Lipophyle transport particles for cosmetic or pharmaceutical active ingredients

Description

[0001] The invention relates to the use of lipophilic transport particles for cosmetic or pharmaceutical active ingredients in the manufacture of pulmonarily applicable inhalants, wherein the transport particles have polyglycerol fatty acid esters as their main component and, due to the absence of polymorphic transformations, do not exhibit volume changes even during prolonged storage, nor do they cause the problem of displacement of the adhering or encapsulated active ingredient due to increased structuring of the crystal lattice and associated compaction, so that the active ingredient charge level and release profile are stable.

[0002] Inhalers for the pulmonary administration of pharmaceutical agents offer several advantages. Firstly, they allow for the targeted treatment of respiratory diseases. Secondly, drugs that would not survive passage through the gastrointestinal tract and are therefore usually administered intravenously can be delivered pulmonarily with comparable effectiveness, provided the drug-carrying particles are sufficiently small. This also leads to improved patient adherence to therapy. To effectively deliver a pharmaceutical agent to the lungs, it should preferably be inhaled in the form of particles with a median aerodynamic diameter between 1 µm and 5 µm.While this is not the size one would expect for transport deep into the lungs and alveoli, the problem with smaller particles is that they are carried out of the lungs by the exhaled airflow before the pharmaceutical agent can dissociate and be absorbed. Larger particles, on the other hand, are mostly unable to penetrate deep enough into the lungs.

[0003] To provide particles that can effectively transport pharmaceutical agents into the lungs, it is generally possible to use either hydrophilic or lipophilic particles. Commonly used are sugars, such as α-lactose monohydrate, cyclodextrins, mannitol, and dextrose monohydrate, as well as metal stearate, such as calcium, magnesium, or zinc stearate, and amino acids such as leucine or trileucine (Piyush Mehta, "Imagine the Superiority of Dry Powder Inhalers from Carrier Engineering", Journal of Drug Delivery, Volume 2018, Article ID 5635010, January 14, 2018).The requirements placed on transport particles encompass numerous aspects, particularly high encapsulation efficiency for the active ingredients, good surface properties, reproducibility, low toxicity, good release properties and deagglomeration at the site of action, and low hygroscopicity for good storage stability in the inhalation device. Lipophilic transport particles offer good prerequisites regarding hygroscopicity, storage stability, reproducibility, and encapsulation capacity; however, this comes with the disadvantage that lipids or triglycerides tend to undergo polymorphic transformation and can therefore alter their surface properties during storage.A volume increase due to polymorphic transformation, known as "blooming," must be avoided in lipophilic transport particles intended for pulmonary administration, as the resulting significant volume changes would preclude their use in therapeutics or diagnostics. Furthermore, polymorphic transformation would lead to a more structured and compact crystal lattice formation, causing the displacement of the adhering or encapsulated drug and thus negatively impacting the controllability of the drug charge and release profile. This would result in an undesirable "burst effect" upon release, in which unpredictable amounts of the drug would be released suddenly.However, for other applications of micronized transport particles, such as dermal or transdermal applications of cosmetic or pharmaceutical agents, the occurrence of polymorphic transformation would negate all the advantages of such lipophilic transport particles. Lipophilic transport particles for inhalation are disclosed, for example, in Silva et al., Powder Technology 239 (2013), pages 183-192.

[0004] The challenge therefore is to provide lipophilic transport particles for cosmetic or pharmaceutical active ingredients that are in stable crystalline modification and are also suitable for pulmonary drug application.

[0005] The problem can be solved by means of such transport particles comprising one or more polyglycerol fatty acid esters according to claim 1. The invention therefore relates to the use of lipophilic transport particles suitable for pharmaceutical and cosmetic active ingredients in the manufacture of inhalants for pulmonary application according to claim 1. Preferred embodiments are set forth in dependent claims 2 to 18.

[0006] Surprisingly, it has now been established for the first time that transport particles comprising polyglycerol fatty acid esters, abbreviated PGFEs, as their main component according to claim 1 are suitable for providing morphologically stable, lipophilic, pulmonarily applicable transport particles when such PGFEs are used which are each obtainable from a complete or partial esterification of a linear or branched polyglycerol having two to eight glyceryl units with one or more fatty acids each having 6 to 22 carbon atoms.

[0007] The simplest polyglycerols that can be used as starting materials for a targeted esterification are linear and branched diglycerols with the molecular formula C 6 O 5 H 14, which are industrially produced synthetically in a known manner, for example by reacting glycerol with 2,3-epoxy-1-propanol under base catalysis to form ether bonds or by thermally condensing under base catalysis, whereby the fraction containing mainly diglycerols can subsequently be separated.

[0008] Diglycerols can exist in three different structural isomeric forms: the linear form, in which the ether bridge forms between the first carbon atoms of the two glycerol molecules used; the branched form, in which the ether bridge forms between the first carbon atom of the first and the second carbon atom of the second glycerol molecule used; and a nucleo-dentrimeric form, in which the ether bridge forms between the second carbon atoms of each molecule used. In the alkaline-catalyzed condensation of two glycerol molecules, the linear form is formed in approximately 80% of cases and the branched form in approximately 20%, while the nucleo-dentrimeric form is formed only to a very small extent.

[0009] Similarly, polyglycerols with more than two and up to eight glyceryl units can be used for esterification with fatty acids. Generally, polyglycerols are abbreviated as "PG" and given a subscript n indicating the number of polyglyceryl units, i.e., "PG n". For example, triglycerols would be denoted as PG 3 and have the molecular formula C 9 O 7 H 20. Complete esterification with a fatty acid, for example, with stearic acid, would then take place at all free hydroxyl groups of the PG n molecule; in the case of a linear PG 3, this would be at the first and second carbon atoms of the first glyceryl unit, at the second carbon atom of the second glyceryl unit, and at the second and third carbon atoms of the third glyceryl unit. The molecular formula for this example could therefore be given as C 9 O 7 H 15 R 5, where R would stand for a fatty acid residue, in the chosen example with the molecular formula C 18 OH 35 .

[0010] The abbreviation PG(n)-Cm complete ester or, where applicable, PG(n)-Cm partial ester has also become established for polyglycerols esterified with saturated unbranched fatty acids. The bracketed "n," similar to the designation of polyglycerols, indicates the number of glyceryl units in the molecule, and m represents the number of carbon atoms of the saturated fatty acid used for the esterification reaction. Thus, n represents the number of glyceryl units with the molecular formula C₃O₂H₅R or C₃O₃H₅R₂ for marginal glyceryl units, where R can represent a fatty acid residue or the hydrogen atom of a free hydroxyl group. PG(2)-C₁₈ complete ester would therefore denote polyglycerol fatty acid complete esters with the molecular formula C₇₈O₆H₁₅O₆ of the main component.In the case of PG partial esters, the number of fatty acid residues is averaged, with the overall formula simultaneously indicating the fraction with the most frequently occurring esterification variants. A more precise designation for polyglycerol fatty acid partial esters results from the additional specification of the hydroxyl number, which is a measure of the content of unesterified hydroxyl groups and thus provides information about the degree of esterification of the partial ester. The esterification reactions preferably proceed from the outside in, presumably for steric reasons. Therefore, the hydroxyl groups that allow the fatty acid residue the highest degrees of freedom are esterified first. The first esterification reaction on a linear polyglycerol thus preferably takes place at the hydroxyl group of the first carbon atom of an outermost polyglyceryl unit, and the second esterification reaction then takes place at the hydroxyl group of the third carbon atom of the outermost polyglyceryl unit.Subsequently, the hydroxy groups at already esterified positions are esterified immediately adjacent to carbon positions, and so on.

[0011] Fatty acids, as used here, are defined as aliphatic monocarboxylic acids with 6 to 22 carbon atoms, preferably unbranched and saturated with an even number of carbon atoms, but they can also be odd-numbered, branched, and / or unsaturated. Saturated and / or unbranched fatty acids are preferably used for the esterification of the PGFEs used as the main component of the transport particles. Furthermore, it is advantageous to use unbranched, saturated fatty acids with 16, 18, 20, or 22 carbon atoms for the esterification, i.e., palmitic, stearic, arachidic, or behenic acid.

[0012] Advantageous PGFEs are those that, when examined using differential scanning calorimetry, exhibit only an endothermic minimum during heating and only an exothermic maximum during cooling. This is because longer storage times, elevated temperatures, or energy input due to shear forces during application can occur, which, in the case of unsuitable components of the transport particles, can lead to their polymorphic transformation and difficult-to-control properties of the corresponding inhalant. Additional polymorphic forms would become apparent in differential scanning calorimetry through the occurrence of a local exothermic maximum during sample heating and a local endothermic minimum during sample cooling.The "blooming" phenomenon, which only occurs after a period of storage and is characterized by a significant increase in volume due to a polymorphism of a component, is macroscopically visible. This phenomenon can be avoided by using transport particle components that do not exhibit polymorphism. Triglycerides, such as glyceryl tripalmitate or glyceryl tristearate, can exhibit polymorphisms, meaning they can exist in a crystalline, unstable α-modification, a metastable β'-modification, or a stable β-modification, and can transition from one modification to another. These modifications differ primarily in the thickness of lamellar-packed, crystalline subunits, also known as subcellular units.For the α-modification of glyceryl tristearate, for example, an average of 6 lamellar structures per subcellular unit was determined under certain conditions. After complete conversion to the β-modification, an average of 10.5 lamellar structures per subcellular unit was observed, along with an increase in crystal thickness of approximately 67%. The fact that the calculated expected increase of 75% is not achieved is presumably due to the fact that the individual lamellae of the β-modification exhibit a denser lamellar packing as a result of an oblique orientation compared to the α-modification (see DG Lopes, K. Becker, M. Stehr, D. Lochmann et al. in Journal of Pharmaceutical Sciences 104: 4257-4265, 2015). Such a denser lamellar packing can then lead to the already discussed, undesirable expulsion of the adhering or enclosed active ingredient.

[0013] Since the transport particle components are present in the final product, it is further advantageous if the PGFEs used exhibit a stable subcellular form below their solidification temperature, with a substantially constant thickness of the lamellar crystallites at 40°C and 75% relative humidity for at least 6 months, i.e., under the storage conditions of an accelerated shelf-life test. This thickness is determined by small-angle X-ray scattering (SAXS) evaluated using the Scherrer formula. SAXS allows conclusions to be drawn about the size, shape, and internal surface area of ​​crystallites. The thickness of the respective crystallites can be calculated using the Scherrer formula, according to which D = Kλ / FWHM cos(θ). Here, D denotes the thickness of the crystallite, and K is the dimensionless Scherrer constant, which provides information about the shape of the crystallite and can generally be approximated to 0.9.FWHM stands for "full width at half maximum," meaning the width of the peak of an intensity maximum at half the height relative to the background, measured in radians (rad), and θ is the Bragg angle, i.e., the angle of incidence of the radiation onto the lattice plane. While a sample of glycerol tripalmitate stabilized with 10% polysorbate 65 exhibits a crystallite thickness of 31 nm, corresponding to seven lamellae, after six months of storage at room temperature, and its crystallite thickness nearly doubles to 52 nm, corresponding to 12 lamellae, after six months of storage at 40°C, the proposed polyglycerol fatty acid partial esters mostly show crystallite thicknesses of 20 to 30 nm, corresponding to 2 to 4 lamellae, and remain stable in their original modification after six months of storage at 40°C.In contrast, polyglycerol esters usually show a slightly increased crystallite thickness of 30 to 40 nm, corresponding to 5 to 8 lamellae, indicating a higher degree of organization, and are also stable in unchanged modification under the storage conditions of an accelerated shelf-life test.

[0014] It is also advantageous if, under the aforementioned conditions, the lamellar spacing of the PGFEs used remains essentially constant, as determined by wide-angle X-ray scattering (WAXS). Individual investigations of the proposed polyglycerol fatty acid esters below their respective solidification temperatures using WAXS show an intensity maximum for all investigated polyglycerol fatty acid esters. This maximum corresponds to a deflection angle of 21.4°, approximately 2θ, or twice the Bragg angle. From this, a spacing of the lattice planes of 415 pm is derived, which correlates with the lamellar packing density of the investigated molecules. This spacing can be structurally attributed to the α-modification, in which the respective lamellar structures are arranged parallel to each other in a hexagonal lattice with stacked, plane-forming molecules.No other modifications could be identified. The stability of the identified α-modification was also investigated using WAXS at both room temperature and 40°C for 6 months each. Again, only the α-modification, which was surprisingly stable for the polyglycerol fatty acid esters studied, was found.

[0015] For the provision of the transport particles, PGFEs from the following group are preferably selected: PG(2)-C18 total esters, PG(2)-C22 partial esters with a hydroxyl number of 15 to 100, PG(2)-C22 total esters, PG(3)-C16 / C18 partial esters with a hydroxyl number of 100 to 200, PG(3)-C22 partial esters with a hydroxyl number of 100 to 200, PG(3)-C22 total esters, PG(4)-C16 partial esters with a hydroxyl number of 150 to 250, PG(4)-C16 total esters, PG(4)-C16 / C18 partial esters with a hydroxyl number of 150 to 250. PG(4)-C16 / C18 complete esters, PG(4)-C18 partial esters with a hydroxyl number of 100 to 200, PG(4)-C22 partial esters with a hydroxyl number of 100 to 200, PG(6)-C16 / C18 partial esters with a hydroxyl number of 200 to 300, PG(6)-C16 / C18 complete esters, PG(6)-C18 partial esters with a hydroxyl number of 100 to 200, wherein in the polyglycerol fatty acid esters with two fatty acid residues differing due to the number of their carbon atoms, those with the lower number to 35% to 45%,Those with the higher number, correspondingly complementary, are present at 55% to 65% and the listed full esters preferably have a hydroxyl number of less than 5.

[0016] An advantageous property of the PGFEs for lipophilic transport particles according to claim 1 is their hydrophobicity, which can be determined by measuring the contact angle. The hydrophobicity is determined by measuring the contact angle between the PGFE in its solid state and a droplet of purified water. According to Young's equation, cosθ = (γSv - γSL) / γLV, where γSL is the interfacial tension between the PGFE and water, γLV is the surface tension of the water droplet, and γSv is the interfacial tension between the PGFE and the surrounding air. θ is the contact angle. Therefore, the larger the contact angle θ, the greater the interfacial tension between the PGFE and the water, and consequently, the higher the hydrophobicity of the PGFEs under investigation.The contact angles of the proposed polyglycerol fatty acid esters also correlate with the HLB value commonly used in pharmaceutical technology, which, on a scale of 0 to 20, indicates the ratio of lipophilic to hydrophilic molecular fractions, with the hydrophilic fraction increasing with a higher HLB value. The contact angle of the PFFE used for the lipophilic transport particles under storage conditions should only be subject to moderate changes for the provision of transport particles containing one or more pharmaceutical active ingredients, so that the stability of the release kinetics of the pharmaceutical active ingredient(s) from the transport particles is not negatively affected. Therefore, it is preferred that the polyglycerol fatty acid esters used as the main component of the transport particles exhibit a contact angle with water of less than 10° from the initial value after 16 weeks at both 40°C and 20°C.A relatively high contact angle of 40° would, for example, be detrimental to the desired consistency of the release kinetics. This deviation in the contact angle for glycerol tristearin with water under the specified conditions is due to a rearrangement from the α- to the β-modification during storage. The solidification temperature of the PFFEs used for the transport particles is preferably below 75°C, but above 40°C. Here, the solidification temperature is defined as the temperature at which the maximum of the highest exothermic peak of the heat flux occurs during cooling in a sample analysis using differential scanning calorimetry.

[0017] Due to their synthesis, PGFEs are always mixtures of different molecules, especially in the case of partial esters. However, it is also possible to post-synthetically mix such PGFEs for the provision of suitable transport particles according to claim 1, which are obtained from esterification reactions that differ from one another due to the reactants used or the reaction conditions.

[0018] The term "active ingredient" here refers to a pharmaceutical or cosmetic active ingredient. A pharmaceutical active ingredient is defined as a substance that can be used as a pharmacologically active component of a medicinal product. Substances in this context include chemical elements and chemical compounds, as well as their naturally occurring mixtures and solutions; plants, plant parts, plant constituents, algae, fungi, and lichens in processed or unprocessed form; animal carcasses, including those of living animals, as well as body parts, body constituents, and metabolic products of humans or animals in processed or unprocessed form; microorganisms, including viruses, and their constituents or metabolic products.Medicinal products are substances or preparations of substances intended for use in or on the human or animal body and are intended as agents with properties for curing, alleviating, or preventing human or animal diseases or pathological conditions, or which can be used in or on the human or animal body or administered to a human or animal in order to restore, correct, or modify physiological functions through a pharmacological, immunological, or metabolic action, or to make a medical diagnosis.Also considered medicinal products are objects that contain a medicinal product as defined above or on which a medicinal product as defined above is applied and that are intended to come into permanent or temporary contact with the human or animal body, as well as substances and preparations of substances that, also in combination with other substances or preparations of substances, are intended to reveal the nature, condition or function of the animal body or to serve the purpose of detecting pathogens in animals, without being applied to or in the animal body.A cosmetic active ingredient is a substance or mixture of substances that, when applied dermally, can be said to have a health-promoting or health-maintaining effect on the skin or skin appendages such as hair and nails, such as hyaluronic acid, collagen, dexpanthenol, aloe vera extract, allantoin or bisabolol, for which a pharmacological effect does not necessarily have to be scientifically proven.

[0019] The provided transport particles fulfill their purpose when loaded with an active ingredient, particularly a pharmaceutical active ingredient. This is achieved, for example, by means of a spray-drying process according to claim 4, in which the active ingredient and the PFFE(s) are first dissolved and / or suspended in a suitable organic solvent and then separated from the solvent again by spray drying. Suitable solvents include, for example, the ether tetrahydrofuran, the alcohol ethanol, the ketone acetone, the ester ethyl acetate, or the alkane heptane. It has been shown that loading with a pharmaceutical active ingredient of up to 30% by weight is possible using spray drying.

[0020] Another suitable manufacturing process for the transport particles of the present invention, in which the transport particles are loaded with a pharmaceutical active ingredient, is high-pressure homogenization. According to claim 6 or 7, a mixture of PFFE or a PFFE mixture with water is first prepared by stirring at a temperature above the melting point of the PFFE or the PFFE mixture. The desired pharmaceutical active ingredient(s) and, if necessary, a non-ionic surfactant are added to this mixture. The mixture is then forced through a homogenization nozzle under high pressure of 100 to 2000 bar, collected, and generally subjected to this procedure several times until the desired droplet size of the lipid phase of an O / W emulsion is achieved. The mixture is then cooled to form a suspension of drug-loaded transport particles in water.

[0021] The PFFEs used to manufacture the lipophilic transport particles should be in a solid state at temperatures of 40°C or lower so that the resulting transport particles can also be solid at the same temperatures. When loading them with pharmaceutical active ingredients, it is therefore important to consider that a eutectic mixture with the pharmaceutical active ingredient(s) may form, which should then also be in a solid state at 40°C or lower. The same applies to the addition of emulsifiers such as non-ionic surfactants, which may be required depending on the active ingredient.

[0022] For the pulmonary application of pharmaceutical agents, it has proven advantageous for the transport particles to have a mass-related median aerodynamic diameter (MMAD) of 0.5 µm to 5 µm. The transport particles according to the present invention therefore possess this MMAD. The theoretical MMAD can be calculated from the tapped density, the geometric diameter determined by light diffraction, and the form factor determined by polarization microscopy. It has been shown that transport particles with MMADs of 0.5 µm and 5 µm can be produced from the PGFEs according to claim 1 and, in particular, the PGFEs according to claim 13, especially when the tapped density is less than 0.4 g / cm³.

[0023] For the storage properties of the transport particles, it is advantageous if they have a water content of less than 2.5% as determined by Karl Fischer titration.

[0024] For the loading of transport particles with glucosteroids, such as dexamethasone, it is advantageous if the transport particles contain not only polyglycerol fatty acid esters but also an emulsifier, preferably a non-ionic surfactant. In particular, the combination of PG(2)-C18 ester with poloxamer 188 leads to good encapsulation efficiency for dexamethasone.

[0025] Depending on the active ingredient to be loaded onto the transport particles, adding liquid lipids to the PFFEs can also improve their encapsulation effectiveness. However, the amount added must be kept so small that the transport particles remain in a solid state. It can also be beneficial to dissolve cosmetic active ingredients, such as fat-soluble vitamins, in liquid lipids first.

[0026] Lipophilic transport particles according to claim 1 can advantageously be loaded with pharmaceutical active ingredients from the group of non-steroidal anti-inflammatory drugs. The production according to the spray-drying method of claim 4 has proven effective, enabling a loading of the transport particles with the active ingredient ibuprofen of up to 30% by weight.

[0027] Loading with pharmaceutical active ingredients from the glucosteroid group is, however, more advantageously carried out using the high-pressure homogenization process according to claim 6 or 7. For dexamethasone, for example, an inclusion efficiency of the transport particles in aqueous suspension of more than 90 wt% was achieved.

[0028] For the pulmonary administration of transport particles, whether loaded with or without an active ingredient, nebulizers for transport particles suspended in a carrier liquid are available, as are metered-dose aerosol nebulizers in which the transport particles are dissolved and / or suspended in a propellant and released in portions at the push of a button, or dry powder inhalers in which the transport particles are presented in portions for inhalation with the airflow. Regardless of the device used to enable the inhalation of the transport particles, all variants comprising such a device and the transport particles are hereby subsumed under the term "inhalation device."

[0029] The invention will be explained in more detail below with reference to examples and illustrations, without being limited to these. Example 1 Provision of micronized, lipophilic, ibuprofen-loaded transport particles for a powder inhaler by spray drying:

[0030] A solution of 1.08 g of PG(3)-C22 partial ester-

[137] , where the number in square brackets indicates the hydroxyl number, and 0.46 g of ibuprofen is prepared by dissolving the components in 60 g of tetrahydrofuran to achieve a solids content of 2.5 wt%. The solution is sprayed in a Procept 4M8-Trix closed-ring spray dryer in nitrogen as the inert gas. A drying column and a small cyclone separator with a pressure differential of 60 mbar are used. The inlet temperature is set to at least 5°C above the boiling point of the solvent, and the airflow velocity to 0.3 m³ / min. The solution is forced through a 0.2mm bi-fluid nozzle at a rate of 3.5 g / min with a nozzle pressure of 0.9 bar, corresponding to 3 l / min.The separated, ibuprofen-loaded transport particles are removed from the spray drying unit and stored under vacuum for 10 hours to remove residual solvent. This yields transport particles loaded with ibuprofen to 30% by weight, with a theoretical MMAD of 4.10 µm. The bulk density is 0.215 g / cm³, the tapped density is 0.342 g / cm³, the true density is 1.069 g / cm³, and the water content is 0.45%. The differential pressure calorimetry for the eutectic mixture of ibuprofen and PG(3)-C22 partial ester-

[137] yields the values ​​listed below: 1) immediately after preparation of the ibuprofen-loaded transport particles; 2) after one month of storage at 20°C; 3) after one month of storage at 40°C. ad 1) ad 2) ad 3) Start of the melting process: 58.0°C (± 0.06°C) 58.1°C (± 0.07°C) 58.1°C (± 0.07°C) Melting point: 60.9°C (± 0.12°C) 60.8°C (± 0.07°C) 60.8°C (± 0.14°C) Crystallization temperature: 57.9°C (± 0.06°C) 58.1°C (± 0.07°C) 58.0°C (± 0.00°C) Heat of fusion: 139.2°C (± 5.1°C) 139.2°C (± 6.2°C) 139.8°C (± 5.4°C). Example 2 Provision of micronized, lipophilic, dexamethasone-loaded transport particles as a suspension for a nebulizer by means of high-pressure homogenization

[0031] To PG(2)-C18 ester melted at 70°C, 0.1 wt% dexamethasone is added and stirred at 750 rpm with a magnetic stirrer for 60 minutes to obtain a clear solution. 100 ml of preemulsion for high-pressure homogenization are prepared at 70°C by mixing 10 wt% of the clear solution, 2.5 wt% poloxamer 188, and 87.5 wt% purified water for two minutes at 20,500 rpm using an Ultraturrax T25 (Janke & Kunkel, IKA, Germany). The preemulsion is subjected to high-pressure homogenization in three successive passes, also at 70°C, using a high-pressure piston homogenizer with a Panda K2 NS1001L gap valve (GEA NiroSoavi, Germany). The particle size is determined using a Mastersizer 2000 (Malvern, United Kingdom), which is a device for analyzing laser beam diffraction based on static light scattering.Approximately 10–30 µl of the suspension to be analyzed are added to the measuring cell, which already contains 20 ml of high-purity water to achieve a turbidity between 4% and 6%. A particle refraction index of 1.55 and a particle absorption index of 0.01 are set to ensure a residual value of less than 1 in every measurement. The pump speed is 1750 revolutions per minute. Data analysis is performed based on Mie theory. The median particle size (d 50 ) is therefore 212 nm. The dynamic differential calorimetry of the nanosuspension, compared with the clear solution of PG(2)-C18 ester and dexamethasone, shows that the addition of polyoxamer 188 provides no evidence of a polymorphic transformation of the stable crystal modification of PGFE.

[0032] The properties of some PGFEs are explained below using illustrations as examples.

[0033] The partial ester PG(4)-C18 shows, when investigated by gas chromatography coupled with mass spectrometry (GC-MS), the following: Fig. 1 The main quantitative structure shown.

[0034] Fig. 2 shows the results of investigations of PG(4)-C18 using differential scanning calorimetry, where the temperature values ​​on the x-axis of the diagram are assigned to the heat flux in mW / g on the y-axis. The left diagram in Fig. 2 The graph shows two nearly identical curves from two measurements of the partial ester PG(4)-C18, each exhibiting exactly one endothermic minimum that can be attributed to the energy-consuming transition from the solid to the liquid phase during the melting of the partial ester. The right-hand diagram in Fig. 2The partial ester PG(4)-C18 exhibits precisely one exothermic maximum, which can be attributed to the energy-releasing transition from the liquid to the solid phase during the solidification of the partial ester. The measurements were performed using a DSC 204 F1 Phoenix from Nietzsch Gerätebau GmbH, 95100 Selb, Germany. A 3-4 mg sample was weighed into an aluminum crucible, and the heat flux was continuously recorded at a heating rate of 5 K per minute. A second run was performed at the same heating rate.

[0035] Fig. 3In contrast to the desired behavior of polyglycerol fatty acid esters, the typical behavior of a polymorphic triacylglycerol during a dynamic difference calorimetry investigation upon heating is shown. Here, two local endothermic minima with an intervening exothermic maximum can be observed. The first endothermic, left-hand minimum occurs due to the melting of the unstable α-modification, followed by the exothermic maximum during crystallization into the more stable β-modification, which in turn melts upon further temperature increase, as evidenced by the second endothermic, right-hand local minimum.

[0036] Fig. 4 shows the PG(4)-C18 partial ester investigated by differential scanning calorimetry upon warming after 6 months of storage at room temperature. Fig. 5Figure 1 shows the PG(4)-C18 partial ester, investigated by differential scanning calorimetry, upon heating after 6 months of storage at 40°C. In both cases, no exothermic maximum is observed that could indicate crystallization into a more stable modification after melting.

[0037] For the WAXS and SAXS analyses, a point-focusing camera system, S3-MICRO, formerly Hecus X-ray Systems Gesmbh, 8020 Graz, Austria, now Bruker AXS GmbH, 76187 Karlsruhe, Germany, equipped with two linear position-sensitive detectors with a resolution of 3.3–4.9 angstroms (WAXS) and 10–1500 angstroms (SAXS), was used. The samples were placed in a glass capillary approximately 2 mm in diameter, which was subsequently sealed with wax and placed in the capillary rotation unit. The individual measurements were performed at room temperature and exposed to an X-ray beam with a wavelength of 1.542 angstroms for 1300 seconds.

[0038] Fig. 6 Figure 1 shows the results of the WAXS analysis of various polyglycerol fatty acid esters, including PG(4)-C18 partial esters (labeled), below their solidification temperature, all of which exhibit an intensity maximum at 2θ of 21.4°. The Bragg angle corresponds to a lattice plane spacing of 415 pm, typical for the lamellar packing of the α-modification. The intensity maximum persists both after storage for over 6 months at room temperature and in Fig. 7 shown, as well as being stable when stored for over 6 months at 40°C, as shown in Fig. 8 shown.

[0039] Fig. 9Figure 1 shows the results of the SAXS analysis of various polyglycerol fatty acid partial esters. A lamellar spacing of 65.2 angstroms can be derived for PG(4)-C18 partial esters. According to the Scherrer formula, the crystallite thickness is 12.5 nm, with a Scherrer constant of 0.9, a wavelength of 1.542 angstroms, an FWHM value of 0.0111, and a Bragg angle θ of 0.047 rad. The values ​​of the SAXS analysis of PG(4)-C18 partial esters remained constant even after six months of storage at both room temperature and 40°C (not shown).

[0040] The evaluation of the differential calorimetry also allows conclusions to be drawn about the solidification temperature of the PG(4)-C18 partial ester. The peak of the exothermic maximum during cooling of the sample rises between 53.4°C and 57.0°C, with the maximum at 55.2°C, which marks the solidification temperature.

[0041] Fig. 10Figure 1 shows a diagram illustrating the measurement of the contact angle (see paragraph

[0020] ). For PG(4)-C18 partial esters, the contact angle is approximately 84°, which correlates with an HLB value of approximately 5.2. Compared to other polyglycerol fatty acid esters, PG(4)-C18 partial esters are among the more hydrophilic polyglycerol fatty acid esters, as shown in Figure 2. Fig. 11 visible (there = PG4-C18). Fig. 12 The graph shows the change in the contact angle for PG(4)-C18 partial esters, center diagram, compared to the initial measurement (left column) after 16 weeks at room temperature (center column) and after 16 weeks at 40°C (right column). The contact angle changes by no more than 10°, so the hydrophobicity can be described as stable compared to monoglycerol fatty acid esters, such as tristearyl glycerol. The same applies to the [unclear text] also in Fig. 12 PG3-C16 / C18 partial esters shown, left diagram, and PG6-C18 partial esters, right diagram.

Claims

1. Use of lipophilic carrier particles which are suitable for pharmaceutical and cosmetic active ingredients in the manufacture of inhalation products for pulmonary application, characterized in that the carrier particles have a mass median aerodynamic diameter (MMAD) of 0.5 µm to 5 µm, a tamped density of less than 0.4 g / cm3 and one or more polyglycerol fatty acid esters as the major component, which can respectively be obtained from a complete or partial esterification of a linear or branched polyglycerol containing two to eight glyceryl units with one or more fatty acids respectively containing 6 to 22 carbon atoms.

2. Use of lipophilic carrier particles as claimed in claim 1, characterized in that the carrier particles are loaded with at least one of the active ingredients during the manufacture.

3. Use of lipophilic carrier particles as claimed in claim 2, characterized in that the carrier particles have an active ingredient content of more than 10% by weight.

4. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that, following i) dissolution and / or suspension of the polyglycerol fatty acid ester or polyglycerol fatty acid esters with a pharmaceutical active ingredient in an organic solvent, and ii) subsequently, removal of the solvent by means of spray drying, the carrier particles contain at least one of the active ingredients.

5. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the pharmaceutical active ingredient is assigned to the non-steroidal antirheumatic agents (NSAR) group.

6. Use of lipophilic carrier particles as claimed in one of claims 1 to 3, characterized in that, following i) manufacture of a mixture of the polyglycerol fatty acid ester or polyglycerol fatty acid esters with water and at least one pharmaceutical active ingredient by stirring at a temperature which is above the melting temperature of the polyglycerol fatty acid ester or the polyglycerol fatty acid esters, ii) subsequent spraying of the mixture once or multiple times through a high pressure homogenization nozzle to form an O / W emulsion, and iii) cooling the lipid phase to form solid particles in water, the carrier particles contain at least one of the active ingredients.

7. Use of lipophilic carrier particles as claimed in claim 6, characterized in that in addition, at least one non-ionic surfactant is added to the mixture in step i).

8. Use of lipophilic carrier particles as claimed in one of claims 1, 2, 3, 6 or 7, characterized in that at least one active ingredient is assigned to the glucosteroids group.

9. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the carrier particles contain one or more incorporated liquid lipids.

10. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the fatty acids for the synthesis of the polyglycerol fatty acid esters are either saturated or unbranched or both saturated as well as unbranched.

11. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the fatty acids for the synthesis of the polyglycerol fatty acid esters of the carrier particles contain 16, 18, 20 or 22 carbon atoms.

12. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that an investigation of the polyglycerol fatty acid ester or individual polyglycerol fatty acid esters by means of heat flux differential scanning calorimetry produces, upon heating up, respectively only one endothermic minimum and upon cooling down, respectively only one exothermic maximum.

13. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the carrier particles contain at least one polyglycerol fatty acid ester from the following group: PG(2)-C18 full esters, PG(2)-C22 partial esters with a hydroxyl value of 15 to 100, PG(2)-C22 full esters, PG(3)-C16 / C18 partial esters with a hydroxyl value of 100 to 200, PG(3)-C22 partial esters with a hydroxyl value of 100 to 200, PG(3)-C22 full esters, PG(4)-C16 partial esters with a hydroxyl value of 150 to 250, PG(4)-C16 full esters, PG(4)-C16 / C18 partial esters with a hydroxyl value of 150 to 250, PG(4)-C16 / C18 full esters, PG(4)-C18 partial esters with a hydroxyl value of 100 to 200, PG(4)-C22 partial esters with a hydroxyl value of 100 to 200, PG(6)-C16 / C18 partial esters with a hydroxyl value of 200 to 300, PG(6)-C16 / C18 full esters, PG(6)-C18 partial esters with a hydroxyl value of 100 to 200, wherein, in the polyglycerol fatty acid esters containing two fatty acid residues which are different because of the number of their carbon atoms, those with the smaller number are present in an amount of 35% to 45%, those with the corresponding, complementary larger number are present in an amount of 55% to 65% and the specified full esters preferably have a hydroxyl value of less than 5.

14. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the polyglycerol fatty acid ester or the individual polyglycerol fatty acid esters have a solidification temperature between 43°C and 56°C.

15. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the carrier particles contain a post-synthesis mixture of polyglycerol fatty acid esters which are respectively obtainable from esterification reactions which are different from each other because of the respective reaction partners or reaction conditions which are employed.

16. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the carrier particles have a water content of less than 2.5%.

17. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the carrier particles contain an emulsifier.

18. Use of lipophilic carrier particles as claimed in one of the preceding claims, characterized in that the carrier particles contain a non-ionic surfactant,