Composition containing polyglycerol fatty acid esters
By using a mixture of polyglycerol fatty acid esters and free polyglycerol in a specific ratio, the problems of shape instability and storage instability in 3D printing are solved, and the material achieves stable shape and storage at low temperatures, which is suitable for 3D printing of active substances in pharmaceuticals or cosmetics.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- IOI OLEO GMBH
- Filing Date
- 2021-01-29
- Publication Date
- 2026-06-05
Smart Images
Figure HDA0004363972000000011
Abstract
Description
Technical Field
[0001] Many polyglycerol fatty acid esters possess excellent properties for serving as a matrix in pharmaceuticals or cosmetics, or even in applications such as the food industry, or generally in all areas where storage stability is required. Specifically, compared to many other lipid-based materials such as triglycerides, some polyglycerol fatty acid esters do not exhibit any actual polymorphism and therefore do not undergo any volume changes during long-term storage, particularly any volume increase known as "blooming". Background Technology
[0002] WO 2020 / 083411 A1 discloses suitable polyglycerol fatty acid esters or blends thereof for use in hot melt coating methods. Hot melt coating offers advantages over other coating or sheathing methods because the coating material can be used without solvents, and in this way, there is no need for complex drying steps to remove undesirable, potentially toxic solvent residues from the product. The use of polyglycerol fatty acid esters in the preparation of products to be introduced into humans or animals also has the advantage that at least the esterification of polyglycerol with an even number of fatty acids results in… in vitro and in vivo Polyglycerol fatty acid esters, which are toxic decomposition products, should be eliminated as much as possible.
[0003] In addition to using matrices such as the aforementioned polyglycerol fatty acid esters in hot melt coating methods, materials with comparable properties are also required in the field of 3D printing. However, simply using materials intended for hot melt coating directly will not be successful in this regard, because for 3D printing methods, the starting material must be sufficiently softened or liquefied by heating so that it can be pushed through the printhead nozzle, allowing it to harden appropriately after building a predefined molded article to form an object with a stable shape. Specifically, while polyglycerol fatty acid esters (such as those described in WO 2020 / 008411 A1) can indeed be pushed through a 3D printing nozzle, the shape stability of the resulting molded article is insufficient to guarantee stability during industrial packaging steps and product handling. Furthermore, the problem arises that, at least when large volumes of pharmaceutical or cosmetic active substances are mixed with the corresponding matrix, the physical properties of the starting material used for 3D printing may change in a way that makes the product shape unstable and unstable during storage, or prevents it from being printed into a product of uniform quality due to increased brittleness.
[0004] EP 3 482 774 B1 discloses a system that can be produced by 3D printing, which... in vivoIt self-emulsifies upon contact with a physiologically hydrophilic phase and contains a lipophilic phase, a surfactant with an HLB value greater than 8, and optionally a co-surfactant, wherein the surfactant consists of PEG esters, poloxamer, ethoxylated oils, ethoxylated vitamin E, and / or sugar residues derived from fatty acids. The disadvantages of this composition are that toxic degradation products cannot be definitively excluded, and improvements may be needed regarding shape and storage stability. Furthermore, the problem arises that, according to the cited examples, the blending of pharmaceutically active substances only reaches slightly less than 7% by weight of the starting material for 3D printing, meaning that for each type of blend, new studies must be conducted on the processability of the starting mixture containing the blend, as each individual pharmaceutically active substance has an unfavorable tendency for stratification and phase separation even when the starting material is not blended. Compositions (such as 50% to 95%, preferably 85%, by weight of glyceryl stearate having 5% to 50%, preferably 15%, by weight of polyethylene glycol 300-6000 (preferably PEG 1500)) can indeed still be processed in 3D printing methods, although they have adhesive properties, they are not entirely stable during storage. Fresh PEG may contain ethylene oxide and dioxane. Over time, formaldehyde may form. In addition, they are potential allergens. Summary of the Invention
[0005] The object of the present invention described below is to provide a composition that has the advantages of polyglycerol fatty acid esters known for use in hot melt coating methods, particularly the absence of polymorphism, and allows the composition to be processed by 3D printing, which can be done independently of the amount of other pharmaceutical and cosmetic active substances or other additives specifically used for the proportions of blends or fillers commonly used in practice, and provides a product that is shape-stable and stable during storage.
[0006] This objective is achieved by the composition as claimed in claim 1, the method of producing it as claimed in claim 10, the 3D printing method as claimed in claim 24, the method for preparing starting materials for the 3D printing method as claimed in claim 11, and the molded parts produced by 3D printing as claimed in claim 18, wherein advantageous embodiments are defined in the respective dependent claims.
[0007] For compositions containing polyglycerol fatty acid esters to be used in 3D printing methods, they must produce starting materials that are neither too soft nor too brittle as the final product. In the case of compositions containing polyglycerol fatty acid esters, this is no small matter. When using polyglycerol fatty acid esters, the elasticity of the starting material (which, as is commonly done in practice, forms filaments for 3D printing methods) depends on the number of free hydroxyl groups in the composition. One perspective is that the number of free hydroxyl groups can be influenced by the degree of esterification of the polyglycerol fatty acid esters used, but surprisingly, blends of polyglycerol fatty acid monoesters and free polyglycerol are more targeted and efficient. While strong bonds (such as ionic or covalent bonds) result in a harder and more brittle composition, an increased proportion of hydrogen bonding via free hydroxyl groups produces lower bond strength and therefore higher elasticity, as greater degrees of freedom facilitate the reorientation of individual molecules. Furthermore, with an increase in the number of glycerol units in both polyglycerol fatty acid monoesters and free polyglycerol, the bonds between smaller molecules are less prone to breakage due to the spatial effects of shear within the composition and more flexible reorientation, but the elasticity of the composition increases due to the longer molecular chains. Surprisingly, the excellent processing properties in 3D printing methods and the stability of the printed product in shape and storage without volume changes due to polymorphism are achieved in compositions containing at least three components: first, polyglycerol fatty acid esters obtained by esterification of polyglycerol containing 2 to 10 glycerol units with fatty acids containing 12 to 22 carbon atoms; second, free polyglycerol containing 2 to 10 glycerol units; and third, additional polyglycerol fatty acid monoesters containing 2 to 10 glycerol units and fatty acids containing fatty acid residues having 12 to 22 carbon atoms.
[0008] The advantageous processability of the proposed composition can be further improved by using a polyglycerol fatty acid ester, which can be obtained only by esterification of polyglycerol containing 2 to 6 glycerol units, as component 1, in addition to the aforementioned third component, and a polyglycerol containing only 3 to 6 glycerol units as component 2. It has also proven advantageous that component 1 is not present as a full ester, but as a partial ester with a hydroxyl value of 50 mg KOH / g to 350 mg KOH / g. Preferably, the saponification value of this first component is 100 mg KOH / g to 250 mg KOH / g. The melting point of component 1 at 35°C or higher, with a maximum of 80°C, has also proven advantageous, as a low melting point allows for lower processing temperatures, which, in the case of heat-sensitive active substances processed with the proposed composition, means that harmless low temperatures can be used in the method.
[0009] The above discussion leads to the conclusion that the hydroxyl value of the second component of the composition is also related to the overall elasticity of the composition. Preferably, this hydroxyl value is between 800 mg KOH / g and 1400 mg KOH / g, while the third component, namely the polyglycerol fatty acid monoester, should preferably have a hydroxyl value between 400 mg KOH / g and 650 mg KOH / g.
[0010] The mixing ratio of the three components relative to each other also affects the properties of the composition. Good results are obtained when the weight percentage of the first component is at least 50%, the weight percentage of the second component is at least 5%, and the weight percentage of the third component is at least 10%, wherein the sum of the weight percentages of the three components is preferably at least 98%.
[0011] Along with other solids as additives, the composition also has sufficient consistency to provide a balanced composition with the desired properties in the starting material of the 3D printing method. It contains polyglycerol fatty acid esters, which can be obtained from the partial esterification of hexaglycerol with palmitic acid, as components 1 and 3, the latter containing fatty acid residues with 16 carbon atoms.
[0012] The proposed composition can be produced in a simple manner by melting and mixing components 1, 2, and 3 at, for example, 80°C, advantageously not exceeding or only slightly exceeding the melting temperature of each component. Next, the mixture is cured at a temperature of 15°C to 25°C (i.e., approximately room temperature) and a pressure of 750 hPa to 1250 hPa. Generally, allowing the mixture to cure on its own is sufficient. Homogeneity of the mixture can sometimes be aided by moderate stirring of the melt.
[0013] If the composition is to be used in a 3D printing method, it has proven advantageous to initially pulverize and solidify the mixture so that it can be sieved through a sieve with an aperture of 800 μm or smaller, and the sieved material can be picked up. This sieved material can be fed into the 3D print head nozzle using a suitable system with a melting chamber and a high-viscosity fluid pump, and then used in the 3D printing method. The fracture strength of the starting material should be tested before use in the 3D printing method. For this purpose, while the starting material is still flowable during production, a portion of the starting material is cast into plates 155 mm long, 45 mm wide, and 15 mm thick. After hardening, these plates are placed on two metal cubes, each with a side length of 30 mm, spaced 60 mm apart, and with their sides parallel, bridging the metal cubes longitudinally. For measurement, a stamping tool, also made of metal, with a rounded stamped edge, 69 mm long, and oriented perpendicular to the space between the metal cubes, is used to increase the force acting on the center of the plates between the metal cubes until the plates break. To cause this type of plate to break under the stated conditions, the applied force should not exceed 90 N.
[0014] When processing via 3D printing, using filaments as starting material is simpler because they can be pushed through the printhead nozzle using only an electric motor. Here, feeding the filaments wound on a spool via a dual worm gear unit has proven advantageous. To transform sieved material already suitable as a starting material for 3D printing into more easily processed filaments, the sieved material is preferably extruded through an extruder nozzle at a temperature at least 1°C below the melt temperature of the first component of the polyglycerol fatty acid ester-containing composition. In principle, the thickness of the filament is determined by the shape of the printhead nozzle. The diameter of the printhead nozzle can be selected according to the shape specifications of the part to be printed. A larger nozzle has the advantage of higher material throughput, thus accelerating production. The more intricate the part to be printed, the smaller the cross-section should be selected to provide sufficient accuracy for printing. Filaments with a consistent, uniform cross-sectional diameter of 1.52 mm to 1.96 mm have proven advantageous in processing, where cross-sectional variations in filaments with an ellipticity up to 0.06 are tolerable. The ellipticity (O) of the cross-section of the corresponding filament under consideration is defined here as its maximum diameter (D). max ) and its minimum diameter (D min The sum of the differences between O and D is O = 2 x (D) max - D min ) / (D max + D min Preferably, the prepared filaments are wound onto a spool with a minimum outer diameter of 0.23 mm, but the outer diameter can also be larger. Winding onto a small-diameter spool without breakage can be considered an indication of sufficient flexibility for processing in 3D printing methods. Due to the composition containing polyglycerol fatty acid esters, filament production can be carried out at an extruder nozzle with a material throughput of up to 7 kg / h, provided that the sieved powder has been transformed into a soft mass due to the temperature employed.
[0015] In principle, there are two possibilities for incorporating active substances or other substances into products produced by 3D printing methods. These substances are already incorporated into the starting material for 3D printing, which is then printed to form a predefined molded part; or the starting material remains free of active substances or other substances, which are subsequently introduced into cavities or chambers of at least partially prepared molded articles. Incorporating micronized solids into compositions containing polyglycerol fatty acid esters to form starting materials for 3D printing methods is preferably done by blending one or more micronized solids into the molten component of the composition containing polyglycerol fatty acid esters, wherein their weight percentage in the total mixture should not exceed 10%, so that the processability of the starting material obtained in this way is maintained. In this respect, the type of substance blended as a micronized solid is not actually important. Preferably, the micronized solids are from the pharmaceutical active substances group or the cosmetic active substances group.
[0016] In a second possibility of incorporating active substances or other substances into products produced by a 3D printing method, the composition itself containing polyglycerol fatty acid esters (preferably as filaments) can be printed to form a molded article having one or more cavities and / or chambers. A simple way to achieve this, for example, is to 3D print a molded article in the form of a cup, into which the active substance or other substance (which may be solid, semi-solid, or liquid) can be introduced as a filler material. The opening of the molded article can then be closed by a second molded component (e.g., in the form of a lid), which is adapted to be fitted onto the molded article in an interlocking and / or friction-fit manner, preferably printed from the same starting material. A more ingenious solution is to incorporate the filler material into the molded article during the initial printing process until sufficiently filled cavities have been formed, then introduce the filler material, and then complete the 3D printing, wherein preferably, the filled cavities can be closed to form chambers containing the filler material. All the advantages of the 3D printing method can be utilized in this way. Therefore, different substances (such as two or more different pharmaceutically active substances) can be introduced into separate chambers of the same molded article. The release of active substances can be controlled by varying the wall thickness.
[0017] Because of the polyglycerol fatty acid ester compositions proposed in this application, 3D printing methods are feasible that allow the incorporation of active substances or other substances into the starting material used in the 3D printing method, and also allow the incorporation of solid, semi-solid, or liquid filler materials into articles of appropriate shape. Furthermore, these two variations can be combined such that the solids mixed with the starting material can be released directly from the material of the printed article, and the filler material located in the chamber or cavity can only escape from the chamber or cavity after the wall adjacent to the filler material has decomposed or through channels of a preferably narrow shape.
[0018] Preferably, in the applied 3D printing method, the printing process is initiated by pushing a composition containing polyglycerol fatty acid esters, either in powder form or as filaments and with or without admixtures, through a printhead nozzle having an inlet and an outlet. Then, a predefined layer-by-layer construction of a three-dimensional article is performed by corresponding predefined movements of the printhead nozzle outlet in various planes. Preferably, in this respect, a temperature-controlled printhead nozzle is used, the temperature of which during the printing process is 1°C to 4.9°C higher than the melting temperature of the starting material.
[0019] The filler material can be introduced in various ways. As described above, closing the opening of the filled cavity with a second molding component or introducing filler material into suitable cavities that have already been formed in a part of the molded article before completion as a whole, and then printing them into chambers or more complete cavities during the completion of the molded article. A third possibility is to fill the cavities or chambers of the formed molded article with filler material via cannulation, preferably before the molded article is fully hardened. Clearly, the aforementioned filling possibilities can be combined in any way.
[0020] If the filler material contains one or more pharmaceutically active substances, these pharmaceutically active substances are preferably glucocorticoids, mineralocorticoids, androgens, estrogens, progestins, azole antifungals, ACE inhibitors, or AT1 antagonists. Pharmaceutically active substances from this group are also suitable as blends in compositions containing polyglycerol fatty acid esters. Attached Figure Description
[0021] Figure 1 a Figure 1 b illustrates a cup-forming component according to an embodiment of this application.
[0022] Figure 2 a Figure 2 b illustrates a cover forming component according to an embodiment of this application. Detailed Implementation
[0023] The invention will now be described in more detail and in a non-limiting manner with the aid of the accompanying drawings and two embodiments. Example 1
[0024] 80.5% by weight of hexaglycerol palmitate with an average hydroxyl value of 160 was used as component 1. 8.0% by weight of hexaglycerol was used as component 2, and 11.5% by weight of hexaglycerol monopalmitate was used as component 3. The components were mixed together and melted. The melt was homogenized by stirring and allowed to solidify statically at room temperature of 20°C and a pressure of 1005 hPa. A portion of the melt was placed into five identical molds and molded into plates of 155 mm x 45 mm x 15 mm in this manner. After hardening, these plates were subjected to bending fatigue tests as described above. The average force required for the plates to fracture was 83 N. The solidified block was crushed and passed through a sieve with an 800 μm aperture. The sieved material was extruded at 49°C to form a filament with a uniform continuous cross-section of 1.75 mm and a maximum ellipticity of 0.02. The filament was wound onto a spool with a minimum diameter of 23 mm. A filament roll was inserted into the 3D printer, and 3D printing began at a nozzle temperature of 50.5°C. The printed part was a handleless cup shape. Figure 1 a, 1b (dimensions in mm). A filler material consisting of 10 mg of micronized prednisolone is introduced into the cup-forming part. In forming the cup-forming part ( Figure 1 Simultaneously, print the adapter cup forming part from the same starting material (a, 1b, dimensions in mm). Figure 1 a, 1b, dimensions in mm) opening cover forming component ( Figure 2 a, 2b (dimensions in mm). Utilizing a cover to form the component ( Figure 2 a, 2b, dimensions in mm), forming the cup-shaped component ( Figure 1 The openings (a, 1b, in mm) are closed to form the finished product containing prednisolone. Example 2
[0025] Component 1 consists of 67.7% by weight of hexaglycerol palmitate with an average hydroxyl value of 160. Component 2 consists of 13.6% by weight of hexaglycerol, and component 3 consists of 9.6% by weight of hexaglycerol monopalmitate. Micronized dexamethasone is added at 9.1% by weight. The components are mixed together and melted. The melt is homogenized by stirring and allowed to solidify at room temperature (20°C) and a pressure of 1005 hPa. The solidified mass is pulverized and passed through a sieve with an 800 μm aperture. The sieved material is extruded at 49°C to form a filament strand with a uniform, continuous cross-section of 1.75 mm and a maximum ellipticity of 0.02. The filament is wound onto a spool with a minimum diameter of 23 mm. A spool of filament is inserted into a 3D printer, and 3D printing begins at a nozzle temperature of 50.5°C. The printed part is in the form of a flattened cylinder, providing a dexamethasone-containing product in tablet form.
Claims
1. A 3D printing method, characterized in that... The method Includes the following steps: i) The starting material is pushed through a printhead nozzle having an inlet and an outlet, wherein the starting material is prepared by the following steps: a) Component 1, i.e., a polyglycerol fatty acid ester that can be obtained by esterification of polyglycerol containing 2 to 10 glycerol units with a fatty acid containing 12 to 22 carbon atoms, component 2, i.e., free polyglycerol containing 2 to 10 glycerol units, and component 3, i.e., a polyglycerol fatty acid monoester containing 2 to 10 glycerol units and a fatty acid residue containing 12 to 22 carbon atoms, are melted and mixed together; b) The mixture of step a) is solidified at a temperature of 15°C to 25°C and a pressure of 750 hPa to 1250 hPa; c) The solidified mixture of step b) is pulverized; d) The pulverized solidified mixture of step c) is sieved through a sieve with a pore size of 800 μm or smaller, and the sieved pulverized solidified mixture is collected. ii) Predefined three-dimensional parts are constructed layer by layer by corresponding predefined movements of the nozzle outlet of the printhead in each plane.
2. The 3D printing method as described in claim 1, characterized in that, The molded component includes one or more chambers and / or one or more cavities, wherein at least one of the chambers or at least one cavity contains a filling material.
3. The 3D printing method as described in claim 2, characterized in that, The modified step ii) specifically involves the addition of step ii-b1) to the following sub-step: ii-a) Proceed step by step to build a portion of the molded component until all the chambers or cavities set for filling have been generated as fillable partial or complete cavities; ii-b) Fill the portion or complete cavity provided for filling with the filling material; ii-c) Complete the molding of the part.
4. The 3D printing method according to any one of claims 1-3, characterized in that, The printhead nozzle is heated to a temperature 1°C to 4.9°C above the melting temperature of the starting material.
5. The 3D printing method according to any one of claims 2-3, characterized in that, The filler material is or contains a pharmaceutically active substance, and the filler material is in solid, semi-solid, or liquid form.
6. The 3D printing method as described in claim 1, characterized in that, The weight percentage of component 1 is at least 50%, the weight percentage of component 2 is at least 5%, the weight percentage of component 3 is at least 10%, and the sum of the weight percentages of components 1 to 3 is at least 98%.
7. The 3D printing method as described in claim 1, characterized in that, Before picking up the sieved powder and pressing it through the printhead nozzle, the starting material is extruded through the extruder nozzle head at a temperature at least 1°C lower than the melting temperature of component 1 to form filaments.
8. The 3D printing method as described in claim 7, characterized in that, The sieved powder, which has turned into a soft mass due to temperature conditions, is fed into the extruder nozzle head at a throughput of up to 7 kg / h.
9. The 3D printing method as described in claim 1, characterized in that, One or more micronized solids, totaling no more than 10% by weight of the total amount of the mixture according to claim 1, are mixed together with the molten component.
10. The 3D printing method as described in claim 9, characterized in that, The solid is associated with the group formed from pharmaceutically active substances or cosmetically active substances.
11. The 3D printing method as described in claim 2, characterized in that, The one or more filler materials contain at least one pharmaceutically active substance from the group consisting of: glucocorticoids, mineralocorticoids, androgens, estrogens, progestins, azole antifungals, ACE inhibitors, or AT1 antagonists.