TW201323014A - Taste masked pharmaceutical composition - Google Patents

Abstract

This application relates to taste masked multi-layered particles comprising a pharmaceutically active ingredient, comprising: (a) an inert core, (b) one or more coating layer(s) comprising the pharmaceutically active ingredient and a binder, (c) an intermediate coating layer (seal coating) free from a low molecular weight water-soluble ionic compound, comprising a water-soluble pharmaceutical film-forming compound selected from (i) HPMC and PEG or (ii) PVP and (d) an outer coating layer (final or taste masking coating) free from a low molecular weight water-soluble ionic compound comprising (i) a poly(meth)acrylate or (ii) a mixture comprising 60-90% (w/w) EC and 10-40% (w/w) HPMC, wherein the pharmaceutically active ingredient is water-soluble and comprises either at least one basic group and/or a bitter taste. Further disclosed are methods for the production of such particles and pharmaceutical compositions comprising them.

Description

Masking pharmaceutical composition

The present invention relates to the manufacture of pharmaceutical compositions, and in particular to the formulation of intermediates for the preparation of active ingredients to be incorporated into pharmaceutical compositions.

The manufacture of a pharmaceutical composition includes several aspects, one of which provides the active ingredient in a suitable form. It is desirable that the active ingredient is prepared in such a manner that the patient who ingests the pharmaceutical composition does not stop using the unpleasant taste (especially those who are accompanied by a poor taste).

This taste is particularly necessary in the field of veterinary medicine because animals are generally more sensitive to taste than humans and cannot simply be "persuaded" to swallow the compositions regardless of their unpleasant sensation. In most cases, animal pharmaceutical compositions contain specific flavoring agents (e.g., meat flavoring agents for carnivorous animals). However, such flavoring simply increases the taste of the drug itself and is used to mask the taste, but if the diseased animal can still perceive the taste of the compound, this is insufficient in many cases. Conversely, animals should be especially discouraged from the bitterness or other undesirable compounds that are intended for oral use in veterinary medicine. This severely limits the use of pharmaceutical compositions in veterinary medicines.

On the other hand, in terms of the expected activity of the compound, it is desirable to optimize the release of the active ingredient of the pharmaceutical composition in the patient. This is especially useful for oral compositions which are desired to dissolve in, for example, the stomach immediately after administration.

For each pharmaceutical composition, the problem of the proper formulation of the active ingredient must be addressed. This problem exists with all active compounds used in all types of medical treatment. When only adding flavoring is not enough to mask the bad taste of the active compound In particular, oral dosage forms require a taste mask.

In medicine, when a solid dosage form is developed, it is usually masked by applying a film coat composed of a medium-flavored polymer to the entire tablet. However, this usually does not solve the problems discussed in the text, and is particularly unsuitable for the treatment of carnivorous animals for the following reasons: film-coated lozenges are usually moderately odorous and do not attract animals and therefore are not actively taken; and such Animals (especially cats) are accustomed to bite the food several times to break it, thereby destroying the mask and releasing the drug with poor taste. For the same reason, the film-coated lozenge is not separable to optimize the individual dosage regimen. In some cases, especially when a precise dose adjustment is required (which is easier to achieve by using a liquid dosage form), the lozenge is even an inappropriate dosage form. Thus, in the case of a complete liquid pharmaceutical formulation, this problem needs to be addressed to provide an acceptable convenient dosage form with appropriate properties to ensure patient compliance.

In summary, the present invention is directed to improving the convenience of oral pharmaceutical compositions.

In principle, metabolic disorders such as diabetes can be treated by oral administration of various pharmaceutical compositions, such as those containing DPP IV-inhibitors. DPP IV inhibitors belonging to the class of xanthine derivatives are generally disclosed in WO 02/068420 A1.

Compound 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino- Piperidin-1-yl]-xanthine is clearly described in Example 1 (52) of WO 2005/085246 A1. Polymorphic forms of mono- and dihydrochloride salts and free bases and hydrochlorides are described in WO 2007/014886 A1. These applications disclose chemical compounds of this compound and its salts, hydrates and other forms.

The previously unpublished international patent application PCT/EP2011/054440 relates to a pharmaceutical composition for the treatment of metabolic disorders or metabolic diseases of carnivorous non-human animals such as dogs (Canis or Cat (Cat)) , which comprises the compound 1-[(3-cyano-pyridine-2) in the form of the free base and each of the other chemical forms including solvates, prodrugs, stereoisomers and salts (especially monohydrochloride) -yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine. These diseases are selected from the group consisting of ketoacidosis, pre-diabetes, type 1 or type 2 diabetes, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, high blood concentration fatty acids, hyperlipidemia and/or high blood glucose concentrations. , X syndrome (metabolic syndrome), atherosclerosis, pancreatic inflammation and / or adipose tissue inflammation, preferably ketoacidosis, pre-diabetes and / or type 1 or type 2 diabetes, more preferably type 2 diabetes.

This application discloses oral administration of the active ingredient. However, it does not teach the particular granulation or manufacturing technique of the active compound. Especially due to the bitter taste of the substance, it is still necessary to properly mask the taste of the compound.

Other examples of active ingredients intended for oral use are those for treating heart disease. Heart disease includes, for example, coronary heart disease, cardiomyopathy, cardiovascular disease, heart failure, hypertensive heart disease, or valvular heart disease. These different classes of heart disease are treated by therapy or combination therapy and thus using different classes of compounds. Therapy includes administration of one or more of the following examples: ACE inhibitors, beta-blockers, angiotensin II receptor antagonists, diuretics, Ca ²⁺ - sensitizers, antiarrhythmics, cardiac Glycoside or heart rate slowing drug (eg i _F -channel blocker).

In this regard, European Patent Application EP 224 794 A2 discloses many A cyclic amine derivative of the same general formula (including its chemical synthesis method), a molecule of 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-yl) )-Methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one is one of them. It is described as producing an activity that reduces the frequency of heartbeats in mice. Its enantiomer (chemical name is (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-(S)- Base)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one) has the international non-proprietary name (INN) Silo Cliodine (cliobradine). The derivatized hydrochloric acid can be named as cilostatin hydrochloride. Ciloleidine and its hydrochloride are highly water soluble.

WO 01/78699 A2 discloses that structurally diverse heart rate-lowering substances (such as calcium channel blockers, beta-blockers and i _f -channel blockers) are used in combination with cardiac active substances for treatment and even induction, as needed The use of hypertrophy associated with hypertrophy (specifically for the treatment of idiopathic hypertrophic cardiomyopathy (HCM) in humans and livestock). One of the mentioned i _f -channel blockers is cilostatin. This application discloses the provision of the active ingredient in the form of a simple mixture with other ingredients, in the form of granules, and in the form of a dragee based on the same granules coated with a mixture of talc and sugar. Also disclosed are solutions comprising the active ingredient dissolved in a liquid. However, especially cilostatin has the disadvantage of bitterness.

EP 1 362 590 A1 additionally discloses that cilostatin can be used for the treatment or prevention of heart failure. While examples of this disclosure disclose administration of the active ingredient by injection, all disclosure includes, for example, a drinking solution that is significantly easier for the patient to manipulate. EP 1762179 A1 discloses another use of heart rate-lowering substances, such as i _f -channel blockers and especially cilostatin: they can also be used to improve the diagnostic quality of ultrasound cardiography.

Other pharmaceutically active compounds which are suitable for oral administration and which require and/or desire to mask taste are known per se to those skilled in the art and are described in more detail below.

To address the problem of taste masking of active ingredients for incorporation into pharmaceutical compositions, current state of the art has developed specific techniques. These are primarily based on coating techniques that coat (ie, cover) the active ingredient by other substances, wherein the other substance is used as a physicochemical barrier against evaporation, dissolution or diffusion of the active ingredient. The coated granules are then used as a component of a complete pharmaceutical composition. The barrier function of the protective coating should continue as long as the pharmaceutical composition is stored and/or the patient can otherwise perceive the ingredient. However, it should dissolve or become permeable immediately when it is desired to become active. In practice, a multi-phase system is provided while at the same time maintaining the active ingredient in a separate phase separate from the remainder of the composition.

In this context, the current state of the art, which has been established for a long time, is to prepare particles comprising the active ingredient in sequence by a granulation step and a coating step. This can be exemplified by EP 292 840 A2: According to its Example I (page 95), the active ingredient is mixed with starch, sugar, polyvinylpyrrolidone and magnesium stearate, followed by compression of the mixture and processing into granules. These particles are then mixed with other components and compressed into tablets. The lozenge was finally described as being coated with a mixture of sugar and talc, thereby forming a so-called dragee (Example II, page 96).

EP 409 254 A1 discloses particles comprising a core and a film layer covering the core, which in particular solves the dissolution profile of the particles. The disclosed core comprises an active substance and a water swelling agent; and the film layer contains at least ethyl cellulose and a substance selected from the group consisting of ethyl cellulose, HPMC (hydroxypropyl methyl fiber) , MC (methylcellulose), L-HPC (low-substituted hydroxypropylcellulose) and PVP (polyvinylpyrrolidone). The authors describe the desire to achieve a odor time of at least 20 seconds (based on human taste). The disclosed coating layer actually allows for a cut-off time of 1 to 57 seconds.

Current state of the art also describes coatings consisting of two or more coating layers, especially double layers. For example, US Pat. No. 4,874,413 teaches coating an inert core containing an active substance, surrounding a first layer of the core and containing a biologically inert excipient or filler (clay (such as kaolin) or water soluble polymer), and surrounding the The first layer comprises a second layer of a mixture of a cationic copolymer acrylate resin and a basic compound such as calcium carbonate, aluminum hydroxide or magnesium carbonate. In addition, the teachings can be used to fix the active ingredient to the core and the acrylate resin for the second coating layer by means of a binder material such as polyvinylpyrrolidone, methylcellulose or a pharmaceutically suitable gum. It may be selected from methacrylate and neutral methacrylate copolymers. This patent case shows a mixture of kaolin clay and povidone (polyvinylpyrrolidone) as a first layer and a mixture of calcium carbonate and Eudragit E-100 copolymer methacrylate resin as the second layer. In both cases, isopropanol and acetone were used as solvents for preparing the respective coating layers and allowed to evaporate after the addition of each material.

WO 03/075895 A1, for example, discloses a solid composition for odorless veterinary, which consists of a pellet or lozenge substrate in which fine particles of a physiologically compatible medium-flavored solid carrier material are embedded. The fine particles of the carrier material have an average diameter of from 0.09 to 0.8 mm and are coated with an active material, and the active material layer is covered with a protective layer of a physiologically compatible polymer matrix. Therefore, the active ingredient is not present in the core but is present in the second The first layer of layer protection. In the particles, the outer layer achieves the same function as in the literature cited above, wherein the active material is in the core and exhibits the same disadvantages. The essence of this teaching is only the fact that the manufacturing process begins with an inert core and the active ingredient is applied to the core by a coating step.

The same disadvantages mentioned are the effect that the highly soluble compound tends to be at least partially dissolved in the coating solution during the coating step, so that a small amount of this substance is therefore also distributed in the coating layer after drying. In some cases, this may not be important. However, the animal is therefore still able to perceive extremely unpleasant substances, thereby stopping the ingestion of the preparation.

Multiple layering techniques can be used to make particles containing more than one active ingredient. EP 2 127 643 A1 discloses a granule composed of an inert core which is coated with a (first) active ingredient which is additionally coated with a release-regulating polymer and finally coated with a so-called functional ingredient. The functional ingredient can be, for example, an inhibitor of the first active ingredient and thus allows for immediate adjustment of the activity of the compound. However, in particular, the release-modulating polymer does not completely inhibit the release of the active compound, but acts as a diffusion barrier that only results in a time delayed release. These particles therefore do not address the issues discussed herein.

European Patent Application EP 551 820 A1 addresses the same problems particularly associated with complete liquid medical formulations. The teachings describe the preparation of particles comprising the active ingredient by fluidized bed granulation. In the second step, the particles are coated with a paint, which is also referred to as microencapsulation. A number of theoretically possible coating materials (especially polymers) have been disclosed. An exemplary substance is Eudragit ® NE 30 D Combined with HPMC, with MC and with triethyl citrate. However, the essence of this development lies in the fact that the active ingredient is not used in its own form (especially not as a water-soluble salt), but in its least water-soluble form (such as free acid or free base). Thus, this teaching does not encompass salts or other water soluble forms of the pharmaceutically active ingredient.

The problem of seeking appropriate taste is also addressed by WO 2006/074185 A2. This is solved by dissolving or dispersing a pH-dependent polymer and a so-called "non-plasticizing active pharmaceutical ingredient" in a solvent which itself is granulated (and thus forms a core containing the active ingredient) or used as A material that forms a coating on a solid support. The masking outer coating layer can then be applied after two routes as desired. The essence of this development lies in the effect that the pH-dependent polymer itself is used as a taste masking agent, which means that the active compound and the protective agent do not separate into two phases to form a single phase. Due to the physicochemical interaction between the compound and the polymer, this single phase is insoluble and remains intact as long as taste perception can occur. This specification clarifies that the characteristics of an effective active pharmaceutical ingredient that can be used in this technique are the fact that they are relatively non-tacky and will generally remain relatively non-tacky so that the coated solid carrier can be combined with the first taste-masking material. It works regardless of whether or not up to about 25% by weight of a conventional anti-adherent (e.g., talc or magnesium stearate) is added. Conversely, "plasticizing" active pharmaceutical ingredients cannot meet this requirement. Therefore, this teaching cannot be widely applied to all types of active ingredients.

The granules (or pellets) provided by all of these techniques are generally not themselves used as a pharmaceutical substance, but rather represent a formulation intermediate to be incorporated into a more complex pharmaceutical composition. The composition may be in the form of, for example, a solid (such as a lozenge) or a liquid (such as Suspension), another burden of the stability and/or disintegration of the granules containing material incorporated.

Wagner et al. (2000) scientific publication (title "Development of disintegrating multiple-unit tablets on a high-speed rotary tablet press", European Journal of Pharmaceutics and Biopharmaceutics, Vol. 50 , pp. 285-291) Aspect) material parameters (such as the coating polymer used, their pellet size and pellet properties, the proportion of pellets in the mixture, and the type of filler-bonding agent) and (on the other hand) mechanical parameters ( Complex interactions such as productivity and feeder type). It reveals that Avicel PH 101 is the most suitable filler-bonding agent for bulk tablets and Eudragit FS 30 D is used for the advantageous coating of granules in terms of coating elasticity and thickness. It teaches that pellets coated with Eudragit FS 30 D can withstand the stress of the tablet. However, they show disadvantages associated with the disintegration process of the tablet.

The current state of the art is not sufficient to address one of the more specific aspects of the taste. This aspect relates to the odor of a pharmaceutically active ingredient which is water-soluble (especially highly water-soluble) and which contains at least one base and/or bitter taste.

Due to the base and/or bitter taste, it is necessary to mask the olfactory and/or taste of the compound to the patient. On the other hand, the water solubility of the compound generally leads to the phenomenon that at least traces of the compound have diffused into the particles and/or the coating layer during the coating process (i.e., prior to drying of the coating layers), simply because of the The compound is at least partially dissolved by the solvent of each coating layer material during coating. Thus, although a major portion of the compound can be masked by established coating techniques, a trace amount of the compound can still be perceived by the patient, which is used for therapeutic purposes. This pharmaceutical composition for stopping the ingested animal is unacceptable.

The most notable examples of such still imperfect coating techniques are discussed below.

US 2005/287211 A1 discloses particles comprising a core of microcrystalline cellulose spheres which are coated with three layers (substance layer, intermediate layer and outer coating layer). The intermediate layer of the disclosed examples comprises povidone or hydroxypropyl methylcellulose (HPMC) as the sole polymer. The disclosed outer coating layer comprises, for example, a mixture of HPMC and ethyl cellulose or a poly(meth) acrylate. However, all of the exemplified intermediate layers additionally comprise a strongly water-soluble ionic compound, in most cases NaH ₂ PO ₄ , Na ₂ HPO ₄ , Na ₂ CO ₃ or citrate. This affects the physicochemical properties of the coatings not only during the dissolution of the particles (as addressed by the various publications) but also during the particle manufacturing process, resulting in results not being acceptable for the above needs.

WO 2009/011967 A1 discloses a granule comprising a sucrose core coated with a layer of material (non-steroidal anti-inflammatory drug), a first protective layer comprising a mixture of HPMC or HPMC and polyethylene glycol (PEG), optionally An enteric layer or intermediate coating layer (methacrylate/acrylate polymer with triethyl citrate) and an optional second protective layer comprising HPMC (such as a mixture of HPMC and PEG). In this case, one of the coating layers also contains a strong water-soluble ionic compound. As mentioned earlier, this assembly is not optimal for the manufacture of granules. Additionally, the definition of an enteric layer refers to the dissolution process under specific physiological conditions, and the invention discussed herein does not primarily address this aspect.

WO 2010/007515 A2 discloses a particle comprising a core comprising an active substance which is protected by an inner layer (inflated in the gastrointestinal tract or a dissolved polymer, such as a mixture of HPMC and PEG), an intermediate layer having a specific physiological activity (a protease inhibitor and/or an absorption enhancer embedded in a PEG-bonded polymer), an outer layer (a polymer that swells or dissolves in the gastrointestinal tract) Another outer layer having an enteric film polymer (methacrylate copolymer or cellulose acetate-phthalate), as used for the inner layer) and, if desired. In particular, by applying a protease inhibitor and/or an absorption enhancer and selecting a polymer that is resistant to dissolution in the gastrointestinal tract (second outer coating) and other polymers (inner layer) that are not resistant to dissolution in the gastrointestinal tract, the particles are The dissolution process is optimized. The invention discussed herein does not address the aspect of affecting the dissolution process and/or activity of the drug substance by the addition of specific acting proteins. Furthermore, the particle manufacturing disclosed in this application is not optimal in terms of the dissolution of the active ingredient during the manufacturing process.

WO 2008/075372 A1 discloses a granule comprising a starch-containing sugar globule core which is sequentially covered by a layer of a seal coat, a layer of material as a second coating (drug and HPMC) and a material comprising Surelease. An outer layer of RTM (ethylcellulose mixed with coconut oil) and HPMC mixed in a ratio of 6:1 (weight/weight). However, these particles do not contain other protective layers. It has also been found that storage of the active material in the intermediate layer rather than in the bottommost possible layer is disadvantageous. This affects the dissolution characteristics and manufacturing process.

Finally, the particles of WO 2008/027993 A2 consist of an inert core, a drug-containing amorphous layer (having a crystallization-inhibiting polymer (also known as a solubility-enhancing polymer) and a solubility-enhancing organic acid), a protective seal package. Coating layer (povidone) and finally "time-lapse coating" (TPR coating; water-insoluble polymer and enteric polymer). All examples reveal a plasticizer o-phthalate A coating layer is applied in addition to diethyl acid or triethyl citrate. Therefore, this particular architecture is intended to delay the release of time after the release, but is not optimized for particle manufacturing.

Therefore, there is still a need in the art for the palatability of pharmaceutical compositions especially for veterinary drugs by masking the taste of water-soluble (especially highly water-soluble) and at the same time containing at least one base and/or bitter pharmaceutically active compound. optimization. The compositions should also allow the ingredient to be released immediately in the patient's body when needed.

This requirement is particularly relevant for pharmaceutical active ingredients of DPP IV-inhibitors, i _f -channel blockers, phosphodiesterase III inhibitors, cyclooxygenase 2 inhibitors, and benzodiazepine receptor agonists. lasting.

The masking technique should allow acceptable formulation intermediates to be incorporated into oral dosage forms of pharmaceutical compositions, particularly in the field of veterinary medicines containing active ingredients of poor taste.

The masking technique should be applicable to the inclusion of the material-containing particles containing the active ingredient in the inner core and in the form of a coating layer covering the core of the inert or already coated core, the underlying layer and/or optionally containing other active ingredients. Granules of the active ingredient.

The masking techniques required should be especially useful for their highly pharmaceutically active ingredients in water and/or other solvents used in the coating layer.

This desired masking technique should be advantageously applied to both solid and non-solid (especially liquid) formulations (at least with fewer variants). The dosage form should also allow for subdividing into tablets or volume to adjust the dosage without destroying the taste of the pharmaceutically active ingredient.

The desired masking technique should advantageously be highly flexible in terms of the amount of pharmaceutically active ingredient to be incorporated into the pharmaceutical composition.

This required masking technique should advantageously be cost effective and easy to apply in standard equipment.

This problem is solved by the present invention comprising a viscous multi-layered granule comprising a pharmaceutically active ingredient comprising: a) an inert core; b) one or more coating layers comprising the pharmaceutically active ingredient and a binder; c) no low molecular weight water soluble An intermediate coating layer (sealing coating) of a ionic compound, comprising a water-soluble pharmaceutical film forming compound selected from the group consisting of: (i) hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG); (ii) poly(1-vinylpyrrolidin-2-one) (PVP); and d) an outer coating layer (final or taste-masking coating) which does not contain a low molecular weight water-soluble ionic compound, which comprises: (i) poly (meth) acrylate; or (ii) comprising 60 to 90% (w/w) ethylcellulose (EC) and 10 to 40% (w/w) hydroxypropyl methylcellulose (HPMC) a mixture; wherein the pharmaceutically active ingredient is water soluble and comprises at least one base and/or bitter taste.

In other words: the solution to the above problem lies in the assembly of well-coated drug-loaded subunits (multilayer particles or pellets). According to the present invention, The layered stepwise coated inert particles (or spherical carriers or pellets) begin to make the subunits. For this purpose, the layers are first layered one or more times by a layer comprising a particular pharmaceutically active ingredient; the drug is then coated with an intermediate coating layer (sealing coating) and an outer coating layer (final or taste-masking coating). Floor.

A second aspect of the invention provides a method of making the multilayer particles.

Another aspect of the invention provides the use of certain compounds or mixtures of compounds in the assembly of an intermediate coating (sealing coating) or outer coating (final or taste-masking) of the multilayer particles.

Other aspects of the invention provide for the use, medical use, and pharmaceutical compositions of the multi-layered particles of the invention.

These and other aspects of the invention are described herein with reference to the following drawings and examples. The illustrations and examples are intended to illustrate and not to limit the scope of the patent application.

As explained in more detail below and illustrated by the examples of the present invention, the multilayer particles of the present invention are taste-masked and at the same time they exhibit advantageous solubility characteristics. In particular, the exemplified alkaline butylated methacrylate copolymer shows an excellent outer coating layer which is insoluble in a neutral pH environment (patient's diet and oral cavity) but at acidic pH (stomach) It dissolves quickly, thereby allowing the particles to disintegrate and release the drug. They additionally provide an acceptable mouthfeel to the patient, i.e., no gritty.

Thus, the multilayer structure of the granules of the present invention allows for the formulation of palatable pharmaceutical compositions which are especially useful in veterinary medicine and which even have pharmaceutically active ingredients which would otherwise be rejected by the sensitized patient. Therefore, the acceptability and compliance of each pharmaceutical composition are improved.

The features of the multilayer particles of the invention (especially mechanical stability) additionally allow for Functional pharmaceutical compositions (in solid and complete liquid or paste form) provide precise dose adjustment.

The present invention provides the above-described taste-masking multilayer particles.

According to the present invention, "particles" are substantially solid pieces obtained by, for example, the following method; the word "pellets" can be used interchangeably with "particles". They are generally used as a formulation intermediate especially for pharmaceutical compositions, which means that they provide a pharmaceutically active ingredient in a form that can be incorporated into the final composition of the pharmaceutical composition. An integral solid preparation of such a material (e.g., a solid pharmaceutical composition); or, the particles of the invention may comprise a suspension in the form of a substantially non-solid (e.g., pasty or especially liquid) composition (especially a pharmaceutical liquid composition) Solid phase.

The particles of the present invention are "multilayered", which means that the characteristics thereof are well-designed structures in which the inert particles (or spherical carriers or pellets) are coated with one or more layers containing a specific pharmaceutically active ingredient. It is coated with an intermediate coating layer (sealing coating) and an outer coating layer (final or taste-masking coating). The details of this architecture and its available materials are explained below.

For the purposes of the present invention, "masking" means that a molecule having a poor taste is not perceived by the patient, and is not only masked by another, more pleasant taste or flavor. Particularly in terms of the natural taste of humans or animals, the "masking" of the present invention should be understood as a functional term. A statistically significant amount (more than 60%, preferably more than 70%, even more preferably more than 80) as compared to a pharmaceutical composition that is substantially masked or unmasked with a substantially equivalent pharmaceutical composition and comprising the same pharmaceutically active ingredient. %, optimally over 90% or even over 95%) The task of concealing the taste of the medicinal active ingredient is considered to be solved by the designated patient population without stopping the active ingestion of the pharmaceutical composition comprising the multi-layered granules.

The taste masking multilayer particles of the present invention are useful as pharmaceutical compositions for human medical and animal medical applications. By medical care is meant all types of treatment that can be performed by oral pharmaceutically active compounds, including prevention, immunization, and treatment.

The multilayer particles of the invention are particularly suitable and intended for use in veterinary medicine. This feature of the invention is not intended to be construed as limiting the patient population to animals. It should be understood as a quality feature. Animals (e.g., cats) are characterized by an excellent taste compared to humans, and the examples provided herein show that such preferred solutions do address even the problems associated with cats as a designated patient population. When the taste masking system is so effective that even a taste sensitive animal (such as a cat or a dog) as a patient population specifically treated with a derivative fully formulated pharmaceutical composition (up to the above predetermined percentage) does not stop actively ingesting the derivative fully formulated pharmaceutical composition. In particular, the invention encompasses multilayer particles.

The use of the multi-layered granules of the present invention for veterinary use is preferred because the need for odor of the pharmaceutically active ingredient is particularly long in this technical field. This is especially true for groups of compounds that are explicitly presented by the present invention and described in more detail below.

For the purposes of the present invention, a "pharmaceutically active ingredient" is itself a chemical or biological substance which is useful for preventing, immunizing or treating diseases of an animal or a human patient. The pharmaceutically active ingredient is usually incorporated in a chemical form that is most suitable for medical treatment, such as a solvate, salt or ester. Preferred examples of pharmaceutically active ingredients will be explained below.

From a chemical point of view, the pharmaceutically active ingredient associated with the present invention is "water" Soluble and contains at least one base and/or bitter taste."

As noted above, the invention must be authored for such highly preferred compounds: (i) perceived by the patient and (ii) dissolved in the coating material during storage of the particulate and/or derivative formulation and/or It is dissolved in the solution of the coating material during the manufacture of the particles. For example, the coating of the present invention allows for a highly complex taste mask.

Water solubility in most cases allows the water molecules to agglomerate and establish a hydration layer due to the polar group as part of the compound. The ionic compound which is quantitatively dissolved by at least one anion and at least one cation during the solvation in water is preferred.

It is preferred to have a bitter taste compound, since in particular this taste must be masked and masked by the teachings of the present invention. For example, several N-containing groups are polar or even cations and at the same time cause bitter taste.

The essence of the invention is the unique architecture of the multilayer particles comprising the inert core and coating layers described below.

According to the invention, "inert core" is a granule (or a spherical carrier or pellet). It has been found to be advantageous to use particles having a diameter of from about 50 to 300 μm, preferably with minor variations. Preferred subranges are defined below.

The material used in the inert core is chemically inert, which means that it does not react with any of the other ingredients of the multilayer particles of the present invention and in particular does not interfere with the intended pharmacological mechanism produced by the pharmaceutically active ingredients of the multilayer particles. Examples of materials for the inert core are cellulose (especially microcrystalline cellulose), starch, lactose, sugar, mannitol, or mixtures thereof.

The coating method as described below is usually opened with the material for the inert core beginning. In accordance with the present invention, it is desirable that each individual particle of the starting material be used as a single core for each of the multilayer particles of the present invention. This method is a statistical method with a Gauss distribution curve for the results of each step. This forms a statistical result and means that the layers already have an average thickness. Preferably, the multi-layered particles having more than only one single inert core particle are screened out and thus are not incorporated into the pharmaceutical composition.

Methods for the coating process (i.e., subsequent addition of layers to smaller particles) are known per se to those skilled in the art. Such methods are described, for example, in the textbook "Developing Solid Oral Dosage Forms-Pharmaceutical Theory and Practice", Chapter 34, edited by Yihong Qiu, Yisheng Chen and Geoff G. Z. Zhang; Elsevier (2009).

In addition, the apparatus used in the granulation process is known to those skilled in the art, for example, "Developing Solid Oral Dosage Forms-Pharmaceutical Theory and Practice", Chapter 34, Yihong Qiu, Yisheng Chen and Geoff GZZhang; Elsevier (2009) ).

The "one or more coating layers comprising the pharmaceutically active ingredient and the binder" laminated to the core particles according to the present invention contain a pharmaceutically active ingredient which is usually in a chemical form suitable for medical treatment. It additionally contains a binder which is intended to form the respective coating layers in a mixture and other components as needed.

Useful binder materials include, but are not limited to, tragacanth, gelatin, starch, cellulosic materials (such as methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose), alginic acid and its salts, and polyethylene. Alcohol, PVP, guar gum, polysaccharide acid, sugar, invert sugar and the like. Preferably, hydroxypropyl methylcellulose (HPMC) and/or polyvinylpyrrolidone (PVP) are used.

The material HPMC (also known as hydroxypropyl methylcellulose; the name HPMC is based on DIN EN ISO 1043-1:2002-06, E 464) is a mixed ether of cellulose with 2-hydroxypropyl and methyl. It is technically usually produced by reacting cellulose with methyl chloride and propylene oxide. It is commercially available under the trade name Pharmacoat® from, for example, the supplier Harke Pharma.

The material PVP (also known as poly(1-vinylpyrrolidin-2-one) or povidone; the name PVP according to DIN EN ISO 1043-1:2002-06) has the following structural formula and a molecular weight of 2,500 to Vinyl polymer of 750,000 g/mol (which additionally depends on the degree of polymerization): It is characterized by a K value calculated from an aqueous solution of 1% or 5% viscosity. PVP is technically usually obtained by free radical polymerization of 1-vinylpyrrolidin-2-one.

The binder can be used in an amount of up to 60% by weight/weight. It has been found that the drug layer on the pellets is advantageously composed of up to 40% (weight/weight), preferably from 5 to 20% (weight/weight) of binder. A better range is defined below. In another preferred aspect of the invention, the drug layer on the pellets is comprised of from 1 to 30% (weight/weight) of binder.

The coating material of the layer may advantageously be applied as a liquid solution or suspension of the binder material contained in the water, and the water is allowed to evaporate after the addition of the material.

Although a fluidized bed coating process is used, it is preferred to spray the liquid mixture onto the core particles. Preferably, the pharmaceutically active ingredient is included The coating layer of the binder accumulates to a thickness exceeding 20 μm (and more preferably over 30, 40, 50, 60, 70, 80 and 100 μm and optimally 50 to 100 μm). This variability allows the pharmaceutically active ingredient to be added to the extent that the active ingredient is brought to the desired concentration in the final prepared pharmaceutical composition.

This coating step can be repeated to allow the addition of a second coating layer comprising the pharmaceutically active ingredient. The material of this optional second layer can be the same as the first layer. However, in order to optimize the physicochemical parameters, variations of this composition are also suitably included in the scope of the present invention. The second layer can be added to the same or a different thickness than the first layer. In this way, a double coating layer comprising a pharmaceutically active ingredient in a total amount of more than 200 μm can be obtained. Example 1 of the present specification shows a process comprising two layers of particles, wherein each layer comprises a pharmaceutically active ingredient and a binder and has a total thickness of about 140 μm.

"Intermediate coating layer (sealing coating) comprising a water-soluble pharmaceutical film-forming compound" is to be understood as a complete coating layer surrounding/on a layer containing a pharmaceutically active ingredient, which is used for the following two purposes: (i The mechanical stability of the integral granules and in particular the integrity of the pharmaceutically active ingredient-containing layer; and (ii) the prevention of the pharmaceutically active ingredient, particularly during the manufacture of the granules and during storage of the complete multi-layered granules and the fully formulated pharmaceutical composition A barrier that dissolves within the particle. In addition to the water-soluble pharmaceutical film-forming compound, other components may be present in the coating layer as needed.

According to the invention, the coating layer is laminated to one or more coating layers comprising the pharmaceutically active ingredient and the binder. It has been found to be advantageous to coat the coating with water or an organic solvent suspension or solution, which may also be a mixture of water and, for example, ethanol.

Suitable water-soluble film-forming compounds are those which are defined as pharmaceutically acceptable compounds. From a chemical point of view, they may be referred to as hydrophilic polymers or mixtures thereof. According to the invention, the water-soluble pharmaceutical film-forming compound is especially selected from the group consisting of (i) a mixture of hydroxypropylmethylcellulose (HPMC) and polyethylene glycol (PEG) or (ii) poly(1-vinylpyrrolidine). -2-ketone) (PVP). According to another aspect of the present invention, the water-soluble pharmaceutical film forming compound is selected from, for example, HPMC, PVP, methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose or carboxymethylcellulose. Sodium or a mixture of one or more of these compounds.

This material has been discussed above as hydroxypropyl methylcellulose (HPMC).

The material polyethylene glycol (PEG) is composed of a large group of polyethers having the following structural formula and having a molecular weight of 200 to 5,000,000 g/mol (depending on the degree of polymerization): H-[-O-CH ₂ -CH ₂ -] _n - OH and the like are generally obtained by anionic polymerization of ethylene oxide (ethylene oxide) or polycondensation of 2-chloroethanol (chloroethanol). Depending on the chain length, they include a liquid to waxy overall appearance. It is soluble in water and several organic solvents. According to the invention, it is preferred to use PEG having a molecular weight of from 4,000 to 8,000 (preferably about 6,000) g/mol, which is commonly referred to as PEG 4000, PEG 8000 and PEG 6000 and the like, the name being dependent on the molecular weight. The PEG is commercially available under the trade name Carbowax Sentry® from, for example, the supplier Dow Chemicals, Schwalbach, Germany.

In a preferred mode of the invention, the coating layer material additionally comprises talc and/or magnesium stearate. In another aspect of the invention, the coating layer additionally comprises one or more of the following anti-adhesive agents: such as talc, magnesium stearate, mountain Calcium citrate, stearic acid, calcium aramate, hydrogenated castor oil or triglyceride.

The mixture for this coating layer can advantageously be added to the individual granules in the form of an aqueous solution or suspension. The use of aqueous processes is particularly advantageous in terms of cost, work safety and environmental reasons.

This material poly(1-vinylpyrrolidin-2-one) (PVP) has been described above.

According to the present invention, PVP and optionally talc are preferably added in the form of a solution contained in an organic solvent such as ethanol and/or acetone.

The thickness of the seal coat layer (c) may vary depending on the particular particles. Preferably, it accounts for 5 to 40% (weight/weight), more preferably 10 to 30% (weight/weight), even more preferably 15 to 25% (weight/weight) of the drug-laminated particles.

With reference to the following considerations, those skilled in the art can experimentally develop the desired thickness in each case: the seal coat is used as a protective coat to mechanically stabilize the intact granule and the layer containing the pharmaceutically active ingredient for later use. The coating step and the migration of the pharmaceutically active ingredient into the outer layer are prevented during application of the final coating or even during storage (see above). The seal coat is considered to be sufficiently thick when no compound is detected (or only traces) on the surface outside the particles. A suitable detection method is energy dispersive X-ray analysis (EDS). However, the final conclusion is based on a statistical analysis of the derivatized fully formulated pharmaceutical compositions performed in the above-described population of expected taste-sensitive patients.

"A coating layer comprising (i) a poly(meth)acrylate or (ii) a mixture of 60 to 90% (w/w) ethylcellulose (EC) and 10 to 40% (w/w) HPMC ( The final or taste-masking coating" is the complete coating layer surrounding/on the intermediate coating layer (sealing coating). Without wishing to be bound by this theory, it is believed that this coating is particularly responsible for the taste-masking properties of the multilayer particles of the present invention. In particular, it inhibits diffusion of the pharmaceutically active ingredient to the surface of the granule during manufacture and storage of the granule and/or derivatized pharmaceutical composition. It is additionally used for the mechanical stability of the overall granules and especially for the underlying integrity.

Poly(meth)acrylate materials suitable for the present invention are polymers derived from the polymerization of acrylates and methacrylates.

Current state of the art reveals a wide range of chemical derivatives of the polymer by adding certain side chains (R) to the backbone, ie by interacting with different methacrylates (eg, neutral ester groups (-COOCH) ₃ or -COOC ₄ H ₉ ), an anionic group (-COOH), a cationic group (-COOCH ₂ CH ₂ N(CH ₃ ) ₂ ), and a neutral ionic group (-COOCH ₂ CH ₂ N ⁺ (CH ₃ ) ₃ Cl ^- )) Derived by polymerization.

It is preferred to use a poly(meth)acrylate having a neutral or cationic group.

This material is commercially available in different physical forms such as aqueous dispersions, organic solutions, granules or powders. In terms of the coating method, it is preferred to use a powder or a solution suitable for the solvent to be used in each coating method.

Other physicochemical properties of this material can be found in the literature, such as Eudragit ® Application Guidelines, Evonik Röhm GmbH, Business Line Pharma Polymers, Darmstadt, Germany, which is also a commercial supplier of this material.

Representative of this material which can be used in the present invention is characterized by its specific solubility characteristics which are dependent on the pH of the surrounding medium and which are preferably insoluble in the neutral pH environment but soluble in acidic pH. Such available representative systems (for example):

- a cationic copolymer based on a ratio of 2:1:1 of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, preferably having from 40,000 to 50,000 (more preferably about 47,000) Molecular weight of g/mol (or as European The basic butylated methacrylate copolymer or INCI name disclosed in the European Pharmacopoeia is dimethylaminoethyl methacrylate copolymer or the IUPAC name is poly(butyl methacrylate-co- - (2-dimethyl-aminoethyl methacrylate)-co-methyl methacrylate) 1:2:1); it can be, for example, under the trade name Eudragit ® E or its powder form Eudragit ® E PO Available from Evonik Röhm GmbH, Business Line Pharma Polymers, Darmstadt, Germany.

- a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylate (trimethylammonium methacrylate methacrylate) having a quaternary ammonium group in a ratio of about 1:2:0.1 Preferably, it has a molecular weight of 30,000 to 40,000 (more preferably about 32,000) g/mol (or an ammonium methacrylate copolymer, type B, as disclosed in the European Pharmacopoeia); it can be, for example, under the trade name Eudragit ® RS or its powder form Eudragit ® RS PO was purchased from Evonik Röhm GmbH.

- a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylate (trimethylammonium methacrylate methacrylate) having a quaternary ammonium group in a ratio of about 1:2:0.2 Preferably, it has a molecular weight of 30,000 to 40,000 (more preferably about 32,000) g/mol (or an ammonium methacrylate copolymer, type A, as disclosed in the European Pharmacopoeia); it can be, for example, under the trade name Eudragit ® RL or its powder form Eudragit ® RL PO is available from Evonik Röhm GmbH.

- a copolymer based on ethyl acrylate and methyl methacrylate in a ratio of about 2:1, preferably having a molecular weight of at least 500,000 (more preferably 700,000 to 800,000, optimally about 750,000) g/mol (or 30) % polypropylene The acid ester dispersion, as disclosed in the European Pharmacopoeia; it can be purchased, for example, from Evonik Röhm GmbH under the trade name Eudragit® NE in a 30% dispersion.

In one mode of the invention, the poly(meth)acrylate component is blended with magnesium stearate, which is especially useful when the coating is applied to the individual particles using an organic solvent process. Without wishing to be bound by this theory, it is assumed that the combination of these two compounds fulfills such functions: poly(meth) acrylates as functional coatings, which in particular allow for granules (stabilized at neutral pH, at pH-dependent disintegration of disintegration in acidic pH; magnesium stearate as an anti-adhesive. Talc and/or colloidal vermiculite may be added as needed to counteract electrostatic charging. In another aspect of the invention, other anti-adhesive agents are, for example, talc, magnesium stearate, calcium behenate, stearic acid, calcium aramate, hydrogenated castor oil or triglycerides.

In another approach, the poly(meth)acrylate coating can be applied by an aqueous process. In this case, the formation comprises sodium lauryl sulfate (as a wetting agent and dispersing agent), stearic acid (as a salt forming agent and additionally for forming a colloidal solution with poly(meth)acrylate) and/or hard A total mixture of magnesium oleate (as an anti-adhesive) is preferred. Other anti-adhesive agents are, for example, talc and/or vermiculite. Moreover, the intended function of these other components is based on the best knowledge so far and is not relevant to the present disclosure. Add talc and/or colloidal vermiculite as needed to counter electrostatic charging.

Alternatively, a mixture of 60 to 90% (w/w) ethylcellulose (EC) and 10 to 40% (w/w) HPMC may be used as the material of the outer coating layer.

The material ethylcellulose (EC; name according to DIN EN ISO 1043-1: 2002-06) is a cellulose ether having an ethyl group. It is technically usually produced by reacting alkaline cellulose with ethyl chloride (which can form an EC type having a different degree of substitution). Ethylcellulose having a degree of substitution of about 1.1 to 1.4 is soluble in water; those having a higher degree of substitution are soluble in organic solvents. Commercially available EC types having a degree of substitution of from about 2.2 to 2.6 are thermoplastic and have a softening point of from about 150 to 160 °C. Commercially available EC types have different molecular weights which further affect the physicochemical properties (e.g., viscosity) of the material.

According to the present invention, an EC having a degree of polymerization having a degree of substitution of 2.2 to 2.6 and/or having a viscosity of 41 to 49 mPa 测定s (determined as a 5% solution contained in 80% toluene and 20% ethanol) is used. good. The EC is commercially available under the trade name Ethocel® Std. 451 from, for example, the supplier Dow Chemical.

This material HPMC has been described above.

In accordance with the present invention, the ratio of HPMC to EC can be varied within a specified range to achieve the desired release characteristics, particularly with reference to the following considerations. Without wishing to be bound by this theory, it is assumed that in the blend of EC and HPMC of the present invention, the HPMC first dissolves upon ingestion by the patient and thus leaves pores in the EC film. Moisture can then penetrate through the pores into the core of the pellets and thereby allow the pharmaceutically active ingredient to be released in lag time (i.e., the time required to wash the HPMC from the membrane). The EC/HPMC film composition and coating thickness (see below) can be optimized in a manner that produces a lag time that is deemed sufficient to allow the dosage form to be ingested without drug release.

For both options (poly(meth)acrylate and EC/HPMC film), the coating thickness can be varied/optimized and the coating applied to the pellets The method is to obtain the desired drug release characteristics or to make the method (ie, aqueous and organic solvent spray methods) feasible. Such variations are well known to those skilled in the art. Preferred values are disclosed in more detail below.

Furthermore, the final coating layer may advantageously comprise other materials. For example, magnesium stearate is used to resist electrostatic charging during processing. Another example is for reducing the electrostatically charged cerium oxide of the product. Other examples are talc, magnesium stearate, calcium behenate, stearic acid, calcium aramate, hydrogenated castor oil or triglycerides.

The intermediate coating layer (sealing coating) (c) and other features of the outer coating layer (final or taste-masking coating) (d) are characterized by "free of low molecular weight water-soluble ionic compounds".

Without wishing to be bound by this theory, it has been found that this feature is an important reason for the taste-masking efficiency of the granules and the derivatized pharmaceutical compositions and thus the effectiveness of the present invention. However, current state of the art teaches compounds such as NaH ₂ PO ₄ , Na ₂ HPO ₄ , Na ₂ CO ₃ or citrates, especially salts of strong acids and strong bases, which are useful as solubilizing aids for such particles and therefore It helps to administer pharmaceutical ingredients to patients. However, in the case of masking the taste of a water-soluble pharmaceutically active ingredient comprising at least one base and/or bitter taste, it has been found to be advantageous to avoid the use of such compounds.

However, it has been found to be useful as a low ionic compound such as talc, stearic acid, sodium lauryl sulfate or magnesium stearate, especially for lubricants, colorants and/or anti-adhesives and the like (especially oxides) Or a weak acid salt) is not very important for the taste masking and is therefore allowed as an optional component. This aspect will be explained in more detail below.

The choice of other compounds in layers (c) and (d) is therefore limited by their ability to dissolve in water. For the purposes of this application, it is not critical and is therefore a water-insoluble ionic compound, as long as 1 g of the compound is dissolved at a temperature of 25 ° C and an atmospheric pressure of 1013.25 hPa with not less than 100 ml of water. More preferably, they have a total of 1 g dissolved in at least 250, 500, 750, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000 and more than 20,000 ml of water under the same conditions. The solubility value of each substance.

According to the present invention, low molecular weight compounds are defined as those having a molecular weight of less than 750 Da (more preferably less than 700, 600, 500, 400, 300, 200 and 150 Da).

Preferably, the different coating materials are applied to the individual particles as a liquid solution or suspension in a suitable solvent. This solvent may be selected from (pure) water or an organic solvent.

A preferred mode of the present invention is the above-mentioned taste-masking multilayer particle of the present invention, wherein the pharmaceutically active ingredient is selected from one or more of the following compound groups: α) DPP IV inhibitor; β) i _f - channel blocker γ) phosphodiesterase III inhibitor; δ) cyclooxygenase 2 inhibitor; and/or ε) benzodiazepine receptor agonist.

Such compound groups have not previously been defined by their chemical class, but are defined by their high specificity for one or (theoretical) more than one of the five specific targets, which is sufficient High to allow the use of these compounds based on Medical treatment that specifically binds to the interaction of the target. The binding characteristics of such compounds to their specific targets are the interaction of these compounds with the three-dimensional structure of a specified region of the target protein, which is usually based primarily on ionic interactions, hydrogen bonding, and van der-Van-der- Waals) and/or hydrophilic/hydrophobic interactions. Thus, all compounds belonging to one of these groups should be considered as a group of hydrophilic/hydrophobic, ionic, etc. groups having similar stereochemistry and similar architectures disposed on the compound scaffold.

The related facts have proven to be particularly useful for pharmaceutically active ingredients which are readily soluble and/or diffusible in water or any other solvent, especially a solvent used to add a coating material to each particle.

Among such materials, the present invention can be used for those having a poor taste such as bitterness. This taste is usually due to the specific ionic groups on each compound, and on the other hand it is necessary to specifically interact with the target to produce a medical effect.

According to the present invention, "DPP IV inhibitors" are compounds which interact with and inhibit the enzyme dipeptidyl peptidase IV (DPP IV). It is believed that inhibition of DPP IV reduces GLP-1 proteolysis and thus prolongs the half-life of endogenous full-length (active) GLP-1 and thereby increases plasma concentrations of glucagon (eg, peptide 1 (GLP-1)) . Therefore, GLP-1 induces pancreatic β-cell secretion of insulin in a glucose-dependent manner. An additional advantageous feature of reducing glucagon concentration in vivo and prolonging the increase in GLP-1 elevation in the pancreatic β-cell function line. In particular, long-term enhancement of pancreatic β-cell function may be referred to as a disease-regulating effect; GLP-1 agonism maintains the number of β-cells by increasing cell proliferation and reducing apoptosis, and these effects may be referred to as β-cell regeneration effects. this invention Other effects of elevated GLP-1 include slowing gastric movement and inducing satiety.

In conclusion, DPP IV inhibitors can be used to treat metabolic or metabolic diseases (eg ketoacidosis, pre-diabetes, type 1 or type 2 diabetes, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, high blood concentration fatty acids) , hyperlipidemia and / or high blood concentration of glycerol, X syndrome (metabolic syndrome), atherosclerosis, pancreatic inflammation and / or adipose tissue inflammation), especially for the treatment of type 1 or type 2 diabetes (even better type 2) diabetes).

Suitable compounds are disclosed in WO 2005/085246 A1, in particular in the patent EP 1758905 B1.

The experimental part of the present application includes a DPP IV inhibitor (i.e., 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2) by amaranth. -butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride, which is particularly preferred herein for the treatment of metabolic diseases (especially An example of a compound of type 2 diabetes).

Such multi-layered particles can be used to treat metabolic disorders, particularly type 2 diabetes, for example by incorporation into various medical formulations.

According to the present invention, "i _f -channel blockers" are compounds which interact with and inhibit the i _f -channel. It is believed that it can be used to treat myocardial disease associated with hypertrophy and even induce its degradation, specifically for the treatment of idiopathic hypertrophic cardiomyopathy (HCM) in humans and livestock.

Useful compounds are disclosed in EP 065229 B1 (especially zatebradine (see below) and US 3708485 (especially alinidine (see below)).

A highly suitable and excellent compound is disclosed in EP 224 794 B1, wherein a preferred i _f -channel blocker is also useful for the treatment or prevention of heart failure (+)-3-[(N-(2-( 3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetra Hydrogen-2H-3-benzoazepin-2-one. It has an international non-proprietary name (INN) cilobradine. Its hydrochloride form is known as cilostatin hydrochloride.

The experimental part of the present application includes an example of a taste masking of a compound for treating heart disease in this group of compounds; one of the chemical classes of the cyclic amine derivative (ie, bitter siroliide (or the corresponding hydrochloride form)) representative. It can be used in particular in this taste-masking form for human and animal therapy, for example by incorporation into various medical formulations for the treatment of heart disease.

According to the present invention, "phosphodiesterase III inhibitor" is a compound which interacts with and inhibits phosphodiesterase III (PDE 3). Without wishing to be bound by this theory, it is believed that inhibition of PDE 3 causes peripheral vasodilation, which results in a decrease in blood pressure and translates into less pre-cardiac load and post-load and thus reduces the workload of the failing heart.

Useful compounds are disclosed in WO 2005/084647 A1 and in particular in the patent application EP 008391 B1.

A notable example of one of these compounds is (RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydroanthracene. Azin-3(2H)-one, which is also known as INN pimobendan and is described, for example, in EP 008391 B1 and WO 2005/084647 A1. Pimobenzene is known and used as a cardiotonic, hypotensive, and antithrombotic compound, and is also used as a sensitizer and enhances the binding efficiency of myocardial fibrils to existing calcium ions without increasing the oxygen and energy expenditure. Shrinkage affecting agent. According to the invention, this activity is also due to the name A molecule of a phosphodiesterase III inhibitor.

In particular, phosphodiesterase III inhibitors (especially pimobendan) in the form of a taste mask of the invention can be used in human and animal therapy, for example by incorporation for the treatment of the above mentioned diseases (especially heart disease (especially congestive heart) Depletion)) in each medical formulation.

According to the present invention, "cyclooxygenase 2 inhibitor" is a compound which interacts with and inhibits cyclooxygenase 2 (COX-2), in particular, selectively inhibits COX-2 but not COX-1. By. The cyclooxygenase system is responsible for the conversion of arachidonic acid to the enzyme of prostaglandin H2, which is the first step in the synthesis of prostaglandins, which are inflammatory mediators. Without wishing to be bound by this theory, it is believed that this specific inhibition results in an anti-inflammatory effect associated with analgesic and antipyretic effects.

Useful compounds are disclosed in EP 002482 B1. A significant example of one of these compounds is 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1, 1-dioxide (also known as INN meloxicam), which is a non-steroidal compound.

In particular, the cyclooxygenase 2 inhibitors of the present invention in the form of a masking form (especially, the company) can be used for human and animal therapy, for example, by incorporation as an analgesic and/or antipyretic for the treatment of inflammatory diseases (including Various medical formulations of osteoarthritis-related inflammation or (other) rheumatic diseases.

According to the present invention, "benzodiazepine receptor agonists" are compounds which interact with and bind to a benzodiazepine receptor (especially without subtype selectivity). Without wishing to be bound by this theory, it is believed that a low affinity partial agonist of a benzodiazepine receptor that does not have subtype selectivity may Effective treatment of epilepsy (especially idiopathic epilepsy) and / or behavioral abnormalities (especially anxiety).

A number of suitable compounds are disclosed in WO 97/09314 A1 and WO 2005/004867 A2, for example the compound 1-(4-chlorophenyl)-4-piperidinoimidazolidin-2-one. Preferred compounds which can be used for this purpose are 1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazole-2 as disclosed in WO 2004/032938 A1. a ketone, which has been referred to as INN ipitotoin.

In particular, the benzodiazepine receptor agonist (especially iliptoxin) in the form of a masking form of the invention can be used in human and animal therapy, for example by incorporation for the treatment of central nervous system disorders (especially epilepsy, special In each medical formulation of epilepsy and/or anxiety.

The pharmaceutically active ingredient is usually incorporated in a chemical form that is most suitable for medical treatment, such as solvates, salts or esters. It is most preferably in the form of a salt and the corresponding hydrochloride salt in such a form, for example the following molecule: 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2- Butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine and the corresponding monohydrochloride (representative of DPP IV inhibitor); and (+)- 3-[(N-(2-(3,4-Dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy Base-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and/or the corresponding hydrochloride salt (represented by i _f -channel blockers).

A preferred mode of the present invention is the above-described taste-masking multilayer particle of the present invention, which additionally comprises between the inert core and the coating layers (b) to (d) and/or at the coating layer (d) One or more other layers on.

For the purposes of this application, the other layers may be coating layers (ie, forming a complete coating or closure film surrounding the underlying particles), or may be located only in other coating layers. Other material layers between or above.

For example, one of the coating layers disclosed herein may be coated more than once and thus constitute the subject of this aspect of the invention. Additionally, a protective layer can be obtained, for example, from current state of the art.

Alternatively, a material that does not form a closed film but still plays a beneficial role is added. Such materials may be, for example, anti-adhesives that improve the further processing of each particulate material. Such anti-adhesive agents are known per se to those skilled in the art. They may additionally be composed, for example, of pigments and/or flavoring agents which are advantageously added to the outer coating layer (final or taste-masking coating). Moreover, such materials are known per se to those skilled in the art.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the material for the inert core is cellulose (preferably microcrystalline cellulose).

As noted above, the chemically inert material for the inert core can be selected from different materials. Preferred materials are cellulose, especially microcrystalline cellulose. In particular, the material has been shown to be suitable for the further processing of the material and the physical properties of the final formulated multilayer particles. In particular, the microcrystalline cellulose imparts a final formulated multi-layered granule such that it can be incorporated into, for example, a tablet formulation and is not broken during the compression step of the tableting process.

Microcrystalline cellulose particles of the trade name Cellets® 100 are commercially available from the company Syntapharm (Harke Group), Mülheim, Germany.

In another preferred embodiment, the inert core particles are preferably selected from pharmaceutically acceptable materials that exhibit minimal or negligible expansion upon contact with water. Preferred materials are selected from the group consisting of lactose, carbohydrates, sugar alcohols (mannitol, sorbitol, maltitol), glucose, blank pellet cores, calcium phosphate, cellulose (preferably microcrystalline cellulose (MCC)), and starches. A mixture thereof, more preferably lactose, is agglomerated α-lactose-monohydrate [Ph. Eur./USP-NF/JP] having a particle size d ₅₀ of about 180 μm.

Lactose having the above characteristics (e.g., agglomerated lactose) is also suitable for the core due to its particle size, non-hygroscopicity, and the fact that it undergoes at least partial plastic deformation upon compression so that the core does not break into pieces in the tablet machine. .

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the binder for the coating layer (b) comprising the pharmaceutically active ingredient is selected from the group consisting of HPMC and PVP or a mixture thereof and other components as needed. The superior HPMC hydroxypropyl methylcellulose USP replaces type 2910 (apparent viscosity 4.8-7.2 mPas) and/or PVP K30 and other components as needed.

These materials have been described above. A preferred material for this coating layer (HPMC hydroxypropyl methylcellulose, USP Substituting Type 2910; apparent viscosity 4.8-7.2 mPas) is available from Harke Pharma GmbH, Mülheim, Germany under the trade name Pharmacoat® 606.

Further, a material PVP K30 having a molecular weight of 44 to 54 kg/mol is preferred. The PVP line is commercially available under the trade name Kollidon® 30 from, for example, the supplier BASF, Ludwigshafen, Germany.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the coating layer (b) comprises 80 to 95% (weight/weight) (preferably 82.5 to 90% (weight/weight), more preferably 84.5 to 87.5. % (w/w) of the pharmaceutically active ingredient and 5 to 20% (w/w) (preferably 10 to 17.5% (w/w), more preferably 12.5 to 15.5% (w/w) of the binder.

In particular, this ratio has shown the physical characteristics of the material during its coating and On the other hand, the stability and flexibility of the final coated granules during storage and/or tableting are advantageous. Variations within these ranges are available to those skilled in the art.

Another non-secondary mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the coating layer (b) comprises 60 to 70% (weight/weight) of the pharmaceutically active ingredient, and 25 to 35% (weight/weight) of HPMC. A binder and 0.5 to 3% (w/w) magnesium stearate.

In particular herein, magnesium stearate is a beneficial lubricant which has a beneficial effect especially on the coating process. This is evidenced by an example. Suitable magnesium stearate is, for example, Parteck ® LUB MST sold by the supplier Merck KGaA, Darmstadt, Germany.

A preferred mode of the present invention is the taste-masking multi-layered granule of the present invention, wherein the intermediate coating layer (sealing coating) (c) additionally comprises talc, preferably 10 to 30% (w/w) talc, more preferably 15 Up to 25% (w/w) talc, preferably 21 to 23% (w/w) talc.

In another preferred aspect of the invention, the intermediate coating layer (sealing coating) (c) additionally comprises preferably from 5 to 30% (weight/weight) of talc.

This applies to both options of the seal coats encompassed by the present invention.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the material (i) (HPMC and PEG) used for the intermediate coating layer (sealing coating) (c) is selected from HPMC hydroxypropyl methyl group. Cellulose USP replaces type 2910 (apparent viscosity 2.4-3.6 mPas) and/or PEG 6000.

In particular, this material has been shown to be useful for the mechanical stability and flexibility of the process itself and the derived particles. A representative example of the HPMC can be a trade name Pharmacoat ® 603 (sold by Harke Pharma GmbH, Müilheim, Germany) was purchased. This material PEG is described above.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the material (i) for the intermediate coating layer (sealing coating) (c) comprises 65 to 75% (w/w) of HPMC, 7.5. Up to 12.5% (w/w) PEG 6000 and 19 to 23% (w/w) talc.

Example 1 has proven to be particularly suitable for this mixture.

In another preferred aspect of the invention, the intermediate coating layer (sealing coating) (c) preferably comprises from 60 to 90% (w/w) HPMC, from 1 to 15% (weight/weight) PEG 6000 and 9 to 25% (w/w) talc.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the material (ii) PVP used for the intermediate coating layer (sealing coating) (c) is selected from the group consisting of PVP K 30.

These materials are all described above. Example 2 has proven to be particularly suitable for this mixture.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the material (ii) for the intermediate coating layer (sealing coating) (c) comprises 70 to 80% (w/w) of PVP and 20 Up to 25% (w/w) talc.

Example 2 has proven to be particularly suitable for this mixture.

In another preferred embodiment, the intermediate coating layer (sealing coating) (c) ((ii)) comprises 70 to 95% (weight/weight) PVP and 5 to 30% (weight/weight) talc.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the material for the outer coating layer (final or taste-masking coating) (d) (i) poly(meth)acrylic acid An ester-based basic butylated methacrylate copolymer.

As described above, several representative examples of the poly(meth)acrylate-based polymer can be used as an integral part of the coating layer other than the multilayered particles of the present invention. However, especially the basic butylated methacrylate copolymer has been shown to produce the desired solubility characteristics (i.e., high stability at about neutral pH and tend to dissolve at acidic pH). This is evidenced by Example 1 (especially for the measurements recorded in Figures 1 to 3 (i.e., for fully formulated multi-layered granules and full-size tablet containing such granules)).

As described above, the polymer may be referred to as a cationic copolymer based on a ratio of 2:1:1 of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, which preferably has Molecular weight of 40,000 to 50,000 (more preferably about 47,000) g/mol. It is preferably used in powder form for the suspension to be coated when the coating layer is formed.

This material can be purchased, for example, under the trade name Eudragit® E or its powder form Eudragit® E PO from Evonik Röhm GmbH, Business Line Pharma Polymers, Darmstadt, Germany.

In light of the above explanation and in particular as exemplified in Example 1 of the present specification, the following mode in this aspect of the invention is preferred because the derivatized particles have applicability with respect to stability, flexibility, in the coating process and (finally Most importantly) advantageous properties of the solubility characteristics and effective taste: the taste-masking multilayer particles of the present invention, wherein the material (i) for the outer coating layer (final or taste-masking coating) (d) comprises 50 to 80% ( Weight/weight) poly(meth)acrylate, 0 to 8% (w/w) sodium lauryl sulfate, 0 to 35% (w/w) stearic acid and/or 0 to 35% (weight /weight) magnesium stearate; - Poly(meth) acrylate and stearic acid in a weight ratio of 80:20 to 60:40 (more preferably 75:25 to 65:35, preferably 70:30); and/or - at least 50% (weight/weight) (based on the weight of the particles below the coating), preferably from 100 to 300% (weight/weight), more preferably from 150 to 250% (weight/weight), even more preferably from 180 to 220% ( Weight/weight), optimum coating concentration of 190 to 210% (weight/weight).

Example 1 in particular confirms the advantageous effect of the thickness of this final coating layer (based on poly(meth) acrylate).

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the material (ii) for the outer coating layer (final or taste-masking coating) (d) is selected from a viscosity range of 41 to 49 mPas ( The 5% solution in a mixture of 80% toluene and 20% ethanol and the ethoxy group content of 48.0 to 49.5%) has an EC and/or methoxy content of 28 to 30% and a hydroxypropyl content of 7 to HPMC with 12% viscosity and 4 to 6 mPas (measured as 2% aqueous solution).

Example 2 of the present specification has demonstrated the effectiveness of this alternative taste masking coating of such selected materials.

A suitable EC (ethylcellulose) for this taste-masking coating is, for example, the product Ethocel® 45 cps STD Premium sold by the supplier Dow Chemicals, Schwalbach, Germany. Suitable magnesium stearate for use in this taste-masking coating is, for example, Parteck ® LUB MST sold by the supplier Merck KGaA, Darmstadt, Germany.

A preferred mode of the invention is a taste-masking multilayer particle of the invention wherein the material (ii) for the outer coating layer (final or taste-masking coating) (d) comprises from 50 to 75% (weight/weight) EC , 15 to 40% (w/w) HPMC and 0 to 25% (w/w) magnesium stearate, preferably 50 to 60% (w/w) EC, 20 to 25% (w/w) HPMC and 17.5 to 22.5% (w/w) hard Magnesium citrate.

Examples of such coatings and preferred suspensions for coating the material (i.e., by spraying onto uncoated particles (so-called "SC pellets" according to Example 1) using a fluid bed-based method) The liquid system is provided in Table 1 below. Other experimental settings are equally preferred. It is also to be understood that each compound exerts a specific physicochemical function; such functions are assumed based on the best knowledge so far, but are not intended to limit the invention.

A preferred mode of this aspect of the invention consists of the taste-masking multi-layered particles of the present invention, wherein the material (ii) used for the outer coating layer (final or taste-masking coating) (d) constitutes at least 25% ( Weight/weight) (based on the weight of the granules below the coating), preferably 25 to 100% (weight/weight), more preferably 50 to 90% (weight/weight), even more preferably 70 to 80% (weight) / weight), the optimum coating concentration of 72.5 to 77.5% (w/w).

Representative examples having such values are described in Example 2.

A preferred mode of this aspect of the invention is the taste-masking multilayer particle of the present invention, wherein the outer coating layer (final or taste-masking coating) (d) is characterized by: in mode (i) (poly(methyl) In the acrylate), the thickness is 50 to 150 μm, preferably 60 to 140 μm, more preferably 70 to 130 μm, even more preferably 75 to 125 μm, most preferably 77 to 119 μm; or in mode (ii) (including The mixture of EC and HPMC) has a thickness of 10 to 150 μm, preferably 12 to 120 μm, more preferably 15 to 100 μm, and most preferably 20 to 50 μm. All such values should be understood as having a deviation of ±10 μm.

As described in Example 1 for the coating of mode (i) (poly(meth)acrylate), a deviation of ±10 μm can be obtained by using the aqueous coating solution and the final coating step of 200% coating concentration. The outer coat. These particles exhibit advantageous taste masking effects and advantageous solubility characteristics and are therefore preferred embodiments. Those skilled in the art can apply variations of the method (especially using organic solvents and/or different coating concentrations) to obtain the outer coating layers (final or taste-masking coatings) in (i) and (ii) (d) Other specified thickness values. These particle systems are also preferred.

As noted above, the multi-layered particles of the present invention may comprise additional layers which, in the context of the present application, may be a coating layer (ie, a complete coating or seal that surrounds the underlying particles) Closed film) or only a complete or incomplete layer of other materials located between or on other coating layers.

A preferred mode of this aspect of the invention relates to the taste masking multilayer particles of the present invention, wherein the inert core is between one of the coating layers (b) to (d) or at the coating layer (b) to One or more of the layers (d) and the coating layer (d) and/or on the coating layer (d) preferably comprise from 0.1 to 5% (weight/weight) based on the final particles More preferably, it is 0.2 to 2.5% (weight/weight), and most preferably 0.2 to 1% (weight/weight) of colloidal cerium oxide (metahydrate).

As exemplified in Example 2, it has been found to be advantageous to add the material to the particles after drying of the coating and before adding the next coating during the manufacturing process, especially as an anti-adhesive.

One preferred mode of this aspect of the invention relates to the taste masking multilayer particles of the present invention, wherein the other layers are the final outer coating on the coating layer (final or taste-masking coating) (d) and are used in this (etc.) other The material of the coating layer is selected from HPMC having a methoxy group content of 28 to 30%, a hydroxypropyl group content of 7 to 12%, and a viscosity ranging from 4 to 6 mPas (as determined by a 2% aqueous solution).

This has been found to be extremely advantageous for multi-layered particles intended to be incorporated into a complete liquid formulation, especially an oily liquid pharmaceutical composition. This other layer serves two purposes: (i) resistance to mechanical protection of other particles in the suspension and (ii) resistance to water which may tend to diffuse into the particles via an oily suspension.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein one or more of the (etc.) layer materials comprise other substances, preferably selected from one or more of the following filler materials, binders, Wetting agent, flow aid, lubrication Agents, dispersants, colorants and/or anti-adhesives: mannitol, starch, talc, titanium dioxide, sodium lauryl sulfate, sodium lauryl sulfate, stearic acid, magnesium stearate, vermiculite and medium chain three Acid glyceride.

Further, one or more of the preferred taste-receiving multi-layered particles of the present invention are one or more of the material (preferably used in one of the seal coat and/or the final coat). Other substances: flavoring agents, pigments, and substances used to reduce electrostatic charging, more preferably meat flavoring agents, pigments, and/or cerium oxide.

For example, it has been found that an anti-adhesive (preferably magnesium stearate such as Magbric Magnesium ParTeck ® LUB MST available from supplier Merck KGaA, Darmstadt, Germany) is selected as the coating layer (b). The ingredients are beneficial. The anti-adhesive material optionally incorporated may be added in the form of a suspension contained in a solvent, such as suspended in a solution/suspension for adding each coating layer during each coating step. Alternatively, the layers can be added to the dried granules in powder form after they have been established and dried.

In another/other preferred mode of the invention, the material for the intermediate coating (sealing coating) (c) additionally comprises talc and/or magnesium stearate.

In the case of an outer coating layer, it has been found to be advantageous when blending the coated poly(meth)acrylate component with magnesium stearate as an anti-adherent agent, this combination is in the form of an organic solvent method. It is especially useful when the coat is applied to the individual particles. Talc and/or colloidal vermiculite (cerium oxide) may be added as needed to counteract electrostatic charging.

In another approach, when the poly(meth)acrylate coating is applied by an aqueous method, to form sodium sulfate containing sodium (as a wetting and dispersing agent), A preferred mixture of stearic acid (as a salt former and additionally for forming a colloidal solution with poly(meth)acrylate) and/or magnesium stearate (as an anti-adhesive) is preferred. Other anti-adhesive agents are, for example, talc and/or vermiculite. Talc and/or colloidal vermiculite may be added as needed to counteract electrostatic charging.

Colorants may include, but are not limited to, titanium dioxide and dyes suitable for use in foods and natural colorants (such as grape skin extract, red beet powder, beta-carotene, annatto, carmine, turmeric, paprika, etc.). The colorant can be used in an amount of from about 0.05 to about 3.5% (weight/weight) of the total dosage form.

However, as described above, the feature "free of low molecular weight water-soluble ionic compound" is limited. As noted above, the choice of such compounds is limited by their ability to dissolve in water.

Further, a non-secondary embodiment of the present invention relates to the taste-masking multilayer particle of the present invention, wherein: - the inert core has a characteristic diameter of 50 to 300 μm, preferably 75 to 250 μm, more preferably 100 to 200 μm; Wherein the final coated granules are characterized by a total diameter of from 80 to 800 μm, preferably from 90 to 600 μm, more preferably from 100 to 400 μm; and/or - wherein the pharmaceutically active ingredient incorporated into the chemical form is the final multi-layer granule 1 to 50% (weight/weight), preferably 2 to 25% (weight/weight), more preferably 3 to 22.5% (weight/weight) and most preferably 5 to 20% (weight/weight).

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the pharmaceutically active ingredient (α) (DPP IV inhibitor) is selected from the group consisting of 1-[(3-cyano-pyridin-2-yl)methyl] 3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine or any suitable form thereof and/or Salt, preferably 1-[(3-cyanide) -pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]- Astragalus monohydrochloride.

This compound has been found to be particularly useful for the treatment of metabolic diseases via the designated target DPPIV. On the other hand, it is water soluble (especially in its salt form) and its characteristics tend to be bitter, especially rejected by animal patients. Therefore, it is necessary to mask the taste of especially this compound. As demonstrated by Example 1, the invention disclosed herein allows for effective masking of the taste of this compound to make it applicable to current types of patients.

A preferred mode of the invention comprises 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3 -(R)-Amino-piperidin-1-yl]-xanthine monohydrochloride as a pharmaceutically active ingredient of the present invention, comprising: a) an inert core comprising microcrystalline cellulose; b) Two coating layers each comprising 60 to 90% (w/w) of pharmaceutically active ingredient and 10 to 40% (w/w) of HPMC binder; c) an intermediate coating layer (sealing coating), Containing 65 to 75% (w/w) HPMC, 7.5 to 12.5% (w/w) PEG 6000 and 19 to 23% (w/w) talc; and d) outer coating (final or odor pack) a coating comprising 50 to 80% (w/w) of a basic butylated methacrylate copolymer, 5 to 8% (w/w) of sodium lauryl sulfate, 8 to 35% (weight/weight) And stearic acid and 18 to 26% (w/w) magnesium stearate, wherein the material used for the outer coating layer (d) (final or taste-masking) is 190 to 210% (weight/weight) The coating concentration.

Example 1 illustrates the multilayered particles and a method of producing the same. The method described therein is summarized in the flow chart of Table 2.

As can be seen in Table 2, the lamination of the pharmaceutically active ingredient can be divided into two steps. Regardless of the nature of the compound, this is generally preferred when a high drug loading must be achieved. This may especially be due to technical reasons (i.e., technical parameters of the fluidized bed apparatus) because each fluidized bed processing apparatus used has a specific minimum/maximum load capacity. Therefore, each process can only operate to a certain value before the maximum load capacity is reached. For example, 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amine Base-piperidin-1-yl]-xanthine monohydrochloride, which is reached when the mass of the material has increased to about 300% of the initial amount (ie, up to 3 times the weight of the initial material) Load capacity.

Each of the processed materials can also be divided into two or more sub-batches that are separately processed separately and have no significant effect on product quality. For example, the pellets produced in the first coating step (so-called IR1 pellets, according to Example 1) can be divided into sub-batch, which are then laminated by the drug until several times (in this case 3 times) The quality increase. The two or more sub-batches are then mixed and otherwise processed together or subdivided into sub-batch based on the size of the equipment selected for the next coating step.

As otherwise illustrated in Example 1, the seal coat can be applied by an aqueous process. Despite the risk of migration of the drug into the outer seal coat during the process, the resulting multi-layered particles are shown to be useful in the treatment of cats that do not stop ingesting the derivatized pharmaceutical dosage form.

Example 1 discloses a multilayer particle comprising 1-[(3-cyano-pyridin-2-yl)-methyl 3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride and base A taste-masking coating of a butylated methacrylate copolymer comprising 62.5% (w/w) of a basic butylated methacrylate copolymer (Eudragit® E PO), 6.2% by weight /wt) sodium lauryl sulfate, 9.3% (w/w) stearic acid and 21.9% (w/w) magnesium stearate, and are added as an aqueous solution to a total of about 200% solids Sediment (percentage is based on the amount of "SC pellets" starting material).

Surprisingly, it has been found that even in the case of highly water-soluble active substances, all drug layering and polymer coating steps can be carried out using aqueous and organic solvent coating methods and that the bitter-free active ingredient migrates to a critical extent and enters the outer polymer. In the layer. This was confirmed by SEM combined with x-ray/EDS (energy dispersive X-ray analysis).

Manufactured from the general procedures 1 to 4 of Example 1 containing 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8 - [3-(R)-Amino-piperidin-1-yl]-xanthine monohydrochloride as the active ingredient The total composition of the final taste-masking multilayer particles of the present invention is provided in Table 5. It represents a preferred aspect of the invention. Some of the functions that the components are most likely to have are listed therein; however, this does not limit the scope of the invention in any way.

The data of Example 1 shows that the multilayered particles coated with the basic butylated methacrylate copolymer showed a gradual delayed release at pH 6.8 (depending on the thickness of the coating) and immediate release at pH 1. Therefore, they can effectively mask the taste of the pharmaceutically active ingredient in the oral cavity (pH 6.8), and promote immediate release of the drug in the stomach (pH 1).

In particular, particles coated with a basic butylated methacrylate copolymer at a coating concentration of about 200% and/or an outer coating layer (d) thickness of 77 to 119 μm exhibit desired drug release characteristics (regardless of The solvent used in the coating method).

One preferred mode of this aspect is a taste-masking multi-layered granule as described above, wherein the pharmaceutically active ingredient in the chemically incorporated form comprises from 5 to 25% (weight/weight) of the final multi-layer granule (calculated as the free base) Preferably, it is 10 to 23% (weight/weight), more preferably 18 to 22% (weight/weight), most preferably 20 to 21% (weight/weight).

This value has been shown to be effective in terms of the efficacy of the compound and, on the other hand, the need to design a pharmaceutical composition having a concentration of the active ingredient.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the pharmaceutically active ingredient (β) (i _f -channel blocker) is selected from the group consisting of zalidine (1-(7,8-dimethoxy) Base-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one-3-yl)-3-[N-methyl-N-[(2-(3,4-) Dimethoxyphenyl)ethyl]amino]-propane), 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)piperidin-3-yl) -methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, its enantiomer cilostatin ( (+)-3-[(N-(2-(3,4-Dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8 -dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one) or allienidine (2-(N-allyl-2,6-di) Chloro-anilino)-2-imidazoline), the best cilostatin hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)) -) piperidine-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2 - ketone hydrochloride).

These compounds, especially cilostatin and cilostatin hydrochloride, have been found to be useful in the treatment of heart disease (especially for the treatment of heart failure) via a designated target (i _f -channel). On the other hand, it is water soluble (especially in its salt form) and has a bitter taste that tends to be rejected especially by animal patients. Therefore, it is necessary to mask the taste of especially this compound. As demonstrated by Example 2, the invention disclosed herein allows for effective masking of the taste of the compound and with effective solubility characteristics in the mouth or in the intestine of the patient to make it applicable to current types of patients.

A preferred mode of the invention is a taste-masking multilayer particle of the invention comprising cilostatin hydrochloride as a pharmaceutically active ingredient comprising: a) an inert core comprising microcrystalline cellulose; b) a coating layer Containing 60 to 70% (w/w) of pharmaceutically active ingredient and 25 to 35% (w/w) of HPMC binder and 0.5 to 3% (w/w) of magnesium stearate; c) intermediate coating layer (sealing coating) comprising 70 to 80% (w/w) PVP K 30, 20 to 25% (w/w) talc and 0.5 to 5% (w/w) cerium oxide; and d An outer coating (final or taste-masking) comprising 50 to 60% (w/w) EC, 20 to 25% (w/w) HPMC, 17.5 to 22.5% (w/w) a mixture of magnesium stearate and 0.5 to 3% (w/w) cerium oxide, wherein the material used for the outer coating layer (d) (final or taste-masking) is 72.5 to 77.5% (weight/weight) The coating concentration.

Example 2 illustrates the multilayered granules and a method of producing the same. The method described therein is summarized in the flow chart of Table 10.

As previously mentioned, it can usually be optimized by experimentally aqueous or organic The coating was applied by a solvent spray method. For this compound, it was found that the coating layer containing the pharmaceutically active ingredient was added as an aqueous solution and the latter two layers were added as an organic solution, wherein the solvent used in the intermediate coating step was 94.4% (v/v) acetone and A mixture of 5.6% (v/v) ethanol, the solvent used in the final coating step consisted of a 1:1 mixture (vol/vol) of methanol and dichloromethane because the drug has high solubility in water.

The thickness of the outer coating layer (final or taste-masking coating) may vary between, for example, 50-300% solid deposits (percentage based on the initial amount of each SC pellet as defined in the cited examples) to Obtain the desired dissolution behavior. In this example, a thickness sufficient to coat the final coating to about 75% (based on the initial amount of SC pellets used in the process (result of step 2)) was found.

According to the dissolution data collected in Example 2, the dissolution of the EC/HPMC-coated pellets was delayed, thereby effectively masking the taste and/or odor of the bitter-tasting active ingredient cilostatin hydrochloride. This can be confirmed by an acceptance test on an experimental cat.

Typically, EC/HPMC films exhibit sustained release behavior that is almost independent of pH. In this case, however, the product surprisingly shows a slower release at pH 6.8 (which is advantageous for the present invention) (i.e. provides an effective mask in the mouth) and a more rapid release in the acidic stomach. Without wishing to be bound by this theory, this may be explained by the lipophilic character of a particular pharmaceutically active ingredient which is slightly more lipophilic at neutral pH than at acidic pH. This is expected to result in a slower release at neutral pH with the coated coating, sufficient to apply the drug to a treating patient (especially an animal such as a cat) using each multi-layered particle.

One preferred mode of this aspect is a taste-masking multi-layered particle as described above, wherein the pharmaceutically active ingredient in the chemically incorporated form comprises from 2 to 10% by weight of the final multi-layered granule (calculated as the hydrochloride salt) Preferably, it is from 3 to 7.5% (weight/weight), more preferably from 4 to 6% (weight/weight), most preferably from 5.25 to 5.75% (weight/weight).

This value has been shown to be effective in terms of the efficacy of the pharmaceutically active ingredient and, on the other hand, the need to design a pharmaceutical composition having a concentration of the active ingredient.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the pharmaceutically active ingredient (γ) (phosphodiesterase III inhibitor) is pimoben ((RS)-6-[2-(4-A) Oxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazine-3(2H)-one).

Consistent with the above explanation, this compound can be used to treat heart disease via the designated target phosphodiesterase III. On the other hand, it is desirable to have a taste. According to the invention, this compound can now be used, inter alia, for the oral administration of particularly susceptible animals such as cats or dogs.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the pharmaceutically active ingredient (δ) (cyclooxygenase 2 inhibitor) is Meinung Xikang (4-hydroxy-2-methyl-N-(5) -Methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide).

Consistent with the above explanation, this compound is particularly useful for the treatment of inflammatory diseases via the designated target cyclooxygenase 2. On the other hand, it is desirable to have a taste. According to the invention, this compound can now be used, inter alia, for the oral administration of particularly susceptible animals such as cats or dogs.

A preferred mode of the present invention is the taste-masking multilayer particle of the present invention, wherein the pharmaceutically active ingredient (ε) (benzodiazepine receptor agonist) is selected from the group consisting of 1-(4-chlorophenyl)-4-piperidin Pyridazolidin-2-one and Ipiteptin (1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one), Preferably, it is iripyridin.

Consistent with the above explanation, the compounds of this group can be used to treat central nervous system disorders (such as epilepsy (especially idiopathic epilepsy) and/or behavioral abnormalities in humans and animal patients via the specified benzodiazepine receptors ( Especially anxiety disorder)). On the other hand, it is desirable to have a taste. According to the invention, this compound can now be used, inter alia, for the oral administration of particularly susceptible animals such as cats or dogs.

One aspect of the invention is directed to a method of making the multilayered particles of the present invention wherein the coating layers are gradually assembled from the material of the inert core and the single coating step is separated by a drying step.

As noted above, the methods used in the granulation process (i.e., subsequent addition of layers to smaller particles) are known per se to those skilled in the art. The claimed method begins with the core material and then adds each layer of material starting from the innermost layer of material. Preferably, each coating material is added in liquid form (i.e., a solution or suspension contained in a fluid carrier such as water or other suitable solvent (e.g., ethanol or acetone or a mixture thereof), and the liquid is allowed to be coated after it is applied And dry before adding the next layer. It can also be added in powder form and this is especially suitable for the final outermost layer or other intermediate layer.

For the coating of the intermediate coating layer (sealing coating) (c) and the outer coating layer (final or taste-masking coating) (d) (especially the outer coating layer), it has been found that the coating material is expected to be preferred. It is applied to each particle in the form of a liquid solution or suspension contained in a suitable solvent. The solvent may be selected from (pure) water or an organic solvent (such as acetone, A) Alcohol, ethanol or dichloromethane or a mixture thereof). While the use of water systems is cost effective, the use of organic solvents can have the advantage of a faster drying step, thereby reducing the time during which the active ingredients diffuse into the layers. Further, it is particularly preferable to select an organic solvent for a pharmaceutically active ingredient having a high dissolution rate in water. Therefore, the organic solvent further hinders the diffusion of the active material into the outer layer during the lamination step. Thus, by using an organic solvent, the migration of the active substance can be minimized and thus an extremely effective taste and/or odor masking can be ensured. Additionally, the layers formed using organic solvents may be more compact and have a generally more uniform appearance than those using water. However, such subtle differences can be utilized if it is desired to optimize the dissolution behavior of the particles relative to the barrier function.

Two examples of the present application exemplify this effect: in the case where the animal does not taste the effects of the respective active ingredients, water and an organic liquid are selected as a solvent for containing 1-[(3-cyano-pyridin-2-yl) )methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride as The outermost layer of the multi-layered particles of the active ingredient is acceptable.

For the preparation of multi-layered granules comprising the drug cilostatin hydrochloride, it has been found that the application of the outermost two layers (i.e., the seal coat and the final coat) with an organic solvent is the best solution.

Those skilled in the art can analyze this effect and modify the solvent, which may include selecting a suitable solvent mixture. For example, energy dispersive X-ray analysis (EDS) techniques can be used to analyze the extent of pharmaceutically active ingredients that may still be present in each outer coating layer. This can be applied to the final constituent particles and to monitor the manufacturing process by analyzing the samples taken during the process.

The preferred method is carried out in a fluidized bed, preferably a Wurster fluid bed coating process (Wurster process).

The fluidized bed is typically formed in a storage vessel when the solid particulate material is placed under suitable conditions to cause the mixture to behave as a fluid. This is typically accomplished by introducing a pressurized fluid or gas, such as air, through the particulate media. This results in the medium subsequently having many of the properties and characteristics of a normal fluid (e.g., the ability to flow freely under gravity or to twitch using fluid type techniques). According to the invention, the fluidized bed can be used to spray a coating suspension onto the particulate material to obtain an overall tight coating layer surrounding the individual particles.

The method itself is known to those skilled in the art and can be applied to the objects and limitations described herein.

A preferred mode of the present invention is the method of the present invention, wherein the amount of the material (i) used for the outer coating layer (final or taste-masking coating) (d) is at least 50% (weight/weight) based on The weight of the particles to be coated in this step is preferably from 100 to 300% (weight/weight), more preferably from 150 to 250% (weight/weight), even more preferably from 180 to 220% (weight/weight). , preferably 190 to 210% (weight/weight).

As demonstrated by Example 1, this mode is particularly advantageous for the addition of the above coating layer (d) (i) comprising a poly(meth)acrylate or equivalent material, preferably a basic butylated methacrylate copolymer. ) (finally or to cover the coating). It allows the resulting multilayer particles to have good stability and good dissolution characteristics.

A preferred mode of the present invention is the method of the present invention, wherein the amount of the material (ii) used for the outer coating layer (final or taste-masking coating) (d) is at least 25% (weight/weight) based on Preferably, the weight of the particles below the coating is) 25 to 100% (weight/weight), more preferably 50 to 90% (weight/weight), even more preferably 70 to 80% (weight/weight), most preferably 72.5 to 77.5% (weight/weight).

As demonstrated by Example 2, this mode is particularly advantageous for the addition of a coating layer comprising a mixture of 60-90% (w/w) ethylcellulose (EC) and 10-40% (w/w) HPMC (d). (ii) (final or taste-masking coating) and its preferred embodiments (described above).

From the foregoing examples and description, it has been discovered that one of the primary efforts of the present invention is to provide a coating material that can be used in a particular coating layer comprising particles of a particular pharmaceutically active ingredient to produce an effective odor and with advantageous solubility characteristics and mechanical characteristics. These advantageous coating materials and/or specific mixtures thereof have been developed for the intermediate coating layers (sealing coatings) of the multilayer particles and the outer coating layers (final or taste-masking coatings).

Accordingly, one aspect of the present invention relates to the use of the following materials for assembling an intermediate coating layer (sealing coating) (c) of a low molecular weight water-soluble ionic compound of the multilayer particles of the present invention: (i) comprising a hydroxypropyl group a mixture of methylcellulose (HPMC) and polyethylene glycol (PEG); or (ii) poly(1-vinylpyrrolidin-2-one) (PVP).

Multilayered granules comprising such materials for the intermediate coating layer (sealing coating) are exemplified in the examples and show a odor in particular when combined with the outer coating layer of the invention (final or scented coating).

One of the preferred uses of this aspect is that the material (i) for the intermediate coating layer (sealing coating) (c) comprises 65 to 75% (w/w) of HPMC, 7.5 to 12.5% (weight/ Weight) PEG 6000 and 19 to 23% (w/w) slip The use of stone.

Another non-sub-optimal use of this aspect is that the material (ii) for the intermediate coating layer (sealing coating) comprises 70 to 80% (weight/weight) of PVP and 20 to 25% (weight/weight). ) the use of talc.

The advantages of such uses are shown in the examples and can be understood from the above. These advantages are particularly long-lasting when combined with the use of other suitable materials for the outer coating layer of the present invention.

One of the preferred aspects of the present invention relates to the use of the following materials for assembling a coating layer (final or taste-masking coating) (d) other than a low molecular weight water-soluble ionic compound of the present invention: (i) poly (meth) acrylate; or (ii) a mixture comprising 60 to 90% (w/w) EC and 10 to 40% (w/w) hydroxypropyl methylcellulose (HPMC).

Multilayered granules comprising such materials for the outer coating layer (final or smear coating) are exemplified in the examples and show a odor in particular when combined with the intermediate coating layer (sealing coating) of the invention.

One preferred use of this aspect is that the material used to coat the outer layer (final or taste-masking coating) comprises the use of a substance selected from the group consisting of flavoring agents, pigments, and materials for reducing electrostatic charging.

These allow for the manufacture of multilayer particles of the invention having the advantages of such materials as already explained above.

One of the preferred uses of this aspect is that the amount of material (i) used for the outer coating layer (d) (the final or taste-masking coating with poly(meth)acrylate) is at least 50% (weight/ Weight) (based on the weight of the particles to be coated in this step), It is preferably from 100 to 300% (weight/weight), more preferably from 150 to 250% (weight/weight), even more preferably from 180 to 220% (weight/weight), most preferably from 190 to 210% (weight/weight).

As described above and as demonstrated in Example 1, this mode allows the resulting multilayer particles to have good stability and good dissolution characteristics.

One of the non-suboptimal uses of this aspect is the final or odor of the outer coating layer (d) (having a mixture comprising 60 to 90% (weight/weight) EC and 10 to 40% (weight/weight) HPMC. The coating material (ii) is added in an amount of at least 25% by weight (based on the weight of the particles below the coating), preferably from 25 to 100% (weight/weight), more preferably from 50 to 90. % (weight/weight), even more preferably 70 to 80% (weight/weight), preferably 72.5 to 77.5% (weight/weight).

As described above and as demonstrated in Example 2, this mode allows the resulting multilayer particles to have good stability and good dissolution characteristics.

One aspect of the present invention to provide a sample of the present invention is a multi-layer particles in the treatment of the following diseases: α) metabolic disorders (via the target DPP IV); beta]) heart (via i _f - target channel); gamma]) heart disease ( Targeted by phosphodiesterase III; δ) inflammatory disease (via cyclooxygenase 2 target); and/or ε) central nervous system disease (via benzodiazepine receptor target).

Particles including each of the pharmaceutically active ingredients are disclosed above. According to this aspect of the invention, it may itself be administered orally (i.e., without other excipients for treating a patient). For example, they can be added to food. The multi-layered particles of the present invention have made such use achievable because they are physically stable and generally quite stable so that the patient remains intact even if the patient bites the particle during, for example, food intake.

One of the preferred uses of this aspect of the invention is for the use of the animal.

For this purpose, an appropriate amount of each material can be added to the animal's food by, for example, a person caring for the animal. This is very advantageous if it is desired to use low doses of pharmaceutically active ingredients to prevent various diseases.

Preferably, the granules used in this manner comprise a suitable flavoring agent in the outer coating. For example, it has been shown that the application of a meat flavoring agent is effective in attracting the particles to the carnivorous animal.

One aspect of the present invention provides a composition comprising the multilayered particles of the present invention.

In one aspect, the invention provides a pharmaceutical composition comprising the multi-layered granule of the invention for use in a method of treating a disease: a) a metabolic disease (via a DPP IV target); a) a heart disease (via i _f - channel target); γ) heart disease (via phosphodiesterase III target); δ) inflammatory disease (via cyclooxygenase 2 target); and / or ε) central nervous system disease (via benzo Diazoxide receptor target).

In general, the multi-layered granules of the present invention can be incorporated into pharmaceutical compositions in all forms suitable for treating various conditions, preferably for oral administration. They may especially be incorporated into solid dosage forms (such as lozenges) and liquid-based dosage forms (such as oily suspensions) or pasty dosage forms. Liquid or pasty dosage forms typically provide a very flexible dosage choice by adjusting the delivery volume. Tablets comprising the multilayered particles of the present invention can be divided without damaging the protective layer, thus also providing dose adjustment (eg, by forming score lines) possibility.

It has been shown in the acceptance test that oily suspensions and lozenges containing the multi-layered granules of the invention (both seasoned) result in the desired result: they are well accepted by the patient (eg cat) and are actively taken in most cases Ingestion.

In this aspect of the invention, the multi-layered particles are preferably sized to form a mouthfeel acceptable to the patient (e.g., a cat), which means that they should not be too large as this would result in a sandy texture. Reduce patient acceptance. Particularly for use in a tablet mixture, the particles of the invention preferably have mechanical stability sufficient to resist compression and breakage or chewing of the resulting tablet. The film garment preferably has sufficient flexibility to allow for deformation during standard compression processes.

Essentially, all types of additive materials suitable for such pharmaceutical dosage forms can be combined with the multi-layered granules of the present invention to prepare the final constituent drug associated with the intended route of administration and dosage regimen for each patient population.

Preferred mode of the invention is a pharmaceutical composition of the invention in solid form, preferably from 20 to 4000 mg/unit (more preferably from 20 to 500 mg/unit, even more preferably from 30 to 400 mg/unit, most preferably 40 to 300 mg/unit capsule or lozenge.

The solid dosage form preferably comprises an excipient that will support the intended medical effect. Such other excipients are generally known to those skilled in the art. Suitable excipients are, for example, anti-adherents (used to reduce the adhesion between the powder (particles) and the surface of the tablet machine and thereby prevent sticking to the tablet press), and the binder (the solution that binds the components together) Agent or dry binder), coating (protecting other tablet ingredients from being degraded by moisture in the air, and making larger or poorly tasted tablets easier to swallow), disintegrant (allowing the tablet to be diluted) Time collapse), filling Agents, thinners, flavoring agents, colorants, glidants (to promote powder flow by reducing intergranular friction and adhesion), lubricants (to prevent agglomeration and adhesion to presses or capsule filling machines), preservatives, Adsorbents, sweeteners, etc.

Preferred carriers and/or disintegrants are selected from the group consisting of sugars and sugar alcohols (e.g., mannitol, lactose, starch, cellulose, microcrystalline cellulose, and cellulose derivatives (e.g., methylcellulose)) and the like. Group of things.

Preferred binders are selected from the group consisting of povidone (also known as povidone), methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxymethylcellulose, starch, gelatin And similar.

Preferred ingredients are one or several flow regulators selected from the group consisting, for example, of vermiculite (preferably colloidal anhydrous vermiculite), calcium citrate, magnesium ruthenate, talc, and the like.

Preferred disintegrants are selected from the group consisting of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, crosslinked polyvinylpyrrolidone, and the like.

Preferred lubricants are selected from the group consisting of magnesium stearate, calcium stearate, glyceryl behenate, polyethylene glycol, stearic acid, talc, and the like.

Preferred carriers are mannitol, starch and/or lactose. The carrier material may be composed of coarse particles or spray dried materials having a size greater than 200 μm and a size equal to or less than 200 μm.

Preferred starches are selected from the group consisting of corn (maize) starch, natural starch, gelatinized starch, partially gelatinized starch, starch powder, starch granules, chemically modified starch, and swellable physical modified starch.

As noted above, especially for use in lozenge mixtures, the particles of the present invention have been shown to generally have mechanical stability sufficient to resist compression and breakage or chewing of the resulting lozenge.

In order to obtain such features, it is preferred to incorporate the multi-layered particles of the invention having the following characteristics: - the final coated multilayer particles are from 0.08 to 0.8 mm (preferably 0.1 to 0.4 mm); - the coating is sufficiently flexible a coating which may be based on physical parameters of the polymer or by using an appropriate amount of a suitable plasticizer; and/or - using microcrystalline cellulose pellets as a core material because the pellets are compressed Will undergo plastic deformation.

In addition, it is preferred to use a mixture of press compositions of a suitable composition, i.e., preferably using a tableting excipient that undergoes plastic deformation and ensuring that the mass ratio of the coated pellets in the tablet mixture is no more than 50% (as in the examples of the present specification) Said).

Such variations are readily apparent to those skilled in the art.

It is preferred to obtain a highly loaded active ingredient (drug load) on the particles as this affects the final size of the tablet. On the other hand, an excessively high amount of multi-layered particles in the tableting mixture can result in insufficient compressibility of the mixture, which results in mechanical instability of the tablets and an increased risk of film cracking due to excessive deformation of the pellets. In addition, tablet disintegration and drug dissolution may change in an undesired manner, such as disintegration due to "sticking" of the pellets and/or drug release due to film disruption being too fast compared to the expected value.

Containing 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino- Piperidin-1-yl]-xanthine monohydrochloride as a medical activity A method of making a pharmaceutical composition of a sexual component is described in Example 1, which discloses in detail a method of preparing a multi-layered granule comprising the pharmaceutically active ingredient, which is incorporated into a lozenge formulation for treating a patient.

An example of a fully constitutive tablet base and a preferred mode for carrying out the invention are disclosed in Example 1. In addition to the drug containing the multi-layered granules, the pharmaceutical compositions shown contain other materials which are themselves known in the state of the art and can be tailored to the particular needs, their properties and their concentrations. This preferred ingredient set is intended to be used as a filler and/or a binder, a disintegrant, a flavoring agent, a pigment, a glidant, and a lubricant, respectively (as outlined in Table 8). These functions correspond to the best knowledge so far, but are not intended to limit the invention in any way.

This composition especially contains a flavoring agent for attracting the tablet to the carnivores. In particular, this ingredient can be adjusted according to the needs of the pharmacist. For example, dogs and/or cats may prefer meat; other non-carnivorous animals or humans may prefer other flavors.

As evidenced by such examples, the multi-layered granules and pharmaceutical compositions, especially the compressed lozenges comprising the multi-layered granules of the present invention, meet all of the requirements for drug loading and dissolution behavior. The aqueous coating process for the final coating, especially as described in Example 1, is surprisingly well suited for the water-soluble drug substance 1-[(3-cyano-pyridin-2-yl)methyl]-3 -Methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride.

A preferred mode of the invention is a solid pharmaceutical composition of the invention comprising a final concentration of from 0.1 to 1000 mg/unit, preferably from 2 to 50 mg/unit, even more preferably from 3 to 40 mg/unit, optimally 4 To 30 mg/unit of medicinal activity ingredient.

This has been shown to be useful for contemplated therapies (such as those obtainable by the formulations of such examples). Those skilled in the art can adjust the appropriate concentration based on the intended treatment and the patient population to be treated.

A preferred mode of the invention is a solid pharmaceutical composition of the invention in the form of a tablet, preferably a tablet having one or more score lines for segmentation.

The advantages of the tablet form have been explained above. The presence of one or more score lines on/into the tablets allows the tablets to be broken into pieces to adjust the amount of pharmaceutically active ingredient applied. This line is especially valuable when it is expected that various patient populations (such as companion animals (such as dogs) characterized by large populations of varying size).

Another preferred mode of the invention is a pharmaceutical composition of the invention in a completely liquid form.

In some cases, it may be advantageous to prepare a pharmaceutical composition in the form of a liquid formulation, as this dosage form ensures extremely accurate quantification of each drug. The multilayer particles of the present invention can be used in this form of administration.

The composition of a suitable liquid formulation is known per se to those skilled in the art. As exemplified in Example 2, it is advantageous and therefore preferred to use a mixture of the matrix triglyceride and to add hydrophilic and/or hydrophobic colloidal vermiculite to optimize the physicochemical properties of the composition.

Mixtures of hydrophilic and hydrophobic colloidal vermiculite are particularly preferred, which ensure that the proper viscosity behavior of the suspension remains nearly constant during storage. Commercially available cerium oxide (aragonite) is, for example, Aerosil ® 200 (hydrophilic) and Aerosil ® R972 (hydrophobic), both by Evonik Röhm, Darmstadt, Germany. Their respective brand names are sold.

The suspension preferably exhibits a high viscosity during storage to prevent sedimentation of the suspended multilayer particles. However, if oscillated, the viscosity of the suspension can be reduced instantaneously so that it can be easily applied via a syringe-like oral dispenser. This behavior can be achieved, for example, by a mixture of the hydrophilic and hydrophobic colloidal vermiculite mentioned.

Further preferably, the composition contains a flavoring agent to render the formulation attractive to a patient, for example, containing a meat flavoring agent to attract a carnivore (e.g., a cat).

In the case of cilostatin hydrochloride, it is preferred to suspend each of the multiple layers of the particles in the liquid composition to an extent of about 3.8% (weight/volume) to form a concentration of the pharmaceutically active ingredient of 2 mg/ml.

If such coated granules are to be incorporated into a liquid matrix, it must be ensured that the suspending medium does not interact with the blister on the pellets in a manner that will impair the desired drug release characteristics. This can be accomplished by the addition of another protective layer (as described above) to the surface of the particles and/or by the addition of other excipients to the liquid matrix, as will be described below. It is especially good to combine the teachings.

Another preferred mode of the invention is a pharmaceutical composition of the invention in a completely liquid form, which is an oily suspension, more preferably an oily suspension comprising a viscosity enhancer selected from one or more of the following: cerium oxide, Hydrophobic cerium oxide, EC (cellulose ether), poly(1-vinylpyrrolidin-2-one) (PVP), aluminum stearate, xanthan gum, carrageenan and/or starch derivatives.

To contain hydrophilic and hydrophobic colloidal cerium oxide (light weight is 0.5:1 to 50:1, more preferably 1:1 to 25:1, more preferably 2:1 to 10:1, optimal 2.25:1) These completely liquid oily pharmaceutical compositions of mixtures of up to 5:1) are especially preferred.

Those skilled in the art can vary the concentration of each cerium oxide within these ranges. The ratio and contact of the two compounds which are generally beneficial to the physicochemical behavior of the suspension (i.e., the high viscosity during storage and the reduced viscosity due to the mechanical energy generated by the oscillation) are feasible and preferred. This effect stabilizes the suspension during storage, but allows it to be applied easily by, for example, a syringe or by dropping into a food preparation, after shaking.

Another preferred mode of the invention is a pharmaceutical composition of the invention in a completely liquid form, which is an aqueous suspension, more preferably an aqueous suspension comprising a stabilizer selected from one or more of the following: cellulose ether, card Carbopol, xanthan gum, carrageenan, microcrystalline cellulose.

Such a complete liquid pharmaceutical combination comprising a pharmaceutically active ingredient having a final concentration of 0.1 to 20 mg/ml (preferably 0.5 to 5 mg/ml, more preferably 0.75 to 4 mg/ml, optimally 0.5 to 3 mg/ml) Especially good.

This has been shown to be useful for contemplated therapies (such as those obtainable by the formulations of such examples). Those skilled in the art can adjust the appropriate concentration based on the intended treatment and the patient population to be treated.

A preferred embodiment of this aspect of the invention is a pharmaceutical composition of the invention, wherein the pharmaceutically active ingredient (α) (DPP IV inhibitor) for treating a metabolic disease is selected from the group consisting of 1-[(3-cyano-pyridine) -2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine or Any suitable form thereof and/or a salt thereof is preferably 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8-[3-(R)-Amino-piperidin-1-yl]-xanthine monohydrochloride.

Consistent with the above explanation, these compounds have been shown to be highly suitable for the treatment of metabolic diseases (diabetes, especially type 2 diabetes) in human and animal patients and are The specific dosage range obtained by the present invention is formulated with an intermediate (i.e., by the multilayer particles of the present invention).

The following modes are preferred in this aspect of the invention: - for the treatment of animals (preferably mammals, more preferably carnivorous mammals, best cats (cats)) a composition; - such a pharmaceutical composition for treating diabetes, preferably type 2 diabetes; - a pharmaceutical composition of this aspect in solid form, comprising 2 to 50 mg/unit, more preferably 3 to 40 Mg/unit, even better 4 to 30 mg/unit.

An equally preferred embodiment of this aspect of the invention is a pharmaceutical composition of the invention, wherein the pharmaceutical active ingredient (β) for treating heart disease (especially heart failure) via an i _f -channel target (i _f - Channel blocker) is selected from zalidine (1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3) -yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane), 3-[(N-(2-( 3,4-dimethoxy-phenyl)-ethyl)piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H -3-benzoazepin-2-one, its enantiomer cilostatin ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)) -) piperidine-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2 -ketone) or allienidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline), the best cilostatin hydrochloride ((+)- 3-[(N-(2-(3,4-Dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy Base-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride).

Consistent with the above explanation, these compounds have been shown to be highly suitable for the treatment of heart disease (especially congestive heart failure) in human and animal patients and are The present invention formulates intermediates (i.e., by the multilayer particles of the present invention) within a particular dosage range.

The following modes are preferred in this aspect of the invention: - for the treatment of animals (preferably mammals, more preferably carnivorous mammals, best cats (cats)) a composition; a pharmaceutical composition of this aspect in a completely liquid form, comprising a pharmaceutically active ingredient having a final concentration of 0.5 to 5 mg/ml, preferably 0.75 to 4 mg/ml, more preferably 0.5 to 3 mg/ml. .

An equally preferred embodiment of this aspect of the invention is a pharmaceutical composition of the invention, wherein the pharmaceutically active ingredient (γ) (phosphodiesterase III inhibitor) for treating heart disease via a phosphodiesterase III target Pimoben ((RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazine-3 (2H)-ketone).

One of the preferred modes of this aspect is for treating the medical combination of an animal, preferably a mammal, preferably a carnivorous mammal, a best dog (Canine) or a cat (Cat). Things.

An equally preferred embodiment of this aspect of the invention is a pharmaceutical composition of the invention, wherein the pharmaceutically active ingredient (δ) for treating an inflammatory disease via a cyclooxygenase 2 target (cyclooxygenase 2 inhibitor) )Mei Nong Xikang 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-di Oxide).

One of the preferred modes of this aspect is for treating the medical combination of an animal, preferably a mammal, preferably a carnivorous mammal, a best dog (Canine) or a cat (Cat). Things.

A likewise preferred embodiment of this aspect of the invention is a pharmaceutical composition of the invention, wherein the pharmaceutically active ingredient (ε) for the treatment of central nervous system diseases via a benzodiazepine receptor target (benzodiazepine) A purine receptor agonist) is selected from the group consisting of 1-(4-chlorophenyl)-4-piperidinoimidazolidin-2-one and ilipinoin (1-(4-chlorophenyl)-4-(4) -morpholinyl-2,5-dihydro-1H-imidazol-2-one), preferably irinoteux.

Consistent with the above explanation, these compounds have been shown to be highly suitable for the treatment of central nervous system diseases (such as epilepsy (especially idiopathic epilepsy) and behavioral abnormalities (especially anxiety disorders)) in humans and animals. Within the specific dosage range obtained by the multilayered particles of the invention.

The following modes are preferred in this aspect of the invention: - for the treatment of animals (preferably mammals, more preferably carnivorous mammals, best dogs (Canis)) Composition; - a pharmaceutical composition for treating epilepsy and/or anxiety (preferably epilepsy, more preferably idiopathic epilepsy); - allowing oral administration of up to 60 mg/kg/day (more Preferably, the pharmaceutical composition of this aspect is 5 to 40 mg/kg/day; - the pharmaceutical composition of this aspect is administered no more than 5 times per day, preferably once or twice per day.

Another aspect of the present invention relates to a package of a completely liquid oily pharmaceutical composition of the present invention comprising a glass vial and a pharmaceutical composition filled therein.

In particular, this form of packaging has been shown to be useful for storing the complete liquid oily pharmaceutical compositions of the present invention because they strongly inhibit the diffusion of moisture through the walls of the vials. To the substantially anhydrous pharmaceutical composition.

Also preferably, dark glass (such as green or even better brown glass) is used to further protect the components from, for example, illumination.

In terms of providing a complete therapy for a single patient or treating a patient population (eg, a breed of livestock), those skilled in the art can develop a suitable amount depending on the amount to be filled (eg, for a single use). Wait for the size of the glass vial.

One subject of the invention relates to a pharmaceutical composition comprising cilostatin ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-perpenic) Pyridin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one), Ciloleidine hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-) Methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one hydrochloride), zalidine (1-( 7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one-3-yl)-3-[N-methyl-N-[( 2-(3,4-Dimethoxyphenyl)ethyl]amino]-propane) or allienidine (2-(N-allyl-2,6-dichloro-anilino)-2 - imidazoline), and it is used to treat animals (preferably mammals, more preferably carnivorous mammals, even better cats (cats) or dogs (canis), best cats) (Cat family)) In the method of heart disease.

Consistent with the above explanation, it is preferred to use cilostatin or cilostatin hydrochloride, and it is more preferred to use cilostatin hydrochloride.

Consistent with the above explanation, the inventors have discovered that in particular, the compound in which the specified if-channel is targeted is highly advantageous for treating heart disease in such animals.

Thus, another aspect of the invention is cilostatin ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3- (S)-yl)-methyl]-(7,8-dimethoxy- 1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one), cilostatin hydrochloride ((+)-3-[(N-(2-(3,4) -dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro- 2H-3-benzoazepin-2-one hydrochloride), zalidine (1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzene) And azin-2-one-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane) or alkene Propididine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline) is used in the treatment of animals (preferably mammals, more preferably carnivorous breastfeeding) The use of animals, even better cats (cats) or dogs (Canis), best cats (felines) for heart disease.

Consistent with the above explanation, it is preferred to use cilostatin or cilostatin hydrochloride, and it is more preferred to use cilostatin hydrochloride.

According to another aspect, it is preferred to use the above-described multilayer particles to treat heart disease (especially heart failure) of a companion animal (such as a cat (cat) or a dog (Canine)), for example, borrowing Incorporated into each medical formulation.

It is preferred to use a liquid pharmaceutical composition having a final concentration of the active ingredient of 0.5 to 5 mg/ml, preferably 0.75 to 4 mg/ml, more preferably 0.5 to 3 mg/ml.

Instance Example 1

Compound formulation for treating diabetes

This example is intended for the compound 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyne-) as disclosed in, for example, PCT/EP2011/054440 A formulation of 1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride. The target is manufactured to a total weight of about 180-260 mg and has a dose of 21.68 mg of 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyne-1 -yl)-8-[3-(R)-amine Lozenges of benzyl-piperidin-1-yl]-xanthine monohydrochloride (corresponding to 20 mg of the corresponding free base).

For this purpose, a four-step process is used, which is summarized in Table 2 and will be described in more detail below.

Steps 1 and 2: Drug stratification (method of IR1 and IR2 pellets)

400 g of microcrystalline cellulose particles (100 μm Celllets®; available from Syntapharm; Harke Group, Mülheim an der Ruhr, Germany) having an average diameter of 100 μm were placed in a fluid bed apparatus (Glatt, Binzen, Germany). For the first lamination step, 600 g of 1-[(3-cyano-pyridin-2-yl)methyl]-3- which is dissolved in pure water at a concentration of about 20% (w/v) Methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine monohydrochloride and 90 g HPMC (at 20 ° C) And a 2% (w/v) aqueous solution having a viscosity of 4.8-7.2 mPa*s; a trade name of Pharmacoat® 606 from ShinEtsu, Tokyo, Japan) (ie a ratio of about 15% (weight/weight)) Spray onto the inert carrier material and subsequently dry. The resulting IR1 pellets were divided into two parts according to the geometry of the apparatus and the same treatment was carried out according to step 2.

For step 2, 400 g of IR1 pellets were placed in the same fluidized bed apparatus as before and sprayed with the same mixture of 600 g of active ingredient and 90 g of HPMC that had been used in step 1.

The total composition of the resulting IR2 pellets is shown in Table 3.

Step 3: Sealing the coating (the method of preparing SC pellets)

The result of step 2 is then covered by a protective layer ("sealing coating") to produce so-called SC pellets.

For this purpose, 600 g of IR2 pellets were placed in the same fluidized bed apparatus as used in steps 1 and 2, and 168 g of HPMC (apparent viscosity at 20 ° C and 2% (w/v) aqueous solution) a mixture of 2.4-3.6 mPa*s; sold under the trade name Pharmacoat 603® from ShinEtsu, Tokyo, Japan), 21 g PEG 6000 and 50 g talc (dispersed in pure water to produce about 11% in the spray liquid) (Weight/volume) solids were sprayed onto the IR2 pellets and subsequently dried.

The total composition of the SC pellets is shown in Table 4.

Step 4: Final coating (masking coating; final method for preparing multilayer particles), water-based coating

In substantially the same manner as in the previous step, the following mixture was added to the SC pellets: 62.5% (w/w) of the basic butylated methacrylate copolymer (specific poly(meth)acrylic acid) An ester based on a 2:1:1 ratio of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate with a molecular weight of about 47,000 g/mol of cationic copolymer) Trade name Eudragit ® E PO from Evonik Röhm, Darmstadt, Germany), 6.2% (w/w) sodium lauryl sulfate, 9.3% (w/w) stearic acid and 21.9% (w/w) hard Magnesium citrate, which is dispersed in pure water to produce about 16% (w/v) solids contained in the spray liquid.

The method is carried out in four different modes (different thicknesses of the final coating added): (a) adding 50% of the final coating material (according to placement in a fluidized bed chamber) Stop the method after the weight of the SC pellets (50% coating concentration); (b) stop the method after adding 100% of the final coating material (ibid.) (100% coating concentration); (c) The process was stopped after adding 150% of the final coating material (ibid.) (150% coating concentration); (d) the method was stopped after adding 200% of the final coating material (ibid.) (200% coating concentration).

Therefore, the final coating consists of a mixture of basic butylated methacrylate copolymer, sodium lauryl sulfate, stearic acid and magnesium stearate 62.5/6.2/9.3/21.9 (all in % (weight/weight) It consists of and has about 50, 100, 150, and 200% solid deposits (% by weight based on the "SC pellets" initial material).

The active ingredient 1-[(3-cyanide) prepared by steps 1 to 4 and after stopping the final coating method (ie, mode (d); 200% coating concentration) after adding 200% of the final coating material -pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]- The total composition of the final taste-masking multilayer particles of Astragalus monohydrochloride is provided in Table 5.

Surprisingly, it has been found that even in the case of such highly water-soluble drugs, all of the drug layering and polymer coating steps can be carried out using aqueous and organic solvent coating methods without the bitter tasting active ingredient migrating into the outer polymer layer. This is shown by SEM in combination with x-ray/EDS (energy dispersive X-ray analysis) by which chloride ions from pharmaceutically active ingredients are not detected in the final outer coating layer.

In another control experiment, the Raman spectrum of the particle fraction was determined. From this experiment, it was found that the final coating layer comprising the butylated methacrylate copolymer having a coating concentration of 200% showed a thickness of 77 to 119 μm ± 10 μm.

Modification of step 4: final coating (masking coating; final method for preparing multilayer particles), organic solvent coating method

In the modification of the aqueous coating method, in addition to the organic solvent coating method, Repeat step 4 in the same way. For this purpose, 444 g of a basic butylated methacrylate copolymer (Eudragit ® E PO) in powder form and 186 g of magnesium stearate were dissolved in isopropanol/acetone (3:2 by volume) Medium to produce about 17% (w/v) solids contained in the spray liquid. The final coating material was sprayed onto the SC pellets that had been placed in the fluidized bed apparatus as previously described.

In addition, the process is carried out in four different modes (different thicknesses of the final coating added) to form materials of comparable composition (a) to (d) (ie, the formation comprises a ratio of 70.5/29.5 (all in %) (weight/weight) of basic butylated methacrylate copolymer and magnesium stearate and having about 50, 100, 150 and 200% solid deposits (% by weight based on "SC pellets" initial The content of the material) of the final coated multilayer particles).

Final dissolution test after aqueous coating

The dissolution characteristics of the final multilayer particles produced according to the foregoing procedure (where step 4 comprises an aqueous coating process) were analyzed.

For this purpose, according to the European Pharmacopoeia (Ph. Eur.), Na ₂ HPO ₄ buffer (pH 6.8) or hydrochloric acid (pH 1) is used as a dissolution medium in the dissolution apparatus 2 to analyze each particle (prototype (a), ( b), (c) and (d), the thickness of the final coating is different). The dissolved samples were analyzed via HPLC/UV (detection of active ingredients).

The dissolution experiment was carried out at two different pH values (pH 6.8 and pH 1, respectively simulating the pH environment in the patient's mouth and stomach).

The results are provided in Table 6 below and corresponding Figure 1. Figure 1A shows the dissolution profile measured at pH 1 and Figure 1B shows the dissolution profile measured at pH 6.8. The amount of drug released has been normalized to the theoretical drug content in the sample, which allows the maximum value to be above 100%, and the maximum of each curve is comparable; It becomes apparent for the plateau that is finally reached in each curve (which can theoretically also be used to define 100% release).

Dissolution experiment after final organic solvent coating

Analysis according to the foregoing steps (where the coating method of step 4 is changed, that is, Solvent coating method) The dissolution characteristics of the final multilayer particles produced.

For this purpose, the individual particles (prototypes (a), (b), (c) and (d), which differ in thickness of the final coating), were treated as previously described. The dissolution experiment was carried out at two different pH values (pH 6.8 and pH 1).

The results are provided in Table 7 below and corresponding Figure 2. Figure 2A shows the dissolution profile measured at pH 1 and Figure 2B shows the dissolution profile measured at pH 6.8.

Dissolution experiment result

All of these data sets revealed that the multilayered particles coated with the basic butylated methacrylate copolymer showed a gradual delayed release (depending on the thickness of the coating) at pH 6.8 and immediate release at pH 1. Therefore, they can mask the taste of the pharmaceutically active ingredient in the oral cavity (pH 6.8), and promote immediate release of the drug in the stomach (pH 1).

62.5/6.2/9.3/21.9 mixture of alkaline butylated methacrylate copolymer, sodium lauryl sulfate, stearic acid and magnesium stearate by aqueous coating method (all in % (weight /weight) of the coated granules and the basic butylated methacrylate copolymer and hard fat which have been subjected to the organic solvent coating method in a ratio of 70.5/29.5 (all in % (weight/weight)) This is true for magnesium coated particles.

In particular, coated particles having a coating concentration of about 200% exhibit the desired drug release characteristics (regardless of the solvent used in the final coating process).

Lozenge formulation

According to the composition outlined in Table 8, 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8- [3-(R)-Amino-piperidin-1-yl]-xanthine monohydrochloride and a 200% coating concentration via a basic butylated methacrylate copolymer according to the aforementioned aqueous coating step The coated multilayer particles are mixed into a full lozenge formulation. The ingredients listed are purchased from commercial suppliers. Colloidal cerium oxide is available from Evonik Röhm, Darmstadt, Germany under the trade name Aerosil® 200. Crosslinked PVP is under the trade name Kollidon ® CL Available from BASF, Ludwigshafen, Germany.

All components except the multi-layered granules were sieved together, placed in a polyethylene bag and pre-mixed by hand. The multilayer particles are separately sieved. The components are then placed in a 40 1 mixing vessel and mixed to obtain a final tableting mixture. The tablet mixture was compressed into tablets containing 5, 10 and 20 mg of the pharmaceutically active ingredient by using standard equipment.

Tablet dissolution test

The tablets prepared as described above were analyzed in a dissolution experiment. This dissolution experiment was carried out at two different pH values (pH 6.8 and pH 1) as previously described for the particles. As a control, the multilayer particles comprising the 200% poly(meth)acrylate aqueous coating as described above were measured in the same manner. This measurement is intended to detect the release of the drug by HPLC/UV (relative to the active ingredient in the tablet) The percentage of the total amount is quantified.

The results are provided in Table 9 below and in corresponding Figure 3.

From these data, it was found that at pH 6.8 and pH 1, the release of the active ingredient from the tablet containing the drug-loaded pellet was slower than that of the uncompressed pellet due to the disintegration of the tablet.

Additionally, the film coat on the multi-layered particles has mechanical stability sufficient to maintain integrity throughout the tableting process and can mask the taste and/or odor of the drug in the tablet formulation.

Example 2

Compound formulation for treating heart disease

This example is intended for the compound (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl] - Liquid formulation of (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride.

For the manufacture of multilayer particles for incorporation into liquid dosage forms, a three-step process is used, which is summarized in Table 10.

Step 1: Drug lamination

As described in Example 1, microcrystalline cellulose particles having an average diameter of 100 μm were used as a starting material and laminated with an active ingredient and a binder (using water as a solvent). Will be composed of 66.6% (w/w) of pharmaceutically active ingredients, 31.7% A layer material consisting of (weight/weight) HPMC (Pharmacoat ® 606; see Example 1) and 1.7% (w/w) magnesium stearate was dispersed in pure water to produce about 19% of the liquid contained in the spray liquid. s solid type.

The resulting composition of the obtained IR pellets is provided in Table 11.

Step 2: Sealing and coating

The IR pellets prepared in step 1 were further processed in the same apparatus by spraying a seal coat onto the IR pellets. The material used for the seal coat was dispersed in a 94:6 mixture of acetone and ethanol by PVP K 30 (available from the trade name Kollidon ® 30 from the supplier BASF, Ludwigshafen, Germany) / talc in a weight percentage of 75.4:22.5 ( Quality/quality). After coating the PVP K 30 / talc mixture and drying the organic solvent, 0.5% (w/w) of highly dispersible (gelatinous) cerium oxide (Aerosil ® 200; by another step (intermediate step); Added from Evonik) to the seal wrap.

The total composition of the SC (sealed coated) pellets (cilostatin seal coated pellets) obtained in this step is provided in Table 12.

Step 3: Final coating (masking coating)

The SC pellets produced in step 2 were further processed in the same apparatus by spraying the final coating onto the SC pellets. The material used for the final taste and/or odor masking coating consists of EC/HPMC/magnesium stearate in a weight percentage of 55.2:23.8:19.8 (the ratio of EC/HPMC in the film coat is about 70:30) . For this purpose, EC, HPMC and magnesium stearate were dispersed in a 1:1 mixture (vol/vol) of methanol and dichloromethane and sprayed onto the SC pellets.

The coating was applied to a thickness of 75% (based on the initial amount of SC pellets).

As described in step 2, 0.5% of colloidal vermiculite Aerosil® 200 was added to the final product prior to sieving.

The selected EC was Ethocel ® 45 cps STD Premium (available from Dow Chemical, Schwalbach, Germany). The selected HPMC used for this layer was Methocel ® E5 Premium LV (available from Dow Chemical). The Aerosil ® 200 series is supplied by Evonik.

The overall composition of the final multilayer particles is provided in Table 13.

Table 14 discloses the inclusion of (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one hydrochloride salt-masked multilayer particles (steps 1 to 3 according to this example) The detailed overall composition of the preparation and the assumed physicochemical functions of each material.

Dissolution experiment

The dissolution characteristics of the multilayer particles produced in this example were tested in the same manner as the particles in Example 1 at two different pH values (6.8 and 1). The measured value is the total percentage of material released after each time (normalized to theoretical drug content).

The results are provided in Table 15 and shown in Figure 4.

Based on these data, the dissolution of the EC/HPMC coated pellets is delayed, thus effectively masking the bitter taste drug (+)-3-[(N-(2-(3,4-dimethoxy-phenyl)) -) piperidine-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2 - The taste and/or odor of the ketone hydrochloride. This can be confirmed by the acceptance test of the experimental cat using the derivatized fully formulated liquid composition prepared as described below.

Typically, EC/HPMC membranes exhibit sustained release behavior independent of pH. Of course In this case, however, the product surprisingly shows a slower release at pH 6.8 (which is advantageous for the present invention) (i.e. provides an effective mask in the mouth) and a more rapid release in the acidic stomach. This can be explained by the lipophilic character of the active ingredient, cilostatin HCl, which is slightly more lipophilic at neutral pH. This can result in a slower release with the coated coating.

Liquid pharmaceutical composition

To prepare a liquid pharmaceutical composition, the final multi-layered granules comprising the active ingredient cilostatin prepared in the above manner are incorporated into an oily liquid. This liquid system is represented by the weight ratio of medium chain triglyceride (Miglyol ® 821, available from Sasol, Hamburg, Germany), hydrophilic colloidal cerium oxide (Aerosil ® 200, Evonik), hydrophobic rubber as shown in Table 16. A mixture of cerium oxide (Aerosil ® R972, Evonik) and a meat flavoring agent.

The multilayered granules produced according to step 3 were suspended in the liquid composition to a level of about 3.8% (weight/volume) such that the concentration of the pharmaceutically active ingredient was 2 mg/ml (calculated as the hydrochloride salt).

It has been found that a combination of an oily solvent, especially a mixture of hydrophilic and hydrophobic vermiculite, ensures that the suspension has an appropriate viscosity behavior that remains nearly constant during storage. During storage, the suspension showed a high viscosity to prevent the suspended cilostatin pellets from settling. If oscillated, the viscosity of the suspension is reduced instantaneously so that it can be easily applied via a syringe-like oral dispenser.

Figure 1 is a dissolution curve of a multilayer particle prototype coated with an alkali-butylated methacrylate copolymer according to Example 1 at various coating concentrations (aqueous method) at pH 1 and pH 6.8 (mean ± SD) ,n 3) A: dissolution curve at pH 1 B: dissolution curve at pH 6.8.

Figure 2 is a dissolution curve of a multilayer particle prototype coated with an alkali-butylated methacrylate copolymer according to Example 1 at various coating concentrations (organic solvent method) at pH 1 and pH 6.8 (mean ± SD,n 3) A: dissolution curve at pH 1 B: dissolution curve at pH 6.8.

Figure 3 is a dissolution curve of the active ingredients of the multi-layered granules and tablets prepared according to Example 1 at pH 1 and pH 6.8 (mean ± SD, n 3) A: dissolution profile of 200% poly(meth)acrylate aqueous coated granules at pH 1 and pH 6.8 B: dissolution profile of the derived troche at pH 1 and pH 6.8.

Figure 4 is a dissolution profile of a multilayer particle prototype coated with EC/HPMC (70:30) according to Example 2 at pH 1 and pH 6.8 (mean, n 3).

Claims (74)

A taste-masking multilayer particle comprising a pharmaceutically active ingredient comprising: a) an inert core; b) one or more coating layers comprising the pharmaceutically active ingredient and a binder; c) a tundish containing no low molecular weight water-soluble ionic compound a coating layer (sealing coating) comprising a water-soluble pharmaceutical film forming compound selected from the group consisting of (i) hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG); or (ii) poly(1) -vinylpyrrolidin-2-one) (PVP); and d) an outer coating layer (final or taste-masking coating) which does not contain a low molecular weight water-soluble ionic compound, which comprises: (i) poly(meth)acrylic acid Or ester; or (ii) a mixture comprising 60-90% (w/w) ethylcellulose (EC) and 10-40% (w/w) hydroxypropyl methylcellulose (HPMC), wherein The pharmaceutically active ingredient is water soluble and comprises at least one base and/or bitter taste. The taste-masking multilayer particle of claim 1, wherein the pharmaceutically active ingredient is selected from the group consisting of: α) DPP IV inhibitor; β) i _f - channel blocker; γ) phosphodiesterase III inhibitor; δ) epoxy Synthase 2 inhibitor and / or ε) benzodiazepine receptor agonist. The taste-masking multilayer particle of claim 1 or 2, further comprising one or both of the inert core and the coating layers (b) to (d) and/or one of the coating layers (d) Multiple other layers. The taste-masking multilayer particle of claim 1 or 2, wherein the material of the inert core is cellulose, preferably microcrystalline cellulose. The taste-masking multilayer particle of claim 1 or 2, wherein the binder for the coating layer (b) containing the pharmaceutically active ingredient is selected from the group consisting of HPMC and PVP or a mixture thereof and other components as needed, preferably HPMC hydroxypropyl methylcellulose USP replaces type 2910 (apparent viscosity 4.8-7.2 mPas) and/or PVP K30 and other components as needed. The taste-masking multilayer particle of claim 1 or 2, wherein the coating layer (b) comprises 80 to 95% (weight/weight), preferably 82.5 to 90% (weight/weight), more preferably 84.5 to 87.5% ( The weight/weight of the pharmaceutically active ingredient, and 5 to 20% (w/w), preferably 10 to 17.5% (w/w), more preferably 12.5 to 15.5% (w/w) of the binder. The taste-masking multilayer particle of claim 1 or 2, wherein the coating layer (b) comprises 60 to 70% (weight/weight) of the pharmaceutically active ingredient, 25 to 35% (weight/weight) of the HPMC binder, and 0.5 Up to 3% (w/w) magnesium stearate. The taste-masking multilayer particle of claim 1 or 2, wherein the intermediate coating layer (sealing coating) (c) additionally comprises talc, preferably 10 to 30% (w/w) talc, more preferably 15 to 25% (weight/weight) talc, preferably 21 to 23% (w/w) talc. A taste-masking multilayer particle according to claim 1 or 2, wherein the intermediate coating layer is used (Sealing coating) The material (i) (HPMC and PEG) of (c) is selected from the group consisting of HPMC hydroxypropyl methylcellulose USP substitution type 2910 (apparent viscosity 2.4-3.6 mPas) and/or PEG 6000. The taste-masking multilayer particle of claim 1 or 2, wherein the material (i) for the intermediate coating layer (sealing coating) (c) comprises 65 to 75% (w/w) of HPMC, 7.5 to 12.5% (W/W) PEG 6000 and 19 to 23% (w/w) talc. The taste-masking multilayer particle of claim 1 or 2, wherein the material (ii) PVP for the intermediate coating layer (sealing coating) (c) is selected from the group consisting of PVP K 30. The taste-masking multilayer particle of claim 1 or 2, wherein the material (ii) for the intermediate coating layer (sealing coating) (c) comprises 70 to 80% (w/w) of PVP and 20 to 25% (weight/weight) talc. A taste-masking multilayer particle according to claim 1 or 2, wherein the material for the outer coating layer (final or taste-masking coating) (d) (i) poly(meth)acrylate-based basic butylated methyl group Acrylate copolymer. The taste-masking multilayer particle of claim 1 or 2, wherein the material (i) for the outer coating layer (final or taste-masking coating) (d) comprises 50 to 80% (w/w) of poly(methyl) ) acrylate, 0 to 8% (w/w) sodium lauryl sulfate, 0 to 35% (w/w) stearic acid and/or 0 to 35% (w/w) magnesium stearate. The taste-masking multilayer particle of claim 14, wherein the material (i) for the outer coating layer (final or taste-masking coating) (d) comprises a weight ratio of 80:20 to 60:40, more preferably 75:25. Up to 65:35, the best 70:30 poly(meth) acrylate and stearic acid. The masking multilayer particle of claim 1 or 2, wherein the material (i) for the outer coating layer (final or taste-masking coating) (d) is at least 50% (weight/weight) based on the coating. The weight of the particles below is preferably from 100 to 300% (weight/weight), more preferably from 150 to 250% (weight/weight), even more preferably from 180 to 220% (weight/weight), most preferably from 190 to 210. % (weight/weight) coating concentration. The taste-masking multilayer particle of claim 1 or 2, wherein the material (ii) for the outer coating layer (final or taste-masking coating) (d) is selected from a viscosity range of 41 to 49 mPas (for inclusion in 80) 5% solution in a mixture of % toluene and 20% ethanol and having an ethoxy group content of 48.0 to 49.5%) having an EC and/or a methoxy group content of 28 to 30% and a hydroxypropyl group content of 7 to 12% HPMC with a viscosity ranging from 4 to 6 mPas (measured as 2% aqueous solution). The taste-masking multilayer particle of claim 1 or 2, wherein the material (ii) for the outer coating layer (final or taste-masking coating) (d) comprises 50 to 75% (weight/weight) of EC, 15 to 40% (w/w) HPMC and 0 to 25% (w/w) magnesium stearate, preferably 50 to 60% (w/w) EC, 20 to 25% (w/w) HPMC And 17.5 to 22.5% (w/w) magnesium stearate. The taste-masking multilayer particle of claim 1 or 2, wherein the material (ii) for the outer coating layer (final or taste-masking coating) (d) constitutes at least 25% (weight/weight) (based on the undercoat) The weight of the granules, preferably 25 to 100% (weight/weight), more preferably 50 to 90% (weight/weight), even more preferably 70 to 80% (weight/weight), most preferably 72.5 to 77.5% (Weight/weight) coating concentration. The masking multilayer particle of claim 1 or 2, wherein the coating layer is outside the particle (final or taste-masking coating) (d) is characterized by a thickness of 50 to 150 μm, preferably 60 to 140 μm, more preferably 70 to 130 in the mode (i) (poly(meth)acrylate) Μm, even more preferably 75 to 125 μm, optimally 77 to 119 μm; or in mode (ii) (including a mixture of EC and HPMC), the thickness is 10 to 150 μm, preferably 12 to 120 μm, more preferably 15 Up to 100 μm, preferably 20 to 50 μm. The taste-masking multilayer particle of claim 3, wherein the one or more layers of the inert core and the coating layers (b) to (d) are located between one or more of the coating layers (d) Containing preferably 0.1 to 5% (w/w) based on the weight of the final granules, more preferably 0.2 to 2.5% (w/w), most preferably 0.2 to 1% (w/w) of colloidal cerium oxide . The taste-masking multilayer particle of claim 3, wherein the other coating layer is a final outer coating on the coating layer (final or taste-masking coating) (d), and the material system for the other coating layer It is selected from HPMC having a methoxy group content of 28 to 30%, a hydroxypropyl group content of 7 to 12%, and a viscosity ranging from 4 to 6 mPas (measured as a 2% aqueous solution). The taste-masking multi-layered particle of claim 1 or 2, wherein one or more of the (etc.) layer materials comprise other substances, preferably selected from one or more of the following filler substances, binders, and wetting agents. , Glidants, lubricants, dispersants, colorants and/or anti-adhesives: mannitol, starch, talc, titanium dioxide, sodium lauryl sulfate, sodium lauryl sulfate, stearic acid, magnesium stearate, Vermiculite and medium chain triglycerides. The masking multilayer particle of claim 1 or 2, wherein the (etc.) layer material One or more (preferably for use in one of the seal coat and/or final coat) comprises other materials selected from the group consisting of flavoring agents, pigments, and materials for reducing electrostatic charging, preferably meat. Flavor, pigment and / or cerium oxide. The taste-masking multilayer particle of claim 1 or 2, wherein the inert core has a characteristic diameter of 50 to 300 μm, preferably 75 to 250 μm, more preferably 100 to 200 μm. The taste-masking multilayer particle of claim 1 or 2, wherein the final coated particle has a total diameter of from 80 to 800 μm, preferably from 90 to 600 μm, more preferably from 100 to 400 μm. The taste-masking multilayer particle of claim 1 or 2, wherein the pharmaceutically active ingredient in the chemical form is from 1 to 50% (weight/weight), preferably from 2 to 25% (weight/weight) of the final multi-layered granule. More preferably 3 to 22.5% (weight/weight) and most preferably 5 to 20% (weight/weight). The taste-masking multilayer particle of claim 2, wherein the pharmaceutically active ingredient (α) (DPP IV inhibitor) is selected from the group consisting of 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl -7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine or any suitable form thereof and/or a salt thereof, preferably 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piper Pyridin-1-yl]-xanthine monohydrochloride. The taste-masking multilayer particle of claim 28, which comprises the pharmaceutically active ingredient 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl) 8-[3-(R)-Amino-piperidin-1-yl]-xanthine monohydrochloride, and it comprises: a) an inert core comprising microcrystalline cellulose; b) two coatings Layers, each containing 60 to 90% (w/w) of the doctor Pharmaceutical active ingredient and 10 to 40% (w/w) HPMC binder; c) intermediate coating layer (sealing coating) comprising 65 to 75% (w/w) HPMC, 7.5 to 12.5% (weight) /wt) PEG 6000 and 19 to 23% (w/w) talc; and d) outer coating (final or taste-masking) comprising 50 to 80% (w/w) of basic butyl a methacrylate copolymer, 5 to 8% (w/w) sodium lauryl sulfate, 8 to 35% (w/w) stearic acid and 18 to 26% (w/w) stearic acid Magnesium, wherein the material used to coat the outer layer (d) (final or taste-masking) constitutes a coating concentration of from 190 to 210% (weight/weight). The taste-masking multi-layered granule of claim 28 or 29, wherein the pharmaceutically active ingredient in the chemically incorporated form comprises from 5 to 25% (weight/weight) of the final multi-layered granule (calculated as the free base), preferably from 10 to 23 % (weight/weight), more preferably 18 to 22% (weight/weight), most preferably 20 to 21% (weight/weight). The taste-masking multilayer particle of claim 2, wherein the pharmaceutically active ingredient (β) (i _f -channel blocker) is selected from zatebradine (1-(7,8-dimethoxy-) 1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one-3-yl)-3-[N-methyl-N-[(2-(3,4-dimethyl) Oxyphenyl)ethyl]amino]-propane), 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)piperidin-3-yl)- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one, its enantiomer cilobradine ((+)-3-[(N-(2-(3,4-Dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7, 8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one) or alenidine (2-(N-allyl-2) ,6-dichloro-anilino)-2-imidazoline), the best cilostatin hydrochloride ((+)-3-[(N-(2-(3,4-dimethoxy)- Phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzo Nitroin-2-one hydrochloride). The taste-masking multilayer particle of claim 31, comprising a pharmaceutically active ingredient, cilostatin hydrochloride, and comprising: a) an inert core comprising microcrystalline cellulose; b) a coating layer comprising from 60 to 70 % (w/w) of the pharmaceutically active ingredient and 25 to 35% (w/w) HPMC binder and 0.5 to 3% (w/w) magnesium stearate; c) intermediate coating layer (sealed package) Included, comprising 70 to 80% (w/w) PVP K 30, 20 to 25% (w/w) talc and 0.5 to 5% (w/w) cerium oxide; and d) outer coating a layer (final or taste-masking) comprising from 50 to 60% (w/w) EC, from 20 to 25% (w/w) HPMC, from 17.5 to 22.5% (w/w) stearic acid a mixture of magnesium and 0.5 to 3% (w/w) cerium oxide, wherein the material for the outer coating layer (d) (final or taste-masking) comprises a package of 72.5 to 77.5% (weight/weight) Clothing concentration. The taste-masking multilayer particle of claim 31 or 32, wherein the pharmaceutically active ingredient in the chemical form is present in an amount of from 2 to 10% by weight (based on the hydrochloride salt) of the final multi-layered particle, preferably 3 To 7.5% (weight/weight), more preferably 4 to 6% (weight/weight), most preferably 5.25 to 5.75% (weight/weight). The masking multilayer particle of claim 2, wherein the pharmaceutically active ingredient (γ) (phosphodiesterase III inhibitor) is pimobendan ((RS)-6-[2-(4- Methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazine-3(2H)-one). The taste-masking multilayer particle of claim 2, wherein the pharmaceutically active ingredient (δ) (cyclooxygenase 2 inhibitor) is meloxicam (4-hydroxy-2-methyl-N-(5-A) Benzyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide). The taste-masking multilayer particle of claim 2, wherein the pharmaceutically active ingredient (ε) (benzodiazepine receptor agonist) is selected from the group consisting of 1-(4-chlorophenyl)-4-piperidinimidazoline- 2-ketone and ipitoto (1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one), preferably It is iripyridone. A method of producing a multi-layered particle according to any one of claims 1 to 36, wherein the coating layers are gradually assembled from the inert core material, and the drying steps are separated between the single coating steps. The method of claim 37, which is carried out in a fluidized bed, is preferably a Wurster fluidized bed coating process. The method of claim 37 or 38, wherein the material (i) for the outer coating layer (final or taste-masking coating) (d) is added in an amount of at least 50% (weight/weight) (based on this step) The weight of the coated particles is preferably from 100 to 300% (weight/weight), more preferably from 150 to 250% (weight/weight), even more preferably from 180 to 220% (weight/weight), most preferably from 190 to 210. % (weight / weight). The method of claim 37 or 38, wherein the material (ii) for the outer coating layer (final or taste-masking coating) (d) is added in an amount of at least 25% (weight/weight) (based on the undercoat) The weight of the granules, preferably 25 to 100% (weight/weight), more preferably 50 to 90% (weight/weight), even more preferably 70 to 80% (weight/ Weight), optimal 72.5 to 77.5% (weight/weight). Use of the following material for assembling an intermediate coating layer (sealing coating) (c) containing no low molecular weight water-soluble ionic compound in the multilayer particles as defined in any one of claims 1 to 36: i) comprises a mixture of hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG); or (ii) poly(1-vinylpyrrolidin-2-one) (PVP). The use of claim 41, wherein the material (i) for the intermediate coating layer (sealing coating) (c) comprises 65 to 75% (weight/weight) of HPMC, 7.5 to 12.5% (weight/weight) PEG 6000 and 19 to 23% (w/w) talc. The use of claim 41, wherein the material (ii) for the intermediate coating (sealing coating) (c) comprises 70 to 80% (weight/weight) of PVP and 20 to 25% (weight/weight) Talc. Use of a material for assembling a coating layer (final or taste-masking coating) other than a low molecular weight water-soluble ionic compound as defined in any one of claims 1 to 36 (d) : (i) poly(meth) acrylate; or (ii) comprising 60 to 90% (w/w) EC and 10 to 40% (w/w) hydroxypropyl methylcellulose (HPMC) mixture. The use of claim 44, wherein the material for the outer coating layer (final or taste-masking coating) (d) comprises other materials selected from the group consisting of flavoring agents, pigments, and materials for reducing electrostatic charging. The use of claim 44 or 45, wherein the outer coating layer (d) has The material (i) of the final or taste-masking coating of the poly(meth)acrylate is added in an amount of at least 50% by weight (based on the weight of the particles to be coated in this step), preferably 100 to 300% (weight/weight), more preferably 150 to 250% (weight/weight), even more preferably 180 to 220% (weight/weight), most preferably 190 to 210% (weight/weight). The use of claim 44 or 45, wherein the final or taste is used to coat the outer layer (d) (having a mixture comprising 60 to 90% (weight/weight) EC and 10 to 40% (weight/weight) HPMC. The coating material (ii) is added in an amount of at least 25% by weight (based on the weight of the particles below the coating), preferably from 25 to 100% (weight/weight), more preferably from 50 to 90. % (weight/weight), even more preferably 70 to 80% (weight/weight), optimally 72.5 to 77.5% (weight/weight). A taste-masking multilayer particle according to claim 1 or 2 for use in the treatment of: alpha) metabolic disease (via DPP IV target); beta) heart disease (via i _f -channel target); gamma) heart disease (via Phosphodiesterase III target; δ) inflammatory disease (via cyclooxygenase 2 target); and/or ε) central nervous system disease (via benzodiazepine receptor target). The taste-masking multilayer particle of claim 48 is for use in treating an animal. A pharmaceutical composition comprising the multi-layered granule according to any one of claims 1 to 36, which is for use in a method for the treatment of: a) metabolic disease (via DPP IV target); β) heart disease (via i _F -channel target); γ) heart disease (via phosphodiesterase III target); δ) inflammatory disease (via cyclooxygenase 2 target); and/or ε) central nervous system disease (via benzene And diazonium receptor targets). A pharmaceutical composition according to claim 50, which is for use in treating an animal. A pharmaceutical composition according to claim 50 or 51 which is in solid form, preferably in a mass of from 20 to 4000 mg/unit (more preferably from 20 to 500 mg/unit, even more preferably from 30 to 400 mg/unit, most preferably 40 to 300 mg/unit capsule or lozenge. The pharmaceutical composition of claim 52, which comprises a final concentration of from 0.1 to 1000 mg/unit (preferably from 2 to 50 mg/unit, even more preferably from 3 to 40 mg/unit, optimally from 4 to 30 mg/unit) Pharmaceutical active ingredients. The pharmaceutical composition of claim 52, which is in the form of a tablet, preferably having one or more score lines for the divided tablet. A pharmaceutical composition according to claim 50 or 51 which is in a completely liquid form. The pharmaceutical composition according to claim 55, which is an oily suspension, more preferably an oily suspension comprising one or more of the following viscosity enhancers: cerium oxide, hydrophobic cerium oxide, EC (cellulose ether) ), poly(1-vinylpyrrolidin-2-one) (PVP), aluminum stearate, xanthan gum, carrageenan and/or starch derivatives. The pharmaceutical composition according to claim 56, which comprises a mixture of hydrophilic and hydrophobic colloidal cerium oxide, and preferably has a weight of 0.5:1 to 50:1, more preferably 1:1 to 25:1, more preferably 2 : 1 to 10:1, best 2.25:1 to 5:1. The pharmaceutical composition according to claim 55, which is an aqueous suspension, more preferably an aqueous suspension comprising one or more of the following stabilizers: cellulose ether, carbopol, xanthan gum, horn Vegetable gum, microcrystalline cellulose. The pharmaceutical composition according to claim 55, which comprises a medicine having a final concentration of 0.1 to 20 mg/ml, preferably 0.5 to 5 mg/ml, more preferably 0.75 to 4 mg/ml, most preferably 0.5 to 3 mg/ml. Active ingredient. The pharmaceutical composition according to claim 50 or 51, wherein the pharmaceutically active ingredient (α) (DPP IV inhibitor) for treating a metabolic disease is selected from the group consisting of 1-[(3-cyano-pyridin-2-yl)- 3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthine or any suitable form thereof and/or Or a salt thereof, preferably 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-( R)-Amino-piperidin-1-yl]-xanthine monohydrochloride. A pharmaceutical composition according to claim 60, which is for use in the treatment of an animal (preferably a mammal, more preferably a carnivorous mammal, preferably a cat (feline)). The pharmaceutical composition of claim 60 for use in the treatment of diabetes (preferably type 2 diabetes). The pharmaceutical composition of claim 60, which is in solid form, which comprises from 2 to 50 mg/unit, more preferably from 3 to 40 mg/unit, even more preferably from 4 to 30 mg/unit. The pharmaceutical composition according to claim 50 or 51, wherein the pharmaceutically active ingredient (β) (i _f -channel blocker) for treating heart disease (especially heart failure) via an i _f -channel target is selected from Zalidine (1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzoazepin-2-one-3-yl)-3-[N -methyl-N-[(2-(3,4-dimethoxyphenyl)ethyl]amino]-propane), 3-[(N-(2-(3,4-dimethoxy)) -phenyl)-ethyl)piperidin-3-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine- 2-ketone, its enantiomer, cilostatin ((+)-3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-piperidin-3- (S)-yl)-methyl]-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one) or allienidine (2-(N-allyl-2,6-dichloro-anilino)-2-imidazoline), the best cilostatin hydrochloride ((+)-3-[(N-(2) -(3,4-dimethoxy-phenyl)ethyl)-piperidin-3-(S)-yl)-methyl]-(7,8-dimethoxy-1,3,4, 5-tetrahydro-2H-3-benzoazepin-2-one hydrochloride). A pharmaceutical composition according to claim 64, which is for use in the treatment of an animal (preferably a mammal, more preferably a carnivorous mammal, preferably a cat (feline)). The pharmaceutical composition according to claim 64, which is in a completely liquid form and which comprises the pharmaceutical having a final concentration of 0.5 to 5 mg/ml, preferably 0.75 to 4 mg/ml, more preferably 0.5 to 3 mg/ml. Active ingredient. The pharmaceutical composition according to claim 50 or 51, wherein the pharmaceutically active ingredient (γ) (phosphodiesterase III inhibitor) for treating heart disease via phosphodiesterase III target is pimobenone (RS) -6-[2-(4-Methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazine-3(2H)-one). A pharmaceutical composition according to claim 67, which is for use in the treatment of an animal (preferably a mammal, more preferably a carnivorous mammal, a preferred dog (Canis) or a cat (Cat). The pharmaceutical composition according to claim 50 or 51, wherein the pharmaceutically active ingredient (δ) for treating an inflammatory disease via a cyclooxygenase 2 target (cyclooxygenase 2 inhibitor) is a hydroxy- 4-hydroxyl group -2-Methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide). The pharmaceutical composition of claim 69, which is for use in treating an animal (preferably feeding A milk animal, preferably a carnivorous mammal, is preferably a dog (Canis) or a cat (Cat). The pharmaceutical composition according to claim 50 or 51, wherein the pharmaceutically active ingredient (ε) (benzodiazepine receptor agonist) for treating central nervous system diseases via a benzodiazepine receptor target is selected From 1-(4-chlorophenyl)-4-piperidinolimidazolidin-2-one and iptinoin (1-(4-chlorophenyl)-4-(4-morpholinyl)-2, 5-Dihydro-1H-imidazol-2-one), preferably eptitudin. The pharmaceutical composition according to claim 71, which is for use in the treatment of an animal (preferably a mammal, more preferably a carnivorous mammal, preferably a dog (Canis)). The pharmaceutical composition of claim 71 for use in the treatment of epilepsy and/or anxiety, preferably epilepsy, and more in the case of idiopathic epilepsy. A package of a pharmaceutical composition according to claim 56 or 57, which comprises a glass vial and the pharmaceutical composition filled therein.