BR102012009556A2 - Microparticles of BIOCOMPATIBLE, BIODEGRADABLE AND MUCOADESIV POLYMERS AND COPOLYMERS IN THE POLYMERIC MATRI CONTAINING PHYOSTEROLES. - Google Patents

Abstract

BIOCOMPATIBLE, BIODEGRADABLE AND MUCOADESIVE POLYMER MICROPARTMENTS AND COPOLYMERS IN THE POLYMERIC MATRI CONTAINING PHYOSTEROLES. The present invention relates to the process of obtaining biocompatible, biodegradable and mucoadhesive polymer microparticles and copolymers in the polymeric matrix containing phytosterols solubilized in edible vegetable oil. This invention is particularly useful in controlled and site-specific drug delivery systems. It also refers to the use of medicinal, pharmaceutical, cosmetic, nutritional, chemical, immunological, anti-inflammatory, antinociceptive, antioxidant, hypocholesterolemic, antiogenic, hypoglycemic and antimutagenic properties in the human, veterinary and environmental fields. The invention relates to liquid, semi-solid and solid pharmaceutical and nutraceutical forms such as solutions, suspensions, ampoules, syrups, ointments, creams, emulsions, aerosols, powders, capsules, tablets, tablets and dragees, all of which contain microparticles obtained. by the descriptive process.

Description

MICROPART1CELLS OF BIOCOMPATIBLE, BIODEGRADABLE AND MUCOADESIVE POLYMERS AND COPOLIMER IN THE POLYMERIC MATRIX CONTAINING PHYOSTEROIS.

Field of the Invention

The present invention relates to the process of obtaining biocompatible, biodegradable and mucoadhesive polymer microparticles and copolymers in the polymeric matrix acting on the encapsulated drug delivery system containing edible vegetable oil-soluble phytosterols and the use of medicinal, pharmaceutical properties. , cosmetic, nutritional, chemical, immunological, anti-inflammatory, antinociceptive, antioxidant, hypocholesterolemic, anti-atherogenic, hypoglycemic and anti-mutagenic in the human, veterinary and environmental field.

The invention also relates to pharmaceutical forms and

liquid, semi-solid and solid nutraceuticals such as solutions, suspensions, ampoules, syrups, ointments, creams, emulsions, aerosols, powders, capsules, tablets, tablets and dragees, all of which contain microparticles obtained by the process described.

20

Invention History

The present invention relates to the process of obtaining biocompatible, biodegradable and mucoadhesive polymer microparticles and copolymers in the polymeric matrix acting on the encapsulated drug delivery system containing edible vegetable oil-soluble phytosterols with medicinal, pharmaceutical, cosmetic properties , nutritional, chemical, immunological, anti-inflammatory, antinociceptive, antioxidant, hypocholesterolemic, anti-atherogenic, hypoglycemic and anti-mutagenic in the human, veterinary and environmental fields.

The technology for obtaining microparticles consists of forming a layer of an encapsulating agent, usually one or more polymers that act as a protective film for encapsulated active substances (SUAVE et al, 2006).

Microencapsulation of active substances, both in solid and liquid form, has numerous applications in various sectors, such as agrochemical, pharmaceutical, cosmetic, food, environmental, nutraceutical among others (SANTOS; FERREIRA; GROSSO, 2000).

Microparticles, microspheres and microcapsules are micrometric systems that differ in morphology and internal structure (JYOTHI, 2010; PEREIRA, 2006). The microspheres are matrix systems and the microcapsules are reservoir systems, containing an inner core 15 covered by one or more polymeric layers of varying thickness (PEREIRA, 2006).

The association of anionic biopolymers - cationic biopolymers in microparticulate form has been used to transport proteins, drugs and other substances through the gastrointestinal or nasal mucosa, acting as a specific release system at these sites (CRCAREVSKA; DODOV; GORACINOVA, 2008; SPIN -NETO et al., 2008), cell transplantation, where the microparticle membrane acts as an immunoprotective barrier, enzyme mobilization, drug delivery systems (GASEROD; SANNES; SKJAK-BRAEK, 1999), 25 oil microencapsulation. (CHANG; DOBASHI, 2003; PENiCHE et. A /., 2004) and microencapsulation of lipophilic drug dissolved in edible oil, with possibility of application in controlled release systems for oral use (RIBEIRO et al, 1999). The material used for encapsulation should be selected according to the physical and chemical properties of the active substance, the intended application and the method used to form the microparticles (SUAVE ef a /., 2006).

Preferably, biocompatible, biodegradable polymers,

including naturally occurring polymers used in microparticle formation are, without limitation, collagen, chitosan, alginate, fibrin, fibrinogen, cellulose, starch, dextran, dextrin, hyaluronic acid, heparin, glycosaminoglycans, polysaccharides and elastin 10 (SANTOS; FERREIRA; THICK , 2000; SUAVE et al., 2006) preferably in this invention, the natural alginate, starch and chitosan polymers, and the polyoxyethylene propylene copolymer.

The selection of the microencapsulation process should be based on the type of material to be encapsulated (PEREIRA, 2006; CHAN, 2011), its application (PEREIRA, 2006; CHAN, 2011), economic and safety reasons (CHAN, 2011). , desired release mechanism, maintenance requirements for active substance stability during the microencapsulation process and in the end product, process yield, high encapsulation rate, free flowing powder (CHAN; UM; 20 HENG, 2000) without aggregation or adherence (PEREIRA, 2006).

As used herein, "biocompatible" refers to a polymer that, either in its intact form or in its decomposed state, that is, in its degradation products, is not, or at least minimally toxic to living tissue; or at least minimally and repairably harms living tissue, and / or is not, or at least minimally and / or controllably, causes an immune reaction in living tissue.

As used herein "biodegradable" is a polymer or product capable of safely degrading by biological means. As used herein "mucoadhesion" is used when adhesion specifically surrounds the mucus layer.

Phytosterols are found in various parts of plant species, including seeds, fruits and oils, with cyclopentanoperhydrophenanthrene as the basic skeleton (MOGHADASIAN, 2000; FERNANDES; CABRAL, 2007).

In plants they are found in their free form, esterified or as glycoside esters and vary in amount and distribution among vegetable oils (European Commission Commission & Consumer Protection, 2002; Verley et al., 2002).

The most abundant phytosterols are sitosterol, stigmasterol, campesterol and Î ”5-avenasterol, classified as 4-demethylesterol (VERLEYEN et al. 2002; MOREAU; WHITAKER; HICKS, 2002; KRITCHEVSKY; CHEN, 2005).

Increased blood cholesterol concentration is a factor

at risk for heart disease as well as atherosclerosis-related disease (EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION, 2002).

Since the 1950s, it has been recognized that phytosterols reduce cholesterol concentration by inhibiting its absorption in the gut (European Commission Commission & Consumer Protection, 2002; Duchateua et al., 2002).

Due to their proven hypocholesterolemic and anti-atherogenic action, phytosterols, as natural constituents of edible oils, have become functional food ingredients, especially sitosterol, campesterol, stigmasterol and brassicasterol when the goal is to lower cholesterol in the body (DUCHATEAUA et al. 2002; SÍNNJOKI et al, 2003; FOLEY etal., 2010). Other activities have also been attributed to phytosterols, such as protection against some cancers, including colon, breast and prostate cancer, as well as immunomodulatory and anti-inflammatory actions (AWAD; FINK, 2000; QUÍLEZ; GARCÍA-LORDA; SALAS- SALVADO, 2003; BERGER; JONES; ABUMWEIS, 2004).

Alginates are structural components of brown seaweed, such as Laminaria hyperborea (GASEROD; SMIDSROD; SKJAK-BRAEK, 1998 SiMPSON et al., 2004) and as capsular polysaccharides in some soil bacteria (SIMPSON et al, 2004). This anionic natural polymeric biomaterial (FLORCZYC et al, 2011) is commonly used for the production of microparticles (WITTAYA-AREEKUL; KRUENATE; PRAHSARN, 2006).

Alginates are unbranched copolymeric polyisaccharides composed of 1,4-beta-D-15 manuronic (M) and α-L-guluronic (G) bonded acid residue blocks (GASEROD; SMIDSROD; SKJAK-BRAEK, 1998; CHAN; LEE; HENG , 2002). The structural composition, sequence of the arrangement and molecular weight of the alginate are determinant factors of its physical properties (CHAN; LEE; HENG, 2002).

Alginate has mucoadhesiveness (WITTAYA-AREEKUL; 20 KRUENATE; PRAHSARN, 2006; ROWE; SHESKEY; QUINN, 2009), biocompatibility (FLORCZYK et al., 2011), biodegradability (LEE et al., 2006), immunogenicity, thickener property and ability to gel in the presence of multivalent counterions such as Ca + 2 and Ba + 2 (FLORCZYK et al., 2011; SIMPSON et al, 2004). The hydrogel is formed because guluronic residue blocks bind to cations resulting in a three-dimensional network of alginate filaments held together through ionic interactions (SIMPSON et al, 2004; LEE et al, 2006; REIS et al, 2006). Above a certain critical molecular mass alginate properties are mainly governed by the monomeric composition and structure of the block. In general an increase in the amount of guluronate (G) provides more mechanically resistant gels with increased stability in the presence of non-gelling ions such as Na +.

High-guluronate gels exhibit high porosity and low shrinkage during gel formation. High manuronate (M) gels become less dense and more elastic and further shrink during gel formation with concomitant reduction in porosity (REIS et al, 2006; SIMPSON et ol., 2004; FUNDEANU et oi , 1999).

Microparticles obtained with high G alginate have a larger pore size which restricts the ability of alginate gel 15 to act as an insurmountable barrier to small molecules such as flavorings and vitamins. However, an alginate gel can maintain the release of molecules of different intensities, depending on the barriers created within the gel. If, for example, the gel contains another macromolecule, the effective porosity will decrease and sustained release will occur at a slower rate. For this reason it is sometimes advantageous to add a filler such as natural starch or silicon dioxide to the alginate solution. Other suitable fillers include, but are not limited to, polysaccharides such as dextrins, dextran, gum locust, gum arabic, methylcellulose, ethylcellulose, hydroxypropylceulose, proteins such as gelatin and other hydrogel-forming substances such as ethylene propylene oxide copolymers. (ROWE; SHESKEY; QUINN, 2009). Starch is a biodegradable polymer with excellent biocompatibility, no toxicity and mucoadhesive (WANG et al., 201 consisting of linear amylose and branched amylopectin, two polysaccharides based on α- (D) -glucose. Both polymers are arranged in a semicrystalline structure. , and in starch grain, amylopectin forms the crystalline portion (ROWE; SHESKEY; QUINN, 2009).

Starch has been studied as an excipient in new drug delivery systems for nasal use and other site-specific release systems. Modified pregelatinized starches are 10 excipients used in hydrophilic matrix systems for controlled drug release. It can be used alone or in combination with other polymers in controlled release systems (WANG et al, 2010; CHAN, 2011).

It is an excellent biomaterial because amylopectin has a chemical structure similar to human glycogen, facilitating its use in vivo. Starch is also easily degraded to oligosaccharides, maltose and glucose by serum amylase (BJÖRSES et al, 2011).

In the agrochemical industry, starch has been used in the controlled release of pesticides and herbicides, as it is biodegradable in various agricultural environments (GLENN et al, 2010).

Starch has good molecular compatibility with alginate as intermolecular interactions occur between polymers. Associations are effective and convenient ways to improve the performance of polymeric materials (WANG et al, 2010).

Poloxamers consist of series of synthetic copolymeric blocks of poly (ethylene oxide-A-propylene oxide-B-ethylene oxide-A) (PEO-PPO-PEO). All poloxamers are chemically similar in composition, differing only in the relative amounts of propylene and ethylene oxides added during manufacture and therefore have varying molecular weights. They consist of nonionic surfactants having excellent wetting and solubilizing properties (ROWE; SHESKEY; QUINN, 2009).

Poloxamer 407 is an ABA type three block copolymer which

It consists of poly (oxyethylene) units (A = 70%) and poly (oxypropylene) units (B = 30%). An aqueous solution of this copolymer at a concentration> 20% (MOEBUS; SIEPMANN; BODMEIER, 2009) or 15 - 50% (ROWE; SHESKEY; QUINN, 2009) forms a heat-reversing gel that is transformed from a low solution. viscosity at 4 ° C in a semi-solid gel under heating to room or body temperature.

This reverse thermal gelation and low toxicity are properties that make poloxamer 407 a material that can be used in drug delivery systems. Its association with the alginate allows the pores to be filled with the alginate gel and consequently acts as a diffusion barrier for the encapsulated materials as well as for the dissolution medium, thus decreasing the calcium ion exchange and consequently the degradation of the gel. calcium alginate (MOEBUS; SIEPMANN; BODMEIER, 2009).

Stabilization of the polymer / oil system may be performed mechanically, using high rotation during dispersion, or by increasing the concentration of one or more polymers or by using surfactant.

Poloxamer 407 exhibits hydrophilic-lipophilic balance (EHL) between

18 and 23, which confers on it oil-in-water emulsifying property (ZANIN et al., 2002; CULPI et al, 2010). However, at a concentration of 15%, besides acting as a filler material, it stabilizes the polymers / oil system without agitation during the whole microencapsulation process (ROWE; SHESKEY; QUINN, 2009).

Phytosterols are lipophilic, practically insoluble in water, poorly absorbed by the body, poorly soluble in edible oils and soluble in organic solvents (BERGSTRÕM; WINTERSTEINERi 1942; ZAWISTOWSK1, 2001; BUDAVARIi 2001; SÃYNAJOK et al „2003).

The pharmacological action of phytosterols occurs in solubilized form, making it necessary to solubilize them (ZAWISTOWSKl, 2001). The solubilization of phytosterols in organic solvents is not interesting for its intended purpose, as it requires the guarantee of complete elimination of the solvent for application in internal formulations (PONCELET, 1992).

Since phytosterols are easily oxidized when exposed to aqueous medium, oxygen, light and temperature, requiring methodologies that minimize these problems (BERGSTRÕM; WINTERSTEINER, 1942; SÃYNAJOK et al., 2003), the solubilization of phytosterols in edible oil with subsequent encapsulation. It is promising because it has reduced oxidation and optimized pharmacological action (LAMPI ef al., 2002).

Preferably the edible oils used for phytosterol solubilization include, but are not limited to, soybean oil, corn oil, coconut oil, cottonseed oil, olive oil, palm oil, peanut oil, sunflower oil, canola oil. more particularly canola oil as a lipid matrix for the production of sterol microparticles. Canola Oil (Canadian Oil Low Acid) is the result of a genetic improvement of rapeseed that has reduced erucic acid, glucosinolates, associated with rapeseed toxicity and saturated fat. It contains a high content of monounsaturated lipids and a median amount of polyunsaturated, presenting an excellent balance between omega-3 and omega-6 fatty acids (ÁGUILA et al., 2002).

Monounsaturated and polyunsaturated lipids are effective in reducing serum cholesterol levels, acting in the prevention of depression and behavioral disorders, protection of cardiovascular diseases, reduction of risk of rheumatoid arthritis and reduction of systemic blood pressure (ÁGUILA; APFEL; MANDARIM-DE-LACERDA, 1997; ÁGUILA et al., 2002).

Canola oil has from 0.7 to 1.0% of phytosterols in its

composition, which are found in the unsaponifiable matter of the oil.

Therefore, due to the nutritional properties resulting from the presence of monounsaturated, polyunsaturated fatty acids and significant amounts of sterols, canola oil is suitable for use as a phytosterol solubilizer in the microencapsulation process.

The alginate, preferably sodium alginate, gels in the presence of divalent cations. Gelation is dependent on ionic bonding (Mg + 2 <Ca + 2 <Zn + 2 <Sr + 2 <Ba + 2) and in the control of cation addition to obtain homogeneous or inhomogeneous gels. Although zinc ions can be used in the production of alginate microparticles, calcium is the main cation used because it is considered clinically safe, easily accessible and inexpensive 25 (REIS et al., 2006). The concentration of calcium chloride used ranges from 0.5 to 3%, preferably 2%, for the amount of alginate used and the desired characteristics for the microparticles.

Gels can be made with either a constant alginate concentration or a concentration gradient across the cross section of the gelled microparticle, called a homogeneous and nonhomogeneous droplet respectively (GASEROD; SMISDROD; SKJAK-BRAEK, 1998). Hydrogels in general are not homogeneous due to the existence of ionically associated clusters that originate inhomogeneous regions (RIBEIRO et al, 2005).

The degree of homogeneity can easily be controlled by adjusting the concentration and index of gelling (Ca2 +) and non-gelling (Na +) cations in the gel solution (GASEROD; SMISDROD; SKJAK-BRAEK, 1998; FUJIWARA ef al., 2010). The presence of non-crosslinking Na + ions results in more homogeneous gelled drops (SIMPSON et al, 2004).

In addition to the filler material for encapsulated material release control, it is necessary to coat the microparticle with cationic polymers such as poly-lysine or chitosan.

Chitosan is a cationic polyamine derived from

partial deacetylation of chitin (ROWE; SHESKEY; QUINN, 2009), which occurs in crustacean exoskeleton (GASEROD; SMIDSROD; SKJAKBRAEK, 1998). It consists of a linear polyelectrolyte with hydroxyl and amino reactive groups, showing compatibility and binding capacity with the alginate polyion (RIBEIRO et al, 2005). It is biocompatible, biodegradable, non-toxic, non-irritating, antioxidant and mucoadhesive (ROWE; SHESKEY; QUINN, 2009).

The chitosan composition consists of varying amounts of bound residues of β- (1-4) N-acetyl-2-amino-2-deoxy-D-glucose (residues A) and 2-amino-2-deoxy-D-glucose (waste D) (ARANAZ, 2009).

Chitosan ranges in molecular weight, between 10,000 - 1,000,000, the degree of deacetylation and viscosity. The degree of deacetylation to obtain a soluble product must be greater than 80-85% (ROWE; SHESKEY; QUINN, 2009). Chitosans of lower molecular weight (20,000 Da) are evenly distributed throughout the microparticle, with a significant decrease in the interaction between polymers with increasing acetyl groups. Chitosans of higher molecular weight are mainly accumulated on the surface because they are too large to enter the pores of the gel. In this case, the amount of acetyl groups minimally interferes with alginate-chitosan interactions.

Chitosan binds faster and to a greater extent at higher concentrations of calcium chloride present in the chitosan solution 10, because the alginate gelation reaction competes with the polycation precipitation reaction, leading to the formation of a more porous gel. which allows for greater diffusion and thus more binding of chitosan molecules in the gel network (GASEROD; SMIDSROD; SKJAK-BRAEK, 1998). Thus, a high content of alginate-chitosan bonds occurs the more porous the alginate gel and the lower the average molecular weight of chitosan used [GASEROD; SANNES; SKJAK-BRAEK, 1999).

Microparticles produced by the one-stage process, where the gelling cation and chitosan are in the same solution, 20 favor the binding of chitosan to the alginate, preferably on the surface of the microparticle, and characterize a membrane where small pores do not allow posterior diffusion. polycation internally to the microparticle, restricting both bonding and diffusion in the matrix.

This membrane is less permeable than that obtained by the two-stage process, where the alginate is primarily gelled with the cation, forming the microparticle, which is later coated with chitosan (GASEROD; SMIDSROD; SKJAK-BRAEK, 1998; GASEROD; SANNES SKJAK-BRAEK, 1999). In non-homogeneous microparticles there is a reinforcement in the formation of the superficial polyelectrolyte complex, allowing a greater number of superficial bonds with chitosan, thus increasing the membrane resistance (RIBEIRO et al., 1999; CALIJA et al., 2011).

Uncoated calcium alginate microparticles are

destabilized by chelators such as phosphate, lactate and citrate or in the presence of non-gelling cations such as sodium or magnesium ions. These ions exchange with non-cooperatively bound calcium ions, leading to a swelling of the gel. In such media, such as the human body, for example, there is a need for a stabilizing agent such as a polycationic membrane bound to the alginate gel. Once microparticles are formed, exposure to solutions with higher concentrations of competitive ions such as hydrogen or sodium has less influence on the stability of the polyanion-polycation 15 complex (GASEROD; SANNES; SKJAK-BRAEK, 1999).

The reaction time between alginate and chitosan can range from 10 minutes to 24 hours (FUNDUEANU et al., 1999; RIBEIRO et al., 2005; COOK et al., 2011). These time differences are explained by the type of chitosan used during the process. Smaller molecular weight polymers slowly penetrate the matrix, requiring an incubation period of at least 8 hours to form a significantly thicker membrane. Using higher molecular weight polymers this time is reduced to 1-4 hours of reaction and favors ionic bonds on the surface of the microparticles.

Pure chitosan precipitates at pH values greater than 6.0 -

6.5 while alginate precipitates at pH values below 3.6. (SIMSEK-EGE; BOND; STRINGER, 2003). Thus, pH has a strong influence on the degree of ionization of polyelectrolyte functional groups for complex membrane formation, because the number of alginate-chitosan ionic bonds is directly related to the yield and permeability of these membranes (GASEROD; SMIDSROD; SKJAK-BRAEK , 1998).

A pH between 5.0 and 5.3 promotes a more complete complexation of polycations, as both alginate and chitosan molecules have an extended conformation (SIMSEK-EGE; BOND; STRINGER, 2003; FLORCZYC et al, 2011). At this pH the alginate chains would keep most of their available ionized carboxylic groups.

In work by Fundueanu and collaborators (1999) in which

Alginate microparticles were placed in an acidic solution at pH 3 and partial replacement of calcium ions with protons occurred. At this pH, calcium content decreased the degree of substitution by 20%. The residual presence of Ca + 2 ions in the microparticle was attributed to 15 Ca + 2 ions located next to the "egg box" structure, since in fact 20% represent the frequency of guluronic acid blocks. In other words, after treatment at low pH, calcium ions remain only within the electronegative cavities of the G-blocks that provide a more stable complex. By treating the microparticles with a lower pH solution (pH 2 and 1), calcium was completely displaced from the polymeric network, no longer contributing to the stabilization of the microparticles which, however, maintained their macroscopic structure with mechanical properties similar to those of the microparticles. ionically bonded.

This behavior was explained considering the formation of

hydrogen bonds that provide a stable structure. Raising the pH again to 3.25 and 3.75 and treating the microparticles with progressive amounts of 0.1 N NaOH solution led to a successive increase in microparticle porosity. Finally, if an excess of NaOH is added to the microparticles, complete dissociation and solubilization occurs.

In the development of controlled release dosage forms, the instability of alginate microparticles at pH 5 greater than 5 becomes a limiting factor. The alginate-chitosan complex slowly erodes in phosphate buffer with pH above 6.8 and this property leads to the suppression of the initial release of the encapsulated product that occurs in uncoated microparticles. This is due to the fact that the chitosan membrane 10 remains a structure, at least partially during release (Ribeiro et al, 2005).

Related patents:

Purified starch and microparticles based on such starch. United States Patent: 7,119,195 (B2), Gustavsson et al., October 10, 2006.

Method for the preparation of starch particles. United States Patent: 6,755,915 (B1), Van Soest et al., June 29, 2004.

20

Process for preparing beads as food additive. World Intellectual Property Organization: WO 98/15192, Bouwmeesters et al., April 16, 1998.

Chitosan gelatin to microparticles. World intellectual Property Organization: WO 98/30207, Watts et al., July 16, 1998.

Methods of preparing microparticles of phytosterols or phytostanols. European Patents Specification: Zawistowski, EP 1,148,793 (BI), February

03, 2000.

30

Biocompatible compositions as carriers or excipients for pharmaceutical and nutraceutical formulations and for good protection. World intellectual Property Organization: Tien et al., WO 02/094224 (Al), November 28, 2002.

35

Hydrogel microbeads having a secondary layer. World intellectual Property Organization: WO 01/30144 (Al), Quong, May 03, 2001. Continuous spray-capture production system. World intellectual Property Organization: WO 2007/084500 (A2), Piechocki et al., July 22, 2007.

Microparticles comprising a fat soluble fraction comprising DHA and their production. World intellectual Property Organization: WO 2010/149759 (Al), Hansen, Fuest, December 29, 2010.

Mucoadhesive granules containing nano and / or chitosan microspheres and process for obtaining mucoadhesive granules. INPI: PI0705072-0 (A2), Silva, Martins, Santana, December 09, 2008.

Detailed Description of the Invention

The present invention relates to the process of obtaining biocompatible, biodegradable and mucoadhesive polymer microparticles and copolymers in the polymeric matrix acting on the encapsulated drug delivery system containing edible vegetable oil soluble phytosterols.

A system containing 1.0% (w / w) sodium alginate and 0.3% (w / w) cornstarch dispersed in water was prepared and heated in a water bath at 50 ± 10 ° C until gel formation. (Phase A) and a 15.0% (w / w) 407 poloxamer dispersion dispersed in water and heated in a water bath at 37 ± 10 ° C until gelation (Phase B).

Stigmasterol was dissolved 1% (w / w) in canola oil and taken to heating in a water bath at 37 ± 10 ° C, forming the system (Phase C).

A (Phase A) containing gelled sodium alginate and cornstarch was added to the gelled poloxamer 407 (Phase B), both at 37 ± 10 ° C at a rate of 50% each (w / w), forming the polymeric mixture ( Phase D) kept in a water bath at 37 ± 10 ° C under manual agitation for homogenization.

Canola oil containing the solubilized stigmasterol (Phase C) at a temperature of 37 ± 10 ° C was added to the gelled polymeric mixture (Phase D) at a ratio of 20:80 (w / w) under manual stirring and kept in a water bath at 37 ° C. ± 10 ° C until complete oil dispersion forming the system (Phase E).

The polymer / oil dispersed system (Phase E) was dripped into a 2% (w / w) CaCb solution containing 0.5% chitosan (w / w) previously solubilized in a 1% (w / w) acetic acid solution. p) (Phase F) for the formation of insoluble hydrogel (microparticles) by cross-linking calcium ions with the carboxylic groups of sodium alginate guluronic acid residues by the one-stage external ion gelation technique.

The formed microparticles remained in contact with the gelling solution (Phase F) for 60 minutes, washed twice with 0.05 M CaCb solution containing 1% Tween® 80 (w / w) (Phase G), vacuum filtered and air column dried at 50 ± 5 ° C to constant weight.

15

Claims (24)

1. Microparticles of BIOCOMPATIBLE, BIODEGRADABLE AND MUCOADESIVE POLYMERS AND COPOLIMER IN THE POLYMERIC MATRIX CONTAINING PHYOSTEROLS A process characterized by the obtaining of biocompatible, biodegradable and mucoadhesive polymer-containing polymers in the polymeric matrix containing soluble polymer-containing soluble polymer. edible vegetable oil. The process of obtaining according to claim 1 comprises the steps: a) Preparation of a hydrogel containing system (Phase A). b) Preparation of a water dispersed copolymer system (Phase B). c) Solubilization of sterols in edible oil forming system (Phase C). d) Adding (Phase A) to (Phase B) forming (Phase D) e) Adding (Phase C) to (Phase D) under agitation forming the system (Phase E). f) Dripping the system (Phase E) over the (Phase F) for gelling the microparticles. g) Washing the microparticles (Phase G). h) Microparticle drying A process according to claims 1 and 2 wherein the drugs are one or more phytosterols, the lipid phase is composed of one or more edible vegetable oils, the natural polysaccharides are alginates, starch and chitosan, the nonionic synthetic copolymer is polyoxyethylene- polyoxydopropylene, the gelling metal ions are calcium ions. Phytosterols according to claims 1 to 3 are used from 0.1 to 3.0%, preferably from 0.5 to 1.5% and most preferably from 0.5 to 1.0% solubilized in edible oil. The group of phytosterols according to claims 1 to 3 are all of natural origin, including derivatives thereof. The lipid phase according to claims 1 to 3 is used from 1.0 to 50.0%, preferably from 1.0 to 30.0% and most preferably 1.0 to 20.0%. The alginate polymer, most preferably sodium alginate according to claims 1 to 3, is used from 1.0 to 10.0%, preferably from 1.0 to 5.0% and most preferably from 1.0 to 3, 0% solubilized in water. The natural sodium alginate polysaccharide according to claims 1 to 3 comprises those of low and medium viscosity and guluronic residue content between 65 and 75%, more preferably 65 - 70%. The polymer starch, most preferably natural starch according to claims 3 to 3, is used from 0.1 to 5.0%, preferably from 0.1 to 3.0% and more preferably from 0.1 to 1.0%. . The natural polysaccharide starch according to claims 1 to 3 comprises natural rice, potato, cassava and wheat starches, most preferably corn starch. The chitosan polymer according to claims 3 to 3 is used from 0.1 to 3.0%, preferably from 0.1 to 1.0% and most preferably from 0.5 to 1.0% solubilized in 1.0 acetic acid. %. The natural chitosan polysaccharide according to claims 1 to 3 are those with a viscosity between 20 and 500 cps, a deacetylation degree greater than 80%, more preferably 85 - 98% and a viscosity molecular mass between 20,000 - 500,000 Da, more preferably between 45,000 and 60,000 Da. The polyoxylene-polyoxydopropylene copolymer, most preferably poloxamer 407 as claimed in claims 1 to 3, is used from 15 to 50%, preferably from 15 to 30% and most preferably from 15 to 20% solubilized in water. 14. Calcium gelling metal ions according to 1 and 2 are used from 1.0 to 5.0%, preferably from 1.0 to 3.0% and more preferably from 1.0 to 2.0% in aqueous solution. The process of dripping the dispersion onto the gelling solution according to claim 2 is conducted with the gelling solution at pH 3.6 to 6.3, more preferably at pH 5.0 to 5.5. A process according to claims 1 and 2 wherein the microparticles are recovered by filtration or centrifugation. A process as claimed in claim 16 wherein the microparticles are oven dried or fluid bed dried or lyophilized. Microparticles according to claim 17 wherein the size of the dried microparticles is between 1 - 2000 μm, preferably 100-1500 μm, more preferably 400 - 1200 μm. Microparticles according to claims 16 to 18 are characterized as microspheres or microcapsules. A process according to claim 1 wherein the vehicles used are organic, inorganic and aqueous. The method according to claims 1 and 2 for obtaining microparticles is one-stage external ion gelation. A process for obtaining the microparticles according to claim 1 wherein the polysaccharides are biocompatible, biodegradable and mucoadhesive, with sodium alginate and chitosan also being antioxidants. Use of the medicinal, pharmaceutical, cosmetic, nutritional, chemical, immunological, anti-inflammatory, antinociceptive, antioxidant, hypocholesterolemic, anti-atherogenic, hypoglycemic and antimutagenic properties in the human, veterinary and environmental field of the microparticles obtained in claim 1. 24. Use of pharmaceutical, nutraceutical and solid, semi-solid and solid dosage forms such as solutions, suspensions, ampoules, syrups, ointments, creams, emulsions, aerosols, powders, capsules, tablets, tablets and dragees, all of which contain microparticles according to claims 1 and 2.