Granules obtainable by continuous melt granulation

Abstract

The present invention relates to water-soluble or water-dispersible granules obtainable by continuous melt granulation. The granules comprise at least one binder, at least one filler and at least one active ingredient. Torque overload may be avoided when using the combination of filler (e.g., mannitol or HMO) and binder (e.g., sorbitol) disclosed herein.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to edible water-dispersible powders.

[0002] [Background of the invention] Fat-soluble active ingredients cannot be dissolved in water because of their fat solubility. Therefore, it is common to encapsulate fat-soluble active ingredients. Water-dispersible microcapsules containing fat-soluble micronutrients (e.g. fat-soluble vitamins) are commercially available from DSM® Nutritional Products (Switzerland).

[0003] Microcapsules often have poor flowability, mainly due to their small particle size. To obtain a flowable powder, the microcapsules are granulated.

[0004] Granulation is a size-enlarging process that is often carried out by wet granulation, which uses a solvent (water or organic solvent) to initiate bonds between solid particles (e.g., microcapsules). A disadvantage of wet granulation is the need to remove the solvent at the end of the granulation process. In the case of using water as the solvent, a significant amount of energy is required to distill off the water. A further disadvantage of wet granulation is the risk of hydrolysis of the active ingredient. In the case of organic solvents, potentially harmful residues and / or adverse effects on the environment are of concern.

[0005] Dry granulation and melt granulation are known alternatives to wet granulation. Melt granulation works on a similar principle to wet granulation, but uses a molten binder as the granulation fluid to establish liquid bridges between the particles to be granulated. Upon cooling to room temperature, the binder solidifies and forms bridges between the individual powder particles, resulting in a solid final product with a granular structure.

[0006] In most cases, melt granulation is carried out in a heated powder bed. This is a batch process: the processing of a subsequent batch must wait until the current one is finished. The disadvantages of a batch process can be overcome by using a continuous process.

[0007] Continuous granulation is often carried out using an extruder. Extrusion granulation can be carried out using a solvent ("continuous wet granulation") or with heat ("continuous melt granulation").

[0008] Continuous melt granulation can be carried out in an extruder. A potential problem during any extrusion process is torque overload. When torque overload occurs, the transmitted torque exceeds the set torque point of the extruder's torque limiter. When this occurs, the frictional forces are no longer strong enough to transmit the torque from the drive shaft to the driven member, and the driven member slips between the friction disks. When the torque exceeds the limit, the torque limiter acts as a clutch and quickly disengages the drive from the driven system, removing much of the inertial energy from the drive train, usually within milliseconds or fractions of a millisecond. In an ideal (i.e., stable / optimized) process, the torque limiter is simply a backup: the drive is rarely (if ever) disengaged from the driven system because torque overloads do not occur.

[0009] A process for continuous melt granulation with reduced risk of torque overload is needed. The resulting granules should be flowable, storage stable and / or water dispersible. A low amount of fines (i.e., non-granulated residue) is desirable.

[0010] [Summary of the Invention] The problem underlying the present invention is solved by continuous melt granulation of a mixture containing at least one active ingredient. Preferred active ingredients are water-soluble and water-dispersible (pro)vitamins.

[0011] The continuous melt granulation process is preferably carried out in an extruder. In a preferred embodiment of the present invention, a co-rotating twin screw extruder continuously mass produces free-flowing granules; no die is required at the end of the extruder [see Figure 1 in N. Kittikunakorn et al., "Twin-screw melt granulation: Current progress and challenges," International Journal of Pharmaceutics, 588, (2020), 119670].

[0012] In addition to at least one active ingredient, the mixture of the present invention further comprises at least one edible binder. During continuous melt granulation, the binder of the mixture is melted or at least softened.

[0013] The mixture of the present invention further comprises at least one edible filler. The amount of the filler exceeds the amount of the binder. In contrast to hot melt extrusion, during continuous melt granulation, the filler does not need to be melted. The melting temperature of the at least one edible filler is higher than the melting temperature of the at least one binder.

[0014] The process of the present invention is a process for producing granules by continuous melt granulation, in which the mixture according to the invention is fed into an extruder, preferably a twin-screw extruder, which very effectively avoids torque overload when using mannitol as filler and sorbitol as binder.

[0015] A preferred mixture comprises mannitol, sorbitol and at least one active ingredient, Thus, the mixture contains 5% to 15% by weight of sorbitol, based on the total weight of the mixture; The weight ratio of mannitol to sorbitol is 5:1 to 9:1, preferably 8:1 to 9:1. The at least one active ingredient is preferably a vitamin or a pro-vitamin.

[0016] In one embodiment, the mixture comprises a HMO, sorbitol and at least one active ingredient, Thus, the mixture contains 5% to 15% by weight of sorbitol, based on the total weight of the mixture; The weight ratio of HMO to sorbitol is 4:1 to 10:1, 5:1 to 10:1, 5:1 to 9:1, 6:1 to 9:1, 6.5:1 to 9:1, or 7:1 to 9:1.

[0017] The granules of the invention comprise or consist of the mixture of the invention. [Brief description of the drawings]

[0018] [Figure 1] Figure 1 shows monitored torque (Nm) during an unstable continuous melt granulation process. A portion of the data is shown starting at time 700 seconds and ending at time 800 seconds. A single torque spike can shut down the entire process (i.e. torque overload). Therefore, the time dependence of the torque is an indicator of the stability of the process. If the composition of the granules is not properly selected, it can be difficult to prevent torque overload. [Diagram 2] Figure 1 shows monitored torque (Nm) during a stable continuous melt granulation process. A portion of the data is shown starting at time point 700 seconds and ending at time point 800 seconds. There are no significant torque spikes, which is an indication of process stability. There is no risk of torque overload. This process stability often correlates with consistency in granule quality attributes.

[0019] [Detailed Description of the Invention] The granules of the present invention can be obtained by continuous melt granulation of a dry edible mixture comprising primary particles and at least two edible excipients. During continuous melt granulation, the primary particles are agglomerated. Thus, the granules of the present invention are preferably units formed of a large number of particles. The primary particles of the granules are smaller than the granules.

[0020] Both edible excipients are preferably water-soluble or water-dispersible. The melting temperature of the first edible excipient is low enough to melt or at least soften during continuous melt granulation. When melted or softened, the first edible excipient establishes crosslinks between primary particles. The crosslinks then solidify at room temperature. Thus, the first edible excipient acts mainly as a binder. In one embodiment, the first edible excipient is a polyol. In one embodiment, the first edible excipient is sorbitol.

[0021] The melting temperature of the second edible excipient is relatively high. The second edible excipient mainly acts as a bulking agent. In one embodiment, the second edible excipient is mannitol. In one embodiment, the second edible excipient is a mixture containing human milk oligosaccharides (HMO), such as 2'-O-fucosyllactose, or a mixture of human milk oligosaccharides, such as a mixture containing 2'-fucosyllactose and difucosyllactose.

[0022] The granules of the present invention may contain only one type of primary particle or preferably contain several types of primary particles. The primary particles of the granules of the present invention preferably contain or consist of the active ingredient. Examples of primary particles are vitamin C crystals, thiamine mononitrate crystals, niacinamide crystals, and pyridoxine hydrochloride crystals. In the case of a fat-soluble active ingredient, the primary particles are preferably water-soluble or water-dispersible microcapsules that encapsulate the fat-soluble active ingredient. Such microcapsules can be obtained by spray drying an emulsion that contains a lipophilic active ingredient and at least one emulsifier.

[0023] The granules of the invention are preferably water-soluble or water-dispersible. A composition comprising or consisting of such granules may be suitable for preparing a beverage.

[0024] [Filler of the present invention] Fillers are excipients used to increase the volume of the granules of the present invention. Fillers can have additional functions. Some fillers (e.g. dietary fiber or human milk oligosaccharides) also have health benefits.

[0025] The granules of the present invention are intended for edible use, therefore toxic and non-edible fillers are generally excluded.

[0026] The granules of the present invention are preferably water-soluble or water-dispersible. Thus, fillers having a solubility of less than 1 g / 100 mL water, or less than 0.5 g / 100 mL water, or less than 0.1 g / 100 mL water are not preferred.

[0027] Usually, the melting temperature of the filler is higher than the melting temperature of the binder. However, this does not exclude the possibility that the filler is also (partially) melted or softened during continuous melt granulation. The melting temperature of the filler is preferably at least 150°C, more preferably at least 155°C, and most preferably at least 160°C, and is preferably 151°C to 240°C, more preferably 160°C to 240°C, and most preferably 160°C to 180°C.

[0028] In one embodiment, the filler is inulin, human milk oligosaccharides (HMO), or mannitol. In one embodiment, the HMO comprises 2'-fucosyllactose (2'-FL). In one embodiment, the filler is a mixture comprising 2'-fucosyllactose and difucosyllactose (DFL). In one embodiment, the filler comprises granulated standard inulin. Standard inulin has an average degree of polymerization (DP) of 10 to 20. Less preferred fillers are microcrystalline cellulose and pregelatinized starch.

[0029] In one embodiment, the filler is mannitol. When used in combination with sorbitol, the risk of torque overload during continuous melt granulation in the extruder may be avoided or at least reduced.

[0030] [Binder of the present invention] Binders are excipients used to hold the components of a formulation together. To do so, they are melted or softened during continuous melt granulation. Usually, the melting temperature of the binder is lower than that of the filler and often lower than that of any added active ingredient. The melting temperature of the binder is preferably less than 140°C, more preferably less than 130°C, even more preferably less than 120°C, and most preferably less than 110°C. The melting temperature of the binder is preferably between 50°C and 110°C, more preferably between 60°C and 100°C, and most preferably between 70°C and 100°C.

[0031] The granules of the present invention are preferably water-soluble or water-dispersible. Thus, binders having a solubility of less than 1 g per 100 mL of water, or less than 0.5 g per 100 mL of water, or less than 0.1 g per 100 mL of water are not preferred.

[0032] In one embodiment, the binder is a polyol, pectin, inulin, cellulose-based hydrophilic pharma- ceutically acceptable excipient, povidone, copovidone, polydextrose, gums and / or co-processed pharma- ceutically acceptable excipients. In one embodiment, the binder is sorbitol, ribose (e.g., D-ribose), mannitol, xylitol, erythritol, maltitol or isomalt. In one embodiment, the binder is apple pectin or beet pectin. In one embodiment, the binder is hypromellose (HPMC) or hydroxypropyl cellulose (HPC). In one embodiment, the binder is acacia gum, xanthan gum or guar gum. In one embodiment, the binder is polyvinylcaprolactam-polyvinyl, acetate-polyethylene glycol graft copolymer; the latter is commercially available as Soluplus®. In one embodiment, the binder is sorbitol, preferably having a melting temperature of less than or equal to 98° C. Such sorbitol is commercially available from Roquette®.

[0033] In one embodiment, the binder is ribose (such as D-ribose), polyethylene glycol, sorbitol or xylitol. In one embodiment, the binder is preferably a polyol, more preferably a sugar alcohol, even more preferably sorbitol or ribose (e.g., D-ribose), and most preferably sorbitol having a melting temperature of 98° C. or less. Such sorbitol is commercially available from Roquette®. Sorbitol is a stereoisomer of mannitol.

[0034] [Active ingredient of the present invention] In one embodiment, the mixture of the present invention comprises at least one water-soluble or water-dispersible active ingredient. Preferred active ingredients are water-soluble and water-dispersible vitamins such as vitamin B1, vitamin B2, vitamin B3, vitamin B6 and / or vitamin B12. Crystalline and / or amorphous particles of ascorbic acid, thiamine mononitrate, niacinamide crystals or pyridoxine hydrochloride crystals are commercially available from DSM® Nutritional Products, Switzerland. Particles containing riboflavin, cyanocobalamin or biotin are also commercially available from DSM® Nutritional Products, Switzerland. In a preferred embodiment, the mixture of the present invention comprises at least two, preferably at least three, more preferably at least four and most preferably at least five water-soluble or water-dispersible vitamins. In a more preferred embodiment, the mixture of the present invention comprises at least two, preferably at least three, more preferably at least four and most preferably at least five water-soluble or water-dispersible vitamins, but does not comprise much vitamin C. As used herein, "substantially free of vitamin C" may mean less than 5% by weight, preferably less than 3% by weight, and most preferably less than 1% by weight, of vitamin C, based on the total weight of the mixture. In one embodiment, the vitamin C is ascorbic acid or an edible ester thereof.

[0035] In an alternative embodiment, the mixture of the invention comprises a plurality of microcapsules. Microencapsulation is a protection technique for encapsulating solid or liquid active ingredients into microparticles, for example with a diameter of 1 to 900 μm. The size of the granules therefore depends inter alia on the size of the microcapsules: larger microcapsules result in larger granules. One advantage of microencapsulation is that the solid or liquid active ingredient is completely coated and isolated from the external environment. Microencapsulation may make fat-soluble active ingredients water-dispersible or water-soluble. Spray drying is a preferred method for the microencapsulation of fat-soluble active ingredients. Before spray drying, the fat-soluble active ingredient is mixed with at least one encapsulating agent, which usually provides an emulsion. Gum arabic is a commonly used encapsulating agent. Spray drying is one of the most widely used microencapsulation techniques, since it rapidly evaporates water and maintains a low temperature inside the particles. Spray-dried microcapsules containing fat-soluble vitamins are commercially available from DSM® Nutritional Products, Switzerland. Vitamins A, D, E, and K are exemplary fat-soluble vitamins. It is quite unusual to encapsulate a mixture of fat-soluble vitamins. Generally, fat-soluble vitamins are encapsulated separately. When providing a mixture of fat-soluble vitamins, different types of microcapsules are mixed.

[0036] [Mixture of the present invention] The mixture of the present invention is suitable for continuous melt granulation (i.e., solvent-free).The mixture of the present invention is a powder mixture that can be fed into equipment suitable for continuous melt granulation (e.g., an extruder).

[0037] In contrast to wet granulation, no solvent is required when carrying out continuous melt granulation.Therefore, the mixture of the present invention contains less than 10% by weight, preferably less than 8% by weight, more preferably less than 5% by weight, and most preferably less than 3% by weight of solvent based on the total weight of the mixture.This is particularly true, but not exclusively, when the solvent is water.Therefore, the preferred mixture of the present invention contains less than 10% by weight, preferably less than 8% by weight, more preferably less than 5% by weight, and most preferably less than 3% by weight of water based on the total weight of the mixture.

[0038] In one embodiment, the mixture of the present invention comprises or consists of a filler, a binder and at least one active ingredient. In one embodiment, the active ingredient is a water-soluble or water-dispersible vitamin. In an alternative embodiment, the mixture of the present invention comprises or consists of a filler, a binder and a microcapsule.

[0039] In one embodiment, the mixture of the invention comprises or consists of a filler, a binder and at least one active ingredient, the filler is a human milk oligosaccharide or a mixture of human milk oligosaccharides, and the at least one active ingredient is a water-soluble or water-dispersible vitamin. In one embodiment, the mixture of the invention comprises or consists of a filler, a binder and a microcapsule, the filler is a human milk oligosaccharide or a mixture of human milk oligosaccharides.

[0040] Fillers are necessary to increase the size: they increase the volume of the granules of the invention. The mixture of the invention preferably comprises 40% to 95%, 50% to 95%, 60% to 90%, or 70% to 90% by weight of at least one filler, based on the total weight of the mixture. The mixture of the invention comprises a plurality of fillers. However, preferably, the invention may comprise only one filler. In one embodiment, the filler is a polyol, more preferably a sugar alcohol, even more preferably a stereoisomer of sorbitol, and most preferably mannitol. In the context of the present invention, stereoisomers of the same polyol are not identical sugar alcohols. In one embodiment, the filler is a human milk oligosaccharide or a mixture of human milk oligosaccharides, more preferably 2'-O-fucosyllactose (2'-FL), even more preferably crystalline or non-crystalline 2'-O-fucosyllactose (2'-FL), and most preferably crystalline 2'-O-fucosyllactose.

[0041] Typically, the mixture of the present invention contains less binder than filler. The weight ratio of filler to binder is preferably 4:1 to 10:1, 5:1 to 10:1, 5:1 to 9:1, 6:1 to 9:1, 6.5:1 to 9:1, or 7:1 to 9:1. The mixture of the present invention preferably contains 5% to 15% by weight, more preferably 6% to 14% by weight, and most preferably 8% to 13% by weight of at least one binder, based on the total weight of the mixture.

[0042] The mixture of the present invention may contain multiple binders. However, it is preferred that the mixture of the present invention contains only one binder. Thereby, the binder is preferably a polyol, more preferably a sugar alcohol, even more preferably sorbitol or ribose, and most preferably sorbitol. The preferred ribose is D-ribose.

[0043] In one embodiment, the mixture of the present invention comprises at least one water-soluble or water-dispersible vitamin. In the case where the mixture of the present invention also comprises vitamin C, the mixture of the present invention comprises, in total, preferably 1% to 20% by weight, more preferably 1% to 15% by weight, even more preferably 1% to 10% by weight, and most preferably 1% to 8% by weight of water-soluble and / or water-dispersible vitamins based on the total weight of the mixture. In the case where the mixture of the present invention comprises almost no vitamin C, the mixture of the present invention comprises, in total, preferably 0.1% to 15% by weight, more preferably 0.5% to 10% by weight, even more preferably 1% to 8% by weight, and most preferably 1% to 5% by weight of water-soluble and / or water-dispersible vitamins based on the total weight of the mixture. Exemplary water-soluble and / or water-dispersible vitamins are ascorbic acid and its edible esters (vitamin C), thiamine, riboflavin, niacin, vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine), folacin, vitamin B12, biotin, and pantothenic acid.

[0044] In one embodiment, the mixture of the present invention comprises microcapsules. When granulating the mixture of the present invention, there is a certain risk that some microcapsules may be damaged. This risk can be reduced by creating a low shear environment in the extruder (e.g., by selecting suitable kneading elements). However, this risk can also be reduced by reducing the concentration of microcapsules in the mixture of the present invention. The mixture of the present invention comprises 0.1% to 55% by weight, 1% to 40% by weight, 1% to 30% by weight, 1% to 20% by weight, 5% to 20% by weight, or 2% to 10% by weight of microcapsules, based on the total weight of the mixture. Typically, the microcapsules described herein encapsulate at least one fat-soluble active ingredient. Preferred fat-soluble active ingredients are fat-soluble micronutrients, such as fat-soluble vitamins and pro-vitamins. Beta-carotene is an example of a fat-soluble pro-vitamin. In one embodiment, the mixture of the present invention comprises only one type of microcapsule. However, in a preferred embodiment, the mixture of the present invention comprises various types of microcapsules. In the case of various types of microcapsules, the mixture of the invention preferably comprises at least two, more preferably at least three, even more preferably at least four and most preferably at least five fat-soluble active ingredients. In one embodiment, the mixture of the invention comprises microcapsules comprising vitamin A, microcapsules comprising vitamin E, microcapsules comprising beta-carotene, microcapsules comprising vitamin D and / or microcapsules comprising vitamin K. In a preferred embodiment, the mixture of the invention comprises microcapsules comprising an ester of vitamin A (such as vitamin A acetate), microcapsules comprising an ester of vitamin E (such as vitamin E acetate), microcapsules comprising beta-carotene, microcapsules comprising vitamin D3 and / or microcapsules comprising vitamin K1.

[0045] [Granules of the present invention] Preferred granules can be obtained by continuous melt granulation (i.e. without solvent) of the mixture of the invention, preferably using a twin-screw extruder. Thus, the granules of the invention comprise or consist of the mixture of the invention.

[0046] The mixture of the present invention comprises primary particles. During continuous melt granulation, bridges are formed between the primary particles of the mixture. Thus, the granules of the present invention are larger than the size of the primary particles. The preferred granules of the present invention have a mass median particle size D50 (volume basis) of 0.5 mm to 6 mm, preferably 1 mm to 5 mm, more preferably 1.5 mm to 4.5 mm, and most preferably 2 mm to 4 mm, measured using dynamic image analysis. In the case of crystals consisting of an active ingredient, the granules of the present invention may contain more than 100, more than 1000, more than 5000, or even more than 10000 crystals. In the case of microcapsules, the granules of the present invention may contain more than 10, more than 100, more than 500, or even more than 1000 microcapsules.

[0047] Each granule may contain only one type of active ingredient. In a preferred embodiment, however, the granules of the invention contain various active ingredients. In the case of various types of active ingredients, the granules of the invention preferably contain at least two, more preferably at least three, even more preferably at least four and most preferably at least five active ingredients. In one embodiment, the granules of the invention contain vitamin B1, vitamin B2, vitamin B3, vitamin B6 and / or vitamin B12, but preferably no fat-soluble vitamins. In an alternative embodiment, the granules of the invention contain microcapsules containing vitamin A, microcapsules containing vitamin E, microcapsules containing beta-carotene, microcapsules containing vitamin D and / or microcapsules containing vitamin K. In a preferred embodiment, the granules of the invention contain microcapsules containing an ester of vitamin A (such as vitamin A acetate), microcapsules containing an ester of vitamin E (such as vitamin E acetate), microcapsules containing beta-carotene, microcapsules containing vitamin D3 and / or microcapsules containing vitamin K1.

[0048] In one embodiment, the granules of the present invention comprise a filler, a binder and at least one active ingredient, Thus, the mixture comprises 5% to 15% by weight of a binder, based on the total weight of the mixture; and The weight ratio of the filler to the binder is from 4:1 to 10:1; and The melting temperature of the binder is lower than the melting temperature of the filler, and The melting temperature of the filler is 151°C to 240°C.

[0049] The granules of the present invention are preferably water-soluble or water-dispersible. This can be achieved by selecting a water-soluble or water-dispersible binder, by selecting a water-soluble or water-dispersible filler, and by selecting a water-soluble and / or water-dispersible active ingredient. In the case of a fat-soluble active ingredient, water-soluble and / or water-dispersible microcapsules are preferably selected.

[0050] [Method of Invention] The method of the present invention is continuous melt granulation, and preferably continuous twin-screw melt granulation. The differences between batch melt granulation and continuous twin-screw melt granulation are listed in Table 1 of N. Kittikunakorn et al., "Twin-screw melt granulation: current progress and challenges," International Journal of Pharmaceutics, 588, (2020), 119670. In a preferred embodiment of the present invention, the dry, powder mixture disclosed herein is fed into an extruder suitable for continuous melt granulation. Thereby, a volumetric powder feeder is not preferred. In a preferred method of the present invention, the mixture of the present invention is fed into an extruder described herein using a gravimetric powder feeder. The gravimetric powder feeder provides a controlled and consistent feeding process while taking into account changes in powder properties over time and process deviations.

[0051] In the process of the invention, a twin screw extruder is preferably used. Twin screw extruders with co-rotating screws are particularly preferred. The co-rotating screws of the preferred extruders are modular and can be configured in different setups, resulting in different zones. The purpose of the first zone near the inlet of the extruder is transport. The transport zone is often called the conveying zone. It is also possible that there is one or more kneading zones. The kneading zone is usually located between two conveying zones, and there is preferably a shaping zone at the outlet of the extruder.

[0052] In most cases, each zone has different screw elements. The conveying zone has conveying elements that transport the material towards the exit of the granulator [see section 2.1 of N. Kittikunakorn et al., "Twin-screw melt granulation: current progress and challenges," International Journal of Pharmaceutics, 588, (2020), 119670]. The kneading zone has kneading elements, such as narrow or wide kneading disks. A typical forming zone has at least one size control element that minimizes the amount of oversized granules. An exemplary size control element is shown in Figure 1(f) of J. Vercruysse et al. "Impact of screw configuration on the particle size distribution of granules produced by twin screw granulation," International Journal of Pharmaceutics 479 (2015) 171-180. These size control elements are not knives used to cut the extruded strands. In fact, when performing continuous melt granulation, spaghetti-like strands are not extruded. Extruders that are suitable for continuous melt granulation do not have a die at the exit. The size controlling element is the screw element within the extruder.

[0053] Hot melt extrusion is different from continuous melt granulation as described herein. When performing hot melt extrusion, a strand having, for example, a cylindrical diameter is extruded through a die. The length of the strand is not limited (i.e. it can be unlimited). To obtain separated pellets, the strand obtained by hot melt extrusion must be chopped into pieces. The pellets obtained are not granules consisting of distinguishable primary particles. When performing hot melt extrusion, the chopping step can be performed at any time after extrusion, including directly at the extruder die. Dies with integrated knives are commercially available.

[0054] The above does not apply to the method of the present invention. When performing continuous melt granulation, strands are not extruded. Instead, granules are continuously mass-produced at the end of the extruder. Since no strands are produced, the knife / cutting step is not necessary, greatly simplifying the process. When performing continuous melt granulation, a die at the end of the extruder is not required. In a preferred embodiment of the present invention, the mixture of the present invention is fed into a twin-screw extruder that does not have a die and does not have a knife cutting device.

[0055] In the process of the invention, the screw configuration of the twin-screw extruder is usually selected so that the extruder has at least one kneading zone. Thus, the at least one kneading zone is preferably closer to the powder inlet of the extruder than the end of the extruder. The kneading zone comprises kneading elements. The kneading elements are preferably kneading disks as disclosed in US 2005 / 0041521. The kneading disks may be coincident or non-coincident and are preferably arranged at a stagger angle of 30° to 90°. A stagger angle of about 30° is preferred, as this limits the stress on the powder mixture. In the context of the present invention, "stagger angle" refers to the angle of vertex offset of two directly successive kneading disks, as explained in paragraph

[0007] of US 2005 / 0041521. By way of example, the expression "kneading disks are arranged at a stagger angle of 30°" means that the vertex offset angle of the successive kneading disks is 30°. There may be more than two consecutive kneading discs in the kneading zone of the extruder. Figure 2 of US 2005 / 0041521 shows a side view of a kneading zone with five consecutive kneading discs, the kneading discs being arranged at a staggered angle.

[0056] Temperature control is important when performing continuous melt granulation. In a preferred method of the present invention, the extruder has several zones that can be heated or cooled individually. When continuously melt granulating the mixture disclosed herein, the temperature zone close to the powder inlet of the extruder is usually heated. When selecting a suitable temperature, it is necessary to consider that the material in the extruder moves quite fast so that the contact between the material and the heating element is quite short. In some cases, therefore, it may be recommended to set the temperature of some zones of the extruder at a temperature higher than the melting temperature of the binder of the mixture.

[0057] In a preferred embodiment of the present invention, the conveying zone and / or the kneading zone of the extruder is heated to a temperature of, for example, 90 to 210°C, 90 to 200°C, 100°C to 190°C, 100°C to 200°C, 150°C to 210°C, 160°C to 200°C, 120°C to 190°C, or 165°C to 190°C.

[0058] In one embodiment, after the hottest zone is reached, the temperature is reduced in stages, for example: Conveying Zone 1 (25° C.) - Conveying Zone 2 (170° C.) - Kneading Zone 3 (170° C.) - Conveying Zone 4 (55° C.) - Conveying Zone 5 (30° C.) - Conveying Zone 6 (25° C.) - Forming Zone 7 (no temperature control).

[0059] It is not preferable to mass produce hot granules. Hot granules may still be relatively soft and sticky. As a result, hot granules may form lumps. This should be avoided. Therefore, it is preferable to cool the material in the extruder before it is mass produced by the extruder. In a preferred embodiment of the present invention, at least one zone after the kneading zone is cooled to a temperature of less than 60°C, preferably less than 40°C, and most preferably less than 26°C.

[0060] [Example] Example 1a (Premix - Fat-soluble Vitamins) In Example 1a, a powdered premix was provided that contained a mixture of microcapsules. Each type of microcapsule contained a fat-soluble vitamin or a precursor of a fat-soluble vitamin. All microcapsules were obtained from DSM® Nutritional Products (Switzerland).

[0061] The premix provided in Example 1a contained Vitamin A acetate, beta carotene, Vitamin D3, Vitamin E acetate and Vitamin K.

[0062] Example 1b (Premix - Water-soluble Vitamins) In Example 1b, a powdered premix was provided containing a mixture of water-soluble vitamins. All vitamins were obtained from DSM® Nutritional Products (Switzerland).

[0063] The premix provided in Example 1b contained thiamine, riboflavin, niacin, vitamin B6, pantothenic acid, vitamin B12, biotin and optionally vitamin C.

[0064] Example 2 (Ribose as a binder) In Example 2, a dry mix was provided that contained 47.13% by weight of inulin Orafti® GR (filler), 10% by weight of D-ribose (binder) and 42.87% by weight of the premix of Example 1a, based on the total weight of the dry mix, so that the weight ratio of filler to binder was 4.7:1.

[0065] Preliminary experiments have shown that the lowest possible processing temperature for D-ribose that still produces granules with desirable quality characteristics is about 80°C.

[0066] Orafti® GR is a granulated inulin powder (average degree of polymerization ≧10) available from Beneo, Mannheim, Germany. Its melting point is measured in the range of 190-195° C.

[0067] The dry blend of Example 2 was then fed into a ThermoFisher® Eurolab® extruder using a gravimetric loss-in-weight feeder at the powder inlet. The extruder had a length to diameter (L / D) ratio of 25 / 1 and a screw diameter of 16 mm. The co-rotating screws of the extruder were fully modular and could be configured in various setups. The extruder was divided into several zones that could be heated or cooled separately.

[0068] In Example 2, five extrusion runs were carried out using various temperature schemes. The temperature zones close to the powder inlet (zones 2, 3, and 4) were heated to temperatures between 104° C. and 130° C. The temperature of the zones close to the end of the extruder (zones 5 and 6) was kept at 25° C. Cooling the end of the extruder allowed the material to solidify and prevented sticking of the granules coming out of the extruder.

[0069] In Example 2, the extruder had one kneading zone with three wide kneading disks arranged at a staggered angle of 60° (i.e., the angle of apex misalignment between any two immediately successive kneading disks was 60°).

[0070] All five extrusion runs yielded acceptable granules, however, regardless of the temperature scheme applied, the resulting granules exuded oil, indicating that some microcapsules were damaged during the extrusion process.

[0071] Example 3 (sorbitol as binder) In Example 3, the process of Example 2 was repeated, except that instead of D-ribose, sorbitol was used as the binder. Preliminary experiments showed that the lowest possible processing temperature for sorbitol that still produced granules with desirable quality characteristics was about 85° C. (i.e., slightly higher than for D-ribose).

[0072] In Example 3, five extrusion runs were performed. The same temperature scheme and screw configuration as in Example 2 were applied.

[0073] In all five experiments, reasonable granules were obtained, with less oil oozing out of the granules, indicating that sorbitol performed better than ribose.

[0074] Next, various grades of sorbitol were investigated to further reduce the energy required to produce good water-soluble granules. Samples were analyzed by Differential Scanning Calorimetry (DSC) to determine the grade of sorbitol with the lowest melting energy. When sorbitol grade Xtab300S (available from Roquette®) is used as the binder, the energy required to produce good water-soluble granules is lower than the other grades (see table below).

[0075] [Table 1]

[0076] [Example 4 (Effect of binder on granule properties)] In Example 4, the effect of the binder on the sphericity of the obtained granules was investigated. The following compositions were tested:

[0077] [Table 2]

[0078] Granules having the following composition were then produced by continuous melt granulation:

[0079] [Table 3]

[0080] In each case, granules were formed; however, differences in their sphericity were observed. The length to thickness (L / T) ratio, a sensitive measure of granule sphericity, was measured on a Partan 3D (Microtrac Inc, Montgomeryville, PA, USA) particle size and shape analyzer using the method described in the operating manual (Version June 2017, Rev. I) and the results are summarized in the table below.

[0081] [Table 4]

[0082] PEG4000 produced granules with the lowest sphericity with L / T of 3.60. This demonstrates that PEG is not a suitable binder to form spherical granules, which are necessary for dosing in a microdosing packaging line. Sorbitol produced granules with the lowest L / T ratio (2.11), which suggests that sorbitol produced good spherical particles that could be dosing in a microdosing packaging line.

[0083] [Example 5 (Inulin-torque overload)] In Example 5, the process of Example 3 was repeated. However, instead of the premix of Example 1a (fat-soluble vitamins), the premix of Example 1b (water-soluble vitamins) was used. Good quality granules were obtained. However, only for a short period of time. Shortly after starting the continuous melt granulation, torque overload occurred. It was not possible to find a stable process that could be run for a very long time (e.g., for periods of more than 1 hour). This compromises the advantage of the process being meant to be continuous.

[0084] Example 6 (mannitol as a bulking agent) In Example 6, the process of Example 5 was repeated, except that instead of inulin, mannitol (Pearlitol® 160C; melting point approximately 165° C.) was used as the filler.

[0085] First, a dry blend containing 83.65 wt. % mannitol (filler), 10 wt. % sorbitol (binder), and 6.35 wt. % of the premix of Example 1b (containing vitamin C), based on the total weight of the dry blend, was melt granulated continuously in an extruder. In this first attempt, the weight ratio of filler to binder was about 8.4:1.

[0086] Second, a dry blend containing 87.91 wt. % mannitol (filler), 10 wt. % sorbitol (binder), and 2.09 wt. % of the premix of Example 1b (without vitamin C), based on the total weight of the dry blend, was continuously melt granulated in an extruder. In this second attempt, the weight ratio of filler to binder was about 8.8:1.

[0087] As in Example 4, a screw configuration was used consisting of a single kneading zone with three kneading elements arranged at a stagger angle of 30°. The temperature zones close to the powder inlet (zones 2 and 3) were heated to a temperature of 170° C. to 180° C. The temperature of the zones close to the end of the extruder (zones 4, 5, and 6) was gradually reduced: zone 4 (55° C.) - zone 5 (35° C.) - zone 6 (25° C.).

[0088] Both attempts were successful. The torque overload observed in Example 5 can be prevented by switching the packing (inulin → mannitol), which is beneficial to have a continuous process.

[0089] [Example 7 (Advantages of the Mannitol / Sorbitol Combination)] In Example 7, the advantage of using mannitol as a filler and sorbitol as a binder was confirmed using the screw configuration and temperature zones of Example 6.

[0090] In the first experiment of Example 7, a placebo mixture consisting of only mannitol (filler) and sorbitol (binder) was continuously melt granulated in an extruder. In this placebo mixture, the weight ratio of filler to binder was about 9:1. The first experiment was successful. No torque overload occurred.

[0091] In a second experiment of Example 7, microcapsules containing fat-soluble vitamins were continuously melt granulated using mannitol as the filler and sorbitol as the binder. Depending on the fat-soluble vitamin selected, the weight ratio of filler to binder was 7:1 to 8.9:1. No torque overload occurred regardless of the fat-soluble vitamin selected.

[0092] [Example 8 (HMO as filler)] A dry mix was provided containing 90% by weight of 2'-O-fucosyllactose (2'-FL) and 10% by weight of sorbitol based on the total weight of the dry mix. 2'-FL obtained from DSM® Nutritional Products (Switzerland) contains a small amount of difucosyllactose (DFL).

[0093] The powder mixture was then fed into a ThermoFisher® Eurolab® extruder using a gravimetric loss-in-weight feeder at the powder inlet of the extruder. The extruder had a length to diameter (L / D) of 25 / 1 and a screw diameter of 16 mm. The co-rotating screws of the extruder are fully modular and can be configured in a variety of setups. There is usually a conveying (i.e. transporting) zone followed by a kneading zone. At the end, there is a forming zone. Each zone may have different screw elements.

[0094] The extruder had one kneading zone with three wide kneading disks arranged at a staggered angle of 30° (i.e., the angle of apex misalignment between any two directly successive kneading disks amounted to 30°).

[0095] The extruder was divided into several zones that could be heated or cooled separately. The powder inlet (zone 1) was not heated, while the temperature zones following the powder inlet (zones 2 and 3) were heated to a temperature of 120°C. The temperature of the zones near the end of the extruder (zones 4, 5, and 6) was maintained (i.e., cooled) at temperatures between 55°C and 25°C. Cooling was beneficial to prevent the production of a soft, sticky material (i.e., to avoid the formation of lumps).

[0096] Good quality water-soluble granules were obtained. The process was stable (i.e., no torque overload occurred). Long-term processability (more than 1 hour) was achieved, suggesting the possibility of its continuous manufacture.

[0097] The above process was then repeated except that microcapsules containing Vitamin E acetate were added to the powdered dry mix. The microcapsules were obtained from DSM® Nutritional Products (Switzerland).

[0098] Again, good quality water-soluble granules were obtained. The process was stable (i.e., no torque overload occurred). Long-term processability (>1 hour) was achieved, suggesting the possibility of continuous manufacturing.

Claims

1. A mixture for continuous melt granulation comprising a filler, a binder and at least one active ingredient, the mixture comprises 5% to 15% by weight of a binder, based on the total weight of the mixture; and the weight ratio of the filler to the binder is from 4:1 to 10:1; and The melting temperature of the binder is lower than the melting temperature of the filler; and A mixture in which the melting temperature of the filler is 151°C to 240°C.

2. 10. The mixture of claim 1, wherein the filler and the binder are non-identical polyols.

3. 10. The mixture of claim 1, wherein the filler and the binder are non-identical sugar alcohols.

4. 4. The mixture according to claim 1, wherein the filler is a stereoisomer of the binder.

5. 4. The mixture according to claim 1, wherein the filler is mannitol.

6. 4. The mixture according to claim 1, wherein the binder is sorbitol.

7. 2. The mixture of claim 1, wherein the bulking agent comprises 2'-O-fucosyllactose.

8. 8. The mixture of claim 7, wherein the filler is a mixture comprising 2'-O-fucosyllactose and difucosyllactose.

9. The mixture according to claim 7 or 8, wherein the 2'-O-fucosyllactose is crystalline 2'-O-fucosyllactose.

10. 4. The mixture of claim 1, wherein the weight ratio of the filler to the binder is from 5:1 to 9:1, from 6:1 to 9:1, or from 7:1 to 9:

1.

11. 4. The mixture of claim 1, wherein the mixture comprises 0.1% to 10% by weight of at least one water-soluble or water-dispersible vitamin, based on the total weight of the mixture.

12. 4. The mixture of claim 1, wherein the mixture comprises less than 10% by weight of water, based on the total weight of the mixture.

13. Granules comprising the mixture according to any one of claims 1 to 3.

14. Granules comprising the mixture according to any one of claims 1 to 3.

15. 14. Granules according to claim 13, wherein the granules have a mass median particle size D50 (volume based) of 0.5 mm to 6 mm, as measured using dynamic image analysis.

16. The granules according to claim 13, wherein the granules are obtained by continuous melt granulation of the mixture.

17. 14. The granules of claim 13, wherein the granules are water-soluble or water-dispersible.

18. Use of the mixture according to any one of claims 1 to 3 for continuous melt granulation.

19. A method for producing granules, comprising feeding the mixture according to any one of claims 1 to 3 into an extruder.

20. 20. The method of claim 19, wherein the extruder is a twin-screw extruder without a cutting device.

21. 20. The method of claim 19, wherein the method does not include cutting the extruded strands.

22. 20. The method of claim 19, wherein the extruder has at least one kneading zone, and the at least one kneading zone has at least two kneading elements arranged at a stagger angle that is between 30° and 60°.

23. 23. The method of claim 22, wherein the at least one kneading zone of the extruder is heated to a temperature of 90 to 210°C, 90 to 200°C, 100 to 190°C, 100 to 200°C, 150 to 210°C, 160 to 200°C, 120 to 190°C, or 165 to 190°C.

24. Granules obtained from the method of claim 19.

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