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  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Definitions

• the present invention relates to pharmaceutical compositions comprising a sphingosine-1 phosphate receptor agonist.
• Sphingosine-1 phosphate (hereinafter “S1P”) is a natural serum lipid.
• S1P receptors namely S1P1 to S1P8.
• S1P receptor agonists have accelerating lymphocyte homing properties.
• S1P receptor agonists are immunomodulating compounds which elicit a lymphopenia resulting from a re-distribution, preferably reversible, of lymphocytes from circulation to secondary lymphatic tissue, evoking a generalized immunosuppression.
• Naive cells are sequestered, CD4 and CD8 T-cells and B-cells from the blood are stimulated to migrate into lymph nodes (LN) and Peyer's patches (PP), and thus infiltration of cells into transplanted organs is inhibited.
• LN lymph nodes
• PP Peyer's patches
• S1P receptor agonists show structural similarities, which result in related problems in providing a suitable formulation.
• an S1P receptor agonist containing formulation which is well-adapted for oral administration in a solid form, e.g. as a tablet or capsule.
• the present invention provides a solid pharmaceutical composition suitable for oral administration, comprising a S1P receptor agonist and a sugar alcohol.
• compositions comprising a sugar alcohol provide formulations which are particularly well suited to the oral administration of S1P receptor agonists.
• the compositions provide a convenient means of systemic administration of S1P receptor agonists, do not suffer from the disadvantages of liquid formulations for injection or oral use, and have good physicochemical and storage properties.
• the compositions of the present invention may show a high level of uniformity in the distribution of the S1P receptor agonist throughout the composition, as well as high stability.
• the compositions of the invention may be manufactured on high speed automated equipment, and thus do not require hand encapsulation.
• S1P receptor agonists are typically sphingosine analogues, such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives.
• S1P receptor agonists are, for example:
• a S1P receptor agonist for use in a combination of the invention may also be a selective S1P1 receptor, e.g. a compound which possesses a selectivity for the S1P1 receptor over the S1P3 receptor of at least 20 fold, e.g. 100, 500, 1000 or 2000 fold, as measured by the ratio of EC50 for the S1P1 receptor to the EC50 for the S1P3 receptor as evaluated in a 35S-GTP ⁇ S binding assay, said compound having an EC50 for binding to the S1P1 receptor of 100 nM or less as evaluated by the 35S-GTP ⁇ S binding assay.
• Representative S1P1 receptor agonists are e.g. the compounds listed in WO 03/061567, the contents of which being incorporated herein by reference, for instance a compound of formula
• Acyl may be a residue R y —CO— wherein R y is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or phenyl-C 1-4 alkyl. Unless otherwise stated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.
• the carbon chain as R 1 is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy.
• the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted.
• the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.
• Preferred compounds of formula I are those wherein R 1 is C 13-20 alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R 1 is phenylalkyl substituted by C 6-14 -alkyl chain optionally substituted by halogen and the alkyl moiety is a C 1-6 alkyl optionally substituted by hydroxy. More preferably, R 1 is phenyl-C 1-6 alkyl substituted on the phenyl by a straight or branched, preferably straight, C 6-14 alkyl chain. The C 6-14 alkyl chain may be in ortho, meta or para, preferably in para.
• each of R 2 to R 5 is H.
• a preferred compound of formula I is 2-amino-2-tetradecyl-1,3propanediol.
• a particularly preferred S1P receptor agonist of formula I is FTY720, i.e. 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form (referred to hereinafter as Compound A), e.g. the hydrochloride, as shown:
• a preferred compound of formula II is the one wherein each of R′ 2 to R′ 5 is H and m is 4, i.e. 2-amino-2- ⁇ 2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl ⁇ propane-1,3-diol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound B), e.g the hydrochloride.
• a preferred compound of formula III is the one wherein W is CH 3 , each of R′′ 1 to R′′ 3 is H, Z 2 is ethylene, X is heptyloxy and Y is H, i.e. 2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanol, in free form or in pharmaceutically acceptable salt form (referred to hereinafter as Compound C), e.g. the hydrochloride.
• Compound C e.g. the hydrochloride.
• the R-enantiomer is particularly preferred.
• a preferred compound of formula IVa is the FTY720-phosphate (R 2a , is H, R 3a is OH, X a is O, R 1a and R 1b are OH).
• a preferred compound of formula IVb is the Compound C-phosphate (R 2a is H, R 3b is OH, X a is O, R 1a and R 1b are OH, Y a is O and R 4a is heptyl),
• a preferred compound of formula V is Compound B-phosphate.
• a preferred compound of formula V is phosphoric acid mono-[(R)-2-amino-2-methyl-4-(4-pentyloxy-phenyl)-butyl]ester.
• a preferred compound of formula VIII is (2R)-2-amino-4-[3-(4-cyclohexyloxybutyl) benzo[b]thien-6-yl]-2-methylbutan-1-ol.
• Examples of pharmaceutically acceptable salts of the compounds of formulae I to XIII include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, or, when appropriate, salts with metals, such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine.
• the compounds and salts of the present invention encompass hydrate and solvate forms.
• Binding to S1P receptors can be determined according to the following assays.
• SIP receptors and G i proteins are cloned, and equal amounts of 4 cDNAs for the EDG receptor, G i - ⁇ , G i - ⁇ and G i - ⁇ are mixed and used to transfect monolayers of HEK293 cells using the calcium phosphate precipitate method (M. Wigler et al., Cell. 1977;11;223 and D S. Im et al., Mol. Pharmacol. 2000;57;753). Briefly, a DNA mixture containing 25 ⁇ g of DNA and 0.25 M CaCl 2 is added to HEPES-buffered 2 mM Na 2 HPO 4 .
• Subconfluent monolayers of HEK293 cells are poisoned with 25 mM chloroquine, and the DNA precipitate is then applied to the cells. After 4 h, the monolayers are washed with phosphate-buffered saline and refed media (90% 1:1 Dulbecco's modified essential media (DMEM):F-12+10% fetal bovine serum). The cells are harvested 48-72 h after addition of the DNA by scraping in HME buffer (in mM: 20 HEPES, 5 MgCl 2 , 1 EDTA, pH 7.4) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer.
• HME buffer in mM: 20 HEPES, 5 MgCl 2 , 1 EDTA, pH 7.4
• GTP ⁇ S binding experiments are performed as described by D S. Im et al., Mol. Pharmacol. 2000; 57:753.
• Ligand-mediated GTP ⁇ S binding to G-proteins is measured in GTP binding buffer (in mM: 50 HEPES, 100 NaCl, 10 MgCl 2 , pH 7.5) using 25 ⁇ g of a membrane preparation from transiently transfected HEK293 cells.
• Ligand is added to membranes in the presence of 10 ⁇ M GDP and 0.1 nM [ 35 S]GTP ⁇ S (1200 Ci/mmol) and incubated at 30° C. for 30 min.
• Bound GTP ⁇ S is separated from unbound using the Brandel harvester (Gaithersburg, Md.) and counted with a liquid scintillation counter.
• composition of the invention preferably contains 0.01 to 20% by weight of S1P receptor agonists, more preferably 0.1 to 10%, e.g. 0.5 to 5% by weight, based on the total weight of the composition.
• the sugar alcohol may act as a diluent, carrier, filler or bulking agent, and may suitably be mannitol, maltitol, inositol, xylitol or lactitol, preferably a substantially non-hygroscopic sugar alcohol, e.g. mannitol (D-mannitol).
• a single sugar alcohol may be used, or a mixture of two or more sugar alcohols, e.g a mixture of mannitol and xylitol, e.g. in a ratio of 1:1 to 4:1.
• the sugar alcohol is prepared from a spray-dried composition, e.g. mannitol composition, having a high specific surface area.
• a spray-dried composition e.g. mannitol composition
• the use of this type of mannitol composition may assist in promoting uniform distribution of the S1P receptor agonist throughout the mannitol in the compositon.
• a higher surface area may be achieved by providing a sugar alcohol, e.g. mannitol, preparation consisting of particles having a smaller mean size and/or a rougher surface on each particle.
• the use of a spray-dried sugar alcohol, e.g. mannitol, e.g. with a mean particle size of 300 ⁇ m or less, has also been found to improve compressibility and hardness of tablets formed from the composition.
• the single point surface area of the sugar alcohol preparation is 1 to 7 m 2 /g, e.g. 2 to 6 m 2 /g or 3 to 5 m 2 /g.
• the mannitol preparation may suitably have a mean particle size of 100 to 300 ⁇ m, e.g. 150 to 250 ⁇ m and a bulk density of 0.4 to 0.6 g/mL, e.g. 0.45 to 0.55 g/mL.
• a suitable high surface area mannitol is Parteck M200, available commercially from E. Merck.
• the composition preferably contains 75 to 99.99% by weight of the sugar alcohol, more preferably 85 to 99.9%, e.g 90 to 99.5% by weight, based on the total weight of the composition.
• the composition preferably further comprises a lubricant.
• Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oil such as hydrogenated castor oil (e.g. Cutina® or Lubriwax® 101), mineral oil, sodium lauryl sulfate, magnesium oxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer, or a mixture of any of the above.
• the lubricant comprises magnesium stearate, hydrogenated castor oil or mineral oil. Colloidal silicon dioxide and polyethylene glycol are less preferred as the lubricant.
• the composition preferably contains 0.01 to 5% by weight of the lubricant, more preferably 1 to 3% by weight, e.g. about 2% by weight, based on the total weight of the composition.
• the composition may comprise one or more further excipients such as carriers, binders or diluents.
• the composition may comprise microcrystalline cellulose (e.g. Avicel®), methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch (e.g. corn starch) or dicalcium phosphate, preferably in an amount of from 0.1 to 90% by weight, e.g. 1 to 30% by weight, based on the total weight of the composition.
• a binder e.g. microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose is used, it is preferably included in an amount of 1 to 8%, e.g.
• a binder increases the granule strength of the formulation, which is particularly important for fine granulations.
• Microcrystalline cellulose and methylcellulose are particularly preferred where a high tablet hardness and/or longer disintegration time is required. Hydroxypropyl cellulose is preferred where faster distintegration is required.
• xylitol may also be added as an additional binder, for example in addition to microcrystalline cellulose, e.g. in an amount up to 20% by weight of the sugar alcohol, e.g. xylitol.
• the composition further comprises a stabiliser, preferably glycine HCl or sodium bicarbonate.
• the stabiliser may be present in an amount of e.g. 0.1 to 30%, preferably 1 to 20% by weight.
• compositions may be in the form of a powder, granule or pellets or a unit dosage form, for example as a tablet or capsule.
• compositions of the present invention are well-adapted for encapsulation into an orally administrable capsule shell, particularly a hard gelatin shell.
• compositions may be compacted into tablets.
• the tablets may optionally be coated, for instance with talc or a polysaccharide (e.g. cellulose) or hydroxypropylmethylcellulose coating.
• each unit dosage will suitably contain 0.5 to 10 mg of the S1P receptor agonist.
• compositions of the invention may show good stability characteristics as indicated by standard stability trials, for example having a shelf life stability of up to one, two or three years, and even longer. Stability characteristics may be determined, e.g. by measuring decomposition products by HPLC analysis after storage for particular times, at particular temperatures, e.g. 20°, 400 or 60° C.
• compositions of the present invention may be produced by standard processes, for instance by conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. Procedures which may be used are known in the art, e.g. those described in L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al, Pharmazeutician Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutica fürtechnik, 4th Ed. (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later editions.
• the present invention relates to a process for producing a pharmaceutical composition, comprising:
• the S1P receptor agonist e.g. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride
• the mixing step (a) may suitably comprise blending the S1P receptor agonist and the sugar alcohol, e.g. mannitol in any suitable blender or mixer for e.g. 100 to 400 revolutions.
• the process may be carried out by dry mixing the components.
• the milling step (b) may suitably comprise passing the mixture obtained in (a) through a screen, which preferably has a mesh size of 400 to 500 ⁇ m.
• Process step (a) may comprise the step of mixing the total amount of S1P receptor agonist at first with a low amount of sugar alcohol, e.g. from 5 to 25% by weight of the total weight of sugar alcohol, in order to form a pre-mix. Subsequently the remaining amount of sugar alcohol is added to the pre-mix.
• Step (a) may also comprise the step of adding a binder solution, e.g. methylcellulose and/or xylitol, e.g. an aqueous solution, to the mixture. Alternatively the binder is added to the mix dry and water is added in the granulation step.
• a binder solution e.g. methylcellulose and/or xylitol, e.g. an aqueous solution
• the milled mixture obtained in (b) may optionally be blended once more before mixing with the lubricant.
• the lubricant e.g. magnesium stearate
• the S1P receptor agonist is preferably first dry-mixed with the desired sugar alcohol, e.g. mannitol, and the obtained sugar alcohol/S1P receptor agonist mixture is then dry-mixed with a binder such as hydroxypropyl cellulose or hydroxypropylmethyl cellulose. Water is then added and the mixture granulated, e.g. using an automated granulator. The granulation is then dried and milled.
• a binder such as hydroxypropyl cellulose or hydroxypropylmethyl cellulose.
• an additional amount of binder may be added in step (c) to the mixture obtained in (b).
• the process may comprise a further step of tabletting or encapsulating the mixture obtained in (c), e.g. into a hard gelatin capsule using an automated encapsulation device.
• the capsules may be coloured or marked so as to impart an individual appearance and to make them instantly recognizable.
• the use of dyes can serve to enhance the appearance as well as to identify the capsules.
• Dyes suitable for use in pharmacy typically include carotinoids, iron oxides, and chlorophyll.
• the capsules of the invention are marked using a code.
• compositions of the present invention are useful, either alone or in combination with other active agents, for the treatment and prevention of conditions e.g. as disclosed in U.S. Pat. No. 5,604,229, WO 97/24112, WO 01/01978, U.S. Pat. No. 6,004,565, U.S. Pat. No. 6,274,629 and JP-14316985, the contents of which are incorporated herein by reference.
• compositions are useful for:
• organ or tissue transplant rejection for example for the treatment of the recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants, and the prevention of graft-versus-host disease, such as sometimes occurs following bone marrow transplantation; particularly in the treatment of acute or chronic allo- and xenograft rejection or in the transplantation of insulin producing cells, e.g. pancreatic islet cells;
• autoimmune disease e.g. multiple sclerosis, arthritis (for example rheumatoid arthritis), inflammatory bowel disease, hepatitis, etc.;
• the present invention provides:
• composition as defined above for use in treating or preventing a disease or condition as defined above.
• a method of treating a subject in need of immunomodulation comprising administering to the subject an effective amount of a composition as defined above.
• a method of treating or preventing a disease or condition as defined above comprising administering to the subject a composition as defined above.
• Micronized Compound A e.g. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride salt (FTY720), is screened and 116.7 g of the screened compound is mixed with 9683.3 g mannitol (Parteck M200 from E. Merck). The mixture is then milled in a Frewitt MGI device (Key International Inc. USA) using a 30 mesh screen. Magnesium stearate is screened using a 20 mesh screen and 200 g of the screened compound blended with the FTY720/mannitol mixture to produce a product composition.
• FTY720 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, hydrochloride salt
• the product composition is then compacted on a tablet press using a 7 mm die to form 120 mg tablets, each containing: Compound A, e.g. FTY720* 1.4 mg Mannitol M200 116.2 mg Magnesium stearate 2.4 mg Total 120 mg *1 mg of Compound A in free form is equivalent to 1.12 mg of FTY720.
• Compound A e.g. FTY720* 1.4 mg Mannitol M200 116.2 mg
• Total 120 mg *1 mg of Compound A in free form is equivalent to 1.12 mg of FTY720.
• example 2 the process of example 1 is repeated except that the magnesium stearate is replaced by Cutina® (hydrogenated castor oil).
• Cutina® hydrogenated castor oil
• Compound A e.g. FTY720, and mannitol (Parteck M200 from E. Merck) are each screened separately using an 18 mesh screen.
• 1.9 g screened FTY720 is mixed with 40 g screened mannitol for 120 revolutions in a blender at 32 rpm. The FTY720/mannitol mixture is then screened through a 35 mesh screen.
• the screened FTY720/mannitol mixture is added to a granulator along with a further 340.1 g mannitol and 12 g hydroxypropylcellulose.
• the mixture is mixed for 3 minutes. Water is then added at a rate of 100 ml/minute and the mixture granulated for 2 minutes. The granulation is transferred into a tray dryer and dried at 50° C. for 150 minutes.
• the mixture is then milled in a Frewitt MGI device using a 35 mesh screen.
• Magnesium stearate is screened and 6 g of the screened compound is blended for 90 revolutions at 32 rpm with the FTY720/mannitol mixture to produce a product composition showing a substantially uniform distribution of the S1P receptor agonist throughout the mannitol in the blend.
• each capsule contains: FTY720* 0.56 mg Mannitol M200 114.04 mg Hydroxypropylcellulose 3.6 mg Magnesium stearate 1.8 mg Total 120 mg
• example 3 the process of example 3 is repeated except that the magnesium stearate is replaced by Cutina® (hydrogenated castor oil).
• Cutina® hydrogenated castor oil
• Micronized Compound A e.g. FTY720
• FTY720 is screened using a 400 ⁇ m (40 mesh) screen.
• 58.35 g of the screened compound is mixed with 4841.65 g mannitol (Parteck M200 from E. Merck) in a 25 L Bohle bin blender for 240 blending revolutions.
• the mixture is then milled in a Frewitt MGI device using a 400 ⁇ m mesh screen, and the milled mixture is blended once more.
• Magnesium stearate is screened and 100 g of the screened compound is blended with the FTY720/mannitol mixture to produce a product composition showing a substantially uniform distribution of the S1P receptor agonist throughout the mannitol in the blend.
• the product composition is then filled into size 3 hard gelatin shells on an Hoflinger & Karg 400 encapsulation device. 120 mg of the product composition is added to each capsule. Therefore each capsule contains: FTY720* 1.4 mg Mannitol M200 116.2 mg Magnesium stearate 2.4 mg Total 120 mg
• capsules are manufactured using the components and in the amounts as described in Example 6a, but the FTY720 is first mixed with 14 mg mannitol (before screening). This mixture is then screened as described above. The screened mixture is then blended with the remaining mannitol and the magnesium stearate is added, followed by additional blending and filling into capsules.
• capsules are prepared as described in example 6, except that each capsule contains each component in the following amounts:
• Example 7 Example 8 FTY720* 2.8 mg 5.6 mg Mannitol M200 114.8 mg 112 mg Magnesium stearate 2.4 mg 2.4 mg Total 120 mg 120 mg
• capsules are prepared as described in examples 6 to 8, except that the magnesium stearate is replaced in each case by Cutina® (hydrogenated castor oil).
• Cutina® hydrogenated castor oil
• capsules or tablets are prepared as described in examples 1 to 11, except that FTY720 is replaced in each case by 2-amino-2- ⁇ 2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl ⁇ propane-1,3-diol hydrochloride.
• Capsules containing the following ingredients are prepared, by weighing each component and mixing in a mortar, then filling into capsules:
• Example 23 Example 24 FTY720 5 mg 1 mg D-mannitol 83.7 mg 117 mg Corn starch 24 mg — Avicel ® PH101 12 mg — Hydroxypropylcellulose 0.3 mg 7 mg Talc 3 mg 3 mg Lubri wax ® 101 2 mg 2 mg Total 130 mg 130 mg
• Example 25 Example 26
• Example 27 FTY720 5 g 10 g 100 g D-mannitol 991 g 986 g 897 g Methylcellulose SM-25 4 g 4 g 3 g Total 1000 g 1000 g 1000 g
• the FTY720 and a proportion of the D-mannitol equal to twice the weight of the FTY720 are mixed in a Microspeed Mixer MS-5 type (Palmer, USA) for 2 minutes at 1200 rpm. The remaining D-mannitol is added to the mixture and mixed for another 2 minutes.
• 80 or 60 milliliters of 5% methylcellulose SM-25 solution is supplied from a hopper and granulated under the same conditions.
• the mixture is extruded through a screen with 0.4 mm apertures using an extruder RG-5 type.
• the extruded material is dried at 65° C. by a fluidized-bed granulator STREA I Type (Patheon, Canada) and then sieved through a 24 mesh sieve. Fine particles which pass through a 60 mesh sieve are removed.
• the obtained fine granules are filled Into capsules by a Zuma capsule-filling machine (100 mg per capsule).
• Tablets containing the following ingredients are produced: Example Example Example Example 28 29 30 31 FTY720 1 1 1 1 D-mannitol 62.3 62.3 62.0 62.0 Xylitol* 26.7(5.4) 26.7(5.4) 26.6 26.6 Methylcellulose — — 0.4 0.4 Microcrystalline 24.0 — 24.0 — cellulose Low-substituted — 24.0 — 24.0 Hydroxypropylcellulose Hydrogenated oil 6.0 6.0 6.0 6.0 Total 120.0 120.0 120.0 120.0 *The amount of xylitol indicated in brackets was used as a binder.
• FTY720, D-mannitol and xylitol are placed in a fluid-bed granulator (MP-01 model, Powrex), mixed for five minutes, and granulated under spray of binder solution, followed by drying till the exhaust temperature reaches 40° C.
• the granulation conditions are as shown below.
• Dried powder is passed through a 24-mesh sieve, added to the specified amount of filler and lubricant, and mixed in a mixer (Tubular Mixer, WAB) for three minutes to make the powder for compression.
• a mixer Trobular Mixer, WAB
• the resulting powder is compressed by a tabletting machine (Cleanpress correct 12 HUK, Kikushui Seisakusho) with a punch of 7 mm I.d. ⁇ 7.5 mm R at a compression force of 9800 N.
• a tabletting machine (Cleanpress correct 12 HUK, Kikushui Seisakusho) with a punch of 7 mm I.d. ⁇ 7.5 mm R at a compression force of 9800 N.
• Granulation Conditions Item Setting Charge-in amount 1170 g Volume of intake-air 50 m 3 /min Temperature of intake-air 75° C. Flow rate of spray solution 15 mL/min Spray air pressure 15 N/cm 2 Spray air volume 30 L/min Volume of binder solution 351 mL

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