Solid pharmaceutical composition and method for producing a solid pharmaceutical composition

Abstract

The present invention relates to a method for the production of templated carrier particles having a primary structure and an internal secondary structure, comprising the steps of: a) combining a carrier material with a template material, wherein the carrier material forms a primary structure and an internal secondary structure; b) transforming the template material; c) removing the transformed template material; and d) obtaining carrier particles having an internal secondary structure. Furthermore, the present invention relates to carrier particles having an internal secondary structure obtainable by the method according to the present invention. The method of the present invention can further be used to produce a compressed carrier material by further comprising the step of compressing the carrier particles having an internal secondary structure to obtain a compressed carrier material. Furthermore, the present invention relates to a solid pharmaceutical composition comprising the carrier particles or compressed carrier material produced according to the method of the present invention.

Description

Technical Field

[0001] The present invention relates to a method for the production of templated carrier particles having a primary structure and an internal secondary structure, comprising: a) combining a carrier material with a template material, wherein the carrier material forms a primary structure and an internal secondary structure; b) converting the template material; c) removing the converted template material; and d) obtaining carrier particles having an internal secondary structure. Further, the present invention relates to carrier particles having an internal secondary structure obtainable by the method according to the invention. The method of the invention can further be used to produce a compressed carrier material by further comprising the step of compressing the carrier particles having an internal secondary structure to obtain a compressed carrier material. Further, the present invention relates to a solid pharmaceutical composition comprising carrier particles or a compressed carrier material produced according to the method of the invention.

Background Art

[0002] The delivery of drugs in solid pharmaceutical compositions involves several difficulties in design. The disintegration time of solid pharmaceutical compositions delays the onset of the therapeutic effect. The drug loading capacity limits the maximum dose per solid pharmaceutical composition. Insufficient mechanical stability may have a negative impact on the shelf life of solid pharmaceutical compositions. The swallowing of solid pharmaceutical compositions can be a problem for patients, especially children and / or elderly patients.

[0003] Improving the desired drug delivery characteristics of solid pharmaceutical compositions usually has an undesirable effect on other characteristics of the solid pharmaceutical compositions. For example, a mechanically stable and hard solid pharmaceutical composition usually has a longer disintegration time (see, for example, Kitazawa, S. et al., 1975, The Journal of pharmacy and pharmacology, 27(10), 765-770), but may be more difficult to swallow.

[0004] Templated drug carrier particles are widely used in modern drug delivery, for site-specific (e.g., tissue-specific) delivery of active pharmaceutical components (see, e.g., Rosenholm, JM, et al., 2010 Nanoscale, 2(10), 1870-1883). Techniques for generating hollow carrier particles in liquid are known in the art (see, e.g., WO1999047253, Donath, E., et al., 1998, Angewandte Chemie International Edition, 37(16), 2201-2205). However, the application of carrier particles to improve the properties of solid pharmaceutical compositions in administerable forms has not received much attention. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 1999 / 047253 [Non-patent literature]

[0006] [Non-Patent Document 1] Kitazawa, S. et al., 1975, The Journal of pharmacy and pharmacology, 27(10), 765-770 [Non-Patent Document 2] Rosenholm, JM, et al., 2010 Nanoscale, 2(10), 1870-1883 [Non-Patent Document 3] Donath, E., et al., 1998, Angewandte Chemie International Edition, 37(16), 2201-2205 [Overview of the project] [Problems that the invention aims to solve]

[0007] Therefore, improved means and methods are needed to obtain solid pharmaceutical compositions having desired drug delivery properties.

[0008] The above technical problems are resolved by the embodiments disclosed herein, as defined in the claims. [Means for solving the problem]

[0009] Therefore, the present invention relates particularly to the following embodiments. Embodiment 1. A method for producing carrier particles having an internal secondary structure, a) A step of combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material. b) A step of converting the template material, c) The step of removing the converted template material, d) A step of obtaining carrier particles having an internal secondary structure. Methods that include... Embodiment 2. The method according to Embodiment 1, wherein the template material is an inorganic material or is mainly composed of an inorganic material. Embodiment 3. The method according to Embodiment 1 or 2, wherein the carrier material is an inorganic material or is mainly composed of an inorganic material. Embodiment 4. The method according to Embodiment 3 or 4, wherein the carrier material and the template material are inorganic salts or consist mainly of inorganic salts. Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein the step of combining the carrier material with the template material includes chemical precipitation, stratification, and / or crystallization of the carrier material onto the template material. Embodiment 6. The method according to any one of Embodiments 1 or 5, wherein the step of converting the template material includes heating it to a temperature of 600°C to 1200°C. Embodiment 7. The method according to Embodiment 6, wherein the step of converting the template material includes heating it to a temperature of 600°C to 900°C. Embodiment 8. The method according to Embodiment 6 or 7, wherein the step of converting the template material includes calcination. Embodiment 9. The method according to any one of Embodiments 6 to 8, wherein the step of converting the template material includes the subsequent addition of water. Embodiment 10. The method according to Embodiment 9, wherein the addition of water is an exothermic reaction. Embodiment 11. The method according to any one of Embodiments 1 to 10, wherein the step of removing the template material includes dissolving the converted template material to form an internal secondary structure. Embodiment 12. The method according to any one of Embodiments 2 to 12, wherein the template material contains calcium carbonate. Embodiment 13. The method according to any one of Embodiments 3 to 13, wherein the carrier material comprises at least one salt and / or composite selected from the group consisting of calcium phosphate and magnesium phosphate. Embodiment 14. The method according to Embodiment 13, wherein the carrier particles have a diameter of 1 to 300 μm. Embodiment 15. The method according to Embodiment 13 or 14, wherein the carrier particles have a surface area between 15 m² / g and 400 m² / g. Embodiment 16. The method according to any one of Embodiments 13 to 15, wherein the internal secondary structure includes pores having a diameter size in the range of ≥0.2 μm and ≤1.5 μm. Embodiment 17. The method according to any one of Embodiments 13 to 16, wherein the total volume of the internal secondary structure in the obtained carrier particle having an internal secondary structure is in the range of ≥10% to ≤90% of the volume of the particle. Embodiment 18. Carrier particles having an internal secondary structure that can be obtained by the method described in any one of Embodiments 1 to 17. Embodiment 19. Carrier particles according to Embodiment 18, having a packing capacity of ≥60 v / v%. Carrier particles according to embodiment 18 or 19, containing a therapeutic agent. Embodiment 21. A method for the production of a compressed carrier substance, a) i) a step of producing carrier particles according to any one of embodiments 1 to 17, and / or ii) a step of providing carrier particles according to any one of embodiments 18 to 20, and b) compressing the carrier particles having an internal secondary structure to obtain the compressed carrier substance A method comprising: Embodiment 22. A solid pharmaceutical composition containing carrier particles according to any one of embodiments 18 to 20 or the produced compressed carrier substance according to embodiment 21. Embodiment 23. The solid pharmaceutical composition according to embodiment 22, the produced compressed carrier substance according to embodiment 21, or the carrier particles according to embodiment 20, wherein the therapeutic agent is selected from the group consisting of anxiolytics, sedatives, narcotic agents, antidepressants, anti - migraine agents, anti - inflammatory agents, and anti - infective agents. Embodiment 24. The solid pharmaceutical composition according to embodiment 22 or 23, containing at least one adjuvant. Embodiment 25. The solid pharmaceutical composition according to embodiment 24, wherein the at least one adjuvant is selected from the group consisting of disintegrants, lubricants, and fluidity - enhancing agents. Embodiment 26. The solid pharmaceutical composition according to embodiment 24 or 25, wherein the at least one adjuvant is selected from the group consisting of taste - modifying agents, odor - modifying agents, and appearance - modifying agents. Embodiment 27. The solid pharmaceutical composition according to embodiment 26, wherein the taste - modifying agent is selected from the group consisting of artificial sweeteners, acidity regulators, gums, cellulose derivatives, hard fats, and salts. Embodiment 28. The solid pharmaceutical composition according to any one of embodiments 22 to 27, the produced compressed carrier substance according to embodiment 19, or the carrier particles according to embodiment 20, for use in a treatment. Solid pharmaceutical composition for use in the treatment of senile diseases or disorders, compression carrier substance for use as described in Embodiment 28, or carrier particles for use as described in Embodiment 28. Embodiment 30. Solid pharmaceutical composition for use in the treatment of pediatric diseases or disorders, compression carrier substance for use as described in Embodiment 28, or carrier particles for use as described in Embodiment 28, or Solid pharmaceutical composition for use as described in Embodiment 29, compression carrier substance for use as described in Embodiment 29, or carrier particles for use as described in Embodiment 29, wherein the senile disease or disorder is a senile and pediatric disease or disorder. Embodiment 31. Solid pharmaceutical composition for use in the treatment of a disease or disorder selected from the group consisting of anxiety disorder, bipolar disorder, pain, infection, migraine, sleep disorder, and depressive disorder, compression carrier substance for use as described in Embodiment 28, or carrier particles for use as described in Embodiment 28, or Solid pharmaceutical composition for use as described in Embodiment 29 or 30, compression carrier substance for use as described in Embodiment 29 or 30, or carrier particles for use as described in Embodiment 29 or 30, wherein the pediatric disease or disorder, the senile disease or disorder, or the senile and pediatric disease or disorder is selected from the group consisting of anxiety disorder, bipolar disorder, pain, infection, migraine, sleep disorder, and depressive disorder. Embodiment 32. Solid pharmaceutical composition for use in the treatment of veterinary diseases or disorders, compression carrier substance for use as described in Embodiment 28, or carrier particles for use as described in Embodiment 28. Embodiment 33. Solid pharmaceutical composition according to any one of Embodiments 22 - 27 for use for diagnostic purposes, the produced compression carrier substance according to Embodiment 21, or the carrier particles according to Embodiment 20. Embodiment 34. A solid pharmaceutical composition according to Embodiment 33, a compressed carrier material produced according to Embodiment 33, or carrier particles according to Embodiment 33, for use in scintigraphy. [Modes for carrying out the invention]

[0010] Accordingly, in the first embodiment, the present invention relates to a method for producing carrier particles having an internal secondary structure, comprising the steps of: a) combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material; b) transforming the template material; c) removing the transformed template material; and d) obtaining carrier particles having an internal secondary structure.

[0011] Surprisingly, it has been found that carrier particles, when produced using template materials that undergo transformation as described herein, exhibit desired drug delivery properties. Therefore, the means and methods provided herein are useful in the medical care of patients, particularly pediatric and geriatric patients (but not limited to). The improved means and methods provided herein make it possible to obtain solid pharmaceutical compositions with enhanced drug delivery properties, including, but not limited to, efficacy, safety, pharmacokinetic properties, physical stability, chemical stability, drug filling capacity, and / or disintegration time.

[0012] The term “carrier particles,” as used herein, refers to materials that are non-toxic or substantially non-toxic to a subject and can thereby be used to improve the desired drug delivery properties of a solid pharmaceutical composition. The carrier particles described herein have no or substantially no therapeutic effect when administered to a subject unless filled with a therapeutic agent. In some embodiments, the carrier particles described herein are pharmacologically inert unless filled with a therapeutic agent. In some embodiments, the carrier particles described herein are insoluble or substantially insoluble in water. The desired drug delivery properties described herein for a solid pharmaceutical composition include, but are not limited to, efficacy, safety, pharmacokinetic properties (e.g., bioavailability), physical stability, chemical stability, drug-filling capacity, and / or decay time. In some embodiments, the desired drug delivery properties for a solid pharmaceutical composition are physical stability, drug-filling capacity, and decay time. In some embodiments, the desired drug delivery characteristics of the solid pharmaceutical composition are a high drug-filling capacity of the solid pharmaceutical composition (e.g., ≥50v / v%, ≥55v / v%, ≥60v / v%, ≥65v / v%, ≥70v / v%, ≥75v / v%, ≥80v / v%, preferably ≥60v / v%, more preferably between 60v / v% and 85v / v%), a short disintegration time of the solid pharmaceutical composition (e.g., ≤15 seconds, ≤14 seconds, ≤13 seconds, ≤12 seconds, ≤11 seconds, ≤10 seconds, preferably ≤10 seconds), and / or physical stability (e.g., ≥200N, ≥210N for an 11mm tablet). The tablet hardness is ≥220N, ≥230N, ≥240N, or ≥250N, or ≥40N, ≥50N, or ≥60N for a 6mm tablet, preferably ≥50N for a 6mm tablet (see, for example, Example 4). The carrier particles according to the present invention can have any shape, and preferably the carrier particles according to the present invention have a shape similar to a sphere, spheroid, and / or bead (see, for example, Figure 1). When the template material is removed, at least one pore may be present in an otherwise substantially uniform structure (see, for example, Figure 2). The carrier particles can preferably form a hollow structure in a dry environment.Therefore, the carrier particles described herein do not disintegrate or substantially disintegrate upon drying.

[0013] As used herein, the term “primary structure” refers to the layer of carrier material encompassing the template material. In some embodiments, the primary structure includes further structural elements (e.g., petals, as shown in Figure 1) that increase the surface area of ​​the carrier particles.

[0014] As used herein, the term "internal secondary structure" refers to a hollow internal structure in which the inner surface of the hollow internal structure is dense at the crystallization initiation point (see, for example, Figure 2). Thus, the internal secondary structure enables crystallization inside the carrier particle.

[0015] The term "carrier material," as used herein, refers to a material or mixture containing the raw materials for the carrier particles of the present invention. In some embodiments, the carrier material described herein is an inorganic salt or contains inorganic salts to a considerable extent. In some embodiments, the carrier material described herein is insoluble in water or sparingly soluble in water. In some embodiments, the carrier material is soluble in a solvent. In some embodiments, the carrier material or a precursor of the carrier material is a liquid. In some embodiments, the carrier material described herein is nonpolymer or contains nonpolymers to a considerable extent.

[0016] The term “template material,” as used herein, refers to a solid material containing particles suitable for acting as a template that enables the formation of the primary structure of carrier particles. The particles in the template material preferably have the shape of spheres, spheroids, and / or beads. In some embodiments, the template material described herein is nonpolymeric or contains nonpolymeric to a considerable extent. In some embodiments, the template material described herein has a uniform or substantially uniform particle size distribution. In some embodiments, the template material described herein has a distribution width (defined by formula: (D90-D10) / D50) of ≤ about 5, ≤ about 4.5, ≤ about 4, ≤ about 3.5, ≤ about 3, ≤ about 2.8, ≤ about 2.4, ≤ about 2, ≤ about 1.8, ≤ about 1.6, ≤ about 1.4, ≤ about 1.2, ≤ about 1, ≤ about 0.9, ≤ about 0.8, ≤ about 0.7, ≤ about 0.6, ≤ about 0.5, ≤ about 0.4, ≤ about 0.3, ≤ about 0.2, or ≤ about 0.1. Therefore, the template material is any material that is convertible and has sufficient stability to hold the carrier material. During the step of combining the carrier material with the template material, a template material that is poorly soluble in the liquid being combined should be used to avoid dissolution of the template material. In some embodiments, the template materials described herein are sparingly soluble in at least one organic solvent selected from the group consisting of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, gamma-butyrolactone, and tetrahydrofuran. In some embodiments, the template materials described herein are sparingly soluble in water. In some embodiments, the template materials described herein are sparingly soluble in aqueous solutions (e.g., saline solution) containing solubility modifiers.In some embodiments, the term "slightly soluble in" as used herein refers to a concentration of <approximately 100 mg / L, <approximately 80 mg / L, <approximately 60 mg / L, <approximately 40 mg / L, <approximately 20 mg / L, <approximately 10 mg / L, <approximately 9 mg / L, <approximately 8 mg / L, <approximately 7 mg / L, <approximately 6 mg / L, <approximately 5 mg / L, <approximately 4 mg / L, <approximately 3 mg / L, <approximately 2 mg / L, <approximately 1 mg / L, <approximately 0.9 mg / L) at 25°C. This refers to solubility of g / L, <approximately 0.8 mg / L, <approximately 0.7 mg / L, <approximately 0.6 mg / L, <approximately 0.5 mg / L, <approximately 0.4 mg / L, <approximately 0.3 mg / L, <approximately 0.2 mg / L, <approximately 100 μg / L, <approximately 90 μg / L, <approximately 80 μg / L, <approximately 70 μg / L, <approximately 60 μg / L, <approximately 50 μg / L, <approximately 40 μg / L, <approximately 30 μg / L, <approximately 25 μg / L, or <approximately 20 μg / L.

[0017] In some embodiments, the template material described herein contains a salt. In some embodiments, the template material described herein contains an organic salt. In some embodiments, the template material described herein is a carbonate or contains a carbonate to a considerable extent. In some embodiments, the template material described herein contains a basic oxide.

[0018] The term “converting,” as used herein, refers to altering the properties of a template material by a combination of at least one physical step and at least one chemical step that enable the removal of the template material. The physical step of “converting” includes providing energy to the material. In some embodiments, the energy is applied in the form of a temperature increase and / or a pressure change. In some embodiments, the physical step of “converting” induces an endothermic chemical reaction in the template material. The chemical step of “converting” includes providing chemical reactants to the template material. In some embodiments, the reactants provided in the chemical step of “converting” react with the template material but not with the carrier material, or not substantially react with it. In some embodiments, the chemical reactants provided in the chemical step of “converting” are provided in liquid form, soluble form, and / or gaseous form.

[0019] The method of the present invention enables the production of carrier particles having an internal secondary structure. In some embodiments, although not bound by theory, the carrier particles can be filled with drugs not only on the surface of the carrier particle but also inside the internal secondary structure, so these internal secondary structures enable high drug filling. The filled drug or drug can leave the carrier by diffusion through the walls of the porous carrier. In some embodiments, the method of the present invention enables the production of carrier particles that have a certain stability at the target site (e.g., in the patient's mucosa). Thus, these carrier particles can remain at the target site (e.g., by adhesion to the mucosa) and enable specific drug delivery. In some embodiments, the filled drug is continuously released at the absorption site, so the method of the present invention enables the production of carrier particles that mask the unpleasant taste of the filled drug. The release rate of the filled drug can be controlled by the geometry of the template material and / or by diffusion rate modifiers such as disintegrants. Thus, the unpleasant taste has a low degree of diffusion to the perception site (e.g., the tongue).

[0020] The internal secondary structures described herein enable efficient drug filling inside the carrier particles. Furthermore, the internal secondary structures can be used to fill, for example, a solvent through the pores. In some embodiments, the methods of the present invention enable the production of carrier particles that can be filled with less effort and / or have particularly high filling capacity.

[0021] In some embodiments, the method of the present invention enables the production of carrier particles having a particularly large surface area, which is beneficial for interparticle forces. These interparticle forces act between the carrier particles in the absence of water, increasing the mechanical stability of the carrier particle cluster. This increased mechanical stability reduces the need for further stabilizing materials when using carrier particles in pharmaceutical compositions, such as solid pharmaceutical compositions, such as tablets. In some embodiments, the interparticle forces acting between carrier particles produced according to the method of the present invention are weakened by water, which allows for a shorter disintegration time of pharmaceutical compositions containing carrier particles according to the present invention, such as solid pharmaceutical compositions, such as tablets.

[0022] Therefore, the present invention is at least in part based on the surprising finding that the method of the present invention enables the production of carrier particles having internal secondary structures useful for enhancing one or more desired drug delivery properties.

[0023] In certain embodiments, the present invention relates to a method according to the present invention in which the template material is an inorganic material or is primarily made of an inorganic material.

[0024] When used herein in the context of materials, the term "consisting of" means that a material consists of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of that material.

[0025] In certain embodiments, the present invention relates to a method according to the present invention in which the carrier material is an inorganic material or is primarily composed of an inorganic material.

[0026] In certain embodiments, the present invention relates to a method according to the present invention in which the carrier material and template material are inorganic salts or mainly composed of inorganic salts.

[0027] The inventors have found that inorganic materials / salts enable the creation of stable, non-toxic carrier particles having a specific, desired size of internal secondary structure that is beneficial for enhancing one or more desired drug delivery properties.

[0028] Therefore, the present invention is at least in part based on the surprising finding that the method of the present invention enables the production of carrier particles having internal secondary structures useful for enhancing one or more desired drug delivery properties.

[0029] In a particular embodiment, the present invention relates to a method according to the present invention, wherein the template material is suspended in a liquid before the carrier material is combined with the template material.

[0030] The template material can be suspended in the reaction vessel with stirring in the liquid to be combined (e.g., water) (as described, for example, in Example 1). The set stirring rate ensures stable turbulent mixing to prevent particle aggregation, thereby allowing for individual particle processing.

[0031] In certain embodiments, the present invention relates to a method according to the present invention, wherein the step of combining a carrier material with a template material comprises adding the template material and the carrier material described herein to a combining liquid. In some embodiments, the combining liquid described herein is at least one organic solvent selected from the group consisting of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, gamma-butyrolactone, and tetrahydrofuran. In some embodiments, the combining liquid described herein is water. In some embodiments, the combining liquid described herein is an aqueous solution (e.g., brine) containing a solubility modifier.

[0032] During the step of combining the carrier material with the template material, an appropriate ratio of the amount of template material to the amount of liquid being combined should be used to avoid dissolving the template material. This appropriate ratio is determined by the solubility of the template material in the liquid being combined. In some embodiments, the amounts of template material and the liquid to be combined are selected so that the template material dissolves in the liquid to be combined in amounts of less than about 0.05% (w / w), less than about 0.04% (w / w), less than about 0.03% (w / w), less than about 0.02% (w / w), less than about 0.01% (w / w), less than about 0.0095% (w / w), less than about 0.009% (w / w), less than about 0.0085% (w / w), less than about 0.0008% (w / w), less than about 0.0075% (w / w), less than about 0.007% (w / w), less than about 0.0065% (w / w), less than about 0.06% (w / w), less than about 0.0055% (w / w), or less than about 0.005% (w / w).

[0033] In certain embodiments, the present invention relates to a method according to the present invention in which the step of combining a carrier material with a template material includes chemical precipitation, stratification, and / or crystallization of the carrier material onto the template material.

[0034] As used herein, the term "chemical precipitation" refers to the process of converting a chemical substance from a solution to a solid by converting it into an insoluble form.

[0035] In certain embodiments, the present invention relates to a method for forming a carrier material by a chemical reaction with the surface of a template material, by combining a precursor of the carrier material. In some embodiments, the soluble precursor of the carrier material described herein is phosphoric acid.

[0036] The inventors have found that a conversion grade is relevant to an embodiment in which a carrier material is formed by a chemical reaction with the surface of a template material, by combining a precursor of the carrier material.

[0037] Furthermore, the inventors found that if the conversion grade is too low, holes may form in the particles or the shell may be destroyed, while if the conversion grade is too high, the size of the lumen may decrease, for example, more external crystals of dicalcium phosphate may be formed, which then further convert into hydroxyapatite slabs.

[0038] In some embodiments, the conversion grades described herein are between about 30% and about 60%, between about 35% and about 55%, or between about 40% and about 50%.

[0039] The temperatures used in chemical precipitation described herein may have a substantial effect on the materials.

[0040] For example, dicalcium phosphate is a more thermodynamically unstable form than hydroxyapatite in its as-is state. Therefore, the addition of orthophosphate to calcium carbonate at too low a temperature, and rapidly or uncontrolled, causes precipitation of dicalcium phosphate, resulting in more dicalcium phosphate and consequently, individual crystals that are more difficult to process.

[0041] In some embodiments, the temperature during chemical precipitation is about 60°C or higher, preferably between about 60°C and about 100°C, more preferably between about 70°C and about 95°C, and more preferably between about 80°C and about 95°C.

[0042] In certain embodiments, the present invention relates to a method according to the present invention, wherein a soluble precursor of a carrier material is added to a template material in solution and distributed onto the template material by the addition of a reactant that converts the soluble precursor of the carrier material into an insoluble carrier material. In some embodiments, the soluble precursor of the carrier material described herein is sodium phosphate or calcium chloride (e.g., Despotovic, R., et al., 1975, Calc. Tis Res. 18, 13-26).

[0043] As used herein, the term "layering" refers to a technique for adding at least one layer of a carrier onto a template material.

[0044] Any layering technique known in the art may be used (see, for example, Decher, GHJD, et al., 1992, Thin solid films, 210, 831-835; Donath, E., et al., 1998, Angewandte Chemie International Edition, 37(16), 2201-2205; Caruso, F, et al., 1998, Science, 282(5391), 1111-1114). In some embodiments, to prepare at least one layer on a template material, and particularly to prepare a multilayer film on a template material, electrostatic interactions (e.g., Decher, GHJD, et al., 1992, Thin solid films, 210, 831-835), hydrogen bonding (e.g., Such, GK et al., 2010, Chemical Society Reviews, 40(1), 19-29), hydrophobic interactions (e.g., Serizawa, T., Kamimura, S., et al., 2002, Langmuir, 18(22), 8381-8385), and / or covalent coupling (e.g., Zhang, Y., et al., 2003, Macromolecules, 36(11), 4238-4240), electroplating and electrodeposition (e.g., Chandran, R., Panda, SK & Mallik, A. A short review on the advancements). The electroplating of CuInGaSe2 thin films (as described in Mater Renew Sustain Energy 7, 6 (2018)) is utilized.

[0045] As used herein, the term "crystallization" refers to the process of converting a chemical substance from a supersaturated solution.

[0046] In a particular embodiment, the present invention relates to a method according to the present invention, wherein a carrier material is added to a template material in a supersaturated solution and distributed onto the template material by initiating chemical precipitation.

[0047] In certain embodiments, the present invention relates to a method according to the present invention in which the step of combining a carrier material with a template material includes chemical precipitation and crystallization of the carrier material on the template material.

[0048] In certain embodiments, the present invention relates to a method according to the present invention in which the step of combining a carrier material with a template material includes chemical layering and crystallization of the carrier material on the template material.

[0049] In certain embodiments, the present invention relates to a method according to the present invention in which the step of combining a carrier material with a template material includes chemical precipitation and stratification of the carrier material on the template material.

[0050] The chemical precipitation process can be carried out by pumping a solution of the template material precursor onto the carrier material or into a liquid containing the carrier material (for example, as described in Example 1). During this process, the carrier material begins to grow on the surface of the template material (for example, in the form of a crystalline lamellar structure), and thus can form a stratum layer. In certain embodiments, the template material described herein is converted into a carrier material. In certain embodiments, the template material described herein is converted into a carrier material by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70%.

[0051] Chemical precipitation, stratification, and / or crystallization enable a fine and / or uniform distribution of the support material on the template material. This fine and / or uniform distribution influences the formation of the internal secondary structure.

[0052] Therefore, the present invention is at least in part based on the remarkable finding that the method of the present invention enables the production of carrier particles having a particularly fine and / or uniform internal secondary structure by using chemical precipitation, stratification, and / or crystallization of the carrier material on a template material.

[0053] In certain embodiments, the present invention relates to a method according to the present invention, wherein the step of converting a template material includes heating it to a temperature of about 600°C to about 1200°C, preferably about 600°C to about 900°C, preferably about 600°C to 839°C, and preferably about 650°C to about 700°C.

[0054] In a particular embodiment, the present invention relates to a method according to the present invention in which the step of transforming a template material includes heating it to a temperature of 840°C to 1200°C.

[0055] These conditions can be optimized to avoid interparticle condensation during the heating step, which can lead to redispersibility issues. In some embodiments, no further agents are needed to avoid interparticle condensation (see, for example, Example 1), while in other embodiments, agents to avoid interparticle condensation (e.g., anti-sintering agents) are added during and / or before the heating step described herein. Such anti-sintering agents are described, for example, Okada, M., et al., 2014, Journal of nanoparticle research, 16(7), 1-9.

[0056] The conversion of template materials described herein can be carried out at any suitable temperature or any suitable temperature range. To enable the conversion of template materials described herein, the minimum suitable temperature for conversion is set to a specific temperature, for example, about 210°C (e.g., for silver carbonate and gold carbonate as template materials), about 840°C (e.g., for calcium carbonate as template material), about 900°C, about 1000°C, or about 1200°C (e.g., for potassium carbonate and / or sodium carbonate as template materials). Those skilled in the art can determine a suitable minimum temperature from the decomposition temperature of the template material. Increasing the temperature can shorten the conversion time, but melting of the carrier material can lead to undesirable effects on the carrier particles, such as the formation of incomplete carrier particles or a decrease in the hardness of the carrier particles. To avoid melting of the carrier material, the maximum suitable temperature for conversion of template materials described herein is set below the melting temperature of the carrier material. Deformation and / or loss of desired structures that enhance the surface area of ​​the carrier particles (e.g., petals on the surface of the carrier particles, see Figure 1) may already occur at temperatures below the melting temperature of the carrier material. Therefore, in certain embodiments, the maximum suitable temperature for the conversion of the template material described herein is set about 100°C, about 200°C, about 400°C, about 500°C, or about 600°C lower than the melting temperature of the carrier material.

[0057] In a particular embodiment, the present invention relates to a method according to the present invention, wherein the step of converting a template material includes heating the template material to a temperature from approximately the decomposition temperature of the template material to approximately the melting temperature of the carrier material, preferably from approximately the decomposition temperature of the template material to a temperature about 400°C lower than the melting temperature of the carrier material, more preferably from approximately the decomposition temperature of the template material to a temperature about 500°C lower than the melting temperature of the carrier material.

[0058] In a particular embodiment, the present invention relates to a method according to the present invention in which the step of transforming a template material includes heating it to a temperature of 840°C to 1600°C, preferably 840°C to 1200°C, more preferably about 1100°C.

[0059] The duration of heating for converting the template material described herein varies depending on various factors such as the template material, carrier material, temperature range, particle size, and / or the desired surface area of ​​the carrier particles.

[0060] The duration of heating for transforming the template material described herein may be, for example, about 1 hour, as described in Example 1. In certain embodiments, the duration of heating for transforming the template material described herein may be between about 5 minutes and about 24 hours, between about 10 minutes and about 12 hours, or between 20 minutes and about 4 hours.

[0061] The heating of the template material described herein (for example, to a specific range of temperatures, e.g., between 840°C and 1200°C or between 600°C and 900°C) can be achieved by any heating pattern, such as a linear rise in temperature, or by using one or more preheating steps. The preheating steps described herein may include maintaining the temperature at a specific temperature level for a certain period of time, and then heating the template material to a specific range of temperatures, e.g., between 840°C and 1200°C or between 600°C and 900°C. Preheating allows for the removal of undesirable volatile components, such as solvents.

[0062] In some embodiments, the pressure decreases while the template material is heated to a specific temperature range, for example, 840°C to 1200°C, in order to transform it.

[0063] In some embodiments, the pressure is increased while the template material is heated to a specific temperature range, for example, 840°C to 1200°C, in order to transform it.

[0064] In some embodiments, heating to transform the template material induces an endothermic chemical reaction.

[0065] In some embodiments, an inert substance (e.g., a noble gas) is supplied to avoid side reactions while the template material is heated to a specific temperature range, for example, 840°C to 1200°C, in order to convert it.

[0066] In some embodiments, heating for transforming the template material induces the evaporation of the volatile fraction of the template material.

[0067] Heating to a specific temperature range, for example, 840°C to 1200°C, can initiate the transformation of the template material, but it does not change the support material, or change it to a similar degree. This makes it possible to remove the transformed template material based on its altered properties. Lower temperatures (e.g., approximately 600°C to 839°C or 600°C to 900°C) can be used to maintain a larger petal structure, thereby increasing the hardness of the resulting tablets.

[0068] If the temperature is higher than the recommended range, the fine petal structure of the particles melts and is reduced, decreasing the flexibility of the petals, and therefore the hardness of tablets produced using such overheated materials is greatly reduced. Pharmaceutical compacts made using overheated materials exhibit capping and lamination and cannot be used adequately in pharmaceutical formulations.

[0069] Therefore, the present invention is at least in part based on the remarkable finding that a method of the present invention, comprising a heating step for the conversion of a template material, enables the production of carrier particles having internal secondary structures beneficial for enhancing one or more desired drug delivery properties.

[0070] In certain embodiments, the present invention relates to a method according to the present invention in which the step of transforming a template material includes calcination.

[0071] As used herein, the term "heating" refers to heating a solid or a mixture containing a solid to a high temperature (for example, 840°C to 1200°C or 600°C to 900°C) while supplying air or oxygen to the solid or mixture.

[0072] In some embodiments, the calcination according to the present invention induces the decomposition of a template material containing a carbonate (e.g., a carbonate, e.g., calcium carbonate) into carbon dioxide.

[0073] In some embodiments, the calcination method according to the present invention induces the decomposition of a template material containing a metal carbonate into a metal oxide, preferably a basic oxide.

[0074] In some embodiments, the calcination process according to the present invention induces the decomposition of the hydrated template material by removing water.

[0075] In some embodiments, the calcination process according to the present invention induces the decomposition of volatile substances in the template material.

[0076] Therefore, the present invention is at least in part based on the remarkable finding that a method of the present invention, comprising a calcination step for the conversion of a template material, enables the production of carrier particles having internal secondary structures beneficial for enhancing one or more desired drug delivery properties.

[0077] In certain embodiments, the present invention relates to a method according to the present invention in which the step of transforming a template material includes the subsequent addition of water.

[0078] The subsequent addition of water according to the present invention transforms the template material in a chemical reaction, but does not change, or substantially changes, the support material. This makes it possible to remove the transformed template material based on its altered properties.

[0079] In some embodiments, the subsequent addition of water according to the present invention reacts with the metal oxide.

[0080] Therefore, the present invention is at least in part based on the remarkable finding that the conversion step method of the present invention, which includes the addition of water, enables the production of carrier particles having internal secondary structures beneficial for enhancing one or more desired drug delivery properties.

[0081] In certain embodiments, the present invention relates to a method according to the present invention in which the addition of water enables an exothermic reaction.

[0082] As used herein, the term "exothermic reaction" refers to a reaction in which the overall standard enthalpy change is negative.

[0083] The subsequent addition of water according to the present invention transforms the template material in an exothermic chemical reaction, but does not change, or substantially changes, the support material. This makes it possible to remove the transformed template material based on its altered properties.

[0084] The basic oxides described herein are non-toxic or substantially non-toxic at the doses used in the context of the present invention. In some embodiments, the subsequent addition of water according to the present invention reacts with a basic oxide. In some embodiments, the subsequent addition of water according to the present invention reacts with at least one basic oxide selected from the group consisting of lithium oxide, sodium oxide, potassium oxide, rubidium oxide, cesium oxide, magnesium oxide, calcium oxide, strontium oxide, barium oxide, and bismuth(III) oxide. In some embodiments, the subsequent addition of water according to the present invention reacts with magnesium oxide and / or calcium oxide.

[0085] The exothermic reactions described herein can facilitate the subsequent removal of the template material. The force released during the exothermic reaction and / or the properties of the product of the exothermic reaction can decrease density and / or increase solubility. For example, 3.34 g / cm³ 3 The exothermic reaction between calcium oxide of density and water is 2.21 g / cm³. 3 This yields calcium hydroxide of a certain density.

[0086] Therefore, the present invention is at least in part based on the surprising finding that, in the method according to the present invention, the addition of water through an exothermic reaction supports the formation of a secondary structure and facilitates the subsequent removal of the template material.

[0087] In certain embodiments, the present invention relates to a method according to the present invention, wherein the step of removing the template material includes dissolving the converted template material to form an internal secondary structure.

[0088] The internal secondary structure can be formed by removing the converted template material by dissolving it in a solvent that dissolves the converted template material, rather than the support material.

[0089] In some embodiments, the step of removing the template material includes dissolving the converted template material in water or an aqueous solution. In some embodiments, the pH of the aqueous solution is changed before dissolving the converted template material to increase the solubility of the converted template material or decrease the solubility of the carrier material in the aqueous solution.

[0090] In some embodiments, the step of removing the template material includes dissolving the converted template in an organic solvent.

[0091] The removal of the template material by dissolution is particularly gentle with respect to the support material. Therefore, this gentle removal supports the maintenance of the primary structure of the support material and enables the formation of an internal secondary structure, which is particularly beneficial for crystallization during the drug filling process.

[0092] Therefore, the present invention is at least in part based on the surprising finding that a method according to the present invention, in which the step of removing the template material includes dissolving the converted template material, supports the formation of an internal secondary structure.

[0093] In certain embodiments, the template material of the present invention contains a metal carbonate.

[0094] In a particular embodiment, the template material of the present invention comprises at least one metal carbonate selected from the group consisting of Li2CO3, LiHCO3, Na2CO3, NaHCO3, Na3H(CO3)2, MgCO3, Mg(HCO3)2, Al2(CO3)3, K2CO3, KHCO3, CaCO3, Ca(HCO3)2, MnCO3, FeCO3, NiCO3, Cu2CO3, CuCO3, ZnCO3, Rb2CO3, PdCO3, Ag2CO3, Cs2CO3, CsHCO3, BaCO3, and (BiO)2CO3.

[0095] In certain embodiments, the template material of the present invention comprises at least one metal selected from the group Fe, Mg, Al, Mn, V, Ti, Cu, Ga, Ge, Ag, Au, Sm, U, Zn, Pt, and Sn. In certain embodiments, the template material of the present invention comprises at least one nonmetal selected from the group Si, S, Sb, I, and C.

[0096] In certain embodiments, the template material of the present invention contains more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, or more than 99% of metal carbonates.

[0097] In certain embodiments, the template material of the present invention contains more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, or more than 99% of Li2CO3, LiHCO3, Na2CO3, NaHCO3, Na3H(CO3)2, MgCO3, Mg(HCO3)2, Al2(CO3)3, K2CO3, KHCO3, CaCO3, Ca(HCO3)2, MnCO3, FeCO3, NiCO3, Cu2CO3, CuCO3, ZnCO3, Rb2CO3, PdCO3, Ag2CO3, Cs2CO3, CsHCO3, BaCO3, and (BiO)2CO3 in a proportion of at least one metal carbonate selected from the group.

[0098] In certain embodiments, the template material of the present invention contains more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, or more than 99% magnesium carbonate.

[0099] In certain embodiments, the present invention relates to a method according to the present invention in which the template material contains calcium carbonate.

[0100] In certain embodiments, the template material of the present invention contains more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, or more than 99% calcium carbonate.

[0101] In some embodiments, the calcium carbonate described herein includes anhydrous calcium carbonate, a complex containing calcium carbonate and / or hydrated calcium carbonate, such as CaCO3·H2O, and / or calcium carbonate hexahydrate.

[0102] In some embodiments, the calcium carbonate described herein is anhydrous calcium carbonate.

[0103] The metal carbonates described herein can be used as main components for generating a carrier material having distinct properties on the surface of a template material (e.g., insoluble metal phosphates obtained by the reaction of metal carbonates with H3PO4), and can be converted as described herein.

[0104] Therefore, the present invention is at least in part based on the surprising finding that the method of the present invention is particularly efficient when the template material contains a metal carbonate, such as calcium carbonate.

[0105] In certain embodiments, the present invention relates to a method according to the present invention in which the carrier material comprises at least one salt and / or composite selected from the group consisting of calcium phosphate and magnesium phosphate.

[0106] In certain embodiments, the present invention relates to a method according to the present invention in which the carrier material comprises at least one salt and / or composite of magnesium phosphate.

[0107] In certain embodiments, the present invention relates to a method according to the present invention in which the carrier material comprises at least one salt and / or composite of calcium phosphate.

[0108] Calcium phosphate and magnesium phosphate exhibit particularly low solubility in water and reasonable heat resistance. Furthermore, calcium phosphate and magnesium phosphate are typically pharmacologically inert and non-toxic. Therefore, calcium phosphate and magnesium phosphate are robust, non-toxic, and can convert the template materials described herein without decomposition.

[0109] Therefore, the present invention is at least in part based on the surprising finding that the method of the present invention is particularly efficient when the carrier material contains at least one salt and / or composite selected from the group of calcium phosphate and magnesium phosphate.

[0110] The template material can have various structures, for example, powders (e.g., powders having a D50 of about 1.9 μm, about 2.3 μm, about 3.2 μm, about 4.5 μm, about 5.5 μm, about 6.5 μm (μmo), or about 14 μm, powders having a particle size range of about 1 to 100 μm, about 100 μm to 300 μm, or about 300 μm to 600 μm) or nanoparticles.

[0111] In certain embodiments, the present invention relates to a method according to the present invention, wherein the template material comprises particles having a diameter of 1 to 300 μm. In certain embodiments, the present invention relates to a method according to the present invention, wherein the template material comprises particles, with about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, and about 99% of the particles having a diameter of 1 to 300 μm. In certain embodiments, the present invention relates to a method according to the present invention, wherein the template material comprises particles having a median diameter of about 1 to 300 μm, about 1 to 250 μm, about 1 to 200 μm, about 1 to 150 μm, about 1 to 100 μm, about 1 to 90 μm, about 1 to 80 μm, about 1 to 70 μm, about 1 to 60 μm, about 1 to 50 μm, about 1 to 40 μm, about 1 to 30 μm, or about 1 to 20 μm.

[0112] The particle size of the template material affects the diameter of the carrier particles. In certain embodiments, the present invention relates to a method according to the present invention in which the particles of the template material have a diameter median that is substantially the same as the diameter median of the carrier particles. In embodiments in which the template material and the carrier material are joined by lamination and / or crystallization as described herein, the carrier particles have a diameter median that is similar to or larger than that of the template material.

[0113] In embodiments in which the template material and the carrier material are combined by chemical precipitation as described herein, the carrier particles have a median diameter similar to or smaller than that of the template material.

[0114] Those skilled in the art can predict the carrier material from the template material, the carrier material, and the techniques used to combine the template material with the carrier material as described herein.

[0115] In a particular embodiment, the present invention relates to a method according to the present invention in which the carrier particles have a diameter of 1 to 300 μm.

[0116] Apart from adapting the parameters and materials used in the method of the present invention, particles of a specific size can be obtained by methods known in the art, including milling and sieving (see, for example, Patel, RP, et al., 2014, Asian Journal of Pharmaceutics (AJP), 2(4), DAVID, J. and PETER, R., 2006, Fundamentals of Early Clinical Drug Development: From Synthesis Design to Formulation, 247, US5376347A). Particle size and shape measurements can be prepared using any method known in the art, such as laser diffraction or in-situ microscopy (Kempkes, M., Eggers, J., & Mazzotti, M., 2008, Chemical Engineering Science, 63(19), 4656-4675, Allen, T. (2013). Particle size measurement. Springer).

[0117] For certain applications, specific small carrier particle diameters are desired. In certain embodiments, the present invention relates to a method according to the present invention in which carrier particles have a diameter of about 1–20 μm, about 1–15 μm, about 1–10 μm, or about 1–5 μm for use in intrapulmonary and / or nasal administration. For certain applications, specific small carrier particle diameters are desired to increase the diffusion surface and accelerate the release of the packed drug.

[0118] In some applications, larger carrier particle diameters are desired to enhance the fluidity of the carrier particles and facilitate further processing. In certain embodiments, the present invention relates to a method according to the present invention in which the carrier particles have a diameter of about 5 to 300 μm, about 10 to 250 μm, about 15 to 200 μm, or about 20 to 150 μm.

[0119] Therefore, the present invention is at least in part based on the surprising finding that a method of the present invention having carrier particles within a specific range of diameters may be particularly useful for further processing (e.g., fluidity) and / or application (e.g., diffusion surface) of carrier particles produced according to the method of the present invention.

[0120] In a particular embodiment, the present invention relates to a method according to the present invention in which the carrier particles have a surface area between 15 m² / g and 400 m² / g or between 30 m² / g and 400 m² / g.

[0121] In a particular embodiment, the present invention relates to a method according to the present invention, wherein the carrier particles have a surface area between approximately 15 m² / g and 400 m² / g, between approximately 30 m² / g and 400 m² / g, between approximately 50 m² / g and 350 m² / g, between approximately 70 m² / g and 320 m² / g, between approximately 90 m² / g and 300 m² / g, or between approximately 100 m² / g and 280 m² / g, as measured by 5-point BET (Brunnauer-Emmet-Teller) surface area analysis using nitrogen as the gas.

[0122] Alternatively, the surface area of ​​the carrier particles can be measured by any method known in the art (see, for example, Akashkina, LV, Ezerskii, ML, 2000, Pharm Chem J 34, 324-326, and Bauer, JF, 2009, Journal of Validation Technology, 15(1), 37-45).

[0123] The surface area of ​​the carrier particles can be changed, for example, by the particle size of the carrier material, by the carrier material itself, and / or by changing the surface structure using parameters used in the method of the present invention (e.g., heat, heating duration).

[0124] In a particular embodiment, the present invention relates to carrier particles according to the present invention, in which the carrier particles are used as an adsorbent.

[0125] When multiple particles come into contact, the specific surface area of ​​the carrier particles described herein increases, enabling strong van der Waals interactions. This effect results in higher tensile strength in the final formulation. These van der Waals interactions can be reduced by the addition of water, which can support the breakdown of particle clusters.

[0126] Therefore, the present invention is at least in part based on the surprising finding that the method of the present invention enables mechanical stability and disintegration ability when the carrier particles have a surface area between 15 m² / g and 400 m² / g, preferably between 30 m² / g and 400 m² / g.

[0127] In a particular embodiment, the present invention relates to a method according to the present invention in which the internal secondary structure includes pores having a diameter size in the range of ≥0.2 μm and ≤1.5 μm.

[0128] In certain embodiments, the present invention relates to a method according to the present invention in which the internal secondary structure includes pores having a diameter size of ≥ approximately 0.2 μm, ≥ approximately 0.3 μm, ≥ approximately 0.4 μm, ≥ approximately 0.5 μm, ≥ approximately 0.6 μm, ≥ approximately 0.7 μm, ≥ approximately 0.8 μm, ≥ approximately 0.9 μm, ≥ approximately 1 μm, ≥ approximately 1.1 μm, ≥ approximately 1.2 μm, ≥ approximately 1.3 μm, or approximately 1.5 μm.

[0129] In a particular embodiment, the present invention relates to a method according to the present invention, wherein the internal secondary structure includes pores having diameter sizes in the range of ≥ approximately 0.2 μm to ≤ 1.5 μm, ≥ approximately 0.3 μm to ≤ 1.5 μm, ≥ approximately 0.4 μm to ≤ 1.5 μm, ≥ approximately 0.5 μm to ≤ 1.5 μm, ≥ approximately 0.6 μm to ≤ 1.5 μm, ≥ approximately 0.7 μm to ≤ 1.5 μm, ≥ approximately 0.8 μm to ≤ 1.5 μm, ≥ approximately 0.9 μm to ≤ 1.5 μm, ≥ approximately 1 μm to ≤ 1.5 μm, ≥ approximately 1.1 μm to ≤ 1.5 μm, ≥ approximately 1.2 μm to ≤ 1.5 μm, or ≥ approximately 1.3 μm to ≤ 1.5 μm.

[0130] The pore size of the carrier particles can be measured by any method known in the art (see, for example, Markl, D. et al., 2018, International Journal of Pharmaceutics, 538(1-2), 188-214).

[0131] The porous structure formed by the method of the present invention allows for particularly large pores. This large pore diameter promotes drug loading in carrier particles and accelerates drug release from carrier particles.

[0132] Pore ​​diameters exceeding 90% of the template material particle diameter result in unstable carrier particles. Therefore, the maximum pore diameter is determined by the size of the template material particles.

[0133] In certain embodiments, the present invention relates to a method according to the present invention in which the internal secondary structure comprises pores having diameter sizes of ≤ about 270 μm, ≤ about 225 μm, ≤ about 180 μm, ≤ about 135 μm, ≤ about 90 μm, ≤ about 81 μm, ≤ about 72 μm, ≤ about 63 μm, ≤ about 54 μm, ≤ about 45 μm, ≤ about 36 μm, ≤ about 27 μm, or ≤ about 18 μm. Accordingly, the present invention is at least in part to the surprising finding that a method of the present invention comprising pores having certain diameter sizes in the internal secondary structure is particularly useful for the subsequent drug loading and drug release of carrier particles produced according to the method of the present invention.

[0134] In certain embodiments, the present invention relates to a method according to the present invention in which the total volume of the internal secondary structure in obtained carrier particles having an internal secondary structure is in the range of ≥10% to ≤90% of the particle volume, as determined by SEM-FIB and SEM image analysis of crosssection images of the particles embedded in the resin. Alternative analytical methods for determining the internal structure and particle volume ratio include calculating porosity as the ratio of the tap bulk of the carrier material to the true crystalline density of the carrier material.

[0135] The total volume of the internal secondary structure refers to the volume inside the particle resulting from the removal of the template material (see, for example, Figure 2). In certain embodiments, the total volume of the internal secondary structure described herein is the average internal volume of the carrier particles obtained according to the method of the present invention.

[0136] In certain embodiments, the total volume of the internal secondary structure described herein is the median internal volume of the carrier particles obtained according to the method of the present invention.

[0137] In certain embodiments, the present invention relates to a method according to the present invention in which the total volume of the internal secondary structure in the obtained carrier particles having an internal secondary structure is more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, or more than about 80% of the particle volume.

[0138] In certain embodiments, the present invention relates to a method according to the present invention in which the total volume of the internal secondary structure in the obtained carrier particles having an internal secondary structure is more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, or more than about 80% of the particle volume.

[0139] In a particular embodiment, the present invention relates to a carrier particle having an internal secondary structure in which the total volume of the internal secondary structure is ≥ approximately 10% to ≤ 90%, ≥ approximately 15% to ≤ 90%, ≥ approximately 20% to ≤ 90%, ≥ approximately 25% to ≤ 90%, ≥ approximately 30% to ≤ 90%, ≥ approximately 35% to ≤ 90%, ≥ approximately 40% to ≤ 90%, ≥ approximately 45% to ≤ 90%, ≥ approximately 50% to ≤ 90%, ≥ approximately 55% to ≤ 90%, and ≥ approximately 60% of the particle volume. ~≦90%, ≥65%~≦90%, ≥70%~≦90%, ≥10%~≦80%, ≥15%~≦80%, ≥20%~≦80%, ≥25%~≦80%, ≥30%~≦80%, ≥35%~≦80%, ≥40%~≦80%, ≥45%~≦80%, ≥50%~≦80%, ≥55%~≦80%, ≥60%~≦80%, ≥65%~≦80%, ≥70%~≦80%, ≥1 0%~≦70%, ≥approx. 15%~≦70%, ≥approx. 20%~≦70%, ≥approx. 25%~≦70%, ≥approx. 30%~≦70%, ≥approx. 35%~≦70%, ≥approx. 40%~≦70%, ≥approx. 45%~≦70%, ≥approx. 50%~≦70%, ≥approx. 55%~≦70%, ≥approx. 60%~≦70%, ≥approx. 65%~≦70%, ≥approx. 10%~≦60%, ≥approx. 15%~≦60%, ≥approx. 20%~≦60%, ≥approx. 25%~≦60%, ≥ The present invention relates to a method in the range of approximately 30% to ≤60%, ≥35% to ≤60%, ≥40% to ≤60%, ≥45% to ≤60%, ≥50% to ≤60%, ≥55% to ≤60%, ≥10% to ≤50%, ≥15% to ≤50%, ≥20% to ≤50%, ≥25% to ≤50%, ≥30% to ≤50%, ≥35% to ≤50%, ≥40% to ≤50%, or ≥45% to ≤50%.

[0140] In certain embodiments, the present invention relates to carrier particles having an internal secondary structure that can be obtained by a method according to the present invention.

[0141] In a particular embodiment, the present invention relates to carrier particles according to the present invention, wherein the carrier particles have a packing capacity of ≥72v / v%, ≥70v / v%, ≥68v / v%, ≥66v / v%, ≥64v / v%, ≥62v / v%, or ≥60v / v%.

[0142] In a particular embodiment, the present invention relates to carrier particles according to the present invention, wherein the carrier particles have a packing capacity of ≥60 v / v%.

[0143] The term "filling capacity," as used herein, refers to the volume of a carrier particle that can be used to fill a drug, compared to the total volume of the carrier particle. Thus, a carrier particle with a filling capacity of 60 v / v% can be filled with a drug that occupies 60% of the carrier particle's volume. The volume of the carrier particle is calculated from its diameter. Therefore, the volume of the internal structure is part of the carrier particle's volume for the purposes of this calculation.

[0144] In some embodiments, the drug packed into the carrier particles consists of a packing solvent, which is removed to complete the packing.

[0145] The drug to be filled is dissolved in the filling solvent and brought into contact with the carrier particles to ensure complete wetting of the carrier particles. The filling solvent can be removed by any solvent removal method known to those skilled in the art. In some embodiments, the filling solvent is removed by a method selected from the group consisting of evaporation, vacuum-assisted evaporation, air drying, vacuum freeze-drying, freeze-drying at atmospheric pressure, spray drying, spray drying in a fluidized bed apparatus, microwave-assisted drying, electrospray-assisted drying, dielectric drying, fluidized bed-assisted drug filling, and solvent adsorption methods.

[0146] In some embodiments, the solvent adsorption method includes high-shear granulation.

[0147] The selection of an appropriate packing solvent depends on the solvent toxicity, the partial vapor pressure of the solvent, the properties of the drug to be packed (e.g., the pH stability and / or solubility of the drug to be packed), and / or the properties of the carrier material.

[0148] In some embodiments, the packing solvent described herein comprises at least one organic solvent, preferably selected from the group consisting of dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, gamma-butyrolactone, and tetrahydrofuran. In some embodiments, the packing solvent described herein is water.

[0149] Some packing solvents, such as water, have high surface tension and therefore may require further means to support their entry into the pores(s) of the carrier particles of the present invention, despite their very large pore diameters. In some embodiments, the packing solvents described herein include at least one surfactant, such as a tenside. In some embodiments, the addition of the packing solvent is carried out under increased pressure to support the packing solvent by entering the interior of the carrier particles.

[0150] In some embodiments, the filling of carrier particles according to the present invention involves the addition of an antisolvent that reduces the solubility of the agent to be filled in the filling solvent. In some embodiments, the antisolvent is at least one antisolvent selected from the group consisting of water, dichloromethane, diethyl ether, toluene, ethanol, methanol, dimethyl sulfoxide, supercritical CO2, dimethyl ketone, 2-propanol, 1-propanol, saturated alkanes, alkenes, alkadienes, fatty acids, glycerol, silicone oil, gamma-butyrolactone, and tetrahydrofuran.

[0151] In some embodiments, the packing solvent is removed, for example, by evaporation through increased temperature and / or decreased pressure. The maximum temperature for removing the packing solvent is determined according to the thermal stability of the packed agent.

[0152] In certain embodiments, the present invention relates to carrier particles according to the present invention, in which the carrier particles are used as a placebo.

[0153] In a particular embodiment, the present invention relates to carrier particles according to the present invention, wherein the carrier particles contain a therapeutic agent.

[0154] As used herein, the term “therapeutic agent” refers to a compound or composition that, when administered to a subject in a therapeutically effective dose, produces a therapeutic benefit to that subject. A therapeutic agent may be any type of drug, medicine, pharmaceutical, hormone, antibiotic, growth factor, and / or bioactive substance used to treat, control, or prevent a disease or condition. Those skilled in the art will understand that the term “therapeutic agent” is not limited to drugs approved by regulatory authorities.

[0155] The carrier particles of the present invention can enable the delivery of site-specific therapeutic agents by adhering to a target site. In certain embodiments, the carrier particles of the present invention adhere to mucous membranes. In certain embodiments, the carrier particles of the present invention adhere to nasal, buccal, sublingual, intrabronchial, vaginal, urethral, ​​or rectal tissues to enable the delivery of site-specific therapeutic agents.

[0156] In certain embodiments, the therapeutic agent described herein is an enzyme that acts topically (e.g., buccal application of lysozyme).

[0157] In certain embodiments, the therapeutic agents described herein are peptides, hormones, and / or small molecules that act locally (e.g., application of bronchial corticosteroids) and / or systemically (e.g., application of insulin to the bronchi). In certain embodiments, the therapeutic agents described herein are antidiabetic drugs, such as insulin. Accordingly, in certain embodiments, the carrier particles of the present invention enable nasal, buccal, sublingual, intrabronchial, vaginal, urethral, ​​or rectal administration of therapeutic agents that are typically administered by injection or infusion.

[0158] The carrier particles of the present invention enable the delivery of site-specific therapeutic agents and can avoid substantial first-pass effects and / or disintegration due to site-specific conditions (e.g., gastric acid) and / or enzymes (e.g., digestive enzymes or hepatic enzymes). In certain embodiments, the therapeutic agent described herein is a therapeutic agent that is disintegrated by the GI tubule and / or liver.

[0159] In some embodiments, it is known to those skilled in the art that the therapeutic agents described herein have a therapeutic effect when administered orally in an effective amount to a target. In certain embodiments, the therapeutic agents described herein are small molecules. In some embodiments, the therapeutic agents described herein have molecular weights of <1600Da, <1500Da, <1400Da, <1300Da, <1200Da, <1100Da, <1000Da, <900Da, <800Da, <700Da, <600Da, or <500Da.

[0160] The carrier particles according to the present invention, in which the carrier particles contain a therapeutic agent, can be used for the storage of the therapeutic agent, for treatment and / or for analytical methods, or can be further processed.

[0161] Therefore, the present invention is at least in part based on the surprising finding that carrier particles according to the present invention, which contain a therapeutic agent, can have multipurpose uses.

[0162] In certain embodiments, the present invention relates to a method for producing a compressible carrier material, wherein the production of the compressible carrier material comprises a production method according to the present invention, the method further comprising the step of compressing carrier particles having an internal secondary structure to obtain a compressible carrier material.

[0163] In certain embodiments, the present invention relates to a method for producing a compressible carrier material, comprising the steps of: a) producing carrier particles according to the present invention; and b) compressing the carrier particles having an internal secondary structure to obtain a compressible carrier material.

[0164] In certain embodiments, the present invention relates to a method for producing a compressible carrier material, comprising the steps of: a) providing carrier particles according to the present invention; and b) compressing the carrier particles having an internal secondary structure to obtain a compressible carrier material.

[0165] In certain embodiments, the present invention relates to a method for producing a compressible carrier material, comprising the steps of: a) producing and providing carrier particles according to the present invention; and b) compressing the carrier particles having an internal secondary structure to obtain a compressible carrier material.

[0166] As used herein, the term "compressed carrier material" refers to a cluster of two or more carrier particles that have an adhesive force acting between them.

[0167] As used herein, the term “compression” refers to applying pressure to two or more particles (e.g., carrier particles) to form a compressed carrier material such that the carrier particles remain at least partially adhered to each other upon pressure release. Techniques for compression are known to those skilled in the art (see, for example, Odeku, OA et al., 2007, Pharmaceutical Reviews, 5(2)). Examples of techniques for compression include, but are not limited to, tableting, roller compression, slugging, briquetting, and / or centrifugation.

[0168] The compression carrier materials described herein are particularly stable and can be used to obtain particularly stable pharmaceutical compositions (see, for example, Example 3). During compression, a large surface area of ​​the carrier particles described herein leads to the formation of strong interparticle van der Waals adhesion, thereby enabling mechanical stability. Upon ingestion, water enters between the particles (e.g., by capillary forces), reducing the distance-dependent van der Waals adhesion and causing the compression carrier material to disintegrate.

[0169] Therefore, the present invention is at least in part based on the remarkable finding that the compression carrier material described herein enables a certain level of mechanical stability and / or rapid decay time.

[0170] In certain embodiments, the present invention relates to carrier particles for use in solid pharmaceutical compositions.

[0171] In certain embodiments, the present invention relates to a solid pharmaceutical composition comprising carrier particles according to the present invention.

[0172] In certain embodiments, the present invention relates to a solid pharmaceutical composition comprising a compressible carrier material produced according to the present invention.

[0173] In certain embodiments, the solid pharmaceutical compositions described herein are solid pharmaceutical compositions for oral, sublingual, buccal, nasal, bronchial, rectal, urethral, ​​and / or vaginal administration.

[0174] In certain embodiments, the solid pharmaceutical composition described herein is a granule, tablet, capsule, or suppository.

[0175] In certain embodiments, the solid pharmaceutical composition described herein is a solid pharmaceutical composition for oral administration.

[0176] In certain embodiments, the solid pharmaceutical composition described herein is a solid pharmaceutical composition for oral administration that disintegrates with water to facilitate swallowing and / or enable site-specific delivery.

[0177] In certain embodiments, the solid pharmaceutical composition described herein is a solid pharmaceutical composition for oral administration, selected from the group consisting of effervescent tablets, orally disintegrating tablets, dispersible tablets, effervescent granules, orally disintegrating granules, and dispersible granules.

[0178] In certain embodiments, the solid pharmaceutical compositions described herein are solid pharmaceutical compositions for oral administration, comprising film-coated tablets and / or film-coated granules. The films coating the tablets or granules described herein may have various functions, such as masking taste, masking odor, altering appearance, and modifying the release of the therapeutic agent. In certain embodiments, the film-coated tablets and / or film-coated granules described herein are designed for at least one modified release mode selected from the group of immediate release, delayed release (e.g., timed release), and pH-controlled release. Methods for designing modified-release tablets are known to those skilled in the art (see, for example, US6419954, Pietrzak, K. et al., 2015, European Journal of Pharmaceutics and Biopharmaceutics, 96, 380-387, and de Sousa Rodrigues, LA, et al., 2013, Colloids and Surfaces B: Biointerfaces, 103, 642-651). In these embodiments, the present invention enables rapid and effective release of the therapeutic agent at a desired time, and / or compact storage of the therapeutic agent in the release compartment of the film-coated tablets and / or film-coated granules described herein. In certain embodiments, the film-coated granules described herein are contained in a tablet, and the coating enables pH-controlled release even after the tablet has disintegrated or been broken.

[0179] In certain embodiments, the solid pharmaceutical compositions described herein are tablets or capsules that can disintegrate before ingestion or disintegrate in the mouth.

[0180] Some of the aforementioned design limitations of solid pharmaceutical compositions are associated with a lack of physical resistance (e.g., in blister packs) and the inability to incorporate high concentrations of therapeutic agents. The present invention provides means and methods for producing dense and stable solid pharmaceutical compositions containing high concentrations of therapeutic agents.

[0181] Therefore, the present invention is at least in part based on the surprising finding that the solid pharmaceutical compositions described herein have specific desired drug delivery properties.

[0182] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein the therapeutic agent is selected from the group consisting of anxiolytics, sedatives, narcotics, antidepressants, anti-migraine agents, anti-inflammatory agents, and anti-infective agents.

[0183] In certain embodiments, the present invention relates to a compressed carrier material produced according to the present invention, wherein the therapeutic agent is selected from the group consisting of anxiolytics, sedatives, narcotics, antidepressants, anti-migraine agents, anti-inflammatory agents, and anti-infective agents.

[0184] In certain embodiments, the present invention relates to carrier particles according to the present invention, wherein the therapeutic agent is selected from the group consisting of anxiolytics, sedatives, narcotics, antidepressants, anti-migraine agents, anti-inflammatory agents, and anti-infective agents.

[0185] In a particular embodiment, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein the therapeutic agent is an anxiolytic.

[0186] In certain embodiments, the present invention relates to a compressible carrier material produced according to the present invention, wherein the therapeutic agent is an anxiolytic.

[0187] In a particular embodiment, the present invention relates to carrier particles according to the present invention, wherein the therapeutic agent is an anxiolytic.

[0188] The term “anxiolytic,” as used herein, refers to a pharmaceutical compound used to treat symptoms in patients having anxiety or emotional disorders, including stress, anxiety, neurosis, and obsessive-compulsive disorder. Anxiolytics are typically divided into two broad classifications: benzodiazepines and non-benzodiazepines. In some embodiments, the anxiolytics described herein are benzodiazepines. In some embodiments, the anxiolytics described herein are benzodiazepines selected from the group clonazepam, diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlordiazepoxide, alprazolam, clobazam, clorazepate, and etizolam.

[0189] In some embodiments, the anxiolytics described herein are non-benzodiazepines. In some embodiments, the anxiolytics described herein include at least one non-benzodiazepine selected from the classes of serotonin 1A agonists, barbiturates, carbamates, antihistamines, opioids, and Z drugs. In some embodiments, the anxiolytics described herein include buspirone, amobarbital, aprobarbital, butabarbital, mefobarbital, methhexital, pentobarbital, phenobarbital, primidone, secobarbital, thiopental, meprobamate, carisoprodol, cibamate, lorbamate, zaleplon, zolpidem, zopiclone, eszopiclone, chlorpheniramine, dexchlorpheniramine, dimenhydrinate, and diphenhydramine. It contains at least one non-benzodiazepine selected from the group consisting of promethazine, trimeprazine, gabapentin, pregabalin, tramadol, tapentadol, morphine, diamorphine, hydromorphone, oxymorphone, oxycodone, hydrocodone, methadone, propoxyfene, meperidine, fentanyl, codeine, carfentanyl, remifentanil, alfentanil, sufentanil, phenibat, mebicar, and gamma-hydroxybutyrate.

[0190] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein the therapeutic agent is a sedative.

[0191] In certain embodiments, the present invention relates to a compressible carrier material produced according to the present invention, wherein the therapeutic agent is a sedative.

[0192] In certain embodiments, the present invention relates to carrier particles according to the present invention, wherein the therapeutic agent is a sedative.

[0193] The term “sedative,” as used herein, refers to a substance that induces sedation by reducing irritability or agitation. In some embodiments, the sedatives described herein include at least one sedative selected from the classes of barbiturates, benzodiazepines, Z drugs, general anesthetics, phytoesedatives, methacarone / methacarone analogs, skeletal muscle relaxants, opioids, and antipsychotics. In some embodiments, the sedatives described herein include amobarbital, aprobarbital, butabarbital, mefobarbital, methhexital, pentobarbital, phenobarbital, primidone, secobarbital, thiopental, clonazepam, diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, and temazepam. Chlordiazepoxide, alprazolam, clobazam, chlorazepate, etizolam, zaleplon, zolpidem, zopiclone, eszopiclone, chlorpheniramine, dexchlorpheniramine, dimenhydrinate, diphenhydramine, promethazine, trimeprazine, ketamine, esketamine, afloquaron, chlorocalon, diprocalon, etakalon, metakalon, methylmetakalon, mebrocalon It contains at least one sedative selected from the group consisting of meclocalon, nitromethakalon, cannabinoids, baclofen, meprobamate, carisoprodol, cyclobenzaprine, metaxalon, methocarbamol, tizanidine, clonidine, chlorzoxazone, orphenadrine, gabapentin, pregabalin, tramadol, tapentadol, morphine, diamorphine, hydromorphone, oxymorphone, oxycodone, hydrocodone, methadone, propoxyfen, meperidine, fentanyl, codeine, carfentanyl, remifentanil, alfentanil, sufentanil, olanzapine, clozapine, thiothixen, haloperidol, fluphenazine, prochlorperazine, trifloperazine, roxapine, quetiapine, asenapine, gamma-hydroxybutyrate, and dextromethorphan.

[0194] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein the therapeutic agent is a narcotic drug.

[0195] In certain embodiments, the present invention relates to a compressible carrier material produced according to the present invention, wherein the therapeutic agent is a narcotic drug.

[0196] In certain embodiments, the present invention relates to carrier particles according to the present invention, wherein the therapeutic agent is a narcotic drug.

[0197] As used herein, the term "narcotic agent" refers to a psychoactive compound having the property of causing numbness or paralysis. In some embodiments, the narcotic agents described herein include at least one narcotic agent selected from the classes of barbiturates, benzodiazepines, Z drugs, general anesthetics, and opioids. In some embodiments, the narcotic agents described herein include amobarbital, aprobarbital, butabarbital, mefobarbital, methhexital, pentobarbital, phenobarbital, primidone, secobarbital, thiopental, clonazepam, diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlordiazepoxide, alprazolam, clobazam, clorazepate, etizolam, zaleplon, zolpidem, and zopiclone. It contains at least one narcotic drug selected from the group consisting of eszopiclone, chlorpheniramine, dexchlorpheniramine, dimenhydrinate, diphenhydramine, promethazine, trimeprazine, ketamine, esketamine, tramadol, tapentadol, morphine, diamorphine, hydromorphone, oxymorphone, oxycodone, hydrocodone, methadone, propoxyfen, meperidine, fentanyl, codeine, carfentanil, remifentanil, alfentanil, sufentanil, and dextromethorphan.

[0198] In some embodiments, the sedatives described herein are also anxiolytics. In some embodiments, the narcotic agents described herein are also anxiolytics. In some embodiments, the sedatives described herein are also narcotic agents.

[0199] In a particular embodiment, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein the therapeutic agent is an antidepressant.

[0200] In certain embodiments, the present invention relates to a compressible carrier material produced according to the present invention, wherein the therapeutic agent is an antidepressant.

[0201] In a particular embodiment, the present invention relates to carrier particles according to the present invention, wherein the therapeutic agent is an antidepressant.

[0202] As used herein, the term "antidepressant" refers to a therapeutic agent that possesses properties useful in treating depressive disorders.

[0203] In some embodiments, the antidepressants described herein are selected from the classes SSRI, SNRI, SMS, SARI, NRI, NDRI, TCA, TeCA, and MAOI. In some embodiments, the antidepressants described herein are agomelatine, esketamine, ketamine, tandospirone, thianeptine, metralindol, moclobemide, pyrrindol, troxatone, caloxazone, selegiline, isocarboxazide, phenelzine, tranylcypromine, amoxapine, maprotiline, mianserin, mirtazapine, setiptiline, amitriptyline, amitriptyline oxide, clomipramine, desipramine, dibenzepine, dimethacrine, dosurepin, doxepin, imipramine, rof These are antidepressants selected from the group consisting of epramine, melitracene, nitroxazepine, nortriptyline, noxiptyline, opipramole, pipofezin, protriptyline, trimipramine, bupropion, atomoxetine, leboxetine, teniroxazine, biloxazine, trazodone, bilazodone, vortioxetine, desvenlafaxine, duloxetine, levomirunacipran, milnacipran, venlafaxine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

[0204] In a particular embodiment, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein the therapeutic agent is an anti-migraine agent.

[0205] In certain embodiments, the present invention relates to a compressed carrier material produced according to the present invention, wherein the therapeutic agent is an anti-migraine agent.

[0206] In certain embodiments, the present invention relates to carrier particles according to the present invention, wherein the therapeutic agent is an anti-migraine agent.

[0207] As used herein, the term "anti-migraine agent" refers to a therapeutic agent that possesses properties useful in treating acute migraine symptoms.

[0208] In some embodiments, the anti-migraine agent described herein is a drug selected from the group of paracetamol, NSAIDs, and triptans. In some embodiments, the anti-migraine agent described herein is an NSAID selected from the group of acetylsalicylic acid, ibuprofen, naproxen, diclofenac, indomethacin, piroxicam, and phenylbutazone. In some embodiments, the anti-migraine agent described herein is a triptan selected from the group of sumatriptan, alumotriptan, eletriptan, flovatriptan, naratriptan, rizatriptan, and zolmitriptan. In some embodiments, the anti-migraine agent described herein is a combination of an NSAID and a triptan. In some embodiments, the anti-migraine agent described herein is a combination of an NSAID and an antiemetic, for example, an NSAID and domperidone.

[0209] In a particular embodiment, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein the therapeutic agent is an anti-inflammatory agent.

[0210] In certain embodiments, the present invention relates to a compressible carrier material produced according to the present invention, wherein the therapeutic agent is an anti-inflammatory agent.

[0211] In a particular embodiment, the present invention relates to carrier particles according to the present invention, wherein the therapeutic agent is an anti-inflammatory agent.

[0212] As used herein, the term “anti-inflammatory agent” refers to a therapeutic agent that reduces inflammation and / or swelling. In some embodiments, the anti-inflammatory agents described herein are selected from the group consisting of NSAIDs, anti-leukotrienes, immunoselective anti-inflammatory derivatives, glucocorticoids, and steroids. In some embodiments, the anti-inflammatory agents described herein are selected from the group consisting of acetylsalicylic acid, ibuprofen, naproxen, diclofenac, indomethacin, piroxicam, phenylbutazone, prednisone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone (tramcinolone), fluticasone, infliximab, adalimumab, certolizumab pegol, golimumab, etanercept, curcumin, IL-1RA, canakinumab, allopurinol, colchicine, prednisone, pentoxifylline, rosuvastatin, and oxypurinol.

[0213] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein the therapeutic agent is an anti-infective agent.

[0214] In certain embodiments, the present invention relates to a compressible carrier material produced according to the present invention, wherein the therapeutic agent is an anti-infective agent.

[0215] In certain embodiments, the present invention relates to carrier particles according to the present invention, wherein the therapeutic agent is an anti-infective agent.

[0216] As used herein, the term “anti-infective agent” refers to a therapeutic agent having properties useful in treating infection by a pathogen. Anti-infective agents may, among other things, have properties that prevent, inhibit, suppress, reduce, adversely affect, and / or interfere with the growth, survival, replication, function, and / or dissemination of a pathogen. In some embodiments, the anti-infective agents described herein include at least one therapeutic agent selected from the classes of amoebicides, anthelmintics, antifungals, antimalarials, antibiotics, and antivirals.

[0217] As used herein, the term "anthelmintic" refers to a therapeutic agent having properties useful in treating infections of helminths, such as trematodes, roundworms, and tapeworms. Anthelmintic agents may, among other things, have properties that prevent, inhibit, suppress, reduce, adversely affect, and / or interfere with the growth, survival, replication, function, and / or dissemination of helminths. In some embodiments, the anthelmintic agents described herein include at least one therapeutic agent selected from the group consisting of pyrantel, ivermectin, mebendazole, albendazole, praziquantel, and miltefosine.

[0218] In some embodiments, the anti-infective agents described herein are antifungal agents. The term “antifungal agent,” as used herein, refers to a therapeutic agent having properties useful in the treatment of fungal infections. Antifungal agents may, among other things, have properties that prevent, inhibit, suppress, reduce, adversely affect, and / or interfere with the growth, survival, replication, function, and / or dissemination of fungi. In some embodiments, the antifungal agents described herein include at least one antifungal agent selected from the classes of azole antifungals, echinocandines, and polyenes. In some embodiments, the antifungal agents described herein include at least one antifungal agent selected from the group consisting of voriconazole, itraconazole, posaconazole, fluconazole, ketoconazole, clotrimazole, and miconazole.

[0219] In some embodiments, the antiinfective agents described herein are amoebicides. The term “amoebicides,” as used herein, refers to therapeutic agents having properties useful in treating amoebic infections. Amoebicides may, among other things, have properties that prevent, inhibit, suppress, reduce, adversely affect, and / or interfere with the growth, survival, replication, function, and / or dissemination of amoebas. In some embodiments, the amoebicides described herein include at least one therapeutic agent selected from the group consisting of nitazoxanides, chloroquine, paromomycin, metronidazole, and tinidazole.

[0220] In some embodiments, the anti-infective agents described herein are antibiotics. The term “antibiotic,” as used herein, refers to a therapeutic agent having properties useful in the treatment of bacterial-related diseases. Antibiotics may, among other things, have properties that prevent, inhibit, suppress, reduce, adversely affect, and / or interfere with the growth, survival, replication, function, and / or dissemination of bacteria. In some embodiments, the antibiotics described herein include macrolides (e.g., erythromycin), penicillins (e.g., nafcillin), cephalosporins (e.g., cefazolin), carbapenems (e.g., imipenem), monobactams (e.g., aztreonam), other beta-lactam antibiotics, beta-lactam inhibitors (e.g., sulbactam), oxalins (e.g., linezolid), aminoglycosides (e.g., gentamicin), chloramphenicol, sulfonamides (e.g., sufonamides) (e.g., oxalins (e.g., linezolid), aminoglycosides (e.g., gentamicin), chloramphenicol, sulfonamides) (e.g., The formulation includes at least one antibiotic selected from the following classes: sulfamethoxazole, glycopeptides (e.g., vancomycin), quinolones (e.g., ciprofloxacin), tetracyclines (e.g., minocycline), trimethoprim, metronidazole, clindamycin, mupirocin, rifamycin (e.g., rifampin), streptogramins (e.g., quinupristin and dalfopristin), lipoproteins (e.g., daptomycin), and polyenes (e.g., amphotericin B).In some embodiments, the antibiotics described herein include at least one antibiotic selected from the group consisting of erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim, rifampin, metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, gatifloxacin, moxifloxacin, gemifloxacin, enoxacin, fleroxacin, minocycline, linezolid, temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid, and any combination thereof.

[0221] In some embodiments, the antiinfective agents described herein are antiviral agents. The term “antiviral agent,” as used herein, refers to a therapeutic agent having properties useful in the treatment of a virus-related disease. Properties useful in the treatment of a virus-related disease may include, among other things, properties that prevent, inhibit, suppress, reduce, adversely affect, and / or interfere with the growth, survival, replication, function, and / or dissemination of the virus. In some embodiments, the antiviral agents described herein include at least one antiviral agent selected from the classes of nucleoside analogs, pyrophosphate analogs, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogs, acyclic nucleoside phosphonate analogs, and 5-substituted 2'-deoxyuridine analogs.

[0222] In some embodiments, the antiviral agents described herein include abacavir, acyclovir, adefovir, amantadine, amprenavir, asunaprevir, atazanavir, boceprevir, brivudine, cidofovir, cobicistat, dasabuvir, daclatasvir, darunavir, delavirdin, didanosine, dipivoxil, docosanol, dolutegravir, efavirenz, elbasvir, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, favipiravir, homivirsen, fosamprenavir, foscarnet, ganciclovir, grazoprevir, idoxuridine, imiquimod, indinavir, interferon alphacon 1, lamivudine, laninamivir octanoate 1 It contains at least one antiviral drug selected from the group consisting of tel, ledipasvir, lopinavir, maraviroc, nelfinavir, nevirapine, ombitasvir, oseltamivir, palivizumab, paritaprevir, pegylated interferon alfa-2a, penciclovir, peramivir, podofilox, raltegravir, ribavirin, rilpivirine, rimantadine, ritonavir, RSV-IGIV, saquinavir, simeprevir, sofosbuvir, stabudine, telaprevir, terabivudine, tenofovir alafenamide, tenofovir disoproxil fumarate, tipranavir, trifluridine, valacyclovir, valganciclovir, vaniprevir, variZIG, vidarabine, VZIG, zalcitabine, zanamivir, and zidovudine.

[0223] In some embodiments, the therapeutic agent of the present invention is a drug of the drug class described herein. In some embodiments, the therapeutic agent of the present invention is a prodrug of the therapeutic agent described herein, which exerts a therapeutic effect after being activated, for example, at a target site on a carrier particle. The prodrug and its design are known to those skilled in the art (see, for example, Rautio, J. et al., 2008, Nature Reviews Drug Discovery, 7(3), 255-270; Dubey, S., and Valecha, V., 2014, World Journal of Pharmaceutical Research, 3(7), 277-297). In some embodiments, the therapeutic agent of the present invention is a pharmaceutically acceptable salt of the therapeutic agent described herein. In some embodiments, the therapeutic agent of the present invention is a structural analog of the therapeutic agent described herein and is used for an equivalent therapeutic indication to the therapeutic agent described herein.

[0224] The means and methods provided herein can improve the drug delivery and action of the anxiolytics, sedatives, narcotics, antidepressants, anti-migraine agents, anti-inflammatory agents, and / or anti-infective agents described herein. For example, some of the therapeutic agents described herein require rapid absorption to develop their full therapeutic potential. Other therapeutic agents described herein are typically administered to patients who have swallowing problems or require long-term intake. The means and methods provided facilitate absorption and promote the intake of therapeutic agents.

[0225] Accordingly, the present invention is at least in part based on the remarkable finding that the means and methods provided by the present invention can enhance and / or support the therapeutic effects of anxiolytics, sedatives, narcotic drugs, antidepressants, anti-migraine drugs, anti-inflammatory drugs, and / or anti-infective drugs.

[0226] In certain embodiments, the present invention relates to a solid pharmaceutical composition comprising at least one adjuvant.

[0227] As used herein, the term "adjuvant" refers to a component of a solid pharmaceutical composition that is generally non-toxic to the recipient at the dosage used and is neither a carrier particle nor a compressed carrier material nor a therapeutic agent.

[0228] In some embodiments, the adjuvants described herein include at least one adjuvant selected from the group consisting of anti-adherents, binders, fillers, coatings, disintegrants, taste modifiers, smell altering agents, appearance modifiers, flowability enhancement agents, lubricants, preservatives, and adsorbents.

[0229] In some embodiments, the adjuvants described herein improve the adhesion of carrier particles to a target site, such as a mucous membrane.

[0230] In some embodiments, the adjuvant content described herein is between 0.1% and 40% by weight, based on the weight of the solid pharmaceutical composition.

[0231] The adjuvant can facilitate the formation of the solid pharmaceutical composition according to the present invention, or further enhance its desired drug delivery properties.

[0232] Therefore, the present invention is at least in part based on the surprising finding that the solid pharmaceutical composition according to the present invention can be further improved by at least one adjuvant.

[0233] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein at least one adjuvant is selected from the group consisting of disintegrants, lubricants, and flow enhancers.

[0234] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein at least one adjuvant is a disintegrant.

[0235] The term “disintegrant,” as used herein, refers to an agent for the preparation of a solid pharmaceutical composition that disintegrates the solid pharmaceutical composition and releases a therapeutic agent upon contact with moisture. Agents having disintegrating properties are known to those skilled in the art (see, for example, Desai, PM t al., 2016, Journal of Pharmaceutical Sciences, 105(9), 2545-2555). In some embodiments, the content of the disintegrant described herein is between 2% by weight and 25% by weight based on the weight of the solid pharmaceutical composition. In some embodiments, the disintegrant described herein comprises at least one disintegrant selected from the group consisting of cellulose derivatives, starch, bentonite, sodium alginate, pectin, and cross-linked polyvinylpyrrolidone. In some embodiments, the disintegrant described herein comprises at least one disintegrant selected from the group consisting of sodium cellulose glycolate, tyrose, primojel, explodeb, bentonite, sodium alginate, pectin, and crospovidone.

[0236] In certain embodiments, the disintegrants described herein are disintegrants that alter the properties for site-directed drug delivery (e.g., increase mucosal adhesion). In certain embodiments, the disintegrants described herein are disintegrants that become gel-like in an alkaline environment. In certain embodiments, the disintegrants described herein contain croscarmellose sodium.

[0237] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein at least one adjuvant is a lubricant.

[0238] As used herein, the term "lubricant" refers to an agent that prevents the ingredients of a solid pharmaceutical composition from agglomerating together and / or from adhering to equipment that comes into contact with the solid pharmaceutical composition during the production process.

[0239] Agents having lubricating properties are known to those skilled in the art (see, for example, Wang, J., et al., 2010, European Journal of Pharmaceutics and Biopharmaceutics, 75(1), 1-15, US5843477, and Paul, S. et al., 2018, European Journal of Pharmaceutical Sciences, 117, 118-127).

[0240] In some embodiments, the content of the lubricant described herein is between 0.25% and 5% by weight, based on the weight of the solid pharmaceutical composition.

[0241] In some embodiments, the lubricants described herein are hydrophilic lubricants. In some embodiments, the lubricants described herein are hydrophobic lubricants. In some embodiments, the lubricants described herein are solid fatty acids or salts thereof. In some embodiments, the lubricants described herein include at least one lubricant selected from the group consisting of stearic acid, palmitic acid, and myristic acid. In some embodiments, the lubricants described herein include at least one lubricant selected from the group consisting of magnesium silicate, stearic acid, sodium stearyl fumarate, boric acid, Carbowax (PEG) 4000 / 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, metal stearate (Mg, Ca, Na), Sterotex, talc, wax, Stear-O-Wet, and glyceryl behenate.

[0242] In some embodiments, the lubricants described herein have the additional properties of flow enhancers. In some embodiments, the lubricants described herein have the additional properties of disintegrants.

[0243] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein at least one adjuvant is a flow enhancer.

[0244] As used herein, the term “flow enhancer” refers to an agent that reduces interparticle friction and adhesion. Agents having flow-enhancing properties are known to those skilled in the art (see, for example, Augsburger, LL, and Shangraw, R. F, 1966, Effect of glidants in tableting. Journal of Pharmaceutical Sciences, 55(4), 418-423; Armstrong, NA, 2008, In Pharmaceutical Dosage Forms-Tablets (pp. 267-284). CRC Press). A particular flow enhancer enhances flow only within a specific concentration range. Therefore, the concentration of a flow enhancer in a solid pharmaceutical composition depends on the particular flow enhancer. In some embodiments, the flow enhancers described herein include silica gel, fumed silica, talc, and at least one flow enhancer selected from the group consisting of magnesium carbonate and sodium hydrated silica aluminate.

[0245] Techniques for predicting and determining appropriate liquidity are known to those skilled in the art (see, for example, Hildebrandt, C, et al., 2019, Pharmaceutical development and technology, 24(1), 35-47; Morin, G., & Briens, L, 2013, AAPS Pharmscitech, 14(3), 1158-1168).

[0246] Disintegrants, lubricants, and / or flow enhancers can facilitate the formation of the solid pharmaceutical composition according to the present invention, or further enhance its desired drug delivery properties.

[0247] Therefore, the present invention is at least in part based on the surprising finding that the properties of the solid pharmaceutical composition according to the present invention can be further improved by disintegrants, lubricants, and / or flow enhancers.

[0248] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein at least one adjuvant is selected from the group consisting of taste modifiers, odor modifiers, and appearance modifiers.

[0249] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein at least one adjuvant is a fragrance modifier.

[0250] The term “odor modifier,” as used herein, refers to any adjuvant capable of inducing an odor change detectable by a human subject and / or an olfactometer. Olfactometers, e.g., flow-olfactometers, dynamic dilution olfactometers, and field olfactometers, are known to those skilled in the art. Odor modifiers that can be used to alter the odor of solid pharmaceutical compositions are also known to those skilled in the art (see, for example, US20120164217, US6667059). In some embodiments, the odor modifiers described herein are scenting agents selected from the group of lemon oil, fragrance oils derived from flowers, e.g., lilac, honeysuckle, rose, carnation, and other such oils having a GRAS status.Oils that are GRAS (Grain Oil Standard) include basil (ocimum basilicum), bergamot (citrus bergamia), black pepper (piper nigrum), cassia (cinnamomum cassia), cinnamon (cinnamomum zeylanicum), clary sage (salvia sclarea), clove (eugenia caryophyllata), coriander (coriandrum sativum), cumin (cuminum cyminum), fennel (foeniculum vulgare), geranium (pelargonium graveolens), ginger (zingiber officinale), grapefruit (citrus x paradisi), juniper berry (juniperus communis), lemon (citrus limon), lemongrass (cymbopogon flexuosus), lime (citrus aurantifolia), marjoram (origanum majorana), and European mint (melissa). This list includes, but is not limited to, plants such as oregano (Origanum vulgare), peppermint (Mentha piperita), petitgrain (Citrus aurantium), Roman chamomile (Anthemis nobilis), rosemary (Rosmarinus officinalis), spearmint (Mentha spicata), tangerine (Citrus reticulate), thyme (Thymus vulgaris), wild orange (Citrus sinensis), and ylang-ylang (Cananga odorata).

[0251] In some embodiments, the content of the odor modifier described herein is between 0.1% and 10% by weight based on the weight of the solid pharmaceutical composition. A higher specific surface area of ​​the carrier particles enhances the effect of the odor modifier.

[0252] In some embodiments, the odor modifiers described herein alter the odor perceived by the subject ingesting the solid pharmaceutical during ingestion.

[0253] In some embodiments, the odor modifiers described herein alter the odor perceived by the subject after ingestion of a solid pharmaceutical product.

[0254] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein at least one adjuvant is a cosmetic modifier.

[0255] When used herein, the term "appearance modifier" refers to an adjuvant that alters the color and / or shape of a solid pharmaceutical composition.

[0256] Appearance modifiers and their uses are well known to those skilled in the art (see, for example, Biswal, PK et al., 2015, International Journal of Pharmaceutical, Chemical & Biological Sciences, 5(4)).

[0257] In some embodiments, the appearance modifiers described herein alter the appearance of the solid pharmaceutical composition as is. In some embodiments, the appearance modifiers described herein alter the appearance of the disintegrated solid pharmaceutical composition.

[0258] In some embodiments, appearance modifiers enable identification of solid pharmaceutical compositions according to the present invention, perception of flavor (e.g., red for cherry), brand identification, quality perception, and / or anti-counterfeiting.

[0259] In some embodiments, the content of the appearance modifier described herein is between 0.1 and 2% by weight based on the weight of the solid pharmaceutical composition. The high specific surface area of ​​the carrier material enhances the effect of the appearance modifier.

[0260] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein at least one adjuvant is a flavor modifier.

[0261] As used herein, the term “flavor modifier” refers to an adjuvant that alters the flavor of a solid pharmaceutical composition. Flavor determination can be performed by various mass spectrometry techniques or by human sensory evaluation. Flavor modifiers are well known to those skilled in the art (see, for example, Ahire, S. B, et al., 2012, Pharma Science Monitor, 3(3), US20070122475, WO1998043675).

[0262] In some embodiments, the flavor modifiers described herein are selected from the group consisting of lemon, orange, grapefruit, berry flavors, peppermint, licorice, and menthol.

[0263] In some embodiments, the flavor modifiers described herein are selected from the group consisting of manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin, methyl salicylate, carbomer 934, carbomer 971, carbomer 974, PEG-5M, carrageenan, chondroitin sulfate, dextran sulfate, alginic acid, dielan gum, xanthan gum, and zinc salts.

[0264] The content of the flavor modifier described herein is determined according to the strength of the flavor modifier. A high specific surface area of ​​the carrier particles can enhance the flavor-altering effect of the flavor modifier.

[0265] In some embodiments, the content of the appearance modifier described herein is between 0.1% and 20% by weight, based on the weight of the solid pharmaceutical composition.

[0266] The use of odor modifiers and appearance modifiers described herein, particularly taste modifiers, can improve the odor, taste, and / or appearance of the solid pharmaceutical composition according to the present invention. The improved odor, taste, and / or appearance can promote the ingestion of the solid pharmaceutical composition according to the present invention.

[0267] Therefore, the present invention is at least in part based on the surprising finding that taste modifiers, odor modifiers, and / or appearance modifiers can facilitate the ingestion of solid pharmaceutical compositions according to the present invention.

[0268] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the present invention, wherein the flavor modifier is selected from the group consisting of artificial sweeteners, acidity modifiers, gums, cellulose derivatives, hard fats, and salts. The high surface area of ​​the carrier particles of the present invention can enhance the olfactory effect of the flavor modifier described herein.

[0269] As used herein, the term “artificial sweetener” refers to an adjuvant that provides a sweetness similar to that of sugar. Artificial sweeteners may be derived from the production of plant extracts or processed by chemical synthesis. In some embodiments, the artificial sweeteners described herein are selected from the group consisting of sucralose, thaumatin, neohesperidin, aspartame, saccharin, acesulfame, erythritol, xylitol, sorbitol, and stevia.

[0270] The concentration of the artificial sweetener to be used in the solid pharmaceutical composition according to the present invention is known to those skilled in the art and is determined according to the strength of the artificial sweetener.

[0271] The term "acidity modifier," as used herein, refers to an adjuvant that alters the perceived acidity of a pharmaceutical composition upon ingestion. In some embodiments, the acidity modifiers described herein are citric acid, phosphoric acid, and / or salts thereof.

[0272] The concentration of the acidity regulator to be used in the solid pharmaceutical composition according to the present invention is known to those skilled in the art and is determined according to the strength of the acidity regulator and the acidity to be corrected.

[0273] The term "gum", as used herein, refers to an adjuvant that changes the viscosity perceived upon ingestion of a pharmaceutical composition. In some embodiments, the gums described herein improve the adhesion of carrier particles at a target site, such as a mucosa.

[0274] In some embodiments, the gums described herein are gums selected from the group consisting of alginate, carrageenan, xanthan, agar, pectin, pectic acid, gum arabic, tragacanth gum and karaya gum, guar gum, and quaternized guar gum.

[0275] The term "cellulose derivative", as used herein, refers to a polysaccharide polymer, such as a cellulose ether derivative and a cellulose ester derivative, that can be used to mask or alter the unpleasant taste of a pharmaceutical composition.

[0276] In some embodiments, the cellulose derivatives described herein are cellulose derivatives selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose. In some embodiments, the cellulose derivatives described herein are water-insoluble polymers, such as ethylcellulose. In some embodiments, the cellulose derivatives described herein are water-soluble polymers, such as polymers of hydroxypropylmethylcellulose. In some embodiments, the cellulose derivatives described herein are nonionic cellulose ethers, such as ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, or hydroxypropylmethylcellulose.

[0277] In some embodiments, the cellulose derivatives described herein are anionic ether derivatives such as sodium carboxymethyl cellulose.

[0278] In some embodiments, the solid pharmaceutical composition according to the invention and / or the carrier particles in the solid pharmaceutical composition according to the invention are coated with a cellulose derivative to mask an unpleasant taste.

[0279] In some embodiments, taste modifiers such as hard fat and / or salts induce or enhance the perception of a pleasant good taste.

[0280] In some embodiments, taste modifiers such as cellulose derivatives or gums reduce the spread of an unpleasant taste (e.g., bitterness).

[0281] The use of taste modifiers, particularly the taste modifiers described herein, can improve the taste of the solid pharmaceutical composition according to the invention or mask the taste of the components of the solid pharmaceutical composition according to the invention. The improved taste can promote the ingestion of the solid pharmaceutical composition according to the invention.

[0282] Thus, the present invention is at least partially based on the surprising finding that artificial sweeteners, acidity regulators, gums, cellulose derivatives, hard fat, and / or salts can promote the ingestion of the solid pharmaceutical composition according to the invention. ]

[0283] In certain embodiments, the present invention relates to a solid pharmaceutical composition according to the invention for use in a treatment.

[0284] In certain embodiments, the present invention relates to a compressed carrier substance produced according to the invention for use in a treatment.

[0285] In certain embodiments, the present invention relates to carrier particles according to the invention for use in a treatment.

[0286] The phrase “for use in treatment” or “for use in treatment of disease or disorder” may also mean “for use in treatment of symptoms of disease or disorder.” Symptoms of disease or disorder may be symptoms described herein and / or symptoms of disease or disorder known to those skilled in the art, for example, symptoms in the ICD-11 description of a particular disease or disorder (World Health Organization, 2018, ICD-11 for Mortality and Mortality Statistics) or symptoms or diagnostic criteria described in DSM-5 (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, 2013).

[0287] The phrase "for use in treatment" or "for use in treatment of disease or disorder" may refer to treatment in any age group, including pediatric patients, adult and / or elderly patients.

[0288] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in treatment, comprising a therapeutic agent described herein.

[0289] In certain embodiments, the present invention relates to a compressed carrier material produced according to the present invention for use in treatment, comprising a therapeutic agent described herein.

[0290] In certain embodiments, the present invention relates to carrier particles for use in treatment, comprising a therapeutic agent as described herein.

[0291] For example, the therapeutic agent can be administered to a patient in an effective dose, where the solid pharmaceutical composition according to the present invention, the compressed carrier material produced according to the present invention, or the carrier particles according to the present invention promote drug delivery and / or enhance the therapeutic effect of the therapeutic agent by improved drug delivery properties.

[0292] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve treatment.

[0293] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in accordance with the present invention, for use in the treatment of senile diseases or disorders. In certain embodiments, the present invention relates to a compressible carrier material for use in accordance with the present invention for use in the treatment of aging diseases or disorders.

[0294] In certain embodiments, the present invention relates to carrier particles for use in accordance with the present invention for use in the treatment of aging diseases or disorders.

[0295] The term “geriatric disease or disorder,” as used herein, refers to a disease or disorder affecting older persons. In some embodiments, the geriatric disease or disorder described herein is a disease or disorder that primarily affects older persons (i.e., older persons constitute a larger patient population than younger adults and children), and in particular, a disease or disorder in which older persons constitute at least 40%, 50%, 60%, 70%, 80%, or 90% of the patient population. In some embodiments, the geriatric disease or disorder described herein is a disease or disorder that increases age-related morbidity and / or mortality. In some embodiments, the phrase “for use in the treatment of geriatric disease or disorder” refers to use in the treatment of a disease or disorder in older patients.

[0296] In some embodiments, the elderly described herein are humans who are above a certain age, such as above 50 years old, 55 years old, 60 years old, 65 years old, 70 years old, 75 years old, 80 years old, or 85 years old. However, some behaviors may accelerate the aging of the body. For example, smokers consume the reserve capacity of their respiratory systems early, making the aging process of the lungs and other organs more rapid. Thus, in certain embodiments, the elderly described herein are defined by other or additional criteria besides age. In some embodiments, the elderly described herein include adults who have a morbidity rate associated with a certain aging process (e.g., tobacco consumption, cancer, diabetes). In some embodiments, the elderly described herein include adults who have a certain accelerated aging morbidity rate (e.g., genetic diseases or disorders). In some embodiments, the elderly described herein are defined by one of the guidelines analyzed and / or described by certain guidelines, such as Singh, S., & Bajorek, B., 2014, Pharmacy practice, 12(4), 489.

[0297] In some embodiments, the senile disease or disorder is at least one disease or disorder selected from the group consisting of osteoporosis, diabetes, cancer, benign prostatic hyperplasia, and cardiovascular disease.

[0298] The symptoms of senile diseases or disorders include, but are not limited to, cognitive decline, depression, incontinence, frailty, vitamin D deficiency, renal insufficiency, and chronic pain.

[0299] Treatment for age-related diseases or disabilities differs from standard medications for adults because the unique needs of elderly patients must be taken into consideration. The aging body is physiologically different from that of younger adults, and, for example, declines in various organ systems become more pronounced with age. Various factors may be relevant to the treatment of elderly patients, depending on, for example, past health problems, lifestyle choices, and remaining reserves. Such factors relevant to the treatment of elderly patients include, for example, limitations in the ability to swallow oral medications, adherence to treatment, changes in absorption, changes in distribution, changes in metabolism, changes in excretion, increased probability of drug interactions, increased probability of adverse drug reactions, increased concerns about quality of life, reduced social support, and decreased functional capacity.

[0300] The means and methods provided by the present invention are particularly useful in the treatment of elderly patients. For example, improved desired drug delivery properties, such as rapid disintegration time, of ODTs containing high doses of the therapeutic agents described herein can improve drug absorption and promote compliance in the context of treating geriatric diseases or disabilities. For example, improved mechanical stability of solid pharmaceutical compositions can enable packaging that is easier to open without damaging the solid pharmaceutical composition and meets the needs of elderly patients with reduced functional capacity.

[0301] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of age-related diseases or disorders.

[0302] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in accordance with the present invention, for use in the treatment of pediatric diseases or disorders.

[0303] In certain embodiments, the present invention relates to a compressible carrier material for use in accordance with the present invention for use in the treatment of pediatric diseases or disorders.

[0304] In certain embodiments, the present invention relates to carrier particles for use in accordance with the present invention for use in the treatment of pediatric diseases or disorders.

[0305] The term “pediatric disease or disorder,” as used herein, refers to a disease or disorder affecting infants and children. In some embodiments, the pediatric disease or disorder described herein is a disease or disorder that primarily affects infants and children (i.e., that infants and children constitute a larger patient population than adults and the elderly), and in particular a disease or disorder in which infants and children constitute at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the patient population. In some embodiments, the phrase “for use in the treatment of a pediatric disease or disorder” refers to use in the treatment of a disease or disorder in infants or children.

[0306] In some embodiments, the infants and children described herein are humans under a certain age, for example, under 21 years, under 20 years, under 19 years, under 18 years, under 17 years, under 16 years, under 15 years, under 14 years, under 13 years, under 12 years, under 11 years, under 10 years, under 9 years, under 8 years, under 7 years, under 6 years, under 5 years, under 4 years, under 3 years, under 2 years, under 1 year, or under 0.5 years. Other or further factors besides age may be relevant to the use in the treatment of pediatric diseases or disorders. In some embodiments, the infants and children described herein are humans under a certain weight, for example, under 44 kg, under 42 kg, under 40 kg, under 38 kg, under 36 kg, under 34 kg, under 32 kg, under 30 kg, under 28 kg, under 26 kg, under 24 kg, under 22 kg, or under 20 kg. In some embodiments, the infants and children described herein are humans defined by another maturation marker or further maturation marker.

[0307] In some embodiments, the pediatric diseases or disorders described herein are pain in pediatric patients and / or infections in pediatric patients.

[0308] In some embodiments, the childhood disease or disorder described herein is at least one disease or disorder selected from the group consisting of anemia, asthma, chickenpox, diphtheria, leukemia, measles, mumps, pneumonia, polio, tuberculosis, pertussis, Lyme disease, fever, Down syndrome, dental caries, cystic fibrosis, Chagas disease, candidiasis, cancer, and bronchiolitis.

[0309] In some embodiments, the childhood illnesses or disorders described herein are mental disorders, such as generalized anxiety disorder and / or childhood-onset bipolar disorder.

[0310] The bodies of infants or newborns are physiologically substantially different from those of adults. Children are not simply “miniature adults.” The immature physiology of infants or newborns must be taken into consideration, and factors relevant to the treatment of pediatric patients must be considered. Such factors relevant to the treatment of pediatric patients include, for example, limitations in the ability to swallow oral medications, adherence to treatment, changes in absorption, changes in distribution, changes in metabolism, changes in excretion, concerns regarding developmental problems, and limitations in functional capacity.

[0311] The means and methods provided by the present invention are particularly useful for the treatment of pediatric patients. For example, improved desired drug delivery properties, such as rapid disintegration time, of an ODT containing a high dose of the therapeutic agent described herein can improve drug absorption and promote compliance in the context of treating pediatric diseases or disorders.

[0312] Furthermore, the means and methods provided herein enable, in particular, weakening the binding of ODT to water (see, for example, Example 6). This property is particularly relevant because a large volume of bound water can lead to localized swelling and subsequent suffocation hazards. While the suffocation hazard is relevant to any patient group, it is particularly relevant in pediatrics, for example, by application by untrained caregivers (e.g., parents) and / or in stressful situations, such as at night. Thus, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of pediatric diseases or disorders.

[0313] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use according to the present invention, wherein the senile disease or disorder is a senile and pediatric disease or disorder.

[0314] In certain embodiments, the present invention relates to a compressible carrier material for use in accordance with the present invention, wherein the aging disease or disorder is an aging and pediatric disease or disorder.

[0315] In certain embodiments, the present invention relates to carrier particles for use according to the present invention, wherein the aging disease or disorder is an aging and pediatric disease or disorder.

[0316] The term “senile and pediatric diseases or disorders,” as used herein, refers to diseases or disorders affecting the elderly, as well as infants and / or children. In some embodiments, the senile and pediatric diseases or disorders described herein are diseases or disorders that primarily affect senile and pediatric patients (i.e., those senile and pediatric patients constitute a larger patient population than non-senile adults), and in particular, those diseases or disorders in which senile and pediatric patients constitute at least 51%, at least 60%, at least 70%, at least 80%, or at least 90% of the patient population. In some embodiments, the phrase “for use in the treatment of senile and pediatric diseases or disorders” refers to use in the treatment of diseases or disorders in senile and pediatric patients.

[0317] Elderly and pediatric patients have overlapping limitations and needs. Factors related to the treatment of elderly and pediatric patients include, for example, limitations in the ability to swallow oral medications, adherence to treatment, changes in absorption, changes in distribution, changes in metabolism, changes in excretion, and limitations in functional capacity.

[0318] The means and methods provided by the present invention are particularly useful for the treatment of elderly and pediatric patients. For example, improved desired drug delivery properties, such as rapid disintegration time, of ODTs containing high doses of the therapeutic agents described herein can improve drug absorption and promote compliance in the context of treating geriatric and pediatric diseases or disorders.

[0319] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of senile and pediatric diseases or disorders.

[0320] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in accordance with the present invention, for use in the treatment of a disease or disorder selected from the group of anxiety disorders, bipolar disorder, pain, infection, migraine, sleep disorders, and depressive disorders.

[0321] In certain embodiments, the present invention relates to a compressible carrier material for use in accordance with the present invention for use in the treatment of a disease or disorder selected from the group of anxiety disorders, bipolar disorder, pain, infection, migraine, sleep disorders, and depressive disorders.

[0322] In certain embodiments, the present invention relates to carrier particles for use in accordance with the present invention for use in the treatment of a disease or disorder selected from the group of anxiety disorders, bipolar disorder, pain, infection, migraine, sleep disorders, and depressive disorders.

[0323] Symptoms of diseases or disorders selected from the group of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders may make it difficult to take therapeutic agents during treatment. The means and methods provided by the present invention facilitate the intake of therapeutic agents in the context of diseases or disorders selected from the group of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders.

[0324] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of a disease or disorder selected from the group of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders.

[0325] In a particular embodiment, the present invention relates to a solid pharmaceutical composition for use in the treatment of anxiety disorders, for use according to the present invention.

[0326] In a particular embodiment, the present invention relates to a compressible carrier material for use in accordance with the present invention for use in the treatment of anxiety disorders.

[0327] In a particular embodiment, the present invention relates to carrier particles for use in accordance with the present invention for use in the treatment of anxiety disorders.

[0328] As used herein, the term “anxiety disorder” refers to a disorder that shares the characteristics of excessive fear and anxiety, as well as associated behavioral disorders.

[0329] Examples of anxiety disorders described herein include, but are not limited to, panic attacks, agoraphobia, acute stress disorder, specific phobias, panic disorder, psychotropic anxiety disorder, organic anxiety disorder, obsessive-compulsive anxiety disorder, post-traumatic stress disorder, separation anxiety disorder, social anxiety disorder, and generalized anxiety disorder. Anxiety as referred to herein also includes situational anxiety (e.g., that a performer experiences before a performance). In certain embodiments, the anxiety disorders described herein are anxiety disorders diagnosed according to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, 2013, American Psychiatric Association).

[0330] Symptoms of anxiety disorders include, but are not limited to, anxiety, emotional instability, fatigue, difficulty concentrating, irritability, muscle tension, sleep disturbances, fear, sweating, tremors, gastrointestinal problems, increased heart rate, increased respiratory rate, suicidal ideation, and suicidal behavior.

[0331] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of anxiety disorders, comprising an anxiolytic, in particular an anxiolytic described herein, for use according to the present invention.

[0332] In certain embodiments, the present invention relates to a compressible carrier material for use in the treatment of anxiety disorders, comprising an anxiolytic, in particular anxiolytic as described herein, for use in accordance with the present invention.

[0333] In certain embodiments, the present invention relates to carrier particles for use in the treatment of anxiety disorders, wherein the compressed carrier material contains an anxiolytic, in particular the anxiolytics described herein.

[0334] Patients with anxiety disorders tend to have poor adherence to treatment, and some symptoms of anxiety disorders, such as panic attacks, require rapid absorption of therapeutic agents to ensure a rapid onset of action. The means and methods provided by the present invention can facilitate the uptake and accelerate the absorption of therapeutic agents in the context of anxiety disorders.

[0335] Therefore, the present invention is at least in part based on the remarkable finding that solid pharmaceutical compositions according to the present invention, compressed carrier materials produced according to the present invention, and / or carrier particles according to the present invention can improve the treatment of anxiety disorders.

[0336] In a particular embodiment, the present invention relates to a solid pharmaceutical composition for use in the treatment of bipolar disorder, for use according to the present invention.

[0337] In a particular embodiment, the present invention relates to a compressible carrier material for use in accordance with the present invention for use in the treatment of bipolar disorder.

[0338] In a particular embodiment, the present invention relates to carrier particles for use in accordance with the present invention for use in the treatment of bipolar disorder.

[0339] As used herein, the term “bipolar disorder” refers to a disorder characterized by abnormally intense moodal states, such as mood episodes, occurring over distinct periods of time. A state of excessive elation or excitement is called a manic episode, and a state of extreme sadness or hopelessness is called a depressive episode. Symptoms of bipolar disorder include, but are not limited to, cyclical mood swings (i.e., cycles between manic episodes, depressive episodes, and normal moods), obsessive fear of harm, severe aggression, territorial aggression, thermal dysregulation, night sweats, difficulty falling asleep, difficulty sleeping, disjointed speech, rapid speech, loud speech, slurred speech, abnormal voice tone, disorganized thinking, excessive ritualization, dependence on transitional objects, hoarding, extreme separation anxiety, hallucinations, delusions, and cravings for sweets.

[0340] Individuals experiencing manic episodes generally also experience depressive episodes or symptoms, or mixed episodes in which features of both mania and depression are present simultaneously. These episodes are usually separated by periods of “normal” mood, but in some individuals, depression and mania may appear rapidly in alternation, known as rapid cycles. Extreme manic episodes may sometimes result in psychotic symptoms, such as delusions and hallucinations. Patients with bipolar disorder have had at least one manic or hypomanic (mild manic) episode. Patients with complete mania and depression are indicated as having bipolar I disorder. In some embodiments, bipolar disorder as described herein refers to bipolar I disorder. Patients with hypomania and depression are indicated as having bipolar II disorder. In some embodiments, bipolar disorder as described herein refers to bipolar II disorder.

[0341] The onset of an episode tends to be acute, and symptoms occur over several days to several weeks. Symptoms of mania or a manic episode include both mood and behavioral changes. Mood changes include: feeling high or excessively happy or sociable for extended periods, and feeling extremely irritable, agitated, "jumpy," or "wired." Behavioral changes include: speaking very rapidly, jumping from one thought to another, having racing thoughts; being easily distracted; increased goal-oriented activity, e.g., taking on new projects; restlessness; being unable to sleep much; unrealistic overconfidence in one's abilities; acting impulsively and engaging only in pleasure-seeking activities; as well as high-risk behaviors, e.g., spending sprees, impulsive sexual behavior, and impulsive corporate investments. Symptoms of depression or a depressive episode include both mood and behavioral changes. Mood changes include: feeling worried or empty for extended periods, and losing interest after enjoying an activity. Behavioral changes include: feeling tired or “stalling”; having trouble concentrating, recalling, and making decisions; feeling restless or irritable; changes in eating, sleeping, or other habits; and thoughts of death or suicide, or suicide attempts.

[0342] In certain embodiments, the treatment of bipolar disorder described herein is the treatment of childhood-onset bipolar disorder. Childhood-onset bipolar disorder can be detected using any method known in the art. In some embodiments, childhood-onset bipolar disorder is detected by the use of the Childhood Bipolar Questionnaire (CBQ).

[0343] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of bipolar disorder, comprising a sedative, particularly the sedative described herein, for use according to the present invention.

[0344] In certain embodiments, the present invention relates to a compressible carrier material for use in the treatment of bipolar disorder, comprising a sedative, particularly the sedative described herein, for use according to the present invention.

[0345] In certain embodiments, the present invention relates to carrier particles for use in the treatment of bipolar disorder, wherein the compressed carrier material contains a sedative, particularly the sedative described herein.

[0346] Patients with bipolar disorder tend to have poor adherence to treatment, and some symptoms of bipolar disorder, such as suicidal ideation during depressive episodes, require rapid absorption of therapeutic agents to ensure a rapid onset of action. The means and methods provided by the present invention can facilitate the uptake and accelerate the absorption of therapeutic agents in the context of bipolar disorder.

[0347] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of bipolar disorder.

[0348] In a particular embodiment, the present invention relates to a solid pharmaceutical composition for use in the treatment of pain, for use according to the present invention.

[0349] In a particular embodiment, the present invention relates to a compressible carrier material for use in the treatment of pain, for use in accordance with the present invention.

[0350] In a particular embodiment, the present invention relates to carrier particles for use in the treatment of pain, for use according to the present invention.

[0351] As used herein, the term "pain" refers to an unpleasant sensory and emotional experience associated with, or similar to, actual or potential tissue damage. Methods for determining pain are known to those skilled in the art and include pain measurement scales, cold-pressure tests, and analgesics.

[0352] In some embodiments, the pain described herein is selected from the group consisting of headache, neck pain, dysphagia, toothache, sore throat, pleuritic pain, arthralgia, bone pain, myalgia, acute pain, delayed pain, neuralgia, painful disorders, paroxysmal severe pain, chronic pain, hyperalgesia, hypoalgesia, hyperalgesia, referred pain, pelvic pain, anorectal pain, cancer-induced pain, withdrawal-induced pain, back pain, and lower back pain.

[0353] In some embodiments, the pain described herein is a symptom of a disease or disorder.

[0354] In some embodiments, the pain described herein is classified into classes of no pain, mild pain, moderate pain, and severe pain, for example, according to a numerical rating scale (NRS-11) (see, for example, Farrar, JT, et al., 2001, Pain, 94(2), 149-158).

[0355] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in accordance with the present invention, a carrier particle for use in accordance with the present invention, and / or a compressed carrier material for use in accordance with the present invention, for use in the treatment of severe pain.

[0356] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in accordance with the present invention, a carrier particle for use in accordance with the present invention, and / or a compressed carrier material for use in accordance with the present invention, for use in the treatment of moderate pain.

[0357] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in accordance with the present invention, a carrier particle for use in accordance with the present invention, and / or a compressed carrier material for use in accordance with the present invention, for use in the treatment of mild pain.

[0358] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of pain, for use according to the present invention, comprising a narcotic agent, in particular a narcotic agent described herein.

[0359] In certain embodiments, the present invention relates to a compressible carrier material for use in the treatment of pain, which contains a narcotic agent, in particular the narcotic agent described herein, for use according to the present invention.

[0360] In certain embodiments, the present invention relates to carrier particles for use in the treatment of pain, wherein the compressed carrier material contains a narcotic agent, in particular the narcotic agents described herein.

[0361] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of pain, comprising an analgesic, for use according to the present invention.

[0362] In certain embodiments, the present invention relates to a compressible carrier material for use in the treatment of pain, comprising an analgesic, for use according to the present invention.

[0363] In certain embodiments, the present invention relates to carrier particles for use in the treatment of pain, wherein the compressed carrier material contains an analgesic.

[0364] In certain embodiments, the analgesic described herein is paracetamol and / or an NSAID. In certain embodiments, the analgesic described herein is an NSAID selected from the group consisting of acetylsalicylic acid, ibuprofen, naproxen, diclofenac, indomethacin, piroxicam, and phenylbutazone.

[0365] The treatment of pain, particularly acute pain, requires rapid absorption of therapeutic agents to ensure a rapid onset of action. Furthermore, certain forms of pain, such as sore throat, can make it difficult to take therapeutic agents. The means and methods provided by the present invention can facilitate the uptake and accelerate the absorption of therapeutic agents in the context of pain.

[0366] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of pain.

[0367] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of infection, for use according to the present invention.

[0368] In a particular embodiment, the present invention relates to a compressible carrier material for use in accordance with the present invention for use in the treatment of infection.

[0369] In a particular embodiment, the present invention relates to carrier particles for use in the treatment of infection, for use in accordance with the present invention.

[0370] As used herein, the term "infection" refers to the invasion of at least one body tissue of a subject by one or more infectious pathogens, their proliferation, and the host tissue's response to the infectious pathogens and the toxins they produce. In some embodiments, the infections described herein are primary infections. In some embodiments, the infections described herein are opportunistic infections. In some embodiments, the infections described herein are secondary infections. In some embodiments, the pathogens causing the infections described herein are viruses, bacteria, fungi, or parasites. In some embodiments, the infections described herein are infections selected from the group of lower respiratory tract infections, HIV infections, diarrheal diseases, tuberculosis, and malaria.

[0371] In some embodiments, the infection described herein is a viral infection. In some embodiments, the infection described herein is a viral infection of a genera selected from the group consisting of Adenoviridae, Anelloviridae, Arenaviridae, Astroviridae, Bunyaviridae, Bunyavirus, Caliciviridae, Coronaviridae, Filoviridae, Flaviviridae, Hepadnaviridae, Herpesviridae, Orthomyxoviridae, Papillomaviridae, Paramyxoviridae, Parvoviridae, Picornaviridae, Pneumoviridae, Polyomaviridae, Poxviridae, Reoviridae, Retroviridae, Rhabdoviridae, Rhabdovirus, and Togaviridae.

[0372] In some embodiments, the infections described herein include Aichi virus, Australian bat lyssavirus, BK polyomavirus, Bannavirus, Bermaforest virus, Bunyambella virus, Bunyavirus La Crosse, and Snowshoe Bunyavirus.Herpesviruses (hare), Cercopa virus, Chandipla virus, Chikungunya virus, Cosavirus A, Cowpox virus, Coxsackievirus, Crimean-Congo hemorrhagic fever virus, Dengue virus, Dorivirus, Dagbe virus, Duvenhage virus, Eastern equine encephalitis virus, Ebola virus, Echovirus, Encephalomyocarditis virus, Epstein-Barr virus, European bat lyssavirus, GB virus C / Hepatitis G virus, Hantan virus, Hendra virus, Hepatitis A virus Hepatitis B virus, Hepatitis C virus, Hepatitis E virus, Hepatitis delta virus, Horsepox virus, Human adenovirus, Human astrovirus, Human coronavirus, Human cytomegalovirus, Human enterovirus 68, Human enterovirus 70, Human herpesvirus 1, Human herpesvirus 2, Human herpesvirus 6, Human herpesvirus 7, Human herpesvirus 8, Human immunodeficiency virus, Human papillomavirus 1, Human papillomavirus 2, Human papillomavirus 16, Human papillomavirus 18, Human parainfluenza Influenza, human parvovirus B19, human respiratory syncytial virus, human rhinovirus, human SARS coronavirus, human spumaretrovirus, human T-lymphophilic virus, human torovirus, influenza A virus, influenza B virus, influenza C virus, Isfahan virus, JC polyomavirus, Japanese encephalitis virus, Junin arenavirus, KI polyomavirus, Kunzin virus, Lagos bat virus, Lake Victoria Marburg virus, Langatt virus Russ virus, Lassa virus, Rosedale virus, Looping virus, Lymphocytic choriomeningitis virus, Machupo virus, Mayarovirus, MERS coronavirus, Measles virus, Mengo encephalomyocarditis virus, Merkel cell polyomavirus, Mocola virus, Molluscum contagiosum virus, Monkeypox virus, Mumps virus, Murray Valley encephalitis virus, New York virus, Nipah virus, Norwalk virus, Onyonnyon virus, Aarf virus, Oropushé virus, Pichinde virus, Poliovirus, Punta(Toro) Phlebovirus, Pumara virus, Rabies virus, Rift Valley fever virus, Rosavirus A, Ross River virus, Group A rotavirus, Group B rotavirus, Group C rotavirus, Rubella virus, Sagiyama virus, Sarivirus A, Sandfly fever Sicilian virus It is an infection with at least one virus selected from the group consisting of (virus), Sapporo virus, SARS coronavirus 2, Semlik Forest virus, Seoul virus, monkey foam virus, monkey virus 5, Sindbis virus, Southampton virus, St. Louis encephalitis virus, tick-borne Poissant virus, Torquenovirus, Tuscany virus, Ukniemi virus, Vaccinia virus, varicella-zoster virus, smallpox virus, Venezuelan encephalitis virus, varicella-stomatitis virus, Western equine encephalitis virus, WU polyomavirus, West Nile virus, Yabasal tumor virus, Yabasal disease virus, yellow fever virus, and Zika virus.

[0373] In some embodiments, the infection described herein is an infection of at least one type of bacterium. In some embodiments, the infection described herein is an infection of Abiotrophia, Achromobacter, Acidaminococcus, Acidivorax, Acinetobacter, Actinobacillus, Actinobaculum, Actinomadura, Actinomyces, Aerococcus, Aeromonas, Afipia, Agrobacterium, Alcaligenes, Alloiococcus Alteromonas, Amycolata, Amycolatopsis, Anaerobospirillum, Anaerorhabdus, “Anguillina”, Arachnia, Arcanobacterium, Arcobacter, Arthrobacter, Atopobium, Aureobacterium, Bacillus, Bacteroides, Balneatrix , Bartonella, Bergeyella, Bifidobacterium, Bilophila, Branhamella, Borrelia, Bordetella, Brachyspira, Brevibacillus, Brevibacterium, Brevundimonas, Brucella, Burkholderia, Buttiauxella, Butyrivibrio, Ca lymmatobacterium, Campylobacter, Capnocytophaga, Cardiobacterium, Catonella, Cedecea, Cellulomonas, Centipeda, Chlamydia, Chlamydophila, Chromobacterium, Chyseobacterium, Chryseomonas, Citrobacter, Cl ostridium, Collinsella, Comamonas, Corynebacterium, Coxiella, Cryptobacterium, Delftia, Dermabacter, Dermatophilus, Desulfomonas, Desulfovibrio, Dialister, Dichelobacter, Dolosicoccus, Dolosigranulum,Edwardsiella、Eggerthella、Ehrlichia、Eikenella、Empedobacter、Enterobacter、Enterococcus、Erwinia、Erysipelothrix、Escherichia、Eubacterium、Ewingella、Exiguobacterium、Facklamia、Filifactor、Flavimonas、Flavobacterium、Flexispira、Francisella、Fusobacterium、Gardnerella、Gemella Globicatella、Gordona、Haemophilus、Hafnia、Helicobacter、Helococcus、Holdemania、Ignavigranum、Johnsonella、Kingella、Klebsiella、Kocuria、Koserella、Kurthia、Kytococcus、Lactobacillus、Lactococcus、Lautropia、Leclercia、Legionella、Leminorella、Leptospira、Leptotrichia、Leuconostoc、Listeria、Listonella、Megasphaera、Methylobacterium、Microbacterium、Micrococcus、Mitsuokella、Mobiluncus、Moellerella、Moraxella、Morganella、Mycobacterium、Mycoplasma、Myroides、Neisseria、Nocardia、Nocardiopsis、Ochrobactrum、OeskoviaOligella、Orientia、Paenibacillus、Pantoea、Parachlamydia、Pasteurella、Pediococcus、Peptococcus、Peptostreptococcus、Photobacterium、Photorhabdus、Plesiomonas Porphyrimonas、Prevotella、Propionibacterium、Proteus、Providencia、Pseudomonas、Pseudonocardia、Pseudoramibacter、Psychrobacter, Rahnella, Ralstonia, Rhodococcus, Rickettsia, Rochalimaea, Roseomonas, Rothia, Ruminococcus, Salmonella, Selenomonas, Serpulina, Serratia , Shewenella, Shigella, Simkania, Slackia, Sphingobacterium, Sphingomonas, Spirillum, Staphylococcus, Stenotrophomonas, Stomatococcus, Streptobacillus, This is an infection caused by at least one bacterium from a genus selected from the group consisting of Streptococcus, Streptomyces, Succinivibrio, Sutterella, Suttonella, Tatumella, Tissierella, Trabulsiella, Treponema, Tropheryma, Tsakamurella, Turicella, Ureaplasma, Vagococcus, Veillonella, Vibrio, Weeksella, Wolinella, Xanthomonas, Xenorhabdus, Yersinia, and Yokenella.

[0374] The strains of the genus Actimomyces europeus, Actimomyces georgiae, and Actimomyces gerencseriae, Actimomyces graevenitzii, Actimomyces israelii, Actimomyces meyeri, Actimomyces naeslundii, Actimomyces neuii neuii, Actimomyces neuii anitratus, Actimomyces odontolyticus, Actimomyces radingae, Actimomyces turicensis、Actimomyces viscosus、Arthrobacter creatinolyticus、Arthrobacter cumminsii、Arthrobacter woluwensis、Bacillus anthracis、Bacillus cereus、Bacillus circulans、Bacillus coagulans、Bacillus licheniformis、Bacillus megaterium, Bacillus myroides, Bacillus pumilus, Bacillus sphaericus, Bacillus subtilis, Bacillus thuringiensis, Borrelia afzelii, Borrelia andersonii, Borrelia bissettii, Borrelia burgdorferi, Borrelia garinii, Borrelia japonica、Borrelia lusitaniae、Borrelia tanukii、Borrelia turdi、Borrelia valaisiana Borrelia caucasica、Borrelia crocidurae、Borrelia recurrentis、Borrelia duttoni、Borrelia graingeri、Borrelia hermsii、Borrelia hispanica latyschewii、Borrelia mazzottii、Borrelia parkeri、Borreliapersica, Borrelia recurrentis, Borrelia turicatae, Borrelia venezuelensi, Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussis, Bordetella trematum, Clostridium absonum, Clostridium argentinense, Clostridium baratii, Clostridium bifermentans, Clostridium beijerinckii, Clostridium butyricum, Clostridium cadaveris, Clostridium carnis, Clostridium celatum, Clostridium clostridioforme, Clostridium cochlearium, Clostridium cocleatum, Clostridium fallax, Clostridium ghonii, Clostridium glycolicum, Clostridium haemolyticum, Clostridium hastiforme, Clostridium histolyticum, Clostridium indolis, Clostridium innocuum, Clostridium irregulare, Clostridium leptum, Clostridium limosum, Clostridium malenominatum, Clostridium novyi, Clostridium oroticum, Clostridium paraputrificum, Clostridium piliforme, Clostridium putrefasciens, Clostridium ramosum, Clostridium septicum, Clostridium sordelii, Clostridium sphenoides, Clostridium sporogenes, Clostridium subterminale, Clostridiumsymbiosum, Clostridium tertium, Clostridium tetani, Escherichia coli, Escherichia fergusonii, Escherichia hermanii, Escherichia vulneris, Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosus, Enterococcus solitarius, Haemophilus aegyptius, Haemophilus aphrophilus, Haemophilus paraphrophilus, Haemophilus parainfluenzae, Haemophilus segnis, Haemophilus ducreyi, Haemophilus influenzae, Klebsiella ornitholytica, Klebsiella oxytoca, Klebsiella planticola, Klebsiella pneumoniae, Klebsiella ozaenae, Klebsiella terrigena, Lysteria ivanovii, Lysteria monocytogenes, Mycobacterium abscessus, Mycobacterium africanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium avium, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacteriumbranderi, Mycobacterium brumae, Mycobacterium celatum, Mycobacterium chelonae, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium fortuitum, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium goodii, Mycobacterium haemophilum, Mycobacterium hassicum, Mycobacterium intracellulare, Mycobacterium interjectum, Mycobacterium heidelberense, Mycobacterium kansasii, Mycobacterium lentiflavum, Mycobacterium leprae, Mycobacterium malmoense, Mycobacterium marinum, Mycobacterium microgenicum, Mycobacterium microti, Mycobacterium mucogenicum, Mycobacterium neoaurum, Mycobacterium nonchromogenicum, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium scrofulaceum, Mycobacterium shimoidei, Mycobacterium simiae, Mycobacterium smegmatis, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium thermoresistabile, Mycobacterium triplex, Mycobacterium triviale, Mycobacteriumtuberculosis, Mycobacterium tusciae, Mycobacterium ulcerans, Mycobacterium vaccae, Mycobacterium wolinskyi, Mycobacterium xenopi, Mycoplasma buccale, Mycoplasma faucium, Mycoplasma fermentans, Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma lipophilum, Mycoplasma orale, Mycoplasma penetrans, Mycoplasma pirum, Mycoplasma pneumoniae, Mycoplasma primatum, Mycoplasma salivarium, Mycoplasma spermatophilum, Pseudomonas aeruginosa, Pseudomonas alcaligenes, Pseudomonas chlororaphis, Pseudomonas fluorescens, Pseudomonas luteola. Pseudomonas mendocina、Pseudomonas monteilii、Pseudomonas oryzihabitans、Pseudomonas pertocinogena、Pseudomonas pseudalcaligenes、Pseudomonas putida、Pseudomonas stutzeri、Rickettsia africae、Rickettsia akari、Rickettsia australis、Rickettsia conorii、Rickettsia felis、Rickettsia honei、Rickettsia japonica、Rickettsia mongolotimonae、Rickettsia prowazekii、Rickettsia rickettsiae、Rickettsia sibirica、Rickettsia slovaca、Rickettsia typhi、Salmonella choleraesuis choleraesuis、Salmonella choleraesuisarizonae, Salmonella choleraesuis bongori, Salmonella choleraesuis diarizonae, Salmonella choleraesuis houtenae, Salmonella choleraesuis indica, Salmonella choleraesuis salamae , Salmonella enteritidis, Salmonella typhi, Salmonella typhimurium, Shigella boydii, Shigella dysentaeriae, Shigella flexneri, Shigella sonnei, Staphylococcus aureus, Staphylococcus auricularis, Staphylococcus capitis capitis, Staphylococcus c. ureolyticus, Staphylococcus caprae, Staphylococcus aureus, Staphylococcus cohnii cohnii, Staphylococcus c. urealyticus, Staphylococcus epidermidis, Staphylococcus equorum, Staphylococcus gallinarum, Staphylococcus haemolyticus, Staphylococcus hominis hominis, Staphylococcus h. novobiosepticius, Staphylococcus hyicus, Staphylococcus intermedius, Staphylococcus lugdunensis, Staphylococcus pasteuri, Staphylococcus saccharolyticus, Staphylococcus saprophyticus, Staphylococcus schleiferi schleiferi, Staphylococcus s.coagulans, Staphylococcus sciuri, Staphylococcus simulans, Staphylococcus warneri, Staphylococcus xylosus, Streptococcus agalactiae, Streptococcus canis, Streptococcus dysgalactiae dysgalactiae, Streptococcus dysgalactiae equisimilis, Streptococcus equi equi, Streptococcus equi zooepidemicus, Streptococcus iniae, Streptococcus porcinus, Streptococcus pyogenes, Streptococcus anginosus, Streptococcus constellatus constellatus, Streptococcus constellatus pharyngidis, Streptococcus intermedius, Streptococcus mitis, Streptococcus oralis, Streptococcus sanguinis, Streptococcus cristatus, Streptococcus gordonii, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus vestibularis, Streptococcus criceti, Streptococcus mutans, Streptococcus ratti, Streptococcus sobrinus, Streptococcus acidominimus, Streptococcus bovis, Streptococcus equinus, Streptococcus pneumoniae, Streptococcus suis, Vibrio alginolyticus, V. carchariae, Vibrio cholerae, C.This is an infection caused by at least one bacterium selected from the group consisting of *Vibrio cincinnatiensis*, *Vibrio damsela*, *Vibrio fluvialis*, *Vibrio furnissii*, *Vibrio hollisae*, *Vibrio metschnikovii*, *Vibrio mimicus*, *Vibrio parahaemolyticus*, *Vibrio vulnificus*, *Yersinia pestis*, *Yersinia aldovae*, *Yersinia bercovieri*, *Yersinia enterocolitica*, *Yersinia frederiksenii*, *Yersinia intermedia*, *Yersinia kristensenii*, *Yersinia mollaretii*, *Yersinia pseudotuberculosis*, and *Yersinia rohdei*.

[0375] In some embodiments, the infection described herein is an infection of at least one fungal species. In some embodiments, the infection described herein is an infection of at least one fungal species belonging to a genus selected from the group consisting of Candida, Aspergillus, Cryptococcus, Histoplasma, Pneumocystis, and Stachybotrys. In some embodiments, the infections described herein are Aspergillus fumigatus, Aspergillus flavus, Aspergillus Niger, Candida albicans, Candida dubliniensis, Candida glabrata (Torulopsis glabrata, Candida guilliermondii (Pichia guilliermondii; Yamadazyma guilliermondii), Candida krusei(Issatchenkia orientalis), Candida.lusitaniae(Clavispora lusitaniae), Candida parapsilosis, Candida pseudotropicalis(C.kefyr;Kluyveromyces cicerisporus;K.fragilis;K.marxianus), Candida tropicalis, Coccidioides immitis, Cryptococcus neoformans, Pneumocystis carinii, Pneumocystis jiroveci, Blastomyces It is an infection caused by at least one fungus selected from the group consisting of dermatitidis and Histoplasma capsulatum.

[0376] In some embodiments, the infection described herein is an infection of at least one parasite. In some embodiments, the infection described herein is an infection of at least one parasite of a genus selected from the group consisting of ectoparasites, protozoa, and helminths, such as tapeworms, trematodes, and / or roundworms. In some embodiments, the infections described herein are Acanthamoeba spp., Ancylostoma duodenale, Necator americanus, Angiostrongylus, Anisakis, Arachnida, Ixodidae and Argasidae, Arachnidae: Trombiculidae, Archiacanthocephala, Moniliformis moniliformis, Ascaris sp. lumbricoides, Babesia B. divergens, B. bigemina, B. equi, B. microfti, B. duncani, Balamuthia mandrillaris, Balantidium coli, Baylisascaris procyonis, Bertiella mucronata, Bertiella studeri, Blastocystis spp., Brugia malayi, Brugia timori, Cestoda, Taenia multiceps, Cimicidae, Cimex lectularius, Cimex hemipterus, Clonorchis sinensis, Clonorchis viverrini, Cochliomyia hominivorax, Cryptosporidium spp., Cyclospora cayetanensis, Demodex folliculorum, Demodex brevis, Demodex canis, Dermanyssus gallinae, Dermatobia hominis, Dicrocoelium dendriticum, Dientamoeba fragilis, Dioctophyme renale, Diphyllobothrium latum, Dracunculus medinensis, Echinococcus granulosus, Echinococcus multilocularis, E.vogeli, E.oligarthrus, Echinostoma echinatum, Entamoeba histolytica, Enterobius vermicularis, Enterobius gregorii, Fasciola hepatica, Fasciola gigantic, Fasciolopsis buski, Giardia lamblia, Gnathostoma spinigerum, Gnathostoma hispidum, Halicephalobus gingivalis, Hymenolepis nana, Hymenolepis diminuta, Insecta, Diptera, Isospora belli, Laelaps echidnina, Leishmania spp., Linguatula serrata, Liponyssoides sanguineus, Loa loa filarial, Mansonella streptocerca, Metagonimus yokogawai, Metorchis conjunctus, Naegleria fowleri, Oestroidea, Calliphoridae, Sarcophagidae, Onchocerca volvulus, Opisthorchis viverrini, Opisthorchis felineus, Clonorchis sinensis, Ornithonyssus bacoti, Ornithonyssus bursa, Ornithonyssus sylviarum, Paragonimus westermani, Paragonimus africanus, Paragonimus caliensis, Paragonimus kellicotti, Paragonimus skrjabini, Paragonimus uterobilateralis, Pediculus humanus capitis, Pediculus humanus humanus, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, Plasmodium malariae, Plasmodium knowlesi, Pthirus pubis, Rhinosporidium seeberi, Sarcocystis bovihominis, Sarcocystis suihominis、Sarcoptes scabiei、Schistosoma haematobium、Schistosoma japonicum、Schistosoma mansoni、Schistosoma intercalatum、Schistosoma mekongi、Schistosoma sp., Siphonaptera, Pulicinae, Spirometra erinaceieuropaei, Strongyloides stercoralis, Taenia saginata, Taenia solium, Thelazia californiensis, Thelazia callipaeda, Toxocara canis, Toxocara cati, Toxascaris leonine, Toxoplasma gondii, Trichinella spiralis, Trichinella britovi, Trichinella nelsoni, Trichinella native, Trichobilharzia regenti, Schistosomatidae, Trichomonas vaginalis, Trichuris trichiura, Trichuris vulpis, Trypanosoma brucei, Trypanosoma cruzi, Tunga penetrans and Wuchereria bancrofti. .

[0377] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of infection, for use according to the present invention, comprising an anti-infective agent, in particular the anti-infective agent described herein.

[0378] In certain embodiments, the present invention relates to a compressible carrier material for use in the treatment of infection, for use in accordance with the present invention, comprising an antiinfective agent, in particular an antiinfective agent described herein.

[0379] In certain embodiments, the present invention relates to carrier particles for use in the treatment of infection, wherein the compressed carrier material contains an anti-infective agent, in particular the anti-infective agents described herein.

[0380] Symptoms of infection, such as loss of appetite, nausea, and vomiting, can make it difficult to take therapeutic agents during treatment. The means and methods provided by the present invention can facilitate the intake and accelerate the absorption of therapeutic agents in the context of infection.

[0381] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of infection.

[0382] In a particular embodiment, the present invention relates to a solid pharmaceutical composition for use in the treatment of migraines, for use according to the present invention.

[0383] In a particular embodiment, the present invention relates to a compressible carrier material for use in accordance with the present invention for use in the treatment of migraines.

[0384] In a particular embodiment, the present invention relates to carrier particles for use in accordance with the present invention for use in the treatment of migraines.

[0385] As used herein, the term “migraine” refers to a headache that may be accompanied by symptoms including nausea, vomiting, or sensitivity to light. The pain associated with a migraine is typically described as a unilateral, throbbing pain. A migraine may be preceded by visual disturbances, such as aura, flashes of light, wavy lines, strange tastes or smells, numbness, tingling, dizziness, tinnitus, or a feeling that the size or shape of a part of the body is distorted. In certain embodiments, the migraine described herein is a migraine without aura. In certain embodiments, the migraine described herein is a migraine with aura.

[0386] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of migraines, for use according to the present invention, comprising an anti-migraine agent, in particular the anti-migraine agent described herein.

[0387] In certain embodiments, the present invention relates to a compressible carrier material for use in the treatment of migraines, for use in accordance with the present invention, comprising an anti-migraine agent, in particular the anti-migraine agent described herein.

[0388] In certain embodiments, the present invention relates to carrier particles for use in the treatment of migraines, wherein the compressed carrier material contains an anti-migraine agent, particularly the anti-migraine agent described herein.

[0389] Migraine symptoms, such as loss of appetite, nausea, impaired absorption, and vomiting, can make it difficult to take therapeutic medications during treatment. Furthermore, migraine attacks tend to be less severe if treated early. The means and methods provided by the present invention can facilitate the intake and accelerate the absorption of therapeutic medications in the context of migraines.

[0390] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of migraines.

[0391] In a particular embodiment, the present invention relates to a solid pharmaceutical composition for use in accordance with the present invention, for use in the treatment of sleep disorders.

[0392] In a particular embodiment, the present invention relates to a compressible carrier material for use in accordance with the present invention for use in the treatment of sleep disorders.

[0393] In a particular embodiment, the present invention relates to carrier particles for use in accordance with the present invention for use in the treatment of sleep disorders.

[0394] As used herein, the term “sleep disorder” refers to difficulties in falling asleep and maintaining sleep. In some embodiments, the sleep disorders described herein are selected from the group of sleep disorders including chronic insomnia, irregular sleep-wake schedules, shift work inability to maintain a regular sleep schedule, jet lag, and depression-related sleep disorders. The term “insomnia” is used to describe all conditions relating to the perception of sleep by a patient that is inadequate or restful. Sleep disorders are one of the most common symptoms found in general medical practice. Insomnia is a frequent complaint, reported by 13%–45% of the adult population. Symptoms of sleep disorders include, but are not limited to, frequent or continuous difficulty falling asleep at night, frequent nighttime awakenings, and / or early morning awakenings. Insomnia itself can take many forms, but appears to be most closely related to age, sex, and the individual’s psychopathological state, and is particularly important in older adults and women. Treatment of sleep disorders may include both inducing and prolonging sleep in patients who require it.

[0395] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of sleep disorders, for use according to the present invention, comprising a narcotic agent, in particular a narcotic agent described herein.

[0396] In certain embodiments, the present invention relates to a compressible carrier material for use in the treatment of sleep disorders, comprising a narcotic agent, particularly a narcotic agent described herein, for use according to the present invention.

[0397] In certain embodiments, the present invention relates to carrier particles for use in the treatment of sleep disorders, wherein the compressed carrier material contains a narcotic agent, particularly the narcotic agents described herein.

[0398] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of sleep disorders, comprising a sedative, particularly the sedative described herein, for use according to the present invention.

[0399] In certain embodiments, the present invention relates to a compressible carrier material for use in accordance with the present invention, for use in the treatment of sleep disorders, comprising a sedative, particularly the sedative described herein.

[0400] In certain embodiments, the present invention relates to carrier particles for use in the treatment of sleep disorders, wherein the compressed carrier material contains a sedative, particularly the sedative described herein.

[0401] The symptoms of sleep disorders require rapid absorption of therapeutic agents to ensure a rapid onset of action. The means and methods provided by the present invention can facilitate the uptake and accelerate the absorption of therapeutic agents in the context of sleep disorders.

[0402] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of sleep disorders.

[0403] In a particular embodiment, the present invention relates to a solid pharmaceutical composition for use in the treatment of depressive disorders, for use according to the present invention.

[0404] In a particular embodiment, the present invention relates to a compressible carrier material for use in accordance with the present invention for use in the treatment of depressive disorders.

[0405] In a particular embodiment, the present invention relates to carrier particles for use in accordance with the present invention for use in the treatment of depressive disorders.

[0406] As used herein, the term “depressive disorder” refers to a mental disorder typically characterized by a persistent sad mood and / or a loss of interest or pleasure in most activities.

[0407] In certain embodiments, the depressive disorders described herein are depressive disorders selected from the group consisting of major depressive disorder, unipolar depression, anxiety-distressed depression, dysthymia (also known as dysthymic disorder), atypical depression, depression (mood), melancholic depression, psychotic depression, geriatric depression, psychosocial stress-related depression, and postpartum depression.

[0408] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of depressive disorders, comprising an antidepressant, particularly an antidepressant as described herein, for use according to the present invention.

[0409] In certain embodiments, the present invention relates to a compressible carrier material for use in the treatment of depressive disorders, comprising an antidepressant, particularly the antidepressant described herein, for use according to the present invention.

[0410] In certain embodiments, the present invention relates to carrier particles for use in accordance with the present invention, for use in the treatment of depressive disorders, wherein the compressed carrier material contains an antidepressant, in particular the antidepressant described herein.

[0411] Patients with depressive disorders tend to have poor adherence to treatment, and some symptoms of depressive disorders, such as suicidal ideation during depressive episodes, require rapid absorption of therapeutic agents to ensure a rapid onset of action. The means and methods provided by the present invention can facilitate the uptake and accelerate the absorption of therapeutic agents in the context of depressive disorders.

[0412] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or carrier particles according to the present invention can improve the treatment of depressive disorders.

[0413] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use according to the present invention, wherein the childhood disease or disorder is selected from the group of anxiety disorders, bipolar disorder, pain, infection, migraine, sleep disorders, and depressive disorders.

[0414] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use according to the present invention, wherein the geriatric disease or disorder is selected from the group of anxiety disorders, bipolar disorder, pain, infection, migraine, sleep disorders, and depressive disorders.

[0415] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use according to the present invention, wherein the senile and pediatric diseases or disorders are selected from the group of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders.

[0416] In certain embodiments, the present invention relates to a compressible carrier material for use according to the present invention, wherein the childhood disease or disorder is selected from the group of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders.

[0417] In certain embodiments, the present invention relates to a compressible carrier material for use according to the present invention, wherein the geriatric disease or disorder is selected from the group of anxiety disorders, bipolar disorder, pain, infection, migraine, sleep disorders, and depressive disorders.

[0418] In certain embodiments, the present invention relates to a compressible carrier material for use according to the present invention, wherein senile and pediatric diseases or disorders are selected from the group of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders.

[0419] In certain embodiments, the present invention relates to carrier particles for use according to the present invention, wherein the childhood disease or disorder is selected from the group of anxiety disorders, bipolar disorder, pain, infection, migraine, sleep disorders, and depressive disorders.

[0420] In certain embodiments, the present invention relates to carrier particles for use according to the present invention, wherein the geriatric disease or disorder is selected from the group of anxiety disorders, bipolar disorder, pain, infection, migraine, sleep disorders, and depressive disorders.

[0421] In certain embodiments, the present invention relates to carrier particles for use according to the present invention, wherein senile and pediatric diseases or disorders are selected from the group of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders.

[0422] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in the treatment of veterinary diseases or disorders.

[0423] In certain embodiments, the present invention relates to a compressible carrier material for use in the treatment of veterinary diseases or disorders.

[0424] In certain embodiments, the present invention relates to carrier particles for use in the treatment of veterinary diseases or disorders.

[0425] When used herein, the term "veterinary disease or disorder" refers to any disease or disorder in a non-human animal that can be treated with the therapeutic agents described herein.

[0426] In some embodiments, the non-human animals described herein refer to vertebrate organisms. In some embodiments, the non-human animals described herein refer to mammals. In some embodiments, the non-human animals described herein refer to non-human animals selected from the groups of cattle, pigs, mice, rats, cats, dogs, camels, llamas, horses, goats, rabbits, sheep, hamsters, guinea pigs, whales, birds (e.g., ducks, chickens, geese), non-human primates, monkeys, apes, baboons, and chimpanzees.

[0427] In some embodiments, the veterinary diseases or disorders described herein refer to at least one disease or disorder selected from the group consisting of anthrax, brucellosis, campylobacteriosis, pustulosis, cryptosporidiosis, E. coli, influenza, leptospirosis, listeriosis, Q fever, rabies, ringworm, and salmonellosis.

[0428] The administration of treatments to non-human animals can be complicated due to the limited cooperation of these animals. Veterinary diseases or disorders may further hinder administration. For example, non-human animals may have difficulty swallowing drugs due to veterinary diseases or disorders, or due to a lack of willingness to cooperate. The means and methods of the present invention enable, facilitate, and / or accelerate the nasal, buccal, sublingual, intrabronchial, vaginal, urethral, ​​and / or rectal administration of therapeutic agents to non-human animals.

[0429] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve the treatment of veterinary diseases or disorders.

[0430] In certain embodiments, the present invention relates to a solid pharmaceutical composition for use in diagnostic purposes.

[0431] In a particular embodiment, the present invention relates to a compressible carrier material for use in diagnostic purposes.

[0432] In a particular embodiment, the present invention relates to carrier particles for use in diagnostic purposes.

[0433] In certain embodiments, the present invention relates to a solid pharmaceutical composition, a compressed carrier material, and / or carrier particles containing and / or filled with a diagnostic marker.

[0434] The term “diagnostic marker” as used herein may refer to any marker useful in imaging techniques during administration to a subject. In some embodiments, the diagnostic markers described herein include metals selected from the group Fe, Mg, Al, Mn, V, Ti, Cu, Ga, Ge, Ag, Au, Sm, U, Zn, Pt, and Sn. In certain embodiments, the diagnostic markers described herein include at least one nonmetal selected from the group Si, S, Sb, I, and C. In some embodiments, the diagnostic markers described herein include at least one contrast agent. In some embodiments, the diagnostic markers described herein include at least one enriched isotope. In some embodiments, the enriched isotopes are technetium-99m, iodine-123, and / or thallium-201. In some embodiments, the diagnostic markers described herein emit gamma radiation.

[0435] In a particular embodiment, the present invention relates to a solid pharmaceutical composition for use in scintigraphy.

[0436] In a particular embodiment, the present invention relates to a compressible carrier material for use in scintigraphy.

[0437] In a particular embodiment, the present invention relates to carrier particles for use in scintigraphy.

[0438] The use of the means and methods of the present invention in scintigraphy may be made possible by certain diagnostic markers described herein.

[0439] In the context of diagnostic purposes, simple, rapid, and / or target-specific delivery (e.g., of diagnostic markers) can be crucial for the speed and accuracy of diagnostic procedures. The means and methods of the present invention can improve, facilitate, and / or accelerate the delivery of diagnostic markers in diagnostic procedures.

[0440] Therefore, the present invention is at least in part based on the remarkable finding that a solid pharmaceutical composition according to the present invention, a compressed carrier material produced according to the present invention, or a carrier particle according to the present invention can improve or facilitate a diagnostic procedure.

[0441] In this specification, “a,” “an,” and “the” are used to refer to one or more (i.e., at least one, or one or more) grammatical objects of the article.

[0442] "Or" should be understood to mean either one of the alternatives, both of them, or any combination thereof.

[0443] "And / or" should be understood to mean either one or both of the alternatives.

[0444] Throughout this specification, unless otherwise required by context, the terms “comprise,” “comprises,” and “comprising” are understood to imply that they encompass the step or element, or group of steps or elements, described, but do not exclude any other step or element, or group of steps or elements.

[0445] The terms "include" and "comprise" are used synonymously. "Preferably" means selecting one from a set of options without excluding other options. "For example" means an example that is not limited to the examples listed. "Consisting of" means that whatever follows the phrase "consisting of," it includes and is limited to those things.

[0446] When used herein, the terms “about” or “approximately” mean “within 20%,” more preferably “within 10%,” and even more preferably “within 5%” of a given value or range.

[0447] Throughout this specification, references to “one embodiment,” “embodiment,” “specific embodiment,” “related embodiment,” “a particular embodiment,” “additional embodiment,” “some embodiment,” “specific embodiment,” or “further embodiment,” or any combination thereof, mean that the specific features, structures, or characteristics described in relation to an embodiment are included in at least one embodiment of the present invention. Therefore, the occurrence of the aforementioned phrases in various places throughout this specification does not necessarily all refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in one or more embodiments in any suitable manner. Also, it is understood that the positive description of a feature in one embodiment may serve as a basis for excluding a feature in a particular embodiment.

[0448] The “effective dose” of a drug, such as a therapeutic agent, refers to the amount effective in terms of dosage and duration required to achieve the desired therapeutic or prophylactic outcome. Furthermore, the effective dose may depend on the individual patient’s medical history, age, weight, family history, genetic makeup (e.g., HLA genotype), stage of myocarditis, the type of prior or concomitant treatments, if any, and other individual characteristics of the target being treated.

[0449] As used herein, “Subject” means animals such as primates (e.g., humans, non-human primates, e.g., monkeys, and chimpanzees), non-primates (e.g., cattle, pigs, camels, llamas, horses, goats, rabbits, sheep, hamsters, guinea pigs, cats, dogs, rats, mice, horses, and whales), or mammals, including birds (e.g., ducks or geese).

[0450] The present invention is further described in the following embodiments, but these embodiments are not intended to limit the scope of the present invention as set forth in the claims. [Brief explanation of the drawing]

[0451] [Figure 1] Electron microscope scan of carrier particles before removal of template material. The lamellar structure of the plate-like layers is visible as petals. [Figure 2] Electron microscope scan of templated inverted particles (TIPs) prepared according to the present invention. Hollow voids are created when the template material is removed from the particles. [Figure 3] A schematic diagram of an embodiment of the present invention. [Figure 4] A) Cross-section of TIP particles embedded in epoxy resin. The larger inner diameter (indicated by the longest arrow) is 23.6 micrometers, and the shorter inner diameter (indicated by the next longest arrow) is 18.8 micrometers. The distances between the smaller arrows (shell thickness) are (a) 5.87 micrometers, (b) 4.63 micrometers, (c) 6.06 micrometers, (d) 5.27 micrometers, and (e) 5.14 micrometers, respectively. TM4000 5kV 7.5mm × 2.50k BSE L, scale 20.0 μm B) Overall view of several particles. [Figure 5]Ivermectin-filled TIP particles. The ball-like structure corresponds to the filled ivermectin. TM4000 5kV 7.8mm × 3.00k BSE H, scale 10.0μm. [Figure 6] Disintegration of Partek ODT. This photo was taken 10 seconds after placing the tablet in distilled water. The total disintegration time is approximately 60 seconds. [Figure 7] TIP ODT disintegration. The photo was taken 6 seconds after contact with distilled water. At this point, the tablet has completely disintegrated. [Figure 8] Photographs of tablet disintegration taken one minute after dropping a tablet into distilled water. A) Comparison of disintegration times of a tablet prepared according to the method disclosed in CN1292803C (left) and TIP ODT (right). B) Disintegration time test of a compressed material prepared according to the method disclosed in US8940203. The photograph was taken one minute after dropping the porous material into distilled water. No observable signs of disintegration are seen. [Figure 9] A diagram of the porous ceramic material produced after extraction from the crucible. [Figure 10] Tablets made from particles prepared using the method disclosed in US8940203 (Example 1). The tablets are weak and crumble after being ejected from the die. [Figure 11] SEM micrograph of a ceramic material produced using the method disclosed in US8940203 (Example 1). The structure was cut to reveal internal pores. The porous structure is clearly visible in the photograph (large pores). [Figure 12] Magnified image of a single pore. The surrounding material is microporous sintered hydroxyapatite. [Figure 13] A porous ceramic prepared by a sintering method, cut to reveal its internal porous structure. [Examples]

[0452] (Example 1) Generation of templated drug carriers The template material (200 g calcium carbonate, Natura 330, Lehmann & Foss & Co., Germany) was suspended in water with vigorous stirring (200-700 RPM) in a smooth glass-lined or baffled reaction vessel (vessel volume 1.2 liters) containing 650 ml of water. The combination of the set stirring speed and the geometry of the reactor and stirrer must ensure Re > 10e+4 (i.e., stable turbulent mixing). The chemical precipitation process was carried out by pumping an orthophosphoric acid solution (41.1 ml of H3PO4 (85%) diluted to 150 ml with deionized water) into the calcium carbonate suspension aqueous solution at a rate of 1.4 g of acid solution per minute. During this process, hydroxyapatite (Ca 10 Lamellar structures of (PO4)6(OH)2) begin to grow on the surface of the template material, thus forming plate-like layers (primary structure). The stoichiometric amounts of the reaction are as follows: 2CaCO3 (solid) + 1.2H3PO4 (liquid) → 0.2Ca 10 (PO4)6(OH)2 + 1.6H2O + 2CO2 (gas)

[0453] The template material and carrier material were heated at 1100°C for 1 hour to induce CaO formation in the template material. Water (2 liters) was added using a Buchner funnel to induce Ca(OH)2 formation in the template material, dissolving and removing the converted template material. This step was repeated 15 times. After filtration to remove water and dissolved template material, carrier particles with an internal secondary structure were obtained.

[0454] (Example 2) Filling the solvent with therapeutic agent 3.5 g of midazolam hydrochloride (Haenseler AG, Switzerland) was dissolved in ethanol (50 ml). 100 g of granular carrier material was mixed with the ethanol / drug solution and dried in a rotary evaporator at a water bath temperature of 40°C and a pressure of 100 mbar.

[0455] (Example 3) Addition of adjuvants, such as odor modifiers, flavor modifiers, and disintegrants. The resulting drug-filled particles were mixed with an ethanol solution of raspberry aroma (Givaudan, Switzerland) with a flavor concentration of 1 drop per 10 ml, and dried in a vacuum cabinet for 2 hours. A cyclamate and saccharin powder mixture, Sanaro SA, Switzerland (1%, w / w) was added to the dried powder of the filled and flavored carrier particles. The powders were blended in a Turbula blender for 10 minutes.

[0456] Subsequently, a disintegrant was added. Sodium starch glycolate (Pharmatrans SANAQ, Switzerland) in an amount corresponding to 5% (w / w) was blended with the pre-prepared powder mixture.

[0457] (Example 4) compression The carrier particles obtained in Example 1 were compressed using a Korsch XP1-R&D single punch press to obtain 6 mm concave tablets with a tensile strength of ≥2.5 MPa.

[0458] Tensile strength calculated according to Stanley, P.; Newton, JM. The tensile fracture stress of capsule-shaped tablets. J. Pharm. Pharmacol. 1980, 32(12), 852-854 and Pitt, KG; Newton, JM; Stanley, P. Tensile fracture of doubly-convex cylindrical discs under diametral loading. J. Mater. Sci. 1988, 23, 2723-2728.

[0459] The registered tablet has a hardness of 60 N and a corresponding tensile strength of 2.51 MPa.

[0460] (Example 5) Manufacturing of templated inverted particle (TIP) drug carriers Ground calcium carbonate (Ph.Eur, USP NF, BP grade) was used as the starting material. 200 g of carbonate powder was processed in a stirrer reactor vessel with a volume of 2.5 L, selected for the required batch size.

[0461] Carbonate particles were treated with 150 ml of 4M phosphoric acid (Ph.Eur, USP NF, BP grade) to obtain conversion rates between 40 v / v% and 50 v / v%. The total volume of 4M phosphoric acid was introduced at a pumping rate of 2.5 ml / min.

[0462] The reactor treatment was carried out in deionized water. The rate of orthophosphate addition was controlled at 2.5 ml / min. The temperature of the reaction vessel must be maintained at 90-95°C throughout the entire activation step, i.e., during the addition of orthophosphate.

[0463] The obtained material is filtered, washed with water, and dried. During the final washing step, it is recommended to treat the particles under increased shear stress to reduce surface roughness and increase the fluidity of the final product. This intermediate material is referred to herein as TIP-L.

[0464] TIP-L consists of 40-50% hydroxyapatite in the petal, which is firmly bonded to the surface of the remaining 60-50% calcium carbonate.

[0465] The next step is baking in a high-temperature oven at a temperature range of 650°C to 700°C. The baking step was carried out at a constant temperature for 14 hours or longer.

[0466] The baked material was washed with 0°C water in approximately 30L of water per 200g of TIP material to dissolve any remaining template material. The washed material was dried in a shelf dryer and packaged in bags or drums.

[0467] (Example 6) The TIP material is a single hollow particle with an outer diameter of approximately 20–60 microns, consisting of a porous hydroxyapatite shell and a hollow cavity that accounts for at least 30% (v / v) of the single TIP particle. The TIP particle has a polyhedral geometry with an aspect ratio close to 1. Each TIP particle is a single unit (Figure 4A) and does not substantially aggregate with other particles (Figure 4B).

[0468] By filling TIP particles with a pharmaceutical API and using a simple solvent evaporation method, particles with a flat surface and acceptable fluidity were obtained, resulting in hard but rapidly disintegrating tablets suitable for the development of ODT / ODF formulations (Figure 5).

[0469] The filled API material was contained within the TIP particles, primarily in the hollow cavities of each individual TIP particle (Figure 5). Depending on the molecule, the API existed within the cavities in either a crystalline or amorphous form.

[0470] Ivermectin loading was achieved by a solvent evaporation process.

[0471] 0.100 g of ivermectin (LOT) was dissolved in 100 ml of anhydrous ethanol and mixed with 0.200 g of TIP material. Solvent removal was performed in a rotary evaporator (Buechi, Switzerland) at a pressure of 300 mbar and a temperature of 50-60°C. The rotation speed of the container was set to 50 RPM. The nitrogen gas injection rate was 200 cc per minute. After 15 minutes, the pressure was set to 200 mbar for 30 minutes, then to 100 mbar for 15 minutes, and then to 20 mbar for 15 minutes.

[0472] The filling process stops (topped) when the remaining powder in the container has dried and there are no visible traces of liquid.

[0473] The resulting powder is visually inspected under SEM for traces of external crystallization. The filling of internal cavities in the TIP particles is confirmed using the SEM micrograph in Figure 5.

[0474] The filled tip material is blended with a disintegrant (3%, w / w), a sweetener (approximately 1%, w / w), and an aroma (approximately 0.5%, w / w).

[0475] A simple powder blending process was used to mix the TIP particles. The resulting powder mixture was directly compressed into tablets under a compression force of 0.5 tons.

[0476] TIP material is suitable for solidifying oil-containing solutions, such as oil-soluble vitamins or aromas. Tablets prepared using TIP material have high mechanical strength; for example, a 5 x 1 mm tablet can reach a hardness of 50 N, which is equivalent to a tensile strength of 6.4 MPa.

[0477] The resulting TIP tablets disintegrate very rapidly, requiring only a minimal amount of liquid (e.g., 30% w / w). This minimal liquid requirement makes the TIP material highly attractive for ODT / FDT solid dosage forms. After tablet disintegration, the TIP particles remained intact. The TIP particles do not bind to more than 30% water.

[0478] (Example 7) Reference method published in CN1292803C Reference template materials were prepared as described herein and according to the steps of CN1292803C. In this method, polystyrene beads were used to produce the template material. PVC beads were prepared by spheroidization according to the "solvent exchange" mechanism as described in [J. Wang, F. Wang, H. Duan, Y. Li, J. Xu, Y. Huang, B. Liu, T. Zhang, ChemSusChem 2020, 13, 6426]. Polyvinyl chloride plastic was dissolved in dimethylacetamide and carefully dropped into a liquid containing a water-ethanol mixture. Beads were immediately formed. These beads were dried and used as templates in the next step.

[0479] PVC beads moistened with a binder (dissolved polystyrene, Styropor) are placed in a 10mm tableting die and lightly secured with upper and lower punches so that the beads adhere to each other and take the shape of a tablet.

[0480] The resulting aggregates were dried to ensure pores between the particles. The hydroxyapatite particles were mixed with a dispersant to obtain a homogeneous mass, into which the template composite was immersed to ensure complete penetration of the HA-PVA-PVB (a mixture of Mowiol 8-88, Sigma-Aldrich, polyvinyl alcohol, and trace amounts of polyvinyl butyral) mixture into the porous structure. The resulting mold was dried in an oven at 80-100°C for 1 hour. These last two steps were repeated five times. After the fifth drying, the mold was placed in a muffle oven. The oven temperature was increased to 600°C at a rate of 5°C per minute. After reaching that temperature, the oven was maintained at 600°C for 2 hours. By the end of the 2-hour hold, the temperature was set to 1100°C at a rate of 5°C / min. The oven was maintained at 1100°C for 4 hours, after which heating was stopped and the oven was allowed to cool to room temperature overnight.

[0481] The resulting sintered mold was cut open to examine its internal structure. SEM images of the generated material are shown in Figure 13.

[0482] As shown in Figure 13, a porous structure was formed, with pores the same size as the PVC template used. The resulting structure was compressed into a 7 x 2 mm tablet (approximately 70 mg) and tested for hardness. The resulting compression was too weak to test, and the measured hardness was 0 or undetectable. The tablet was very difficult to handle and crumbled to its primary particles with just a light touch of a finger.

[0483] The molded porous structure (as shown in Figure 6) was lost after compression. Because the tablets were brittle, it was impossible to test for tablet disintegration.

[0484] conclusion Reference methods for generating particles with a hollow structure are unsuitable for further use in oral drug delivery. Tablets formed using this method are weak and unmanageable, neither by patients nor by trained healthcare professionals. The overall templated structure is lost after it is compressed into a tablet.

[0485] (Example 8) Reference method published in US8940203 Poly(N-isopropylacrylamide-co-methacrylic acid) (pNIPAM-MA) was not synthesized but purchased from Sigma-Aldrich (lot MKCF2244). All other steps were carried out according to Example 1 of US8940203.

[0486] Slurry preparation 1.25 g of hydroxyapatite (Hap, 21223-1KG, Sigma-Aldrich) was held at 800°C for 1 hour. 0.05 g of dispersant (polyacrylic acid) (PAA, Sigma-Aldrich, Lot STBG0155V) was added and homogenized in a 50 ml glass beaker. 1 ml of pNIPAM-MA hydrogel solution (1 volume of distilled water per 1 volume of pNIPAM-MA) was mixed using a homogenizer (Polytron PT2100, Switzerland).

[0487] Polyethylene particles were sieved from pulverized low-density polyethylene to obtain a size fraction between 850 and 1000 micrometers. 120 mg of the resulting polyethylene particles were added to a beaker containing pNIPAM-MA hydrogel and mixed uniformly by hand.

[0488] The resulting mass was transferred from the beaker to a 50 ml ceramic crucible. The crucible was then used as the geometric shape for molding.

[0489] Sintering procedure The sintering of the prepared material in the crucible was carried out in accordance with patent US8940203.

[0490] This process consists of the following four stages. Stage 1: Heat to 650°C for 2 hours (approximately 5°C per minute), hold for 30 minutes. Stage 2: Heat to 1100°C at 20°C per minute, hold for 10 minutes. Stage 3: Hold at 1100℃ for 3 hours and 10 minutes. Stage 4: Cool to 25°C.

[0491] The resulting porous ceramic (Figure 9) followed a crucible shape, where the sintering step was performed. Due to the weak structure of the resulting ceramic, the shape was lost during extraction (Figure 9). SEM images (HITACHI TM4000, Japan) were obtained from the surface of the resulting pellets and ground powder (Figures 11 and 12).

[0492] Porous ceramic pellets were crushed through a 1000-micron sieve, and the resulting powder (100 mg) was compressed into a tablet (5 mm in diameter) under a compressive force of 1000 kg. The compressed powder formed a brittle tablet that disintegrated immediately after being removed from the die. Because the powder crumbled upon light touch, it was not possible to measure its hardness after removal from the die (Dr. Schleuniger, Switzerland) (Figure 10).

[0493] Due to the failure to form tablets, the resulting tablet disintegration time was not measured. SEM images show blocks of sintered HA particles with hollow cavities in a PE polymer template of the size used. These blocks can be ground into smaller particles; however, the hollow structure is lost during this process. Therefore, API filling is only possible through adsorption onto the surface of the ground material.

[0494] The fluidity of intact material is immeasurable because it is a single particle. The fluidity of ground material is poor due to the coarse and irregular shape of the particles.

[0495] conclusion The proposed method for generating particles with a hollow structure is unsuitable for further use in oral drug delivery. Tablets formed using this method are weak and unmanageable, neither by patients nor by trained healthcare professionals. The overall templated structure is lost after the crushing step or after compressing it into a tablet.

[0496] (Example 9) Comparison of products from Partek ODT, Examples 7 and 8, and the product from the method of the present invention. The primary objective was to study the formation and properties of particles, including TIP materials, according to the previously mentioned description, and to compare their characteristics with TIP requirements.

[0497] List of comparative experiments 1. Particle morphology. TIPs are single-particle hollow capsules with a porous shell, having a diameter of approximately 50–100 microns. Materials produced according to the methods of Examples 6, 7, and 8 are examined and measured under a SEM microscope. 2. Particle Compressibility. Tablets with a diameter of 11 mm are prepared from equal amounts of material prepared according to the methods of Examples 6, 7, and 8. The tablets are compressed under a compression pressure of 1 ton and measured using a tablet hardness tester. Predicted hardness > 50 N. 3. Tablet Disintegration. The materials prepared according to the methods of Examples 6, 7, and 8 are mixed with 3 w / w% croscarmellose sodium and compressed under a compressive force of 0.5 tonns. TIP material is used to prepare TIP-ODT. TIP-L material is used to prepare TIP-L ODT. The amount of croscarmellose sodium is the same for TIP and TIP-L ODT. The tablets are studied for disintegration time. Predicted value for complete disintegration <10 seconds. 4. Drug loading. The materials prepared according to the methods of Examples 6, 7, and 8 are loaded with the ivermectin drug substance from a saturated ethanol solution of ivermectin. Drying is carried out in a drying cabinet under a chemical hood. The predicted loading capacity is 50%. The success of loading without crystallization of excess particles is examined under a SEM microscope (Preisig et al., Drug loading into porous calcium carbonate microparticles by solvent evaporation, EJPB, 87-3, 2014).

[0498] Characterization of TIP and TIP-L materials SEM images of the TIP material are shown in Figure 4.

[0499] TIP: Characterization and Comparative Analysis of ODTs The tablet disintegration time of tablets prepared using TIP was compared with conventional and patented formulations. Formulations from patents US8940203 and CN1292803C were compared with TIP tablets. As a conventional ODT formulation, a ready-to-use mixture, EMPROVE® ESSENTIAL Partek® ODT (Partek ODT) mannitol-based mixture, was used. The results of the comparative analysis are presented in Table 1. Parameters were measured for tablets or porous structures with a diameter of 11 mm and a weight of approximately 300 mg. Tablets were compressed with a compressive force of 500 kg. Formulations prepared according to patents US8940203 and CN1292803C were not compressed and were used as is after sintering and removal from the mold.

[0500] [Table 1]

[0501] Figures 6 (Partek ODT) and 7 (TIP-ODT) show video screenshots 10 seconds after disintegration. As can be seen from the experimental results and video screenshots, TIP ODT disintegrates significantly more rapidly than the Partek ODT mixture. Formulations prepared according to Examples 7 and 8 do not disintegrate, as shown in Figure 8A / B. The hardness of TIP-L ODT is higher than that of Partek ODT and TIP ODT. Tablets prepared according to the formulations from Examples 7 and 8 are not stable enough to be measured using standard drug testing equipment. The decrease in tablet hardness after heat treatment is due to the change in the elasticity of the TIP particle petals under thermal stress. In embodiments of the present invention, for example, the following items are provided. (Item 1) A method for producing carrier particles having an internal secondary structure, a) A step of combining a carrier material with a template material, wherein the carrier material forms a primary structure around the template material. b) A step of converting the template material, c) The step of removing the converted template material, d) A step of obtaining carrier particles having an internal secondary structure. Methods that include... (Item 2) The method according to item 1, wherein the template material is an inorganic material or is primarily composed of an inorganic material. (Item 3) The method according to item 1 or 2, wherein the carrier material is an inorganic material or is mainly composed of an inorganic material. (Item 4) The method according to item 3 or 4, wherein the carrier material and the template material are inorganic salts or are mainly composed of inorganic salts. (Item 5) The method according to any one of items 1 to 4, wherein the step of combining the carrier material with the template material includes chemical precipitation, stratification, and / or crystallization of the carrier material onto the template material. (Item 6) The method according to any one of item 1 or 5, wherein the step of converting the template material includes heating it to a temperature of 600°C to 1200°C. (Item 7) The method according to item 6, wherein the step of converting the template material includes heating it to a temperature of 600°C to 900°C. (Item 8) The method according to item 6 or 7, wherein the step of converting the template material includes firing. (Item 9) The method according to any one of items 6 to 8, wherein the step of converting the template material includes the subsequent addition of water. (Item 10) The method according to item 9, wherein the aforementioned addition of water is an exothermic reaction. (Item 11) The method according to any one of items 1 to 10, wherein the step of removing the template material includes dissolving the converted template material to form an internal secondary structure. (Item 12) The method according to any one of items 2 to 12, wherein the template material comprises calcium carbonate. (Item 13) The method according to any one of items 3 to 13, wherein the carrier material comprises at least one salt and / or composite selected from the group consisting of calcium phosphate and magnesium phosphate. (Item 14) The method according to item 13, wherein the carrier particles have a diameter of 1 to 300 μm. (Item 15) The method according to item 13 or 14, wherein the carrier particles have a surface area between 15 m² / g and 400 m² / g. (Item 16) The method according to any one of items 13 to 15, wherein the internal secondary structure includes pores having a diameter size in the range of ≥0.2 μm and ≤1.5 μm. (Item 17) The method according to any one of items 13 to 16, wherein the total volume of the internal secondary structure in the obtained carrier particle having an internal secondary structure is in the range of ≥10% to ≤90% of the volume of the particle. (Item 18) A carrier particle having an internal secondary structure that can be obtained by the method described in any one of items 1 to 17. (Item 19) Carrier particles as described in item 18, having a packing capacity of ≥60 v / v%. (Item 20) Carrier particles as described in item 18 or 19, containing a therapeutic agent. (Item 21) A method for producing a compressible support material, a)i) the step of generating carrier particles as described in any one of items 1 to 17, and / or ii) The step of providing carrier particles as described in any one of items 18 to 20, b) The step of compressing the carrier particles having an internal secondary structure to obtain the compressed carrier material. Methods that include... (Item 22) A solid pharmaceutical composition comprising carrier particles as described in any one of items 18 to 20 or a compressed carrier material produced as described in item 21. (Item 23) The therapeutic agent is selected from the group consisting of an anxiolytic, a sedative, a narcotic, an antidepressant, an anti-migraine agent, an anti-inflammatory agent, and an anti-infective agent, and is a solid pharmaceutical composition according to item 22, a compressed carrier material produced according to item 21, or a carrier particle according to item 20. (Item 24) A solid pharmaceutical composition according to item 22 or 23, comprising at least one adjuvant. (Item 25) The solid pharmaceutical composition according to item 24, wherein at least one adjuvant is selected from the group consisting of disintegrants, lubricants, and flow enhancers. (Item 26) The solid pharmaceutical composition according to item 24 or 25, wherein the at least one adjuvant is selected from the group consisting of taste modifiers, odor modifiers, and appearance modifiers. (Item 27) The solid pharmaceutical composition according to item 26, wherein the flavor modifier is selected from the group consisting of artificial sweeteners, acidity modifiers, gums, cellulose derivatives, hard fats, and salts. (Item 28) A solid pharmaceutical composition according to any of items 22-27, a compressed carrier material produced according to item 19, or carrier particles according to item 20, for use in treatment. (Item 29) A solid pharmaceutical composition for use as described in item 28, a compressed carrier material for use as described in item 28, or carrier particles for use as described in item 28, for use in the treatment of geriatric diseases or disorders. (Item 30) A solid pharmaceutical composition for use as described in item 28, a compressed carrier material for use as described in item 28, or carrier particles for use as described in item 28, for use in the treatment of pediatric diseases or disorders, The solid pharmaceutical composition for use described in item 29, the compressed carrier material for use described in item 29, or the carrier particles for use described in item 29, wherein the aforementioned senile disease or disorder is a senile and pediatric disease or disorder. (Item 31) A solid pharmaceutical composition for use as described in item 28, a compressed carrier material for use as described in item 28, or carrier particles for use as described in item 28, for use in the treatment of a disease or disorder selected from the group of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders, or A solid pharmaceutical composition for use according to item 29 or 30, a compressed carrier material for use according to item 29 or 30, or carrier particles for use according to item 29 or 30, wherein the pediatric disease or disorder, the geriatric disease or disorder, or the geriatric and pediatric disease or disorder is selected from the group consisting of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders. (Item 32) A solid pharmaceutical composition for use as described in item 28, a compressed carrier material for use as described in item 28, or carrier particles for use as described in item 28, for use in the treatment of veterinary diseases or disorders. (Item 33) A solid pharmaceutical composition according to any of items 22-27, a compressed carrier material produced according to item 21, or carrier particles according to item 20, for use in diagnostic purposes. (Item 34) A solid pharmaceutical composition as described in item 33, a compressed carrier material produced as described in item 33, or carrier particles as described in item 33, for use in scintigraphy.

Claims

1. A method for producing carrier particles having an internal secondary structure, a) A step of combining a carrier material with a template material, wherein orthophosphoric acid is added to the template material, the carrier material forms a primary structure around the template material, the template material contains calcium carbonate, and the carrier material contains at least one salt and / or compound of calcium phosphate, which is hydroxyapatite (Ca10(PO4)6(OH)2), b) A step of converting the template material, comprising heating the template material and the carrier material to induce the formation of CaO in the template material, c) a step of removing the converted template material, wherein water is added to induce Ca(OH)₂ formation in the template material, dissolve and remove the converted template material, the dissolution and removal of the converted template material resulting in the formation of an internal secondary structure and at least one pore in the carrier particles, d) A step of obtaining a carrier particle having an internal secondary structure, wherein the internal secondary structure is available through the at least one pore. Includes, Here, the primary structure is a layer of the carrier material surrounding the template material, and the internal secondary structure is a hollow internal structure. method.

2. The method according to claim 1, wherein the step of combining a carrier material with a template material includes chemical precipitation, lamination, and / or crystallization of the carrier material on the template material.

3. The method according to any one of claims 1 or 2, wherein the step of converting the template material includes heating it to a temperature of 600°C to 1200°C.

4. The method according to claim 3, wherein the step of converting the template material includes heating it to a temperature of 600°C to 900°C.

5. The method according to claim 3 or 4, wherein the step of converting the template material includes calcination.

6. The method according to claim 1, wherein the addition of water is an exothermic reaction.

7. The method according to claim 1, wherein the carrier particles have a diameter of 1 to 300 μm.

8. The carrier particles are 15 m ２ / g to 400m ２ The method according to claim 1 or 7, having a surface area between / g.

9. The method according to any one of claims 7 to 8, wherein the internal secondary structure includes pores having a diameter size in the range of ≥0.2 μm and ≤1.5 μm.

10. The method according to any one of claims 7 to 9, wherein the total volume of the internal secondary structure in the obtained carrier particle having an internal secondary structure is in the range of ≥10% to ≤90% of the volume of the particle.

11. A carrier particle having an internal secondary structure, which can be obtained by the method described in any one of claims 1 to 10, wherein the carrier particle is A primary structure which is a layer of carrier material surrounding a template material, wherein the template material contains calcium carbonate, the primary structure is formed by reacting the calcium carbonate with orthophosphoric acid, and the carrier material contains at least one salt and / or composite of calcium phosphate which is hydroxyapatite (Ca10(PO4)6(OH)2), The internal secondary structure is a hollow internal structure, and At least one pore created by the removal of the template material This includes, wherein the internal secondary structure is accessible through the at least one pore. Carrier particles.

12. The carrier particle according to claim 11, having a packing capacity of ≥60 v / v%.

13. Carrier particles according to claim 11 or 12, comprising a therapeutic agent.

14. A method for producing a compressible support material, a) i) A step of generating carrier particles according to any one of claims 1 to 10, and / or ii) The step of providing carrier particles according to any one of claims 11 to 13, b) The step of compressing the carrier particles having an internal secondary structure to obtain the compressed carrier material. Methods that include...

15. A solid pharmaceutical composition comprising carrier particles according to any one of claims 11 to 13 or a compressed carrier material produced according to claim 14.

16. The carrier particle according to claim 13, wherein the therapeutic agent is selected from the group consisting of an anxiolytic, a sedative, a narcotic, an antidepressant, an anti-migraine agent, an anti-inflammatory agent, and an anti-infective agent.

17. The solid pharmaceutical composition according to claim 15, comprising at least one adjuvant.

18. The solid pharmaceutical composition according to claim 17, wherein at least one adjuvant is selected from the group consisting of disintegrants, lubricants, and flow enhancers.

19. The solid pharmaceutical composition according to claim 17 or 18, wherein the at least one adjuvant is selected from the group consisting of taste modifiers, odor modifiers, and appearance modifiers.

20. The solid pharmaceutical composition according to claim 19, wherein the flavor modifier is selected from the group consisting of artificial sweeteners, acidity modifiers, gums, cellulose derivatives, hard fats, and salts.

21. A solid pharmaceutical composition according to any one of claims 15 and 17-20, a compressed carrier material produced according to claim 12, or carrier particles according to claim 13, for use in treatment.

22. A solid pharmaceutical composition for use according to claim 21, a compressed carrier material for use according to claim 21, or carrier particles for use according to claim 21, for use in the treatment of senile diseases or disorders.

23. A solid pharmaceutical composition for use according to claim 21, a compressed carrier material for use according to claim 21, or carrier particles for use according to claim 21, for use in the treatment of pediatric diseases or disorders.

24. A solid pharmaceutical composition for use according to claim 21, a compressed carrier material for use according to claim 21, or carrier particles for use according to claim 21, for use in the treatment of a disease or disorder selected from the group consisting of anxiety disorders, bipolar disorders, pain, infections, migraines, sleep disorders, and depressive disorders.

25. A solid pharmaceutical composition for use according to claim 21, a compressed carrier material for use according to claim 21, or carrier particles for use according to claim 21, for use in the treatment of a veterinary disease or disorder.

26. A solid pharmaceutical composition according to any one of claims 15 and 17-20, a compressed carrier material produced according to claim 14, or carrier particles according to claim 13, for use in diagnostic purposes.

27. A solid pharmaceutical composition according to claim 26, a compressed carrier material produced according to claim 26, or carrier particles according to claim 26, for use in scintigraphy.

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