Method for producing a liposomal formulation, and formulation obtained using the method

Abstract

While well-established liposomal formulations offer the prospect of an increased bioavailability, the speed of action and efficacy thereof does not yet approximate that of a direct injection. The aim of the invention is to overcome the aforementioned disadvantage. This is achieved by combining heating cavitation of a pre-temperature-controlled, pre-homogenized mixture and rapid cooling of the obtained liposomal formulation. Thus, for the first time, liposomal formulations can be obtained which have a permeation rate that results in an increase in the activity of the transported supplement within minutes in a similar manner to a local injection. Additionally, improved stability and a longer shelf life are obtained, which the inventor attributes to the lower content of accompanying agglomerates and crystallites as a result of the method. In combination with other substances which are supplied therewith as directly as possible to the energy management of different tissues of the body regardless of preceding utilization mechanisms, the liposomal vesicles demonstrate a permeation rate which can produce acute improvements in the same manner as an injection.

Description

[0001]FRL001 PCTprio Page 1 of 21 Process for the preparation of a liposomal formulation and formulation obtained by the process SCIENTIFIC FIELD The present invention can be assigned to the scientific field of liposome production. Liposomes are vesicles whose shell is formed from at least two layers of amphiphilic molecules. Thus, a liposome potentially offers the possibility of encapsulating an active ingredient. If a liposome is created from amphiphilic molecules that are native to or compatible with an organism, substances can be more easily transported through membranes and released into a target area; the latter has long been used in moisturizing creams to transport aqueous phases more quickly through the skin barrier, thereby building volume and smoothing / tightening the skin.Typical methods for producing liposomes include the dripping of a hydrophilic phase into a lipid phase, the homogenizing extrusion of liposome mixtures through fine pores, the high-pressure homogenization of emulsions, or the ultrasonic conditioning of aqueous solutions. Furthermore, the present invention encompasses liposomal formulations according to the process, as are generally known in the field of dietary supplements. Such formulations often serve to supplement the supply necessary for a balanced metabolism and, in the intended dosage, contain the average daily or weekly dose of compounds and minerals required to provide helpful nutrients in the case of an unbalanced or seasonally unbalanced diet. Furthermore, formulations of this type also serve as an accompanying supplement to dietary, therapeutic, or even healing concepts in the medical field.FRL001 PCTprio Page 2 of 21 The general use of liposomal formulations is known. Reference is made, for example, to WO 002007002897 A or EP 0 736 299 A1. GENERAL BACKGROUND The present invention relates to a method according to the preamble of the independent claim and to method-related formulations according to the dependent claim. Regarding fundamentals and background information, reference is made to documents such as EP 2537515 A1, DE 202013002498 U1 or DE 202018005540 U1, as well as DE 20 2023001 867 U1. DESCRIPTION OF THE PRIOR ART The present invention is based on formulations as also described in DE 202023001978 U1; Such formulations can be obtained by ultrasonic treatment of emulsions. Established formulations that can contribute to human energy balance are described, for example, in documents US 6080788 A, US 6 479540 B1, and US 20080103202 A1.The problem is that established, marketable formulations always contain sweeteners and texture additives to ensure taste acceptance in the market. Another problem is that these additives also introduce a texture effect during subsequent drying and can result in irregularly composed granules. It is known from GB 2178661 A1 that a direct injection of coenzyme Q10 together with creatine phosphate or a corresponding precursor compound can support and increase the performance of muscle tissue within 21 minutes. The disadvantage is that injection has very low customer acceptance. Alternative methods using micropowder compressed air injectors or similar have also failed to gain acceptance. Effects similar to those measurable with injection have not yet been reported for the known liposomal formulations.This disadvantage can be attributed to the fact that established liposomal formulations do not achieve optimal bioavailability in the sense of kinetics that at least approximate an injection due to micelles of different composition, a wider range of average micelle size, emulsion instability, and additives that are active in parallel and complementary utilization cycles. US 2007 / 0203076 A1 illustrates, using the example of creatine compared to creatinine in Figure 1B, what the term 'bioavailability' specifically encompasses: Targeted delivery to a specific area, such as a muscle, requires the penetration—also called permeation—of multiple membranes, mucous membranes, and barriers.Against this background, the term 'bioavailability' can be considered vague; rather, the aim is to specifically increase the ability of liposomal vesicles to permeate mammalian membranes and mucous membranes, so that even upon oral ingestion or indirect topical application, intact vesicles can reach the flowing systems in the body and effectively release the transported supplements at their destination. The object of the present invention was to provide a process by which liposomal vesicles can be produced that can permeate mammalian membranes more quickly and uniformly. FRL001 PCTprio Page 4 of 21 A further aspect of the present invention was to provide formulations according to the process.A further aspect of the present invention was therefore to overcome the disadvantages of the prior art and also to provide a formulation of the type 'Q10 + Creatine', which, despite the necessary accompanying substances, is capable of providing the core components with a high degree of bioavailability when taken orally, thus supporting muscular energy balance within minutes. This object is achieved according to the features of the independent claim. Advantageous features, measures, and embodiments emerge from the dependent claims and the following description.SUMMARY OF THE INVENTION According to the invention, a process for producing a liposomal formulation comprises the process steps a) preparing a hydrophilic, water-based, first mixture b) preparing an oleophilic, second mixture c) heating the second mixture to a pre-temperature which is 10°C to 30°C above the temperature of the highest melting point d) adding the first mixture to the second mixture with constant, thorough stirring and while maintaining the pre-temperature until a third, mechanically pre-homogenized mixture of the first and second mixture is present e) immediately transferring the pre-homogenized third mixture to a homogenizer and homogenizing the third mixture under cavitation until the temperature of the third mixture has increased by 10°C to 30°C without reaching a boiling temperature, f) rapidly cooling the homogenized, third mixture by at least 10°C within 60 seconds.DESCRIPTION OF THE INVENTION AND ADVANTAGEOUS FEATURES According to the invention, the process for producing a liposomal formulation comprises several process steps, beginning with a) preparing a hydrophilic, water-based first mixture. For this purpose, water-soluble solids, salts, and hydrophilic liquid components are mixed and stirred until a homogeneous first mixture is obtained. Step b) Preparing an oleophilic second mixture: For this purpose, oleophilic solids, fat-soluble additives, and olephilic liquid components are mixed and stirred until a second mixture with evenly distributed components is obtained.Step c) Heating the second mixture to a pre-temperature that is 10°C to 30°C above the highest melting point temperature. 'Highest melting point' refers to the highest melting point of the components of the second mixture individually; typically, these are fat or oil components, where the fat or oil with the highest melting point determines the corresponding temperature. A temperature at least 10°C to 30°C higher ensures that none of the components of the second mixture are incompletely melted or partially particulate or crystalline.As the temperature increases, the viscosity of the second mixture also decreases, making stirring easier and more effective. Preferably, the stirring resistance is used as a measured value, and stirring is continued until a constant stirring resistance is reached, particularly preferably combined with temperature control to achieve the ideal, cost- and energy-saving combination of pre-temperature and stirring time. Step d) Addition of the first mixture to the second mixture with constant, thorough stirring and while maintaining the pre-temperature until a third, mechanically pre-homogenized mixture of the first and second mixtures is obtained. 'Intense stirring', in the context of the present invention, refers to stirring processes with increased shear and vortex forces that rapidly and efficiently mix the liquid phases without mechanically altering the molecular sizes or molecular masses of the individual components.The result is a pre-homogenized third mixture of all components. Here, too, the stirring resistance is preferably used as a control parameter and indicator of uniform mixing. Step e) immediate transfer of the pre-homogenized third mixture to a homogenizer and homogenization of the third mixture under cavitation until the temperature of the third mixture has risen by 10°C to 30°C without reaching a boiling point. 'Immediate', in the context of the present invention, refers to the rapid transfer to a homogenizer without demixing or mechanical alteration of the third mixture. The objective is therefore to subject the third mixture to homogenizing cavitation without any discernible separation or separation of the mixed phases.The inventor assumes that through the formation and implosion of vapor-filled cavities in the mixture, the uniformly blended components are combined with high, local energy, forming a larger proportion of the energetically more active, smaller vesicles. Stirring of the mixture is preferably continued during homogenization, and the stirring resistance is used as a supplementary control and monitoring parameter. Upon reaching a temperature at least 10°C higher, a more uniform total amount of liposomal vesicles with a smaller diameter is generally obtained. Boiling processes should be avoided, as these increasingly consume energy for the evaporation of liquid, which changes the mixing ratios and reduces the yield of liposomal vesicles. Higher temperatures of up to 30°C are preferably used if the mixture contains salts and / or higher-melting and crystallizing components.More on this below. Step f) Rapid cooling of the homogenized, third mixture by at least 10°C within 60 seconds. Rapid cooling freezes finely distributed vesicles and unavoidable accompanying substances such as salts and higher-melting fats and oils in finely divided form, preventing the formation of larger vesicles, agglomerates, or crystals. The inventor assumes that amphiphilic agglomerates can influence the quality of the vesicle shell and, through the formation of larger agglomerates, can also impair the liposomal formulation. This may explain why rapidly thermally cooled formulations exhibit a higher permeation rate and improved stability in comparison.By combining heating cavitation of a pre-tempered, pre-homogenized mixture with rapid cooling of the resulting liposomal formulation, liposomal formulations were obtained for the first time. Their permeation rate could provide an increase in the activity of the transported supplements within minutes, similar to a local injection. In addition, there is improved stability and storage life, which the inventor attributes to the process-related lower content of accompanying agglomerates and crystallites. An ultrasonic homogenizer is preferably used as the homogenizer in step e). Ultrasonic homogenizers are easier to control and, with an appropriately adjusted amplitude, convert a high proportion of the input energy into cavitation, whereas mechanical homogenizers produce cavitation on the surfaces of the agitators, which is more difficult to control.This may explain why the uniformity and quantity of liposomal vesicles was greater with ultrasonic homogenizers at the same temperature increase. FRL001 PCTprio Page 8 of 21 Preferably, in a second sub-step f), the homogenized third mixture is then filled into containers pre-conditioned to 25°C with a maximum volume of 1000 ml. Pre-cooled containers with light protection, preferably brown glass or violet glass containers, support rapid cooling and can provide the liposomal formulation in a marketable form, packaged directly in commercially available quantities. Alternatively, in a step g), the homogenized third mixture is combined with extenders and excipients immediately after the first sub-step f), cooled by spray drying, and obtained as spray-dried granules. The granules are preferably coated, particularly preferably coated with another liposomal formulation.An advantageous formulation comprises coenzyme Q10 and a creatine source, the formulation being a stable, liposomal emulsion produced under cell disruption conditions and according to the process. Preferably, the formulation comprises coenzyme Q10 and a creatine source, the formulation being a stable, liposomal emulsion produced under cell disruption conditions. Liposomal emulsions comprise microdroplets. In this case, the emulsion is obtained and / or produced under cell disruption conditions. By using physiologically compatible, as uniform and homogeneous as possible, liposome building blocks can be obtained through the high pressure and shear forces applied in cell disruption processes. These droplet fractions stabilize the enclosed material and can also be transported more quickly through membranes.Bioavailability is thus better and more uniform, shelf life is increased, and storage stability is good to very good. These advantages are significantly improved by the process-based production; even topical applications and permeation through the gastrointestinal tract into the blood plasma are significantly more effective and faster. A more uniformly adjusted liposomal formulation can also be converted into a more homogeneous dry product, particularly advantageously; the use of at least partially amphiphilic fatty building blocks can support this: By exclusively amphiphilic fatty building blocks, the emulsion does not break even when it is atomized into the finest droplets and simultaneously dehydrated. The formulation preferably comprises at least one lecithin, particularly preferably a lecithin consisting of at least 20% by weight of phosphatidylcholine.The formulation preferably comprises at least one further amino acid compound, particularly preferably selected from the group of compounds comprising lysine, carnitine, creatine, creatine ethyl ester malate, cystine, and cysteine. The formulation preferably further comprises at least one sugar, wherein the at least one sugar comprises sugars that can be degraded exclusively in the human metabolism without insulin. The formulation preferably comprises at least one further vitamin, which is at least one vitamin selected from the group consisting of thiamine, vitamin E, vitamin C, vitamin B, vitamin B1, and vitamin B12. In addition to a vitamin present, the formulation preferably comprises at least one further vitamin precursor compound.The formulation preferably comprises at least one fat that can be metabolized without bile acid, which is at least one fat selected from the group consisting of medium-chain triglycerides, medium-chain fatty acids, and medium-chain fatty acid salts. Further advantages emerge from the exemplary embodiments. It is understood that the features and advantages described above and the following exemplary embodiments are not to be construed as limiting. Additional measures, advantageous features, and additional feature combinations, as explained in the description, in the scientific field, and in the documents cited and cited therein, can be implemented both individually and in different combinations within the scope of the independent claims in the claimed subject matter, without departing from the scope of the invention.DETAILED EXPLANATION OF THE INVENTION USING EXEMPLARY EMBODIMENTS For the purposes of this description, weight, quantity, and temperature specifications are to be viewed in a commercial context. Common industrial process controls (e.g., for animal feed) implement weight quantities with a relative accuracy of 10%; temperatures are maintained within a 3°C fluctuation. Accuracies from the food industry are preferred, where weight quantities are regulated with a relative accuracy of 5% and temperatures are set with a 1°C fluctuation. Control methods and devices from the medical field are particularly preferred, which set weight quantities with a 0.1% relative accuracy and determine / specify temperatures with a 0.1°C fluctuation.Advantageous formulations according to the process are explained in detail below using various examples: FRL001 PCTprio Page 11 of 21 Example 1: Joint Gel a) Mixture 1: L-carnitine (20 g), vitamin C (1 g), sunflower lecithin (15 g), and glucosamine sulfate (30 g) are dissolved in water (311 g); then, glycerol (529 g) and propylene glycol (30 g) are added and stirred. b) Mixture 2: Tocopherol acetate (1 g), medium-chain triglycerides (MCT) (55 g), and coenzyme Q10 (6 g) are dissolved and dispersed under warm conditions.c) Heating mixture 2 to a pre-temperature of 30°C; d) Adding the first mixture to the second mixture while continuously stirring thoroughly and maintaining the pre-temperature until a third, mechanically pre-homogenized mixture of the first and second mixtures is obtained; e) Immediately transferring the pre-homogenized third mixture to a homogenizer and homogenizing the third mixture under cavitation until the temperature of the third mixture has increased by 10°C to 30°C without reaching a boiling temperature; f) Rapidly cooling the homogenized third mixture by at least 10°C within 60 seconds. The liposomal formulation is then gelled with 0.5 to 1% by weight of xanthan gum.When applied topically to inflamed and painful joints in mammals, particularly horses and camels, the gel provides rapid, acute relief of symptoms. Mobilization programs can thus be carried out more quickly and effectively, which can be explained by good to very good permeation through the skin to the bone / into the joint and the extracellular space. Example 2: Food additive pro-ATP. The preparation is carried out analogously to Example 1 with the following components: a) Mixture 1: Ribose (450g), L-carnitine (50g), sunflower lecithin (120g) are dissolved in water (343g) and stirred. b) Mixture 2: Tocopherol acetate (2g), medium-chain triglycerides (MCT) (20g), coenzyme Q10 (10g), and boswellia resin (7g) are dissolved and dispersed under warm conditions. Processing is carried out according to the following parameters: Pre-mix temperature: 30°C; final temperature of the third mix: 50°C; cooled to: 35°C.The liquid, liposomal formulation supports mitochondrial energy balance while also providing anti-inflammatory and anti-inflammatory resin components in the gastrointestinal tract and muscles. With consistent training sessions that regularly slightly exceed the limits of exertion, muscle strength can be supported and immobilizing muscle soreness can be counteracted. Example 3: Antioxidant Mitochondrial Protection. The preparation is carried out analogously to Example 1 with the following components: a) Mixture 1: Glutathione (reduced; the SH group is not oxidized or bound; 35 g), vitamin C (35 g) are dissolved in water (520 g) and stirred. b) Mixture 2: Xylitol (380 g), sunflower lecithin (20 g) are dissolved and dispersed in warm water. Processing is carried out according to the procedure with the following parameters: Pre-temperature: 25°C; final temperature of the third mixture: 40°C; cooled to: 30°C.The liposomal formulation passes through the gastrointestinal tract through rapid permeation and transports the antioxidant SH group unchanged into various tissue areas. There, the SH group of the cysteine ​​serves as antioxidant protection; this relieves the mitochondrial energy balance and allows more energy to be provided for the muscles. FRL001 PCTprio Page 13 of 21 Example 4: Retinal Support The preparation is analogous to Example 1 with the following components: a) Mixture 1: Glycerol (622 g), water (111 g), vitamin B12 (0.02 g), vitamin D (1:100,000, 8 g) and sunflower lecithin (35 g) are dissolved and stirred. b) Mixture 2: Tocopherol acetate (2 g), vitamin A (1 g = 1,000,000 IU 0.8 g), MCT (175 g), coenzyme Q10 (20 g), olive oil preparation (25.08 g, contains 30 wt% carotenoids, of which 28.4% lutein and 1.45% zeaxanthin) are dissolved and dispersed in heat.Processing is carried out according to the procedure with the following parameters: Pre-temperature: 15°C; final temperature of the third mixture: 30°C; cooled to: 20°C. The liposomal formulation contains lutein and zeaxanthin, important messenger substances / receptor components necessary in the retina. Thanks to the liposomal formulation, these messenger substances, combined with vitamins D and A, reach the retina effectively via the bloodstream, even when ingested orally, and can support / refresh the receptors present there and prevent macular degeneration. Example 5: Blood Pressure Stabilizer. Production is carried out analogously to Example 1 with the following components: a) Mixture 1: L-arginine (80g), ascorbic acid (10g), and citric acid (60g) are dissolved in water (425g) and stirred. b) Mixture 2: Maca extract (20g), tocopherol acetate (1g) and sunflower lecithin (100g) as well as xylitol (280) are dissolved and dispersed in the heat.Processing is carried out according to the following parameters: Pre-mix temperature: 15°C; final temperature of the third mixture: 30°C; cooled to: 20°C. The liposomal formulation contains maca, L-arginine, and coenzyme Q10, an effective source of nitric oxide for cGMP (cyclic guanosine monophosphate), an indirect messenger substance – also called 'second messenger' – for blood pressure regulation. In addition, this also supports mitochondrial support of enervation, neurotransmitter signaling pathways, and cavernous body functions. It is crucial that the supporting components for cGMP effectively reach the corresponding tissue. Due to the increased permeability of the liposomal formulation, this formulation works faster and more effectively.Example 6: Antioxidant Protection The preparation is carried out analogously to Example 1 with the following components: a) Mixture 1: Magnesium ascorbate (105 g), ascorbic acid (25 g), and water (390 g) are dissolved and stirred. b) Mixture 2: Sunflower lecithin (120 g), ascorbyl palmitate (1 g), and xylitol (359 g) are dissolved and dispersed in warm water. Processing is carried out according to the procedure with the following parameters: initial temperature: 25°C; final temperature of the third mixture: 45°C; cooled to: 30°C. The liposomal formulation provides vitamin C as an antioxidant agent extremely quickly and effectively, even when ingested orally. The measurable increase in vitamin C activity in blood plasma was significantly faster and higher after oral administration than when consuming vitamin C-containing foods or juices with a comparable amount of vitamin C.Example 7: Beverage additive and energy supplier FRL001 PCTprio Page 15 of 21 Production is carried out analogously to Example 1 with the following components: a) Mixture 1: Xylitol (357 g), L-carnitine (30 g), creatine ethyl ester (100 g), sunflower lecithin (20 g), and water (390 g) are dissolved and stirred. b) Mixture 2: MCT (50 g) and coenzyme Q10 (15 g) are dissolved and dispersed in warm water. Processing is carried out according to the procedure with the following parameters: Pre-temperature: 50°C; final temperature of the third mixture: 65°C; cooled to: 55°C. The liposomal formulation comprises an aqueous-stable creatine ethyl ester, which remains stable in the aqueous phase / dilution in a drink prior to ingestion and, combined with the other additives, effectively and quickly permeates into the corresponding muscle groups to support mitochondrial energy balance.Example 8: Combination Granules. Production is carried out analogously to Example 1 with the following components: a) Mixture 1: Water (642 g), maltodextrin (300 g) are dissolved and stirred. b) Mixture 2: MCT (30 g), coenzyme Q10 (10 g), and sunflower lecithin (18 g) are dissolved and dispersed under warm conditions. Processing is carried out according to the procedure with the following parameters: Pre-temperature: 40°C; final temperature of the third mixture: 60°C; cooled to: 50°C. The liposomal formulation is spray-dried. The microscale granules are finally coated with an aqueous solution of a liposomal coating mixture consisting of 25 parts by weight of sunflower lecithin, 75 parts by weight of gum arabic, and 1500 parts by weight of creatine monohydrate and dried. The weight ratio of granulate to coating mass in the finished, free-flowing, powdery product is 9 to 16.The combined, releasable liposomal vesicles transport coenzyme Q10 and a creatine source to the various tissues in parallel, thus effectively addressing combined insufficiency or demand. Example 9: Supplement for HIT training units. Production is carried out analogously to Example 1 with the following components: a) Mixture 1: Ribose (494 g), L-carnitine (30 g), magnesium hydrogen citrate (5 g), ascorbic acid (1 g), sunflower lecithin (12 g), and water (333 g) are dissolved and stirred. b) Mixture 2: MCT (100 g) and coenzyme Q10 (25 g) are dissolved and dispersed in warm water. Processing is carried out according to the procedure with the following parameters: Pre-temperature: 50°C; final temperature of the third mixture: 65°C; cooled to: 55°C.The liposomal formulation supports the energy balance of the muscles with rapidly permeating supplements; especially during high-intensity training cycles, abbreviated as HIT training, this formulation can effectively supplement and support short, intense exertion. In another advantageous embodiment, a formulation according to the process consists of water, xylitol, L-carnitine, creatine ethyl ester malate, medium-chain triglycerides, coenzyme Q10, and lecithin with a phosphatidylcholine content of at least 94%. The formulation was obtained by preparing the previously described mixture and immediately subsequently forming the liposomal protective shells through overpressure homogenization under cell disruption conditions. Specifically: approximately 400g water, 100g creatine ethyl ester malate, 30g carnitine, 355g xylitol, and 20g lecithin are prepared as mixture 1.In parallel, 15g of Q10 is prepared in 50g of medium-chain triglycerides at 50°C as mixture 2 FRL001 PCTprio Page 17 of 21. Both are mixed and pre-homogenized. The dispersion is then homogenized under cell disruption conditions using cavitation, and the temperature is increased to 65°C. Finally, the liposomal formulation is cooled to 55°C within 60 seconds. The liposomal formulation thus prepared has an intense, orange-yellow color and shows no structures, streaks, or inhomogeneities even under UV light. A shelf life of 12 months was achieved even in simple, inexpensive glass containers without UV or light protection. In an initial study, strength athletes, compared to a placebo test group, experienced short-term, noticeable increases in explosive strength within 5 to 10 minutes of ingestion, in the sense of a continuously available, increased performance of 4% to 11%.Surprisingly, a very uniform, fine granulate was obtained from the formulation prepared as described above by spray drying. The test subjects described these granules as organoleptically pleasant even when ingested directly, and they enabled comparable performance increases of 5% to 10.5%. INDUSTRIAL APPLICABILITY Established liposomal formulations offer the promise of increased bioavailability, but this does not approach the speed and effectiveness of direct injection. The challenge is to overcome this disadvantage.The solution is achieved by combining warming cavitation of a pre-tempered, pre-homogenized mixture with rapid cooling of the resulting liposomal formulation. For the first time, liposomal formulations can be obtained whose permeation rate can provide an increase in the activity of the transported supplements within minutes, similar to a local injection. In addition, there is improved stability and storage capacity, which the inventor attributes to the process-related lower content of accompanying agglomerates and crystallites. Combination with other substances that feed as directly as possible into the energy balance in various tissues of the body, independent of upstream utilization mechanisms, demonstrates a permeation rate of the liposomal vesicles according to the process, which can produce acute improvements in the same way as an injection.

Claims

FRL001 PCTprio Page 19 of 21 CLAIMS 1. A process for producing a liposomal formulation, comprising the process steps a) preparing a hydrophilic, water-based, first mixture b) preparing an oleophilic, second mixture c) heating the second mixture to a pre-temperature which is 10°C to 30°C above the temperature of the highest melting point d) adding the first mixture to the second mixture with constant, intimate stirring and while maintaining the pre-temperature until a third, mechanically pre-homogenized mixture of the first and second mixture is present e) immediately transferring the pre-homogenized third mixture to a homogenizer and homogenizing the third mixture under cavitation until the temperature of the third mixture has increased by 10°C to 30°C without reaching a boiling temperature, f) rapidly cooling the homogenized, third mixture by at least 10°C within 60 seconds.The process according to claim 1, characterized in that an ultrasonic homogenizer is used as the homogenizer in step e).

3. The process according to claim 1 or 2, characterized in that in step f), the homogenized, third mixture is filled into containers preheated to 25°C and having a maximum volume of 1000 ml.

4. The process according to claim 1 or 2, characterized in that in a step g), the homogenized, third mixture is combined with additives and auxiliary substances immediately after step f), cooled by spray drying, and obtained as spray-dried granules. FRL001 PCTprio Page 20 of 21.

5. The method according to the preceding claim, characterized in that the granules are coated, preferably with a further liposomal formulation.

6. Liposomal formulation obtained by the method according to one of the preceding claims.