• 专利附录
  • 专利说明
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    • 专利摘要:
    EFERVESCENT COMPOSITION IN SOLID FORM FOR USE IN VAGINAL APPLICATIONS FOR THE TREATMENT OF VAGINAL INFECTIONS. The present invention relates to an effervescent composition in solid form for use in vaginal applications for the treatment of vaginal infections.
    公开号:BR112013018953B1
    申请号:R112013018953-3
    申请日:2012-01-24
    公开日:2020-12-29
    发明作者:Giovanni Mogna；Gian Paolo Strozzi；Luca Mogna
    申请人:Probiotical S.P.A；
    IPC主号:
    专利说明:

    [001] The present invention relates to an effervescent composition in solid form for use in vaginal applications for the treatment of vaginal infections.
    [002] It is known that the composition of intestinal and urogeenital microflora represents a critical point for the health and well-being of an individual. The vaginal ecosystem consists of epithelial cells that line the vagina and uterus, glandular cells that secrete in the lumen of the organ and complex bacterial flora represented by different species of microorganisms.
    [003] These microorganisms have the ability to ferment glycogen from the decomposition of parabasal cells of the eutrophic vaginal mucosa, with a consequent production of lactic acid, the final effect of which is the establishment and maintenance of an acid vaginal environment (with values of pH of 4-4.5 under physiological conditions).
    [004] H + from lactic acid contributes to the formation of hydrogen peroxide. This molecule is toxic to a large number of bacterial species, which lack the catalase enzyme. At the level of vaginal secretions, concentrations of 0.75-5 μg / mL are easily achieved and are abundantly sufficient for the toxic effect to be expressed.
    [005] The combined action of hydrogen peroxide, peroxidaseuterine (produced by the cervix and endometrium) and ions of Cl-and I- also limits bacterial growth by directly activating polymorphonucleated, which exert a bactericidal action in spaces - epithelial cells.
    [006] In women, due to a variety of exogenous and endogenous factors, such as the consumption of antibiotics, tension states, hormonal modulations associated with pregnancy and the menstrual cycle or ingestion of high concentrations of estrogen, an imbalance often occurs in the vaginal ecosystem. The change in the balance of the vaginal ecosystem leads to a prevalence of the so-called "opportunistic" microorganisms (for example, Candida albicans and glabrata) and / or pathogenic microorganisms (for example, Neisseria gonorrhoeae and Trichomonas vaginalis), which can lead to candidiasis, vaginitis or forms of vaginosis.
    [007] Epidemiological data show that vaginal infections today affect more than one billion women worldwide each year, with serious socioeconomic repercussions.
    [008] The therapy generally adopted is an antibiotic and / or fungicide which, usually, has given good results in the short term, but proves to be unable to prevent recurrent infections due to its increasing resistance against pathogens. In addition, not all individuals who need to be treated are able to undertake and tolerate antibiotic or fungicide therapy.
    [009] The use of microorganisms capable of restoring the correct composition of the vaginal microflora is known.
    [0010] However, the mode of distribution of microorganisms to the vaginal environment represents a very critical factor. It is known, for example, that soft gelatin capsules, generally known as soft gel, require suspension of the probiotic component in an oily matrix which, after application of the product, tends to constitute a barrier capable of reducing or inhibiting almost entirely the ability of said probiotic component to colonize the vaginal mucosa. In addition, the oily matrix could have a toxic effect on microorganisms, to such an extent as to significantly reduce their number and viability.
    [0011] For example, the capsules can take a relatively long time to dissolve and, in any case, they do not ensure an adequate dispersion of the active ingredient throughout the vaginal environment.
    [0012] For example, hydrophilic suspensions or hydrogels require an application method that is neither easy nor very comfortable. In fact, individuals should lie down for at least 20-30 minutes after applying them, in order to prevent the product from leaking.
    [0013] Finally, traditional vaginal pills represent a problem of high mortality rate of microorganisms during their manufacture and, in addition, they are not able to guarantee an adequate distribution of microorganisms to the vaginal environment.
    [0014] Thus, there is still a need for a composition capable of distributing probiotic bacteria to the vaginal environment and which ensures their complete dispersion / distribution.
    [0015] In addition, there is still a need for a pharmaceutical form that can be easily administered and is practical to use.
    [0016] In particular, there is still a need for a composition that constitutes a valid alternative to therapy with antibiotics and / or fungicide and, at the same time, represents an improvement over the known forms of administration.
    [0017] The Applicant has surprisingly found that a probiotic formulation in the form of a properly prepared solid composition is able to solve the problems that persist in the prior art.
    [0018] The object of the present invention is an effervescent composition in solid form, as presented in the attached independent claim.
    [0019] Other preferred embodiments of the present invention are shown in the attached dependent claims.
    [0020] Table 1 shows the bacterial strains tested by the Applicant and which constitute the objective of the present invention.
    [0021] Table 2 shows an example of a composition according to the invention.
    [0022] Table 3 shows the mortality data for the probiotic bacteria according to the different pressures exerted and the stability of the tablets (expressed as the half-life of the bacterial load) after 2 years of storage at 25 ° C.
    [0023] Table 4 shows a composition that is not in conformity with the present invention.
    [0024] Table 5 shows a composition in the form of a tablet which does not conform to the present invention.
    [0025] The applicant conducted a long and intense research activity with the objective of identifying the best qualitative and quantitative composition for the preparation of the composition of the present invention, as well as the operational conditions for the preparation of the same.
    [0026] The composition of the present invention is an effervescent composition. Effervescence is due to the formation of carbon dioxide that occurs when an acid-base system comprising an organic acid and a salt of the carbonate and / or bicarbonate anion comes into contact with the water / moisture present inside the cavity - vaginal. The acid-base system is able to maintain stable intravaginal pH within a range of 3 to 5.5, preferably 4 to 5. Advantageously, intravaginal pH is 4.2 to 4.5.
    [0027] The composition of the present invention is an effervescent composition in solid form. In a preferred embodiment, the organic acid is in a solid form, preferably a powder or granules, and the carbonate and / or bicarbonate anion salt is in a solid form, preferably a powder or granules.
    [0028] In a preferred embodiment, the effervescent composition in solid form is in the form of a tablet, egg, lozenge or granules.
    [0029] Organic acid is selected from the group consisting of or, alternatively, comprising citric acid, malic acid, tartaric acid, fumaric acid, lactic acid and mixtures thereof. In a preferred embodiment, the organic acid is citric acid.
    [0030] The Applicant has found that the use of adipic acid and / or ascorbic acid as the organic acid present in the acid-base system mentioned above causes a toxic effect on microorganisms, resulting in their mortality even at the time of preparation. composition in solid form, for example, as a powder or granules. In the case of preparing a tablet, said mortality occurs after the components are mixed to obtain a composition in solid form, for example, as a powder or granules, but before compression. Therefore, the composition of the present invention does not contain adipic acid and / or ascorbic acid.
    [0031] The anion salt of carbonate and / or bicarbonate is selected from the group consisting of or, alternatively, comprising: sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, glycine carbonate sodium, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, sodium lactate, potassium lactate, carbonate lactate and mixtures thereof. Preferably, said salt is selected from the group consisting of or, alternatively, comprising a bicarbonate anion salt. In a preferred embodiment, the salt is sodium bicarbonate.
    [0032] In a preferred embodiment, the amount of the carbonate or bicarbonate canyon salt is comprised from 1 to 15% by weight relative to the total weight of the composition. Preferably, it is comprised from 3 to 13% by weight in relation to the total weight of the composition, even more preferably, it is comprised between 4 to 12% by weight in relation to the total weight of the composition. Advantageously, it is comprised between 5 to 10% by weight in relation to the total weight of the composition.
    [0033] In a preferred embodiment, the amount of sodium bicarbonate is comprised from 1 to 15% by weight in relation to the total weight of the composition. Preferably, it is comprised from 3 to 13% by weight in relation to the total weight of the composition, even more preferably, it is comprised between 5 to 10% by weight in relation to the total weight of the composition. Advantageously, it is comprised between 5 to 10% by weight in relation to the total weight of the composition.
    [0034] In a preferred embodiment, the acid-base system consists of citric acid and sodium bicarbonate in an amount, by weight, as described above.
    [0035] The Applicant has found that when the anion salt decarbonate or bicarbonate, for example, sodium bicarbonate, is more than 15% by weight in relation to the total weight of the composition, a toxic effect is manifested against microorganisms due to an osmotic effect.
    [0036] The amount of organic acid to be used in the acid-base system is calculated once the amount of the carbonate or bicarbonate anion salt used according to the concentrations described above has been determined. The amount of organic acid used is stoichiometric and is a function of the salt used and serves only for the purpose of forming carbon dioxide. In the presence of this salt, organic acid is able to develop effervescence due to the formation of carbon dioxide after hydration inside the vaginal cavity.
    [0037] The effervescent tablet, properly formulated, is able to distribute a large population of lactic bacteria for rapid colonization of the entire epithelium and vaginal mucosa. Thanks to the stabilized effervescent system and controlled pH, the lactic acid bacteria are distributed to the vaginal cavity in a good physiological condition, which allows them to grow and multiply.
    [0038] Advantageously, the composition of the present invention, in the form of an effervescent tablet, is able to guarantee an optimal distribution of the bacteria on the vaginal mucosa. In addition, the said composition is able to guarantee and maintain an anaerobic or microaerophilic environment within the vaginal cavity thanks to the formation of carbon dioxide.
    [0039] The Applicant has found that a mixture comprising, alternatively, consisting of [microcrystalline cellulose: arabinogalactan], preferably in a weight ratio of 1: 1 to 3: 1, is able to preserve the number and viability of microorganism cells when desired to obtain a tablet from the composition in powder form.
    [0040] In a preferred embodiment, the composition of the present invention comprises a mixture containing [microcrystalline cellulose: arabinogalactan] in a weight ratio of 1: 1 to 3: 1.
    [0041] Preferably, plant-derived arabinogalactan is used. Advantageously, larin-derived arabinogalactan (eg FiberAid® from the Larex® product series distributed by Lonza Inc. USA) is used.
    [0042] The Applicant also found that the use of corn starch as the aggregating substance in the composition of the present invention provides unsatisfactory results when the powdered composition is used to prepare tablets, since the tablets obtained after compression of the powder are coated.
    [0043] A mixture comprising or, alternatively, that consists of [microcrystalline cellulose: arabinogalactan] in a proportion by weight from 1: 1 to 1: 3, on the contrary, allows the tablets to be obtained without coating .
    [0044] Therefore, the tablets obtained from the composition of the present invention do not contain corn starch. Instead of corn starch, a mixture containing [microcrystalline cellulose: arabinogalactan] is used in a weight ratio preferably from 1: 1 to 3: 1.
    [0045] Microcrystalline cellulose can be partially or completely replaced with cellulose in powder form. Both microcrystalline cellulose and cellulose in powder form are present in the list of food additives such as E460.
    [0046] Arabinogalactan is a biopolymer consisting of arabinose and galactose mo-numbers. There are two types of arabinogalactins: those derived from plants and those of microbial origin.
    [0047] Microcrystalline cellulose (or cellulose in powder form) is present in an amount comprised from 2 to 45% by weight in relation to the total weight of the composition, preferably from 5 to 25%.
    [0048] Arabinogalactan is present in an amount comprised between 5 and 30% by weight in relation to the total weight of the composition, preferably from 10 to 20%.
    [0049] Preferably, the composition of the present invention may further comprise at least one additional component selected from the group comprising: sodium carbonoxy methyl cellulose, anhydrous calcium hydrogen phosphate and hydroxy propyl methyl cellulose.
    The said at least one additional component is present in the composition of the present invention in a total amount ranging from 3 to 70% weight / weight, more preferably 6 and 40% weight / weight and, even more preferably from 10 to 25% weight / weight in relation to the total weight of the composition.
    [0051] According to a preferred embodiment of the invention, the composition of the present invention further comprises magnesium stearate in an amount of 0.5% to 7% weight / weight, preferably 1% to 3.5% weight / weight in relation to the total weight of the composition.
    [0052] According to a preferred embodiment of the invention, the composition of the present invention may further comprise silicon dioxide in an amount of 0.5% to 4% weight / weight, preferably 1% to 2% weight / weight in relation to the total weight of the composition.
    [0053] According to a preferred embodiment of the invention, the composition of the present invention may further comprise sucrose palmitate in an amount of 0.5% to 7% weight / weight, preferably 1% to 3.5% weight / weight in relation to the total weight of the composition.
    [0054] According to a preferred embodiment of the invention, the composition of the present invention may further comprise a mixture of glycerides (saponifiable fats) in an amount of 0.5% to 10% w / w, preferably 2% to 7 % weight / weight in relation to the total weight of the composition.
    [0055] According to a preferred embodiment of the invention, the composition may further comprise from 0.5% to 10% weight / weight, preferably from 1% to 5% weight / weight of sucrose ester, the percentages being expressed in relation to the total weight of the composition.
    [0056] The composition of the invention is for vaginal applications for the treatment of vaginal infections, such as vaginitis, vaginosis, canndiasis, gonorrhea, herpes and venereal ulcer.
    [0057] In a preferred embodiment, the composition is in the form of a tablet. Alternatively, the tablet can be coated with one or more polymeric materials known in the art.
    [0058] In relation to the microbial population of the formulations according to the present invention, it is advantageous to use probiotic microorganisms, used individually or in mixture, even one that consists of different genera or species.
    [0059] Probiotic microorganisms are, by definition, microorganisms, predominantly bacteria of human origin, which are capable of inducing beneficial effects if taken regularly in a sufficient amount and for an adequate amount of time.
    [0060] The composition of the present invention comprises at least one strain of probiotic bacteria having the ability to reduce and / or eliminate the presence of pathogens selected from the group comprising: Candida albicans, Candida glabrata, Candida parapsilo-sis, Candida krusei , Candida tropicalis, Gardnerella vaginalis, Trichomonias vaginalis, Neisseria gonorrhoeae, Escherichia coli, Herpex Simplex and Haemophilus ducreyi.
    [0061] Preferably, said bacterial strain belongs to at least one species selected from the group consisting of: Lactobacillus plantarum, Lactobacillus pentosus, Lactobacillus casei, Lactobacillus casei ssp. paracasei, Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus delbrueckii, Lactobacillus delbrueckii ssp. bulbaricus, Lactobacillus delbrueckii ssp. delbrueckii, Lactobacillus ferentum, Lactobacillus gasseri, Lactobacillus reuteri, Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium animalis ssp. lactis, Bifidobacterium adolescentis, Bifidobacterium pseudocatenulatum, Bifidobacterium catenulatum or Bifidobacterium infantil.
    [0062] Among the bacterial species mentioned above, it has been shown that the bacterial strains listed in Table 1 are particularly preferred.
    [0063] In a preferred embodiment, bacterial strains are selected from: Lactobacillus salivarius CRL 1328, Lactobacillus paracasei CRL 1289, Lactobacillus gasseri CRL 1259, Lactobacillus crispatus CRL 1251, Lactobacillus crispatus CRL 1266, Lactobacillus CRL 1266, Lactobacillus CRL 1266, Lactobacillus plantarum LP 02 and Lactobacillus fermentum LF 10.
    [0064] In a preferred embodiment, the composition of the present invention, preferably in the form of a tablet, comprises at least two strains selected from the group mentioned above.
    [0065] In a preferred embodiment, the composition of the present invention, preferably in the form of a tablet, comprises at least three strains selected from the group mentioned above.
    [0066] In a preferred embodiment, the composition of the present invention, preferably in the form of a tablet, comprises at least four strains selected from the group mentioned above.
    [0067] The strains selected from: Lactobacillus salivarius CRL1328, Lactobacillus paracasei CRL 1289, Lactobacillus gasseri CRL 1259, Lactobacillus crispatus CRL 1266 and Lactobacillus fermentum LF 10 proved to be advantageous.
    [0068] In the tablets according to the invention, microorganisms, preferably used in the form of a lyophilized culture having a viable count generally comprised between 10 and 200 billion colony forming units (Colony Forming Unit - CFU ) / g are preferably present in an amount of 0.5 to 20% weight / weight, preferably 1 to 15% weight / weight, even more preferably 3 to 10% weight / weight in relation to the total weight of the pill.
    [0069] In one of the preferred modalities, in order to increase the probiotic effectiveness of the formulations according to the present invention, specific prebiotic components are introduced into the powder mixture, so that a symbiotic composition is obtained. The prebiotic component is generally a nondigestible mixture of saccharide nature, at least partially soluble in water or in an aqueous solution, which stimulates the growth and / or activity of one or more probiotic bacterial strains, as described above. Among these prebiotics, dietary fibers are preferred.
    [0070] Preferably, said prebiotic fiber is selected from the group comprising: fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), transgalacto-oligosaccharides (TOS), xylooligosaccharides (XOS), chitosan oligosaccharides (COS ), α-galactosides (such as raffinose and stachyose), pectins, gums, partially hydrolyzed gums, inulin, psyllium, gum arabic, alfalfa, oats or bamboo fibers, citrus fibers and, in general, fibers that they contain a soluble polymer and an insoluble portion in a variable proportion from one to the other.
    [0071] Advantageously, said prebiotic fiber is selected from fructooligosaccharides (FOS), galactooligosaccharides (GOS) and xylooligosaccharides (XOS). These fibers are not used by yeasts of the genus Candida, which thus gives a competitive advantage to the bacterial strains present in the composition of the present invention.
    [0072] Preferably, the prebiotic component is present in the composition in an amount of up to 70% weight / weight, preferably comprised from 5 to 50% weight / weight, even more preferably 10 to 30% weight / weight in relation the total weight of the composition.
    [0073] In a preferred embodiment, the composition according to the invention may contain additional active components, for example, vitamins, minerals, plant extracts or other compounds with an effect that is synergistic with or complementary to that of the microorganism population present in the formulations according to the invention.
    [0074] Preferably, said additional active components are present in the composition in an amount of up to 70% weight / weight, preferably comprised from 0.5 to 40% weight / weight, even more preferably from 1 to 20% weight / weight relative to the total weight of the composition.
    [0075] The combination of technological excipients of compression and effervescence according to the present invention ensures an adequate cohesion of the powders of the tablet and provides the desired release kinetics of the active ingredients after ingestion of the same.
    [0076] The mixing of the various components, usually in powder form, can be done by adding the components in any order, taking care to add the culture of microorganisms, preferably in the form of a lyophilisate, as the last ingredient , to prevent the possibility that an excessive mixing time may cause a mechanical shock in the bacterial cell wall, with consequent poor and reduced stability of the final product.
    [0077] Formulations produced according to the method of the present invention are characterized by an excellent fluidity, a parameter that favors the uniform loading of the matrices (that is, the space destined to accommodate the specific amount of powder to be compacted ) on compression machines. Said compression machines typically comprise a device for loading the dies (usually represented by a feeder for distributing the powder mixture) and a metal disk of suitable radius, in whose thickness the dies themselves are obtained; these are present in variable numbers depending on the machine and the powder compression step occurs there thanks to the simultaneous synergistic movement of two moving parts of the machine, defined as extruders.
    [0078] During the compression stage, the lower extruder defines, with its position, the volume of the matrix (and thus the amount of powder loaded at a time), while the upper extruder, positioned on the outside the matrix during loading with the powder mixture, it is able to be lowered during the compression stage and comes in contact with the powder present in the matrix, thus imposing, thanks to the force exerted, a mechanical deformation more or less accentuated on the particles that make up the powder. At the end of the compression step, the upper extruder rises, thus moving away from the matrix and, subsequently, the lower extruder also rises, expelling the newly formed tablet from the matrix.
    [0079] Said compression machines also comprise a series of devices to control the main operating parameters (position of the lower extruder at the beginning of the compression cycle, lower position reached by the upper extruder during the compression cycle, rotation speed of the disk on which the arrays are present, and so on).
    [0080] There are alternating and rotating compression machines, according to the general modes of operation of the machine and, consequently, the number of tablets that are capable of producing in a given unit of time. Pills can therefore be produced using compression machines known in the art and using variable-size extruders, preferably double-radius convex and oval round extruders.
    [0081] The compressive force applied during manufacture is assessed by quantifying, with a hardness tester, the force required to break a tablet. This force is measured in Kp (Kiloponds) (1 Kp = 9.807 Newtons (N)). The negative effect of compression on the microorganism population manifests itself both when the applied forces are high, for example, in tablets with a hardness of 10-12 Kp and when they are low, such as, for example, in tablets with a hardness of 5-6 Kp. The disadvantage of using high forces is a greater reduction in the number of microorganisms while, with low forces, a reduced cohesion of the tablet is generally achieved. Advantageously, the tablets of the present invention show a compression force comprised between 5 and 12 Kp, depending on the type of tablet to be obtained.
    [0082] In manufacturing tests on tablets containing L. paracasei LPC 00, L. acidphilus LA 02 and L. salivarius CRL 1328 (Table 2), the Applicant obtained very positive results, both in terms of survival and in terms of subsequent stability.
    [0083] In particular, a mortality rate ranging from 4 to 15% was observed when the applied compression force was such as to obtain tablets with a hardness ranging from 5 to 6 Kp and a mortality ranging from 10 to 25% when the compression force applied was such as to obtain tablets with a hardness comprised between 10 and 12 Kp. Another advantage of the method according to the invention is that it allows the production of sufficiently cohesive tablets even at low compression forces, for example, tablets with a hardness of 5-6 kp.
    [0084] The tablets prepared in accordance with the present invention have been tested to evaluate the disintegration time according to the European Pharmacopoeia, Ed .. X, ref. 2.9.1. The friability of the uncoated tablets was tested according to ref. 2.9.7 and crush resistance according to ref. 2.9.8.
    [0085] Table 2 shows an example of a composition according to the invention.
    [0086] Table 3 shows the mortality data for the probiotic bacteria (composition shown in Table 2), according to the different pressures exerted and the stability of the tablets (expressed as the half-life of the bacterial load) after 2 years of storage at 25 ° C. The tablets obtained with the formulations according to the invention had a thickness of about 7.7 mm in the case of tablets with a high degree of hardness and about 8.4 mm in the case of tablets with a low degree of toughness.
    [0087] In Table 3, stability is expressed as the half-life probiotic component of the formulation, that is, the time that elapses before the initial viable cell count is reduced by half.
    [0088] The following was also measured: (1) Number of viable cells at 1 x 109CFU / g of powder expected at time zero (2) Number of viable cells at 1 x 109CFU / g of powder found in time zero (3) Mortality% due to compression (4) Number of viable cells 1 x 109CFU / tablet after 2 years at 25 ° C (5) Half-life in days
    [0089] The above data were obtained by evaluating the number of probiotic bacteria present in the powder composition and in the composition after compression using the method of counting the levels of plaque, according to methods known to those skilled in the art.
    [0090] In the case of the powdered composition, in a comprised amount of 1 and 4 grams of sample it was resuspended in an adequate volume of a sterile liquid medium, in general, a 0.85% saline solution of sodium chloride , to which bacteriological peptone is added in a proportion of 1 g / liter.
    [0091] After dissolving the powder and subsequent homogenization with an appropriate piston driven instrument, the number of cells / mL is reduced by means of subsequent serial 10 dilutions.
    [0092] In practice, 1 ml of the most concentrated dilution is transferred each time, using a sterile pipette, to 9 ml of diluent; this operation is performed a series of times that are sufficient to bring the amount of microorganisms present per ml of diluent to a number between 10 and 300 so that, after being transferred to a petri dish and adding a culture medium on suitable agar, they form separate and thus countable colonies.
    [0093] In the case of the tablets, a protocol was observed which provides for pre-crushing of three to five tablets and continued analysis, as described above, regarding the powder composition.
    [0094] Experimental data demonstrate low mortality, both in the form of tablets with a high degree of hardness (about 16.4% of the initial population) and in those with a lower degree of hardness (about 8, 2% of the initial population). Another advantageous aspect of the composition of the present invention is the improved stability, over time, of the probiotic microorganisms (probiotic component) present there compared to the stability of a formulation typical of the prior art. This advantage is due to the use of a mixture that contains [microcrystalline cellulose: arabinogalactin] in a weight ratio comprised, preferably, from 1: 1 to 3: 1. This mixture is able to considerably limit the mechanical damage caused to the probiotic bacterial cells by the compression step and allows the tablets to be obtained without coating.
    [0095] The Applicant found that the half-life of the probiotic component in the powder composition and in tablets of variable hardness manufactured with a formulation according to the invention are very similar, demonstrating the fact that the technological components used are capable of minimizing the mechanical damage caused by the compression step.
    [0096] Advantageously, the tablets according to the invention exhibit a high survival rate of the probiotic microorganisms even after the compression step.
    [0097] Another advantageous aspect is the ability to release carbon dioxide as the tablets disintegrate, resulting in the creation of an anaerobic or microaerophilic environment particularly favorable for vaginal colonization by used probiotics.
    [0098] Effervescence is also capable of ensuring an adequate and homogeneous distribution of the probiotic active ingredient to the vaginal environment by increasing the efficiency of colonization.
    [0099] The compositions of the present invention make it possible to obtain tablets containing probiotic microorganisms that are effective and stable over time, even at uncooled temperatures, because the components that make up the composition were chosen and selected for the purpose to reduce mortality due to mixing and mortality due to compression without impairing the cohesion of the powder. For this reason, the composition of the present invention, preferably in the form of a tablet, contains neither adipic acid nor ascorbic acid, the amount of the carbonate or bicarbonate anion salt present is less than 15%, eg - only in relation to the total weight of the composition and a mixture of microcrystalline cellulose and arabinogalactan is used instead of corn starch.
    [00100] The Applicant arrived at these results from a composition that proved to be inadequate (Table 4).
    [00101] The composition of Table 4 shows: mortality of 80.8% due to mixing, mortality of 40.5% due to compression and an overall mortality (mixing + compression) of 88.6%.
    [00102] The composition of Table 4 shows accentuated mortality already at the level of dust, before compression. The dissolution pH (in 1:10 saline solution) is not a problem, since it is equal to 5.22 for the first formulation and 5.53 for the second.
    [00103] Adipic acid has been found to be toxic. But this toxicity accounts for only a certain part of the observed mortality (about 60% of the total mortality). Asascorbic acid was found to be toxic. But this toxicity is responsible for another part of mortality. Removing ascorbic acid from the composition in Table 4 reduces mortality from 73.8 to 26.7%. Adipic acid alone is toxic in any case (45.8% at a pH of 4.24); its toxicity seems to increase in the presence of ascorbic acid. Ascorbic acid thus appears to show a synergistic toxicity with that of adipic acid.
    [00104] However, it is important to note that the sum of toxicity due to adipic acid and ascorbic acid does not take into account the observed mortality.
    [00105] For this reason, the Applicant investigated the presence of other components capable of having a toxic effect in order to justify the total toxicity observed in the composition of Table 4.
    [00106] Therefore, some other component (besides pH, which has already been considered) must justify the remaining toxicity in the same way as adipic acid and ascorbic acid.
    [00107] A degree of mortality was determined to be due to the osmotic pressure, conferred by the bicarbonate present in an excessive amount. This mortality was found to be equal to about 20%. Adipic acid, ascorbic acid and the osmotic effects mediated by bicarbonate are responsible for the observed toxicity. Bi-carbonate itself is not toxic: it becomes so only because of the osmotic effect.
    [00108] Therefore, a composition (Table 5) was prepared without adding adipic acid, ascorbic acid and with an amount of bicarbonate anion (eg sodium bicarbonate) of less than 15% by weight relative to the total weight of the composition.
    [00109] For example, 84 mg of sodium bicarbonate constitute a millimol and the CO2 that is released occupies a total volume of 25.4 ml at 37 ° C and under atmospheric pressure. The amount of citric acid was chosen in such a way as to guarantee complete release of CO2 from sodium bicarbonate at pH values observed after dissolving the tablet.
    [00110] The composition of Table 5 showed problems when subjected to a compression step in order to prepare the tablets.
    [00111] The powder (Table 5) showed poor cohesive properties due to the use of corn starch in a formulation with a low moisture content. All tablets produced by the compression machine were coated even before being passed through the dust removal device.
    [00112] After this compression test, the Applicant proceeded to replace the corn starch with a mixture containing [microcrystalline cellulose: arabinogalactan] in a weight ratio, preferably from 1: 1 to 3: 1. Table 1


    Table 2
    Table 3
    Table 4: inadequate composition

    Table 5: Composition of 1,300 mg
    权利要求:
    Claims (7)
    [0001]
    1. Effervescent tablet in solid form for use in vaginal applications to treat vaginal infections, characterized by the fact that it comprises: - an acid-base system, which includes sodium bicarbonate and citric acid; said bicarbonate being present in an amount comprised from 1 to 15% by weight with respect to the total weight of the composition, with the proviso that said composition is free of adipic acid or ascorbic acid; - a mixture comprising microcrystalline cellulose and arabinogalactan, said microcrystalline cellulose and said arabinogalactan being present in a weight ratio ranging from 1: 1 to 3: 1; - at least one probiotic bacterial strain with the ability to reduce and / or eliminate the presence of pathogens selected from the group comprising: Candida albicans, Candida glabrata, Candida parapsilosis, Candida krusei, Candida tropicalis, Gardnerella vaginalis, Trichomonas vaginalis, Neisseria gonorrhoeae, Escherichia coli, Herpes simplex and Haemophilus ducreyi.
    [0002]
    2. Tablet according to claim 1, characterized by the fact that organic acid is selected from the group consisting of citric acid, malic acid, tartaric acid, fumaric acid, lactic acid and mixtures thereof, preferably organic acid is citric acid.
    [0003]
    3. Tablet according to claim 1 or 2, characterized by the fact that the anion salt of carbonate and / or bicarbonate is selected from the group consisting of: sodium carbonate, potassium carbonate, calcium carbonate, carbonate magnesium, sodium glycine carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, sodium lactate, potassium lactate, sodium lactate carbonate and mixtures thereof, preferably it is a bicarbonate anion salt.
    [0004]
    4. Tablet according to claim 3, characterized by the fact that the anion salt of carbonate and / or bicarbonate is present in an amount of 3 to 13% by weight, in relation to the total weight of the tablet, preferably, in an amount comprised from 4 to 12% by weight, based on the total weight of the tablet, even more preferably in an amount comprised from 5 to 10% by weight, based on the total weight of the tablet.
    [0005]
    5. Tablet according to any one of claims 1 to 4, characterized by the fact that the acid-base system consists of sodium bicarbonate and citric acid, and sodium bicarbonate is present in a amount of 3 to 13% by weight, in relation to the total weight of the tablet, preferably in an amount of 4 and 12% by weight, in relation to the total weight of the tablet, still more preferably, in an amount of 5 to 10% by weight, based on the total weight of the tablet.
    [0006]
    6. Tablet according to any one of claims 1 to 5, characterized by the fact that said at least one probiotic bacterial strain belongs to at least one species selected from the group consisting of: Lactobacillus plantarum, Lac-tobacillus pentosus , Lactobacillus casei, Lactobacillus casei ssp. para-casei, Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus delbrueckii, Lactobacillus delbrueckii ssp. Bulgaricus, Lactobacillus delbrueckii ssp. delbrueckii, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus reuteri, Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium animalis ssp. lactis, Bifidobacterium adolescentis, Bifidobacterium pseudocatenulatum, Bifidobacterium catenulatum or Bifidobacterium infantil; said at least one bacterial strain is preferably selected from among: Lactobacillus saliva- CRL 1328, Lactobacillus paracasei CRL 1289, Lactobacillus gas- seri CRL 1259, Lactobacillus crispatus CRL 1251, Lactobacillus crispa- tus CRL 1266, Lactobacillus 12 - racasei LPC 00, Lactobacillus plantarum LP 02 and Lactobacillus fermen- tum LF LF 10.
    [0007]
    7. Tablet according to any one of claims 1 to 7, characterized by the fact that it is for the treatment of vaginitis, vaginosis, candidiasis, gonorrhea, herpes and venereal ulcer.
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    同族专利:
    公开号 | 公开日
    US20170014335A1|2017-01-19|
    ITMI20110316A1|2012-07-29|
    CO6771428A2|2013-10-15|
    DK2667849T3|2019-10-28|
    ITMI20110107A1|2012-07-29|
    UA114888C2|2017-08-28|
    PL2667849T3|2020-06-15|
    MX2013008547A|2013-12-02|
    AU2012210296A1|2013-08-22|
    KR101913797B1|2018-11-01|
    PE20140259A1|2014-03-08|
    AU2012210296B2|2017-01-05|
    TN2013000310A1|2015-01-20|
    MX347165B|2017-04-18|
    EP2667849B1|2019-07-24|
    BR112013018953A2|2017-07-11|
    ES2751416T3|2020-03-31|
    ECSP13012844A|2015-02-28|
    JP2014503581A|2014-02-13|
    IT1403661B1|2013-10-31|
    US20140065115A1|2014-03-06|
    NZ614002A|2015-11-27|
    EP2667849A1|2013-12-04|
    CN104519866A|2015-04-15|
    US9492377B2|2016-11-15|
    PE20180413A1|2018-03-01|
    CL2013002148A1|2014-05-16|
    KR20140029392A|2014-03-10|
    RU2013137656A|2015-03-10|
    PT2667849T|2019-10-29|
    JP5992446B2|2016-09-14|
    WO2012101500A1|2012-08-02|
    RU2587717C2|2016-06-20|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-07-02| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-08-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-10-27| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-12-29| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/01/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    ITMI2011A000107A|IT1403661B1|2011-01-28|2011-01-28|EFFERVESCENT COMPOSITION IN THE SOLID FORM FOR USE IN VAGINAL APPLICATIONS FOR THE TREATMENT OF VAGINAL INFECTIONS.|
    ITMI2011A000107|2011-01-28|
    ITMI2011A000316|2011-03-01|
    IT000316A|ITMI20110316A1|2011-01-28|2011-03-01|EFFERVESCENT COMPOSITION IN SOLID FORM FOR USE IN VAGINAL APPLICATIONS FOR THE TREATMENT OF VAGINAL INFECTIONS.|
    PCT/IB2012/000095|WO2012101500A1|2011-01-28|2012-01-24|Effervescent composition in solid form for use in vaginal applications for the treatment of vaginal infections|
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