Use of co-processed excipients in the continuous manufacturing of solid dosage forms.

Abstract

The present invention relates to the use of co-processed excipients in the continuous manufacture of solid dosage forms.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to the use of co-processed excipients in the continuous manufacture of solid dosage forms. [Background technology]

[0002] Background of the Invention Continuous pharmaceutical manufacturing offers potential flexibility, quality, and economic advantages over batch operations (Sau L. Lee et al., J. Pharm. Innov. 2015, 10, 191-199). However, the number of feeders on equipment used for continuous manufacturing is typically limited to four to six feeders. As a result, continuous manufacturing of solid pharmaceutical dosage forms such as tablets is limited to compositions consisting of only the API and three to five excipients unless a preblend of multiple excipients is used. However, the use of preblends is economically inefficient and thus partially negates the benefits of continuous manufacturing. Therefore, there is a need to simplify pharmaceutical compositions to contain as few excipients as possible. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Sau L.Lee et al.,J.Pharm.Innov.2015,10,191-199 Summary of the Invention

[0004] The inventors of the present invention have discovered that an effective way to simplify the composition is to introduce a co-processed excipient that combines the functionality of multiple single excipients. Thus, in one aspect, the present invention relates to the use of a co-processed excipient in the continuous manufacture of solid dosage forms. [Brief explanation of the drawings]

[0005] [Figure 1]FIG. 1 shows a flowchart of the continuous mini-batch direct compression method according to the present invention as described in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0006] Detailed Description of the Invention definition It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel one or any novel combination of steps of any method or process so disclosed.

[0007] As used herein, the term "co-processed excipient" refers to any combination of two or more excipients obtained by physical simultaneous processing that does not result in the formation of covalent bonds. Co-processed excipients have functionality that cannot be achieved by blending the excipients. Co-processed excipients can be produced by methods that result in only physical interactions between the components, such as co-drying, spray drying, granulation, extrusion, and high-shear dispersion. Examples of co-processed excipients include, but are not limited to, Di-Pac®, Emdex®, Pharmatose®, Sugar Tab®, Pharmaburst500®, TIMERx®, Ludipress®, Starlac®, Xylitab®, StarCap®, Advantose®, Ludiflash®, Cellactose®, ForMaxx®, Microcelac100®, Avicel®, ProSolv®, SMCC, ProSolv Easytab®, Combilac®, Startab®, Parteck® ODT, Comprecel SMCC90, Pharmacel SMCC90, SANAQ ML011, and SANAQ SP205.

[0008] The term "Di-Pac®" refers to a co-processed excipient consisting of co-crystallized sucrose (97%) and maltodextrin (3%).

[0009] The term "Emdex®" refers to a co-processed excipient consisting of 95% glucose monohydrate and 5% oligosaccharides resulting from the enzymatic hydrolysis of starch.

[0010] The term "Pharmatose®" refers to an excipient consisting of crystalline lactose monohydrate.

[0011] The term "Sugar Tab®" refers to a co-processed excipient consisting of sucrose (90%-93%) and invert sugar (7%-10%).

[0012] The term "Pharmaburst 500®" refers to a co-processed excipient consisting of mannitol (75%-90%), sorbitol (6%-20%), crospovidone (7%-15%) and silicon dioxide (0.1%-1.5%).

[0013] The term "TIMERx®" refers to a co-processed excipient consisting of xanthan gum, locust bean gum, and dextrose.

[0014] The term "Ludipress®" refers to a co-processed excipient consisting of 93% lactose monohydrate, 3.5% povidone with a K value of 30 ("Kollidon® 30"), and 3.5% crospovidone with a bulk density of 0.30-0.40 g / mL ("Kollidon® CL").

[0015] The term "Starlac®" refers to a co-processed excipient made from lactose and corn starch.

[0016] The term "Xylitab®" refers to an additive consisting of xylitol.

[0017] The term "StarCap®" refers to a co-processed excipient made from pregelatinized starch and corn starch.

[0018] The term "Advantose®" refers to a co-processed additive consisting of spray-dried fructose and starch.

[0019] The term "Ludiflash®" refers to a co-processed excipient consisting of 84.0-92.0% D-mannitol, 4.0-6.0% Kollidon® CL-SF, 3.5-6.0% polyvinyl acetate, 0.5-2.0% water, and 0.25-0.60% povidone.

[0020] The term "Kollidon® CL-SF" refers to an excipient consisting of crospovidone.

[0021] The term "Cellactose®" refers to a co-processed excipient obtained by spray drying 75% α-lactose monohydrate and 25% cellulose powder.

[0022] The term "ForMaxx®" refers to a co-processed additive consisting of calcium carbonate and sorbitol.

[0023] The term "Microcelac100®" refers to a co-processed excipient obtained by spray drying 75% α-lactose monohydrate and 25% microcrystalline cellulose.

[0024] The term "Avicel®" refers to a co-processed excipient obtained by spray drying microcrystalline cellulose and sodium carboxymethyl cellulose.

[0025] The term "SMCC90" refers to a co-processed additive obtained by spray drying 98% microcrystalline cellulose and 2% colloidal silicon dioxide.

[0026] The term "ProSolv® Easytab" refers to a co-processed excipient consisting of microcrystalline cellulose (96%), sodium starch glycolate (1.2%), colloidal silicon dioxide (2%), and sodium stearyl fumarate (0.8%).

[0027] The term "Combilac®" refers to a co-processed excipient consisting of 70% alpha-lactose monohydrate, 20% microcrystalline cellulose (MCC) and 10% white native corn starch.

[0028] The term "Startab®" refers to an additive consisting of starch.

[0029] The term "Parteck® ODT" refers to a co-processed excipient consisting of D-mannitol and croscarmellose sodium.

[0030] The term "SANAQ ML011" refers to a co-processed excipient consisting of lactose monohydrate and microcrystalline cellulose.

[0031] The term "SANAQ SP205" refers to a co-processed excipient consisting of microcrystalline cellulose, colloidal silicon dioxide, crospovidone and povidone.

[0032] As used herein, the term "API" refers to an active pharmaceutical ingredient. Preferably, an API is a small molecule, i.e., an organic compound with a molecular weight of 1000 daltons or less. Specific, but non-limiting, examples of APIs are ralmitalonto, arogavat, and fenebrutinib.

[0033] As used herein, the term "filler" refers to a substance that is added to a pharmaceutical composition to increase the weight and / or size of the pharmaceutical composition. Pharmaceutically acceptable fillers are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of fillers include starch (e.g., pregelatinized starch), cellulose (e.g., microcrystalline cellulose) and lactose (e.g., lactose monohydrate). Preferred, but non-limiting examples of fillers include cellulose and lactose.

[0034] As used herein, the term "disintegrant" refers to a substance added to a pharmaceutical composition to help break down (disintegrate) and release an active ingredient, such as, for example, Form B described herein, after administration. Pharmaceutically acceptable disintegrants are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of disintegrants are low-substituted hydroxypropyl cellulose (also known as hydroxypropyl methylcellulose (HPMC) or hypromellose) and croscarmellose sodium. A preferred, but non-limiting, example of a disintegrant is croscarmellose sodium.

[0035] As used herein, the term "acidulant" refers to a pharmaceutically acceptable additive whose pH in a 1% (w / w) aqueous solution is less than 4.0. Acidulants are usually added to enhance flavor or improve the dissolution of (basic) APIs. Some examples of acidulants include citric acid, tartaric acid, fumaric acid, lactic acid, malic acid, succinic acid, phosphoric acid, and acetic acid. Preferably, the acidulant is selected from the group consisting of citric acid, tartaric acid, fumaric acid, lactic acid, and / or malic acid. More preferably, the acidulant is fumaric acid.

[0036] As used herein, the term "lubricant" refers to a substance added to a pharmaceutical composition to help reduce adhesion of powder granules to equipment surfaces. Pharmaceutically acceptable glidants are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of glidants are sodium stearyl fumarate and magnesium stearate. A preferred, but non-limiting example of a glidant is sodium stearyl fumarate.

[0037] As used herein, the term "flow agent" refers to a substance added to a pharmaceutical composition to promote product flow by reducing interparticle friction. Pharmaceutically acceptable flow agents are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of flow agents include silicon dioxide (colloidal), polyethylene glycol PEG6000, fumed silicon dioxide Aerosil® 200, talc, etc. A preferred, but non-limiting example, is silica, colloidal anhydrous.

[0038] As used herein, the term "crospovidone" refers to a crosslinked homopolymer of N-vinyl-2-pyrrolidinone.

[0039] Specific non-limiting examples of "sugar alcohol" as used herein include mannitol and isomalt.

[0040] As used herein, the term "mini-batch" refers to a variation of the batch mixing method in which each batch is reduced in size to minimize the mass of material "in-process." A series of individual mini-batches are transferred to a conventional rotary tablet press, allowing for continuous tablet production by the direct compression method.

[0041] As used herein, the term "direct compression" refers to a tablet manufacturing method in which a physically mixed powder blend of an active pharmaceutical ingredient (API) and excipients is compressed directly into a tablet without an additional wet or dry granulation step.

[0042] As used herein, the term "flowability" refers to the ability of a bulk powder to flow through a device. This is quantified with an appropriate testing device, such as a shear tester. It is usually measured as the ratio of the consolidation stress to the uniaxial collapse stress. c is used to numerically characterize the liquidity.

[0043] As used herein, the term "bulk density" refers to the ratio of the mass of a bulk solid to its volume. It is typically measured by gently placing a known sample mass into a graduated cylinder and carefully flattening the powder without compressing it. The apparent untapped volume is then read to the nearest graduation.

[0044] As used herein, the term "larmitalont" refers to 5-ethyl-4-methyl-N-[4-[(2S)morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide.

[0045] As used herein, the term "arogavat" refers to 6-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methoxy]-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide.

[0046] As used herein, the term "fenebrutinib" refers to 2-[3'-(hydroxymethyl)-1-methyl-5-([5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino)-6-oxo-1,6-dihydro-3,4'-bipyridin-2'-yl]-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one.

[0047] Novel Uses of Co-Processed Excipients In a first aspect, the present invention provides the use of a co-processed excipient in the continuous manufacture of a solid dosage form.

[0048] In a preferred embodiment, the continuous manufacturing is continuous mini-batch direct compression. In one embodiment, the solid dosage form comprises: (i) a nucleus and, optionally, (ii) a coating; and Includes.

[0049] As outlined above, the number of feeders on equipment used for continuous manufacturing is typically limited to 4-6 feeders. Therefore, it is important to limit the number of excipients in a pharmaceutical composition when it is manufactured continuously.

[0050] In one embodiment, the core comprises: (i) APIs; (ii) 1 to 4 co-processed excipients; (iii) 1 to 4 additional additives selected from fillers, disintegrants, lubricants, flow agents, and acidulants; and the total number of additives (ii) and (iii) is ≦5.

[0051] In one embodiment, the core comprises: (i) APIs; (ii) a co-processed excipient; and (iii) a filler, disintegrant or acidulant; (iv) a lubricant; and It consists of:

[0052] In one embodiment, the filler is selected from starch, cellulose, sugar alcohol, calcium phosphate and lactose.

[0053] In one embodiment, the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, and croscarmellose sodium.

[0054] In one embodiment, the acidulant is fumaric acid.

[0055] In one embodiment, the lubricant is selected from sodium stearyl fumarate, polyethylene glycol, and magnesium stearate.

[0056] In one embodiment, the flow agent is selected from colloidal silicon dioxide, polyethylene glycol PEG6000, fumed silicon dioxide Aerosil® 200, and talc.

[0057] In one embodiment, the co-processed excipient is selected from Di-Pac®, Emdex®, Pharmatose®, Sugar Tab®, Pharmaburst500®, TIMERx®, Ludipress®, Starlac®, Xylitab®, StarCap®, Advantose®, Ludiflash®, Cellactose®, ForMaxx®, Microcelac100®, Avicel®, ProSolv® SMCC90, Prosolv Easytab®, Combilac®, Startab®, Parteck® ODT, Comprecel SMCC90, Pharmacel SMCC90, SANAQ ML011, and SANAQ SP205.

[0058] In a preferred embodiment, the co-processed excipient is selected from Ludipress®, Microcelac®, ProSolv SMCC90®, ProSolv Easytab®, Combilac® and Startab®.

[0059] In a preferred embodiment, the co-processed excipient is selected from Combilac and ProSolv® SMCC90.

[0060] In a particularly preferred embodiment, the co-processed excipient is Ludipress®.

[0061] In a particularly preferred embodiment, the co-processed additive is Microcelac®.

[0062] In a particularly preferred embodiment, the co-processed additive is ProSolv SMCC90®.

[0063] In a particularly preferred embodiment, the co-processed excipient is ProSolv Easytab®.

[0064] In a particularly preferred embodiment, the co-processed excipient is Combilac®.

[0065] In a particularly preferred embodiment, the co-processed additive is Startab®.

[0066] In a preferred embodiment, the API is selected from larmitront, arogavat, and fenebrutinib.

[0067] In a particularly preferred embodiment, the API is Larmitalonto.

[0068] In a particularly preferred embodiment, the API is arogavat.

[0069] In a particularly preferred embodiment, the API is fenebrutinib.

[0070] Novel Tablet Blend In a further aspect, the present invention provides a blend for sequential direct compression of tablet cores, comprising: (i) APIs; (ii) a co-processed excipient; and (iii) 1 to 4 additional additives selected from fillers, disintegrants, lubricants, and flow agents; and A blend is provided, comprising:

[0071] In one embodiment, the blend comprises: (i) APIs; (ii) a co-processed excipient; and (iii) a filler or disintegrant; and (iv) a lubricant; and It consists of:

[0072] In one embodiment, the filler is selected from starch, cellulose, sugar alcohol, calcium phosphate and lactose.

[0073] In one embodiment, the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, and croscarmellose sodium.

[0074] In one embodiment, the acidulant is fumaric acid.

[0075] In one embodiment, the lubricant is selected from sodium stearyl fumarate, polyethylene glycol, and magnesium stearate.

[0076] In one embodiment, the flow agent is selected from colloidal silicon dioxide, polyethylene glycol PEG6000, fumed silicon dioxide Aerosil® 200, and talc.

[0077] In one embodiment, the co-processed excipient is selected from Di-Pac®, Emdex®, Pharmatose®, Sugar Tab®, Pharmaburst500®, TIMERx®, Ludipress®, Starlac®, Xylitab®, StarCap®, Advantose®, Ludiflash®, Cellactose®, ForMaxx®, Microcelac100®, Avicel®, ProSolv® SMCC90, Prosolv Easytab®, Combilac®, Startab®, ParteckOD® T, Comprecel SMCC90, Pharmacel SMCC90, SANAQ ML011, and SANAQ SP205.

[0078] In a preferred embodiment, the co-processed excipient is selected from Ludipress®, Microcelac®, ProSolv SMCC90®, ProSolv Easytab®, Combilac® and Startab®.

[0079] In a preferred embodiment, the co-processed excipient is selected from Combilac and ProSolv® SMCC90.

[0080] In a particularly preferred embodiment, the co-processed excipient is Ludipress®.

[0081] In a particularly preferred embodiment, the co-processed additive is Microcelac®.

[0082] In a particularly preferred embodiment, the co-processed additive is ProSolv SMCC90®.

[0083] In a particularly preferred embodiment, the co-processed excipient is ProSolv Easytab®.

[0084] In a particularly preferred embodiment, the co-processed excipient is Combilac®.

[0085] In a particularly preferred embodiment, the co-processed additive is Startab®.

[0086] In a preferred embodiment, the API is selected from larmitront, arogavat, and fenebrutinib.

[0087] In a particularly preferred embodiment, the API is Larmitalonto.

[0088] In a particularly preferred embodiment, the API is arogavat.

[0089] In a particularly preferred embodiment, the API is fenebrutinib.

[0090] It has been found that it is important for tablet blends to have a flowability greater than FFc 4-5 to facilitate a free-flowing material that can be gravimetrically fed into a tablet press and ensure a robust tablet compression process. Thus, in a preferred embodiment, blends according to the invention have a flowability greater than FFc 4-5.

[0091] Furthermore, it has been found that blends having a bulk density greater than 0.4 g / mL improve the reliability of the tablet compression process. Thus, in a preferred embodiment, the blends according to the present invention have a bulk density greater than 0.4 g / mL.

[0092] It has been found that blends according to the invention can be reliably compressed into tablets in a continuous manner, even at high drug loads. In one embodiment, the blends according to the invention have a drug load of 1-30% wt / wt, preferably 2-25% wt / wt, and more preferably 2-20% wt / wt.

[0093] In a particularly preferred embodiment, the API (i) is Larmitalont, the co-processed excipient (ii) is ProSolv SMCC90, the further excipient (iii) is a disintegrant which is croscarmellose sodium, and the lubricant (iv) is sodium stearyl fumarate (see Example 2).

[0094] In a particularly preferred embodiment, the API (i) is Arogavat, the co-processed excipient (ii) is ProSolv SMCC90, the further excipient (iii) is a disintegrant which is croscarmellose sodium, and the lubricant (iv) is sodium stearyl fumarate (see Example 3).

[0095] In a particularly preferred embodiment, the API (i) is fenebrutinib, the co-processed excipient (ii) is combilac, the further excipient (iii) is an acidulant which is fumaric acid, and the lubricant (iv) is magnesium stearate (see Example 4).

[0096] New tableting method In a further aspect, the present invention provides a mini-batch continuous process for producing tablets, comprising: (i) feeding the API, the co-processed excipient, and one to four additional excipients from individual screw feeders into a mini-batch blender; (ii) blending the ingredients of step (i) in a mini-batch blender; (iii) discharging the mini-batches prepared in steps (i) and (ii) into a tablet press; (iv) compressing the blend from step (iii) into tablet cores; (v) repeating steps (i) through (iv) as necessary to produce the desired batch size; (vi) optionally spraying the film coating suspension onto the tablet cores from step (iv); A continuous method is provided, comprising:

[0097] In one embodiment, the one to four additional additives are selected from fillers, disintegrants, lubricants, and flow agents.

[0098] In one embodiment, the filler is selected from starch, cellulose, sugar alcohol, calcium phosphate and lactose.

[0099] In one embodiment, the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, and croscarmellose sodium.

[0100] In one embodiment, the acidulant is fumaric acid.

[0101] In one embodiment, the lubricant is selected from sodium stearyl fumarate, polyethylene glycol, and magnesium stearate.

[0102] In one embodiment, the flow agent is selected from colloidal silicon dioxide, polyethylene glycol PEG6000, fumed silicon dioxide Aerosil® 200, and talc.

[0103] In one embodiment, the co-processed excipient is selected from Di-Pac®, Emdex®, Pharmatose®, Sugar Tab®, Pharmaburst500®, TIMERx®, Ludipress®, Starlac®, Xylitab®, StarCap®, Advantose®, Ludiflash®, Cellactose®, ForMaxx®, Microcelac100®®, Avicel®, ProSolv® SMCC90, Prosolv Easytab®, Combilac®, Startab®, Parteck® ODT, Comprecel SMCC90, Pharmacel SMCC90, SANAQ ML011, and SANAQ SP205.

[0104] In a preferred embodiment, the co-processed excipient is selected from Ludipress®, Microcelac®, ProSolv SMCC90®, ProSolv Easytab®, Combilac® and Startab®.

[0105] In a preferred embodiment, the co-processed excipient is selected from Combilac and ProSolv® SMCC90.

[0106] In a particularly preferred embodiment, the co-processed excipient is Ludipress®.

[0107] In a particularly preferred embodiment, the co-processed additive is Microcelac®.

[0108] In a particularly preferred embodiment, the co-processed additive is ProSolv SMCC90®.

[0109] In a particularly preferred embodiment, the co-processed excipient is ProSolv Easytab®.

[0110] In a particularly preferred embodiment, the co-processed excipient is Combilac®.

[0111] In a particularly preferred embodiment, the co-processed additive is Startab®.

[0112] In a preferred embodiment, the API is selected from larmitront, arogavat, and fenebrutinib.

[0113] In a particularly preferred embodiment, the API is Larmitalonto.

[0114] In a particularly preferred embodiment, the API is arogavat.

[0115] In a particularly preferred embodiment, the API is fenebrutinib.

[0116] In one embodiment, the rate of the process according to the invention is no more than 30 kg, preferably no more than 25 kg, more preferably no more than 20 kg, more preferably no more than 15 kg, most preferably no more than 10 kg of tablet cores per hour.

[0117] In one embodiment of the process according to the present invention, the mini-batch blender is a high shear blender.

[0118] In one embodiment of the process according to the invention, the compression in step (iv) is direct compression.

[0119] In one aspect, the present invention provides a tablet having a core consisting of the blend described herein above when obtained from the process according to the present invention.

[0120] In one aspect, the present invention provides the use of a blend as described herein above in a method according to the present invention. [Example]

[0121] The following examples are given to illustrate the present invention and should not be considered as limiting the scope of the invention, but merely as representative thereof.

[0122] Example 1 - Continuous Mini-Batch Direct Compression Method Device TIFF2025526040000001.tif63166

[0123] method 1. Feeding of additive (i) from a large feeder and feeding of API, additive (ii) and additive (iii) from three small feeders to the mini-batch blender. 2. Blend mini-batches in a mini-batch blender. 3. Discharge the mini-batches prepared in steps 1 and 2 into a tablet press. 4. Press the tablet cores. Perform IPC on the tablet cores for individual tablet weight, hardness, thickness, friability and disintegration time. 5. Repeat steps 1-4 as necessary to produce the desired batch size. 6. Optionally, prepare a film coating suspension and spray the film coat onto the tablet cores obtained from step 4. Perform IPC on the average weight, thickness and disintegration time of the film coated tablets.

[0124] A schematic of this method is shown in Figure 1.

[0125] Example 2 - Larmitalont 150 mg Tablet Formulation TIFF2025526040000002.tif79128 a) SMCC90 is a commercially available additive consisting of silicified microcrystalline cellulose.

[0126] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0127] Tablets can be manufactured according to the continuous method described in Example 1.

[0128] Example 3 - Arogavat 20 mg tablet formulation TIFF2025526040000003.tif63128 a) ProSolv SMCC90 is a commercially available additive consisting of silicified microcrystalline cellulose.

[0129] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0130] Tablets can be manufactured according to the continuous method described in Example 1.

[0131] Example 4 - Fenebrutinib 200 mg Tablet Formulation I TIFF2025526040000004.tif63128 a) Combilac is a commercially available excipient consisting of microcrystalline cellulose, corn starch, and lactose monohydrate.

[0132] All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0133] Tablets can be manufactured according to the continuous method described in Example 1.

Claims

1. Use of co-processed excipients in the continuous manufacturing of solid dosage forms.

2. the solid dosage form comprising: (i) a nucleus and, optionally, (ii) a coating; and 2. The use according to claim 1, wherein the tablet comprises:

3. The nucleus is (i) an API; and (ii) 1 to 4 co-processed additives; and (iii) 1 to 4 additional additives selected from fillers, disintegrants, lubricants, flow agents, and acidulants; 3. The use according to claim 2, wherein the total number of additives (ii) and (iii) is ≦5.

4. The nucleus is (i) an API; and (ii) a co-processed excipient; and (iii) a filler, disintegrant, or acidulant; (iv) a lubricant; and The use according to claim 3, consisting of:

5. 1. A blend for sequential direct compression tablet cores, comprising: (i) an API; and (ii) a co-processed excipient; and (iii) 1 to 4 additional additives selected from fillers, disintegrants, lubricants, flow agents, and acidulants; A blend consisting of:

6. (i) an API; and (ii) a co-processed excipient; and (iii) a filler, disintegrant, or acidulant; (iv) a lubricant; and 6. The blend of claim 5, consisting of:

7. 7. The use according to claim 3 or 4, or the blend according to claim 5 or 6, wherein the filler is selected from starch, cellulose, sugar alcohol, calcium phosphate and lactose.

8. 8. The use of any one of claims 3, 4 and 7, or the blend of any one of claims 5, 6 and 7, wherein the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, and croscarmellose sodium.

9. 9. Use according to any one of claims 3, 4, 7 and 8, or a blend according to any one of claims 5, 6, 7 and 8, wherein the lubricant is selected from sodium stearyl fumarate, polyethylene glycol and magnesium stearate.

10. 10. The use according to any one of claims 3 and 7 to 9, or the blend according to any one of claims 5 and 7 to 9, wherein the flow agent is selected from colloidal silicon dioxide, polyethylene glycol PEG 6000, fumed silicon dioxide Aerosil® 200, and talc.

11. 11. The use of any one of claims 3, 4, and 7 to 10, or the blend of any one of claims 5 to 10, wherein the acidulant is fumaric acid.

12. The co-processed excipient is selected from the group consisting of Di-Pac®, Emdex®, Pharmatose®, Sugar Tab®, Pharmaburst 500®, TIMERx®, Ludipress®, Starlac®, Xylitab®, StarCap®, Advantage®, Ludiflash®, Cellactose®, ForMaxx®, Microcelac 100®, Avicel®, ProSolv®, SMCC90, Prosolv Easytab®, Combilac®, Startab®, Parteck® ODT, and Comprecel®.

12. The use according to any one of claims 1 to 4 and 7 to 11, or the blend according to any one of claims 5 to 11, selected from SMCC90, Pharmacel SMCC90, SANAQ ML011, and SANAQ SP205.

13. 13. The use or blend of claim 12, wherein the co-processed additive is selected from Ludipress®, Microcelac®, ProSolv SMCC90®, ProSolv Easytab®, Combilac® and Startab®.

14. 14. The use or blend of claim 13, wherein the co-processed additive is selected from Combilac and ProSolv® SMCC90.

15. 15. The use according to any one of claims 3, 4 and 7 to 14, or the blend according to any one of claims 5 to 14, wherein the API is selected from larmitront, arogavat and fenebrutinib.

16. 1. A mini-batch continuous process for producing tablets, comprising: (i) feeding the API, the co-processed additive, and one to four additional additives into a mini-batch blender from individual screw feeders; (ii) blending the ingredients of step (i) in said mini-batch blender; (iii) discharging the mini-batches prepared in steps (i) and (ii) into a tablet press; (iv) compressing the blend from step (iii) into tablet cores; (v) repeating steps (i)-(iv) as necessary to produce the desired batch size; (vi) optionally spraying the film coating suspension onto the tablet cores from step (iv); A mini-batch continuous method including:

17. 17. A continuous process according to claim 16, wherein the process speed is at most 30 kg, preferably at most 25 kg, more preferably at most 20 kg, more preferably at most 15 kg, most preferably at most 10 kg of tablet cores per hour.

18. 18. The continuous process of claim 16 or 17, wherein the mini-batch blender is a high shear blender.

19. 19. A continuous process according to any one of claims 16 to 18, wherein the compression in step (iv) is direct compression.

20. 20. A tablet having a core consisting of a blend according to any one of claims 5 to 15 when obtained from the process according to any one of claims 16 to 19.

21. Use of a blend according to any one of claims 5 to 14 in a method according to any one of claims 16 to 19.

22. 16. The blend of any one of claims 5 to 15, having a flowability of greater than FFc 4-5.

23. 23. The blend of any one of claims 5 to 15 and 22, having a bulk density greater than 0.4 g / mL.

24. 24. A blend according to any one of claims 5 to 15, 22 and 23 having a drug loading of 1 to 30% wt / wt, preferably 2 to 25% wt / wt, more preferably 2 to 20% wt / wt.

25. The invention as described herein above.

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