WO2020252545A1

WO2020252545A1 - Nutraceutical composition combining probiotics, vitamins and minerals

Info

Publication number: WO2020252545A1
Application number: PCT/BR2019/050312
Authority: WO
Inventors: Fernando Gabriel ITZAINA SANCHEZ
Original assignee: Farmoquímica S/A
Priority date: 2019-06-18
Filing date: 2019-08-01
Publication date: 2020-12-24
Also published as: BR102019012637A2; UY38404A; AR116521A1

Abstract

The present invention relates to a food supplement in the form of two tablets, a coated tablet based on chelated zinc and copper minerals, vitamins A, B3 and B6, and another simple tablet containing the probiotics Lactobacillus acidophilus and Bifidobacterium lactis. The present invention also relates to a process for preparing the aforementioned tablets and the use thereof, namely in the control of dysbiosis and acne.

Description

Invention Patent Descriptive Report for “NUTRACEUTICAL COMPOSITION COMBINING PROBIOTICS, VITAMINS AND MINERALS”. FIELD OF THE INVENTION

[001] The present invention deals with a food supplement in the form of two tablets, one coated with zinc and copper chelated minerals, vitamins A, B3 and B6 and a second simple tablet containing the probiotics Lactobacillus acidophilus and Bifidobacterium lactis. The food supplement in the form of two tablets according to the present invention is useful in the control of dysbiosis and acne.

BACKGROUND OF THE INVENTION

[002] Several patent and literature documents disclose probiotic formulations that are formulated as nutraceuticals and methods for producing them.

[003] Acne vulgaris is a disease of the pilosebaceous follicle and presents as fundamental characteristics the overproduction of glandular sebum, increased colonization by Propionibacterium acnes, follicular hyperkeratinization and release of inflammation mediators in the follicle and adjacent dermis. The P. acnes bacterium is Gram-positive, anaerobic, of the genus Corynebacterium and is part of the normal resident microbiota of the skin. The proliferation of this bacterium occurs when there is sebum overproduction by the gland, favoring the appearance of acne. In acne patients, P. acnes can reach 120,000 specimens / cm ² on the skin surface. P. avidum and P. propionicum are also present in large amounts on the skin of acne-prone individuals (COSTA, ALCHORNE, GOLDSCHMIDT, 2008; MONTAGNER, COSTA, 2010). Acne is one of the most common skin problems among young people, and can also extend to other age groups. There is ample evidence that acne persists in adulthood in about 50% of individuals. Acne has a recurrence pattern and a prolonged course; it manifests as an acute rash or may present an insidious onset, promoting psychological and social impact, which may lead to depression and anxiety; therefore, its treatment is extremely important (MONTAGNER, COSTA, 2010; COSTA, BAGATIN, 2013).

[004] In 1961, the first official clinical report on the possible benefits of lactobacilli in the treatment of acne was published. Dr. Robert H. Siver, in Baltimore, selected 300 acne patients to conduct a study in which a formulation containing a mix of commercially available probiotics was administered, which contained L. acidophilus and L. bulgaricus. In the clinical study, patients were supplemented with probiotics for two periods of 8 days, separated by a 2-week break between cycles. The results showed that 80% of the patients showed some degree of clinical improvement, and that the intervention was more significant in cases of inflammatory acne. However, the fact that the study was not placebo controlled, there was some limitation as to its results. Despite this, Dr. Siver concluded that there is a possible link between the cutaneous manifestations of acne vulgaris and metabolic processes in the intestinal tract (BOWE, LOGAN; 201 1). Since then, studies have been published on the use of probiotics in the treatment of acne vulgaris and several have shown interesting results. An Italian study involving 40 patients added an oral supplement containing 250 mg of L. acidophilus and B. bifidum as an adjunct to standard treatment in patients with acne. In the study, 50% of patients received only standard treatment, based on antibiotics, and the other 50% received, in addition to antibiotics, probiotic supplementation. The researchers reported better tolerance towards antibiotics and better clinical results among patients supplemented with probiotics (MARCHETTI, CAPIZZI, TULLI, 1987). A Russian study has proven the benefits of associating probiotics with standard treatment in patients with acne. According to the study, 1 14 patients with acne vulgaris (94 and 20 with papular-pustular and nodule-cystic acne, respectively) received the adjunctive treatment. The results obtained were satisfactory, since it was observed a significant improvement of the condition and a response to treatment faster (RUIZ, 2012). Another clinical study, this time involving 56 patients with acne, showed that consumption of industrialized dairy drinks fermented with Lactobacillus improved the clinical aspects of acne after 12 weeks. One part of the patients received fermented milk with 200 mg of lactoferrin (an anti-inflammatory protein in milk), while the other part received only fermented milk. Specifically, the consumption of the drink containing probiotics (fermented) promoted significant reductions in the total number of injuries associated with the marked reduction in sebum production. Although the addition of lactoferrin to the industrialized drink has provided greater effectiveness in reducing inflammatory lesions (56% versus 32.2%), the benefits of probiotic-only drink show that they have an adjuvant role to act in the treatment of acne (KIM et al., 2010). These studies have shown that pre and probiotics consumed orally can reduce systemic markers of inflammation and oxidative stress. Considering that local lipid peroxidation in acne is high, the ability of oral probiotics to limit systemic oxidative stress may be the therapeutic route for the adjuvant treatment of acne. In addition, the oral use of probiotics can regulate the release of pro-inflammatory cytokines within the skin; for example, the specific reduction in IL-1 levels would certainly have a beneficial potential in the treatment of acne. In addition, the use of oral probiotics has the potential to alter the local microbiota and still offer beneficial effects in addition to TGI (BOWE, LOGAN, 201 1).

[005] Studies on probiotics have shown beneficial effects in all age-related subgroups, such as mother-child pairs, preterm infants, newborns, newborns and older and older children (VANDENPLAS et al., 2015).

[006] Patent application PI0917172 discloses a composition of probiotic bacteria which aims to obtain stable formulations with a long shelf life and a process for producing such compositions. US4,956,295 discloses dry Lactobacilli compositions mixed with a silica gel absorbent.

[007] Documents US7.122.370 and US7.229.818 disclose formulations comprising probiotic bacteria with monovalent alginate salts.

[008] EP148281 1 discloses a process for obtaining a food product comprising the steps of: mixing a preparation of microorganisms and other components, drying the mixture, compacting the mixture, coating the mixture and finalizing as a food product.

[009] US2005 / 0266069 discloses a stable probiotic formulation aimed at the intestinal flora, comprising: a plurality of probiotic microspheres comprising each: a nucleus comprising one or more probiotic bacteria, a cellulosic excipient, a disintegrant and one or more additives ; and an enteric coating capable of being resistant to gastric fluids.

[0010] However, none of these bacterial formulations makes use of probiotics used in combination with vitamins and minerals for acne care, even considering that several studies suggest that certain skin diseases (such as acne vulgaris and atopic dermatitis) may be associated with breaks in normal microflora.

[001 1] Adequate levels of vitamin A help to improve the inflammatory process of acne. According to Beckenbach (2015), vitamin A affects human cells in the stages of embryogenesis, reproduction, regulation of the inflammatory process, cell growth and differentiation. Vitamin A was discovered around 1906 and synthesized in mid-1947 and can be found in two main forms, carotenoids and retinols, in foods (CHAPMAN, 2012). Retinoid, a form of vitamin A, is necessary to correct keratinization in skin diseases, having a highly effective inhibitory effect on glands and sebum production, which leads to a reduction in the population of Propionibacterium acne, which is one of the etiogenic factors .

[0012] According to Bieski (2016), isotretinoin is a retinoid found in organisms of animal and plant origin such as carotenoid, is found in dark green vegetables and orange vegetables and its main mechanism of action occurs in the sebaceous gland, reducing its size, activity and the amount of sebum produced by up to 75%, after four weeks of treatment. Vitamin A acts to inhibit the induction of IL-17 by Propionibacterium acnes, reducing the number of Th17 cells since these are IL-17 producing in the pathogenesis of acne (AGAK, 2014).

[0013] The therapeutic effect of nicotinamide on acne vulgaris seems to mainly involve the inhibition of 3 ^' -5 ^' -AMPphosphodiesterase and the transformation of the induced antigen lymphocyte, which inhibits the epithelial proliferation of the pilo-sebaceous unit, primary factor in the development of lesions acne, being an alternative to antibiotics in topical treatments for inflammatory acne.

[0014] Vitamin B6 is used to prevent and treat the states of your deficiency, in the treatment of certain metabolic disorders, in depression and other symptoms associated with PMS and the use of contraceptives, in the prophylaxis of isoniazid-induced peripheral neuritis and for treatment of acute ioniazide intoxication. Vitamin deficiency due to inadequate nutrition or malabsorption syndrome. Deficiency of a single vitamin B is rare, as deficiency is usually multiple. Pyridoxine deficiency can cause xanthurenic aciduria, sideroblastic anemia, neurological problems, seborrheic dermatitis and achilles. Some newborns have a hereditary pyridoxine dependence syndrome and need to take it in the first week of life, to avoid anemia and mental retardation; the signs are hypersensitivity and epileptiform attacks. It is also used in formulations for topical use, for its anti-seborrheic action, in hair treatments for dandruff, seborrheic alopecia and acne. Associated with zinc, it potentiates its action on 5 alpha reductase.

[0015] Among all the functions that zinc performs, one has been emerging in the last articles that is its role in the oral treatment of acne. For a little over 50 years, an association has been made between zinc and dermatological diseases. However, it was not until 1970 that the use of zinc in the treatment of acne was highlighted by Michaelsson and Fitzherbert (MICHAELSSON, 1981). They observed that patients with acne had a lower zinc concentration than patients without acne. In some groups, supplementation with zinc sulfate and zinc gluconate was effective in the treatment of severe acne, but less efficient in moderate acne. When compared to antibiotics they seem to be as effective, but they are still not considered as the first line of treatment for acne. They also observed that when they combine zinc sulfate with erythromycin, the effects are superior to single treatments. In contrast, topical treatment with zinc sulfate was not as effective, as it caused local irritation and this may be linked to differences in absorption and solubility between salts (DRENO et al, 1989; CORDAIN, 2005).

[0016] Many studies have observed a reduction in Propionobacterium acnes and free fatty acids in the skin with the use of zinc, mainly because zinc inhibits the lipase of P. acnes, an antimicrobial effect. However, there was no effect on staphylococcus spp (WEBSTER et al, 1980; VOWELS, YANG, LEYDEN, 1995; CORDAIN, 2005). Zinc modulates inflammation in acne, as it is essential for the antioxidant enzyme SOD-1 (cytosolic superoxide dismutase), responsible for reducing the superoxide radical to hydrogen peroxide and oxygen (ZELKO, MARIANI, FOLZ, 2002).

[0017] Zinc stimulates the topical absorption of erythromycin, modulates insulin, contributing to epithelial anabolism. In this sense, people with insulin resistance usually develop acne, as insulin influences the concentration of IGF-1 and its binding protein, IGFBP-3, which directly regulates keratinocyte proliferation and apoptosis. Hyperinsulinemia leads to an increase in IGF-1 and a decrease in IGFBP-3. This free IGF-1 directly stimulates the proliferation of keratinocytes and its binding protein inhibits this proliferation (BODEN and SHULMAN, 2002). Both insulin and IGF-1 stimulate the synthesis of androgens in the ovary and testicles, but inhibit hepatic synthesis of sex hormone-binding globulin (SHBG) and increases the bioavailability of circulating androgens. In addition, sebum itself is stimulated by insulin and IGF-1 (BARBIERE, SMITH and RYAN, 1998). It is also believed that the endocrine cascade induced by eating with carbohydrates with a high glycemic index leads to hyperinsulinemia, causing all the changes already mentioned (WOLEVER, MEHLING, 2003).

[0018] Copper is an essential mineral for our body. The human body cannot produce copper, which needs to be ingested through food or absorbed by the skin in dermocosmetics. It helps in the formation of some blood cells, hormones and antioxidant enzymes (which are responsible for keeping the skin younger and healthier). It stimulates the production of an enzyme (lysyl oxidase) responsible for the cross-linking of collagen and elastin, which are essential for the formation of strong and flexible connective tissue, it also has an antioxidant action responsible for cell renewal and skin elasticity. It also helps in reducing skin oiliness, excellent for fighting acne

[0019] In view of the above, there is a need to improve compositions containing bacterial cells, having an improved stability and a greater supply of viable bacterial cells.

[0020] In particular, there is a need to provide stable compositions comprising strains of Bifidobacterium and Lactobacillus, which present an additional challenge in terms of processability

SUMMARY OF THE INVENTION

[0021] The present inventors have surprisingly determined that a tablet containing cells from a Bifidobacterium and Lactobacillus strain, may have superior stability. Superior stability is directly related to the process for obtaining the tablet.

[0022] Furthermore, the inventors have determined that the composition of Bifidobacterium and Lactobacillus is especially advantageous in combination with a tablet containing a formulation of vitamin A, vitamin B6, zinc, copper and niacin.

[0023] Based on these surprising determinations, the present invention relates to a process to stabilize a composition comprising cells from a Bifidobacterium and Lactobacillus strain and to the use of a combination of Bifidobacterium and Lactobacillus tablets with tablets of a formulation of vitamin A, vitamin B6, zinc, copper and niacin as an adjunct in the treatment of acne in all its stages.

DETAILED DESCRIPTION OF THE INVENTION

[0024] In a first aspect, the present invention relates to a process for preparing a bacterial composition, which comprises the following steps: a) weighing the inputs; b) mixing and c) direct compression.

[0025] It should be understood that the purpose of the mixing step is to put the bacterial cells in contact and, therefore, the mixing sequence is not important. Thus, bacterial strains can be mixed with the vehicle one before the other or in a concerted manner. It is preferred that all the constituents are mixed at the same time.

[0026] It should be understood that the purpose of the compression step allows a bacterial composition to be obtained in a solid pharmaceutical form such as a tablet.

[0027] The incorporation of probiotic microorganisms in food causes several difficulties. A first goal to achieve is to have an adequate number of UFCs (colony-forming unit) per day. If the concentration of probiotics in the product does not exceed a certain limit value, the beneficial effect is not provided. Thus, based on the observation that an effective dose is in the range of 10 ⁹ UFC per person per day and, assuming that the consumer has to take it within his daily intake, the goal is to provide this amount of UFCs within one to three servings. The bacterial strains of the present invention are strains producing lactic acid and / or probiotics, and are of the species Lactobacillus acidophilus and Bifidobacterium lactis and are in the 10 ⁹ UFC range.

[0028] As mentioned, the manufacture of tablets containing probiotics consists of steps for weighing the inputs, mixing and direct compression. All of these steps are carried out in a controlled environment, that is, with temperature and humidity strictly monitored. The temperature of the production rooms is a maximum of 25 ° C and the humidity is up to 50% U.R.

[0029] In the mixing stage, a dilution is made in one and / or up to three stages: in each stage 25 to 100% of excipient and active content (probiotic strains) are added and mixed at intervals of five to twenty minutes, totaling , at the end of the process, one to three mixtures with 100% of the content in 20 minutes. This type of manipulation is necessary to guarantee the homogeneity of the mixture and, thus, the uniformity of the desired dose of probiotic strains in the tablets.

[0030] Compression of probiotics is a process that requires special care. The force required to generate tablets must be finely controlled so that it does not cause significant impacts on the viability of the strains present in the formulation. The greater the force applied to obtain the tablets, the greater the loss of probiotics during the manufacturing process and over the product's shelf life.

[0031] Probiotics are live microorganisms that, despite being lyophilized, that is, in a latent state, are sensitive to the impact of compression. In this context, the product development in the matrix presented was based on the study “Compression of Probiotics and Enzymes with JRS Technology”. In this study, the technological excipient silicified microcrystalline cellulose (Prosolv® SMCC 90) was used as a matrix for a Lactobacillus strain. This formulation was compared with another similar formulation, with the exception of Prosolv® SMCC 90, which was replaced by conventional microcrystalline cellulose. It was observed that the probiotic survival rate (viability) was 40% lower for the last formulation when compared to the first, using a compression force of 8 kN and approximately 70% less when using a compression force of 10 kN. In this study it can be identified that the choice of a suitable excipient was of great relevance for the survival of probiotic microorganisms. Prosolv® SMCC 90 better absorbs the impact of punches on compression when compared to conventional cellulose, in addition to better accommodating strains within the matrix. Therefore, the matrix selected for the development of the product in question was based on the results of the aforementioned study, ensuring greater effectiveness and quality to the product during its validity period.

[0032] The excipient matrix of the probiotic formulation is composed of a grease agent, an anti-humectant and a lubricant. Examples of a dough agent are: corn starch, lactose, microcrystalline cellulose, among others. Preferably microcrystalline cellulose was used in the formulation. The concentration used of this excipient in the formulation varied between 50 to 90 percent of the total content of the finished product, with the preferred concentration being the arithmetic mean between the lowest and highest concentration. Examples of antiumectant are: pharmaceutical talc, sodium carbonate, silicon dioxide, among others. Preferably, silicon dioxide was used in the formulation. The concentration used of this excipient in the formulation varied between 1 to 3 percent of the total content of the finished product, with the preferred concentration being the arithmetic mean between the lowest and the highest concentration. Examples of lubricants are: sodium stearyl fumarate, stearic acid, magnesium stearate, among others. Preferably, magnesium stearate was used in the formulation. The concentration used of this excipient in the formulation varied between 0.5 to 2 percent of the total finished product content, with the preferred concentration being the arithmetic mean between the lowest and the highest concentration.

[0033] Physical aspects such as humidity and water activity are decisive when choosing the matrix used. The ideal range of The water in the excipients must be (0.01 - 0.2) so that there is no activation of probiotic microorganisms in the tablet and, thus, accelerate the degradation of the product, decreasing the potency and activity of the microorganisms. The excipients compatible with the probiotics must have other characteristics besides low water activity and controlled humidity, they must also be compressible with a low compression force, since the impact of the compression directly interferes in the viability of the probiotic strains. In this context, the development of the product in the matrix presented was carried out taking into account all the factors described, guaranteeing the effectiveness and quality of the product during its validity period.

[0034] Another aspect of extreme relevance is the delivery of probiotic strains of the product to the human body. The product in the form of a tablet disintegrates completely in approximately 1 minute and laboratory analyzes of viability assessment of the strains for 24 months (product shelf life), demonstrated that there was recovery of probiotic microorganisms at a concentration of 10 ⁸ CFU / portion. In addition, the formulation was able to withstand gastrointestinal stress evidenced by the gastric resistance test performed with the product. The loss of viable cells was approximately 1 log, demonstrating that the strains resist the passage of digestive enzymes and bile and are able to reach the intestinal colon region in full condition to act in this location. These results corroborate that the excipient matrix chosen does not interfere with the action of probiotic microorganisms. On the contrary, it is inert and is essential for preserving their survival rate.

[0035] The manufacturing process for vitamin and mineral tablets consists of the weighing, mixing, compression and coating steps.

[0036] The component mixing step is a geometric dilution. The entire content is divided and mixed in up to two stages, so that vitamins and minerals of lower concentration are added and mixed first. Then the components of greatest concentration are added and mixed last, ensuring better homogeneity and uniformity of the formulation content.

[0037] The compression process is carried out by direct compression of the powder.

[0038] The suspension uses a suspension that offers moisture barrier, being very important for the preservation of vitamins and minerals in addition to masking the metallic flavor of the components of the formulation.

[0039] The final composition of probiotics is a composition free of gluten, lactose and sugars. Together, the compositions comprise: Lactobacillus acidophilus NCFM®, 10 ⁹ CFU whose concentration in the formulation can vary between 5 to 25 percent of the total content, with the preferred concentration being the range of 10 to 20 percent of this ingredient in the formulation; Bifidobacterium lactis HN019, 10 ⁹ UFC whose concentration in the formulation can vary between 2.5 to 25 percent of the total content, with the preferred concentration being the range of 5 to 15 percent of this ingredient in the formulation; vitamin A, 600 pg RE (100% IDR); niacin, 16 mg (100% IDR); vitamin B6, 1.3 mg (100% IDR); chelated zinc, 7 mg (100% IDR) and copper, 900 pg (100 IDR). According to RDC Resolution No. 269, of September 22, 2005 Dietary supplementation with Lactobacillus acidophilus has already proved to be a viable treatment for certain conditions of the intestinal tract, including antibiotic-induced imbalances in the gastrointestinal microflora, hypercholesterolemia, E. coli infection, disease chronic granulomatous, lactose indigestion and in controlling the evolution of acne. In addition, lactobacilli synthesize various antimicrobial substances, including lactic acid, acetic acid, benzoic acid and hydrogen peroxide. Aiding in the predigestion of certain foods, dietary supplementation with cultures of Lactobacilli can help in preventing excessive cell proliferation. More specifically, diets high in animal fat, protein or fried foods seem to increase the risk of acne progression. B. lactis, in turn, is a bacterium commonly used as a probiotic, found mainly in yogurts and other dairy products. [0040] Vitamin and mineral preparations are commonly administered to treat specific medical conditions or as general nutritional supplements. Micronutrients are elements or compounds that are present in food in small amounts, or traces, and include vitamins, minerals or other elements, and compounds found in foods for which a recommended daily intake (RDI) has not yet been determined. Some elements such as calcium, sodium, potassium, chloride and phosphorus are consumed in relatively large amounts, while many, such as iron, iodine and zinc, are consumed in small amounts. Vitamins like B12 and folic acid and the minerals copper, selenium and chromium are consumed in very small amounts or trace amounts. As the human body does not synthesize many compounds that are essential for the human body, these specific vitamins and minerals can be obtained from just two sources: food and supplements. The primary source of all nutrients is food. However, most people do not meet the IDR of foods that contain these compounds and essential elements. Thus, supplementation with vitamins and minerals has become a recognized method of meeting accepted medical and health standards.

[0041] The composition of probiotics is especially effective when administered together with vitamins and minerals. The preferred formulation of vitamins and minerals comprises vitamin A, vitamin B6, niacin, copper and zinc.

[0042] In a further aspect, the present invention relates to the use of a combination of the compositions of the present invention as a food, food additive, a nutraceutical product, a dietary supplement or a probiotic. DEFINITIONS

[0043] In the present context, the term "tablet" refers to a compressed powder. The term includes all physical forms and all sizes, such as a pill, a pellet, a tablet, etc.

[0044] The term "bacterial composition" should be understood as a composition comprising bacterial cells, or a cell culture. The cells are preferably alive or dormant, and it is still preferred that the composition contains at least 10 ⁹ colony-forming units per portion of the product. The bacterial cells may belong to a single strain, or be a mixture of cells belonging to different strains .

[0045] The use of the terms "one" and "o" and similar referents in the context of the description of the invention (especially in the context of the following claims) should be interpreted to cover both the singular and the plural, unless otherwise indicated here or clearly contradicted by the context. The terms "comprising", "having", "including" and "containing" are to be interpreted as open terms (ie, "including, but not limited to"), unless otherwise stated. The citation of value ranges here is merely intended to serve as an abbreviated method of referring individually to each separate value within the range, unless otherwise stated in this document, and each separate value is incorporated into the invention as if be individually described here. All methods described herein may be performed in any appropriate order, unless otherwise indicated in this document or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (for example, "as is") provided herein, is intended only to better illuminate the invention and does not represent a limitation within the scope of the invention, unless otherwise stated.

EXAMPLES

Example 1

[0046] Two mixtures are prepared, one containing the inputs of the probiotic tablet and the other containing the inputs of the vitamin and mineral tablet. The probiotic product is mixed in one step: 100% excipient and active content (probiotic strains) are added and mixed in twenty minutes. This type of manipulation is sufficient to guarantee the homogeneity of the mixture and, thus, the uniformity of the desired dose of probiotic strains in the tablets. This procedure is performed in a controlled environment, that is, with temperature and humidity strictly monitored. The temperature of the production rooms is a maximum of 25 ° C and the humidity is up to 50% RH The product mixture containing vitamins and minerals is carried out as follows: the entire content of vitamins and minerals and excipients is added and mixed in a once. This type of manipulation is sufficient to guarantee the homogeneity and uniformity of the formulation content. This procedure is performed in a controlled environment, that is, with temperature and humidity strictly monitored. The temperature of the production rooms is a maximum of 25 ° C and the humidity is up to 50% RH

Example 2

[0047] Two mixtures are prepared, one containing the inputs of the probiotic tablet and the other containing the inputs of the vitamin and mineral tablet. The probiotic product is mixed in two stages: in each stage 50% of the excipient and active content (probiotic strains) are added and mixed in ten minute intervals, totaling, at the end of the process, two mixtures with 100% of the content in 20 minutes. This type of manipulation is sufficient to guarantee the homogeneity of the mixture and, thus, the uniformity of the desired dose of probiotic strains in the tablets. This procedure is performed in a controlled environment, that is, with temperature and humidity strictly monitored. The temperature of the production rooms is a maximum of 25 ° C and the humidity is up to 50% RH The product mixture containing vitamins and minerals is performed by geometric dilution. The entire content is divided and mixed in two stages, so that vitamins and minerals of lower concentration are added and mixed first. Then, the highest concentration components are added and mixed last, ensuring better homogeneity and uniformity of the formulation content. This procedure is performed in a controlled environment, that is, with the temperature Q humidity closely monitored. The temperature of the production rooms is a maximum of 25 ° C and the humidity is up to 50% RH

[0048] Example 3

[0049] Two mixtures are prepared, one containing the inputs of the probiotic tablet and the other containing the inputs of the vitamin and mineral tablet. The probiotic product is mixed in four stages: in each stage 25% excipient and active content (probiotic strains) are added and mixed at 5 minute intervals, totaling, at the end of the process, four mixtures with 100% of the content in 20 minutes. This type of manipulation is sufficient to guarantee the homogeneity of the mixture and, thus, the uniformity of the desired dose of probiotic strains in the tablets. This procedure is performed in a controlled environment, that is, with temperature and humidity strictly monitored. The temperature of the production rooms is a maximum of 25 ° C and the humidity is up to 50% U.R. The product mixture containing vitamins and minerals is performed by geometric dilution. The entire content is divided and mixed in two stages, so that vitamins and minerals of lower concentration are added and mixed first. Then, the highest concentration components are added and mixed last, ensuring better homogeneity and uniformity of the formulation content. This procedure is performed in a controlled environment, that is, with temperature and humidity strictly monitored. The temperature of the production rooms is a maximum of 25 ° C and the humidity is up to 50% U.R.

[0050] The preferred embodiments of this invention are described herein, including the best way known to the inventors for carrying out the invention. Variations of these preferred embodiments may become apparent to those skilled in the art when reading this specification. The inventors believe that those skilled in the art can use variations as appropriate. Consequently, this invention includes all modifications and equivalents of the material recited in the appended claims, as permitted by applicable law. In addition, any combination of the elements described above in all its possible variations is covered by the invention, unless otherwise indicated here or clearly contradicted by the context.

[0051] All documents cited in this specification are incorporated herein in their entirety by reference. Furthermore, although the invention has been described here with an emphasis on a preferred embodiment, it will be obvious to those skilled in the art that variations in preferred concentrations can be used and that it should be understood that the invention can be carried out and incorporated differently from the way specifically described here. Accordingly, the present invention includes all modifications covered within the spirit and scope of the invention, as defined by the claims.

REFERENCES

[0052] AGAK, G.W. et al. Propionibacterium acnes induces an interleukin- 17 response in acne vulgaris that is regulated by vitamin A and vitamin D. The Journal of investigative dermatology. p.366-373, 2014.

[0053] BECKENBACH, L. et al. Retinoid treatment of skin diseases. Journal of the European Academy of.

[0054] BIESKI, G. L. Risks and benefits of using the drug isotretinoin to treat acne. FACIDER RevistaCientífica, Colider MT, n. 09, 2016.

[0055] CHAPMAN, M.S. Vitamin A: History, Current Uses, and

Controversies.Seminars in Cutaneous Medicine and Surgery. Elsevier INC. v.31, p.

[0056] BARBIERI, R.L .; SMITH, S .; RYAN, K.J.The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism. Fertile Steril, vol. 50, pg. 197-212, 1998;

[0057] BODEN, G .; SHULMAN, Gl. Free fatty acids in obesity and type 2 diabetes defining their role in the development of insulin resistance and betacell dysfunction. Eur J. Clin. Invest, vol. 32, pg: 14-23, 2002;

[0058] CORDAIN, L. Implications for the role of diet in acne. Semin Cutan. Med. Surg. Vol. 24, p. 84-91, 2005;

[0059] DRENO, B .; AMBLARD, P. AGACHE, P .; SIROT, S .; LITOUX, P. Low doses of zinc gluconate for inflammatory acne. Minutes. Derm. Venereol Suppl (Stockh), vol. 69, pg. 541-3, 1989.

[0060] VOWELS, BR .; YANG, S .; LEYDEN, J.J. Induction of proinflammatory cytokines by soluble factor of Propionibacterium acnes implications for chronic inflammatory acne. Infect immune, vol. 63, pg: 3158-65, 1995.

[0061] WEBSTER, GF; LEYDEN, JJ; TSAI, CC. Plimorphonuclear leukocyte lysosomal release in response to Proprionobacterium acnes in vitro and its enhancement by sera from inflammatory acne patients. J. Invest. Dermatol, vol. 74, pg: 398-401, 1980.

[0062] WOLEVER, TM, MEHLING, C. Long term effect of varying the source or amount of dietary carbohydrate on postprandial plasma glucose, insulin, triacylglycerol, ande free fatty acids concentrations in subjects with impaired glucose tolerance. Am. J. Clin. Nutr., Vol., 77, pg: 612-621, 2003.

Claims

1 . Probiotic composition characterized by the fact that it comprises: a first composition consisting of Lactobacillus acidophilus

NCFM®, 10 ⁹ UFC and Bifidobacterium lactis HN019, 10 ⁹ UFC formulated in a suitable vehicle; and

a second composition consisting of vitamin A, 600 pg RE; niacin, 16 mg; vitamin B6, 1.3 mg; chelated zinc, 7 mg and copper, 900 pg, formulated in a suitable vehicle.

2. Process for preparing a bacterial composition characterized by the fact that it comprises the following steps: weighing of the inputs, mixing and direct compression, in which the temperature of the production rooms is a maximum of 25 ° C and the humidity is up to 50% U.R.

3. Process, according to claim 2, characterized by the fact that in the mixing stage a dilution is made in one and / or up to three stages, with each stage 25% and / or up to 100% excipient content and active (probiotic strains) are added and mixed at intervals of five and / or up to twenty minutes, totaling, at the end of the process, one and / or three mixtures with 100% of the content in 20 minutes.

4. Process according to claim 2, characterized by the fact that the excipient matrix consists of a grease agent, a stabilizer, an anti-humectant and a lubricant.

5. Process according to claim 4, characterized by the fact that the matrix must consist of a grease agent, an anti-wetting agent and a lubricant.

6. Process according to claim 4, characterized by the fact that the concentration of the dough agent in the formulation varies from 50 to 90 percent of the total content, with the preferred concentration being the arithmetic mean between the lowest and highest concentration, with an antiumectant concentration ranging from 1.0 to 3.0 percent of the total content, with the preferred concentration being the arithmetic mean between the lowest and highest concentration and the lubricant concentration in the formulation ranging from 0.5 to 2.0 percent of the total content, with the preferred concentration being the arithmetic mean between the lowest and highest concentration.

7. Process, according to claim 1, characterized by the fact that the step of mixing the components of the composition of vitamins and minerals is performed a geometric dilution, in which the entire content is divided and mixed in one and / or even two steps, so that vitamins and minerals of lower concentration are added and mixed first and then the components of higher concentration are added and mixed last.

8. Process according to claim 7, characterized by the fact that it also comprises a coating step.

9. Process according to claim 8, characterized by the fact that the coating comprises a suspension that offers moisture barrier.

10. Use of the combination as defined in claim 1 characterized by the fact that it is in the preparation of a food or food additive, a nutraceutical product, a dietary supplement or a probiotic.