MX2013013306A - Method for obtaining a co-processed pharmaceutical excipient for the controlled release of active substances and product obtained with it. - Google Patents

Abstract

Described is a process for obtaining a co-processed excipient for the release of active substances that comprises the following steps: (a) locating a functional excipient in a container for the direct compression thereof in an amount ranging from 5g/L to 500 g/L; (b) adding a dispersion of nanoparticles in a content of solids that depends on the functional excipient of direct compression of: 1:1, 1:0.9, 1:0.8, 1:0.7, 1:0.6, 1:0.5, 1:0.4, 1:0.3, 1:0.2, 1:0.1; (c) adjusting to 1 Lt of constant volume with water, where said water amount will depend on the weight of the functional excipient of direct compression, and the container; (d) maintaining under constant mechanical agitation the composition for 24 hours in order to perform the assembling process by means of the polymer adsorption over the functional excipient of direct compression; (e) letting to rest the composition for a period of 24 hours; (f) decanting the solids settled in the container; (g) drying the excess of humidity at a temperature ranging from 30°C to 40°C, using any furnace drying method, using spray drying; and (h) sieving the collected powders with the purpose of homogenizing the particle size to be compressed, being sieved in meshes of 50, 60 or 70.

Description

"METHOD FOR OBTAINING A PHARMACEUTICAL CO-PROCESSED EXCIPIENT FOR CONTROLLED RELEASE OF ACTIVE SUBSTANCES AND THE PRODUCT OBTAINED WITH THE SAME" FIELD OF THE INVENTION The present invention is related to the principles and techniques used in the Pharmaceutical Industry for the development and manufacture of functional excipients directed to direct compression that are applicable to controlled release systems, and more particularly, it is related to a process for obtaining an excipient. pharmaceutical co-processing for controlled release of active substances and the product obtained with it.

BACKGROUND OF THE INVENTION It is known that not all active substances or ingredients can be easily absorbed by the human body, that is why they require to be administered in the appropriate form, that is, to be able to administer said active substances must be dissolved or mixed with an excipient if it is solid or soft, or with a vehicle if it is liquid. In view of the above, within pharmaceutical research, there is the search for new excipients that allow the development of new dosage forms that improve efficiency and lower the cost of manufacturing medicines.

For the most part, the solid pharmaceutical forms of oral administration are of instant release, the drugs administered are characterized by having a short half-life. In order to favor the therapeutic efficiency of drugs administered orally maintaining effective therapeutic levels for a prolonged period of time, oral drug delivery systems have been developed that allow the release of active substances in a sustained or controlled manner.

A co-processed material is constituted by two or more excipients, which is designed to physically modify the properties that intrinsically present their individual excipients. The manufacture of co-processed materials is carried out by means of unitary operations such as spraying, extrusion, grinding, agglomeration, wet granulation and atomization, among others.

In the state of the technique different excipients have been used to achieve a controlled release, such as the formation of matrices with waxy, polymeric materials and a physical combination of both. However, the poor processing properties of these materials, such as compressibility and flow, limit their use, necessitating the addition of other components in the formulation.

In view of the above, the need to develop new co-processed excipients that present the benefits of the individual components that make them up has emerged.

Various and varied documents related to co-processed excipients and their obtaining method appear in the state of the art, such is the case of Quine, et al., Who describe the development of a co-processed agent for use in direct compression to achieve a sustained release, wherein the direct compression agent is constituted of different proportions of dicalcium phosphate dihydrate and compritol. However, the manufacture of said agent has certain disadvantages, since for its obtaining a process is used that is carried out by a co-precipitation method that uses organic solvents, which are increasingly disused due to their implications in security, economic and ecological.

Also, there is US Patent Application Serial No. US2004 / 0126422 A1 which describes the manufacture of a co-process for controlled release in oral administrations that includes a sustained release coating, an enteric coating, where the technologies involved in the manufacturing process of said co-processing are coating beds, hot extrusion, wet granulation, spheronization. However, these technologies require the use of highly specialized equipment and considerable energy expenditure, requiring a greater number of operations and do not satisfy the needs of controlled release.

On the other hand, Picker, et al evaluate the functionality of a co-processing for direct compression based on corn starch and lactose in an 85:15 proportion and that is manufactured by the "spray drying" method. The co-processing shows good properties of flow and compressibility; however, it is only useful for rapid disintegration of the tablet and rapid release of active substances from the solid dosage form.

Similarly, Kiran, et al describe the preparation of a co-processed excipient for use in direct compression based on pre-gelatinized starch and polyvinyl pyrrolidone in the ratio of 49: 1. The method of preparation consists of gelatinizing potato starch in the presence of polyvinyl pyrrolidone, for the subsequent drying of the dough obtained. The co-processing is an insoluble powder to water and some solvents, presents a good swelling in water, as well as good properties of flow and compressibility. The tablets formulated with this co-processing disintegrate within the first 3.5 minutes and a release of 100% of the content of the active principle is reached after 20 minutes, which makes it impossible to obtain a prolonged or controlled release.

In the North American Patent Application Series No. US2005 / 747067A describes a co-processing for direct compression based on microcrystalline cellulose and particulate calcium carbonate, forming an aqueous dispersion for subsequent drying preferably by spray drying. However, this co-processing is designed for immediate release tablets, providing good functional and aesthetics to the final product, for its high content of calcium carbonate makes it less expensive than the individual use of microcrystalline cellulose.

International Publication No. W02004 / 006904 refers to oral dosage forms containing paracetamol, and more particularly, to acetaminophen as an active agent of reference, which is characterized by the formation of a gel and a rapid release of up to 50% of the active substance, wherein the release is controlled by the swelling of the system, and can be modified by the application of an HPMC coating. However, this technology presents certain disadvantages, such as a rapid release of the active substance and requires the application of a coating to modify the release kinetics.

Japanese Patent JP04273816 refers to a pulsatile delivery system by means of the application of a sustained release inflatable layer on the surface of the substrate by means of a compression coating process. However, this controlled release system requires a coating process.

Also, Japanese Patent JP56164114 refers to the preparation of a controlled release agent consisting of fatty acids and their corresponding metal salts. However, this agent is limited to the use of fatty acids as lipid materials to achieve controlled release.

British Patent GB1002211 refers to controlled release tablets by dissolving the active substance in a solvent forming a controlled release system, using organic solvents, which are increasingly obsolete due to their safety implications , economic and ecological.

The Romanian Patent No. R0117148 describes a three-phase pharmaceutical form with the constant and controlled release of an amorphous active ingredient stabilized with polymers of a single application orally every day, which is particularly suitable for the active ingredients existing in amorphous form or in one or more polymorphic forms, which exhibit poor solubility in the crystalline form depending on the polymorphic form, particle size and the specific surface area of the active ingredient. This process requires different stages to obtain the pharmaceutical form, as well as a highly specialized team and an inherently high cost.

US Patent Application Serial No. US2003 / 215498 discloses rapidly disintegrating tablets based on a lipid coating, for its rapid disintegration its formulation for controlled release systems such as the present invention is impossible to form an insoluble, controlled release platform.

US Patent No. US6,773,720 relates to oral pharmaceutical compositions of amino salicylic acid with a lipophilic matrix with a melting point of less than 90 ° C. However, these compositions have the disadvantage of being limited to a single principle. active.

US Patent Series No. US 4,609,542 discloses a new pharmaceutical form of delayed action and controlled by the adsorption of medicaments in miniaturized granules by high compression forces, this pharmaceutical form consists of pH control agents, coating with lipids. This pharmaceutical form requires several stages of production, generating high cost and use of specialized equipment, being a long and expensive process.

The Romanian Patent No. R0122950 refers to indapamine coated tablets for prolonged release, using HPMC as the coating polymer. However, this system is limited only to the use of indapamine and coating technologies, requiring the use of specialized equipment.

Mexican Patent No. 227,800 refers to a functional direct compression excipient by means of a mixture of crosslinked polymers and / or copolymers that regulate the functionality of the system. To obtain said excipient, the use of highly specialized equipment is required with the consumption of high amounts of energy and the training of personnel for its operation.

As can be seen from the foregoing, in the state of the technology there is a large number of technologies related to co-processed excipients and their method of obtaining them; however, they all have great disadvantages with respect to the subject matter to be claimed and that is described later in the present invention. Disadvantages such as the fact that some of them are referred to a single active principle, or, the method for obtaining them requires several stages, in addition to requiring a highly specialized team and therefore, extremely expensive; among many other disadvantages.

BRIEF DESCRIPTION OF THE INVENTION A co-processed excipient for the controlled release of active substances for direct compression has been developed comprising at least one functional excipient for direct compression and a dispersion of nanoparticles, wherein said dispersion is selected from polymeric nanoparticles and solid lipid nanoparticles, or a mixture of both.

In accordance with the above, the process for obtaining the co-processed excipient that includes at least one functional excipient for direct compression and a dispersion of polymeric nanoparticles, which comprises the steps of: (a) placing a functional excipient in a container for direct compression in an amount ranging from 5 g / L to 500 g / L, based on 1 Kg of polymer dispersion; wherein said functional excipient is dicalcium phosphate dihydrate; (b) adding a dispersion of polymeric nanoparticles in a proportion of solids with respect to the functional excipient for direct compression, which is selected from: 1: 1, 1: 0.9, 1: 0.8, 1: 0.7, 1: 0.6, 1: 0.5, 1: 0.4, 1: 0.3, 1: 0.2, 1: 0.1; wherein said dispersion is selected from the group comprising Eudragit® RL, 100 Eudragit® RL PO, Eudragit® RL 30 D, Eudragit® RL 12.5, Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30 D, Eudragit® RS 12.5, Eudragit® NE 30 D, Eudragit® NE 40 D, Eudragit® NM 30 D, Aquacoat® ECD, Aquacoat® ARC, Aquacoat® CPD, Eudragit® L 30 D-55, Eudragit® L 100-55, Eudragit® L 100, Eudragit® L 12.5, Eudragit® S 100, Eudragit® S 12.5, Eudragit® FS 30 D, Eudragit® E 100, Eudragit® E 12.5, Eudragit® E PO, among others; (c) adjust to 1 Lt of constant volume with water, where said quantity of water will be a function of both the weight of the functional excipient for direct compression, as well as the container; (d) maintaining constant mechanical agitation for 24 hours in order to carry out the assembly process by adsorbing the polymer onto the functional excipient for direct compression; (e) let stand for a period of 24 hr; (f) decanting the solids settled in the container; (g) drying the excess moisture at a temperature ranging from 30 ° C to 40 ° C, using any known oven drying method, preferably using "spray drying"; and, (h) sift the collected dust with the objective of homogenizing the particle size for its compression, passing it through the 60 mesh.

Next, a process is described for obtaining a co-processed excipient that includes at least one functional excipient for direct compression and a dispersion of solid lipid nanoparticles, wherein said dispersion of solid lipid nanoparticles must first be obtained in accordance with an embodiment further of the present invention, which comprises the steps of: (a) heating in a vessel by means of mechanical agitation an amount of 1000ml of water up to a temperature of between 60 ° C and 80 ° C; (b) dissolving an emulsifier in the water previously heated in step a) above, wherein said emulsifier is selected from the group that comprises: lecithin, Tween 20, 40, 60, 65, 80; Span 20, 40, 60, 65, 80; Polyvinyl alcohol, Poloxamers, Brij, of nonionic emulsifiers such as monoglycerides, diglycerides, medium chain glycerides, glyceryl laurate, poloxamers, lecithin; esters of fatty acids such as sorbitan onolaurate (tween 20), sorbitan monostearate (tween 60) and sorbitan monooleate (tween 80), sorbitan monolaurate (span 20), ionic emulsifiers such as sodium lauryl sulfate, phospholipids, alginate salts , or mixtures thereof, among others; (c) melting a lipid at a temperature between 2 ° C and 5 ° C above its melting point, wherein the lipid is selected from the group comprising natural waxes, petroleum-derived waxes, or mixtures thereof; (d) adding the previously melted wax to the solution of the emulsifier obtained in step b), stirring mechanically and using a conventional variable speed agitator of between 50 and 1500 rpm to form an emulsion; (e) subjecting the emulsion obtained in step d) above to homogenization at a speed of 10,000 rpm doing so for cycles not greater than 5 min. each cycle to avoid overheating the system, and repeating the cycles until the desired average particle size is obtained, thus obtaining the dispersion of solid lipid nanoparticles; (f) placing in a container a functional excipient for direct compression in an amount ranging from 5 g / L to 500 g / L, taking as a base 1 kg of dispersion of solid lipid nanoparticles; wherein said functional excipient is dicalcium phosphate dihydrate; (g) adding the dispersion of solid lipid nanoparticles obtained in step e) in a proportion of solids with respect to the functional excipient for direct compression of: 1: 1, 1: 0.9, 1: 0.8, 1: 0.7, 1: 0.6 , 1: 0.5, 1: 0.4, 1: 0.3, 1: 0.2, 1: 0.1; (h) adjust to 1 Lt of constant volume with water, where said quantity of water will be a function of both the weight of the functional excipient for direct compression, as well as the container; (i) keep under constant mechanical agitation for 24 hours in order to carry out the assembly process by adsorption of the polymer on the functional excipient for direct compression; (j) let stand for a period of 24 hr; (k) decanting the solids settled in the container; (I) drying the excess moisture at a temperature ranging from 30 ° C to 40 ° C and using any known oven drying method, preferably using "spray drying"; and, (m) sift the collected dust with the objective of homogenizing the particle size for its compression, making them pass through the 60 mesh.

OBJECTS OF THE INVENTION Taking into account the defects of the foregoing techniques, it is an object of the present invention to provide a co-processed excipient for the controlled release of active substances that is highly functional and that provides the compressibility and flow characteristics in direct compression systems.

A further object of the present invention is to provide a co-processed excipient which, thanks to its characteristics of easy compressibility, allows to modulate the kinetics of release of lipophilic and / or hydrophilic active substances.

Yet another object of the present invention is to provide a co-processed excipient that allows the formation of an insoluble, controlled release platform that lipid materials provide for their hydrophobic qualities.

It is still another object of the present invention to provide a co-processed excipient that allows the delivery rate of the active substance to be decreased, by modifying the proportions of the direct compression material and the polymeric and / or lipid dispersion adsorbed and the ratio of this assembled with the active principle and other excipients.

It is yet another object of the present invention to provide a process for obtaining the co-processed excipient which is extremely simple, and yet highly efficient, economical and fast for the manufacture of the co-processed excipient, allowing a high functional quality of the systems of controlled release of drugs.

BRIEF DESCRIPTION OF THE FIGURES The novel aspects that are considered characteristic of the present invention will be established with particularity in the appended claims. However, the invention itself, both by its organization, as well as by its method of operation, together with other objects and advantages thereof, will be better understood in the following detailed description of a particularly preferred embodiment of the present invention, when read in relation to the accompanying drawings, in which: Figure 1 shows the release profile compared with tablets containing 10% model dye and functional excipient for direct compression dicalcium phosphate dihydrate (Di-Tab®) 90%. The high functionality of co-processing is demonstrated to form an insoluble, controlled release platform.

Figure 2 shows in the release profiles the ability to modulate the release kinetics by varying the proportions of particles adsorbed on the direct compression functional excipient.

DETAILED DESCRIPTION OF THE MODALITIES OF THE INVENTION Nanomedicine is the branch of applied nanotechnology in the field of health, and the advance in this branch of science is aimed at the design of particles, materials and nanometric devices so that they can easily enter most cells without activating no immune response and interact with the physiological materials of a way more direct and efficient, and even more accurate than traditional systems and drugs, and that are able to access areas of the body that have been difficult to penetrate with. the current technologies.

The scientific and technological development tending to increase the effectiveness of medicines, has led to new designs of the active substance administration systems, with the purpose of effectively and selectively depositing the therapeutic substances in concentrations that maximize their effectiveness. This must be achieved by restricting the access of these substances to areas not selected for their effect, which is why the transporter is considered one of the most important factors to be successful in the transfer and localization of the drug.

Within the systems of supply of active substances are the solid lipid nanoparticles, which were developed as an alternative to other drug systems such as emulsions, liposomes and polymeric nanoparticles. The advantages of the use of solid lipid nanoparticles as transporters include the use of physiological lipids in their formulation, avoiding the use of organic solvents in their preparation and the possibility of being used in a broad spectrum for administration on the skin, via orally and intravenously, through traditional medications such as ointments, tablets, capsules, suspensions or injectable solutions.

On the other hand, functional excipients that are directed to direct compression should provide high fluidity, good compressibility under pressure and excellent uniformity in the mixture when combined with pharmaceutical active ingredients or other ingredients.

In view of the foregoing, a co-processed excipient has been developed for the controlled release of active substances for direct compression comprising at least less a functional excipient for direct compression and a dispersion of nanoparticles, wherein said dispersion is selected from polymeric nanoparticles and solid lipid nanoparticles, or a mixture of both.

In accordance with the foregoing, a process for obtaining the co-processed excipient according to a particularly preferred embodiment of the present invention, which includes at least one functional excipient for direct compression and a dispersion of polymeric nanoparticles and it includes the stages of: a) Place in a container a functional excipient for direct compression in an amount ranging from 5g / L to 500g / L, and more preferably in an amount of 100g / liter, based on 1Kg of polymer dispersion; wherein said functional excipient is selected from soluble or insoluble direct compression excipients, preferably being selected from the group comprising dicalcium phosphate dihydrate, microcrystalline cellulose, lactose, sucrose, mannitol, among others; and more preferably selecting dicalcium phosphate dihydrate. ,. b) Add a dispersion of polymeric nanopatures in a proportion of solids with respect to the functional excipient for direct compression, which is selected from: 1: 1, 1: 0.9, 1: 0.8, 1: 0.7, 1: 0.6, 1 : 0.5, 1: 0.4, 1: 0.3, 1: 0.2, 1: 0.1; preferably adding the polymer dispersion in a ratio of 1: 1; wherein said dispersion is selected from the group comprising Eudragit® RL, 100 Eudragit® RL PO, Eudragit® RL 30 D, Eudragit® RL 12.5, Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30 D, Eudragit® RS 12.5, Eudragit® NE 30 D, Eudragit® NE 40 D, Eudragit® NM 30 D, Aquacoat® ECD, Aquacoat® ARC, Aquacoat® CPD, Eudragit® L 30 D-55, Eudragit® L 100-55, Eudragit® L 100, Eudragit® L 12.5, Eudragit® S 100, Eudragit® S 12.5, Eudragit® FS 30 D, Eudragit® E 100, Eudragit® E 12.5, Eudragit® E PO, among others; preferably using Aquacoat® ECD. c) Adjust to 1 Lt of constant volume with water, where said quantity of water will be a function of both the weight of the functional excipient for direct compression, as well as the container. d) Maintain constant mechanical agitation for 24 hours in order to carry out the assembly process by adsorbing the polymer on the functional excipient for direct compression. e) Leave to rest for a period of 24 hr. f) Decant the solids settled in the container. g) Dry the excess moisture at a temperature ranging from 30 ° C to 40 ° C, preferably drying the excess moisture at a temperature of 35 ° C using any known oven drying method, preferably using drying by "spray drying" " h) Sifting the collected dust in order to homogenize the particle size for its compression, making it pass through any of the 50, 60 or 70 meshes, preferably passing through the 60 mesh.

Next, a process for obtaining a co-processed excipient including at least one functional excipient for direct compression and a dispersion of solid lipid nanoparticles is described according to a further embodiment of the present invention, in which first said dispersion of solid lipid nanoparticles, wherein said process comprises the steps of: a) Heat in a container by means of mechanical agitation an amount of 1000ml of water until reaching a temperature between 60 ° C and 80 ° C, preferably until reaching a temperature of 80 ° C. b) Dissolving an emulsifier in an amount ranging from 2.5% by weight to 5% by weight, in the water previously heated in stage a) above, wherein said emulsifier are selected from the group comprising: lecithin, Tween 20, 40, 60, 65, 80; Span 20, 40, 60, 65, 80; Polyvinyl alcohol, Poloxamers, Brij, of nonionic emulsifiers such as monoglycerides, diglycerides, medium chain glycerides, glyceryl laurate, poloxamers, lecithin; esters of fatty acids such as sorbitan monolaurate (tween 20), sorbitan monostearate (tween 60) and sorbitan monooleate (tween 80), sorbitan monolaurate (span 20), ionic emulsifiers such as sodium lauryl sulfate, phospholipids, alginate salts , or mixtures thereof, among others; polyvinyl alcohol or poloxamers are preferably used, and more preferably poloxamers are used. c) Melting a lipid in an amount ranging from 8% by weight to 10% by weight at a temperature between 2 ° C and 5 ° C above its melting point, wherein the lipid is selected from the group comprising natural waxes, waxes derived from petroleum, or mixtures thereof. Wherein said natural waxes are selected from the group comprising carnauba wax, candelilla wax, whale sperm, beeswax, lanolin, wool wax, chinese wax. And said petroleum derived waxes are selected from the group comprising microcrystalline wax, paraffin wax, glyceryl behenate, tricaprin, trilaurine, trimyristin, tripalmitin, triasterin, hydrogenated glycerides, Witepsol® W 35, Witepsol® H 35, Witepsol® H 42, Witepsol® E 85, glyceryl monostearate, glyceryl palmito-stearate, cetyl palmitate, stearic acid, palmitic acid, decanoic acid, behenic acid, N 12 acid, gelucire, compitrol, among others; preferably wax candelilla, gelucire and compritol are used, and more preferably using compritol. .

If more than one wax is used, the melting of the wax is carried out at a temperature between 2 ° C and 5 ° C above the wax with the highest melting point used, d) Addition of the previously melted wax to the solution of the emulsifier obtained in step b), stirring mechanically and using a conventional variable speed agitator of between 50 and 1500 rpm to form an emulsion; e) Submit the emulsion obtained in step d) above to homogenization, for example Ultraturrax, at a speed of 10,000 rpm and doing it in cycles with a duration of no more than 5 minutes each cycle to avoid overheating, where said cycles are repeated to obtain the desired average particle size, where said particle size varies between 100 nm and 450 nm, thus obtaining the dispersion of solid lipid nanoparticles. f) Place in a container a functional excipient for direct compression in an amount ranging from 5 g / L to 500 g / L, and more preferably in an amount of 100 g / l, taking as a base 1 kg of dispersion of solid lipid nanoparticles; wherein said functional excipient is selected from soluble or insoluble direct compression excipients, preferably being selected from the group comprising dicalcium phosphate dihydrate, microcrystalline cellulose, lactose, sucrose, mannitol, among others; and more preferably by selecting dicalcium phosphate dihydrate., g) Add the dispersion of solid lipid nanoparticles obtained in step e) in a proportion of solids with respect to the functional excipient for direct compression of: 1: 1, 1: 0.9, 1: 0.8, 1: 0.7, 1: 0.6, 1: 0.5, 1: 0.4, 1: 0.3, 1: 0.2, 1: 0.1; preferably adding the lipid dispersion in a ratio of 1: 1, h) Adjust to 1 Lt of constant volume with water, where said quantity of water will be a function of both the weight of the functional excipient for direct compression, as well as the container i) Maintain constant mechanical agitation for 24 hours in order to carry out the assembly process by adsorbing the polymer on the functional excipient for direct compression. j) Let stand for a period of 24 hr. k) Decant the solids settled in the container.

I) Dry the excess moisture at a temperature ranging from 30 ° C to 40 ° C, drying the excess moisture preferably at a temperature of 35 ° C and using any known oven drying method, preferably using drying by, " drying spray " m) Sifting the collected dust in order to homogenize the particle size for its compression, making it pass through any of the meshes 50, 60 or 70, preferably passing through the 60 mesh.

The process for obtaining the co-processed excipient that is described in the present invention, will be better understood from the following examples, which are presented only for illustrative purposes, but not limiting, to allow a thorough understanding of the preferred modalities of the present invention, without implying that there can not be other modalities not illustrated in the present invention and that can be carried out based on the detailed description presented herein.

EXAMPLE 1 Obtaining a co-processed excipient constituted by dicalcium phosphate dihydrate and an Aquacoat® ECD polymer dispersion, for which: a) 100 grams of dicalcium phosphate dihydrate were placed in a metal container, b) The equivalent to 75 grams of ethylcellulose was added, c) The volume was adjusted to 1 liter with distilled water, d) It remained in agitation for a period of 24 hours, e) It was allowed to stand for 24 hours so that the solids settled, f) The excess supernatant is decanted, g) The co-processing was placed in a metal tray and dried at a temperature between 30 ° C and 40 ° C. h) The obtained powders were sieved in the # 60 mesh.

The rheological properties of the co-processing obtained were the following: • Apparent density = 40 g / cm3 • Compact density = 28 gr / cm3 • Rest angle = 30.9 ° • Carr index = 17.5 • Hausner index = 1.21 The co-processing shows excellent flow properties and suitable compressibility characteristics EXAMPLE 2 Release profile of a triarylmethane model dye of tablets obtained by direct compression with a co-processing consisting of dicalcium phosphate dihydrate and a lipid dispersion consisting of solid lipid nanoparticles.

I. Obtaining lipid dispersion: a) Compritol was heated to a temperature between 2 ° C and 5 ° C above its melting point; b) Water was heated in another vessel at the same temperature as the wax, in this same vessel the poloxamer is dissolved with mechanical stirring; c) The lipid was added in the container of the previous point and homogenization was carried out at 10,000 rpm, doing it in 4 cycles of 5 minutes each cycle. d) It was allowed to cool to room temperature and was stored until its use.

II. Obtaining the co-processing: a) 100 grams of dicalcium phosphate dihydrate were placed in a metal container, b) The equivalent to 75 grams of Solid Lipid Nanoparticles was added, c) The volume was adjusted to 1 liter with distilled water, d) It was stirred maintaining for a period of 24, e) It was left to stand for 24 hours for the solids to settle, f) The excess supernatant was decanted and the co-processed was placed in a metal tray, g) Dry at a temperature between 30 ° C and 40 ° C. h) The powders obtained in the previous stage were sifted through a mesh # 60.

The use of this co-processed excipient was used to manufacture tablets with a weight of 1 gram containing 90% co-processed and 10% model dye. The release profile obtained is observed in Figure 1.

EXAMPLE 3 Obtaining two co-processed with different proportions of lipid particles adsorbed on a functional excipient for direct compression to form tablets containing a model dye.

I. Obtaining the co-processed: a) 100 grams of dicalcium phosphate dihydrate were placed in a metal container, b) The equivalent of 40 grams of Solid Lipid Nanoparticles was added for co-processing A and 100 grams of Solid Lipid Nanoparticles for coprocessing B, c) The volume was adjusted to 1 liter with distilled water, d) It was subjected to constant agitation for a period of 24 hours, e) It was left to stand for 24 hours for the solids to sediment., f) The excess supernatant was decanted and the co-processed was placed in a metal tray. h) sift the powders obtained in the previous stage by passing them through a # 60 mesh.

With the obtained co-processed tablets are produced with a weight of 1 gram containing 90% co-processed and 10% model dye. The release profile obtained is shown in Figure 2.

Even though in the previous description reference has been made to certain embodiments of the method of obtaining a co-processed excipient for the release of active substances of the present invention, it should be emphasized that numerous modifications to such modalities are possible, but without departing from the true scope of the invention, such as the use of different nanoparticle systems of a different nature to the polymeric and lipid, different assembly processes by adsorption on a excipient of direct compression, the use of different materials with characteristics different from those of direct compression, the use of active substances or ingredients not only of pharmaceutical use and interest, but food, livestock, agricultural, veterinary, cosmetic, etc., training of controlled release matrices by other methods besides compression (for example: chilsonado, extruído), among many other modifications. Therefore, the present invention should not be restricted except as established in the state of the art and the appended claims.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A process for obtaining a co-processed excipient for the release of active substances, characterized in that it comprises the steps of: a) Place in a container a functional excipient for direct compression in an amount ranging from 5 g / L to 500 g / L., b) Add a dispersion of nanoparticles in a proportion of solids with respect to the functional excipient for direct compression of: 1: 1, 1: 0.9, 1: 0.8, 1: 0.7, 1: 0.6, 1: 0.5, 1: 0.4, 1: 0.3, 1: 0.2, 1: 0.1. c) Adjust to 1 Lt of constant volume with water, where said quantity of water will be a function of both the weight of the functional excipient for direct compression, as well as the container. d) Maintain constant mechanical agitation for 24 hours in order to carry out the assembly process by adsorbing the polymer on the functional excipient for direct compression. e) Leave to rest for a period of 24 hr. f) Decant the solids settled in the container. g) Dry the excess moisture at a temperature ranging from 30 ° C to 40 ° C, using any known oven drying method, using drying by "spray drying" h) Sifting the collected dust with the objective of homogenizing the particle size for its compression, making them pass any of the meshes 50, 60 or 70. 2. - The process for obtaining a co-processed excipient for the release of active substances according to claim 1, further characterized in that the functional excipient is added in step a) in an amount of 100 g / liter, 3. - The process for obtaining a co-processed excipient for the release of active substances according to claim 1, further characterized in that the functional excipient is selected from soluble or insoluble direct compression excipients, being selected from the group comprising dicalcium phosphate dihydrate , microcrystalline cellulose, lactose, sucrose, mannitol. , 4 - The process for obtaining a co-processed excipient for the release of active substances according to claim 3, further characterized in that the functional excipient is dicalcium phosphate dihydrate. 5. - The process for obtaining a co-processed excipient for the release of active substances according to claim 1, further characterized in that the dispersion of nanoparticles is added in step b) in a ratio of 1: 1, 6. - The process for obtaining a co-processed excipient for the release of active substances according to claim 1, further characterized in that the nanoparticle dispersion is selected from polymeric nanoparticles and solid lipid nanoparticles. 7. - The process for obtaining a co-processed excipient for the release of active substances according to claim 6, further characterized in that the dispersion is polymeric nanoparticles. 8. - The process for obtaining a co-processed excipient for the release of active substances according to claim 6, further characterized in that the dispersion is of solid lipid nanoparticles. 9. - The process for obtaining a co-processed excipient for the release of active substances according to claim 7, further characterized in that the dispersion of polymeric nanoparticles is selected from the group comprising Eudragit® RL, 100 Eudragit® RL PO, Eudragit® RL 30 D, Eudragit® RL 12.5, Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30 D, Eudragit® RS 12.5, Eudragit® NE 30 D, Eudragit® NE 40 D, Eudragit® NM 30 D, Aquacoat® ECD, Aquacoat® ARC, Aquacoat® CPD, Eudragit® L 30 D-55, Eudragit® L 100-55, Eudragit® L 100, Eudragit® L 12.5, Eudragit® S 100, Eudragit® S 12.5, Eudragit® FS 30 D, Eudragit® E 100, Eudragit® E 12.5, Eudragit® E PO, among others. 10. - The process for obtaining a co-processed excipient for the release of active substances according to claim 9, further characterized in that the dispersion of polymeric nanoparticles is Aquacoat® ECD. 11. - The process for obtaining a co-processed excipient for the release of active substances according to claim 1, further characterized in that the excess moisture in step g) is dried at a temperature of 35 ° C. 12. - The process for obtaining a co-processed excipient for the release of active substances according to claim 8, further characterized in that to obtain the dispersion of solid lipid nanoparticles the steps of: (a) Heat in a container by means of mechanical agitation an amount of 1000ml of water until reaching a temperature between 60 ° C and 80 ° C. (b) Dissolving an emulsifier in the water previously heated in stage a) above, wherein said emulsifier is selected from the group comprising: lecithin, Tween 20, 40, 60, 65, 80; Span 20, 40, 60, 65, 80; Polyvinyl alcohol, Poloxamers, Brij, of nonionic emulsifiers such as monoglycerides, diglycerides, medium chain glycerides, glyceryl laurate, poloxamers, lecithin; esters of fatty acids such as sorbitan monolaurate (tween 20), sorbitan monostearate (tween 60) and sorbitan monooleate (tween 80), sorbitan monolaurate (span 20), ionic emulsifiers such as sodium lauryl sulfate, phospholipids, alginate salts , or combinations thereof, among others. (c) Melting a lipid at a temperature between 2 ° C and 5 ° C above its melting point, wherein the lipid is selected from the group comprising natural waxes, petroleum waxes, or mixtures thereof. (d) Addition of the previously melted lipid to the solution of the emulsifier obtained in step b), stirring mechanically and using a conventional variable speed agitator of between 50 and 1500 rpm to form an emulsion; (e) Submit the emulsion obtained in step d) above to homogenization at a speed of 10,000 rpm, doing it in cycles with a duration of no more than 5 minutes each cycle to avoid overheating, where said cycles are repeated until the size is obtained desired particle average, thus obtaining the dispersion of solid lipid nanoparticles. 13. - The process for obtaining a co-processed excipient for the release of active substances according to claim 12, further characterized in that the amount of emulsifier ranges from 2.5% by weight to 5% by weight. 14. - The process for obtaining a co-processed excipient for the release of active substances according to claim 12, further characterized in that the water in stage (a) is heated to a temperature of 80 ° C. 15. - The process for obtaining a co-processed excipient for the release of active substances according to claim 12, further characterized in that the amount of the lipid ranges from 8% by weight to 10% by weight. 16. - The process for obtaining a co-processed excipient for the release of active substances according to claim 12, further characterized in that the emulsifier of step (b) is selected from polyvinyl alcohol and poloxamer. 17. - The process for obtaining a co-processed excipient for the release of active substances according to claim 16, further characterized in that the emulsifier is poloxamer. 18. - The process for obtaining a co-processed excipient for the release of active substances according to claim 12, further characterized in that the natural waxes are selected from the group comprising carnauba wax, candelilla wax, whale sperm, beeswax, lanolin , wool wax, Chinese wax. 19. - The process for obtaining a co-processed excipient for the release of active substances according to claim 12, further characterized in that the waxes derived from petroleum are selected from the group comprising microcrystalline wax, paraffin wax, glyceryl behenate, tricaprin, trilaurin , trimiristine, tripalmitin, triasterin, hydrogenated glycerides, Witepsol® W 35, -Witepsol® H 35, Witepsol® H 42, Witepsol® E 85, glyceryl monostearate, glyceryl palmito-stearate, cetyl palmitate, stearic acid, palmitic acid, decanoic acid , behenic acid, acid N 12, gelucire, compitrol, among others. 20. - The process for obtaining a co-processed excipient for the release of active substances according to claim 18 or 19, further characterized in that the wax used is wax candelilla, gelucire and compritol. 21. - The process for obtaining a co-processed excipient for the release of active substances according to claim 20, further characterized in that the wax used is compritol. 22. - The process for obtaining a co-processed excipient for the release of active substances according to claim 12, further characterized in that when more than one lipid is used, the casting is brought to a temperature between 2 ° C and 5 ° C above the temperature of the highest melting point lipid used. 23. - A co-processed excipient for the release of active substances obtained with the process claimed in the preceding clauses, characterized in that it comprises: at least one functional excipient for direct compression and a dispersion of nanoparticles. 24. - The co-processed excipient for the release of active substances according to claim 23, further characterized in that the functional excipient is selected from soluble or insoluble direct compression excipients, being selected from the group comprising dicalcium phosphate dihydrate, microcrystalline cellulose, lactose , sucrose, mannitol. 25. - The co-processed excipient for the release of active substances according to claim 24, further characterized in that the functional excipient is dicalcium phosphate dihydrate. 26. - The co-processed excipient for the release of active substances according to claim 23, further characterized in that the dispersion is selected from polymeric nanoparticles and solid lipid nanoparticles, or a mixture of both. 27. - The co-processed excipient for the release of active substances according to claim 26, further characterized in that the dispersion is polymeric nanoparticles. 28. - The co-processed excipient for the release of active substances according to claim 26, further characterized in that the dispersion is of solid lipid nanoparticles. 29. - The co-processed excipient for the release of active substances according to claim 27, further characterized in that the dispersion of polymeric nanoparticles is selected from the group comprising Eudragit® RL, 100 Eudragit® RL PO, Eudragit® RL 30 D, Eudragit® RL 12.5, Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30 D, Eudragit® RS 12.5, Eudragit® NE 30 D, Eudragit® NE 40 D, Eudragit ® NM 30 D, Aquacoat® ECD, Aquacoat® ARC, Aquacoat® CPD, Eudragit® L 30 D-55, Eudragit® L 100-55, Eudragit® L 100, Eudragit® L 12.5, Eudragit® S 100, Eudragit® S 12.5, Eudragit® FS 30 D, Eudragit® E 100, Eudragit® E 12.5, Eudragit® E PO, among others. 30. - The co-processed excipient for the release of active substances according to claim 29, further characterized in that the dispersion of polymeric nanoparticles is Aquacoat® ECD.