
Worsened : 0
Example 16
6 Patients
Seven days treatment
Sulfamethoxazol : 0.10g
Trimethoprim : 0.02g
Metronidazole : 0.20g
Massa
Polyoxaethenum : 2.00g
Completely treated : 5
Remained the same: 1
Worsened : 0
Example 17
7 Patients
Seven days treatment
Clindamycin : 0.05g
Sulfadimidin : 0.10g
Massa
Polyoxaethenum : 2.00g
Completely treated : 4
Remained the same : 3
Worsened : 0
Before treatment using the present combinations, vaginal bacterial samples were taken with cotton swabs (for culture and gram stain) .The most common microorganisms found were E.coli, Enterococcus faecalis, B-group streptococci, Candida albicans, Ureaplasma urealyticum, Mycoplasma
hominis, Gardnerella, Trichomonas vaginalis, Chlamydia trachomatis, and, to a lesser extent, Staphylococci, Proteus, Klebsiella, Haemophylus, etc. Antibiotic sensitivity was examined as well. After taking samples, patients were treated with the above-listed combinations of the present invention.
In addition to providing an unexpected increase in efficacy of each individual component when utilised in the combinations of the present invention, a significantly lower amount of each active ingredient is needed in the present invention as compared to typical monotherapy formulations. The effective treatment of bacterial vaginosis is especially important because of its serious clinical implications and morbidity such as post- hysterectomy vaginal cuff cellulitis, plasmacell endometritis. In pregnant women, such clinical implications include amniotic fluid infection, clinical chorioamnionitis, postpartum endometritis, premature rupture of the membranes, pre-term delivery, and low birth weight.
The compositions of the present invention further displayed unexpected anti-viral activity. For example, in cases where the treatment of Condyloma acuminatum (caused by the human papilloma virus) failed, treatment using the compositions of the present invention along with local Podophyllin treatment proved to be permanently successful in 66% of the cases treated. Moreover, it has been observed that patients with frequently recurring herpes genitalis became permanently free of symptoms following treatment with the preparations of the present invention in 75% of the cases tested.
The following additional examples are contemplated by the present invention for use in treatment compositions:
Combination I :
Chloramphenicol 0.08g
Sulfadimidin 0.20g
Clotrimazol 0.15g
Metronidazole 0.40g
Massa polyoxaethenum 2.00g
Combination II :
Chloramphenicol 0.1 Og Sulfadimidin 0.1 Og
Clotrimazol 0.1 Og
Metronidazole 0.40g
Massa polyoxaethenum 2.00g
Combinationlll :
Unasyn 0.10g
Sulfadimidin 0.10g
Nystatin 0.10g
Metronidazole 0.40g
Massa polyoxaethenum 2.00g
CombinationlV :
Augmentin 0.10g
Sulfadimidin 0.10g
Nystatin 0.10g
Natrium-tetraborat 0.05g
Metronidazole 0.40g
Massa polyoxaethenum 2.00g
CombinationV :
Oxacillin 0.10g
Sulfadimidin O. lOg Nystatin 0.10g
Metronidazole 0.40g
Massa polyoxaethenum 2.00g
Combination VI:
Cefaclor (Ceclor) 0.05g
Sulfadimidin O. lOg
Nystatin O. lOg
Metronidazole 0.40g Massa polyoxaethenum 2.00g
CombinationVII :
Gentamycin 0.05g Sulfadimidin O. lOg
Nystatin O. lOg
Metronidazole 0.40g
Massa polyoxaethenum 2.00g
Combination VIII :
Clarithromycin (Klacid) O. lOg
Sulfadimidin O. lOg
Nystatin O. lOg
Metronidazole 0.40g
Massa polyoxaethenum 2.00g
Combination IX
Chloramphenicol O. lOg
Sulfadimidin O. lOg
Nystatin O. lOg
Natrium- tetraborat 0.05-0. lOg
Metronidazole 0.40g
Massa polyoxaethenum 2.00g
Combination X :
Clindamycin 0.05g
Natrium- tetraborat 0.05g
Sulfadimidin O. lOg
Nystatin O. lOg
Metronidazole 0.40g
Massa polyoxaethenum 2.00g
The present combination can be used in applications such as suppositories, ointments, talc powder, solution, painting solutions, vaginal drops, or impregnated tampons.
For systemic treatment situations, the preparations contain the combination of the active ingredients in the same ratio as described above for localized treatment.
Ointment preparations contain the combination of the active ingredients in the same ratio as in the vaginal suppository,together with ointment base, with yellow Vaseline and other components known per se, if required. This preparation is especially effective in case of tissue damage
(diabetes mellitus , burning, etc.). The talc powder preparation contains the
active ingredient combination in solid form, with carriers such as talc, etc. The painting solutions and vaginal drops are prepared with an appropriate organic solvent. The vaginal drop solutions are useful in pediatric gynecology; but can also be used for adults in adequate doses.
The present compositions can also optionally contain borax (NA2B4O7.4H2O ).
The pharmaceutical compositions mentioned above can be prepared by known techniques used in the preparation of the pharmaceutical compositions.
Claims
1. A pharmaceutical composition, comprising:
(a) one or more antibacterial agents;
(b) one or more antifungal agents effective against a Candida species; and
(c) a nitroimidazole, wherein said one or more antibacterial agents, said one or more antifungal agents, and said nitroimidazole are present in synergistic effective amounts.
2. A pharmaceutical composition as in Claim 1, further comprising a pharmaceutically acceptable carrier.
3. A pharmaceutical composition as in Claim 1 wherein said one or more antibacterial agents include a sulfonamide.
4. A pharmaceutical composition as in Claim 1 , further comprisig borax.
5. A pharmaceutical composition as in Claim 1 wherein said composition is selected from the group consisting of vaginal suppositories, ointments, solutions, painting solutions, vaginal drops , powders and impregnated tampons.
6. A pharmaceutical composition as in Claim 1 wherein said one or more antibacterial agents are selected from the group consisting of chloramphenicol, erythromycin, oxytetracyclin, ampicillin, ciprofloxacin, neomycin, polymyxin, unasyn, augmentin, oxycillin, cefaclor, gentamycin, clarithromycin, clindamycin and sulfadimidin.
7. A pharmaceutical composition as in Claim 1 wherein said antifugal agent is selected from the group consisting of clotrimazol, natamycin and nystatin.
8. A pharmaceutical composition as in Claim 1 being particularly adapted for use in systemic treatment of ascending infections.
9. A pharmaceutical composition as in Claim 1 comprising:
(a) 0.04-0.30 grams of said one or more antibacterial agents;
(b) 0.025-0.30 grams of said antifungal agent; and
(c) 0.10-0.45 grams of said nitroimidazole.
10. A pharmaceutical composition consisting essentially of:
(a) an antibacterial agent;
(b) an antifungal agent effective against a Candida species;
(c) a nitroimidazole; and
(d) a pharmaceutically acceptable carrier, wherein said antibacterial agent, said antifungal agent, and said nitroimidazole are present in synergistic effective amounts.
11. A pharmaceutical composition as in Claim 10 wherein said antibacterial agent is a sulfonamide.
12. A pharmaceutical composition as in Claim 10 wherein said composition is selected from the group consisting of vaginal suppositories, ointments, solutions, painting solutions ,vaginal drops, powders and impregnated tampons.
13. A pharmaceutical composition as in Claim 10 wherein said one or more antibacterial agents are selected from the group consisting of chloramphenicol, erythromycin, oxytetracyclin, ampicillin, ciprofloxacin, neomycin, polymyxin, unasyn, augmentin, oxycillin, cefaclor, gentamycin, clarithromycin, clindamycin and sulfadimidin.
14. A pharmaceutical composition as in Claim 10 wherein said antifungal agent is selected from the group consisting of clotrimazol, natamycin, and nystatin.
15. A pharmaceutical composition as in Claim 10 being particularly adapted for use in systemic treatment of ascending infections.
16. A pharmaceutical composition consisting essentially of:
(a) a first antibacterial agent;
(b) a sulfonamide;
(c) an antifungal agent effective against a Candida species;
(d) a nitroimidazole; and
(e) a pharmaceutically acceptable carrier, wherein said antibacterial agent, said sulfonamide, said antifungal agent, and said nitroimidazole are present in synergistic effective amounts.
. A pharmaceutical composition consisting essentially of
(a) a sulfonamide;
(b) a nitroimidazole; and
(c) a pharmaceutically acceptable carrier. . A pharmaceutical composition as in Claim 17, including borax. . A pharmaceutical composition comprising:
(a) one or more antibacterial agents;
(b) a nitroimidazole; and
(c) a pharmaceutically acceptable carrier. . A pharmaceutical composition as in Claim 19, including borax. . A pharmaceutical composition comprising:
(a) one or more antibacterial agents;
(b) a sulfonamide or sulfonamide and trimethoprim;
(c) a pharmaceutically acceptable carrier. . A pharmaceutical composition as in Claim 21, including borax. . A pharmaceutical composition comprising:
(a) one or more antimicrobial agents acting on transcriptional level (on DNA level or cDNA level);
(b) one or more antimicrobial agents acting on not the transcriptional level; . A pharmaceutical composition as in Claim 23, further comprising optionally borax and/ or carrier(s) and/ or additive(s). . A pharmaceutical composition comprising: two or more antimicrobial agents acting on transcriptional level (on DNA level or cDNA level). . A pharmaceutical composition as in Claim 25, further comprising optionally borax and/ or carrier(s) and/ or additive(s). . A pharmaceutical composition comprising a molecula or compound having folic acid antagonist effect and nitroimidazole substitution in addition, or pharmaceutical compositions comprising the combination of such molecules or compounds. . A pharmaceutical composition as in any of the previous Claims (1-27.) comprising a molecule or compound having folic acid antagonist effect and nitroimidazole substitution in addition. A pharmaceutical composition as in any of the previous Claims (1-28.) combined with vaccination against the pathogen microorganisms of the vagina.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003290377A AU2003290377A1 (en) | 2003-01-03 | 2003-12-30 | Pharmaceutical compositions comprising an antibacterial agent nd antifungal agent and a nitroimidazole for the treatment and prevention of genitourinary infections and their extragenital complications |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0300010 | 2003-01-03 | ||
| HU0300010A HU0300010D0 (en) | 2003-01-03 | 2003-01-03 | Pharmaceutical compositions primarily for the treatment of genitourinary infect, ons and their extragenital complications |
| HU0400015A HUP0400015A2 (en) | 2003-12-18 | 2003-12-18 | Pharmaceutical combinations especially for the treatment and prevention of urologigal infections and their extragenital complications |
| HUP0400015 | 2003-12-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2004060379A2 true WO2004060379A2 (en) | 2004-07-22 |
| WO2004060379A3 WO2004060379A3 (en) | 2004-10-14 |
Family
ID=89981897
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2003/000110 WO2004060379A2 (en) | 2003-01-03 | 2003-12-30 | Pharmaceutical compositions comprising an antibacterial agent nd antifungal agent and a nitroimidazole for the treatment and prevention of genitourinary infections and their extragenital complications |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2003290377A1 (en) |
| WO (1) | WO2004060379A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1671623A1 (en) * | 2004-10-01 | 2006-06-21 | Giuseppe Vrespa | Composition for use in the antibacterial and antiinflammatory treatment of the oral cavity |
| WO2007092590A3 (en) * | 2006-02-08 | 2007-11-08 | Fasgen Inc | Anti-mycobacterial formulation comprising octanesulphonylacetamide (osa), nonanesulphonylacetamide (nsa) and decanesulphonylacetamide (dsa) |
| WO2024085926A3 (en) * | 2022-06-30 | 2024-05-30 | University Of Utah Research Foundation | Compositions and methods of treating, preventing or inhibiting a facultative anaerobe infection |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL45337A (en) * | 1973-08-10 | 1977-04-29 | Saarstickstoff Fatol Gmbh | Therapeutical composition containing an isonicotinic acid hydrazide thioisonicotinic acid amide sulfones and/or sulfonamides for the treatment of mycobacterioses |
| RO80363A2 (en) * | 1980-11-08 | 1983-02-01 | Intreprinderea De Antibiotice,Ro | VAGINAL POLYACTIVE GEL |
| CA1205029A (en) * | 1984-02-21 | 1986-05-27 | George L. Evans | Selective agent for group a streptococci |
| GB2187956B (en) * | 1986-03-22 | 1989-11-15 | Smith & Nephew Ass | Topical antimicrobial composition comprising a silver compound and an azole. |
| US4888327A (en) * | 1987-02-24 | 1989-12-19 | Alcon Laboratories, Inc. | Topical antibiotic compositions |
| HU215443B (en) * | 1994-07-25 | 1999-04-28 | Márton Milánkovits | Pharmaceutical compositions, first of all vaginal suppositorium, containing more active components with bactericide, fungicide, antiprotozoonic and antiviral combined activity |
| AP598A (en) * | 1994-12-20 | 1997-07-21 | Acupharm Pty Limited | Metronidazole combinations. |
| US5707996A (en) * | 1995-11-06 | 1998-01-13 | Macleod Pharmaceuticals, Inc. | Pharmaceutical solution and methods for preparation thereof |
| US20030073646A1 (en) * | 1997-01-22 | 2003-04-17 | Marton Milankovits | Pharmaceutical compositions primarily for the treatment of genitourinary infections |
| IT1296980B1 (en) * | 1997-12-17 | 1999-08-03 | Istituto Pirri S R L | DOUBLE CAPSULE AS A PHARMACEUTICAL FORM FOR THE ADMINISTRATION OF ACTIVE INGREDIENTS IN MULTIPLE THERAPIES |
| CN1108154C (en) * | 1998-03-09 | 2003-05-14 | 锦州市制药五厂 | Drug composition for curing gynaecological vaginitis |
| CN1086124C (en) * | 1998-09-01 | 2002-06-12 | 锦州制药一厂 | Shuangzuoxing suppository and ointment |
-
2003
- 2003-12-30 WO PCT/HU2003/000110 patent/WO2004060379A2/en active Application Filing
- 2003-12-30 AU AU2003290377A patent/AU2003290377A1/en not_active Abandoned
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1671623A1 (en) * | 2004-10-01 | 2006-06-21 | Giuseppe Vrespa | Composition for use in the antibacterial and antiinflammatory treatment of the oral cavity |
| WO2007092590A3 (en) * | 2006-02-08 | 2007-11-08 | Fasgen Inc | Anti-mycobacterial formulation comprising octanesulphonylacetamide (osa), nonanesulphonylacetamide (nsa) and decanesulphonylacetamide (dsa) |
| WO2024085926A3 (en) * | 2022-06-30 | 2024-05-30 | University Of Utah Research Foundation | Compositions and methods of treating, preventing or inhibiting a facultative anaerobe infection |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003290377A8 (en) | 2004-07-29 |
| WO2004060379A3 (en) | 2004-10-14 |
| AU2003290377A1 (en) | 2004-07-29 |
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