EP4680033A1

EP4680033A1 - Colostrum tablets

Info

Publication number: EP4680033A1
Application number: EP24718584.6A
Authority: EP
Inventors: Ivo LAIDMÄE; Jyrki HEINÄMÄKI; Osmo Antikainen; Andres LUST; Ain RAAL; Grigory ZENOV; Väino POIKALAINEN; Lembit LEPASALU
Original assignee: Tartu Ulikool (University of Tartu)
Current assignee: Tartu Ulikool (University of Tartu)
Priority date: 2023-03-13
Filing date: 2024-03-12
Publication date: 2026-01-21
Also published as: WO2024189541A1; GB202303611D0; GB2628100A

Abstract

The invention concerns colostrum and, in particular, colostrum in tablet form, as well as methods to produce such tablets. A method is provided for making colostrum tablets, the method comprising: providing colostrum powder; wet granulating the colostrum powder; dry mixing the granulated colostrum powder with microcrystalline cellulose; adding a lubricant; and compressing the resultant mix.

Description

Colostrum Tablets Field of the Invention The invention concerns colostrum and, in particular, colostrum in tablet form, as well as methods to produce such tablets. 5 Background to the Invention Colostrum, also known as beestings or first milk, is the first form of milk produced by the mammary glands of mammals (including humans) immediately following delivery of the newborn. Most species will begin to generate colostrum just prior to giving birth. Colostrum has an especially high amount of bioactive compounds compared to mature milk to give the 10 newborn the best possible start to life. The colostrum may be, for instance, bovine colostrum (BC). BC is rich in numerous bioactive compounds such as immunoglobulins, growth factors, antibodies, amino acids, oligosaccharides, antimicrobial compounds, immune regulators, vitamins and minerals. Therefore, the use of BC as food supplements or even in 15 pharmaceutical applications has gained a substantial interest in the recent decades. For example, it has been shown the therapeutic potential of BC supplements in the treatment of gastrointestinal diseases and disorders including e.g., inflammatory bowel disease (IBD), short bowel syndrome, nonalcoholic steatohepatitis (NASH), Crohn’s disease, gut infections, immunodeficiency diarrhea. 20 Colostrum can be provided as a supplement for adults as well as for newborns. It can be provided as, for instance, a powder, in capsules or as tablets. Currently, it is mainly provided in the form of tablets. However, tablet compression of high-dose tablets of BC powder is challenging due to the poor physical powder properties (flowability, compactibility) of such fat-rich BC powder. Therefore, virtually all oral BC products marketed to date are hard 25 gelatin capsules or dose powders, where BC powder is encapsulated as a high-dose active with a number of excipients. Tablets as a final dosage form, however, provide many advantages over hard gelatin capsules, such as increased manufacturing efficiency (i.e., production capacity), flexibility and patient compliance. AU2003100587 discloses a method of production of BC tablets involving wet granulation followed by tablet compression. Microcrystalline cellulose (MCC) can be used as a filler but is only added during the making of the granulates. AU2020103927 discloses an immunity-boosting pressed candy comprising milk powder 5 which can be made by a method involving wet granulation. MCC is mixed with the milk powder and other components prior to the wet granulation. WO2014087422 concerns a solid dosage form of milk that can be made of colostrum powder and can have MCC as a pharmaceutically acceptable carrier. The MCC can be Avicel PH 200. The process can involve a granulation step and the granulation can be "wet 10 granulation, hot melt granulation or moisture activated dry granulation (MADG)". Avicel PH200 is only mentioned in connection with MADG, not wet granulation. It is only used as a compressible carrier to improve MADG dry granulation. Statements of the Invention According to the present invention there is provided a method for making colostrum 15 tablets, the method comprising: providing colostrum powder; wet granulating the colostrum powder; dry mixing the granulated colostrum powder with microcrystalline cellulose; adding a lubricant; and compressing the resultant mix. The colostrum powder is preferably obtained from bovine colostrum but may be obtained from other suitable colostrums, for instance, those of sheep and goats. The invention 20 enables colostrum tablets to be produced with higher doses of BC per tablet. Moreover, tablet mass variation is very low, the mechanical strength of the tablets is very good, and the tablets have a short disintegration time. The colostrum powder may be obtained by, for example, spray-drying or lyophilising (freeze drying) the milky fluid of natural BC. 25 The wet granulation of the BC powder may be carried out in, for example, a high-shear granulator. A binder liquid may be employed, for instance, a 7-8% aqueous gelatin solution, thereby obtaining BC containing granules. Alternative binders, such as methyl cellulose, carmellose sodium (sodium carboxymethylcellulose), polyvinyl pyrrolidone (PVP), hypromellose (HPMC) and various starches, may be used. The dry mixing with microcrystalline cellulose may be carried out in, for instance, a Turbulamixer. The microcrystalline cellulose (MCC) is preferably a coarse grained material with an average particle size of from 150 to 300 micrometers, more preferably about 200 micrometers. 5 Accordingly, a preferred aspect of the present invention is a method which uses a coarse MCC and nearly 100% colostrum loaded granules. Such a combination reduces or eliminates the risk of segregation of components which can lead to a significant loss in the uniformity of mass and content quality attributes of the final tablets and potentially serious consequencies for the patients. 10 A preferred example is Avicel PH200, a material which has been used in direct compression methods. The addition of Avicel PH200 provides excellent compression properties to the mix and good mechanical strength (hardness) for the final tablets as well. An advantage of Extra-coarse Avicel PH200 is that its particle diameter is close to the particle diameter of the BC granules avoiding segregation issues that would impair the compression process. 15 The lubricant may be, for instance, magnesium stearate. Other lubricants may include stearic acid, calcium or zinc salts of stearic acid, sodium stearyl fumarate, paraffins, and glyceryl monostearate. The resultant mix may be compressed in, for instance, in an eccentric single-punch or rotary tablet machine. However, the inventors have developed a new method that allows to have 20 higher doses of BC per tablet. Moreover, with the method of the invention, tablet mass variation is very low, mechanical strength of the tablets is very good, and the tablets present a short disintegration time. Plant extract can be added at the stage of dry mixing the granulated colostrum powder with microcrystalline cellulose. Such plant extract can be, for example, at least one of Chamomile 25 and Echinacea powders. Preferably, the amount of plant extract is up to 10%, for instance, about 5%. The plant extract may be added at various stages, for instance, during dry mixing, wet granulation or in a final mixing step (before tablet compression). The present invention also provides a colostrum tablet comprising at least 50% w/w colostrum and having a breaking strength of at least 30 Newtons, preferably at least 60 Newtons. Tablets of the present invention may be formulated for an immediate release of BC powder 5 in the stomach after oral administration. However, they could be formulated to provide other types of BC tablets such as orodispersible tablets, chewing tablets, buccal tablets, or modified-release tablets. Description of the Drawings Figure 1 shows force-time profiles for tablets made by a method in accordance with 10 the present invention; and Figure 2 shows trend curves for punch forces for tablets made by a method in accordance with the present invention; Figure 3A shows the flow properties of seven different binary powder mixtures of bovine colostrum (BC) p0wder and microcrystalline microcellulose (MCC) lubricated with 15 magnesium stearate. The ratio of BC and MCC, and the amount of lubricant, were varied; Figure 3B shows the cumulative particle size distribution of lyophilized bovine colostrum (BC) powders produced in three different dates. The particle size was measured by means of scanning electron microscopy (SEM) and DiameterJ software. Figure 4 shows the Fourier transform infrared (FTIR) spectra of lyophilized bovine 20 colostrum (BC) powders produced on three different dates. Before FTIS spectroscopy analysis, the BC powder was fractioned in three different particle size fractions (A-C). and Figure 5 shows the representative force-time tableting curves for lyophilized BC powder. Detailed Description of the Invention 25 Embodiments of the present invention will now be described, by way of examples only. A. Brief Description of an Embodiment of the Invention A.1 Experimental Natural bovine colostrum in the form of a milky fluid was lyophilized (freeze dried) to form a yellowish poorly/moderately flowing powder. The powder was wet granulated and the 5 granules were mixed with a special type of coarse direct compression diluent to obtain a “hybrid mixture”. applicable for the tablet compression of high-dose BC tablets. The most effective direct compression diluent, microcrystalline cellulose (MCC) is not possible to be included in the granules in a wet-granulation process, since this had a negative impact on the particle structure and compression performance of MCC. 10 The wet granulation of the BC powder was performed in a pilot-scale high-shear granulator (GEA Aeromatic Fielder PMA-1, UK) equipped with a 5-litre mixer/granulator chamber. An aqueous binder solution of gelatin (3-8%) was used in the granulation, the solution having been prepared by dissolving gelatine in distilled water ay 50^C. The pre-weighed powder mixtures were charged into the granulator and pre-mixed at a dry 15 state at 300rpm for 2 minutes. The pre-weighed binder liquid was added into the powder mixture within 3 minutes at a mixing rate of 300 rpm. The mixing rate was then increased to 1000 rpm for a further 5 minutes. In a final stage (“kneading” phase), the wet mass was mixed at 300 rpm for one minute. The granules were discharged from the chamber of the high-shear granulator, and subsequently dried in a drying oven for at least 48 hours prior to 20 analysis and use in tablet compression. The tablet compression was conducted in an instrumented eccentric tablet machine (Manesty, U.K. / Part 1) and Korsch EK-0, Germany / Part 2) equipped with a 13-mm pair of flat-faced punches and an automatic feeding system. Pre-weighed amounts of BC granules and lubricant (magnesium stearate) were manually blended in a glass vial for 1 minute prior 25 to tablet compression. The compression force range was 0-30 kN and the compression speed was 37 rpm. The following compression parameters were monitored: (1) Upper and lower punch compression force (Fup, Flp) and (2) Compression time. The force-time treatment was performed for the tablet compression of the granulated “hybrid masses” to analyze the compression behavior of the masses. The final tablet evaluation consisted of the determination of tablet mass and mass variation, tablet dimensions (diameter and height), and breaking strength. The physical appearance, dimensions, weight and weight variation, and mechanical strength of tablets were investigated. The physical appearance was evaluated visually by 5 photographs. The dimensions, weight and breaking strength of tablets were investigated with an automatic Erweka Tablet Multitester (Erweka GmbH, Langen, Germany) and Erweka Tablet Tester EAC TBH 125 (Erweka GmbH, Langen, Germany). The MCC grades used as a filler/diluent component were Avicel PH-200 and Avicel PH-102. The content of BC powder in the tablets was 50% or 70% (w/w). The general composition of the tablets is shown in Table 10 1. Table 1. Composition Theoretical Theoretical Function Quality quantity (%) quantity (mg/tablet) Colostrum granules “F1” 50.3% 428.6 Active In-house containing 99.4% BC (Pure BC 50%) (426.0) ingredient and 0.6% gelatin 70.4% 600.0 (Pure BC 70%) (596.4) Magnesium stearate 0.2% 1.7 Lubricant Ph.Eur. Extra-granular filler 49.5% 421.7 Filler Ph.Eur. (Avicel PH200), respectively 29.4% 250.3 Theoretical weight (mg) 100 852.0 The results of the tablet compression tests are summarised in Table 2 (N.D.* = Not 15 determined (test failure).

Table 2. C^ode Tablet Max. upper Max. lower Breaking Tablet Tablet nr punch force, punch force, strength of weight height Fup (N) Flp (N) tablet (N) (mg) (mm) Hybrid tablets with the BC content of 50% (w/w) HBCA20050 1 21968 17235 47 963 5.86 HBCA20050 2 21893 17112 36 929 5.76 HBCA20050 3 21856 17127 27 925 5.82 HBCA20050 4 21930 17081 <15 N.D.* N.D.* HBCA20050 5 21874 17051 38 932 5.76 HBCA20050 6 21818 17051 34 945 5.85 Mean ± SD 21890 ± 53 17110 ± 69 33 ± 11 939 ± 15 5.81 ± 0.0 Hybrid tablets with the BC content of 70% (w/w) HBCA20070 1 24038 18937 24 935 6.00 HBCA20070 2 24355 19105 <15 934 6.00 HBCA20070 3 24093 18921 <15 939 6.02 HBCA20070 4 24112 18983 <15 930 6.03 HBCA20070 5 24019 18891 20 932 5.95 HBCA20070 6 24261 19013 15 934 6.01 Mean ± SD 24146 ± 133 18975 ± 77 17 ± 4 934 ± 3 6.00 ± 0.0 The accompanying Figure 1 shows the force-time profiles for these tablets, profiles A being for tablets having 50% (w/w) BC powder and profiles B being for tablets having 70% (w/w) 5 BC powder. A.2 Results and Discussion The following conclusions may be drawn: (1) The “hybrid mixture” formulation makes it possible to load a poorly flowing and compressible BC powde in tablets compressed with MCC (Avicel PH-200). The tablets had an 10 excellent mechanical strength at a loading of 50% (w/w) and a lower mechanical strength at a loading of 70% (w/w). (2) The weight variation of the tablets compressed from the “hybrid mixtures” with Avicel PH-200 was very good. This is due to the particle size of coarse grade Avicel PH-200, which is close to the particle size of high-dose BC granules. 15 (3) The force-time profiles for the tablets based on hybrid mixtures of high-dose BC granules (“F1”) and extra-granular MCC show almost identical compression behaviour. The irregular shape of the descending part of the force-time compression curves may be due to a high content of fatty acids in the BC powder. This could also explain the limited mechanical strength of the tablets at the BC concentration level of 70% (w/w). The above-described embodiment of the invention will now be compared with an example of a method of making BC tablets by means of direct compression of lyophilized BC powder 5 with microcrystalline cellulose, specifically Avicel PH-200. The content of BC powder in the tablets was the same as in the hybrid mixtures, i.e. 50% or 70% (w/w), of the above described embodiment of the invention. The tablets, details of which are shown in Table 3., were compressed from the binary mixtures of BC powder and direct-compression filler/diluent (Avicel PH-200) in an eccentric 10 single-punch tablet machine. The theoretical content of pure BC in the tablets was 50% or 70% (w/w). Table 3. Composition Theoretical Theoretical Function Quality quantity (%) quantity (mg/tablet) Bovine colostrum (BC) 50% 426.0 Active In-house powder ingredient 70% 596.4 Magnesium stearate 0.2% 1.7 Lubricant Ph.Eur. Filler/Diluent (Avicel 49.8% 424.3 Filler Ph.Eur. PH200), respectively 29.8% 253.9 Theoretical weight (mg) 100 852.0

Table 4 The results of tablet compression are summarised in Table 4 and accompanying Figure 2. Code Tablet Max. Upper Max. Lower Breaking Tablet Tablet nr punch force, punch force, strength of weight height Fup (N) Flp (N) tablet (N) (mg) (mm) (n =50) (n = 6) (n = 6) Direct-compression tablets with the BC content of 50% (w/w) DBCA20050 1 N.D. Measured 35 722 N.D. DBCA20050 2 N.D. Measured 37 717 N.D. DBCA20050 3 N.D. Measured 35 708 N.D. DBCA20050 4 N.D. Measured 37 721 N.D. DBCA20050 5 N.D. Measured 36 715 N.D. DBCA20050 6 N.D. Measured 36 726 N.D. Mean ± SD (n=6) 36 ± 1 718 ± 6 - DBCA20050 … … … - - - DBCA20050 50 N.D. Measured - - - Mean ± SD (n=50) N.D. 8310 ± 349 - - - Direct-compression tablets with the BC content of 70% (w/w) DBCA20070 1 N.D. Measured <15 618 N.D. DBCA20070 2 N.D. Measured <15 616 N.D. DBCA20070 3 N.D. Measured <15 623 N.D. DBCA20070 4 N.D. Measured <15 621 N.D. DBCA20070 5 N.D. Measured 17 632 N.D. DBCA20070 6 N.D. Measured 17 648 N.D. Mean ± SD (n = 6) <15 626 ± 12 - DBCA20070 … … … - - - DBCA20070 50 N.D. Measured - - - Mean ± SD (n=50) N.D. 7406 ± 905 - - - The theoretical target weight for the high-dose BC tablets (852 mg) was not possible to achieve due to the low density of the (non-granulated) powder mixture. Such target mass was not within the capacity of a tablet machine with the present direct compression mixture. The mechanical strength of the tablets was not satisfactory, ranging from 0 N to 37 N (i.e., tablets were mechanically very weak). Furthermore, during tablet compression, the maximum compression force (i.e., lower punch force, F_lp) varied greatly suggesting uneven die filling of the mass during tablet compression (see Figure 2). Perhaps surprisingly, this was not observed in tablet weight variation, which was quite small. Since the probe for measuring the maximum upper punch force (F_up) was not working properly in an instrumented tablet machine, only the values for maximum lower punch force (F_lp) were measured during tablet compression. The variation in Flp values is large (the upper curve in Figure 2), and the theoretical target weight for the high-dose BC tablets (852 mg) was not achieved due to the low density of the (non-granulated) powder mixture. The following conclusions may be drawn: 5 (1) When the (non-granulated) direct-compression mixtures of BC powder and MCC at a ratio of 50:50 w/w or 70:30 w/w were compressed, the theoretical target weight for the high-dose BC tablets (852 mg) was not achieved due to the low density of the powder mixture. The maximum weight for such tablets compressed from the direct-compression binary powder mixtures was in the range of 630-730 mg only. Since the granulation of 10 powder mixtures increases the density of the mass, “hybrid mixtures” of BC granules and MCC enable high-dose BC tablets with the target weight of 852 mg (or more) to be achieved. (2) With the direct-compression binary powder mixture of BC powder and MCC (Avicel PH- 200) at a ratio of 70:30 (w/w), the mechanical strength of the tablets was not satisfactory (less than 15 N, and the tablets were mechanically too weak for handling). Furthermore, 15 during tablet compression, the maximum compression force (i.e., lower punch force, F_lp) varied greatly suggesting a non-uniform tablet compression with the present mass. (3) With the direct-compression mixtures of BC powder and MCC (Avicel PH-200) at a ratio of 50:50 (w/w), the mechanical strength of the tablets was improved (20-40 N), but the tablets were still mechanically relatively weak. It is evident that increasing the compression 20 force in a tablet machine, close to the levels of that used with the “hybrid mixtures”, will not provide significant improvements due to the poor compressibility of the BC powder. The major limitation with these direct-compression powder mixtures, however, was the weight of the tablets, which was far below from the target weight (852 mg). Table 5. provides results of tablet compression of lyophilized BC powder and two binary 25 powder mixtures of the invention (BCC and Avicel PH-102 in proportions of 50:50 and 35:65). An eccentric single-punch tablet machine was used. Table 5. Lyophilized BC powder 100% Tablet Mass Maximum Maximum Breaking Tablet Tablet code weighed upper punch lower punch strength of weight height (mg) force, F_up (N) force, F_lp (N) tablet (N) (mg) (mm) A1 701 5831 4838 ND (< 10*) 444 4.250 A2 702 5898 4791 ND (< 10*) 444 4.020 A3 702 6004 4933 ND (< 10*) 442 4.108 B1 802 6084 4933 ND (< 10*) 424 4.010 B2 901 - - ND (< 10*) 412 4.250 B3 - - - - - - Binary powder mixture of lyophilized BC powder : MCC (50:50) A1 601 - - 37 505 3.932 A2 601 11649 10033 36 513 3.960 A3 - - - - - - B1 653 11876 10199 - 506 3.920 B2 700 11836 10104 31 504 3.960 B3 - - - - - - Binary powder mixture of lyophilized BC powder : MCC (35:65) A1 - - - - - - A2 505 - - 60 478 3.788 A3 505 - - 66 482 3.746 B1 504 - - 63 477 3.714 B2 502 6391 5550 67 480 3.718 B3 - - - - - - MCC (Avicel PH102) 100% A1 - - - - - - A2 454 - - 141 414 3.414 A3 451 - - 158 409 3.646 B1 ** 5193 4340 192 415 3.612 B2 ** 5392 4483 239 440 3.526 B3 ** 6444 5408 249 443 3.685 B4 ** 6470 5384 284 458 3.757 B5 ** 6284 5242 245 443 3.505 *Tablets were mechanically too weak (under the detection limit) ** Tablets were motorized compressed using a powder feeding device The following conclusions were drawn: 5 (1) Direct compression of lyophilized BC as such (and with or without lubrication) results in tablets with very poor mechanical strength (hardness). The tablets obtained do not resist any handling and packaging operations. As higher compression forces were used, clear capping defects were observed with the tablets; (2) The mixing of lyophilized BC powder with MCC (Avicel PH-102) significantly enhanced the direct-compression properties of the mass and mechanical strength of the final tablets. The binary powder mixture of lyophilized BC powder and MCC at the ratio of 35:65 w/w ratio is directly compressible Increasing the amount of MCC improves both the flow and direct 5 compression properties of the present tablet mass. (3) The final tablet weights were very much decreased from the original weight of the powder sample placed in the die of an eccentric single-punch machine. It would seem that, during tablet compression, the residual moisture or fatty acids of the BC powder squeezed out from the tablet, thus significantly decreasing the final weight of the tablet. 10 (4) The physical appearance and mechanical strength (hardness) of the tablets compressed from the 35:65 w/w binary mixture of BC powder and MCC are considered as satisfactory. B. Detailed Description of an Embodiment of the Invention B.1 Bovine colostrum powder Lyophilized (freeze-dried) BC powder (Teadus ja Tegu OÜ, Tartu, Estonia) was used in the 15 material characterisation, granulation and tablet compression experiments. The lyophilized BC powder was used in the preformulation studies (physical material characterisation) and formulation development as such without further treatment. The lyophilized BC powder is a yellowish and relatively cohesive powder. B.2 Other ingredients and excipients 20 Echinacea and Chamomile plant extracts in a powder form were investigated as active ingredients to support the food supplement use of BC tablets. Information on the suppliers and properties of the excipients used in immediate-release tablets of lyophiized BC powder5 are summarised in Table 6. Table 6. Material Trade name(s) Supplier Characteristics / Recommended Quality use Microcrystalline Avicel PH-102; FMC White, odorless, Tablet direct cellulose, MCC Avicel PH-200; Biopolymer, crystalline powder compression other grades Cork, Ireland / USP NF, Ph.Eur diluent/filler Emcocel, Vivapur Lactose Pharmatose DFE Pharma, White to off-white Tablet monohydrate Germany; powder / Ph.Eur. diluent/filler Lach-Ner, Czech Republic Magnesium N.A. - Very fine, white Tablet lubricant stearate powder / Ph.Eur. Gelatin N.A. Dr. Oetker, White powder / Tablet binder Poland Food grade Polyvinyl Povidon Alfa Aesar, White powder / Tablet binder pyrrolidone, Germany Ph.Eur. (PVP) Hydroxypropyl Hypromellose Alfa Aesar, White powder / Tablet binder methylcellulose Germany Ph.Eur. (HPMC) Colloidal silicon Aerosil Evonik Light, amorphous Tablet glidant dioxide Industries AG, powder / Ph.Eur. Germany B.3 Methods 5 B.3.1 Physical material characterisation Particle size and size distribution of lyophilized BC powder (100 g) were investigated by means of sieve analysis with the set of three sieves (1000 μm, 500 μm, 150 μm). Particle shape, surface morphology and microstructure of lyophilized BC powder, MCC, lactose monohydrate, Echinacea (“siilkübar”) extract powder, and Chamomile (“kummel”) extract 10 powder were studied by using a high-resolution light microscope. B.3.2 Wet granulation of powder masses Wet granulations of powder mixtures were performed either manually, or by using a pilot- scale high-shear granulator (GEA Aeromatic Fielder PMA-1, UK) equipped with a 5-liter mixer/granulator chamber. For granulation, the aqueous binder solutions of gelatin (3-8% 5 w/w) were prepared by dissolving gelatin in distilled water at 50 ^C. Then, the pre-weighed powder mixtures were charged into the granulator, and pre-mixed at a dry state at 300 rpm for 2 minutes. The pre-weighed binder liquid was added into the powder mixture at a mixing rate of 300 rpm within 3 minutes. Then, the mixing rate was increased at 1000 rpm for the next 5 minutes. In the final stage (“kneading” phase), the wet mass was mixed at 300 rpm 10 for one minute. The granules were discharged from the chamber of the high-shear granulator, and subsequently dried in a drying oven for at least 48 hours prior to analysis and use in tablet compression. B.3.3 Tablet compression B Tablet compression experiments were conducted according to the “state-of-the-art” 15 protocol at a laboratory scale. In the first stage, the tablet compression behaviour of lyophilized BC powder was investigated with an instrumented single-punch tablet machine at the University of Helsinki, Finland. Lyophilized BC powder were compressed into tablets as such and as the 50:50 (w/w) and 35:65 (w/w) powder mixture with MCC (Avicel PH 102). Pure MCC (Avicel PH 102) was used as a reference for a readily compressible, plastically 20 behaving material. Prior to tablet compression lyophilized BC powder and MCC were spread to a thin layer on the trays, and allowed to stabilize at a laboratory room conditions (22 ^C / 65-75% RH) for 24 hours. Tablets were compressed in an instrumented Korsch EK-0 eccentric tableting machine (Erweka Apparatebau, Germany) equipped with 12-mm flat- faced punches. The technical details of the present eccentric tablet machine are: (1) 25 Compression rate 10-60 tablets / min; (2) Compression time 120-1000 ms; and (3) Compression force range 0-30 kN. The instrumentation enablesd the investigation of multiple parameters such as (1) Upper and lower punch compression force (F_up, F_lp); (2) Upper and lower punch displacement; (3) Ejection force (Fej); and (4) Stress relaxation. In the tablet compression experiments, the upper punch was first placed in its lower 30 position and the position of the lower punch was adjusted by using a 3-mm calibration plate between the punches. For compression studies, pure materials and binary powder mixtures were individually weighed out and poured into a pre-lubricated die (acetone suspension of magnesium stearate 5% w/w). The operating speed of the tablet machine was 36 rpm. Immediately after compression, the height of each tablet was measured with a digital 5 micrometer (Sony DZ 521, Tokyo, Japan). The mass of each tablet was measured with an analytical balance (Sartorious CP 2245, Raute, Goettingen, Germany). The crushing strength of tablets was determined using a tablet hardness tester (Erweka EAC TBH 125, Erweka GmbH, Langen, Germany). The compactibility of BC powder and the 1:1 mixture with MCC was evaluated by determining the relationship between the upper punch compression force 10 and tablet crushing strength. In the second stage, the tableting behavior of the first theoretical direct-compression tablet composition (shown in Table 7.) were investigated with a rotary tablet machine (Killian, Germany). The technical details of the present 16-punch pair rotary tablet machine are: (1) Compression rate 300-700 tablets / min; (2) Compression time 30-100 ms; and (3) 15 Compression force range 0-50 kN. The pre-weighed amounts of BC powder and MCC were first manually blended and then the lubricant (magnesium stearate) was added in the powder blend by gently mixing by using mortar and pestle prior to tablet compression. For practical reasons, the composition of the tablets was simplified by replacing the disintegrant (croscarmellose sodium) and glidant (colloidal silicon dioxide) with the corresponding 20 amount of diluent MCC. The ratio of BC powder and MCC was set as 75:25 and 50:50 (w/w). Table 7.

In the third stage, the tableting of the wet-granulated masses (“PM-2” and “F1-F4”) were conducted in an instrumented eccentric tablet machine (Manesty, U.K.) equipped with a 11- mm pair of punches and an automatic feeding system. The pre-weighed amounts of BC 5 granules and lubricant (magnesium stearate) were first manually blended and subsequently mixed in a Turbula mixer for 1 minute prior to tablet compression. The compression force range was 0-30 kN. The following compression parameters were monitored: (1) Upper and lower punch compression force (F_up, F_lp) and (2) Upper and lower punch displacement. The force-displacement treatment was performed for the tablet compression of the present 10 granulated masses to analyze the compression behavior of the masses. The final tablet evaluation consisted of the determination of tablet mass and mass variation, tablet dimensions (diameter and height), breaking strength and disintegration time in vitro. B.3.4 Analytical methods 15 The particle and granule size, shape and surface morphology were investigated by means of scanning electron microscopy, SEM (Zeiss EVO MA 15, Germany). The physico-chemical analysis of BC powder was performed by means of Fourier transform infrared (FTIR) spectroscopy (IRPrestige-21, Shimadzu, Japan). The physical appearance, dimensions, weight and weight variation, and mechanical strength of direct-compression tablets were 20 investigated. The dimensions of tablets were studied with a Sony digital micrometer (Sony DZ 521, Tokyo, Japan). The weight and weight variation of tablets were determined by an analytical balance (Sartorious CP 2245, Raute, Goettingen, Germany). The mechanical strength (hardness) of tablets was determined by using a semi-automatic Erweka EAC Tablet Hardness Tester (TBH 125, Erweka GmbH, Langen, Germany) and an automatic Erweka 25 Tablet Multitester (Erweka GmbH, Langen, Germany). The tablet hardness tester measures the force needed to break down the tablet placed in the measurement chamber. The mechanical strength test of pharmaceutical tablets should comply with the requirements presented in the European Pharmacopoeia (Ph.Eur. 2.9.8 "Resistance to Crushing of Tablets"). 30 The disintegration time of tablets was investigated in vitro by using a Sotax D3 (Sotax AG, Switzerland) disintegration tester. The tablet disintegration tester and test method are according to the Ph.Eur. standards. Distilled water at 35 °C was used as a dissolution medium in the tests. 5 B.4. Results and discussion B4.1 Particle shape, size and size distribution The particle size of the BC powder was found to be mainly in the range of 150 μm and 500 μm (63.5%). The amount of larger particles (with the particle size over 1000 μm) and fine particles (with the particle size less than 150 μm) were 9.0% and 1.6%, respectively. The 10 present results suggest that the particle size of lyophilized BC powder is even larger than that of the established direct-compression excipients (diluents/fillers) used in tablet manufacture. Similar particle size of active(s) and excipients is advantageous, thus preventing the segregation of the powder components during powder blending and tablet compression processes. The relatively large particle size suggest also that lyophilized BC 15 powder could flow, which is the most important powder bulk characteristic in direct compression of tablets. The particle size, shape and morphology of key materials were also investigated by means of light microscopy and scanning electron microscopy (SEM). Lyophilized BC powder consisted of relatively large and irregular particles, which is in a good agreement with the results 20 obtained in sieve analysis. Some loose clusters of powder particles can be seen in the micrographs. Particle size and shape of MCC are characteristic for the present tablet diluents and in line with the results described in the literature. Echinacea (“siilkübar”) extract powder and Chamomile (“kummel”) extract powder were composed of the smallest particles with a spherical round shape. The SEMs verified that the particle size of a 25 lyophilized BC powder is in the range of 100-500 μm. Particle size and shape affects greatly the powder flow behaviour. The results on the flowing test of lyophilized BC powder and the particle size analysis of three consecutive batches of BC powder produced in 2021 are shown in Figure 3. The particle size analysis was conducted using SEM micrographs and Image J (Diameter J) programme (Zenov, 2022). The flow rate of 30 lyophilized BC powder mixed with MCC at different ratios and lubricated with magnesium stearate (1-3%) ranged from 7 ml/s to 11 m/s, and the angle of repose values from 81-85 ^, thus indicating a poor flowing behaviour of a BC powder (Figure 3-A). For further processing, the granulation of the present powder is important to ensure the acceptable (low) mass variation of a final dosage form (i.e., tablets or capsules). The particle size and size distribution of three consecutive batches of lyophilized BC powder were very uniform, thus suggesting a good reproducibility of the production of the powder (Figure 3-B). B.4.2 Physicochemical structure analysis The results of Fourier Transform Infra Red (FTIR) spectroscopy analysis of three consecutive batches of BC powder are shown in Figure 4. Prior to analysis, the BC powder samples from each batch were fractioned by sieving: (A) ^ 1000 ^m; (B) 500-1000 ^m and (C) ^ 500 ^m. The FTIR spectra of all three batches and three specific fractions (A-C) were very similar (uniform), thus verifying a good reproducibility of the production (including lyophilisation) of the powder. The peaks at 1037 cm^-1, 1159 cm^-1 and 1236 cm^-1 are assigned to polysaccharides, and the difference in peak heights suggests that the content of polysaccharides is slightly higher in more freshly produced BC powder compared to the other two older batches This difference could be explained by a Maillard reaction between polysaccharides and protein in the aged batches. The peaks at 1521 cm^-1 and 1635 cm^-1 are assigned to protein bands, and these peaks were virtually identical for all three batches and specific fractions investigated. The peak at 1741 cm^-1 is assigned to the presence of an ester bond, and the two peaks at 2850 cm^-1 and 2918 cm^-1 are characteristic to hydrogen bonding. The similarity of these peaks suggests that the content of fatty acids is uniform within all three batches and fractions analysed (Zenov, 2022). B.4.2 Tablet compression B.4.2.1 Tablet compression behaviour of bovine colostrum powder Tablet compression behaviour of lyophilized BC powder and two binary powder mixtures of BC and MCC (50:50 and 35:65) were investigated with an instrumented eccentric single- punch tablet machine. The objectives of these experiments were (1) to gain understanding of the direct-compression behaviour of lyophilized BC powder as a pure material and (2) to find out the ratio of BC powder and MCC (Avicel PH-102) in the binary powder mixture, which could be applicable in direct-compression of tablets. Table 5 summarizes the results of the tablet compression studies (preliminary tests) 5 conducted with an instrumented eccentric single-punch tablet machine. The key findings of the present experiments were as follows: (1) Direct compression of lyophilized BC as such in an eccentric tablet machine (and with or without lubrication) is extremely challenging resulting in the tablets with very poor mechanical strength (hardness). The tablets obtained do not resist any handling and packaging operations. As higher compression forces were 10 used in a tablet machine, clear capping defects were observed with the tablets; (2) The mixing of lyophilized BC powder with MCC (Avicel PH-102) enhanced the direct-compression properties of the mass and mechanical strength of the final tablets. The binary powder mixture of lyophilized BC powder and MCC at the ratio of 35:65 w/w ratio is considered as directly compressible (if the amount of MCC is lower than 50% w/w, the tableting properties 15 will be significantly impaired). Increasing the amount of MCC improves both the flow and direct compression properties of the present tablet mass. Since lyophilized BC powder is expected to be used at a high dose in the tablets, the poor direct compression properties of the present powder is clearly a limiting factor; (3) The final tablet weights were very much decreased from the original weight of the powder sample placed in the die of an eccentric 20 single-punch machine (Table 4). This kind of compression behaviour was characteristic especially for a lyophilized BC powder and the 50:50 w/w binary mixture containing a higher dose of BC powder. It is evident that during tablet compression the residual moisture or fatty acids of BC powder squeeze out from the tablet, thus significantly decreasing the final weight of the tablet; (4) The representative force-time tableting curves for the lyophilized 25 BC powder and the binary mixtures of BC powder and MCC (50:50 and 35:65) provide further evidence of the limitations in the direct compression of BC powder (Figure 5). The force-time profiles for lyophilized BC powder and the binary mixture (50:50) showed the absence of a clear peak for the maximum compression forces, thus suggesting limited compression behaviour of these masses. As the amount of MCC was increased (35:65), the 30 compression behaviour of the powder mixture was improved. MCC represents an ideal plastically behaving direct-compression excipient material, and thus it can be used as a reference (“golden standard”); (5) The physical appearance and mechanical strength (hardness) of the tablets compressed from the 35:65 w/w binary mixture of BC powder and MCC are considered as satisfactory. The weight variation, friability, in-vitro disintegration time and dissolution of such tablets, however, need to be investigated to verify the 5 applicability of this formulation as a food supplement product. It should be emphasized that the present tablet compression experiments with an instrumented eccentric single-punch tablet machine (University of Helsinki) and rotary tablet machine (University of Tartu), are preliminary tests. The tablets were compressed by 10 a “one-by-one” mode using a motorized compression (in an eccentric single-punch tablet machine) and manual compression (in a rotary tablet machine). In the next step, it would be important to conduct tablet compression tests by using the batch sizes, which enables the simulation of a real tableting process. In the pilot-scale and full production-scale tablet manufacture, much larger powder blends or granulated masses need to be used in fully 15 equipped and operating tablet machines (by using for example a proper feeding device and a full tableting speed). The compositions of two ternary powder mixtures used for the direct compression of BC tablets were as follows: 20 Formula I: Lyophilized BC powder 4.980 g MCC 4.980 g Magnesium stearate 0.051 g Formula II: Lyophilized BC powder 7.497 g 25 MCC 2.450 g Magnesium stearate 0.050 g Formula I is referred to as a “50:50” (BC:MCC) tablet mass, and Formula II to as a “75:25” (BC:MCC) tablet mass. In both tablet formulations, MCC acts as a direct-compression diluent 30 and magnesium stearate as lubricant. The “50:50” (BC:MCC) tablet mass exhibited relatively homogeneous powder blend without any significant signs of the segregation of the powder components. As the amount (ratio) of BC powder was increased in the tablet mass, the homogeneity of the powder blend was impaired. The “75:25” (BC:MCC) tablet mass, however, still presented moderate to good homogeneity of the powder blend. Tthe 5 granulation of powder blends enables improvement of the homogeneity, flowing properties and physical stability of the tablet masses. Based on visual inspection, the flowing properties of the present two tablet masses were somewhat limited. The flowing properties of tablet masses can be improved by adding an effective glidant (such as colloidal silicon dioxide), or via wet- or dry-granulation. 10 B.4.2.2 Immediate-release bovine colostrum tablets via wet-granulation The experimental composition of immediate-release tablets (via a wet-granulated mass) of BC powder is shown in Table 8. For preparing wet-granulated masses, lyophilized BC powder was mixed with the two plant extract powders, MCC and lactose monohydrate in a high- shear mixer for 3 min at a mixing rate of 300 rpm. Then, the granulation binder solution 15 (12.8 g PVP in 100 ml purified water) was sprayed in the mass, while mixing at the rate of 300 rpm. Next, total 65 ml of purified water was sprayed onto the powder mass for 5 min, while mixing the mass at 300 rpm. In the subsequent step, the powder mass was further granulated for 5 min at the mixing rate of 800 rpm. After sampling, it was found that the granules are still too dry and brittle, and consequently, 40 ml of purified water was added by 20 spraying for 5 min in the granule mass at the mixing rate of 800 rpm. In the final stage, the granule mass was mixed (kneaded) for 1 min at the mixing rate of 300 rpm. The final granules were dried on the drying trays as a thin layer at 50 ^C for 48 hours. 25 Table 8. The dried granules were gently screened with a manual sieve (1-mm sieve size), and 0.5% of magnesium stearate (lubricant) was added and mixed with the granules prior to tablet 5 compression in a rotary tablet machine. The granules were brown in colour and exhibited an oily (fatty-like) surface morphology. This was obviously due to the relatively high content of fatty acids (approximately 25%) in the BC powder. Table 9 presents the composition and tablet properties of high-dose BC tablets compressed from the HPMC containing granules (“PM-2HPMC”). HPMC (or hypromellose) is mainly used10 as a film coating agent for tablets, but it has also found uses as a binder agent in wet- granulation and tablet compression. The physical appearance, mass variation and disintegration time in vitro (less than 5 min) of the present tablets were very good and similar to the tablets compressed from the PVP containing granules.

Table 9. A. Tablet composition Composition Quantity Theoretical Function Quality “PM-2HPMC” (%) quantity (mg/tablet) Colostrum powder* 49.1 300.0 Active ingredient In-house (equal to 306 mg of granules) Microcrystalline 24.6 150.3 Filler Ph.Eur. cellulose, MCC Lactose 24.6 150.3 Filler Ph.Eur. Hypromellose, HPMC 1.2 7.3 Binder Ph.Eur. Magnesium stearate 0.5 3.1 Lubricant Ph.Eur. Theoretical weight (mg) 100 611.0 B. Tablet properties Tablet nr. Tablet mass Tablet height Breaking strength Remarks (mg) (mm) (N) 1 614 3.82 24 2 644 4.02 24 3 654 4.12 24 4 658 4.17 29 5 655 4.16 31 6 661 4.15 35 Mean ± SD 648 ± 17 4.07 ± 0.14 28 ± 5 * Lyophilized bovine colostrum powder (Teadus & Tegu OÜ) 5 B.4.2.3 Tablet compression of granules prepared in a high-shear granulator at a pilot scale In the next set of experiments, the high-dose “F1” and “F1.1” granules prepared in a high- shear granulator were used for tablet compression. The BC powder was wet-granulated in a high-shear granulator by using a 3% aqueous gelatin solution as a binder liquid. In the first 10 tableting experiment, it was aimed to compress the tablets containing even up to 97-99% of the active ingredient (BC) and having 500 mg of the target content of BC in the tablets. Table 10 shows the composition of this tablet formulation. The compression of such granulated masses resulted in tablets with an unsatisfactory (too low) mechanical strength, and thus the present granules are not applicable as such (without any external filler/diluent) in the 15 tablet compression of BC (no photograph is presented). Table 10. Composition Quantity Theoretical Function Quality “F1” (%) quantity (mg/tablet) Colostrum powder* 98.9 500.0 Active ingredient In-house (equal to 306 mg of granules) Gelatin 0.6 3.0 Binder Ph.Eur. Magnesium stearate 0.5 2.5 Lubricant Ph.Eur. Theoretical weight (mg) 100 505.5 Composition Quantity Theoretical Function Quality “F1.1” (%) quantity (mg/tablet) Colostrum powder* 97.5 500.0 Active ingredient In-house (equal to 306 mg of granules) Gelatin 2.0 10.3 Binder Ph.Eur. Magnesium stearate 0.5 2.6 Lubricant Ph.Eur. Theoretical weight (mg) 100 512.9 * Lyophilized bovine colostrum powder (Teadus & Tegu OÜ) B.4.2.3 Tablet compression of “hybrid” masses 5 The present invention enables the compression of high-dose BC powder containing tablets for oral administration. The tablets have good compression properties, good mechanical strength, low tablet mass variation and short disintegration time. The tablets were compressed from “hybrid” mixtures of BC containing granules and a special coarse grade of microcrystalline cellulose (Avicel PH-200) (Table 11). Prior to tablet 10 compression, BC powder was wet-granulated in a high-shear granulator by using a 7-8% aqueous gelatin solution as a binder liquid, and then dry-mixed with Avicel PH-200 in a Turbula mixer. For external lubrication, magnesium stearate (0.2% w/w) was used. As shown in Table 11A, the tablets contained 35% of BC powder but the BC powder content could be increased even up to 60-70%. The present tablets are intended for an immediate 15 release of BC powder in the stomach after oral administration, but this “hybrid-mixture” tablet platform (“anchor composition”) can be used as a universal base for formulating other types of tablets for a BC powder, such as orodispersible tablets, chewing tablets, buccal tablets, or modified-release tablets. As seen in Table 11B, the tablets compressed from the “hybrid” mixture of BC containing granules and a special coarse grade of 20 microcrystalline cellulose (Avicel PH-200) exhibited superior compression behavior, mechanical strength, physical appearance, mass variation and disintegration time in vitro (less than 5 min) Table 11. A. Tablet composition Composition code DC-1F1 Quantity Theoretical Function Quality “Hybrid mixture” (%) quantity (mg/tablet) Colostrum granules “F1” 35.4 301.8 Active ingredient In-house (containing 99.4% BC and (BC 300.0) 0.6% gelatin) Magnesium stearate 0.2 1.7 Lubricant Ph.Eur. Coarse microcrystalline 64.4 549.1 Filler Ph.Eur. cellulose, MCC (Avicel PH- 200) Theoretical weight (mg) 100 852.6 B. Tablet properties Tablet nr. Tablet mass Tablet height Breaking strength Remarks (mg) (mm) (N) 1 884 5.98 69 2 890 6.07 60 3 890 6.01 57 4 893 6.04 70 5 896 6.01 63 6 888 6.02 71 Mean ± SD 890 ± 4 6.02 ± 0.03 65 ± 6 5 Chamomile and Echinacea plant extract powders (total up to 5% w/w) can be successfully added in the composition of the present tablets (Table 12). The BC powder was first wet- granulated in a high-shear granulator by using an aqueous gelatin solution as a binder liquid, 10 and consequently mixed with coarse microcrystalline cellulose Avicel PH-200 and the plant extract powders. The tablets were then compressed using this “hybrid” basic mixture of BC containing granules and Avicel PH-200 added with the plant extract powders. For external lubrication, magnesium stearate (0.2% w/w) was used. An instrumented eccentric single- punch tablet machine was used for all abovementioned tableting experiments. The physical 15 appearance, mechanical strength and weight uniformity of all tablets prepared were of high standard. Table 12 A. Tablet composition Composition DC-1F1CE Quantity Theoretical Function Quality “Hybrid mixture CE” (%) quantity (mg/tablet) Colostrum granules “F1” 35.4 301.8 Active ingredient In-house (containing 99.4% BC and (BC 300.0) 0.6% gelatin) Magnesium stearate 0.2 1.7 Lubricant Ph.Eur. Coarse microcrystalline 59.4 506.5 Filler Ph.Eur. cellulose, MCC (Avicel PH- 200) Chamomile extract 2.5 21.3 Active ingredient - Echinacea extract 2.5 21.3 Active ingredient - Theoretical weight (mg) 100 852.6 B. Tablet properties Tablet nr. Tablet mass Tablet height Breaking strength Remarks (mg) (mm) (N) 1 914 6.01 68 2 903 6.05 70 3 910 6.03 64 4 904 6.04 70 5 907 6.02 67 6 908 6.06 72 Mean ± SD 908 ± 4 6.04 ± 0.02 69 ± 3 The tableting process with both formulations (described in Tables 11 and 12) was carried out without any problems or flaws. No sticking of the mass onto the punches or die were observed suggesting good tablet compression properties. The upper punch force values (Fup) needed to compress the tablets with a good quality were low with the present two “hybrid” formulations (DC1F1 and DC1F1CE), thus showing a good compressibility. Furthermore, the expansion work (Wexp) values with the present formulations were small suggesting the formation of tablets with good mechanical properties (hardness). The slightly higher ejection (We) and friction work (Wf) values compared to the other formulations tested, suggest perhaps the need to slightly increase the amount of lubricant in these “hybrid” formulations (DC1F1 and DC1F1CE). In conclusion, the present significantly improves the tablet compression of BC powder, and thus enables the production of high-dose BC tablets with a high pharmaceutical quality. The invention provides: (1) Significantly improved tablet compression properties of a lyophilized BC powder, enabling the fabrication of the high-dose tablets to be used as food supplements (and as an alternative oral dosage form for hard gelatine capsules); (2) By combining high-dose BC granules (consisting of a suitable binder agent) with a coarse MCC (i.e., the special high-particle-size grade of MCC, Avicel PH-200), it is posible to produce 5 high-dose BC tablets with good compression properties, good mechanical strength, low tablet mass variation and short disintegration time; (3) It is possible to incorporate a poorly compressible BC powder (after granulation) and poorly compressible plant extracts into the same tablet; (4) The manufacture of alternative oral solid dosage forms for BC, e.g., conventional immediate-release tablets, chewing tablets, orally dispersible tablets (ODTs), 10 and modified-release tablets at an industrial scale; (5) Combining high-dose BC granules with a coarse MCC (Avicel PH-200) having the particle size closer to the granules prevents the segregation of the components during table compression, thus enhancing the mass uniformity of the final tablets; (6) There is no requirement for the use of elevated temperatures, thus maintaining the nutritional profile of a lyophilized BC powder in a tablet 15 form. B.4.2.4 Industrial-scale tablet manufacture New “hybrid” high-dose BC tablets were manufactured also in a large production-scale in a pharmaceutical industry plant in Estonia. An industrial-scale rotary tablet machine was used for tableting, and the tablets (final products) were packed in standard blister packages. The 20 aim of this test was to verify the tablet manufacturing potential of a “hybrid” tablet prototype developed in this project in an industrial-scale high-speed tablet production and primary package filling operation. The “hybrid” tablet prototype used was based on the composition described in Table 11. It was found that the present “hybrid” tablets for a lyophilized BC powder are feasible for 25 production-scale tablet manufacture, and thus ready for a commercialized tablet product. The physical appearance of the BC tablets produced at an industrial-scale was good (without any visual surface defects), and comparable with the tablets prepared at a laboratory-scale with an eccentric single-punch tablet machine. The mechanical strength of the tablets ranged from 50 N to 80 N, which is high enough and at an acceptable level. The average 30 mass of the tablets was 834 ± 9 mg (n = 10) indicating also extremely low mass variation. B.4.2.5 Storage stability studies A short-term storage stability test was performed for the immediate-release BC tablets to ensure the applicability of the present prototypes as food supplements. The “hybrid” tablets described in Tables 9 and 10 were stored in a closed plastic packages (i.e., the tubes shown 5 in Annex II) at an ambient room temperature (21 ± 2 ^C) and light for 3.5 months. The physical appearance (including the visual inspection of potential changes in colour) and weight of the tablets were investigated, and compared to the corresponding results obtained with the “fresh” tablets. The results of the storage stability studies are summarized in Table 11. 10 The results of the present short-term storage stability study suggest that the present immediate-release tablet prototypes are physically stable when stored in a closed plastic package at a room temperature. No significant changes in physical appearance and weight of the tablets were observed. After a 3.5-month storage stability test, the tablets were still 15 very good to handle and use. Further studies, however, are needed to gain knowledge of the long-term stability of the present tablets. Table 11 Tablet code (ref. Physical appearance Tablet weight Comments table) (visual inspection) (mg) (n = 6) (n = 6) DC-1F1 (Table 3-11) Zero-point Flat-shaped white tablets 890 ± 4 Not any significant (“fresh” tablets) with slightly visible (884-896) changes in physical yellowish dots appearance and A_{fter 3.5 months} Flat-shaped white tablets 893 ± 6 ^{weight of the tablets} (“aged” tablets) with slightly visible (886-899) yellowish dots DC-1F1CE (Table 3-12) Zero-point Flat-shaped tablets with 908 ± 4 Not any significant (“fresh” tablets) intensive brownish dots (903-914) changes in physical After 3.5 months Flat-shaped tablets with 903 ± 8 appearance and (“aged” tablets) intensive brownish dots (896-914) weight of the tablets 20

Claims

CLAIMS 1. A method for making colostrum tablets, the method comprising: providing colostrum powder; wet granulating the colostrum powder; dry mixing the granulated colostrum 5 powder with microcrystalline cellulose; adding a lubricant; and compressing the resultant mix.

2. A method according to Claim 1, wherein the colostrum is bovine colostrum.

3. A method according to Claim 1 or Claim 2, wherein the colostrum powder is obtained by spray-drying or lyophilising (freeze drying) the milky fluid of natural colostrum.

4. A method according to any of the preceding claims, wherein the wet granulation of the powder is carried out in a high-shear granulator.

5. A method according to any of the preceding claims, wherein a binder liquid is employed during the wet granulation.

6. A method according to Claim 5, wherein the binder liquid is an aqueous gelatin solution.

7. A method according to Claim 6, wherein the binder liquid is a 7-8% gelatin solution.

8. A method according to any of the preceding claims, wherein the dry mixing with microcrystalline cellulose is carried out in a Turbula mixer.

9. A method according to any of the preceding claims, wherein the microcrystalline cellulose has a particle size of from 150 to 300 micrometers.

10. A method according to Claim 9, wherein the microcrystalline cellulose has a particle size of about 200 micrometers.

11. A method according to any of the preceding claims, wherein the microcrystalline cellulose is Avicel PH200.

12. A method according to any of the preceding claims, wherein a plant extract is added at the dry mixing stage.

13. A method according to any of the preceding claims, wherein the plant extract is one or more of Chamomile and Echinacea powders.

14. A method according to any of the preceding claims, wherein the lubricant is magnesium stearate.

15. A method according to any of the preceding claims, wherein the mix is compressed in an eccentric single-punch or rotary tablet machine. 5 16. A colostrum tablet comprising at least 30 % w/w colostrum and having a breaking strength of at least 30 Newtons. 17. A colostrum tablet according to Claim 16, wherein the breaking strength is at least 60 Newtons. 18. A colostrum tablet according to Claim 16 or Claim 17, wherein the colostrum content is at least 60% w/w.