WO2016166060A1

WO2016166060A1 - Oral administration system for the controlled release of active ingredients

Info

Publication number: WO2016166060A1
Application number: PCT/EP2016/057923
Authority: WO
Inventors: Miriam FORNACIARI
Original assignee: Fornaciari Miriam
Priority date: 2015-04-14
Filing date: 2016-04-11
Publication date: 2016-10-20
Also published as: ITBO20150177A1

Abstract

An oral administration system capable of performing the controlled release of one or more active ingredients, which comprises a core that comprises the one or more active ingredients and a coating consisting of one or more lipophilic substances, or one or more pH-sensitive polymers, or a mixture of one or more lipophilic substances and one or more pH-sensitive polymers, which coats the core; at the interface between the core and the coating there are maltodextrins derived from starch extracted from plants that belong to the Leguminosae family.

Description

ORAL ADMINISTRATION SYSTEM FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS

The present invention relates to an oral administration system for the controlled release of biologically active ingredients, such as medicines or food supplements.

The oral administration of active ingredients (medicines, food supplements etc.) exhibits a technical limitation owing to the lack of control over the quantity of such ingredients that reaches the intestinal tract, where absorption occurs. In fact, the active ingredients can undergo a degradation, both chemical and enzymatic, in the first part of the digestive tract (i.e. "upstream" of the intestine). Such degradation reduces, sometimes considerably, the quantity of active ingredients that reaches the intestine and which can be absorbed.

This applies to all animals (including humans), but it takes on a particular importance in the species of ruminants, owing to the fact that the active ingredients pass through not only the glandular stomach but also three pre-stomachs (reticulum, rumen and omasum), which are populated by a dense microflora (especially the rumen). The degradation is also influenced by the speed of transit of the active ingredients through the first part of the digestive tract. It has been calculated that only small quantities of active ingredients manage to reach the intestinal tract, while the majority percentage thereof is degraded in the first part of the digestive tract.

Therefore, in order to enable the absorption of the active ingredients in the intestinal tract, thus preserving their efficacy, it is necessary to protect such substances from chemical and biological degradation. The importance of protecting the active ingredients until they reach the intestine is attested by the fact that a conventionally-administered substance in the zootechnical field, such as choline or its salts, when administered directly post-ruminally, is capable of increasing the production of milk in cows, something that does not occur with oral administration of non-protected choline. US 4,533,557 discloses a composition of supplements for ruminants in the form of granules or tablets which comprises biologically active ingredients, chitosan and protective materials constituted by saturated and unsaturated aliphatic monocarboxylic acids with a chain having a number of carbon atoms comprised between 14 and 22. This invention uses a hydrophobic substance (aliphatic monocarboxylic acids) to slow the penetration of the biological fluids inside the granule or tablet, as a consequence decreasing the quantity of biologically active ingredients that are released during the transit of the rumen. Moreover, the presence of the chitosan provides further protection in the transit of the rumen. In fact, at the pH of the ruminal liquid (variable between 5 and 8) the chitosan is poorly soluble, while it dissolves in an acid environment with a pH lower than 5; the presence of this polymer therefore increases the resistance of the (granule or tablet) matrix during the stay in the rumen.

US 5,190,775 discloses a composition of particles or granules for oral administration which has a relative density comprised between 0.3 and 2 g/ml, and comprises active ingredients encapsulated in a hydrophobic coating consisting preferably of hydrogenated vegetable oils coated on the surface with a layer of surfactant, which prevents the encapsulated active ingredients from floating inside the rumen.

US 5,496,571 discloses a composition in the form of microcapsules which is stable in the rumen, and which comprises choline chloride in liquid form coated with an outer layer of hydrogenated and non-hydrogenated animal fat or of hydrogenated vegetable oil.

Other patents disclose methods and compositions in order to obtain a

"by-pass the rumen" effect for the biologically active ingredients. Of these patents, we can cite US 4,713,245, US 3,451,204 and US 4,876,097.

US 4,832,967 discloses a food composition for ruminants which consists of a core that comprises an active ingredient coated by two protective layers: the first layer consists of a polymeric substance that forms a stable film with pH levels higher than 5, while allowing the release of the active ingredient at pH levels lower than 3.5; the second layer consists of a hydrophobic substance.

US 5,912,017 by Massachusetts Institute of Technology discloses the preparation of microcapsules that comprise polymeric multiple layers for controlling the release of medicines, insecticides and fertilizers.

US 2005/0019413 discloses microcapsules that comprise rumen- protected choline chloride. The microcapsules consist of a core that comprises mainly the active ingredient in the form of crystalline powder coated with a double protective layer, the outermost layer consisting of carnauba wax and the innermost layer consisting of a continuous film of a hydrophobic substance such as hydrogenated soya oil. Furthermore the core can contain additional substances such as: fluidifying agents such as for example silicates, aluminosilicates, zeolite, silica, perlite, in quantities not exceeding 8% of the weight of the core; and/or binding agents which have a barrier function against humidity, such as for example stearates, in quantities equal to 7% of the core.

US 2006/0067984 discloses a composition in the form of microcapsules for the controlled release of physiological active ingredients for zootechnical feeding. The composition comprises: a core consisting of an active ingredient and a matrix of carnauba wax or microcrystalline wax; a first layer of hydrophobic coating which consists of a substance selected from fats, fatty acids or mono- or diglyceride hydrogenated oils, esters of fatty acids or long-chain alcohols (from 12 to 22 carbon atoms), with melting point between 40°C and 74°C; a second layer consisting of microcrystalline waxes, paraffin waxes, plant waxes and synthetic waxes with melting point between 80°C and 100°C.

WO 2008015203 A2 discloses microparticles or granules of sizes comprised between 0.1 and 5000 microns for zootechnical/veterinarian use, consisting of a core that comprises one or more substances with a pharmacological action or food supplements; these substances have a cation or anion or neutral function, easily ionizable so as to obtain a net charge, and are thoroughly mixed with or adsorbed on a hydrated silicate of magnesium, aluminum, calcium and sodium, capable of absorbing water and causing a reversible dissolving of such substances. The core is coated by a double layer consisting of fats or waxes, the outer layer having a higher melting point than the inner layer.

In light of the foregoing it therefore appears that, in the state of the art, the methodology used most in order to enable the orally administered active ingredients to reach the intestine without undergoing degradations that could compromise their biological functionality is to develop a system (be it a tablet, a particle, a granule or a similar structure) where such active ingredients are located in an inner core, which is then coated by one or more layers of protective coating, which preserve the integrity of the core. However, such methodology is not devoid of drawbacks, the main one being represented by the fact that the core and the protective coating often have different chemical-physical characteristics: often, the core is polar- hydrophilic, while the coating can consist of lipophilic substances (for example fats or waxes) and is therefore apolar-hydrophobic. Therefore, at the contact surface between the core and the coating, there is an interface where polar substances and apolar substances are located in mutual contact. Because of the poor solubility of the two types of substances, owing to their different chemical nature, the interface constitutes an inhomogeneous and discontinuous area. In particular, the poor adhesion between core and coating causes the formation of microfractures in the coating proper, with consequent anticipated release of the active ingredients contained in the core, before the system has reached the intestinal tract.

This problem is most felt in the administration of active ingredients to ruminant animals in that, before reaching the intestine, the substances ingested by ruminants pass through three pre-stomachs (reticulum, rumen and omasum) and the glandular stomach (abomasum). In all these organs, chemical and enzymatic reactions occur that degrade the orally administered active ingredients, with consequent reduction or loss of their biological function.

In order to improve the adherence between the surfaces of the core and of a lipophilic coating, the use is known of stearic acid at the interface. However, this technique suffers some drawbacks that make its use unsuitable: first of all, the application of stearic acid on the surface of the core and its drying require a rather long time; furthermore, if the melting of the stearic acid does not occur correctly, it can undergo a process of sintering, with consequent loss of the desired chemical/physical characteristics.

According to many of the conventional techniques described above, the active core can be coated by a coating layer that comprises several substances of different types, or by several layers of coating, each substantially constituted by a specific substance. For example it is possible to use: waxes and lipophilic substances; or two or more different lipophilic substances, with different melting points; or two or more pH-sensitive polymers.

These pairings of different substances multiply the difficulties in carrying out the process of coating the active core, increasing the problem of adhesion between the various interfaces that are created, and they imply additional costs owing to the processing time and to the greater difficulty of controlling the process parameters. Furthermore, some systems use lipophilic substances and waxes with a high melting point, in order to increase the ruminal bypass; but the use of substances with a high melting point reduces the absorption of the active ingredient in the intestine and part of it is voided without having been absorbed.

The aim of the present invention is to provide an oral administration system that solves the above mentioned technical problems, eliminates the drawbacks and overcomes the limitations of the known systems in the state of the art.

Within this aim, an object of the invention is to provide an oral administration system that comprises a core that comprises the active ingredients and a protective coating that prevents the degradation of such substances in the transit through the first part of the digestive tract, in which the core and the coating chemically interact, therefore remaining intimately adherent to each other.

Another object of the invention is to provide an oral administration system that makes it possible to release the active ingredients contained in the core of the system in the intestine.

Another object of the invention is to provide an oral administration system that preserves the active ingredients from the chemical and/or enzymatic degradation that occurs in the first part of the digestive tract, especially in ruminant animals.

Another object of the invention is to provide an oral administration system that is highly reliable, easy to implement and low cost.

This aim and these and other objects which will become better apparent hereinafter are achieved by an oral administration system for the controlled release of one or more active ingredients, which comprises a core that comprises the one or more active ingredients and a coating that is constituted by one or more lipophilic substances, or one or more pH- sensitive polymers, or a mixture of one or more lipophilic substances and one or more pH-sensitive polymers coating the core, wherein the system is characterized in that maltodextrins derived from starch extracted from plants that belong to the Leguminosae family are located at the interface between the core and the coating.

Further characteristics and advantages of the invention will become better apparent from the detailed description that follows of a preferred, but not exclusive, embodiment of the system for controlled release according to the present invention.

Starch is a polysaccharide consisting of hundreds or thousands of glucose units joined together by a-glycosidic bonds. It has two components: amylose, which is the linear part of the polysaccharide, in which the glucose molecules are joined with a-(l-4)glycosidic bonds, and amylopectin, which is the branched part, where each branch point is due to the presence of a-(l- 6)glycosidic bonds between two glucose units. In nature, starch accumulates and forms granules in the fruits, seeds and tubers of plants. In granules, starch has a semi-crystalline structure, which determines its almost total insolubility in water at ambient temperature: partial solubilization is possible by increasing the temperature, and leads to the formation of a gel, in which the starch has a more disorganized structure. Gelatinized starch tends to return to the original structure by way of a process known as retrogradation of starch, which is what results in staling of products that are rich in complex carbohydrates, such as bread. Retrogradation does not return starch to its original structure, but to an intermediate rigid structure.

The hydrolysis of starch, chemical or enzymatic, results in smaller polymeric structures (dextrins), in which the glucose units are joined mainly by a-(l-4) glycosidic bonds. If the glucose units are comprised between 3 and 17 in number, such dextrins are referred to as maltodextrins.

Structures derived from starch (in particular, from amylose) are used for their capacity to encapsulate various types of molecules. The encapsulation of guest molecules can offer several advantages such as the stabilization of light-sensitive or oxygen- sensitive substances, modification of reactivity, improvement of solubility, masking of unpleasant tastes and/or odors, and pigmentation.

For example, the encapsulating properties of cyclodextrins (cyclic dextrins formed from 6, 7 or 8 glucose units) are well known: the cyclodextrins form a truncated cone structure, hollow inside, which can accommodate various different guest molecules. Cyclodextrins have the disadvantage of having a rigid inside diameter, which therefore limits the type of molecules that can be incorporated.

Linear amylose can also incorporate guest molecules, although they do so more loosely than cyclodextrins. In an aqueous solution, in fact, amylose is capable of coiling to form a helix, inside which several different molecules can be accommodated. When amylose assumes this helical structure, it is called V-amylose. V-amylose is a amphiphilic macromolecule, in that the portion of the helix directed inwardly, which face the hydrogen atoms, is hydrophobic, while the portion of the helix directed outwardly, which face the hydroxyl groups, is hydrophilic. The inside diameter of the helix can be adjusted by acting on physical parameters such as temperature, in that maltodextrins, by heating, tend to linearize; one turn of the helix can therefore be constituted by a variable number of glucose units from 6 to 8. The names for these are V6-amylose (the most conventional form), V7- amylose and V8-amylose. As a consequence, amylose makes it possible to incorporate a greater variety of guest molecules than cyclodextrins.

However, amylose is used in a limited number of applications, such as the masking of unpleasant tastes and/or odors, the stabilization of oxidizable molecules, the stabilization of molecules on which a particular aroma or scent depends, and the increase of solubility of poorly-soluble molecules. But the use of amylose in the encapsulation of active ingredients for pharmaceutical use is limited for various reasons, including: insolubility in cold water, the risk of retrogradation (which would render the pharmaceutical preparations unstable), the necessity of completely eliminating the fats with which it is complexed in nature, and the difficulty of characterization and standardization of the resulting pharmaceutical preparations. The foregoing description of amylose, in terms of characteristics, properties and uses, also applies to maltodextrins derived from the hydrolysis thereof and having a number of glucosidic units greater than or equal to 6 (the minimum number of glucose units that enables the formation of the helix structure).

Recently it has been found that the starch of leguminous, in particular of the yellow pea plant, which is particularly rich in amylose, when subjected to enzymatic hydrolysis gives rise to maltodextrins with different properties from the properties of starch and of maltodextrins that were known until now. In particular, maltodextrins derived from the starch of yellow pea are soluble in cold water, have low viscosity, reduced tendency to retrogradation, and they do not require the elimination of fats. These properties mean that such maltodextrins are more versatile and offer greater possibilities for use than other polysaccharidic derivatives.

WO 2009/024690 by Roquette relates to the use of maltodextrins or of glucose syrups obtained by hydrolyzing starch extracted from leguminous, for encapsulating organic compounds, in particular hydrophobic compounds. Maltodextrins from starch of yellow pea have applications in the foods, cosmetics and pharmaceutical fields as solubilizing or emulsifying agents and as additives to mask unpleasant tastes.

A first aspect of the present invention relates to a system for orally administering active ingredients such as medicines or food supplements, enabling the controlled release thereof in the intestinal tract of the animal to which the system is administered. In such system, the active ingredients are comprised in a core (which consists of the inner portion of the system), coated by a coating.

In the context of the present invention, the term "system" indicates a structure for the oral administration of active ingredients which can take the pharmaceutical form of a tablet, a capsule, a granule, a particle or similar structures known to the person skilled in the art.

In the present invention furthermore, the expressions "controlled release", "control of the release" and the like refer to the capacity of the systems of the invention to release the active ingredients in the intestinal tract of the animal to which the system is administered, avoiding release in the first part of the digestive tract, where such substances are not absorbed.

Also, the expression "first part of the digestive tract" means the organs downstream of the esophagus and upstream of the intestine; in particular, for monogastric animals it refers to the stomach, and for ruminants it refers to the group made up of the reticulum, rumen, omasum and abomasum.

Moreover, the terms "pH-sensitive polymers" or "polymers sensitive to the pH" refer to natural, partially natural, or synthetic polymers that contain acidic or basic functional groups. Such polymers behave like an acid or like a base according to the pH of the medium in which they are located and they can be used to prepare systems in which the active ingredient is released by taking advantage of the solubilization of those polymers which occurs, according to the pH values, in different segments of the gastrointestinal route. Examples of pH-sensitive polymers are chitosan, copolymers of vinylpiridine and styrene, polymethylmethacrylate (PMMA), polyhydroxyethyl methacrylate (PHEMA), and ethyl cellulose.

Finally, the expression "coating" or "coating of the core" here means the portion of the system according to the invention which consists substantially of one or more lipophilic substances, or one or more pH- sensitive polymers, or a mixture of one or more lipophilic substances and one or more pH-sensitive polymers, which is in direct contact with the core that comprises the active ingredients.

Systems that comprise a core that comprises the active ingredients and a coating that has the function of protecting the core from the degradation that can occur in the first part of the digestive tract are known in the state of the art. The functionality of a controlled release system becomes greater the more fully the surface of the core and the surface of the coating adhere to each other, creating a stable and cohesive interface region. By contrast, poor adhesion generates lack of uniformity and can cause microfractures of the coating, with consequent release (and therefore degradation) of the active ingredients in the first part of the digestive tract. This situation frequently arises if the core and the coating are poorly compatible in chemical/physical terms, for example if the core is hydrophilic and the coating is formed from hydrophobic substances.

It has now been found that maltodextrins derived from the starch of plants that belong to the Leguminosae family, thanks to the chemical and physical properties described earlier, are capable of favoring the adhesion between hydrophilic substances and hydrophobic substances, by way of the formation of chemical bonds with both substances and of inclusion complexes. The end result is that it improves the "barrier" function of the coating and diminishes its possible fractures, thus increasing the protection and the controlled release effect of the active ingredients. Since maltodextrins, as we have said, are amphiphilic molecules, when they come into contact with the active ingredients and the excipients if any that constitute the core of the system, arrange themselves with their hydrophilic portion (which constitutes the outside of the helix) or their hydrophobic portion (which constitutes the inside of the helix) toward the core, according to whether the core contains hydrophilic substances or hydrophobic substances, respectively. The portion of maltodextrins which is not in contact with the core, on the other hand (therefore the hydrophobic portion or the hydrophilic portion, respectively) will come into contact with the coating with which the structure consisting of the core and maltodextrins will be coated. In this manner the maltodextrins, by interacting both with the molecules that constitute the core, and with the molecules of the coating, make it possible to solubilize such molecules with each other, thus creating an interface region that is stable and well emulsified.

The maltodextrins used in the system of the invention are derived from the starch of leguminous plants. In a preferred embodiment, such maltodextrins can be derived from starch extracted from the yellow pea plant. An example of such maltodextrins is the product made by Roquette and commercially available with the name Kleptose® Linecaps.

The use of maltodextrins in the systems of the invention does not entail particular limitations on the active ingredients and any excipients to be included in the core, nor does it limit the choice of the substances with which to form the coating.

Merely by way of example, some active ingredients that can be incorporated in the core of the systems of the invention are: isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, cysteine, glycine, proline, serine, tyrosine, arginine, histidine, choline, betaine, carnitine, glucosamine, B-group vitamins, and salts thereof. In a preferred embodiment, the one or more active ingredients can be present in the core in a quantity comprised between 30% and 85% by weight on the total weight of the core.

As is known in the field of pharmaceutical technology, in addition to the active ingredients the core can also comprise one or more excipients, capable of improving the resulting formulation. The excipients can be, for example, substances with aggregating properties (which make it possible to form a homogeneous core with uniform size) such as bentonite, silicates, microcrystalline cellulose, polyvinylpyrrolidone, calcium sulfate. In the system of the invention, the excipients can preferably be present in a quantity comprised between 0.1% and 40% by weight on the total weight of the core, and more preferably in a quantity comprised between 0.1% and 20% by weight on the total weight of the core. The excipients can be incorporated in the one or more active ingredients in the form of powder or in an aqueous solution. In a preferred embodiment, the same maltodextrins derived from the starch of leguminous plants can be used as an excipient, dispersed in the formulation of the core. More preferably, a quantity of such maltodextrins comprised between 0.1% and 20% by weight on the total weight of the core can be dispersed in the formulation of the core. In the present invention, the coating that coats the core substantially comprises one or more lipophilic substances, or one or more pH-sensitive polymers, or a mixture of one or more lipophilic substances and one or more pH-sensitive polymers; the expression "substantially comprises" is used to mean that the one or more lipophilic substances, or the one or more pH- sensitive polymers, or the mixture of one or more lipophilic substances and one or more pH-sensitive polymers represents the predominant component of the coating in terms of quantity. In a preferred embodiment, the coating that coats the core can consist exclusively of one or more lipophilic substances. In another preferred embodiment, the coating that coats the core can be comprised exclusively of one or more pH-sensitive polymers.

Preferably, the lipophilic substances can be lipids, waxes or mixtures thereof. More preferably, the lipophilic substances can be a mixture of glycerides and fatty acids. Even more preferably, the lipophilic substances can be a mixture of triglycerides and hydrogenated fatty acids. It is likewise preferable that the lipophilic substances present in the coating of the system have a melting point comprised between 50°C and 80°C, and more preferably comprised between 55°C and 65°C.

Preferably, the pH-sensitive polymers can be selected from the group consisting of chitosan, copolymers of vinylpiridine and styrene, polymethylmethacrylate (PMMA), polyhydroxyethyl methacrylate (PHEMA), and ethyl cellulose. Chitosan is a polymer of natural origin, ethyl cellulose is of partially natural origin (in which one or more hydroxyl groups of the cellulose are substituted with a corresponding number of ethyl ether groups), while vinylpiridine- styrene copolymers, PMMA and PHEMA are of synthetic origin. Furthermore, chitosan and PHEMA are hydrophilic, while vinylpiridine- styrene copolymers, PMMA and ethyl cellulose are hydrophobic.

The coating can also comprise one or more excipients, capable of increasing the physical capacities of resistance to an aqueous environment, of resistance to sudden thermal changes, of adhesiveness, of plasticity, and of mechanical strength. In a preferred embodiment, the same maltodextrins derived from the starch extracted from leguminous plants can be used as an excipient, dispersed in the formulation of the coating. More preferably, a quantity of such maltodextrins comprised between 1% and 3% by weight on the total weight of the coating can be dispersed in the formulation of the coating. Maltodextrins dispersed in the substances that constitute the coating can also interact with the surface of the core, at the level of the portions thereof that are chemically compatible with the substances present in the core. By dispersing maltodextrins in the coating, an enhancement is obtained of the adhesion between the core and the coating, which is due to the establishment of a "double interaction" between these two components, again mediated by maltodextrins. To understand the mechanism of such "double interaction", take the example of a hydrophilic core coated with a hydrophobic coating: on the one hand, the maltodextrins present on the surface of the core interact with the substances of the coating by way of their hydrophobic functions; on the other hand, the maltodextrins dispersed in the coating interact with the substances of the core by way of their hydrophilic functions. For a hydrophobic core covered with a hydrophilic coating, the interacting components are inverted, as is evident to a person skilled in the art.

The total quantity of the one or more lipophilic substances, or of the one or more pH-sensitive polymers, or of the mixture of one or more lipophilic substances and one or more pH-sensitive polymers that are present in the coating can be comprised between 10% and 60% by weight on the total weight of the final system, and preferably between 15% and 50% by weight on the total weight of the final system.

In another preferred embodiment, maltodextrins derived from starch extracted from the leguminous plants can be dispersed both in the formulation of the core and in the formulation of the external coating. The presence of maltodextrins in the system of the invention, at the interface between the core and the coating, increases the capacity of the coating to control the release of the active ingredients contained in the core. The presence in maltodextrins of the two functions, hydrophilic and hydrophobic, in fact makes it possible to emulsify the components of the core with those of the coating, even when they are not compatible from the solubility point of view, by keeping the surface of the core in close contact with the surface of the coating and thus preventing fractures and unevenness in the latter.

In the present invention, the maltodextrins are preferably derived from starch extracted from the yellow pea plant.

The systems of the present invention can preferably take a pharmaceutical form selected from the group constituted by tablets, capsules, granules and particles.

In an embodiment of the present invention, the system can also comprise an additional coating, which is arranged externally with respect to the coating referred to up to now and which comprises one or more pH- sensitive polymers. In such embodiment, therefore, the coating referred to up to now is located between the core and the additional coating, which in turn is in contact with the external environment.

In a preferred embodiment, the additional coating can be constituted substantially by one or more pH-sensitive polymers.

Preferably, also for the additional coating, the one or more pH- sensitive polymers can be selected from the group consisting of chitosan, copolymers of vinylpiridine and styrene, polymethylmethacrylate (PMMA), polyhydroxyethyl methacrylate (PHEMA), ethyl cellulose and mixtures thereof.

The system of the invention, described herein in various different embodiments, has applications both in the pharmaceutical field and in the food industry, for example for the oral administration of medicines, food supplements, and nutritional supplements. The system of the invention can also be used in the zootechnical/veterinary sector, for administering active ingredients to ruminant animals: the stability conferred by the presence of maltodextrins derived from the starch of leguminous plants in fact enables this system to overcome the first part of the digestive tract (even of ruminant animals) thus protecting the active ingredients contained in the core from degradation.

The use of maltodextrins in the systems of the invention does not enter into conflict in any way with conventional pharmaceutical techniques for the preparation of the systems with a coated core.

Therefore, a second aspect of the present invention relates to the preparation of the system described herein, which comprises a core and a coating and wherein, at the interface between the core and the coating, there are maltodextrins derived from the starch of leguminous plants.

A first method for preparing the system of the invention comprises the following steps:

(a) mixing one or more active ingredients, maltodextrins derived from starch extracted from leguminous plants and optionally one or more excipients, thus obtaining a core having maltodextrins on its outer surface;

(b) coating the core having maltodextrins on its outer surface, obtained in step (a), with a coating consisting substantially of one or more lipophilic substances, or one or more pH-sensitive polymers, or a mixture of one or more lipophilic substances and one or more pH-sensitive polymers, in order to obtain a system where the maltodextrins are located at the interface between the core and the coating.

The quantity of maltodextrins derived from starch extracted from leguminous plants which is mixed with the active ingredients and the excipients if any in step (a) is comprised between 1% and 50% by weight on the total weight of the resulting core-maltodextrin structure. Preferably, such quantity can be comprised between 1% and 30% by weight on the total weight of the resulting core-maltodextrin structure.

On the basis of this first method, the maltodextrins derived from the starch of leguminous plants can be added to the mixture of active ingredients and any excipients in the form of powder or in the form of aqueous solution. When an aqueous solution is used, it can comprise from 0.04 to 0.95 g/ml of maltodextrins, and preferably from 0.2 to 0.8 g/ml.

A second method for preparing the system of the invention comprises the following steps:

(a) mixing one or more active ingredients and optionally one or more excipients, thus obtaining an agglomerated core;

(b) applying maltodextrins derived from the starch extracted from leguminous plants to the agglomerated core obtained in step (a), thus obtaining a core having maltodextrins on the outer surface;

(c) coating the core having maltodextrins on the outer surface, obtained in step (b), with a coating consisting substantially of one or more lipophilic substances, or one or more pH-sensitive polymers, or a mixture of one or more lipophilic substances and one or more pH-sensitive polymers, in order to obtain a system where the maltodextrins are located at the interface between the core and the coating.

The quantity of maltodextrins derived from the starch extracted from leguminous plants which was applied on the core in step (b) is comprised between 1% and 50% by weight on the total weight of the resulting core- maltodextrin structure. Preferably, such quantity can be comprised between 1% and 30% by weight on the total weight of the resulting core- maltodextrin structure. More preferably, such quantity can be comprised between 1% and 20% by weight on the total weight of the resulting core- maltodextrin structure.

The application of maltodextrins on the agglomerated core, carried out in step (b) of this second method, can usually be done by way of nebulization on the surface of the core of an aqueous solution that comprises the maltodextrins. Alternatively, it is also possible to use any other technique commonly described in pharmaceutical technology manuals for coating solid agglomerates. The structure constituted by the core and the maltodextrins can in fact be formed by way of commonly-described techniques for preparing the cores of two-phase systems in the pharmaceutical, zootechnical and food sectors. These techniques, which use agglomeration or granulation processes of the active ingredients, can be, for example, extrusion, spheronization, fluidized-bed granulation, rotating-plate or at high speed, wet granulation, and agglomeration by way of melt extrusion. If necessary, the cores can be dried with a static or dynamic method (for example by way of a fluidized bed) before being subjected to the step of covering with the coating, as is known to a skilled person in the pharmaceutical technology sector.

The coating can be applied to the structure constituted by the core and the maltodextrins by way of conventional pharmaceutical techniques. For example, it is possible to apply the substances on the core with which it is intended to coat the core, by way of a fluidized bed, by way of spray- cooling, or with a "drum mixer coating" method (also known as "pan coating").

If the system of the invention also comprises the additional coating which comprises one or more pH-sensitive polymers, such additional coating can be applied by way of conventional methods in the pharmaceutical technology sector, which are known and commonly used in the state of the art.

Another aspect of the present invention relates to the use of the controlled release system according to the present invention, where the system is administered to animals: the system of the invention is therefore also used in the zootechnical/veterinary field. In an embodiment, the animals can preferably be mammals; more preferably, the animals can be ruminants. The system of the invention is also used in the medical sector in that it can be administered also to humans.

In light of the foregoing, in practice it has been found that the system according to the invention fully achieves the set aim in that the presence of maltodextrins derived from the starch of leguminous plants makes it possible to optimize the adhesion between the surfaces of the core and of the coating, even when the core and the coating substantially consist of substances whose compatibility from the solubility point of view is poor.

The presence of maltodextrins derived from the starch of leguminous plants in fact increases the stability of the system. In particular, as a consequence of the better adhesion between the two surfaces, the coating is more resistant in chemical/physical terms and therefore the capacity to release the active ingredients is improved.

Furthermore, the methods described herein for preparing the system of the invention require less time and are practical in operating terms, in that they are based on conventional procedures in the pharmaceutical technology sector.

The controlled release system of the invention and the methods for its preparation described herein, thus conceived, are susceptible of numerous modifications and variations, all of which are within the scope of the appended claims; moreover, all the details may be substituted by other, equivalent elements, the correspondence of which is known to the person skilled in the art.

It should be understood that the embodiments described with reference to the controlled release system described herein, containing maltodextrins derived from starch of leguminous plants at the interface between the core and the coating, should also be considered valid with reference to the methods for the preparation of such system. Similarly, the embodiments described with reference to methods for the preparation of the controlled release system according to the invention should also be considered valid with reference to such system. EXAMPLES:

Example 1 : System for the protected administration of lysine, which comprises the active ingredient and Kleptose® Linecaps maltodextrins in the core.

Prepare a 25% pbw solution of Roquette Kleptose® Linecaps at a temperature of 75°C (+/- 5°C). This solution is hot-sprayed, in a granulator, on the core to be coated for 10 minutes (+/- 2 minutes). The core thus obtained is dried in a fluidized bed dryer and subsequently the coating fat is applied by nebulization, after melting, in a pan coater at 65°C.

This system, comprising 70% lysine hydrochloride, was subjected to a "release dissolution test" according to the method described in the USP (United States Pharmacopoeia): 5 g of product was placed in 700 ml of distilled water, at a temperature of 38°C, and subjected to agitation of 100 rpm for 24 hours. The release of the active ingredient was 25% after 24 hours. Example 2: System for the protected administration of lysine, which comprises Kleptose® Linecaps maltodextrins both in the core and in the coating

Prepare a 25% pbw solution of Roquette Kleptose® Linecaps at a temperature of 75°C (+/- 5°C). This solution is hot-sprayed, in a granulator, on the core to be coated for 10 minutes (+/- 2 minutes). The core thus obtained is dried in a fluidized bed dryer and subsequently the coating fat, melted at 75 °C and to which the Roquette Kleptose® Linecaps in powder form has been added, is applied by nebulizing it in a pan coater at 65°C.

This system, comprising 70% lysine hydrochloride, was subjected to a "release dissolution test" according to the method described in the USP (United States Pharmacopoeia): 5 g of product was placed in 700 ml of distilled water, at a temperature of 38°C, and subjected to agitation of 100 rpm for 24 hours. The release of the active ingredient was 20%. Example 3 : System for the protected administration of 50% choline, which comprises Kleptose® Linecaps maltodextrins both in the core and in the coating

Mix the granular choline chloride with the Roquette Kleptose® Linecaps in powder form.

The core thus formed is coated with the coating fat, melted at 75°C and to which the Roquette Kleptose® Linecaps in powder form has been added, by nebulizing it in a pan coater at 65°C.

This system, comprising 50% choline, was subjected to a "release dissolution test" according to the method described in the USP (United States Pharmacopoeia): 5 g of product was placed in 700 ml of distilled water, at a temperature of 38°C, and subjected to agitation of 100 rpm for 24 hours. The release of the active ingredient was 25%.

Example 4: System for the protected administration of 70% methionine, which comprises Kleptose® Linecaps maltodextrins both as granulating substance and at the interface Active

99% methionine 98 kg ingredient

40% Roquette Kleptose®

Granulate core Granulating

Linecaps solution

agent: 5 kg corresponding to 2 kg of

maltodextrins

Kleptose DM (dry matter)

20% Roquette Kleptose®

Excipient: Linecaps solution

Interface 10 kg maltodextrins corresponding to 2 kg of

Kleptose DM (dry matter)

Vegetoil S (hydrogenated

Coating Fat 26.5 kg vegetable fat)

Prepare a 40% pbw solution of Roquette Kleptose® Linecaps at a temperature of 75°C (+/- 5°C). This solution is hot-sprayed on the active ingredient to be granulated, obtaining a core with a granulometry comprised between 500 and 800 microns. The core thus obtained is dried in a fluidized bed dryer. As interface, prepare a 20% pbw solution of Roquette Kleptose® Linecaps at a temperature of 75°C (+/- 5°C). In a mixer, nebulize the solution onto the granular core obtained previously, and dry in a fluidized bed dryer. Then coat with the coating fat, melted at 75°C, nebulizing this mixture in a pan coater at 65°C.

This system, comprising 70% methionine, was subjected to a "release dissolution test" according to the method described in the USP (United States Pharmacopoeia): 5 g of product was placed in 700 ml of distilled water, at a temperature of 38°C, and subjected to agitation of 100 rpm for 24 hours. The release of the active ingredient was 15%.

The disclosures in Italian Patent Application No. BO2015A000177 (102015902344011) from which this application claims priority are incorporated herein by reference.

Claims

1. An oral administration system for the controlled release of one or more active ingredients, which comprises a core that comprises said one or more active ingredients and a coating that is constituted by one or more lipophilic substances, or one or more pH-sensitive polymers, or a mixture of one or more lipophilic substances and one or more pH-sensitive polymers, said system being characterized in that maltodextrins derived from the starch of plants that belong to the Leguminosae family are located at the interface between the core and the coating.

2. The system according to claim 1, wherein the one or more lipophilic substances of the coating are selected from the group consisting of lipids, waxes and mixtures thereof.

3. The system according to claim 2, wherein the lipids are a mixture of triglycerides of hydrogenated fatty acids.

4. The system according to one or more of the preceding claims, wherein the one or more pH-sensitive polymers of the coating are selected from the group consisting of chitosan, copolymers of vinylpiridine and styrene, polymethylmethacrylate (PMMA), polyhydroxyethyl methacrylate (PHEMA), ethyl cellulose and mixtures thereof.

5. The system according to one or more of the preceding claims, wherein maltodextrins derived from the starch of plants that belong to the Leguminosae family are further dispersed in the core or in the coating or both in the core and in the coating.

6. The system according to one or more of the preceding claims, wherein the maltodextrins are derived from starch extracted from the yellow pea plant.

7. The system according to one or more of the preceding claims, wherein said system is selected from the group consisting of a tablet, a capsule, a granule and a particle.

8. The system according to one or more of the preceding claims, comprising a further coating, which comprises one or more pH-sensitive polymers.

9. A method for preparing the system according to one or more of claims from 1 to 8, which comprises the steps of:

(a) mixing one or more active ingredients, maltodextrins derived from starch extracted from leguminous plants and optionally one or more excipients, thus obtaining a core having said maltodextrins on its outer surface, wherein the quantity of maltodextrins derived from starch extracted from leguminous plants is comprised between 1% and 50% by weight on the total weight of the core-maltodextrin structure;

(b) coating the core having maltodextrins on its outer surface, obtained in step (a), with a coating consisting of one or more lipophilic substances, or one or more pH-sensitive polymers, or a mixture of one or more lipophilic substances and one or more pH-sensitive polymers, thus obtaining a system in which the maltodextrins are located at the interface between the core and the coating.

10. The method according to claim 9, wherein the quantity of maltodextrins derived from starch extracted from leguminous plants is comprised between 1% and 30% by weight on the total weight of the core- maltodextrin structure.

11. The method according to claim 9 or 10, wherein the maltodextrins derived from starch extracted from leguminous plants are in the form of powder or in an aqueous solution comprising 0.04 to 0.95 g/ml of said maltodextrins.

12. The method for preparing the system according to one or more of claims 1 to 8, comprising the steps of:

(b) applying the maltodextrins derived from the starch extracted from leguminous plants to the agglomerated core obtained in step (a), thus obtaining a core having maltodextrins on the outer surface, wherein the quantity of maltodextrins derived from the starch extracted from leguminous plants is comprised between 1% and 50% by weight on the total weight of the resulting core-maltodextrin structure;

(c) coating the core having maltodextrins on the outer surface, obtained in step (b), with a coating consisting of one or more lipophilic substances, or one or more pH-sensitive polymers, or a mixture of one or more lipophilic substances and one or more pH-sensitive polymers, thus obtaining a system in which the maltodextrins are located at the interface between the core and the coating.

13. The method according to claim 12, wherein the quantity of maltodextrins derived from the starch extracted from leguminous plants is comprised between 1% and 20% by weight on the total weight of the core- maltodextrin structure.

14. Use of the system according to one or more of claims 1 to 8, wherein administration is performed on animals, including humans.

15. The use according to claim 14, wherein said animals are ruminants.