Process for the production of a granulate and a granulate, in particular a granulate compound of excipients

Abstract

Process for the production of a granulate, comprising the steps of a) preparing a granulation liquid, comprising the steps i) submitting a liquid comprising a binder, ii) adding an organic filler or inorganic filler to the liquid comprising a binder, iii) obtaining a granulation liquid, and b) preparing a granulation base by i) mixing of an inorganic filler selected form a weight increaser, inorganic salt and an inorganic buffer material, a carrier material, a disintegrant, an inorganic filler, and anticaking enhancer, and obtaining the granulation base, and c) preparing the granulation composition by i) contacting of the granulation liquid with the granulation base and obtaining a granulation mixture comprising liquid, and followed by d) sieving and / or extruding of the wet granulation mixture comprising liquid, and e) subjecting the granulation mixture comprising a liquid to a drying process and obtaining the granulation composition. Further the obtained granulate and a granulate as well as the use and a kit comprising the granulate are claimed.

Description

[0001] Process for the production of a granulate and a granulate, in particular a granulate compound of excipients

[0002] Process for the production of a granulate, comprising the steps of a) preparing a granulation liquid, comprising the steps i) submitting a liquid comprising a binder, ii) adding an organic filler or inorganic filler to the liquid comprising a binder, iii) obtaining a granulation liquid, and b) preparing a granulation base by i) mixing of an inorganic filler selected form a weight increaser, inorganic salt and an inorganic buffer material, a carrier material, a disintegrant, an inorganic filler, and anticaking enhancer, in particular dry mixing, and obtaining the granulation base, and c) preparing the granulation composition by i) contacting, in particular spraying or pouring, of the granulation liquid with the granulation base and obtaining a granulation mixture comprising a liquid, and followed by d) sieving and / or extruding of the wet granulation mixture comprising liquid, and e) subjecting the granulation mixture comprising a liquid to a drying process and obtaining the granulation composition. Further the obtained granulate and a granulate as well as the use and a kit comprising the granulate are claimed.

[0003] There is need for further compounds for the production of MUPS tablets. The compounds can be in the form of pellets or granules, or extrudates with sufficient hardness properties, wherein each pellet, granule or extrudate may be coated for a retardation or sustain release as colon targeting. A matrix particle in each described form can be used as well. A typical MUPS tablet comprises multiple compressed functional particles, here compounds in form of a pellet, granule or extrudate. The particles can be compressed in a mixture with powdery excipients, such as disintegrants, fillers etc. The pellets comprising an API (active pharmaceutical ingredient) are usually coated to determine the location after swallowing of the tablet, the speed and timing of the release of the active ingredient. Typically, the tablet releases in the stomach into the individual pellets by the digestive secretion. A particular advantage of coated pellets, in contrast to coated conventional tablet formulations, is, that there is no immediate release of the entire active ingredient after a possible damage to the coating. Consequently, the risk of toxic effects due to overdose is avoided. Due to the different coating options of the individual pellets and their mixture, it is possible to process functional particles of different release kinetics in one dosage form. Further advantage of MUPS formulation is the shorter time frame, multiple small units can reach the section of action or resorption in gastric intestinal tract. Due to the MUPS formulation is disintegrating after swallowing in the stomach and release in multiple small functional units the passage in every fat stage is faster, compared with a single unit like a tablet.

[0004] WO 2010 / 031866A1 discloses a pellet composition and a process for their production. The pellet formulation comprises aqueous lactose as granulation liquid sprayed on HPMC-particle and lactose. The weight relation of lactose and HPMC is 50 : 50 or 40 : 60. The obtained pellets have a particle size of 10 mm up to 25 mm. The granulate is obtained to form the granulation composition after drying without further treatment. The patent application further discusses the flowability, tamped density and bulk density.

[0005] US 6,770,368 B2 discloses spherical granules consisting of spray dried lactose and granular starch with a ratio of 90 to 10 and 25 to 75. The friability is of less or equal to 80 % according to the mentioned test A in the patent.

[0006] A MUPS tablet comprises multiple pellets of different composition. Due to their good flowability it is difficult to obtain and maintain a homogenic pellet composition during storage, mixing and during compression of the composition into tablets. Therefore, there is a need for pellets, granules or extrudates that can increase the maintenance of homogeneity after blending / mixing, in process storage time frame and during compression or compaction by avoiding segregation. Furthermore, a composition and a process for the production of a granulate comprising pellets are needed that can either stabilise mechanically and / or chemically a homogenic blend after mixing.

[0007] The problems are solved by a process of the current invention and the composition of the invention. Subject of the invention is therefore a process for the production of a granulate, in particular comprising excipients, more preferred placebo granulate, comprising the steps a) preparing a granulation liquid, comprising the steps i) submitting a liquid comprising a binder, ii) adding an organic filler or inorganic filler, preferred is an organic filler, in particular lactose and / or potato starch, to the liquid comprising a binder iii) obtaining a granulation liquid, b) preparing a granulation base comprising the steps i) mixing of an inorganic filler selected form a weight increaser, inorganic salt and an inorganic buffer material, in particular pentacalciumhydroxyd-tris(orthophosphate) or calcium sulfate, a carrier material, a disintegrant, an inorganic filler, selected from metal-oxide and / or half-metal oxide, and anticaking enhancer, in particular dry mixing, and obtaining the granulation base, and optionally c) preparing the granulation composition i) contacting, in particular spraying or pouring, of the granulation liquid with the granulation base and obtaining a granulation mixture comprising liquid, d) sieving and / or extruding of the wet granulation mixture comprising liquid, and optionally e) subjecting the granulation mixture comprising a liquid to a drying process and obtaining the granulation composition.

[0008] The granulation liquid can be an aqueous suspension, dispersion or a solution. The binder of the granulation liquid can comprise maize starch as an excipient. An organic filler can comprise lactose, in particular lactose monohydrate and anhydrous lactose, potato starch or corn starch, an inorganic filler, in particular calcium hydrogen sulphate, as excipients or a mixture comprising at least one or at least two of the aforementioned excipients. A preferred a) granulation liquid can comprise, in particular as excipients, 2 to 15 wt.-% binder, in particular maize starch, and 2 to 15 wt.-% of at least one organic filler, in particular comprising lactose, potato starch, or an inorganic filler, in particular calcium hydrogen sulphate, or a mixture comprising at least one ortwo of the aforementioned excipients, and a liquid, wherein the granulation liquid amounts to 100 wt.-%, and wherein the b) granulation base can comprise, in particular as excipients, 20 to 40 wt.-% inorganic filler selected form a weight increaser, inorganic salt and an inorganic buffer material, preferred pentacalciumhydroxyd-tris(orthophosphate) synonym to pentaCalcium hydroxide triphosphate or calcium sulfate, and 35 to 55 wt.-% carrier material, in particular microcrystalline cellulose, 5 to 20 wt.-% disintegrant, in particular maize starch, and 1 to 7 wt.-% inorganic filler, in particular silicon dioxide, wherein the granulation composition amounts to 100 wt.- %.

[0009] The inorganic salt comprises in particular an inorganic cation and an inorganic anion. A preferred inorganic filler selected from a weight increaser, inorganic salt and buffer material is pentacalciumhydroxyd-tris(orthophosphate) or calcium sulfate, inorganic phosphate buffer and / or carbon dioxide silicate buffer. As carrier material microcrystalline cellulose can be used and as disintegrant or disintegration material maize starch can be used. The inorganic filler can be selected from metal-oxide and / or half-metal oxide such as silicates, quartz, silicon dioxide, colloidal silicon dioxide and / or magnesium oxide. Preferred is Aerosil® 200.

[0010] As carrier material microcrystalline cellulose can be used as well as other cellulose materials such as cellulose derivates whose hydroxyl groups are independently of one another at least partially alkylated, hydroxyalkylated, sulfonated, carboxyalkylated or / and xanthogenated. In particular the carrier material may comprise at least one cellulose derivative that is selected from the group consisting of hypromellose (HPMC), hypromellose phthalate, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, ethyl cellulose (EC), carboxymethyl cellulose (CMC), carboxyethyl cellulose (CEC) or / and sodium or / and calcium salts thereof.

[0011] The granulation composition may further comprise additional excipients that are selected from the group consisting of lubricants, fillers, binders, glidants, flow regulation agents, antistatic agents, solubilizers and humectants.

[0012] In a preferred embodiment the a) ii) inorganic filler is different form the inorganic filler or fillers b) i).

[0013] Furthermore, the process may comprise the step, wherein the granulation liquid is sprayed or poured onto the granulation base, in particular the granulation liquid is sprayed or poured onto the granulation base in a mixing device, in particular in a rotating mixing device comprising a blade, more preferred a shovel, wherein the i) mixing device comprises a mixing tool, chopper, mixing housing and a cap for the housing, wherein the mixing tool has a rotor shaft that is guided through the cap or preferably through the bottom, wherein the mixing tool further has at least one mixing arm extending, in particular perpendicular, from the rotor shaft, wherein the arm has at its outer part a blade, in particular a shovel, in particular wherein the blade, in particular shovel, is directed upwards or ii) the mixing device comprises a mixing housing and a cap for the housing and a mixing tool, wherein the mixing tool has a rotor shaft extending through the bottom of the housing, wherein the mixing tool has at least one mixing arm extending, in particular perpendicular, from the rotor shaft, wherein the arm being a blade, in particular a shovel, in particular wherein the blade is at one of its rotatable long edges directed upwards, in particular the device has at least three arms being a blade, wherein each blade is at one of its rotating long edges directed upwards. In a further alternative the mixing device may comprise a rotating housing with blades or shovels fixed at the inner side of the housing. The housing can rotate in a preferred manner horizontally. A horizontal ordered mixing equipment can be used alternatively.

[0014] The granulation is preferred performed with a sieve insert, that provides at the inner side of the insert a lager cross-section of the opening than the cross-section of the opening at the outer side. The cross-section of the opening at the inner side of the insert is particularly 10 % lager than the crosssection at the outer side, more preferred 15 % larger.

[0015] According to a further object of the invention step d) may comprise the step of wet-sieving granulation of the granulation mixture comprising liquid, wherein the wet-sieving granulation can be performed with a sieve insert comprising a perforated insert, perforated plate, perforated conus, wherein the sieve insert has an inner side and an outer side, wherein the perforation of the outer-side is not identical to the perforation of the inner side. It is preferred that the perforation of the insert comprises a triangular, semi-elliptical or triangular to semi-elliptical perforation, in particular the insert perforation which has a slanted and / or conical opening in the direction of the passage. A sieve insert may be selected from CONIDUR®. Not preferred sieve inserts comprise round perforation with identical inner and outer side of the perforation of the sieve insert.

[0016] In particular the mesh size or hole cross section is from 0.8 to 3mm. Preferred granules are obtainable by sieving the granulation mixture comprising liquid through the sieve insert with a habitus comprising cylindric granules, bar-shaped granules and / or biscuit crumbs shape.

[0017] The rotor speed of the wet-sieving granulation device as well as the feeding speed of the granulation mixture comprising liquid may be adapted to the envisaged particle habitus and the particular sieve insert.

[0018] According to a further aspect of the invention the process may comprise a drying step e) comprising the step of fluidized bed drying or infrared drying, in particular batchwise drying or continuously drying. The drying may also be performed in a cyclone mixing system, for example from the company Huttlin. Preferred is the fluidized bed drying or infrared drying as a focus of the process is to avoid that the particles are abraded into smaller particles or powder. In particular, the drying step is performed in more than one step, in particular the drying is performed in a cascade control, to avoid reducing or changing the particle form and / or size. The granulate of the invention may be compound, in particular in form of a snatchy surfaced pellet, more preferred in form of a biscuit crumb. The production steps of the granule preparation according to the present invention are suitable for easy scaling up, if this product would be implemented for big amounts.

[0019] Subject of the invention is also a granulate, preferred comprising the following excipients: 3 to 15 wt.- % binder, in particular maize starch

[0020] 3 to 15 wt.-% organic filler, in particular comprising lactose or potato starch, or an inorganic filler, in particular calcium hydrogen sulphate, 20 to 70 wt.-% inorganic filler selected form a weight increaser, inorganic salt and an inorganic buffer material, in particular penta-calciumhydroxyd- tris(orthophosphate) or calcium sulfate as weight increaser, and optional 30 to 70 wt.-% carrier material, in particular microcrystalline cellulose, and optional 5 to 25 wt.-% disintegration material, in particular maize starch, and optional 1 to 10 wt.-% inorganic filler selected from metal-oxide and / or half-metal oxide, in particular silicon dioxide, preferred silicon dioxide with a particle size of 10 nm to 100 nm, more preferred silanised silicon dioxide particles, wherein the composition of the granule composition amounts to 100 wt.-%.

[0021] A preferred granulate, more preferably final granulate, can comprise granules with at least two different diameters, in particular with three different diameters. The diameter a) may be from 500 pm to 800 pm, the diameter b) may be from 1000 pm to 1300 pm and optionally the diameter c) may range from 1500 pm to 2000 pm, wherein all diameters are perpendicular to all other diameters.

[0022] The granulate may further comprise granules having a habitus of elliptical granules, bar-shaped granules and / or bicuspid granules. Particularly preferred is a granulate comprising surface modified granules. Wherein it is particularly preferred is the surface of the granules is coated with at least one polymer, in particular with a polymer comprising HO-, N-, NH-, CO- and / or COO-groups, or modified with at least one surfactant or at least one further polymer capable of polycondensation and / or polymerisation. The polymer may comprise olefinic cellulose derivates, methacrylic and / or acrylic derivates. The surface polymer comprising

[0023] HO-, N-, NH-, CO- and / or COO-groups of the granules can bond to other HO-, N-, NH-, CO- and / or COO-groups of polymers on neighbouring granules forming strong hydrogen bridges in a preferred supramolecular network which stabilises the obtained position of the particular granules in a homogeneous granulate composition. Therefore, the homogeneity of a composition can be chemically stabilized by a surface coating of the granules with polymers being able to form hydrogen bonds with polymers being a surface coating on neighbouring granules in a composition.

[0024] After the drying process a dry sieving may be performed for a selection of the particle sizes. A preferred sieve comprises a horizontal rotating or oscillating sieve, in particular a pressure sieve or screen. The surface of the granules having a rough surface remains after the drying process, which can be seen form Fig. 1 . The rough surface of the granules resulting from the particular wet-sieving process. Furthermore, subject of the invention may also be a granulate comprising, in particular the following excipients: 5 to 10 wt.-% binder, in particular maize starch, 5 to 10 wt.-% organic filler, in particular comprising lactose or potato starch or an inorganic filler, in particular calcium hydrogen sulphate, 20 to 50 wt.-% inorganic filler selected from a weight increaser, inorganic salt and an inorganic buffer material, in particular pentacalciumhydroxyd-tris(orthophosphate) or calcium sulfate as weight increaser, and optional 30 to 50 wt.-% carrier material, in particular microcrystalline cellulose, and optional 5 to 20 wt.-% disintegration material, in particular maize starch, and optional 1 to 10 wt.-% inorganic filler selected from metal-oxide and / or half-metal oxide, in particular silicon dioxide, preferred silicon dioxide with a particle size of 10 nm to 100 nm, more preferred silanised silicon dioxide particles, wherein the composition of the granule composition amounts to 100 wt.-%. Suitable commercially available silicon dioxides are available under the tradenames Aerosil 200 and Sipernat FP 244. The particle size can be determined via sieving.

[0025] According to a further aspect of the invention, the use of a granulate obtainable according to the process or granules is claimed, wherein the granules are used as a tabletting excipient compound, in particular as direct tabletting excipient compound, preferably in between other universal application for fast disintegrating and / or oral dispersing dosages, application of waxy and oily substrates and controlled release formulation or matrix formulation, more preferred in pharmaceutical compositions, food compositions, beverage compositions, supplements composition, hygienic compositions, dental cleaning or pool compositions as tabletting compound.

[0026] In addition, a kit comprising the granules obtainable according to process of the invention or granules of the invention in a container is claimed, wherein the container comprises a measuring element enabling dosage of a predefined amount of the granules from the container.

[0027] Embodiments

[0028] Measurement Techniques

[0029] Apparatus:

[0030] Huttlin Mixing-Granulation or Glatt System comprising a mixing device, comprising a mixing housing and a cap for the housing, wherein the mixing tool has a rotor shaft that is guided through the cap or bottom, wherein the mixing tool further has at least one mixing arm extending perpendicular from the rotor shaft, wherein the arm has at its outer part a shovel, wherein shovel is directed upwards. Further a chopper is installed preferably through the wall of the mixing housing.

[0031] Alternatively, mixing device (Dinosa) comprises a mixing housing and a cap for the housing and a mixing tool, wherein the mixing tool has a rotor shaft at the bottom of the housing, wherein the tool has three mixing arms extending perpendicular from the rotor shaft, wherein the arm being a shovel, that is at one of its rotating long edges directed upwards. Further a chopper is installed preferably through the wall of the mixing housing.

[0032] Granules Sample Synthesis

[0033] Granules Synthesis

[0034] Example 1 :

[0035] Preparation of granulation compound

[0036] Composition of granules for fast disintegrating tablet:

[0037] 6.41 wt.-% maize starch

[0038] 5.13 wt.-% filler comprising lactose or potato starch

[0039] 29.61 wt.-% penta-calciumhydroxyd-tris(orthophosphate) or calcium sulfate as weight increaser

[0040] 46.16 wt.-% microcrystalline cellulose as carrier material

[0041] 10.97 wt.-% maize starch as disintegration material,

[0042] 1 .74 wt.-% Aerosil 200

[0043] Granulation liquid:

[0044] A liquid comprising 10 wt.-% maize starch in water was prepared (C* PharmaGel 03406, 10 % aqueous). To this liquid 8.0 wt.-% of a filler comprising lactose or potato starch was added. The resulting granulation liquid comprises 10.0 wt.-% maize starch, 8.0 wt.-% of potato starch or lactose and water ad 100 wt.-% of the composition of the granulation liquid.

[0045] In the case of maize starch a pre-gelatinized version of the starch type can be used.

[0046] Granulation base

[0047] The granulation base contains 29.61 wt.-% pentacalciumhydroxydtris(orthophosphate) or calcium sulfate as weight increaser and 46.16 wt.-% microcrystalline cellulose in parts of Avicel PH 105 and PH 102 as carrier material, 10.97 wt.-% maize starch as disintegration / filler material, and 1 .73 wt.-% Aerosil 200.

[0048] Granulation liquid and granulation base were mixed 1 : 1 by weight.

[0049] Example 2:

[0050] Preparation of granulation compound

[0051] Composition of granules for oral dispersible tablet 6.27 wt.-% maize starch

[0052] 5.01 wt.-% filler comprising lactose or potato starch

[0053] 28.93 wt.-% penta-calciumhydroxyd-tris(orthophosphate) or calcium sulfate as weight increaser

[0054] 45.13 wt.-% microcrystalline cellulose as carrier material

[0055] 10.72 wt.-% maize starch as disintegration material,

[0056] 3.95 wt.-% Aerosil 200

[0057] Granulation liquid:

[0058] A liquid comprising 10 wt.-% maize starch in water was prepared (C* PharmaGel 03406, 10 % aqueous). To this liquid 5.0 wt.-% of a filler comprising lactose or potato starch was added. The resulting granulation liquid comprises 10.0 wt.-% maize starch, 8.0 wt.-% of potato starch or lactose and water ad 100 wt.-% of the composition of the granulation liquid. In the case of maize starch a pre-gelatinized version of the starch type can be used.

[0059] Granulation base

[0060] The granulation base contains 28.93 wt.-% pentacalciumhydroxydtris(orthophosphate) or calcium sulfate as weight increaser and 45.13 wt.-% microcrystalline cellulose of Avicel PH 105 as carrier material, 10.72 wt.-% maize starch as disintegration / filler material, and 3.95 wt.-% Aerosil 200

[0061] Granulation liquid and granulation base are mixed 1 : 1 by weight.

[0062] Comparative Example 1 :

[0063] Preparation of granulation compound

[0064] Composition of granules for matrix tablet formulation direct compressible

[0065] 81 .63 wt.-% Composition of granules for fast disintegrating tablet: 6.12 wt.-% Glidant talc

[0066] 12.25 wt.-% Methacrylic Ester Copolymer or Ammonioalkyl Methacrylate Copolymer dry polymer.

[0067] The polymer application can be increased / decreased depending on the solubility of the API and / or the retardation time frame.

[0068] Example 3:

[0069] 81 .63 wt.-% final Granules of example 1 with a particle size 500 pm is taken for applying the functional polymer in fluid bed coating equipment.

[0070] Coating liquid

[0071] 12.25 wt.-% Methacrylic Ester Copolymer dry polymer (EUDRAGIT® NM 30 D) 6.125 wt.-% Talc

[0072] Water add to 20% solid content of the spraying suspension.

[0073] Comparative Examples

[0074] Formulation trials for comparison of manufacturing and properties of the final tablet.

[0075] Market competitor products for easy to use or direct formulation by blending with an API were tested in comparison to granules of Examples 1 and 2.

[0076] The ready to use products were blended with 50% caffeine as model substance. Caffeine was chosen because it is a micronized powder with a high solubility in acid and buffers to indicate one of the worst cases.

[0077] The competitor products for comparison trials were:

[0078] • Firmapress of the company LFA

[0079] • Combilac of the company Meggle (patented in EP1175899 B1)

[0080] • Prosolv of the company JRS

[0081] All examples and comparative examples were compressed on a single punch tablet compression equipment (Korsch XP1)

[0082] The compression force differs from product to product in between 12-25 KN to achieve a proper hardness.

[0083] The compression velocity was adjusted for 10.000 tablets / h

[0084] The punch size is 10 mm

[0085] The resulting tablet height with the different products differs in comparison of the products depending on the product supplier and necessary compression force 0.2-0.5 mm

[0086] Target weight was same.

[0087] Analytical equipment:

[0088] Texture Analyzer. This Equipment was chosen in comparison to a disintegration tester. The Texture Analyzer provides more reliable data to compare fast disintegrating tablets.

[0089] The results are documented with a decomposition diagram and video documentation for visual comparison of the test candidates.

[0090] Test results:

[0091] 1) Firmapress of the company LFA

[0092] It is relatively good compressible, but the tablet doesn’t disintegrate for long time. So, it is not meant for fast disintegrating without adding a fast-disintegrating excipient.

[0093] 2) Combilac of the company Meggle (patented in EP1175899 B1) Disintegrates as quickly as Example 1 granules in a 60ml warm water but has a strong tendency to attach to the punches and would therefore be unsuitable for production without modification. So, no "ready to use" tablet granules. Furthermore, this mixture flows poorly in the tablet press and thus causes weight deviations. The tablets accumulate in the tablet ramp of the tablet press due to poor slipping properties.

[0094] 3) Prosolv of the company JRS

[0095] Flows very poorly in the tablet press and the tablet hardness is not sufficient for acceptable further processing, i.e., possibly coating, packaging, etc. The pressed tablets disintegrate very quickly, would be usable for an ODT.

[0096] 4) Granules of Example 1

[0097] The Example 1 granule provides a fast-disintegrating tablet. The flowability in tablet press is steady. The granule is easy compressible with low compression forces.

[0098] The example 1 granules can be used ready out of the box at future customers.

[0099] 5) Granules of Example 2

[0100] The Example 2 granule provides a fast-disintegrating tablet in between 10 sec., which is suitable for ODT formulation. The flowability in tablet press is steady by adding 0.5% Mg-stearate. The granule is easy compressible with low compression forces.

[0101] 6) Granules of Example 3

[0102] Production equipment

[0103] The product was compressed on a single punch tablet compression equipment (Korsch XP1)

[0104] The compression velocity was adjusted for 10.000 tablets / h

[0105] The punch size is 10mm

[0106] Analytical equipment:

[0107] Dissolution tester

[0108] Trial description:

[0109] The Example 3 granule is a further evolution of Example 1 granules by an additional process step whereon the granules are processed with a sustained release polymer for achieving a matrix granule which can be used for matrix tablets only by adding an arbitrary API. The granule contains 15% functional polymer on granule weight. In the test for compressing a tablet there was used Caffeine as model substance with 50% caffeine content in the final dosage form. This led to 7.5% polymer content in the final dosage form.

[0110] This tablet granule / caffeine blend is easy to compress with low compression forces. In this way of formulating a matrix tablet there isn’t needed to tread the API with a functional polymer first, potentially with the tablet mass, before it is formulated in a matrix system. This system conserves possible sensitive API against water or organic liquid impacts.

[0111] Dissolution result can be seen in Figure 2.

[0112] 7) Formulation of Granules of Example 1 for AvailOm tablet

[0113] Production equipment

[0114] The product was compressed on a single punch tablet compression equipment (Korsch XP1) The compression velocity was adjusted for 10.000 tablets / h

[0115] The punch size is 10mm

[0116] Test aim

[0117] The need of compressing solidified Omega 3 acids is to avoid oily surfaces and achieving easy compression processes. Due to the product seams to re-liquifying impacting compression forces on tablet presses there is needed to use tablet mass which is able to adsorb the liquified part without effecting the active content significant in the releasing.

[0118] Trial description:

[0119] The granules of Example 1 are blended with AvailOM in 1 :1 weight ratio. This is compressed on a single punch tablet press.

[0120] The tablets don’t show significant oily surfaces. The blend is easy to compress with low compression force.

[0121] Analytical results:

[0122] Tablets disintegrate in-between 30 minutes in 1 N HCI.

[0123] Analyses of content

[0124] Fresh tablets storage time 1 month under room conditions.

[0125] 6 samples tested.

[0126] Content EPA: 11 .98% (12,07% / 12.15% / 11 .92% 1 1 1 .85% 1 11 .81 % / 12.08%)

[0127] Content DHA: 9.17% (9.24% / 9.30% / 9.13% / 9.06% / 9.04% / 9.26%)

[0128] Description of Figures

[0129] Figure 1 : Picture of granules after drying

[0130] Figure 2: Dissolution results of granules of Example 3

Claims

Claims1 . Process for the production of a granulate, comprising the steps a) preparing a granulation liquid, comprising the steps i) submitting a liquid comprising a binder, ii) adding an organic filler or inorganic filler or a mixture thereof to the liquid comprising a binder iii) obtaining a granulation liquid, b) preparing a granulation base i) mixing of- an inorganic filler selected form a weight increaser, inorganic salt and an inorganic buffer material,- a carrier material,- a disintegrant and- an inorganic filler selected from metal-oxide and / or half-metal oxide and obtaining the granulation base, c) preparing the granulation composition i) contacting the granulation liquid with the granulation base and obtaining a granulation mixture comprising liquid, d) sieving of the granulation mixture comprising liquid, and e) subjecting the granulation mixture comprising liquid to a drying process and obtaining the granulation composition.

2. Process according to claim 1 , wherein the inorganic filler selected form a weight increaser, inorganic salt and an inorganic buffer material is pentacalciumhydroxydtris(orthophosphate) or calcium sulfate.

3. Process according to claim 1 or 2, wherein the binder of the granulation liquid comprises maize starch.

4. Process according to any of claims 1 to 3, wherein the organic filler comprises lactose, in particular lactose anhydrite, lactose hydrate, potato starch, an inorganic filler, in particular calcium hydrogen sulphate, or a mixture comprising at least one or at least two of the aforementioned excipients.

5. Process according to any of claims 1 to 4, wherein the a) granulation liquid comprises2 to 15 wt.-% binder, in particular maize starch, and2 to 15 wt.-% of at least one organic filler, in particular comprising lactose, potato starch or an inorganic filler, in particular calcium hydrogen sulphate or a mixture comprising at least one or two of the aforementioned excipients, and a liquid, wherein the granulation liquid amounts to 100 wt.-%, and wherein the b) granulation base comprising20 to 40 wt.-% inorganic filler selected form a weight increaser, inorganic salt and an inorganic buffer material, in particular pentacalciumhydroxydtris(orthophosphate) or calcium sulfate, and 35 to 55 wt.-% carrier material, in particular microcrystalline cellulose,5 to 20 wt.-% disintegrant, in particular maize starch,1 to 7 wt.-% inorganic filler selected from metal-oxide and / or half-metal oxide, in particular silicon dioxide, wherein the granulation composition amounts to 100 wt.-%.

6. Process according to any of claims 1 to 5, wherein the granulation liquid is sprayed or poured onto the granulation base, in particular the granulation liquid is sprayed onto the granulation base in a mixing device, wherein the i) mixing device comprises a mixing tool, chopper, mixing housing and a cap for the housing, wherein the mixing tool has a rotor shaft that is guided through the cap or bottom, wherein the mixing tool further has at least one mixing arm extending, in particular perpendicular, from the rotor shaft, wherein the arm has at its outer part a blade, in particular a shovel, in particular wherein the blade, in particular shovel, is directed upwards or ii) mixing device comprises a mixing housing and a cap for the housing and a mixing tool, wherein the mixing tool has a rotor shaft extending through the bottom of the housing, wherein the mixing tool has at least one mixing arm extending, in particular perpendicular, from the rotor shaft, wherein the arm being a blade, in particular a shovel, in particular wherein the blade is at one of its rotatable long edges directed upwards, In particular the device has at least three arms being a blade, wherein each blade is at one of its rotating long edges directed upwards.

7. Process according to any of claims 1 to 6, wherein step d) comprises the step of wet-sieving granulation of the granulation mixture comprising liquid, wherein the wet- sieving granulation is performed with a sieve insert comprising a perforated insert, perforated plate, perforated conus, wherein the sieve insert has an inner side and an outer side, wherein the perforation of the outer-side is not identical to the perforation of the inner side, in particular the perforation of the insert comprises a triangular, semi-elliptical or triangular to semi-elliptical perforation, in particular which has a slanted and / or conical opening in the direction of the passage.

8. Process according to any of claims 1 to 7, wherein step e) the drying process comprises the step of fluidized bed drying or infrared drying, in particular batchwise drying or continuously drying, more preferred drying in a cascade manner.

9. Granulate, in particular produced according to any of the claims 1 to 8, comprising3 to 15 wt.-% binder, in particular maize starch3 to 15 wt.-% organic filler, in particular comprising lactose or potato starch or an inorganic filler, in particular calcium hydrogen sulphate, or a mixture thereof,20 to 70 wt.-% inorganic filler selected form a weight increaser, inorganic salt and an inorganic buffer material, in particular pentacalciumhydroxydtris(orthophosphate) or calcium sulfate as weight increaser, and optional30 to 70 wt.-% carrier material, in particular microcrystalline cellulose, and optional5 to 25 wt.-% disintegration material, in particular maize starch, and optional1 to 10 wt.-% inorganic filler selected from metal-oxide and / or half-metal oxide, in particular silicon dioxide, preferred silicon dioxide with a particle size of 10 nm to 100 nm, more preferred silanised silicon dioxide particles, wherein the composition of the granule composition amounts to 100 wt.-%.

10. Granulate according to claim 9, wherein the granulate comprising granules with at least two different diameters, in particular with three different diameters.

11. Granulate according to claim 9 or 10, wherein the granulate comprising granules a habitus of cylindric granules, bar-shaped granules and / or biscuit crumbs shape.

12. Granulate according to any of claims 9 to 11 , wherein the granulate comprises surface modified granules, in particular the surface of the granules is coated with at least one polymer, in particular with a polymer comprising HO-, N-, NH-, CO- and / or COO-groups, or modified with at least one surfactant or at least one further polymer capable of polycondensation and / or polymerisation.

13. Granulate according to any of claims 9 to 11 , wherein the granulate comprising5 to 10 wt.-% binder, in particular maize starch5 to 10 wt.-% organic filler, in particular comprising lactose or potato starch or an inorganic filler, in particular calcium hydrogen sulphate or a mixture thereof,20 to 50 wt.-% inorganic filler selected from a weight increaser, inorganic salt and an inorganic buffer material, in particular pentacalciumhydroxydtris(orthophosphate) or calcium sulfate as weight increaser, and optional30 to 50 wt.-% carrier material, in particular microcrystalline cellulose, and optional5 to 20 wt.-% disintegration material, in particular maize starch, and optional1 to 10 wt.-% inorganic filler selected from metal-oxide and / or half-metal oxide, in particular silicon dioxide, preferred silicon dioxide with a particle size of 10 nm to 100 nm, more preferred silanised silicon dioxide particles, wherein the composition of the granule composition amounts to 100 wt.-%.

14. Use of the granulate obtainable according to any of claims 1 to 8 or granules according to any of claims 9 to 13, as a tabletting excipient compound, in particular as a direct tabletting excipient compound, more preferred in pharmaceutical compositions, food compositions, beverage compositions, supplements composition, hygienic compositions, dental cleaning or pool compositions as tabletting compound.

15. Kit comprising the granules obtainable according to one of claims 1 to 8 or granules according to one of claims 9 to 13 in a container with a measuring element enabling dosage of a predefined amount of the granules from the container.

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