WO2012175659A1 - N-acetyl cysteine and composition thereof for use in the treatment of vaginal pathologies - Google Patents
N-acetyl cysteine and composition thereof for use in the treatment of vaginal pathologies Download PDFInfo
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- WO2012175659A1 WO2012175659A1 PCT/EP2012/062068 EP2012062068W WO2012175659A1 WO 2012175659 A1 WO2012175659 A1 WO 2012175659A1 EP 2012062068 W EP2012062068 W EP 2012062068W WO 2012175659 A1 WO2012175659 A1 WO 2012175659A1
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- Prior art keywords
- composition
- vaginal
- use according
- treatment
- pathologies
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- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 title claims abstract description 52
- 239000000203 mixture Substances 0.000 title claims abstract description 51
- 229960004308 acetylcysteine Drugs 0.000 title claims abstract description 25
- 230000007170 pathology Effects 0.000 title claims abstract description 24
- 238000011282 treatment Methods 0.000 title claims abstract description 23
- 241000894006 Bacteria Species 0.000 claims description 38
- 230000001580 bacterial effect Effects 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 18
- 244000005700 microbiome Species 0.000 claims description 17
- 239000003242 anti bacterial agent Substances 0.000 claims description 16
- 229940088710 antibiotic agent Drugs 0.000 claims description 15
- 230000009471 action Effects 0.000 claims description 10
- 230000003115 biocidal effect Effects 0.000 claims description 10
- 230000000144 pharmacologic effect Effects 0.000 claims description 10
- 230000000844 anti-bacterial effect Effects 0.000 claims description 8
- 230000001857 anti-mycotic effect Effects 0.000 claims description 7
- 239000002543 antimycotic Substances 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 230000015556 catabolic process Effects 0.000 claims description 6
- 239000006071 cream Substances 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 241000233866 Fungi Species 0.000 claims description 5
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 5
- 230000035755 proliferation Effects 0.000 claims description 4
- 239000004098 Tetracycline Substances 0.000 claims description 3
- 235000019364 tetracycline Nutrition 0.000 claims description 3
- 150000003522 tetracyclines Chemical class 0.000 claims description 3
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 claims description 2
- 229930186147 Cephalosporin Natural products 0.000 claims description 2
- 239000002250 absorbent Substances 0.000 claims description 2
- 230000002745 absorbent Effects 0.000 claims description 2
- 229940124587 cephalosporin Drugs 0.000 claims description 2
- 150000001780 cephalosporins Chemical class 0.000 claims description 2
- 229940059082 douche Drugs 0.000 claims description 2
- 230000036542 oxidative stress Effects 0.000 claims description 2
- 229940040944 tetracyclines Drugs 0.000 claims description 2
- -1 flourochinolones Substances 0.000 claims 1
- 210000001215 vagina Anatomy 0.000 description 12
- 230000000694 effects Effects 0.000 description 8
- 238000011422 pharmacological therapy Methods 0.000 description 8
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- 244000052769 pathogen Species 0.000 description 5
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- 150000004676 glycans Chemical class 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 241000207201 Gardnerella vaginalis Species 0.000 description 3
- 241000186660 Lactobacillus Species 0.000 description 3
- 206010046914 Vaginal infection Diseases 0.000 description 3
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- 244000000010 microbial pathogen Species 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
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- 241000894007 species Species 0.000 description 3
- 241001633064 Atopobium vaginae Species 0.000 description 2
- 208000004926 Bacterial Vaginosis Diseases 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 208000037009 Vaginitis bacterial Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
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- 230000006399 behavior Effects 0.000 description 2
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- 210000004027 cell Anatomy 0.000 description 2
- 210000003756 cervix mucus Anatomy 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
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- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 241000193818 Atopobium Species 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
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- 241000606153 Chlamydia trachomatis Species 0.000 description 1
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- 240000001046 Lactobacillus acidophilus Species 0.000 description 1
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- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 241001430197 Mollicutes Species 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
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- 241000224526 Trichomonas Species 0.000 description 1
- 241000224527 Trichomonas vaginalis Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
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- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
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- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
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- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
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- 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
- A61K31/4164—1,3-Diazoles
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- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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- A—HUMAN NECESSITIES
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- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
Definitions
- the present invention relates to N-acetyl cysteine and a composition thereof for use in the restoration of the vaginal ecosystem and/or in the treatment of vaginal pathologies.
- vaginal pathologies are caused by microorganisms such as bacteria (for example Gardnerella vaginalis), fungi (for example Candida albicans) or protozoa (for example Trichomonas vaginalis) .
- bacteria for example Gardnerella vaginalis
- fungi for example Candida albicans
- protozoa for example Trichomonas vaginalis
- biofilm One of the strategies selected by the microorganisms in order to increase the possibility of survival in the environment and inside the human body is represented by the so- called biofilm.
- biofilm is not however a simple aggregate in which the proximity of the germs one to the other makes their neutralisation more difficult.
- the biofilm represents a form, albeit an extremely primordial form, of three- dimensional organisation of unicellular elements, in which the resulting survival capacity of the entire colony does not correspond to the sum of the survival capacities of the individual elements.
- the non-variable characteristics in the biofilm formation are the need for a surface onto which to adhere and the production of a substance defined "extracellular polymer matrix", which maintains the cohesion between the individual microorganisms that make up the biofilm.
- extracellular polymer matrix which maintains the cohesion between the individual microorganisms that make up the biofilm.
- the macroscopic aspect and the environmental substances included in the matrix are variable.
- the biofilm maturation process comprises 5 stages:
- the first phase entails the slowing of the movement speed of the microorganisms and their adhesion to an organic surface (e.g. mucous membrane, blood, secretions, saliva, urine) or inorganic, possibly rough surface;
- an organic surface e.g. mucous membrane, blood, secretions, saliva, urine
- inorganic possibly rough surface
- the bacteria are moved along the surface until they meet other bacteria; the anchoring of the bacteria to the colony surface sets off a cascade of reactions, which activate the otherwise repressed genes responsible for the biofilm phenotype;
- the central phenomenon of the third phase is the stable intercellular adhesion of biochemical nature (bacterial surface proteins), followed by the production of the extracellular polymer matrix of the polysaccharide type, promoted by the adhesion itself; the bacteria communicate among themselves through biochemical substances, capable of regulating, amongst other things, the density of the bacterial population of the biofilm and consequently the reciprocal behaviour of the elements;
- the fourth phase consists of biofilm growth; this process, defined maturation, involves all the biofilm components. i.e. both the cellular elements and the exopolysaccharide substance; the cellular elements are reproduced so as to form bacterial "towers" immersed in the matrix and connected by channels;
- the extracellular polymer matrix can represent as much as 90% of the biofilm and primarily comprises polysaccharides and proteins with the presence of nucleic acids.
- the extracellular matrix is not limited to keeping the bacterial cells united but is organised in an architecture consisting of a network of channels that allow the distribution of the nutritional substances and the removal of the waste products, while amounting to a primitive circulatory system. Since the availability of nutrients is inevitably reduced with the increased distance of each channel, the bacteria adapt from a metabolic point of view depending on the position within the biofilm, while also taking into account the oxygen gradient recordable between the surface layers and the deepest component.
- the biofilm appears to represent a superior evolutionary level than the level intrinsic to the individual or multiple species that comprise it, which are not limited to an advantageous mutualistic symbiosis, but achieve a supracellular organisation that is capable of maintaining itself and, in a certain way, of reproducing itself.
- the phenomenon of the release of bacteria from the biofilm does not translate into dissolution of the carrier structure with dispersion of the cellular elements, but consists of the detachment of individual bacteria or of bacteria in small aggregates, promoted by the secretion of enzymes capable of modifying the substrate or of degrading the polysaccharide structure at certain peripheral points, without however compromising the persistence of the microcolony .
- the bacteria that reside in the vagina which can be of a varying nature, are the most frequent condition in women of reproductive age.
- bacterial vaginal infections affect around 20% of Caucasian women and 50% of Afro- American women, based on the population studied.
- a healthy vagina is predominantly populated by lactobacilli, which prevent the growth of other vaginal flora.
- lactobacilli The settlement of pathogenic vaginal bacteria causes a loss of these protective lactobacilli, an increase beyond 4.5 in the pH of the vagina and the proliferation of varieties of anaerobic species.
- the most common symptoms can include a light, greyish-white vaginal discharge associated with an unpleasant smell and a slight irritation. If not treated in time, such bacterial infections can lead to more serious pathologies and adverse outcomes in pregnancy such a premature delivery, low birth weight and postpartum endometritis
- Atopobium vaginae is a bacterium of the Atopobium genus, the most studied species; one significant aspect of this bacterium is that it is detected with difficulty in the vagina of healthy women, while it is presence in the vaginal secretions of more than 50% of women with bacterial vaginosis.
- the bacterium seems to be a normal saprophyte of the bacterial flora of the healthy vagina (presumably with a low bacterial load) , but can become predominant due to rapid growth when the conditions for a decrease in the normal lactobacilli flora are met.
- the bacterium will be able to coexist with the better known Gardnerella vaginalis in the course of symptomatic bacterial vaginosis.
- the bacterial biofilm formation contributes to the proliferation of the bacteria within it and to their survival against the attacks of antibiotic therapy.
- the bacteria that make up the biofilm are mostly refractory to the immune defences of the host and to the activity of the antibiotic and pharmacological therapies, since the biofilms themselves constitute a reserve of pathogens that are responsible for recurring forms.
- the antibiotic therapy succeeds at most in destroying the outermost bacteria, which are in a metabolic activity phase, while the innermost cells of the biofilm are refractory to therapy by virtue of the state of vegetative dormancy that they are in.
- the biofilm matrix forms a sort of "protective film”, which prevents or anyhow slows down, the penetration of the antibiotic within the micro- colony, leaving it exposed to bacterial inactivation factors such as beta-lactamases , which destroy the beta-lactam ring typical of many antibiotics such as penicillins, cephamycins and carbapenems .
- the biofilms can organise themselves on the surface of different mucosae, including the vaginal mucosa, or on the surface of medical devices implanted or inserted in the body.
- the intrauterine device and the diaphragm can increase the likelihood of the occurrence of genital infections.
- the biofilms On account of the presence of the polysaccharide sheath, the biofilms have a significant importance for health, given their role in many chronic infections and their importance in a high number of biomedical implant infections; these infections of a recurring nature appear untreatable with antibiotic therapy.
- the main aspect of the present invention is to provide an effective product for use in the treatment of vaginal pathologies caused by microorganisms .
- one aim of the invention is to produce a product for use in the treatment of vaginal pathologies caused by bacteria, fungi and/or protozoa.
- Another aim of the present invention is to provide a product for use that is capable of breaking down the biofilm produced by the pathogenic microorganisms and reducing the load of such pathogenic microorganisms within the biofilm itself .
- the present invention proposes to produce a product for use in the treatment of vaginal infections that is capable of breaking down the colonies of pathogenic microorganisms, by completely eliminating them, in particular by also acting on the microorganisms that are in a state of dormancy in the innermost layers of the biofilm.
- a further aim of the invention is that of creating a product for use that in combination with the traditional antibiotic therapy is capable of preserving the efficacy of the antibiotics on the microorganisms, even in the presence of biofilm .
- N- acetyl cysteine for use in the restoration of the vaginal ecosystem and/or in the treatment of vaginal pathologies via administration by vaginal route .
- compositions comprising N-acetyl cysteine for use in the restoration of the vaginal ecosystem and/or in the treatment of vaginal pathologies, via administration by vaginal route.
- N-acetyl cysteine is a mucolytic substance and is a derivative of the natural amino acid cysteine, from which it differs by virtue of the introduction of an acetyl group on the nitrogen atom of the amino terminal.
- N-acetyl cysteine has shown good properties in terms of combating bacterial infections.
- NAC presents good activity in terms of inhibiting bacterial adhesion and in dissolving the biofilm matrix.
- the present invention is directed at the treatment of the infectious pathologies that affect the female genital area, in particular the vaginal tract.
- the eradication of vaginal pathogens is of particular relevance since it is the first, necessary step in restoring the bacterial flora normally present at the level of the vaginal mucosa and whose role is essential for correct vaginal function.
- compositions preferably a pharmaceutical composition, comprising N-acetyl cysteine for use in restoring the vaginal ecosystem and/or in the treatment of vaginal pathologies.
- Said composition for use is advantageously administered by vaginal route, so as to directly channel the active substances to the site in which they must exert their pharmacological action. A more targeted effect is thus achieved and any collateral effects associated to the routes of administration that also interest other regions of the body other than the vagina are limited.
- the composition for use comprising NAC can be used to treat vaginal pathologies caused by microorganisms selected from the group comprising bacteria, fungi, protozoa and combinations thereof.
- biofilm produced by the bacteria offers a favourable environment for the colonisation and the growth of microorganisms
- pathogens such as fungi and protozoa can in turn settle within or in proximity to the bacterial biofilm.
- microorganisms can be Diphtheroids, Streptococci, Staphylococci, and
- Neisseria gonorrheae Neisseria gonorrheae, Chlamydia trachomatis, Candida, Trichomonas.
- composition for use comprising N- acetyl cysteine is administered individually or administered simultaneously, sequentially or separately in combination with one or more additional active pharmaceutical ingredients such as for example one or more substances having a bactericidal and/or antimycotic pharmacological action .
- composition for use may also comprise, in addition to NAC, one or more additional active pharmaceutical ingredients, such as for example one or more substances having a bacterial and/or antimycotic pharmacological action .
- said one or more substances having bactericidal and/or antimycotic pharmacological action can be antibiotics.
- said antibiotics can be imidazole antibiotics (for example clotrimazole), nitroimidazole antibiotics (for example metronidazole), cephalosporins (for example ceftriaxone or cefixime), flourochinolones (for example ciprofloxacin or ofloxacin), tetracyclines (for example doxycycline) , lincosamide antibiotics (for example clindamycin).
- N-acetyl cysteine and the active pharmacological ingredient where the latter should be represented by an antibiotic of the tetracycline class.
- composition for use of the present invention can further comprise one or more excipients normally used in pharmaceutical practice .
- the composition for use according to the present invention is administered by vaginal route. More specifically, in one preferred embodiment, the composition for use can be administered as a vaginal douche. In another embodiment, the composition for use can be administered as a vaginal pessary. The composition for use can also be administered in the form of cream to be applied vaginally. Lastly, the composition for use can be administered as a gynaecological solution.
- the amount of NAC be of between 10 and 500 mg, more preferably of between 20 and 100 mg, even more preferably the amount of NAC can be equal to 40 mg.
- the amount of NAC be of between 50 and 2,000 mg/lOOml, more preferably of between 100 and 1,500 mg/lOOml, even more preferably the amount of NAC can be equal to 1,000 mg/lOOml.
- composition for use of the invention can be applied intravaginally with the aid of a medical device.
- the composition for use can be released by a medical device placed in the vagina.
- composition for use can also be applied onto an internal absorbent tampon, and is therefore absorbed by the vaginal mucosa during the time that the tampon is in place.
- the biofilm offers bacteria good protection against attack by said substances.
- the composition for use of the invention is nevertheless advantageously capable of breaking down the bacterial biofilm, therefore decreasing the physical resistance of the pathogens to the entry of pharmacological substances within the colony of microorganisms itself and allowing an effective treatment of the vaginal infection.
- composition for use comprising N-acetyl cysteine according to the invention is also capable of combating the vaginal pathologies preventing the proliferation of the bacteria and of other pathogens.
- composition for use of the invention can also be administered as an antioxidant.
- the composition for use can be used to treat the vaginal pathologies by reducing vaginal oxidative stress .
- the present invention also relates to a method for the restoration of the vaginal ecosystem and/or the treatment of vaginal pathologies by administration by vaginal route to a patient of N-acetyl cysteine or a composition thereof, individually or simultaneously, sequentially or separately in combination with one or more additional active pharmaceutical ingredients, such as for example one or more substances having a bactericidal and/or Antimycotic pharmacological action.
- the inventor of the present invention initially conducted in-vitro studies from which the efficacy of N-acetyl cysteine in the breakdown of the biofilm and in the reduction of the number of vital forms of bacteria present in the biofilms produced by bacteria grown in the vagina that were previously cultured, has emerged. These studies have highlighted the activity of NAC, in that it has been observed that this substance caused a decrease in the optical density of the biofilm; in addition, NAC completely inhibited the growth of four strains of bacteria and decreased to 50% the number of remaining bacteria. This study has also highlighted that NAC reduces biofilm formation and can therefore be a valid support to the action of the therapies used to combat the bacteria.
- N-acetyl cysteine administered in vivo repeated the results achieved in the in vivo trial.
- the capacity of N-acetyl cysteine to reduce bacterial biofilm formation was verified; in parallel, the capacity of this compound to break down the biofilm with different degrees of maturity (from initial to fully consolidated) was also evaluated.
- the effects of the substances associated with NAC on the vitality of the bacteria that form the biofilm were determined at the same time.
- N-acetyl cysteine and the composition thereof for use according to the invention fully fulfil the set aim in that they are able to break down the bacterial biofilm and to markedly reduce the bacterial load within the biofilm itself.
- the breakdown action of the biofilm mediated by NAC allows the infection to be combated in significantly reduced timeframes compared to pharmacological therapy alone.
- N-acetyl cysteine and the composition thereof for use are susceptible to numerous modifications and variants, all falling within the scope of the creative design; in addition, all the details can be replaced by other equivalent elements whose correspondence is known to sector technicians .
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Abstract
The present invention relates to N-acetyl cysteine and to a composition comprising N-acetyl cysteine for use in the restoration of the vaginal ecosystem and/or in the treatment of vaginal pathologies characterised in that the administration of N-acetyl cysteine or of the composition comprising N-acetyl cysteine takes place by vaginal route.
Description
N—ACETYL CYSTEINE AND COMPOSITION THEREOF FOR USE IN THE TREATMENT OF VAGINAL PATHOLOGIES.
Field of the invention
The present invention relates to N-acetyl cysteine and a composition thereof for use in the restoration of the vaginal ecosystem and/or in the treatment of vaginal pathologies.
State of the art
A number of vaginal pathologies are caused by microorganisms such as bacteria (for example Gardnerella vaginalis), fungi (for example Candida albicans) or protozoa (for example Trichomonas vaginalis) . The nesting of pathogens of this type in the vagina not only causes the infection thereof due their propagation, but also a reduction in the biological flora normally present in the vaginal environment, which has the role of maintaining the correct physiological conditions (for example the correct pH) of the vagina.
It has been observed that the microorganisms, including those responsible for vaginal pathologies, tend not to remain isolated but to group together in colonies, confirming that tendency to "socialise", which appears intrinsic to living matter from the most elementary forms, with extremely rare exceptions. If said adaptive "behaviour" has had such great success it is an evident sign that has undoubted advantages. The very analysis of said favourable aspects has permitted unexpected defence strategies, that the pathogenic bacteria use to neutralise the
pharmacological therapies and to get around the host's defences, to be highlighted,
One of the strategies selected by the microorganisms in order to increase the possibility of survival in the environment and inside the human body is represented by the so- called biofilm.
The biofilm is not however a simple aggregate in which the proximity of the germs one to the other makes their neutralisation more difficult. On the basis of scanning electron microscopy analysis and of the study of the internal dynamics, it appears that the biofilm represents a form, albeit an extremely primordial form, of three- dimensional organisation of unicellular elements, in which the resulting survival capacity of the entire colony does not correspond to the sum of the survival capacities of the individual elements.
The non-variable characteristics in the biofilm formation are the need for a surface onto which to adhere and the production of a substance defined "extracellular polymer matrix", which maintains the cohesion between the individual microorganisms that make up the biofilm. On the other hand, the macroscopic aspect and the environmental substances included in the matrix (e.g. blood components, mineral crystals, mud particles) are variable. The biofilm maturation process comprises 5 stages:
1. the first phase entails the slowing of the movement speed of the microorganisms and their
adhesion to an organic surface (e.g. mucous membrane, blood, secretions, saliva, urine) or inorganic, possibly rough surface;
2. in the second phase, the bacteria are moved along the surface until they meet other bacteria; the anchoring of the bacteria to the colony surface sets off a cascade of reactions, which activate the otherwise repressed genes responsible for the biofilm phenotype;
3. the central phenomenon of the third phase is the stable intercellular adhesion of biochemical nature (bacterial surface proteins), followed by the production of the extracellular polymer matrix of the polysaccharide type, promoted by the adhesion itself; the bacteria communicate among themselves through biochemical substances, capable of regulating, amongst other things, the density of the bacterial population of the biofilm and consequently the reciprocal behaviour of the elements;
4. the fourth phase consists of biofilm growth; this process, defined maturation, involves all the biofilm components. i.e. both the cellular elements and the exopolysaccharide substance; the cellular elements are reproduced so as to form bacterial "towers" immersed in the matrix and connected by channels;
5. in the fifth phase, the release into the environment of bacteria in planktonic form, or in the form of "bacterial emboli", is observed.
The extracellular polymer matrix can represent
as much as 90% of the biofilm and primarily comprises polysaccharides and proteins with the presence of nucleic acids. The extracellular matrix is not limited to keeping the bacterial cells united but is organised in an architecture consisting of a network of channels that allow the distribution of the nutritional substances and the removal of the waste products, while amounting to a primitive circulatory system. Since the availability of nutrients is inevitably reduced with the increased distance of each channel, the bacteria adapt from a metabolic point of view depending on the position within the biofilm, while also taking into account the oxygen gradient recordable between the surface layers and the deepest component.
The biofilm appears to represent a superior evolutionary level than the level intrinsic to the individual or multiple species that comprise it, which are not limited to an advantageous mutualistic symbiosis, but achieve a supracellular organisation that is capable of maintaining itself and, in a certain way, of reproducing itself. Indeed, the phenomenon of the release of bacteria from the biofilm does not translate into dissolution of the carrier structure with dispersion of the cellular elements, but consists of the detachment of individual bacteria or of bacteria in small aggregates, promoted by the secretion of enzymes capable of modifying the substrate or of degrading the polysaccharide
structure at certain peripheral points, without however compromising the persistence of the microcolony .
The bacteria that reside in the vagina, which can be of a varying nature, are the most frequent condition in women of reproductive age. In particular, bacterial vaginal infections affect around 20% of Caucasian women and 50% of Afro- American women, based on the population studied.
Normally, a healthy vagina is predominantly populated by lactobacilli, which prevent the growth of other vaginal flora. The settlement of pathogenic vaginal bacteria causes a loss of these protective lactobacilli, an increase beyond 4.5 in the pH of the vagina and the proliferation of varieties of anaerobic species. The most common symptoms can include a light, greyish-white vaginal discharge associated with an unpleasant smell and a slight irritation. If not treated in time, such bacterial infections can lead to more serious pathologies and adverse outcomes in pregnancy such a premature delivery, low birth weight and postpartum endometritis
Recent studies have indicated that the bacteria that develop in the vagina are equipped with a certain number of virulence properties. The biofilm that the bacterium tends to form promotes the incorporation of other groups of bacteria in its layers, promoting the colonisation of the vagina by other anaerobic bacteria.
Atopobium vaginae is a bacterium of the
Atopobium genus, the most studied species; one significant aspect of this bacterium is that it is detected with difficulty in the vagina of healthy women, while it is presence in the vaginal secretions of more than 50% of women with bacterial vaginosis. The bacterium seems to be a normal saprophyte of the bacterial flora of the healthy vagina (presumably with a low bacterial load) , but can become predominant due to rapid growth when the conditions for a decrease in the normal lactobacilli flora are met. The bacterium will be able to coexist with the better known Gardnerella vaginalis in the course of symptomatic bacterial vaginosis.
As has been mentioned above, the bacterial biofilm formation contributes to the proliferation of the bacteria within it and to their survival against the attacks of antibiotic therapy. The bacteria that make up the biofilm are mostly refractory to the immune defences of the host and to the activity of the antibiotic and pharmacological therapies, since the biofilms themselves constitute a reserve of pathogens that are responsible for recurring forms. Indeed, the antibiotic therapy succeeds at most in destroying the outermost bacteria, which are in a metabolic activity phase, while the innermost cells of the biofilm are refractory to therapy by virtue of the state of vegetative dormancy that they are in. The biofilm matrix forms a sort of "protective film", which prevents or anyhow slows down, the
penetration of the antibiotic within the micro- colony, leaving it exposed to bacterial inactivation factors such as beta-lactamases , which destroy the beta-lactam ring typical of many antibiotics such as penicillins, cephamycins and carbapenems .
The biofilms can organise themselves on the surface of different mucosae, including the vaginal mucosa, or on the surface of medical devices implanted or inserted in the body. The intrauterine device and the diaphragm, for example, can increase the likelihood of the occurrence of genital infections. Signalling molecules, produced by the microorganisms themselves, influence the formation, the development of the biofilms and the interaction between the microorganisms. On account of the presence of the polysaccharide sheath, the biofilms have a significant importance for health, given their role in many chronic infections and their importance in a high number of biomedical implant infections; these infections of a recurring nature appear untreatable with antibiotic therapy.
It therefore follows that the efficacy of the antibiotic treatments generally used to eradicate the infections is limited, on account of the presence of the biofilm, compared to the effective potentialities of such treatments.
Summary of the invention
The main aspect of the present invention is to provide an effective product for use in the
treatment of vaginal pathologies caused by microorganisms .
Within the scope of this aspect, one aim of the invention is to produce a product for use in the treatment of vaginal pathologies caused by bacteria, fungi and/or protozoa.
Another aim of the present invention is to provide a product for use that is capable of breaking down the biofilm produced by the pathogenic microorganisms and reducing the load of such pathogenic microorganisms within the biofilm itself .
In greater detail, the present invention proposes to produce a product for use in the treatment of vaginal infections that is capable of breaking down the colonies of pathogenic microorganisms, by completely eliminating them, in particular by also acting on the microorganisms that are in a state of dormancy in the innermost layers of the biofilm.
A further aim of the invention is that of creating a product for use that in combination with the traditional antibiotic therapy is capable of preserving the efficacy of the antibiotics on the microorganisms, even in the presence of biofilm .
This aspect, and these and other aims that will become clearer below, are achieved by the N- acetyl cysteine for use in the restoration of the vaginal ecosystem and/or in the treatment of vaginal pathologies via administration by vaginal
route .
The aspects and the aims of the invention are also achieved by a composition comprising N-acetyl cysteine for use in the restoration of the vaginal ecosystem and/or in the treatment of vaginal pathologies, via administration by vaginal route.
Further characteristics and advantages of the invention will become clearer in the following detailed description of the invention.
Detailed description of the invention
N-acetyl cysteine, or NAC, is a mucolytic substance and is a derivative of the natural amino acid cysteine, from which it differs by virtue of the introduction of an acetyl group on the nitrogen atom of the amino terminal.
It has been observed that N-acetyl cysteine has shown good properties in terms of combating bacterial infections. In particular, it has been observed that NAC presents good activity in terms of inhibiting bacterial adhesion and in dissolving the biofilm matrix.
Recent studies conducted by the inventor of the present invention have confirmed the efficacy of NAC in the breakdown and in the reduction of the number of vital forms of bacteria present in the biofilms. Furthermore, the observation of the inventor of the present invention on the activity of N-acetyl in association with antibiotics is of particular interest. In fact, on administering NAC or the composition comprising NAC in combination with the antibiotics, an antibacterial synergistic
effect, i.e. greater than the sum of the antibacterial effects achieved by each substance when administered individually, was observed. This discovery is therefore important for the purposes of achieving the treatment of infectious pathologies determined by film-forming microorganisms, which, as mentioned above, are almost impossible to eradicate with standard antibiotic therapies. In particular, the present invention is directed at the treatment of the infectious pathologies that affect the female genital area, in particular the vaginal tract. The eradication of vaginal pathogens is of particular relevance since it is the first, necessary step in restoring the bacterial flora normally present at the level of the vaginal mucosa and whose role is essential for correct vaginal function.
One aspect of the present invention therefore relates to a composition, preferably a pharmaceutical composition, comprising N-acetyl cysteine for use in restoring the vaginal ecosystem and/or in the treatment of vaginal pathologies. Said composition for use is advantageously administered by vaginal route, so as to directly channel the active substances to the site in which they must exert their pharmacological action. A more targeted effect is thus achieved and any collateral effects associated to the routes of administration that also interest other regions of the body other than the vagina are limited.
In one embodiment thereof, the composition for use comprising NAC can be used to treat vaginal pathologies caused by microorganisms selected from the group comprising bacteria, fungi, protozoa and combinations thereof. In fact, since the biofilm produced by the bacteria, as previously mentioned, offers a favourable environment for the colonisation and the growth of microorganisms, other types of pathogens, such as fungi and protozoa can in turn settle within or in proximity to the bacterial biofilm.
For example, such microorganisms can be Diphtheroids, Streptococci, Staphylococci,
Bacteroids, Mycoplasmas, Peptococcus, Lactobacillus acidophilus, Escherichia coli, Gardnerella vaginalis, Atopobium vaginae,
Neisseria gonorrheae, Chlamydia trachomatis, Candida, Trichomonas.
In addition, in one embodiment of the present invention, the composition for use comprising N- acetyl cysteine is administered individually or administered simultaneously, sequentially or separately in combination with one or more additional active pharmaceutical ingredients such as for example one or more substances having a bactericidal and/or antimycotic pharmacological action .
In a preferred embodiment, the composition for use may also comprise, in addition to NAC, one or more additional active pharmaceutical ingredients, such as for example one or more substances having
a bacterial and/or antimycotic pharmacological action .
Preferably, said one or more substances having bactericidal and/or antimycotic pharmacological action can be antibiotics. More preferably, said antibiotics can be imidazole antibiotics (for example clotrimazole), nitroimidazole antibiotics (for example metronidazole), cephalosporins (for example ceftriaxone or cefixime), flourochinolones (for example ciprofloxacin or ofloxacin), tetracyclines (for example doxycycline) , lincosamide antibiotics (for example clindamycin).
In one embodiment, it is preferable to separately administer N-acetyl cysteine and the active pharmacological ingredient where the latter should be represented by an antibiotic of the tetracycline class.
Naturally, the composition for use of the present invention can further comprise one or more excipients normally used in pharmaceutical practice .
As has been previously mentioned, the composition for use according to the present invention is administered by vaginal route. More specifically, in one preferred embodiment, the composition for use can be administered as a vaginal douche. In another embodiment, the composition for use can be administered as a vaginal pessary. The composition for use can also be administered in the form of cream to be applied vaginally. Lastly, the composition for use can be
administered as a gynaecological solution.
In the event that the composition for use according to the invention should be administered in the form of pessaries or creams it is preferable that the amount of NAC be of between 10 and 500 mg, more preferably of between 20 and 100 mg, even more preferably the amount of NAC can be equal to 40 mg.
In the event that the composition for use according to the invention should be administered in the form of gynaecological solution it is preferable that the amount of NAC be of between 50 and 2,000 mg/lOOml, more preferably of between 100 and 1,500 mg/lOOml, even more preferably the amount of NAC can be equal to 1,000 mg/lOOml.
It is also possible for the composition for use of the invention to be applied intravaginally with the aid of a medical device. Alternatively, the composition for use can be released by a medical device placed in the vagina.
Advantageously, the composition for use can also be applied onto an internal absorbent tampon, and is therefore absorbed by the vaginal mucosa during the time that the tampon is in place.
It has already been explained how, due to its structure and to its composition that presents low permeation to antibiotics and other medicinal products used to eradicate microorganism infections, the biofilm offers bacteria good protection against attack by said substances. The composition for use of the invention is
nevertheless advantageously capable of breaking down the bacterial biofilm, therefore decreasing the physical resistance of the pathogens to the entry of pharmacological substances within the colony of microorganisms itself and allowing an effective treatment of the vaginal infection.
Furthermore, the composition for use comprising N-acetyl cysteine according to the invention is also capable of combating the vaginal pathologies preventing the proliferation of the bacteria and of other pathogens.
Further still, the composition for use of the invention can also be administered as an antioxidant. In particular, in one embodiment, the composition for use can be used to treat the vaginal pathologies by reducing vaginal oxidative stress .
Although the preferred embodiments of the invention have been described with reference to the composition for use herein described, the characteristics of said preferred embodiments are also to be deemed valid with reference to the N- acetyl cysteine for use in the restoration of the vaginal ecosystem and/or in the treatment of the vaginal pathologies herein described.
Lastly, in another aspect the present invention also relates to a method for the restoration of the vaginal ecosystem and/or the treatment of vaginal pathologies by administration by vaginal route to a patient of N-acetyl cysteine or a composition thereof, individually or
simultaneously, sequentially or separately in combination with one or more additional active pharmaceutical ingredients, such as for example one or more substances having a bactericidal and/or Antimycotic pharmacological action.
It is to be understood that the characteristics of the embodiments described with reference to the composition for use of the present invention are also to be deemed valid as regards the herein described method of restoration and/or treatment, even if not expressly repeated.
The inventor of the present invention initially conducted in-vitro studies from which the efficacy of N-acetyl cysteine in the breakdown of the biofilm and in the reduction of the number of vital forms of bacteria present in the biofilms produced by bacteria grown in the vagina that were previously cultured, has emerged. These studies have highlighted the activity of NAC, in that it has been observed that this substance caused a decrease in the optical density of the biofilm; in addition, NAC completely inhibited the growth of four strains of bacteria and decreased to 50% the number of remaining bacteria. This study has also highlighted that NAC reduces biofilm formation and can therefore be a valid support to the action of the therapies used to combat the bacteria.
Following the results achieved in the in-vitro study, the efficacy of N-acetyl cysteine in vivo was then studied via administration by vaginal route, both individually and in association with
other substances.
The individual administration of N-acetyl cysteine in vivo repeated the results achieved in the in vivo trial. In particular, the capacity of N-acetyl cysteine to reduce bacterial biofilm formation was verified; in parallel, the capacity of this compound to break down the biofilm with different degrees of maturity (from initial to fully consolidated) was also evaluated. The effects of the substances associated with NAC on the vitality of the bacteria that form the biofilm were determined at the same time.
46 women presenting bacterial vaginal biofilm were recruited for the in vivo study; 18 women were administered NAC by vaginal route associated with a pharmacological therapy (pessaries, creams or gynaecological solutions with the addition of NAC or antibiotics by oral route with administration of cream, pessaries or gynaecological solutions with NAC) , while the other 18 women were administered only the pharmacological therapy. Lastly, the remaining 10 patients were only treated with NAC by vaginal route. In the groups treated with the compound according to the invention (the 18 patients that received NAC with a pharmacological therapy and the 10 patients to whom only NAC was administered) , a breakdown of the bacterial biofilm was observed from the very first applications, while the same effect was not achieved in women treated without NAC. After 3/4 days of the start of the therapy,
in the patients to whom the composition for use of the invention comprising NAC and a pharmacological therapy was administered, a total breakdown of the bacterial biofilm, reduced by almost 100% and the almost total absence of the bacteria that had caused it, was observed. In the women treated with only NAC, a 55% reduction of the bacterial biofilm was found on the fifth day of administration, but with the presence of the bacteria that had formed it. In the patients treated with only the pharmacological therapy, a 10% reduction of the bacterial biofilm was observed on the sixth day, with maintenance of the bacteria that had formed it and only a 60% reduction of the biofilm mass was observed on the 14th day.
In the light of the above, it has been in practice stated how N-acetyl cysteine and the composition thereof for use according to the invention fully fulfil the set aim in that they are able to break down the bacterial biofilm and to markedly reduce the bacterial load within the biofilm itself. In particular, it has been observed how the breakdown action of the biofilm mediated by NAC allows the infection to be combated in significantly reduced timeframes compared to pharmacological therapy alone.
N-acetyl cysteine and the composition thereof for use, thus devised, are susceptible to numerous modifications and variants, all falling within the scope of the creative design; in addition, all the details can be replaced by other equivalent
elements whose correspondence is known to sector technicians .
Claims
1. Composition comprising N-acetyl cysteine for use in the restoration of the vaginal ecosystem and/or in the treatment of vaginal pathologies via administration by vaginal route.
2. Composition for use according to claim 1 wherein said vaginal pathologies are caused by a microorganism selected from the group comprising bacteria, fungi, protozoa and combinations thereof 3. Composition for use according to claim 1 or
2, wherein said composition is administered simultaneously, sequentially or separately in combination with one or more additional active pharmaceutical ingredients, preferably one or more substances having a bactericidal and/or antimycotic pharmacological action.
4. Composition for use according to claim 1 or 2, further comprising one or more additional active pharmaceutical ingredients, preferably one or more substances having a bactericidal and/or antimycotic pharmacological action.
5. Composition for use according to claim 3 or 4, wherein said one or more substances having a bactericidal and/or antimycotic pharmacological action are antibiotics.
6. Composition for use according to claim 5, wherein said antibiotics are selected from the group comprising nitroimidazole antibiotics, imidazole antibiotics, cephalosporins, flourochinolones, tetracyclines, lincosamide antibiotic and combinations thereof.
7. Composition for use according to one or more of the preceding claims in a pharmaceutical form selected from the group comprising a douche, a vaginal pessary, a cream and a gynaecological solution.
8. Composition for use according to claim 7, wherein the pharmaceutical form is represented by a vaginal pessary or a cream, and wherein NAC is present in an amount of between 20 and 100 mg.
9. Composition for use according to claim 7, wherein the pharmaceutical form is represented by a gynaecological solution, and wherein NAC is present in an amount of between 50 and 2,000 mg/100 ml.
10. Composition for use according to one or more of the preceding claims wherein the composition is released by or applied with a medical device.
11. Composition for use according to one or more of claims 1 to 9, wherein the composition is applied on an internal absorbent tampon.
12. Composition for use according to one or more of the preceding claims, wherein the treatment of the vaginal pathologies comprises the breakdown of the bacterial biofilm.
13. Composition for use according to one or more of the preceding claims, wherein the treatment of the vaginal pathologies comprises the impediment of bacterial proliferation.
14. Composition for use according to one or more of the preceding claims, wherein the treatment of the vaginal pathologies comprises the reduction of vaginal oxidative stress.
15. N-acetyl cysteine for use in the restoration of the vaginal ecosystem and/or in the treatment of vaginal pathologies via administration by vaginal route.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT001151A ITMI20111151A1 (en) | 2011-06-24 | 2011-06-24 | N-ACETYL CISTEIN AND ITS COMPOSITION FOR USE IN THE TREATMENT OF VAGINAL DISORDERS. |
ITMI2011A001151 | 2011-06-24 |
Publications (1)
Publication Number | Publication Date |
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WO2012175659A1 true WO2012175659A1 (en) | 2012-12-27 |
Family
ID=44555384
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2012/062068 WO2012175659A1 (en) | 2011-06-24 | 2012-06-22 | N-acetyl cysteine and composition thereof for use in the treatment of vaginal pathologies |
Country Status (2)
Country | Link |
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IT (1) | ITMI20111151A1 (en) |
WO (1) | WO2012175659A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105232753A (en) * | 2015-11-11 | 2016-01-13 | 青岛麦瑞特医药技术有限公司 | Traditional Chinese medicine external preparation for treating trichomonas vaginitis |
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WO2009052630A1 (en) * | 2007-10-26 | 2009-04-30 | Pacific Therapeutics Ltd. | Compositions and methods for treating fibroproliferative disorders |
WO2009070638A1 (en) * | 2007-11-30 | 2009-06-04 | Toltec Pharmaceuticals, Llc | Compositions and methods for treating vaginal infections and pathogenic vaginal biofilms |
WO2009085317A1 (en) * | 2007-12-31 | 2009-07-09 | Tyco Healthcare Group Lp | Disinfectant compositions, methods and systems |
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2011
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2012
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WO2002041837A2 (en) * | 2000-11-22 | 2002-05-30 | Rxkinetix, Inc. | Treatment of mucositis |
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WO2009052630A1 (en) * | 2007-10-26 | 2009-04-30 | Pacific Therapeutics Ltd. | Compositions and methods for treating fibroproliferative disorders |
WO2009070638A1 (en) * | 2007-11-30 | 2009-06-04 | Toltec Pharmaceuticals, Llc | Compositions and methods for treating vaginal infections and pathogenic vaginal biofilms |
WO2009085317A1 (en) * | 2007-12-31 | 2009-07-09 | Tyco Healthcare Group Lp | Disinfectant compositions, methods and systems |
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VENKATESH M PAMMI ET AL: "Biofilm Inhibitors N-Acetyl Cysteine, EDTA, and Ethanol Exhibit Synergy with Antibiotics Against Biofilms of Candida albicans and Staphylococcus epidermidis", ABSTRACTS OF THE INTERSCIENCE CONFERENCE ON ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 48, 2008, & 48TH ANNUAL INTERSCIENCE CONFERENCE ON ANTIMICROBIAL AGENTS AND CHEMOTHERAPY/46TH ANNUAL MEETING OF; WASHINGTON, DC, USA; 20081025,, pages 111, XP008147334, ISSN: 0733-6373 * |
Cited By (1)
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CN105232753A (en) * | 2015-11-11 | 2016-01-13 | 青岛麦瑞特医药技术有限公司 | Traditional Chinese medicine external preparation for treating trichomonas vaginitis |
Also Published As
Publication number | Publication date |
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ITMI20111151A1 (en) | 2012-12-25 |
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