BR102012013590B1 - Red propolis microencapsulates, process for obtaining microencapsulates, pharmaceutical compositions containing them, process for obtaining pharmaceutical compositions and uses - Google Patents

Abstract

RED PROPOLIS MICROENCAPSULATES, PROCESS FOR OBTAINING MICROENCAPSULATES, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME, PROCESS FOR OBTAINING PHARMACEUTICAL COMPOSITIONS AND USES Red propolis microencapsulates (MPV), process for obtaining MPV, pharmaceutical compositions containing MPV, process for obtaining pharmaceutical compositions containing MPV and uses. The production of MPV is linked to the use of standardized hydroalcoholic tinctures of red propolis, following the spray-dryer technique, in the form of microparticles. Additionally, the present application deals with gastro-resistant pharmaceutical compositions containing said MPVs. MPVs and pharmaceutical compositions containing them have application in the pharmaceutical industries, mainly due to their antimicrobial activities.

Description

FIELD OF THE INVENTION

The present invention belongs to the chemical-pharmaceutical field, more specifically to the area of natural products with utility to public health. Red propolis microencapsulates (MPV), process for obtaining MPV, pharmaceutical compositions containing MPV, process for obtaining pharmaceutical compositions containing MPV and uses are proposed. The production of MPV is linked to the use of standardized hydroalcoholic tinctures of red propolis, followed by the Spray-Dryer technique, in the form of microparticles. Additionally, the present application deals with gastro-resistant pharmaceutical compositions containing said MPVs. MPVs and pharmaceutical compositions containing them have application in the pharmaceutical industries, mainly due to their antimicrobial activities.

FUNDAMENTALS OF THE INVENTION Propolis

Propolis is the generic name for a natural product with resinous, balsamic, gummy and highly adherent characteristics, harvested by bees (Apis mellifera). In hives, propolis is used to close small cracks, embalm dead insects and protect them against the invasion of insects and microorganisms.

Collector bees, through their hind legs, collect plant resins from shoots, fruits, flowers and exudates, which undergo addition of bee secretions. As it is collected from several plant species, propolis is a substance of highly variable composition. This variable composition depends on the geographical origin in which the apiary is located and may vary due to the collection site, botanical origin containing different species of medicinal plants, different times of the year and different geographical conditions including climatic zones.

The chemical constituents of honey and propolis have been identified worldwide (Pietta, P.; Gardana, C.; Scaglianti, M.; Simonetti, P., Journal of Pharmaceutical and Biomedical Analysis, V. 45, p. 390- 399, 2007). Flavonoids, phenolic acids and terpenes are the main substances found and used to track the quality and, in some cases, to demonstrate the authenticity of propolis from some geographic regions (Volpi, N.; Bergonzini, G., Journal of Pharmaceutical and Biomedical). Analysis, V. 42, p. 354-361, 2006). Among the flavonoids and phenolic acids most commonly used as markers, the following can be mentioned: quercetin, kaempferol, naringenin, chrysin, pinocembrin, galangin (flavonoids); gallic acid, caffeic acid, p-coumaric acid, ferulic acid, cinnamic acid and derivatives (phenolic acids), clerodanes (diterpenoids) (Rosalen, P.L.; Castro, M.L.; Cury, J.A., Quimica Nova, V. 30, N. 07 , 1512-1517, 2007); (Tomás-Barberán, F.A.; Martos, I. Cossentini, M.; Ferreres, F., J. Agric. Food Chem., V. 45, p. 28242829, 1997); (Yao, L.; Jiang, Y.; Singanusong, R., Datta, N.; Raymont, K., Food Chemistry, V. 86, p.169-177, 2004); (Weston, R.J., Mitchell, K.R., Allen, K.L., Food Research International, V. 37, p. 166-174, 2004); (Mitamura, T.; Matsuno, T.; Sakamoto, S.; Maemura, M.; Kudo, H.; Suzuki, S.; Kuwa, K.; Yoshimura, S.; Sassa, S.; Nakayama, T. ; Nagasawa, H., Anticancer Research, V. 16, No. 5a, p. 2669-2672, 1996).

Other markers are specific for Brazilian green propolis, such as isosakuranetin, bakarina, drupanin and Artepilin-C. Artepilin C has shown excellent antitumor activity (Kimoto, T.; Koya-Miyata, S., Hino, K.; Micallef, M.J.; Hanaya, T.; Arai, S.; Ikeda, M.; Kurimoto, M. , Virchows Arch, V. 438, pp. 259-270, 2001); (Orsolic, J.N.; Terzic, S.; Sver, L.; Basic, I., Food and Agricultural Immunology, V. 16, N. 3-4, p. 165-179, 2005); (Li H.Z., Kapur, A.; Yang, J.X.; Srivastava, S.; McLeod, D.G.; Paredes-Guzman, J.F.; Daugsch, A.; Park, Y.K.; Rhim, J.S., International Journal of Oncology, V. 31, No. 3, p. 601-606, 2007).

The growing popular use of propolis and its derivatives with antimicrobial action (Sforcin, J.M; Fernandes Jr., A.; Lopes, C. A. M.; Bankova, V. And Funari, S. R. C., J. Ethnopharmacology, V. 73, p. 243 -249, 1998), anti-inflammatory (Khayyal, M.T.; el-Ghazaly, M.A.; el-Khatib, A.S., Drug Experimental and Clinical Research, V. 19, pp. 197-203, 1993), antiviral (Vynograd, N. .; Vynograd, I.; Sosnowisky, Z., Phytomedicine, V. 7, p. 1-6, 2000), anticarcinogenic (Bazo, A.P.; Rodrigues, M.A.M.; Sforcin, J.M.; Camargo, J.L.V., Ribeiro, J.L.; Salvadori , D.M.F., Teratogenis, Carcinogenis and Mutagenis, V. 22, pp. 183-194, 2002) and immunomodulatory (Sforcin, J.M., Kanemo, R. Funari, S.R.C., Journal of Venemous Animal and Toxins, V. 8, p. 19 -29, 2002); (Sá-Nunes, A.; Faccioli, L.H., Sforcin, J. M., Journal of Ethnopharmacology, V.83, p. 9397, 2003) has demonstrated the great therapeutic power of propolis in substitution of conventional synthetic drugs.

The characterization of all these biological activities associated with the tendency to use natural products has resulted in an increase in the demand for propolis and products containing propolis, such as extracts, tablets, capsules, nebulizations or powders (Menezes et al., 1997).

red propolis

In the case of red propolis, it was classified as the 13th subtype of Brazilian propolis found in the regions of mangroves, lakes, rivers and beaches in northeastern Brazil between the states of Sergipe, Alagoas, Pernambuco and Paraíba by the researcher Park et al. (2007). The main botanical origin of red propolis is due to the plant Dalbergia ecastophyllum, locally known as Rabo-de-Bugio, which presents a red resinous exudate released from its sap. Red propolis can also be found in Cuba, in the provinces of Pinar Del Rio (La Coloma), Villa Clara (Manicaragua) and Matanzas (Jagüey Grande) (Anna Lisa Piccinelli et al. J. Agric. Food Chem. 2005, 53, 9010-9016); (Osmany Cuesta-Rubio et al. J. Agric. Food Chem. 2007, 55, 7502-7509 ).

National and international researchers with expertise in propolis have been identifying the constituents of red propolis. Eleven isoflavonoids and 1 chalcone from Cuban red propolis were identified and among these substances we can mention: Formononetin (Biochanin B), Bichanin A, vestitol, ortho-methyl vestitol, medicarpine, homopterocarpine, other pterocarpan derivatives, liquiritigenin and isoliquiritigenin (chalcone) (Anna Piccinelli et al. J. Agric. Food Chem. 2005, 53, 90109016 ). Other flavonoid subclasses were also identified, including new types of flavonoids from red propolis from the northeast region, namely: rutin, quercetin, luteolin, pinocembrin and biochanin A, formononetin, daidzein, liquiritigenin, pinobanksin, dalbergin (neoflavonoids) (Park and eCAM (2008) 5 (4) 435-441).

Researchers studying red propolis from the Marechal Deodoro-Alagoas mangrove region identified the flavonoid chrysin and quercetin, new isoflavonoids in red propolis from Alagoas, vestitol, 2'4'dihydroxymethoxy flavane, isoprenylated benzophenones, as well as ferulic acid and phenolic esters methoxyeugenol, methyleugenol, guiacol, butanedioic acid dimethyl esters, hexadecanoic acid methyl esters (Alencar et al. eCAM (2008) 5 (3) 313-316).

Additionally, researchers identified 14 substances in red propolis from the mangroves of Alagoas, among them triterpenes (cycloartenol, lupeol, elemicin, α-amyrin and β-amyrin), phenolic acids (anethole, eugenol and methyleugenol), isoflavonoids (isosativan, medicarpine) ( Vassya Bankova et al. eCAM (2006) 3 (2) 249-254 ).

With a view to discovering molecules and their therapeutic targets for curing diseases, red propolis has been subjected to several detailed studies on its biological activities.

The presence of several flavonoids and phenolic acids in extracts and tinctures of propolis show that these substances act synergistically in cytostatic/cytotoxic, anti-inflammatory, healing, antimicrobial and antioxidant action. In this way, the cocktail of combined substances, even at low concentrations, will promote a potent action against pathogens.

microencapsulation

The development and production of phytotherapics and opotherapics have been regulated in the country with resolutions that establish quality control methodologies for these products. Standardization studies of phytotherapics and herbal medicines advocate tests in order to guarantee the quality of these classes of drugs from collection, phytochemical screening, qualitative and quantitative determination of phytochemical markers, authenticity test, processing, production, stability study, validation of analytical methodologies , packaging and product quality control.

Development of new drug delivery systems or functional food (nutraceutical) (Lira, C. R. G; et al., Rev. Bras. Farm., (2009) 90 (1): 45-49) in certain therapeutic targets is a necessity to obtain therapeutic success or to demonstrate a physiological benefit to health in the prevention of diseases, and is as important as the discovery of molecules with a certain therapeutic action. Thus, in the present invention, different formulations for pharmaceutical, nutraceutical or veterinary use in solid form, preferably for oral use, were planned.

In the development of new systems for the release of drugs or substances with functional activity (nutraceutical), it is extremely important to choose pharmaceutical excipients with inert properties (without pharmacological or therapeutic action), being essential in a pharmaceutical/food composition, as they have characteristics that ensure stability to the composition, facilitate administration, promote the release of active substances from the chemical-pharmaceutical matrix, thus promoting bioavailability and consequently pharmacological action, as well as consumer acceptability.

For the development of a drug/nutraceutical release system in solid form, it is necessary to have a set of excipients that will adequately release the drug or active substances from a pharmaceutical or food matrix and among them are the excipients: diluents, binders, disintegrants, dyes , flavorings, sweeteners, surfactants or wetting agents, fluidifiers and lubricants. From the point of view of process and production costs, pharmacotechnical incompatibilities between active substances and excipients must be avoided. The choice and number of excipients influence drug release from the matrix and absorption into biological fluids (blood and circulatory system). Thus, the number of excipients should be reduced to the minimum possible and should contain only essential excipients (Croeley, 1999; Robertson, 1999).

Some pharmaceutical excipients can generate negative influences for the pharmaceutical or nutraceutical composition. Diluents are generally the excipients that are used in greater proportion in a composition and their choice must be well defined to avoid problems of drug-excipient or excipient-excipient incompatibility, reduce the stability of the active substance(s). ) in the composition, as well as toxicity problems. Classic examples are the diluents mannitol and sorbitol which can reduce drug absorption, reduce intestinal peristalsis, cause hyperosmolarity and hypersensitivity problems (D.A. Adkin, S.S. Davis, R.A. Sparrow, P.D. Huckle, J.R. Wilding, Br. J. Clin. Pharmacol. 39 (1995) 381-387), (D.A. Adkin, S.S. Davis, R.A. Sparrow, P.D. Huckle, J.R. Wilding, J. Pharm. Sci. (1995) 84 1405-1409), (E. Jantratid, S. Prakongpan, J.B. Dressman, G.I. Amidon, H.E. Junginger, K.K Midha, D.M. Barends; Journal of Pharmaceutical Sciences, (2006) 95 974-984 ).

Microencapsulation techniques are used by the pharmaceutical and food industries in order to solve technological bottlenecks, including: protecting the active substance(s) against extrinsic agents (moisture, light, oxidation) increasing the shelf life of the product , prevent the loss of volatile substances, promote controlled release of active substances, as well as improve specific flow characteristics of powders during specific tablet compression processes or in the filling of gelatinous capsules.

The development of solid microencapsulates can be obtained by the Spray-Dryer technique (nebulization drying) and can solve some industrial problems in the pharmaceutical and food areas due to the insoluble nature of some drugs or the presence of complex matrices containing several substances with different solubilization properties. which can hinder absorption processes and consequently a therapeutic effect.

In the microencapsulation process, pharmaceutical excipients are properly chosen to promote a stable coating wall in an adequate proportion that promotes the encapsulation of the substances of interest in a coating matrix, forming, depending on the particle size, microparticles or even nanoparticles.

A polymeric nanoparticle formulation of propolis (nanofood propolis) was developed using micellar aggregates of cross-linked and random copolymers of N-isopropylacrylamide (NIPAAm) with N-vinyl-2-pyrrolidone (VP) and poly(ethylene glycol) monoacrylate (PEG-A) (Kim, Dong-Myung, Lee, Gee-Dong, Aum, Seung-Hyun, Kim, Ho-Jun, Biological & Pharmaceutical Bulletin, (2008) 31, 1704 1710 ). It is important to highlight that the use of the matrix system proposed by Kim et al., for the formation of propolis microencapsulates, has the high cost of acquiring the excipients as a great disadvantage. In contrast, the invention proposed in the present document uses low-cost excipients, making microencapsulated products and pharmaceutical compositions that use them more affordable.

Chinese patent CN101869234 demonstrates the preparation of propolis nanoemulsions containing ethyl acetate and tween. The preparation of microencapsulates using the matrix system of patent CN101869234 presents as a great disadvantage the high toxicity of ethyl acetate for human consumption. If ingested, ethyl acetate presents a potential risk of intoxication such as loss of consciousness, nausea, vomiting, diarrhea, dizziness and drowsiness.

Document KR20100078349 discloses propolis nano-emulsion preparations using β-cyclodextrin excipient. It is important to highlight that the use of the matrix system with β-cyclodextrin to form propolis microencapsulates makes the product expensive, which is disadvantageous in terms of the market. This disadvantage is potentiated when we compare the use of excipients such as starch, gelatin and aerosil, as proposed in the present document.

Patent KR20090075395 claims propolis nanoparticles for parenteral use containing the excipients N-isopropylacrylamide, N-vinyl-2-pyrrolidinone (VP) and poly(ethylene glycol) acrylate (PEG-A). It is important to highlight that the use of the excipients proposed by the Korean patent in question for the formation of propolis microencapsulates presents a great disadvantage due to the high cost of acquiring these products.

Additionally, document KR20080089723 discloses the preparation of gelatin-containing propolis powder for preparing toothpaste and dental floss. The use of propolis for dental purposes is widely described in the prior art. The matrix system proposed by the document in question is different from that proposed by the present invention, which deals with the matrix system of microencapsulated for use in gastro-resistant capsules/tablets.

Propolis microencapsulates containing a modified starch (Octenyl-starch succinate) and gum arabic were obtained by the Spray-Dryer technique (Silva F. C., Thomazini M.1, Alencar S. M. and Favaro-Trindade C. S., XVIIth International Conference on Bioencapsulation, Groningen, Netherlands; September 24-26, 2009). The use of this matrix system to form propolis microencapsulates presents as a great disadvantage the high cost for the acquisition of starch octenyl-cuccinate, in relation to the pregelatinized starch, proposed in this document.

Research by Nayan Roy (Colloids and Surfaces B: Biointerfaces 76 (2010) 317-325) has incorporated Indian propolis extracts into a matrix containing gold and silver. Such products have high added value, making the value of products derived from this type of microencapsulated product more expensive.

Process for obtaining propolis components in the dry state using gelatin containing propolis solution from the city of Maringá (Paraná) were prepared by spray-dryer drying. The optimization of spray drying conditions and the proportions of gelatin and mannitol were investigated (M.L. Bruschi, M.L.C. Cardoso, M.B. Lucchesi, M.P.D. Gremião, International Journal of Pharmaceutics (2003) 264, 45-55). It is essential to highlight that the use of different types of excipients allows different mechanisms of release of active substances from the pharmaceutical matrix (microencapsulated), in addition to different physiological actions. Some pharmaceutical excipients can generate negative influences for the pharmaceutical or nutraceutical composition. Classic examples are mannitol and sorbitol diluents that can reduce drug absorption, reduce intestinal peristalsis, cause hyperosmolarity and hypersensitivity problems. In this way, it is evident that the microencapsulates proposed in this patent document present outstanding advantages compared to the state of the art, due to the use of excipients suitable for the release of the active elements contained in propolis.

The Brazilian patent application PI05001757 uses only two excipients (gelatin and mannitol) and only demonstrates the process of preparing an intermediate matrix containing propolis extracts, not disclosing the origin of the propolis used. It is important to highlight that the MPV claimed in this document has innovative characteristics in relation to the microencapsulated PI0500175-7, presenting a higher percentage of propolis extract in the composition (25 to 55%) in relation to that document, which presents only 10 to 12%. In this way, the production cost of microencapsulated products with less excipients in the composition is reduced, as well as the development of compositions containing a wide range of concentration of the standardized tincture of red propolis. Additionally, the process for obtaining the MPV proposed in the present patent document can be prepared in cold by the sol-gel dispersion method, containing a ternary system with three excipients (gelatin, pre-gelatinized starch and aerosil), presenting dispersing properties and also non-stick. The preparation process by emulsification was carried out at a controlled temperature of 37 oC, to avoid problems of structural polymorphic modifications of the gelatin with losses of the emulsifier functionality.

None of the described patent documents disclose a dissolution method to assess the degree of release of active substances from the compositions. In addition to the characteristics already described, comparing the microencapsulates obtained in the state of the art with those proposed by the present patent document, none of the microencapsulates mentioned in the state of the art present red propolis from the mangroves of Alagoas as a bioactive substance.

In this way, the modalities of the invention described in this document present considerable advantages compared to the state of the art.

The invention proposed in the present document seeks to fill a technological gap in terms of the application of red propolis as an active element in pharmaceutical compositions for the treatment and prevention of diseases. In this way, red propolis microencapsulates, compositions with the use of MPV, processes for obtaining MPV and uses of these products for the preparation of drugs with cytostatic/cytotoxic, anti-inflammatory, healing, antimicrobial and antioxidant action are proposed.

It should be noted that the use of red propolis is a determining feature in innovation, in terms of propolis technologies, since red propolis has a characteristic composition, which will have a primary role in the activity of microencapsulated and other pharmaceutical compositions, for prevention and treatment. of diseases.

The main advantage of the microencapsulates and pharmaceutical composition proposed in the present invention, compared to the state of the art, is the use of compounds in an intermediate matrix of bioactive coatings that contain inert, non-toxic, low cost, stable pharmaceutical excipients with rheological characteristic for solids. pharmaceuticals, of gastro-resistant release and an external matrix containing usual pharmaceutical excipients. In this way, the composition disclosed herein can be used to solve semi-industrial and industrial technical problems in the food and pharmaceutical fields, as well as some applications of therapeutic use.

The Chinese patent (CN102429141 - Method for preparing propolis microcapsules and application) is a method (process) of preparing propolis microcapsules and their applications (uses). In this document, it was observed in the detailed description of the invention and in the claims the use of Freeze drying (lyophilization) in the preparation of microcapsules, as well as the use of the adjuvant Zeína (corn protein) which was combined with gelatin and pectin.

In the preparation of the patent sought herein, neither zein nor the mixture of gelatine with pectin was used in the preparation. In addition, the Freeze drying technique was not used in the drying process. The active ingredient in the composition was the red propolis extract from Alagoas, which has a GI at the INPI. Excipients (Gelatin, pregelatinized starch and aerosil) were used. So the matrix system for preparing the microcapsules was different. Pregelatinized starch has carbohydrates in its composition and not zein (corn protein). The drying technique used was the Spray-Dryer, therefore, a drying technique different from the Freeze Drying technique (lyophilization). In this way, no changes to the claim framework will be made due to patent document CN102429141 - Method for preparing propolis microcapsules and application. Any change in the components of a process and in the drying process makes the process and the composition different. Therefore, we understand that the components used to form the CN102429141 microcapsules are considered different in relation to the patent sought herein.

The scientific article BRUSCHI ML ET AL. 2003 Gelatin microparticles containing propolis obtained by spray-drying technique: preparation and characterization, deals with a preparation and characterization of gelatin microcapsules containing propolis and reports its preparation and characterization.

In this scientific article, the authors declare the origin or provenance of the propolis that was obtained in an experimental unit of the State University of Maringá (State of

Parana Brazil). The excipients used for the preparation of the microcapsules were gelatin and mannitol and the drying technique was SPRA-DRYER. So, we can say that the propolis used was not the Red propolis of Alagoas. The components used to prepare the microcapsules (gelatin, or gelatin and mannitol) are different in the preparation of the patent sought herein, citing (gelatin, starch and aerosil). Any modification to the components of a process makes the composition different. The preparation process of the microcapsules for spray-dryer drying used the drip preparation process, while the preparation technique cited in our patent document BR102012013590-6 was the SOL-GEL preparation technique. The drying process by SPRAY-DRYING used SPRAY-DRYER equipment from BUCHI® Model MINI SPRAY-DRYER B-191. In the patent sought here, national equipment was used, Labmaq model LM MSD 1.0, different equipment. The technical word spray-dryer drying will be removed from the claim, as the search for prior art showed that the Scientific Document BRUSCHI ML ET AL. 2003 Gelatin microparticles containing propolis obtained by spray-drying technique: preparation and characterization already presents the Spray-dryer technique for drying propolis microcapsules. Only the patent here intended to be the first to cite spray-dryer technique for drying microcapsules of red propolis extract from Alagoas, propolis that received the first GI of bioproduct from Alagoas biodiversity. Therefore, these microcapsules are considered novelty (unpublished) in the scientific and patent literature.

In view of these arguments, it is considered that the drying process is similar at this stage of the process (spray-dryer drying), although in the spray-dryer drying stage for red propolis microcapsules it is considered new (unprecedented).

The scientific article ALENCAR ET AL. 2007 “Chemical composition and biological activity of a new type of Brazilian propolis: Red propolis”, deals with chemical and microbiological characterization of the extract and fractions (chloroform and hexane) of red propolis from Alagoas. In this study Alencar et al. 2007 identifies the flavonoids and isoflavonoids present in the extract and fractions of red propolis, as well as demonstrates the antibacterial activity of red propolis against ATCC strains of Staphylococcus aureus bacteria ATCC 25923 and Streptococcus mutans UA159. The scientific article by Alencar et al. 2007 does not carry out any preparation of red propolis microcapsules from Alagoas.

The patent sought here performs preparation of red propolis microcapsules, as well as demonstrates the antimicrobial activity of the same red propolis microcapsules by means of the Minimum Inhibitory Concentration (MIC) assay using two Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 bacteria considered Gram positive. (+) and Gram negative (-), respectively.

Although the scientific article by ALENCAR ET AL. 2007 “Chemical composition and biological activity of a new type of Brazilian propolis: Red propolis” was the first to cite a technique of antibacterial activity to biologically characterize the extract and fractions (chloroform and hexane) of red propolis from Alagoas, did not perform the test for red propolis microencapsulated from Alagoas. It is worth remembering that the red propolis microencapsulates present in the composition the hydroalcoholic extract and SOL-GEL emulsifying agents, therefore a new modified composition for the red propolis extract added with SOL-GEL emulsifying agents that can be considered unprecedented (novelty in the state of the art ), in relation to natural extracts of red propolis (without technological modification) tested by ALENCAR et AL. 2007.

In view of these arguments, it is considered that the antibacterial characterization process using the MIC technique is not similar at this stage of the process (antimicrobial assay) to the assay by ALENCAR ET AL. 2007 that uses Staphylococcus aureus ATCC 25923 and Streptococcus mutans UA159. In the characterization step, the antimicrobial activity of the red propolis microcapsules was carried out with the new composition using SOL-GEL emulsifying agents, therefore, the composition is considered novelty (unprecedented). In addition, the scientific article by ALENCAR ET AL. 2007 “Chemical composition and biological activity of a new type of Brazilian propolis: Red propolis” does not perform assays with the Gram negative (-) Pseudomonas aeruginosa ATCC 27853 strain, nor with the microcapsules of red propolis from Alagoas, which also makes it the patent document under unprecedented (novelty) and active (alive) trial.

SUMMARY OF THE INVENTION

The present invention presents red propolis microencapsulates, composed of red propolis tincture, diluent, flow promoter and dispersant or emulsifier. The invention also deals with the process of obtaining the microencapsulated by means of the Spray-Dryer technique. Additionally, an embodiment of the invention is presented in terms of composition containing the microencapsulated in solid formulations, preferably in the form of gastro-resistant gelatinous capsules. The disclosed composition comprises i) a core containing red propolis active substance(s) combined with pharmaceutical excipients; ii) an intermediate layer coating the core which can delay the release of the active substance(s) contained in the core and which is pH dependent; iii) an external layer responsible for the lubrication, dilution, fluidity, wettability and disaggregation/dissolution processes of the intermediate layer and inner core. Furthermore, the invention deals with the process of preparing the composition, by performing physical mixtures with the red propolis microencapsulates to ensure content and uniformity of content and encapsulation. Finally, uses for the microencapsulated and the composition in question are presented.

BRIEF DESCRIPTION OF THE FIGURES/DRAWINGS

The embodiment of the invention, together with additional advantages thereof, can be better explained and understood by referring to the accompanying drawings and the following description:

Attached Figure 1 presents a simplified flowchart of the main steps in the process of obtaining MPV.

Attached Figure 2 presents a simplified flowchart of the main steps in the process of obtaining pharmaceutical compositions containing MPV.

Attached Figure 3 shows the Scanning Electron Photomicroscopy of Microencapsulated A, B, C and D of red propolis from Alagoas. Photomicrographs A1, B1, C1 and D1 500x magnification (50μm scale); A2, B2, C2 and D2 1000 times magnification (10μm scale) and A3, B3, C3 and D3 2000 times magnification (10μm scale).

DETAILED DESCRIPTION OF THE INVENTION

The products, processes and uses described in the present invention can be better detailed and understood by referring to the figures present in this document and the following description:

Red Propolis Microencapsulates (MPV)

The microencapsulates presented in this document differ from those already described in the state of the art by the fact that the concentrations of flavonoids, isoflavonoids, chalcones and phenolic acids are differentiated due to the specificity of red propolis.

MPVs, in addition to the tincture with the active ingredients of interest, obtained from red propolis, present in their formulation the usual pharmaceutical excipients with different functionalities, namely: active compound (tincture), diluents, fluidity/anti-adherence promoter, dispersant/emulsifier.

In one embodiment of the present invention, a microencapsulated MPV A, there is a composition of: standardized hydroalcoholic tincture of red propolis from the bioactive extract in a proportion between 5 and 95%, preferably between 20 and 60%; diluent in proportion between 5 and 95%; dispersant in proportion between 5 and 95%; and flow promoter in proportion between 0.01 and 5%.

Another embodiment of the proposed invention, a microencapsulated MPV D, has the following composition: standardized hydroalcoholic tincture from the bioactive extract in a proportion between 5 and 95%, preferably between 20 and 60%; diluent in proportion between 5 and 50%; emulsifier in proportion between 5 and 60%, preferably between 20 and 45%; and a flow promoter in proportion between 0.01 and 5%.

In both embodiments of the invention, both in MPV A and in MPV D, the dispersant system is characterized by being a ternary system, composed of gelatin, pre-gelatinized starch and aerosil.

The red propolis microencapsulates (MPV A and MPV D), as they consist of aerosil excipients in the composition, have non-stick properties that reduce the contact of the intermediate coating matrix with the walls of the preparation container, preventing the formation of aggregates of the gelatin and starch excipients and consequently avoiding variations in the content uniformity of the obtained MPVs.

Also, it is important to highlight that the microencapsulated products proposed in this document are innovative because they present a higher percentage of propolis extract in the composition (25 to 55%), in relation to the state of the art, which has lower concentrations. In this way, production costs are reduced with a lower amount of excipients in the composition, as well as the development of compositions containing a wide range of concentration of the standardized tincture of red propolis. Process of obtaining MPV

The steps for obtaining MPV include the preparation of the crude extract from red propolis, preparation of the standardized hydroalcoholic tincture from the crude extract of red propolis, preparation of sol-gel and emulsifier systems containing red propolis tincture, and drying of the systems. sol-gel and emulsifier containing red propolis tincture, forming the MPV (Figure 1).

- Preparation of the Red Propolis Gross Extract

A 100 g sample of propolis is subjected to an extraction process by maceration in 400 to 750 mL of alcohol 60 to 90 °GL, preferably between 70 to 80 °GL, for a period of 12 to 48 hours. The extraction process is repeated until the active substances are fully extracted. Alternatively, percolation extraction method can be used instead of maceration. Optionally, to accelerate the extraction, the material can be placed in an ultrasonic bath for complete extraction of the active substances in a period between 30 minutes to 3 hours, or it can be submitted to a reflux extraction process in a soxhlet apparatus for a period between 2 to 3 hours. 10 hours.

After the complete extraction of the active substances, the material is concentrated in a rotary evaporator, coupled to a vacuum pump, using a rotation speed of 20 to 120 rpm, in a water bath at a temperature range of 35 to 55°C and pressure between 400 to 700 mmHg. Alternatively, it can be concentrated using a 37°C to 42°C water bath.

A dark solid mass will be obtained with a solvent percentage between 5 and 35%, being called red propolis crude extract. The crude extract should preferably have a solvent percentage between 5 to 12%.

- Obtaining the standardized hydroalcoholic tincture

The bioactive extract of red propolis, obtained in the previous step, is subjected to a washing process with absolute ethanol, followed by evaporation of this solvent for 3 times in order to eliminate the presence of the toxic solvent in the formulation.

The crude extract of red propolis (50 to 75g) with the minimum percentage of solvent (5 to 12%) is used to prepare a standardized hydroalcoholic tincture of red propolis in a concentration between 5% and 30% (w/v), preferably between 10 and 30% (w/v) and more preferably between 15 and 25% (w/v), using solvent system ethanol:distilled water (60:40, v/v) or (70:30, v/v) or (80:20, v/v) or (90:10, v/v), preferably between (70:30, v/v) or (80:20, v/v), with the aid of stirring in an ultrasonic bath for 20 minutes until complete solubilization. No precipitation is observed after a period longer than 24 hours.

Optionally, a standardized hydroalcoholic tincture of red propolis in a concentration preferably between 20% and 30% (w/v) can be subjected to a partitioning process with hexane, followed by the addition of chloroform to remove some interferents, including waxes and fatty material and this procedure will depend on the initial quality of the red propolis obtained in natura. The chloroform extract obtained in this partitioning process (50g to 60g) is concentrated in a rotary evaporator and used to obtain an enriched chloroform extract of red propolis, which can also be called bioactive extract of red propolis.

The bioactive extract of red propolis, obtained in the previous step, is subjected to a washing process with absolute ethanol for 3 times, followed by evaporation of this solvent in order to eliminate the presence of the toxic solvent in the hydroalcoholic tincture of red propolis. Standardized hydroalcoholic tinctures of red propolis are then prepared in a concentration preferably between 15% to 25% (w/v) to obtain the MPV.

- Preparation of sol-gel and emulsifier systems containing red propolis tincture

For the preparation of sol-gel and emulsifier systems containing red propolis tincture, the usual pharmaceutical excipients with different functionalities are used, namely: active compound (standardized hydroalcoholic tincture), diluents, fluidity/anti-adherence promoter, dispersant/emulsifier.

For the preparation of sol-gel and emulsifier systems containing red propolis tincture, a proportion between 5 and 30% of the standardized hydroalcoholic tincture of red propolis, preferably between 15 and 25% is used. This tincture is reserved for later incorporation into the dispersed sol-gel system and into the emulsifying system.

The adjuvants for the preparation of the sol-gel system A containing red propolis tincture are added to a container containing 450 mL of distilled water at a time (one pot mixture). Then, the standardized hydroalcoholic tincture of red propolis (150 mL) is incorporated into the sol-gel dispersed system with an amount of solvent ethanol:water (10:90, v/v) or (20:80, v/v) or ( 30:70, v/v) or (40:60, v/v) or (50:50, v/v) or (60:40, v/v) or (70:30, v/v) or ( 80:20, v/v), preferably from 20 to 45°GL and more preferably from 35°GL containing the adjuvants at room temperature between 25 and 30°C.

The dispersant system is composed of a ternary system (gelatin, pregelatinized starch and aerosil) that remains as an unstable dispersed system that settles in the absence of agitation. The system remains under constant agitation to maintain itself in a gel state, because when the agitation process is interrupted or remains at rest, the system converts to a sol dispersion. This property was obtained thanks to the thixotropic properties of the dispersant (aerosil). In addition, aerosil promoted better dispersion of the standardized hydroalcoholic dye during the preparation of microencapsulates. Another advantage of these aerosil-containing compositions (MPV A and MPV D) is their non-stick property, preventing losses of excipients that were deposited on the walls of the preparation vessel during agitation.

The adjuvants for the preparation of MPV D are prepared in another container with an amount of 550 mL of ethanol: water (30:70, v/v) or (20:80, v/v) or (10:90, v/v ) or (02:98, v/v), preferably between (02:98, v/v) to (10:90, v/v) with the aid of a stirrer. The gelatin is added and solubilized, followed by the addition of the pregelatinized starch and finally the aerosil is added. Then, the standardized hydroalcoholic tincture (150 mL) is slowly incorporated into the emulsifier system containing solvent system ethanol:water (10:90, v/v) or (15:85, v/v) or (20:80, v /v) or (30:70, v/v) or (40:60, v/v) or (50:50, v/v) and preferably between 10 and 40°GL containing adjuvants and more preferably 15°GL under preferred temperature between 30°C and 45°C and more preferably at 37°C. The emulsifying system is composed of a ternary system (gelatin, pregelatinized starch and aerosil) that remains as a stable emulsion under agitation or at rest.

- Drying of the sol-gel and emulsifier systems containing red propolis tincture using Spray-Dryer

The sol-gel and emulsifier systems containing red propolis tincture are then subjected to a spray-dryer drying process under constant agitation, using a 1 mm injection needle. The Spray-Dryer has the following drying conditions: inlet temperature 120 to 180°C, outlet temperature 90 to 130°C, pumping flow of 0.3 L/h and air flow of 4.50 liters. In this way, powders of the sol-gel and emulsifier systems containing red propolis tincture are obtained and these powders are microencapsulated with red propolis. The sol-gel system containing the red propolis tincture, after the SprayDryer, generates the MPV A and the emulsifying system containing the red propolis tincture, after the Spray-Dryer, generates the MPV D.

It is important to highlight that the process proposed here for the preparation of microencapsulates can be carried out at room temperature by the sol-gel dispersion method. Furthermore, the preparation process by emulsification was prepared at a controlled temperature of 37 oC, to avoid problems of structural polymorphic modifications of gelatin with losses of emulsifier functionality.

Pharmaceutical compositions containing MPV

The MPV obtained can be used in various pharmaceutical compositions, preferably as solid formulations, such as powders, tablets, gelatin capsules, among others.

The pharmaceutical compositions proposed in the present document consist of compositions, preferably in the form of hard capsules or tablets, which have i) a core containing active substance(s) of red propolis combined with pharmaceutical excipients; ii) an intermediate layer coating the core which can delay the release of the active substance(s) contained in the core and which is pH dependent; iii) an external layer responsible for the lubrication, dilution, fluidity, wettability and disaggregation/dissolution processes of the intermediate layer and inner core.

It is important to highlight that, in the pharmaceutical compositions proposed here, the MPV constitute the core (i), with the active elements of the red propolis tincture, and the intermediate layer (ii), composed of the ternary systems that constitute the MPV.

In terms of the core of these pharmaceutical compositions, it is formed by active substances from the standardized tincture of red propolis, which are present in MPV.

The core cladding layer consists of a naturally occurring hydrophilic polymer or a combination of more than one naturally occurring hydrophilic polymer(s). In a different embodiment of the invention, the intermediate layer can also be prepared by conjugating one or more natural hydrophilic polymer(s) and one or more synthetic hydrophilic polymer(s). With regard to auxiliary pharmaceutical excipients, such as fluidity and anti-adherence promoting agents, binders and diluents, used in the intermediate layer, these must be included in the intermediate layer with percentages varying between 0.05% and 95% according to their functionality in the matrix pharmaceutical. In terms of the proportion of the intermediate layer in the final pharmaceutical composition, the intermediate layer covering the core should present percentages between 5% and 95%, and preferably between 30 and 75%, in relation to the total weight of the composition.

On the other hand, the outer layer of the composition consists of pharmaceutical excipients with different functionalities, among them we mention diluents, lubricants, fluidity promoting agents, wetting agents, disintegrants, super-disintegrants, whose dissolution of the composition is promoted by the pH change after passing the particulate material through the pylorus. The gastro-resistant release mechanism occurs when the composition containing natural or synthetic polymers with weak or esterified acid function that are insoluble in the gastric medium (stomach) with a pH < 4.0, leave the stomach and enter the duodenum through the pylorus, reach pH > 6.0, dissolve as it travels along the small intestine where the pH increases to 7 to 8 In terms of percentages of pharmaceutical excipients in the outer layer, these can represent between 0.05% and 100% of the total weight of the outer layer, according to its functionality in the pharmaceutical matrix. In terms of the proportion of the outer layer in the final pharmaceutical composition, the outer layer of the composition must have percentages between 0.01% and 50%, preferably between 1 and 15% in relation to the total weight of the composition.

The pharmaceutical composition presented herein may or may not have a gelatin shell, forming hard or soft capsules. Thus, in an embodiment of the invention proposed herein, capsules with a gelatin shell in sizes between 000 and 03 with dark coloring can be obtained.

Furthermore, the pharmaceutical excipients used in the composition can be of different types and in different formulations, with variable compositions between the different types of excipients. Among the excipients used in

compositions, natural or synthetic hydrophilic polymers such as gelatin, corn starch, pregelatinized starch, xanthan gums, guar gum, acacia, magnesium stearate, talc, titanium dioxide, polyvinylpyrrolidone, carbomers, polyvinyl alcohol, polaxamers, colloidal silicon dioxide, stearic acid, sodium starch glycollate (explosol), sodium lauryl sulfate, cellulose, microcrystalline cellulose, and cellulose derivatives such as CMC, methyl cellulose and hydroxypropyl ethyl cellulose.

Process for obtaining pharmaceutical compositions containing MPV

The steps for obtaining pharmaceutical compositions containing MPV can be identified by the following main steps: obtaining red propolis microencapsulates, performing physical mixtures to ensure content and uniformity of content and preparation of red propolis capsules in hard gelatine shells (Figure 2 ).

The MPV obtained can be used in various pharmaceutical compositions, preferably as solid formulations, such as powders, tablets, gelatin capsules, among others.

Preferably, for the preparation of hard gelatine capsules containing MPV, the microencapsulates are subjected to a mixing process by the geometric dilution method with the disintegrating or superdisintegrating type excipients in a proportion between 0.5 and 15% (preferably between 1 to 10%, and more preferably between 2 and 7%) in a time between 5 and 120 minutes, more preferably between 25 and 65 minutes. Then, the microencapsulates are mixed with excipients such as wetting agents in a proportion between 0.5 and 10%, preferably between 1 and 5% and more preferably between 2 and 3.5%, in a period of 5 to 120 minutes, more preferably between 25 and 65 minutes. The mixture was finished by adding a lubricant-like excipient in a proportion between 0.1 and 6%, preferably between 0.3 to 4%; more preferably between 0.75 and 2%, over a period of 2 to 10 minutes, more preferably between 3 and 7 minutes.

Encapsulation can be performed in manual instruments (encapsulation table), semi-industrial and industrial instruments, adjusting the mass of the MPV in terms of the standardized tincture of red propolis. Variations between 90 to 110% of the content of the standardized tincture of red propolis. Variations between 85 to 115% in terms of uniformity of content of the standardized tincture of red propolis. Variations between 75 and 115% of the dissolution percentage for the major flavonoids of the standardized tincture of red propolis.

Uses of MPV and pharmaceutical compositions containing the same

Faced with such biological activities of red propolis microencapsulates, they can be used in a wide range of industrial sectors, such as cosmetics, pharmaceuticals and food.

The use of propolis as an active ingredient in the prevention and treatment of several diseases has already been widely described. However, red propolis has a different composition from other propolis already widely described in the state of the art, which indicates varied physiological activities.

Red propolis has antibacterial biological activities for the bacterial strains of Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC27853, with inhibition of bacterial growth, when subjected to both tincture of red propolis and microencapsulated red propolis.

Due to their proven antibacterial biological characteristic, microencapsulates and pharmaceutical compositions containing microencapsulates obtained by the proposed processes can be used for: treatment of bacterial infections with a broad spectrum of action; treatment of inflammatory processes of bacterial origin; treatment of decubitus wounds in patients with diabetic foot; treatment of inflammatory and infectious processes in general.

The uses described here are new to the state of the art, in terms of activities and performances of red propolis.

Thus, the modalities of the invention described in the present document are presented as an advance in the state of the art since they allow the production of MPV and pharmaceutical compositions containing the same in an economically viable way. In this way, the MPV obtained through the proposed process can be used, isolated or in composition with other products, in several industrial sectors, such as food, cosmetics and pharmaceuticals.

EXAMPLES

The evaluations of the MPV obtained using the proposed process demonstrated the achievement of an adequate, pure product with preserved activity. The results obtained are represented in the tables and figures indicated.

EXAMPLE 1 - Scanning electron microscopy assays of microencapsulated (MPV A, MPV B, MPV C and MPV D)

The scanning electron microscopy test was used to prove that the particles obtained by Spray-Dryer are in the form of microparticles, also called microspheres or also called microencapsulated. The results show that the particles have a size between 50 μm and 10 μm.

The morphology of red propolis Spray-Dryer microencapsulates (MPV) were evaluated with a scanning electron microscope (SEM). The powders were fixed to a double-sided adhesive tape, coated with 40 mA gold, under vacuum and analyzed with a scanning electron microscope, model JEOL JSM-6460 (Tokyo, Japan). SEM was operated at 15 kV with increments of 100, 200, 500, 1000, 2000 and 5000 times (Figure 3).

Photomicrographs of MPV B that contained only a single adjuvant revealed large microparticles, > 50μm (Figure 3B2), an irregular and non-uniform surface for MPV B. MPV C presented a spherical, smooth, agglomerated, non-uniform surface with a brittle appearance and microparticles with sizes between 50μm and 10μm (Figure 3C1 and 3C2).

The photomicrographs of microparticles from MPV A and D showed small particles with a spherical and very smooth surface, not agglomerated, uniform. Photomicrographs revealed spherical particles with particle sizes between 50 and 10μm. The microencapsulates can be classified as red propolis microspheres, regardless of the preparation method (dispersion or emulsification), in these proportions and type of adjuvants used in the composition of the MPV.

EXAMPLE 2 - MIC antimicrobial assay of tincture and microencapsulated red propolis

The following bacterial strains were used for the analysis: BAC 1 - Staphylococcus aureus ATCC 25923; BAC 2 - Pseudomonas aeruginosa ATCC27853, by the Agar diffusion method.

Tabela 2 - Concentração inibitória mínima do MPV A contendo tintura padronizada de própolis vermelha usando método de difusão em ágar.

Tabela 3 - Concentração inibitória mínima do MPV D contendo tintura padronizada de própolis vermelha usando método de difusão em ágar.

The Minimum Inhibitory Concentration (MIC) was determined for the standardized tincture of red propolis (Table 1) and for MPV A and D after the spray-dryer drying process in order to determine whether there was a loss of biological activity after the processing (Table 2 and 3). Table 1 - Minimum Inhibitory Concentration of the standardized hydroalcoholic tincture of red propolis using agar diffusion method.

Table 2 - Minimum inhibitory concentration of MPV A containing standardized tincture of red propolis using agar diffusion method.

Table 3 - Minimum inhibitory concentration of MPV D containing standardized tincture of red propolis using agar diffusion method.

Claims (35)

1. Microencapsulated active ingredients derived from red propolis; 2. Microencapsulated, according to claim 1, characterized in that the active principles are derived from red propolis extracts and present a final percentage of red propolis extract between 25 and 55%; 3. Microencapsulated, according to claim 1, characterized in that it comprises: a) standardized hydroalcoholic tincture of red propolis from the bioactive extract in a proportion between 5 and 95%, preferably between 20 and 60%; b) diluent in proportion between 5 and 95%; c) dispersant in proportion between 5 and 95%; d) and flow promoter in proportion between 0.01 and 5%; 4. Microencapsulated, according to claim 1, characterized in that it comprises: a) standardized hydroalcoholic tincture from the bioactive extract in a proportion between 5 and 95%, preferably between 20 and 60%; b) diluent in proportion between 5 and 50%; c) emulsifier in a proportion between 5 and 60%, preferably between 20 and 45%; d) and a flow promoter in a proportion between 0.01 and 5%; 5. Microencapsulated, according to claims 3 and 4, characterized in that it comprises a dispersant system composed of a ternary system, preferably composed of gelatin, pregelatinized starch and aerosil; 6. Microencapsulated, according to claims 1 to 5, characterized by having non-stick properties; 7. Microencapsulated, according to claims 1 to 6, characterized by containing, among its components, compounds derived from red propolis, preferably standardized tincture of red propolis, for use in the treatment of bacterial infections and inflammatory processes of bacterial origin; 8. Microencapsulated, according to claim 7, characterized in that it contains, among its components, among its components, compounds derived from red propolis, preferably standardized tincture of red propolis and emulsifying agents, for use in the treatment of bacterial infections and inflammatory processes, preferably caused by Gram positive (+) and Gram negative (-) bacteria; 9. Process for obtaining microencapsulated material, characterized by comprising the following steps: a) Preparation of the crude extract from red propolis; b) Preparation of the standardized hydroalcoholic tincture from the crude extract of red propolis; c) Preparation of the sol-gel and emulsifier systems containing red propolis tincture; d) Drying of the sol-gel and emulsifier systems and formation of red propolis microencapsulates; 10. Process for obtaining microencapsulated, according to claim 9, characterized in that, in step a), a sample of propolis is subjected to complete extraction of active substances, with alcohol 60 to 90 °GL, preferably between 70 to 80 °GL , either by maceration or percolation, with subsequent concentration in a rotary evaporator or water bath and obtaining material with a solvent percentage between 5 and 35%, preferably between 5 and 12%; 11. Process for obtaining microencapsulated, according to claim 9, characterized in that, in step b), the crude extract is subjected to solvent washing, preferably absolute ethanol, with subsequent total evaporation of the solvent and solubilized in ethanol solvent: distilled water (60:40, v/v) or (70:30, v/v) or (80:20, v/v) or (90:10, v/v), preferably between (70:30, v/v ) or (80:20, v/v), to obtain a standardized hydroalcoholic tincture of red propolis in a concentration between 5% and 30% (w/v), preferably between 10 and 30% (w/v) and more preferably between 15 and 25% (w/v); 12. Process for obtaining microencapsulated, according to claim 9, characterized in that, in step c), for the preparation of ternary systems containing the tincture of red propolis are used: i) active compound (standardized hydroalcoholic tincture), ii) diluents , iii) flow promoter / non-stick and iv) dispersant / emulsifier; 13. Process for obtaining microencapsulated, according to claim 9, characterized in that, in step c), for the preparation of the sol-gel system A, gelatin, starch pregelatinized and aerosil, at a temperature between 25 and 30 °C, 450 mL of distilled water and 150 mL of standardized hydroalcoholic tincture of red propolis with ethanol:water solvent (10:90, v/v) or (20:80, v/v) or (30:70, v/v) or (40:60, v/v) or (50:50, v/v) or (60:40, v/v) or (70:30, v/v) or (80:20, v/v), preferably from 20 to 45°GL and more preferably from 35°GL; 14. Process for obtaining microencapsulated, according to claim 9, characterized in that, in step c), for the preparation of the emulsifier system D, gelatin, pregelatinized starch and aerosil are added, under agitation, to the ternary dispersant system, 550 mL of ethanol:water (30:70, v/v) or (20:80, v/v) or (10:90, v/v) or (02:98, v/v), preferably between (02: 98, v/v) to (10:90, v/v), 150 ml of the standardized hydroalcoholic tincture containing ethanol:water (10:90, v/v) or (15:85, v/v) solvent system or (20:80, v/v) or (30:70, v/v) or (40:60, v/v) or (50:50, v/v) and preferably between 10 and 40°GL, under temperature preferably between 30°C and 45°C and more preferably at 37°C; 15. Process for obtaining microencapsulated, according to claim 9, characterized in that, in step d), it was prepared by the technique of forming a solgel system using emulsifiers (gelatin, pregelatinized starch and aerosil) containing red propolis tincture, are submitted to a drying process to obtain red propolis microencapsulated; 16. Composition, characterized by comprising microencapsulated red propolis as an active ingredient, alone or together with other actives; Composition, according to claim 16, characterized in that it is preferably solid formulations, such as powders, tablets, capsules, among others and, more preferably, in the form of gelatinous capsules; Composition, according to claim 16, characterized in that it comprises i) a core containing active substance(s) of red propolis combined with pharmaceutical excipients; ii) an intermediate layer coating the core which can delay the release of the active substance(s) contained in the core and which is pH dependent; iii) an external layer responsible for the lubrication, dilution, fluidity, wettability and disaggregation/dissolving processes of the intermediate layer and inner core; 19. Composition, according to claim 18, characterized in that it has a gastro-resistance characteristic; Composition, according to claim 18, characterized in that it has a gelatin shell or not; Composition, according to claim 18, characterized in that it comprises a core (i) composed of the active substances of red propolis, derived from the standardized tincture of red propolis and pharmaceutical excipients; 22. Composition, according to claim 18, characterized in that it comprises an intermediate layer (ii) composed of pharmaceutical excipients, preferably agents that promote fluidity and anti-adherence, binders and diluents, in the percentage between 0.05% and 95% of the total weight of the intermediate layer , according to the functionality of the pharmaceutical excipient in the pharmaceutical matrix and present a proportion between 5% and 95%, preferably between 30 and 75%, in relation to the total weight of the composition; 23. Composition, according to claim 18, characterized in that it comprises an external layer (iii) whose dissolution is promoted by the pH change, composed of pharmaceutical excipients, with different functionalities, preferably diluents, lubricants, fluidity promoting agents, wetting agents, disintegrants, super - disintegrants, in the percentage between 0.05% and 100% of the total weight of the outer layer, according to the functionality of the pharmaceutical excipient in the pharmaceutical matrix, and present a proportion between 0.01% and 50%, preferably between 1 and 15% , in relation to the total weight of the composition; Composition, according to claims 18, 21 to 23, characterized in that it comprises pharmaceutical excipients of different types and in different formulations; Composition, according to claim 24, characterized in that it comprises a natural hydrophilic polymer or a combination of more than one natural hydrophilic polymer(s) or a combination of one or more natural hydrophilic polymer(s) ) and one or more synthetic hydrophilic polymer(s) such as gelatin, corn starch, pregelatinized starch, xanthan gums, guar gum, acacia, magnesium stearate, talc, titanium dioxide, polyvinylpyrrolidone, carbomers, polyvinyl alcohol, polaxamers, colloidal silicon dioxide, stearic acid, sodium starch glycollate (explosol), sodium lauryl sulfate, cellulose, microcrystalline cellulose, and cellulose derivatives such as CMC, methylcellulose, and hydroxypropylethylcellulose; Composition, according to claims 16 to 25, characterized in that it contains, among its components, compounds derived from red propolis, preferably microencapsulated red propolis, for use in the treatment of bacterial infections and inflammatory processes of bacterial origin; 27. Composition, according to claims 26, characterized in that it contains, among its components, among its components, compounds derived from red propolis, preferably microencapsulated from red propolis, for use in the treatment of bacterial infections and inflammatory processes, preferably caused by Gram positive bacteria ( +) and Gram negative (-); 28. Process of preparation of composition, characterized by comprising the following steps: a) Realization of physical mixtures with the microencapsulated red propolis to guarantee content and uniformity of content; a.1) Physical mixtures by the geometric dilution method; a.2) Physical mixtures for incorporation of wetting and disintegrating excipients; a.3) Physical mixtures for incorporation of lubricating excipients; b) Preparation of red propolis capsules; 29. Process of preparation of composition, according to claim 28, characterized by the fact that, in step a) the microencapsulated red propolis are subjected to physical mixtures, for preparation, preferably, of gelatinous capsules; 30. Process of preparation of composition, according to claim 28, characterized in that, in step a.1) the microencapsulates are subjected to a mixing process by the geometric dilution method with excipients of the disintegrant or superdisintegrant type in a proportion between 0.5 and 15%, preferably between 1 to 10%, and more preferably between 2 to 7%, in a time comprised between 5 and 120 minutes, more preferably between 25 and 65 minutes; 31. Process of preparation of composition, according to claim 28, characterized in that, in step a.2) the microencapsulates are mixed with excipients such as wetting agents, in a proportion between 0.5 and 10%, preferably between 1 and 5% , and more preferably between 2 and 3.5%, over a period of 5 to 120 minutes, more preferably between 25 and 65 minutes; 32. Process of preparation of composition, according to claim 28, characterized in that, in step a.3) the microencapsulates are subjected to a lubricant type excipient in a proportion between 0.1 and 6%, preferably between 0.3 to 4% , more preferably between 0.75 and 2%, over a period of 2 to 10 minutes, more preferably between 3 and 7 minutes; 33. Process of preparation of composition, according to claim 28, characterized in that, in step b) the encapsulation is carried out by adjusting the mass of microencapsulated red propolis, in terms of the standardized tincture of red propolis, with the following variations: between 90 at 110% of the content of the standardized tincture of red propolis, between 85 to 115% in terms of uniformity of content of the standardized tincture of red propolis, between 75 and 115% of the percentage of dissolution for the major flavonoids of the standardized tincture of red propolis, encapsulation being by hand instruments or semi-industrial or industrial instruments; 34. Use of microencapsulated, according to claims 1 to 8, characterized by being alone or as an adjuvant, to fight infections and inflammatory processes of bacterial origin; 35. Use of the composition, according to claims 16 to 27, characterized by being alone or as an adjuvant, to fight infections and inflammatory processes of bacterial origin.

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