Method for producing particles containing an active ingredient carrier, particles, use of a fluidization device and use of a particle

Abstract

The invention relates to a method for producing particles (3) containing an active ingredient carrier (2), a particle (3), the use of a fluidization device (1) for producing the particles (3) and the use of a produced particle (3) for producing pharmaceutical dosage forms or for administering it as a pharmaceutical dosage form itself.

Description

[0001] The invention relates to a method for producing particles containing an active ingredient carrier, comprising the process steps of producing a sprayable dispersion containing the active ingredient carrier in the form of a lipid nanoformulation, wherein a stabilizer is added to the dispersion to produce shape-stabilized active ingredient carriers, and feeding the sprayable dispersion to a particle generation facility.

[0002] Furthermore, the invention relates to a particle with a granule size distribution in the range of 50 µm to 3 mm.

[0003] Furthermore, the invention relates to the use of a fluidization device comprising a process chamber through which a fluidization gas flows, as well as the use of a particle.

[0004] Methods for producing granules containing an active ingredient carrier are known: In their scientific article “Post-Processing Techniques for the Improvement of Liposome Stability,” published in Pharmaceutics 2021, 13, 1023 (https: / / doi.org / 10.3390 / pharmaceutics13071023), Yu, JY et al. describe how self-aggregation, coalescence, flocculation, and precipitation of aqueous liposomes during formulation or storage can lead to degradation of the vesicle structure and thus to liposome degradation. To increase liposome stability, the liposomes were post-treated to remove water and produce dry liposome particles, which, compared to aqueous liposomes, exhibit higher stability and better accessibility for drug delivery. Furthermore, the effects of particle generation by freeze-drying, spray-drying and spray freeze-drying on the stability, physicochemical properties and efficiency of encapsulation of active ingredients in dry liposomes are considered.

[0005] Disadvantages of the particle production methods described in the scientific article, namely freeze-drying, spray-drying, and spray freeze-drying, include high production time, high manufacturing costs, difficulties in adjusting the drying temperature, and the use of cryogenic substances. Furthermore, the particles produced using these methods do not exhibit advantageous flow properties.

[0006] The object of the invention is therefore to provide a method that eliminates the disadvantages of the prior art, with which free-flowing particles with precisely controlled particle properties can be produced, which also exhibit improved availability of the active ingredient carriers in the form of the lipid nanoformulation even when the particles are re-dissolved.

[0007] This problem is solved in a process of the type mentioned above by generating the particles through spraying the sprayable dispersion in a process chamber of a fluidization device through which a fluidizing gas flows. This process can be carried out as spray granulation, spray agglomeration, or spray coating, in order to produce the particles in the form of granules, agglomerates, or a coated spray carrier. Due to the process, the particles are uniform and homogeneous in shape, resulting in improved flowability and thus improved storage stability. Additionally, upon redispersion, the particles preferably exhibit a uniform availability of the active ingredient carrier in the form of the lipid nanoformulation. Furthermore, the particle properties can be precisely controlled during spray granulation, spray agglomeration, or spray coating.

[0008] The term "particles" as used below refers in particular to granules, pellets and / or agglomerates.

[0009] Lipids are naturally occurring compounds that include fats, oils, waxes, and fatty acids, among others.

[0010] The term lipid nanoformulation refers below to both liposomes and lipid nanoparticles. Lipid nanoformulations typically range in size from 1 nm to 2000 nm, making them on average approximately 10,000 times smaller than one millimeter.

[0011] Liposomes are small vesicles whose outer shell consists of a lipid bilayer formed by amphiphilic substances and typically range in size from about 50 nm to several micrometers. The amphiphilic nature of the membrane molecules is characteristic – they possess a hydrophilic head and a hydrophobic tail. The hydrophobic parts of both molecules face each other, while the hydrophilic parts point outwards or inwards. If the dispersion medium is lipophilic, they are called reverse-phase liposomes, whose structure is reversed. The membrane molecules are linked to each other by non-covalent bonds. Due to their stable lipid bilayer shell, liposomes are advantageously used for targeted drug delivery, gene transport, and in the cosmetic industry.They are suitable for hydrophilic substances that are enclosed inside the liposome, as well as for hydrophilic substances that are embedded in the lipid bilayer.

[0012] Lipid nanoparticles are predominantly spherical nanoparticles composed of solid and liquid lipids—similar to liposomes—and typically range in size from 20 nm to 200 nm. Lipid nanoparticles consist of a mixture of lipids whose shell is not organized in a lipid bilayer, often with a core of lipids or other molecules present in a solid or liquid phase. What distinguishes lipid nanoparticles from liposomes is the type of lipids used: phospholipids, cholesterol, PEGylated lipids, and ionizable, cationic lipids. These lipids are fat-soluble and / or water-soluble, and when mixed correctly, they form nanoparticles that completely encapsulate drug molecules.A distinction is made between “solid lipid nanoparticles”, which have an ordered crystalline structure but can only enclose a small amount of active ingredient, and “nanostructured lipid carriers” with an unstructured matrix and higher drug uptake.

[0013] Amphiphilia describes the chemical property of a substance to be both hydrophilic (water-loving) and lipophilic (fat-loving). This means that the substance is readily soluble in both polar and nonpolar solvents. Lipid nanoparticles are primarily used for the transport of messenger ribonucleic acid (mRNA) because they have the ability to effectively transport mRNA or other nucleic acids into cells. Lipid nanoparticles are also suitable for the delivery of hydrophobic substances.

[0014] Lipid nanoformulations are used in medicine and pharmaceuticals to transport active ingredients, as they are very well suited to efficiently deliver an encapsulated drug into the body's cells. Depending on their size and structure, lipid nanoformulations are able to be absorbed by body cells because their cell membranes are also composed of lipids. Inside the body cell, the outer shell of the lipid nanoformulation is then broken down, releasing the drug. The active ingredients are typically small molecules that combat diseases directly within the body's cells, or nucleic acids (deoxyribonucleic acid, ribonucleic acid, and other macromolecules) that would not be stable enough to be used as drugs without their outer shell.

[0015] Advantageously, carbohydrates and / or proteins and / or polyols and / or polymers are used as stabilizers. Mono- and disaccharides, as well as oligo- and polysaccharides, are particularly suitable as carbohydrate stabilizers. Glucose, fructose, mannose, maltose, sucrose, trehalose, cellobiose, and / or lactose are expediently used as mono- and disaccharides, and raffinose, chitosan, maltodextrin, inulin, dextran, and / or hyaluronan as oligo- and polysaccharides. Glycine, gelatin, proline, glutamine, betaine, arginine, lysine, and / or histidine are preferred as protein stabilizers. Examples of polyol stabilizers are mannitol, sorbitol, glycerol, ethylene glycol, propylene glycol, and / or polyvinyl alcohol. Kollidon VA 64 is particularly suitable as a polymer stabilizer.Preferably, the stabilizer is added to the sprayable dispersion under the influence of energy to dissolve the stabilizer substantially completely in the sprayable dispersion, the energy input being expediently taking the form of stirring and / or heating the sprayable dispersion. The stabilizers produce shape-stabilized drug carriers that, when sprayed in the fluidization device as spray granulation, spray agglomeration, or spray coating, are less susceptible to damage than drug carriers not treated with stabilizers.

[0016] Furthermore, a spray carrier is placed in the fluidization device prior to the introduction of the sprayable dispersion. Isomalt and / or lactose and / or microcrystalline cellulose and / or mannitol are advantageously used as the spray carrier. Mixtures of the aforementioned materials can also be used as the spray carrier. In this case, the spray carrier is fluidized prior to the introduction of the sprayable dispersion in the fluidization device. This allows the sprayable dispersion to act as a coating agent for the spray carrier when using spray granulation or spray coating, and as a binder when using spray agglomeration, in order to produce uniform and homogeneous particles containing the active ingredient carriers.

[0017] Advantageously, the lipid nanoformulation is characterized after the production of the sprayable dispersion and before its introduction to the particle generation process. For this characterization, the size and / or size distribution of the lipid nanoformulation is expediently measured in the sprayable dispersion. Furthermore, a polydispersity index of the lipid nanoformulation in the sprayable dispersion of less than 0.5, and particularly preferably less than 0.3, is preferably set before its introduction into the fluidization device. The polydispersity index is controlled and influenced by selecting different production parameters.To characterize the drug carriers in the form of a lipid nanoformulation, the method of dynamic light scattering (DLS) is preferably used to analyze the size and size distribution of the lipid nanoformulation.

[0018] Preferably, the sprayable dispersion is diluted with a buffer solution prior to its introduction into the particle generation process. The buffer solution is advantageously a phosphate-buffered salt solution, a tris(hydroxymethyl)aminomethane solution, or a sucrose solution. This allows the sprayability of the dispersion to be positively influenced by dilution.

[0019] Furthermore, if necessary and applicable, other physicochemical parameters can also be analyzed to ensure the quality and quantity of lipid nanoformulations in the form of liposomes and lipid nanoparticles, including the lipid concentration (e.g. by high-performance liquid chromatography methods, HPLC), the liposome charge (e.g. by zeta potential measurement) and the liposome morphology (e.g. by cryogenic electron microscopy, Cryo-TEM).

[0020] According to an advantageous further embodiment, the drug carrier, in the form of a lipid nanoformulation, is loaded with an active ingredient. For drug carriers loaded with active ingredients, an encapsulation test is performed to measure the efficiency of the encapsulation. This allows the resulting particles, in the form of granules or agglomerates, to be used for the manufacture of dosage forms or for administration as a dosage form itself.

[0021] Advantageously, after the supply of the sprayable dispersion is stopped, the produced particles are further fluidized in the fluidization device and thus thermally post-treated. Preferably, the residence time for this thermal post-treatment of the particles in the fluidization device is between 1 and 60 minutes, particularly between 5 and 20 minutes. This thermal post-treatment of the produced particles makes it possible to dry them further and thus adjust the degree of dryness required for further processing.

[0022] Furthermore, the fluidizing gas preferably has a fluidizing gas temperature between -200 °C and 200 °C when flowing through the process chamber, preferably between 20 °C and 200 °C, and expediently between 40 °C and 120 °C. In the aforementioned temperature ranges, the drying of the particles takes place efficiently while simultaneously gently treating the active ingredient carriers in the form of lipid nanoformulations.

[0023] The same applies to the thermal post-treatment of the manufactured particles.

[0024] The manufactured particles can be examined to assess their quality and efficacy. Various tests can be performed for this purpose. These tests can determine the redispersibility of the manufactured particles, the efficacy of the active ingredients contained in the particles, the particle size and particle size distribution, the morphology, the flowability, and the moisture content of the particles using appropriate methods.

[0025] Furthermore, the function of a particle of the type mentioned above is characterized in that the particles have a spray carrier and an active ingredient carrier in the form of a lipid nanoformulation. The particles particularly preferably have a spherical shape factor of greater than or equal to 0.90, and even more preferably a shape factor of greater than or equal to 0.93. Due to the high spherical shape factor of greater than or equal to 0.90, the produced particles are uniform and homogeneous and advantageously also possess very good flowability.

[0026] Advantageously, the lipid nanoformulation is loaded with an active ingredient. This allows the generated particles, in the form of granules or agglomerates, or coated spray carriers, to be used for the manufacture of dosage forms or for administration as a dosage form itself.

[0027] Advantageously, the particle comprises a core and a coating surrounding the core, wherein the core is formed from a spray carrier and the coating comprises the lipid nanoformulation. Preferably, the coating has a layer thickness between 0.1 µm and 1500 µm. Such a layer thickness represents the optimal ratio of core diameter to coating diameter.

[0028] Furthermore, the problem is solved in the aforementioned application by using the fluidization device to carry out a method according to any one of claims 1 to 12. Advantageously, the fluidization device is designed as a fluidized bed device or as a jet bed device.

[0029] In addition, the problem is solved in the use of the type mentioned above by using a particle according to one of claims 13 to 17 for the manufacture of pharmaceutical forms or for the presentation as a pharmaceutical form itself.

[0030] The invention will now be explained in more detail with reference to the accompanying drawing and shown therein Fig. 1 a schematic representation of a process for the production of particles containing an active ingredient carrier, Fig. 2 a schematic representation of a fluidization device designed as a fluidized bed device, Fig. 3 a schematic representation of a fluidization device designed as a jet layer device, Fig. 4 a schematic representation of a preferred embodiment of a particle comprising an active ingredient carrier, Fig. 5 a schematic representation of a drug carrier containing an active ingredient, Fig. 6 a table of the sprayable dispersions investigated in laboratory tests and Fig. Figure 7 shows a representation of six particles produced in laboratory experiments.

[0031] Unless otherwise stated, the following description refers to all embodiments illustrated in the drawing of a process for producing particles 3 containing an active ingredient carrier 2, which takes place on a fluidization device 1.

[0032] In Fig. Figure 1 shows a schematic representation of the process for producing particles 3 containing an active ingredient carrier 2.

[0033] A first process step, essential for the procedure, is the production of a sprayable dispersion 5 containing the active ingredient carrier 2 in the form of a lipid nanoformulation 4. A dispersion 5 is defined as a heterogeneous mixture of at least two substances that are not, or only minimally, soluble in each other or chemically react with each other. In this mixture, one or more substances are finely dispersed as a so-called dispersed phase in another continuous substance, the so-called dispersion medium.

[0034] The dispersed phase consists of the lipid-based drug carriers 2 in the form of the lipid nanoformulation 4, where the term lipid nanoformulation 4 refers to both liposomes and lipid nanoparticles. The drug carriers 2 can be loaded with any drug 6, which is expediently the case in this process.

[0035] Various methods exist for the production of the drug carriers 2 in the form of lipid nanoformulations 4, whereby the drug carriers 2 are immediately available as a sprayable dispersion 5 after their production. The selection of suitable solvents and lipids, such as SoyPC, cholesterol, PEGylated lipids, and other lipids, is crucial for the lipid nanoformulation 4 and its stability. The most frequently used methods are listed below: In the lipid film process, the active ingredient 6 and the lipids are dissolved in an organic solvent, and the resulting solution is then evaporated in an evaporator, preferably a rotary evaporator. After evaporation, a thin lipid film remains, which is dispersed in water while stirring, resulting in the sprayable dispersion 5 containing the lipid nanoformulations 4.

[0036] In the so-called solvent-exchange process, the active ingredient 6 and the lipids are dissolved in an organic solvent. A non-solvent (usually water) is added via syringe, causing the lipids to precipitate as liposomes and form a sprayable dispersion 5 containing the lipid nanoformulations 4. A special case of the solvent-exchange process is the ethanol injection method, in which ethanol is the organic solvent.

[0037] The so-called detergent removal process uses mixed micelles consisting of wall-forming agent, cholesterol, and cholic acid as starting materials. When these mixed micelles are diluted, the cholic acid molecules are removed from the micelles, causing them to transform into liposomes and resulting in a sprayable dispersion containing lipid nanoformulations 4.

[0038] Furthermore, single-jet technology and jet impinging enable the production of lipid nanoformulations 4 with precise control over size and size distribution using high-shear jet mixing technology. These lipid nanoformulations 4 are also available in a sprayable dispersion 5.

[0039] The lipid nanoformulations 4 can be loaded with active ingredient 6 during their fabrication, as partially described above, provided the lipids and active ingredient 6 are soluble in the same solvent. For lipid nanoformulations 4 loaded with active ingredient 6, the effects of various parameters, such as lipid concentration, active ingredient / lipid ratio, and others, are evaluated as part of the formulation screening process to determine the formulation with the highest encapsulation efficiency (EE) of active ingredient 6. Sometimes, the lipid nanoformulations 4 are loaded with the active ingredient 6 only after their fabrication. This can be done using the following methods: - Freeze / thaw cycles: Freezing the lipid nanoformulation 4 with liquid nitrogen and subsequent thawing. This disrupts the membrane structure of the lipid nanoformulation 4, allowing the active ingredient 6 to diffuse into the lipid nanoformulation 4. Electrostatic methods: Some active loading methods are based on electrostatic interactions, in which charged molecules (e.g., nucleic acids) are charged by exploiting charge interactions with the lipid bilayer in liposomes. - Ammonium sulfate gradient: Another method uses an ammonium sulfate gradient, employing a high concentration of ammonium sulfate inside the liposomes and a lower concentration outside. This gradient can promote the active loading of certain drugs into the liposome. - Ultrasound or high-pressure homogenization: In some cases, physical forces such as ultrasound or high-pressure homogenization are used to increase the encapsulation efficiency of certain substances by temporarily destabilizing the lipid bilayer and facilitating the penetration of the substance. - pH gradient: This method utilizes the principle of ion trapping. The pH of the solvent is chosen so that the active ingredient 6 can diffuse into the lipid nanoformulation 4. However, a different pH prevails inside the lipid nanoformulation 4, preventing the active ingredient 6 from diffusing back out.

[0040] After the production of the lipid nanoformulation 4 and thus the sprayable dispersion 5, and before the sprayable dispersion 5 is fed to the particle generation unit 7, the lipid nanoformulation 4 is characterized. For this characterization, the size and / or size distribution of the lipid nanoformulation 4 in the sprayable dispersion 5 is expediently measured by determining a polydispersity index (PDI). The PDI is an indicator of the size distribution of the lipid nanoformulation 4 in the sprayable dispersion 5. If the lipid nanoformulations 4 in the sprayable dispersion 5 are uniform, the resulting size distribution is narrow and the PDI is small, indicating that the sample is monodisperse. A monodisperse sprayable dispersion 5 is assumed for a PDI of less than or equal to 0.3.Accordingly, the polydispersity index of the lipid nanoformulation 4 in the sprayable dispersion 5 is preferably adjusted to less than 0.3 prior to its introduction into the fluidization device 1. For characterizing the active ingredient carriers 2 in the form of a lipid nanoformulation 4, the dynamic light scattering (DLS) method is preferably used for particle size analysis. A Zetasizer NANO ZS from Malvern Panalytical can be advantageously used for this purpose.

[0041] In addition to characterizing the lipid nanoformulation 4, other physicochemical parameters can also be analyzed to ensure the quality and quantity of lipid nanoformulations 4 in the form of liposomes and lipid nanoparticles. For this purpose, samples of the sprayable dispersion 5 are examined using various analytical methods. The lipid concentration is determined, for example, using high-performance liquid chromatography (HPLC), the liposome charge is determined, for example, by zeta potential measurement, and the liposome morphology is determined, for example, by cryogenic electron microscopy (cryo-TEM).

[0042] Furthermore, a buffer solution 8 can be added to the sprayable dispersion 5 prior to its introduction to the particle generation unit 7. Preferably, a phosphate-buffered salt solution (PBS buffer solution), a tris(hydroxymethyl)aminomethane solution (TRIS buffer solution), or a sucrose solution is used as the buffer solution 8. The addition of the buffer solution 8, which is preferably selected according to the dispersion medium, makes it possible to improve the sprayability of the sprayable dispersion 5 by diluting it.

[0043] In addition to the finely dispersed phase in the dispersion medium, a stabilizer 9 is added to the sprayable dispersion 5 to produce shape-stabilized drug carriers 2. The stabilizer 9 ensures that the drug carriers, in the form of the lipid nanoformulation 4, remain more shape-stable during particle production 7 than without the use of a stabilizer 9. The stabilizer 9 is primarily composed of carbohydrates and / or proteins and / or polyols and / or polymers, selected according to the lipid nanoformulation 4. Suitable carbohydrate stabilizers 9 include, in particular, mono- and disaccharides as well as oligo- and polysaccharides. Advantageously, glucose, fructose, mannose, maltose, sucrose, trehalose, cellobiose, and / or lactose are used as mono- and disaccharides, and raffinose, chitosan, maltodextrin, inulin, dextran, and / or hyaluronan as oligo- and polysaccharides.Glycine, gelatin, proline, glutamine, betaine, arginine, lysine, and / or histidine are preferably used as stabilizers 9 in the form of proteins. Examples of stabilizers in the form of polyols are mannitol, sorbitol, glycerol, ethylene glycol, propylene glycol, and / or polyvinyl alcohol. Kollidon VA 64 is particularly used as a stabilizer 9 in the form of polymers. The stabilizer 9 is preferably added to the sprayable dispersion 5 with the input of energy to dissolve the stabilizer 9 substantially completely in the sprayable dispersion 5, the energy input being expediently taking the form of stirring and / or heating the sprayable dispersion 5.

[0044] In addition to the production of the sprayable dispersion 5 containing the active ingredient carrier 2 in the form of a lipid nanoformulation 4, the second process step involves feeding the sprayable dispersion 5 to a particle generation unit 7. Particle generation 7 is achieved by spraying the sprayable dispersion 5 in a process chamber 11 of a fluidization device 1 through which a fluidizing gas 10 flows, either as spray granulation, spray agglomeration, or spray coating, in order to produce the particles 3 in the form of granules 12, agglomerates 13, or a coated spray carrier substrate 24.

[0045] For particle generation according to the second process step, a fluidization device 1 comprising a process chamber 11 through which a fluidizing gas 10 flows is used. Advantageously, the fluidization device 1 is designed as a fluidized bed device 14 or as a jet bed device 15. These are described schematically below.

[0046] Fig. Figure 2 shows a schematic representation of a fluidization device 1 designed as a fluidized bed device 14. The fluidized bed device 14 has a process chamber 11 and a distribution chamber 16 arranged below the process chamber 11, wherein the process chamber 11 and distribution chamber 16 are separated from each other by an inlet device 18 designed as a gas distribution plate 17. The inlet device 18 in the form of the gas distribution plate 17 is expediently designed as a perforated stainless steel plate 19.

[0047] The distribution chamber 16 has a fluidizing gas supply 20 through which a fluidizing gas 10 is supplied to the distribution chamber 16. Air or an inert gas, such as nitrogen, is advantageously used as the fluidizing gas 10. Preferably, the fluidizing gas 10 is preconditioned via a fluidizing gas conditioning system (not shown) with a heat exchanger, filter, and external air supply.

[0048] The process chamber 11 has a fluidization gas discharge 21 by means of which the fluidization gas 10 flowing from the distributor chamber 16 through the gas distributor base 17 and the process chamber 11 is discharged from the fluidized bed device 14 after passing through a filter unit 22.

[0049] Furthermore, the process chamber 11 expediently has an inlet 23 for a spray carrier 24 and an outlet 25 for the produced particles 3 in the form of granules 12 or an agglomerate 13. This is introduced into the fluidization device 1 prior to the introduction of the sprayable dispersion 5. Isomalt and / or lactose and / or microcrystalline cellulose and / or mannitol, or a mixture thereof, are expediently used as the spray carrier 24. The fluidization gas 10 flowing through the process chamber 11 causes the spray carrier 24, introduced into the process chamber 11 via the process chamber 11, to enter a fluid-like state of motion. Preferably, the spray carrier 24 is fluidized in the fluidization device 1 prior to the introduction of the sprayable dispersion 5.In the fluid-like state of motion, an intensive heat and mass exchange occurs between the spray carrier 24 and the fluidizing gas 10 due to a pronounced mixing of the spray carrier 24.

[0050] Process chamber 11 further comprises a spray unit 26 for spraying the sprayable dispersion 5. The spray unit 26 can be arranged at the top, bottom, and / or side of process chamber 11 to spray the sprayable dispersion 5 onto the spray carrier 24 from above as a top spray, from below as a bottom spray, and / or laterally as a tangential spray to generate particles 7. The spray unit 26 is advantageously a two- or multi-component nozzle. In the fluidized bed device 14 according to Fig. 2 The sprayable dispersion 5 is sprayed from below as bottom spray into a sausage insert 28 designed as a riser tube 27 in the process chamber 11.

[0051] In spray granulation in the spray layer device 15, the spray carrier template 24 is created by initially spray-drying the sprayable dispersion 5 in the process chamber 11 and is then sprayed with the sprayable dispersion 5 in such a way that the dispersion medium evaporates, thus achieving layer-by-layer particle growth through droplet and film drying. The spraying process continues until the desired size of the particles 3, which form as granules 12, is reached. The inlet 23 for a spray carrier template 24, as well as the spray carrier template 24 itself, is not required in this case.

[0052] In spray granulation in the fluidized bed unit 14, the spray carrier template 24 is pre-placed in process chamber 11. Here too, the inlet 23 for a spray carrier template 24 is omitted, as is the spray carrier template 24 itself.

[0053] During spray agglomeration in the fluidized bed device 14, the spray carrier template 24 is sprayed with the sprayable dispersion 5 until sufficient adhesive forces develop between the sprayed spray carrier template 24 and they bond together. Simultaneous drying directly solidifies the agglomerate structure. This spraying process is continued until the desired size of the particles 3, which form as agglomerates 13, is reached.

[0054] In the spray coating process in the fluidized bed device 14, the spray carrier template 24 is sprayed with the sprayable dispersion 5 in such a way that the dispersion medium evaporates, thus achieving layer-by-layer particle growth through droplet and film drying. The spraying process is continued until the desired size of the particles 3, which form the coated spray carrier template 24, is reached.

[0055] The parameter settings allow for differentiation between spray granulation / spray coating and spray agglomeration. Specifically, spray granulation / spray coating occurs at higher flow velocities of the fluidizing gas 10 through the process chamber 11 and also at higher temperatures of the fluidizing gas 10 than in spray agglomeration. Furthermore, the sprayed droplets are smaller in spray granulation / spray coating compared to those in spray agglomeration.

[0056] In Fig. Figure 3 shows a schematic representation of a fluidization device 1 designed as a jet layer device 15.

[0057] Unlike the fluidized bed apparatus 14, the jet classifier apparatus 15 does not have an inlet device 18 designed as a gas distribution plate 17 between the process chamber 11 and the distribution chamber 16 located below the process chamber. The inlet device 18 of the jet bed apparatus 15 has two rollers 30, whose position relative to a plate 29 is adjustable and which are expediently designed as slotted rollers 30. By adjusting the rollers 30 relative to the plate 29, the free area through which the fluidizing gas 10 can flow into the jet bed apparatus 15 changes. In this way, the opening ratio of the inlet device 18 and thus the gas inlet velocity can be varied during operation of the jet bed apparatus 15.

[0058] In addition, the sprayable dispersion 5 is applied from above as a top spray in process chamber 11.

[0059] The spray agglomeration, spray granulation, or spray coating process taking place in the jet screening device 15 is otherwise analogous to the spray agglomeration, spray granulation, or spray coating process in the fluidized bed device 14.

[0060] Fig. Figure 4 shows a schematic representation of an embodiment of a preferably manufactured particle 3. The particle 3 has a particle size in the range of 50 µm to 3 mm. Furthermore, the particle 3 is characterized by a spherical shape factor of greater than or equal to 0.93 and has a drug carrier 2 in the form of a lipid nanoformulation 4. The drug carrier 2 in the form of the lipid nanoformulation 4 is shown in an enlarged view in Figure 4. Fig. 5 and loaded with an active ingredient 6. Furthermore, the particle 3 has a core 31 and a coating 32 surrounding the core 31, wherein the core 31 is shown in the Fig. 4 is formed from a spray carrier template 24 and the coating 32 comprises the lipid nanoformulation 4. Preferably, the coating 32 has a layer thickness 33 between 10% and 20% of a diameter 34 of the core 31, wherein the layer thickness 33 is expediently between 0.1 µm and 1500 µm.

[0061] The manufactured particles 3 are used in particular for the manufacture of pharmaceutical dosage forms or for administration as a pharmaceutical dosage form itself.

[0062] The following are examples of implementation: For laboratory tests, three different lipids were selected to produce the sprayable dispersion 5 for the formulation of the lipid nanoformulation 4: phosphatidylcholine from soy (SoyPC), cholesterol (Chol), and PEGylated lipids (PEG). The selection of other lipids is also possible. Two different lipid concentrations, 30 mg / ml and 100 mg / ml, were used. Furthermore, two formulations containing the active ingredient 6 naproxen were also tested at two different ratios of active ingredient 6 to lipid – 3% and 6%.

[0063] The lipid nanoformulation 4 in the form of liposomes is produced using a novel technology based on the principle of jet impinging with the NANOLab® from leon-nanodrugs GmbH. Prior to production, the desired amounts of various lipids and active ingredients 6 are dissolved in the organic phase, i.e., in this case, in ethanol solutions. A 10 mM PBS buffer solution 8 with a pH of 7.4 is used for the aqueous phase. The liposomes are produced using a NANOLab®, supplemented by FR-JET mixing technology, at a total flow rate (TFR) of 80 ml / min and a flow ratio (FRR) of 2:1 (aqueous:organic).

[0064] After preparation, the liposomes are dialyzed overnight against PBS buffer solution 8 (200 ml buffer solution for 1 ml sample) with stirring at 50 to 150 rpm. Dialysis cassettes with a 100 kDa molecular weight cut-off cellulose membrane are used. After dialysis, the samples are filtered with PES filters with a pore size of 0.22 µm.

[0065] The following are listed in the table: Fig. 6 listed sprayable dispersions 5 were created, which are further described by the numbers 1 to 18.

[0066] The aforementioned sprayable dispersions 5 were subsequently characterized with respect to their lipid nanoformulation 4 forming the dispersed phase by dynamic light scattering (DLS). The size and PDI of the lipid formulations 4, here in the form of liposomes, were measured using the Zetasizer NANO ZS from Malvern Panalytical. The liposomes were analyzed undiluted after preparation, diluted in PBS buffer solution 8, diluted 1:10 after dialysis, and diluted 1:10 in PBS buffer solution 8 after filtration with 0.22 µm PES filters. The size of the lipid nanoformulation 4, which depends on the lipid type and the preparation parameters, therefore varied slightly and ranged between 20 nm and 80 nm with a PDI of ≤ 0.3, and in particular ≤ 0.2.

[0067] The determination of the encapsulation efficiency (EE) of the active ingredient 6, here naproxen, in liposomes in the above-mentioned sprayable dispersions 5 comprises the following steps: 1. Dissolution of the liposomes: To a sample with a volume of 0.1 ml to 0.7 ml of dialyzed, naproxen-loaded lipid nanoformulations, 10 ml of ethanol is added and heated to 70°C. The mixture is gently swirled to ensure that all liposomes are lysed. This process disrupts the lipid nanoformulation structure, allowing the encapsulated naproxen to dissolve in the ethanol. 2. Quantification of the active ingredient: After digestion, the sample is diluted to a final volume of 20 ml with additional ethanol. The concentration of the encapsulated naproxen is then determined by measuring the absorbance of the samples using UV-Vis spectrophotometry with a Perkin Elmer Lambda 365 photometer at the wavelength of maximum absorption (232 nm). 3. Calculation of containment efficiency: The containment efficiency is calculated by comparing the amount of naproxen initially added with the amount of naproxen quantified after rupture.

[0068] The formula for containment efficiency is: EE[%] = Amount of naproxen found in the liposomes / Amount of naproxen originally added ⋅ 100

[0069] The results show that the maximum efficiency of the active ingredient encapsulation in the aforementioned sprayable dispersions 5 made of SoyPC or SoyPC / Chol / PEG liposomes with a lipid concentration of 30 mg / ml and an active ingredient content of 3% is approximately 23%.

[0070] Kollidon VA 64, sucrose and lactose were selected as stabilizers 9 to maintain the structural stability and integrity of the drug carriers 2 and to prevent the breaking up, fusion and aggregation of lipid nanoformulations 4 during particle generation 7 in the form of spray granulation or spray agglomeration or spray coating.

[0071] Cellets 500 with a size of 500 µm to 710 µm were selected as spray carrier 24.

[0072] Approximately 1 g to 1.5 g of the sprayable dispersion 5 containing the lipid nanoformulation 4 was diluted with 200 g of 10 mM PBS buffer solution 8 (pH 7.4, containing 16 g NaCl, 0.4 g KCl, 2.84 g Na₂HPO₄, and 0.49 g KH₂PO₄). As stabilizers 9, 2 g of Kollidon VA 64, 2 g of sucrose, or 2 g of lactose—approximately 10% of the solids in the buffer solution 8—were dissolved in the diluted sprayable dispersion 5. The sprayable dispersion 5 was gently stirred to ensure that all stabilizers 9 were completely dissolved.

[0073] From this, using the sprayable dispersion 5 3, 13 and 18, the following four diluted sprayable dispersions 5 containing a stabilizer 9 were prepared: (1) Sprayable dispersion 5 No. 18 plus PBS buffer solution 8 (2) Sprayable dispersion 5 No. 3 plus PBS buffer solution 8 plus Kollidon VA 64 as stabilizer 9 (3) Sprayable dispersion 5 No. 13 plus PBS buffer solution 8 plus sucrose as stabilizer 9 (4) Sprayable dispersion 5 No. 18 plus PBS buffer solution 8 plus lactose as stabilizer 9

[0074] For the laboratory tests, a mini-Glatt with micro-kit container for the sprayable dispersion 5 and a 0.5 mm spray unit 26 designed as a bottom spray and a sausage insert 28 was used as a fluidization device 1.

[0075] The selected fluidization device 1, in the form of a fluidized bed system 14, was preheated for 10 minutes at a fluidization gas temperature of 60 °C. Then, 20 g of Cellets 500 were introduced into the fluidized bed system 14. After a waiting period of 1 to 3 minutes for the temperature to stabilize within the fluidized bed system 14, particle generation 7 was started. The atomizing air pressure of the spray unit 26 was set to 1.0 bar, and the sprayable dispersion 5 was sprayed into the process chamber 11 of the fluidized bed system 14 at an average feed rate of approximately 1.5 g / min. The temperature of the fluidization gas 10 at the gas distributor plate 17 was set to approximately 40 °C to 60 °C, while the temperature of the fluidization gas 10 at the fluidization gas outlet 21 was maintained at approximately 30 °C.To ensure sufficient fluidization of the spray carrier template 24 during particle generation, a fluidization gas pressure of 12 Nm was applied. 3 / h up to 20 Nm 3 Applied per hour. After spraying, 35 of the produced particles underwent a 10-minute post-treatment at 60 °C.

[0076] After particle generation 7 and thermal post-treatment 35 of the particles 3 produced in the fluidization device, the particles 3 were removed from the fluidization device 1 and analyzed. The particle size and particle size distribution were analyzed using an Eyecon 2 from Horiba. The results are presented in Fig. 7 shown.

[0077] Fig. Figure 7a shows untreated Cellets 500 with a mean particle size of 635 µm.

[0078] In Fig. Figure 7b shows Cellets 500 that have been sprayed exclusively with the PBS buffer solution 8. These particles 3 have a mean particle size of 757 µm and thus a coating 32 with a layer thickness 33 of 122 µm compared to the untreated Cellets 500 according to Fig. 7a.

[0079] Fig. Figure 7c shows Cellets 500 sprayed with a sprayable dispersion 5 according to the above-mentioned template (1). The mean particle size of the produced particles 3 is 731 µm, so that the coating 32 has a layer thickness 33 of 96 µm compared to Cellets 500.

[0080] The in Fig. The particles 3 shown in 7d are Cellets 500 sprayed with the sprayable dispersion 5 according to the above-mentioned template (2). These particles 3 have a mean particle diameter of 750 µm and a coating thickness 33 of 115 µm.

[0081] In Fig. Figure 7e shows particles 3 in which Cellets 500 have been sprayed with the sprayable dispersion 5 according to the above-mentioned template (3). These particles 3 have a mean particle size of 734 µm and thus a coating 32 with a layer thickness 33 of 99 µm compared to the untreated Cellets 500 according to Fig. 7a.

[0082] The in Fig. The particles 3 shown in Figure 7f are Cellets 500 sprayed with the sprayable dispersion 5 according to the above-mentioned template (2), wherein the particles 3 have a mean particle diameter of 762 µm and thus a layer thickness 33 of the coating 32 of 127 µm.

[0083] To analyze the integrity of the lipid nanoformulations 4, the fabricated particles 3 were re-dissolved. This analysis is optional. For this purpose, approximately 5 g of the particles 3 loaded with drug carriers 2 in the form of the lipid nanoformulation 4 were weighed out and dissolved in 8 ml of demineralized water. The samples were stirred at 800 rpm for 10 minutes to ensure that the lipid nanoformulations 4, in the form of liposomes in the coating 32, were completely dissolved in the solution. The solution was then filtered through a 0.45 µm or 0.2 µm membrane, and dynamic light scattering (DLS) was performed using the Zetasizer NANO ZS from Malvern Panalytical to measure the size and size distribution of the recovered lipid nanoformulation 4. The measurements were performed at 25 °C.

[0084] In the resolution of the in Fig. 7b and Fig. No DLS signal was detected in particle 3 shown in 7c. This indicates that the lipid nanoformulations 4 were destroyed during particle production 7.

[0085] Upon dissolution of the in the Fig. A DLS signal could be detected in each of the particles 3 shown in Figures 7d to 7f, which were produced using stabilizers 9. Thus, the lipid nanoformulations 4 were preserved through the use of stabilizers 9 during particle production 7. The mean size of the recovered lipid nanoformulations 4 is approximately 150 nm when using Kollidon VA64 and sucrose as stabilizer 9, while the use of lactose as stabilizer 9 results in a mean size of the lipid nanoformulations 4 of over 400 nm. The polydispersity indices for all three experiments are below 0.3, indicating acceptable dispersibility of the recovered lipid nanoformulations 4. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited non-patent literature

[0000] Yu, JY et al. describe in their article in Pharmaceutics 2021, 13, 1023 (https: / / doi.org / 10.3390 / pharmaceutics13071023

[0004]

Claims

[1] A process for producing particles (3) containing an active substance carrier (2), comprising the process steps: Production of a sprayable dispersion (5) containing the active ingredient carriers (2) in the form of a lipid nanoformulation (4), wherein a stabilizer (9) is added to the dispersion (5) to produce shape-stabilized active ingredient carriers (2); and Feeding the sprayable dispersion (5) to a particle generation unit (7), characterized by , that the particle generation (7) is carried out by spraying the sprayable dispersion (5) in a process chamber (11) of a fluidizing device (1) through which a fluidizing gas (10) flows, as spray granulation or as spray agglomeration or as spray coating, in order to produce the particles (3) in the form of granules (12) or agglomerates (13) or a coated spray carrier template (24). [2] Method according to claim 1, characterized by, that carbohydrates and / or proteins and / or polyols and / or polymers are used as stabilizers (9). [3] Method according to claim 2, characterized by , that the stabilizer (9) is supplied to the sprayable dispersion (5) under the supply of energy in order to dissolve the stabilizer (9) substantially completely in the sprayable dispersion (5), wherein the supply of energy is expediently designed as stirring and / or heating of the sprayable dispersion (5). [4] Method according to any one of the preceding claims, characterized by , that in the fluidization device (1) a spray carrier template (24) is placed before the supply of the sprayable dispersion (5), wherein isomalt and / or lactose and / or microcrystalline cellulose and / or mannitol are expediently used as the spray carrier template (24). [5] Method according to claim 4, characterized by, that the spray carrier template (24) is fluidized in the fluidization device (1) prior to the supply of the sprayable dispersion (5). [6] Method according to any one of the preceding claims, characterized by , that a characterization of the lipid nanoformulation (4) is carried out after the production of the sprayable dispersion (5) and before the supply of the sprayable dispersion (5) to the particle generation (7), wherein, for the characterization of the lipid nanoformulation (4), a size and / or a size distribution of the lipid nanoformulation (4) is expediently measured in the sprayable dispersion (5). [7] Method according to claim 6, characterized by , that prior to the introduction of the sprayable dispersion (5) into the fluidization device (1) a polydispersity index of the lipid nanoformulation (4) in the sprayable dispersion (5) is set to less than 0.5, preferably less than 0.

3. [8] Method according to any one of the preceding claims, characterized by , that the sprayable dispersion (5) is diluted with a buffer solution (8) prior to the feed of the sprayable dispersion (5) to the particle generation (7), wherein the buffer solution (8) is advantageously designed as a phosphate-buffered salt solution, as a tris(hydroxymethyl)aminomethane solution or as a sucrose solution. [9] Method according to any one of the preceding claims, characterized by , that the drug carrier (2) in the form of a lipid nanoformulation (4) is loaded with an active substance (6). [10] Method according to any one of the preceding claims, characterized by , that the supply of the sprayable dispersion (5) in the fluidization device (1) is stopped and the produced particles (3) are further fluidized in the fluidization device (1) and thereby thermally post-treated. [11] Method according to claim 10, characterized by, that the residence time for the thermal post-treatment (35) of the particles (3) in the fluidization device (1) is between 1 min and 60 min, in particular between 5 min and 20 min. [12] Method according to any one of the preceding claims, characterized by , that the fluidizing gas (10) has a fluidizing gas temperature between -200 °C and 200 °C when flowing through the process chamber (11), preferably between 20 °C and 200 °C, expediently between 40 °C and 120 °C. [13] Particles (3) with a particle size in the range of 50 µm to 3 mm, characterized by that the particles (3) have a spray carrier template (24) and have an active ingredient carrier (2) in the form of a lipid nanoformulation (4). [14] Particles (3) according to claim 13, characterized by that the particles (3) have a form factor greater than or equal to 0.90, preferably greater than or equal to 0.

93. [15] Particles (3) according to claim 13 or 14, characterized bythat the lipid nanoformulation (4) is loaded with an active ingredient (6). [16] Particles (3) according to any one of claims 13 to 15, characterized by , that the particle (3) has a core (31) and a coating (32) surrounding the core (31), wherein the core (31) is formed from a spray carrier template (24) and the coating (32) has the lipid nanoformulation (4). [17] Particles (3) according to claim 16, characterized by , that the coating (32) has a layer thickness (33) between 0.1 µm and 1500 µm. [18] Use of a fluidization device (1) having a process chamber (11) through which a fluidizing gas (10) flows, for carrying out a method according to any one of claims 1 to 12. [19] Use according to claim 18, characterized by , that the fluidization device (1) is designed as a fluidized bed device (14) or as a jet bed device (15). [20] Use of a particle (3) according to any one of claims 13 to 17 for the manufacture of pharmaceutical dosage forms or for the presentation as a pharmaceutical dosage form itself.

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