Porous pellets and process of manufacturing the same

Abstract

The present disclosure provides porous pellets comprising a cellulose component and a soluble filler as well as methods of making the porous pellets and solid dosage forms comprising the porous pellets. In some embodiments, the pellets are coated with an API coating. In some embodiments, the API coating is coated with an additional coating.

Description

Attorney Docket No.059717-5025-WO POROUS PELLETS AND PROCESS OF MANUFACTURING THE SAME FIELD OF THE DISCLOSURE

[0001] The present disclosure relates to porous pellets comprising an insoluble component or a cellulose component and a soluble filler, methods of manufacturing and using the same, and dosage forms comprising the same. The porous pellets of the present disclosure can be coated or loaded with a poorly soluble active pharmaceutical ingredient (API). CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The present application is an International PCT application claiming priority to U.S. Provisional Patent Application No.63 / 519,906, filed on August 16, 2023, which is incorporated herein by reference in its entirety. BACKGROUND OF THE DISCLOSURE

[0003] Commercially available pellets used as cores for the preparation of API delivery are typically composed purely of microcrystalline cellulose (MCC, e.g., Cellets) or sugar. Cellets have disadvantages in terms of promoting drug dissolution for certain poorly soluble APIs. MCC also has the disadvantage of being prone to moisture uptake and ingress (hygroscopicity), which again can have negative effects on API stability for moisture sensitive drugs. Alternatively, sugar pellets are more soluble but have the disadvantage that they can cause instability of certain APIs (particularly those containing amine groups via Maillard reaction). Finally, mannitol only beads have been shown to be difficult to manufacture and are significantly brittle.

[0004] There is a need in the art for pellets for API delivery that have reproducible properties such as particle size, pore size, pore volume, dissolution time, sphericity, aspect ratio, and / or specific surface area. The present disclosure addresses this unmet need. SUMMARY OF THE DISCLOSURE

[0005] In one aspect, the present disclosure provides a plurality of pellets comprising a cellulose component and a soluble filler in a weight / weight ratio of cellulose component to soluble filler of from about 50:50 to about 20:80, wherein the porosity of the plurality of 1 DB1 / 148490793.1Attorney Docket No.059717-5025-WO pellets, ranges from about 3.0 x 10-3to about 9.0 x 10-3mL / g, the plurality of pellets comprising pores having an average pore size in the range of about 7.0 to about 22.0 nm. In one embodiment, the porosity is as measured by nitrogen adsorption. In one embodiment, the cellulose component comprises one or more of microcrystalline cellulose (MCC), silicified MCC, hydroxypropyl methyl cellulose, methyl cellulose, and / or sodium carboxymethyl cellulose. In one embodiment, the cellulose component consists essentially of MCC. In one embodiment, the cellulose component consists essentially of silicified MCC. In one embodiment, the silicified MCC is SMCC 90. In one embodiment, the soluble filler comprises a polyol. In one embodiment, the polyol is selected from mannitol, erythritol, sorbitol, maltitol, isomalt, and xylitol. In one embodiment, the polyol is mannitol. In one embodiment, the soluble filler comprises a sugar. In one embodiment, the sugar is lactose or sucrose. In one embodiment, the pellets comprise about 60% to about 70%, or about 70% to about 80% by weight of the soluble filler. In one embodiment, the weight / weight ratio of the cellulose component to the soluble filler is about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, or about 1:4. In one embodiment, the pellets have a median diameter of about 100 µm to about 1,200 µm. In one embodiment, the pellets have a median diameter of about 100 to about 600 µm, or about 375 to about 475 µm. In one embodiment, the pellets have a sphericity of at least 0.90. In one embodiment, the pellets have a friability of less than about 0.3. In one embodiment, the pellets have a friability of less than about 0.1. In one embodiment, the pore sizes follow a bimodal pore size distribution. In one embodiment, the cellulose component used as a starting material to manufacture the pellets has a density of about 0.26 to about 0.31 g / mL. In one embodiment, the pellets further comprise a binder. In one embodiment, the binder comprises polyvinyl pyrrolidone (PVP). In one embodiment, the PVP is PVP K30. In one embodiment, the binder comprises a cellulose derivative. In one embodiment, the cellulose derivative consists essentially of hydroxypropyl methylcellulose (HPMC). In one embodiment, the HPMC is HPMC E5. In one embodiment, the binder comprises maltodextrin, gelatin, or starch. In one embodiment, the pellets further comprise a glidant or a lubricant. In one embodiment, the glidant or lubricant is selected from colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, and glyceryl monostearate. In one embodiment, the pellets comprise about 0.001% to about 10%, about 0.01% to about 5%, or about 0.05% to 2 DB1 / 148490793.1Attorney Docket No.059717-5025-WO about 2.5% by weight of the glidant or lubricant. In one embodiment, the pellets further comprise a super disintegrant. In one embodiment, the super disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and magnesium aluminum silicate. In one embodiment, the pellets further comprise an active pharmaceutical ingredient (API). In one embodiment, the pellets are coated with a first coating comprising the API. In one embodiment, the API is selected from a proton pump inhibitor, an antihistamine, a pain killer, a beta blocker, a calcium channel blocker, an anti-erectile dysfunction agent, an anti- migraine agent, and a non-steroidal anti-inflammatory. In one embodiment, the API is selected from cetirizine, diclofenac, lansoprazole, omeprazole, pantoprazole, esomeprazole, metoprolol, propranolol, montelukast, albuterol, ibuprofen, sildenafil, zolpidem, furosemide, amlodipine, tramadol, atenolol, niacin, paroxetine, nifedipine, venlafaxine, desvenlafaxine, naproxen, famotidine, guaifenesin, bisoprolol, tadalafil, chlorpheniramine maleate, pseudoephedrine hydrochloride, indomethacin, disopyramide phosphate, diltiazem hydrochloride, carbamazepine, verapamil hydrochloride, tolterodine tartrate, methylphenidate hydrochloride, carvedilol phosphate, memantine hydrochloride, budesonide, mesalamine, and sumatriptan, or a pharmaceutically salt of any one thereof. In one embodiment, the pellets are coated with a second coating substantially covering the first coating comprising the API. In one embodiment, the second coating comprises a polymer. In one embodiment, the polymer is selected from cellulose, ethylcellulose, methacrylic acid co polymer, dimethyl amino methacrylate, butyl methacrylate, and methyl methacrylate copolymer.

[0006] In another aspect, the present disclosure provides a method of making the plurality of pellets described herein, the method comprising extrusion spheronization of a wet mass comprising the cellulose component and the soluble filler and drying the extrudates to form the plurality of pellets. In one embodiment, the method further comprises coating the plurality of pellets with a first coating comprising an active pharmaceutical ingredient (API). In one embodiment, the coating step comprises aqueous powder coating or dry powder coating. In one embodiment, the API is selected from a proton pump inhibitor, an antihistamine, a pain killer, a beta blocker, a calcium channel blocker, an anti-erectile dysfunction agent, an anti-migraine agent, and a non-steroidal anti-inflammatory. In one embodiment, the API is selected from cetirizine, diclofenac, lansoprazole, omeprazole, pantoprazole, esomeprazole, metoprolol, 3 DB1 / 148490793.1Attorney Docket No.059717-5025-WO propranolol, montelukast, albuterol, ibuprofen, sildenafil, zolpidem, furosemide, amlodipine, tramadol, atenolol, niacin, paroxetine, nifedipine, venlafaxine, desvenlafaxine, naproxen, famotidine, guaifenesin, bisoprolol, tadalafil, chlorpheniramine maleate, pseudoephedrine hydrochloride, indomethacin, disopyramide phosphate, diltiazem hydrochloride, carbamazepine, verapamil hydrochloride, tolterodine tartrate, methylphenidate hydrochloride, carvedilol phosphate, memantine hydrochloride, budesonide, mesalamine, and sumatriptan or a pharmaceutically salt of any one thereof. In one embodiment, the method further comprises coating the pellets with a second coating. In one embodiment, the second coating comprises a polymer. In one embodiment, the polymer is selected from cellulose, ethylcellulose, methacrylic acid co polymer, dimethyl amino methacrylate, butyl methacrylate, and methyl methacrylate copolymer.

[0007] In yet another aspect, the present disclosure provides a method of making the plurality of pellets described herein, the method comprising powder layering the cellulose component and the soluble filler to form the plurality of pellets. In one embodiment, the method further comprises coating the plurality of pellets with a first coating comprising an active pharmaceutical ingredient (API). In one embodiment, the coating step comprises aqueous powder coating or dry powder coating. In one embodiment, the API is selected from a proton pump inhibitor, an antihistamine, a pain killer, a beta blocker, a calcium channel blocker, an anti-erectile dysfunction agent, an anti-migraine agent, and a non-steroidal anti-inflammatory. In one embodiment, the API is selected from cetirizine, diclofenac, lansoprazole, omeprazole, pantoprazole, esomeprazole, metoprolol, propranolol, montelukast, albuterol, ibuprofen, sildenafil, zolpidem, furosemide, amlodipine, tramadol, atenolol, niacin, paroxetine, nifedipine, venlafaxine, desvenlafaxine, naproxen, famotidine, guaifenesin, bisoprolol, tadalafil, chlorpheniramine maleate, pseudoephedrine hydrochloride, indomethacin, disopyramide phosphate, diltiazem hydrochloride, carbamazepine, verapamil hydrochloride, tolterodine tartrate, methylphenidate hydrochloride, carvedilol phosphate, memantine hydrochloride, budesonide, mesalamine, and sumatriptan or a pharmaceutically salt of any one thereof. In one embodiment, the method further comprises coating the pellets with a second coating. In one embodiment, the second coating comprises a polymer. In one embodiment, the polymer is 4 DB1 / 148490793.1Attorney Docket No.059717-5025-WO selected from cellulose, ethylcellulose, methacrylic acid co polymer, dimethyl amino methacrylate, butyl methacrylate, and methyl methacrylate copolymer.

[0008] In yet another aspect, the present disclosure provides a solid dosage form comprising the plurality of pellets described herein. In one embodiment, the solid dosage form is a swallowable tablet, a chewable tablet, or an orally disintegrating tablet. In one embodiment, the solid dosage form further comprises a cushioning agent, a disintegrant, a lubricant, a glidant, and / or a filler.

[0009] In yet another aspect, the present disclosure provides a method of treating a disease or disorder in a subject, comprising administering to the subject the plurality of pellets described herein or the solid dosage form described herein. In one embodiment, the disease or disorder is selected from a gastrointestinal disorder, allergies, inflammation, and pain. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the appended drawings. For the purpose of illustration of the disclosure, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the disclosure can be embodied in different forms and thus should not be construed as being limited to the embodiments set forth herein.

[0011] FIG.1 is a chart depicting the basic procedure to prepare pellets of the disclosure.

[0012] FIGS.2A-2B are representative microscopic images of a batch (202 / E014) with a mannitol:MCC ratio of 65:35.

[0013] FIG.3 is a chart depicting the basic procedure to coat pellets with API and a functional (controlled release or taste masked) coating, forming beads.

[0014] FIG.4 is a dissolution study demonstrating the reproducibility of beads comprising a mannitol:MCC pellet coated with cetirizine HCl and the parameters used for each batch.

[0015] FIG.5 is a graph showing drug release in % with time from different beads coated with an ethylcellulose (ec) dispersion at 10 and 20% weight gain.

[0016] FIGS.6A-6E demonstrate the influence of processing parameters on the sphericity (via SEM) of pellets made from mannitol:MCC using extrusion / spheronization. FIG.6A: 65:35 5 DB1 / 148490793.1Attorney Docket No.059717-5025-WO mannitol:MCC cores, 20 / 30 mesh, 246 / E042A, O.8 R, 1000-1200 rpm, 4 mins. FIG.6B: 65:35 mannitol:MCC cores, 20 / 30 mesh, 202 / E055B, O.8 R, 1200 rpm, 5 mins. FIG.6C: 65:35 mannitol:MCC cores, 20 / 30 mesh, 256 / E003A, 1800 rpm, 3 mins. FIG.6D: 65:35 mannitol:MCC cores, 20 / 30 mesh, 256 / E006A, 1800 rpm, 5 mins. FIG.6E: 65:35 mannitol:MCC cores, 20 / 30 mesh, 256 / E004A, 1800 rpm, 7 mins.

[0017] FIG.7 is a graph showing the release profile from each coated pellet batch for the 20% weight gain.

[0018] FIG.8 is a graph showing the release profile from each coated pellet batch for the 30% weight gain.

[0019] FIG.9 provides examples of pores that can be detected by gas adsorption.

[0020] FIG.10 provides equations for pore size calculation and adsorption in mesopores.

[0021] FIGS.11A-11B are examples of different types of isotherms.

[0022] FIGS.12A-12E are isotherms of mannitol:MCC pellets compared to commercially available pellets.

[0023] FIGS.13A-13F are DFT curves of mannitol:MCC pellets compared to commercially available pellets.

[0024] FIG.14 provides SEM images of mannitol:MCC pellets (202 / E019B and 202 / E048B) compared to commercially available pellets.

[0025] FIG.15 provides SEM images of mannitol:MCC pellets with 65:35 ratio (Batches 256 / E003, E256 / E004 and E256 / E006) showing the improving sphericity with increased spheronization speed and time.

[0026] FIG.16 provides microscope images of the mannitol / MCC pellets (Batch Number E256 / E043) with the diameter, area, and perimeter measurements.

[0027] FIG.17 is an SEM image of a smooth spherical pellet with a 65:35 mannitol:MCC ratio from Batch 256 / E004.

[0028] FIG.18 shows the sticking of wet spheres on the spheronizer wall.

[0029] FIG.19 provides SEM images of mannitol:MCC (65:35) beads of #20-25 size cores used for functional coating B No.258 / E019.

[0030] FIGS.20A-20C are dissolution studies of pellets of the disclosure. FIG.20A is a comparative dissolution profile of uncured 25% Surelease coated mannitol:MCC pellets (65:35) 6 DB1 / 148490793.1Attorney Docket No.059717-5025-WO (258 / E023C) over MCC spheres / Cellets 700 (258 / E022C) and Sugarspheres / Pharm-a-spheres (258 / E024C). FIG 20B is a comparative dissolution profile of 2 hours cured 25% Surelease coated mannitol:MCC (65:35) pellets (258 / E023CA) over MCC spheres / Cellets 700 (258 / E022CA) and Sugarspheres / Pharma-a-spheres (258 / E024CA). FIG.20C is a comparative dissolution profile of 8.5 hours cured 25% Surelease coated mannitol:MCC pellets (258 / E023CB) over MCC spheres / Cellets 700 (258 / E022CB) and Sugarspheres / Pharm-a-sheres (258 / E024CB).

[0031] FIG.21 is a comparative dissolution profile of 2 hr cured 25% Surelease coated mannitol:MCC pellets (258 / E023CA) over similar condition MCC (Cellets 700) (258 / E022CA) and Sugarspheres (Pharm-a-spheres) (258 / E024CA) in 900 mL pH 6.8 phosphate buffer, USP-II, 50 RPM.

[0032] FIG.22 shows a comparative dissolution profile of 25% Surelease coated and 2 hours cured mannitol:MCC (50:50) pellets (263 / E014A) over similar condition mannitol:MCC (65:35) pellets (258 / E023CA), MCC spheres Cellets 700 (258 / E022CA), and Sugar spheres / Pharm-a- spheres (258 / E024CA).

[0033] FIG.23 shows a comparative dissolution profile of 25% Surelease coated and 2 hours cured mannitol:MCC (65:35) pellets (263 / E043A) produced using a 0.7 mm dome type extrusion screen over similarly coated and cured mannitol:MCC (65:35) pellets (258 / E023CA), mannitol:MCC pellets (263 / E014A) produced using radial type extrusion screen and marketed MCC spheres / Cellets 700 (258 / E022CA) and Sugar spheres / Pharm-a-spheres (258 / E024CA).

[0034] FIG.24 provides SEM images of B No.263 / E033A.

[0035] FIG.25 shows a comparative dissolution profile of 15% enteric coated mannitol:MCC (65:35) pellets (263 / E056B) over similarly coated MCC spheres / Cellets 700 (263 / E057B) and Sugar / Pharm-a-spheres (263 / E055B). DETAILED DESCRIPTION OF THE DISCLOSURE

[0036] The following detailed description is exemplary and explanatory and is intended to provide further explanation of the disclosure described herein. Other advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the disclosure. 7 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0037] The present disclosure is described herein using several definitions, as set forth below and throughout the application. Definitions

[0038] The term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” shall mean up to plus or minus 10% of the particular value.

[0039] The terms “solid dosage form,” “tablet,” and “solid preparation” are used synonymously within the context of the present disclosure. These terms should be construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape.

[0040] The aim of the present disclosure was to overcome the drawbacks of existing commercially available pellets for API delivery. Pellets of the Disclosure

[0041] In one aspect, the present disclosure relates to a plurality of pellets comprising an insoluble component or a cellulose component and a soluble filler. In one embodiment, the soluble filler comprises a water-soluble filler. In one embodiment, the cellulose component is selected from microcrystalline cellulose (MCC), hydroxypropyl methyl cellulose, methyl cellulose, and sodium carboxymethyl cellulose. In one embodiment, the cellulose component is MCC. In one embodiment, the MCC comprises MCC with a grade of PH101, PH102, PH105, PH301, or PH302. In one embodiment, the MCC comprises silicified microcrystalline cellulose (e.g., SMCC 50 and SMCC 90). In one embodiment, the insoluble component comprises dibasic calcium phosphate anhydrous, calcium hydrogen phosphate dihydrate, or tribasic calcium phosphate. In one embodiment, the soluble filler comprises a polyol. In one embodiment, the polyol is selected from mannitol, erythritol, sorbitol, maltitol, isomalt, and xylitol. In one embodiment, the polyol is mannitol. In one embodiment, the soluble filler comprises a sugar. In one embodiment, the sugar is selected from lactose and sucrose. In one embodiment, the plurality of pellets comprises MCC and mannitol. In one embodiment, the plurality of pellets comprises an insoluble component or a cellulose component and more than one soluble filler. 8 DB1 / 148490793.1Attorney Docket No.059717-5025-WO In one embodiment, the pellets comprise MCC and more than one polyol. In one embodiment, the pellets comprise MCC, mannitol, and maltitol.

[0042] In one embodiment, the plurality of pellets comprising an insoluble component or a cellulose component and a soluble filler are made using a cellulose component starting material having a particle size of less than about 500 microns, less than about 450 microns, less than about 400 microns, less than about 350 microns, less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 175 microns, less than about 150 microns, less than about 100 microns, less than about 75 microns, or less than about 50 microns. In one embodiment, the plurality of pellets comprising an insoluble component or a cellulose component and a soluble filler are made using a cellulose component starting material having a particle size (D50) of less than about 500 microns, less than about 450 microns, less than about 400 microns, less than about 350 microns, less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 175 microns, less than about 150 microns, less than about 100 microns, less than about 75 microns, or less than about 50 microns. In one embodiment, the plurality of pellets comprising an insoluble component or a cellulose component and a soluble filler are made using a cellulose component starting material having a particle size (D90) of less than about 500 microns, less than about 450 microns, less than about 400 microns, less than about 350 microns, less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 175 microns, less than about 150 microns, less than about 100 microns, less than about 75 microns, or less than about 50 microns. In one embodiment, the plurality of pellets comprising an insoluble component or a cellulose component and a soluble filler are made using a cellulose component starting material having a density of about 0.01 to 1.0 g / mL, about 0.1 to 0.9 g / mL, about 0.1 to 0.8 g / mL, about 0.1 to 0.7 g / mL, about 0.1 to 0.6 g / mL, about 0.15 to 0.6 g / mL, about 0.2 to 0.5 g / mL, about 0.2 to 0.45 g / mL, about 0.26 to 0.31 g / mL, or about 0.34 to 0.45 g / mL. In one embodiment, the pellets comprise about 10% to 80%, about 10% to 70%, about 10% to 60%, about 10% to 50%, about 15% to 45%, about 20% to 40%, about 20% to 30%, or about 30% to about 40% by weight of the insoluble component or cellulose component. In one embodiment, the remaining 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the pellet comprises the soluble filler. In one embodiment, the pellets comprise about 40% to 9 DB1 / 148490793.1Attorney Docket No.059717-5025-WO about 95% by weight, about 60% to about 70% by weight, or about 70% to about 80% by weight of the soluble filler. In one embodiment, the pellets comprise about 65% by weight of the soluble filler and about 35% by weight of the insoluble component or cellulose component. In one embodiment, the pellets comprise about 65% by weight mannitol and about 35% by weight MCC. In one embodiment, the weight:weight ratio of the soluble filler to the insoluble component or cellulose component is about 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, or 4:1. In one embodiment, the pellets comprise a 1.85:1 or a 3:1 w / w ratio of the soluble filler to the insoluble component or the cellulose component. In one embodiment, the weight:weight ratio of the insoluble component or cellulose component to the soluble filler is from about 50:50 to about 20:80. In one embodiment, the weight:weight ratio of the insoluble component or cellulose component to the soluble filler is about 50:50, about 51:49, about 52:48, about 53:47, about 54:46, about 55:45, about 56:44, about 57:43, about 58:42, about 59:41, about 60:40, about 61:39, about 62:38, about 63:37, about 64:36, about 65:35, about 66:34, about 67:33, about 68:32, about 69:31, about 70:30, about 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, about 99:1, about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91, about 10:90, about 11:89, about 12:88, about 13:87, about 14:86, about 15:85, about 16:84, about 17:83, about 18:82, about 19:81, about 20:80, about 21:79, about 22:78, about 23:77, about 24:76, about 25:75, about 26:74, about 27:73, about 28:72, about 29:71, about 30:70, about 31:69, about 32:68, about 33:67, about 34:66, about 35:65, about 36:64, about 37:63, about 38:62, about 39:61, about 40:60, about 41:59, about 42:58, about 43:57, about 44:56, about 45:55, about 46:54, about 47:53, about 48:52, or about 49:51.

[0043] In one embodiment, the pellets have a diameter of about 50 to 1,200 µm, about 100 to 1,200 µm, about 50 to 1,000 µm, about 100 to 1,000 µm, about 50 to 900 µm, about 50 to 800 µm, about 50 to 700 µm, about 50 to 600 µm, about 75 to 600 µm, about 100 to 600 µm, about 175 to 600 µm, about 200 to 600 µm, about 250 to 600 µm, about 300 to 600 µm, about 300 to 500 µm, about 300 to 475 µm, about 375 to 475 µm, or about 400 to 450 µm. In one 10 DB1 / 148490793.1Attorney Docket No.059717-5025-WO embodiment, the pellets have a diameter of about 25 µm, about 50 µm, about 75 µm, about 100 µm, about 125 µm, about 150 µm, about 175 µm, about 200 µm, about 225 µm, about 250 µm, about 275 µm, about 300 µm, about 325 µm, about 350 µm, about 375 µm, about 400 µm, about 425 µm, about 450 µm, about 475 µm, about 500 µm, about 525 µm, about 550 µm, about 575 µm, about 600 µm, about 625 µm, about 650 µm, about 675 µm, about 700 µm, about 725 µm, about 750 µm, about 775 µm, about 800 µm, about 825 µm, about 850 µm, about 875 µm, about 900 µm, about 925 µm, about 950 µm, about 975 µm, about 1,000 µm, about 1,025 µm, about 1,050 µm, about 1,075 µm, about 1,100 µm, about 1,125 µm, about 1,150 µm, about 1,175 µm, or about 1,200 µm. In one embodiment, the diameter of the pellets disclosed herein is the median diameter of the pellets. In one embodiment, the D50 of the pellets is about 100 to 1,200 µm, about 100 to 1,000 µm, about 200 to 1,000 µm, about 200 to 900 µm, about 200 to 800 µm, about 200 to 700 µm, about 200 to 600 µm, about 300 to 600 µm, about 300 to 500 µm, about 300 to 475 µm, about 375 to 475 µm, or about 400 to 450 µm. In one embodiment, the D50 of the pellets is about 400 to 450 µm. In one embodiment, the D50 of the pellets is about 25 µm, about 50 µm, about 75 µm, about 100 µm, about 125 µm, about 150 µm, about 175 µm, about 200 µm, about 225 µm, about 250 µm, about 275 µm, about 300 µm, about 325 µm, about 350 µm, about 375 µm, about 400 µm, about 425 µm, about 450 µm, about 475 µm, about 500 µm, about 525 µm, about 550 µm, about 575 µm, about 600 µm, about 625 µm, about 650 µm, about 675 µm, about 700 µm, about 725 µm, about 750 µm, about 775 µm, about 800 µm, about 825 µm, about 850 µm, about 875 µm, about 900 µm, about 925 µm, about 950 µm, about 975 µm, about 1,000 µm, about 1,025 µm, about 1,050 µm, about 1,075 µm, about 1,100 µm, about 1,125 µm, about 1,150 µm, about 1,175 µm, or about 1,200 µm.

[0044] In one embodiment, the porosity of the plurality of pellets, as measured by BET, is greater than about 3.0 x 10-3mL / g, greater than about 4.0 x 10-3mL / g, greater than about 5.0 x 10-3mL / g, greater than about 6.0 x 10-3mL / g, greater than about 7.0 x 10-3mL / g, greater than about 8.0 x 10-3mL / g, greater than about 9.0 x 10-3mL / g, or greater than about 10.0 x 10-3mL / g. In one embodiment, the porosity of the plurality of pellets, as measured by BET, lies in the range of about 3.0 x 10-3to 9.0 x 10-3mL / g, about 3.5 x 10-3to 9.0 x 10-3mL / g, or about 3.5 x 10-3to 8.8 x 10-3mL / g. In one embodiment, the porosity of the plurality of pellets, as 11 DB1 / 148490793.1Attorney Docket No.059717-5025-WO measured by nitrogen adsorption, lies in the range of about 3.0 x 10-3to 9.0 x 10-3mL / g, about 3.5 x 10-3to 9.0 x 10-3mL / g, or about 3.5 x 10-3to 8.8 x 10-3mL / g. In one embodiment, the porosity of the plurality of pellets, as measured by nitrogen adsorption, is between about 3.0 x 10-3mL / g and about 3.5 x 10-3mL / g. In one embodiment, the porosity of the plurality of pellets, as measured by nitrogen adsorption, is about 3.0 x 10-3mL / g, about 3.5 x 10-3mL / g, about 4.0 x 10-3mL / g, about 4.5 x 10-3mL / g, about 5.0 x 10-3mL / g, about 5.5 x 10-3mL / g, about 6.0 x 10-3mL / g, about 6.5 x 10-3mL / g, about 7.0 x 10-3mL / g, about 7.5 x 10-3mL / g, about 8.0 x 10-3mL / g, about 8.5 x 10-3mL / g, or about 9.0 x 10-3mL / g. In one embodiment, the plurality of pellets is more porous than commercially available MCC or sugar pellets.

[0045] In one embodiment, the pellets comprise pores with an average pore size of greater than about 5.0 nm, greater than about 10 nm, greater than about 15 nm, greater than about 20 nm, greater than about 25 nm, greater than about 30 nm, or greater than about 35 nm. In one embodiment, the pellets comprise pores with an average pore size in the range of about 7.0 nm to about 50.0 nm, about 7.0 nm to about 45.0 nm, about 7.0 nm to about 40.0 nm, about 7.0 nm to about 35.0 nm, about 7.0 nm to about 30.0 nm, about 7.0 nm to about 25.0 nm, or about 7.0 nm to about 22.0 nm. In one embodiment, the pellets comprise pores with an average pore size of 5.0 nm. In one embodiment, the pellets comprise pores with an average pore size of about 5.0 nm, about 6.0 nm, about 7.0 nm, about 8.0 nm, about 9.0 nm, about 10.0 nm, about 11.0 nm, about 12.0 nm, about 13.0 nm, about 14.0 nm, about 15.0 nm, about 16.0 nm, about 17.0 nm, about 18.0 nm, about 19.0 nm, about 20.0 nm, about 21.0 nm, about 22.0 nm, about 23.0 nm, about 24.0 nm, about 25.0 nm, about 26.0 nm, about 27.0 nm, about 28.0 nm, about 29.0 nm, about 30.0 nm, about 31.0 nm, about 32.0 nm, about 33.0 nm, about 34.0 nm, about 35.0 nm, about 36.0 nm, about 37.0 nm, about 38.0 nm, about 39.0 nm, about 40.0 nm, about 41.0 nm, about 42.0 nm, about 43.0 nm, about 44.0 nm, about 45.0 nm, about 46.0 nm, about 47.0 nm, about 48.0 nm, about 49.0 nm, or about 50.0 nm.

[0046] In one embodiment, the pellets have a friability of less than about 0.5, less than about 0.45, less than about 0.4, less than about 0.35, less than about 0.30, less than about 0.25, less than about 0.2, less than about 0.15, less than about 0.1, or less than about 0.05. In one embodiment, the pellets have a friability of about zero or essentially zero. 12 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0047] In one embodiment, the pellets have a sphericity of greater than about 0.90, greater than about 0.91, greater than about 0.92, greater than about 0.93, greater than about 0.94, greater than about 0.95, greater than about 0.96, greater than about 0.97, greater than about 0.98, or greater than about 0.99. In one embodiment, the pellets have a sphericity of about 0.70, about 0.71, about 0.72, about 0.73, about 0.74, about 0.75, about 0.76, about 0.77, about 0.78, about 0.79, about 0.80, about 0.81, about 0.82, about 0.83, about 0.84, about 0.85, about 0.86, about 0.87, about 0.88, about 0.89, about 0.90, about 0.91, about 0.92, about 0.93, about 0.94, about 0.95, about 0.96, about 0.97, about 0.98, or about 0.99.

[0048] In one embodiment, the pellets have a specific surface area, as measured by BET or DFT, of about 0.1 to 10.0 m2 / g, about 0.1 to 9.0 m2 / g, about 0.1 to 8.0 m2 / g, about 0.1 to 7.0 m2 / g, about 0.1 to 6.0 m2 / g, about 0.5 to 6.0 m2 / g, about 0.5 to 5.0 m2 / g, about 0.5 to 4.0 m2 / g, about 0.75 to 3.5 m2 / g, about 0.75 to 3.0 m2 / g, about 0.75 to 2.5 m2 / g, or about 0.9 to 2.3 m2 / g.

[0049] In one embodiment, the pellets dissolve faster than commercially available MCC or sugar pellets. In one embodiment, about 30% to 50% of each pellet dissolves in about 10 minutes, about 50% to 65% of each pellet dissolves in about 15 minutes, about 70% to 85% of each pellet dissolves in about 30 minutes, about 80% to 95% of each pellet dissolves in about 60 minutes, about 90% or greater of each pellet dissolves in about 240 minutes.

[0050] In one embodiment, the pellets comprise a binder. In one embodiment, the binder comprises polyvinyl pyrrolidone (PVP). In one embodiment, the binder is PVP. In one embodiment, the PVP is PVP K30. In one embodiment, the binder comprises a cellulose derivative. In one embodiment, the cellulose derivative comprises hydroxypropyl methylcellulose (HPMC). In one embodiment, the HPMC is HPMC E5. In one embodiment, the cellulose derivative comprises hydroxypropyl cellulose (HPC). In one embodiment, the binder comprises maltodextrin, gelatin, or starch.

[0051] In one embodiment, the pellets comprise a glidant or a lubricant. In one embodiment, the glidant or lubricant are selected from colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate (SSF), talc, and glyceryl monostearate. In one embodiment, the pellets comprise about 0.001% to 25%, about 0.001% to 20%, about 0.001% to 15%, about 0.001% to 10%, about 0.01% to 5%, or about 0.05% to 2.5% by weight of the glidant or lubricant. In one embodiment, the pellets comprise a super disintegrant. In one embodiment, the super 13 DB1 / 148490793.1Attorney Docket No.059717-5025-WO disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and magnesium aluminum silicate.

[0052] In one embodiment, the pellets comprise an active pharmaceutical ingredient (API). In one embodiment, the pellets are coated with the API. In one embodiment, the pellets are completely coated with the API. In another embodiment, the pellets are partially coated with the API. In one embodiment, the API coating further comprises a drug binder and / or an anti- tacking agent. In one embodiment, the drug binder and / or anti-tacking agent comprises hydroxypropyl methyl cellulose (HPMC), PVP, gelatin, talc, or starch. In one embodiment, the API coating comprises both HPMC and talc. In one embodiment, the API is a poorly soluble API. In one embodiment, the API is poorly soluble in water. In one embodiment, the API is poorly soluble in the mouth, esophagus, or stomach of a subject. In one embodiment, the API is a proton pump inhibitor, an antihistamine, a pain killer, a beta blocker, a calcium channel blocker, an anti-erectile dysfunction agent, an anti-migraine agent, or a non-steroidal anti- inflammatory. In one embodiment, the API is cetirizine, diclofenac, lansoprazole, omeprazole, pantoprazole, esomeprazole, metoprolol, propranolol, montelukast, albuterol, ibuprofen, sildenafil, zolpidem, furosemide, amlodipine, tramadol, atenolol, niacin, paroxetine, nifedipine, venlafaxine, desvenlafaxine, naproxen, famotidine, guaifenesin, bisoprolol, tadalafil, chlorpheniramine maleate, pseudoephedrine hydrochloride, indomethacin, disopyramide phosphate, diltiazem hydrochloride, carbamazepine, verapamil hydrochloride, tolterodine tartrate, methylphenidate hydrochloride, carvedilol phosphate, memantine hydrochloride, budesonide, mesalamine, and sumatriptan or a pharmaceutically salt of any one thereof. In one embodiment, the API is a prazole API disclosed herein, including but not limited to, lansoprazole, cetirizine, and naproxen.

[0053] In one embodiment, the API coating is coated with an additional coating. In one embodiment, the additional coating comprises a polymer. In one embodiment, the polymer comprises cellulose, ethylcellulose, methacrylic acid copolymer, dimethyl amino methacrylate, butyl methacrylate, or methyl methacrylate copolymer. In one embodiment, the additional coating further comprises a plasticizer. In one embodiment, the plasticizer is selected from triethyl citrate, dibutyl sebacate, PEG, a fractionated coconut oil, a citrate ester, or a phthalate ester. 14 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0054] In one embodiment, the pellets can comprise inactive ingredients including, but not limited to, colorants, flavors, sodium lauryl sulfate, calcium carbonate, tartaric acid, citric acid, alginic acid, titanium oxide, pH adjusters, surface active agents, or combinations thereof.

[0055] In one embodiment, the pellet comprises a pH modifying material. In one embodiment, the pH modifying material comprises an organic acid. In one embodiment, the organic acid is selected from formic acid, acetic acid, propionic acid, butyric acid, lactic acid, sorbic acid, fumaric acid, malic acid, tartaric acid, or citric acid. In one embodiment, the organic acid is tartaric acid or citric acid. In one embodiment, a plurality of pellets is suspended in a solution with a pH modifying agent. In one embodiment, the pH modifying agent is an organic acid. Exemplary organic acids are described elsewhere herein.

[0056] In one embodiment, the pellets are water soluble. Although not wishing to be limited by theory, insoluble materials can interfere with the full delivery of an API. Although not wishing to be limited by theory, insoluble materials can also become an issue in the formation of complete solutions, plugging needles and filters. In one embodiment, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of each pellet is water soluble. Method of Manufacture

[0057] In another aspect, the present disclosure provides a method of making a plurality of pellets, comprising extrusion spheronization of a wet mass comprising an insoluble component or a cellulose component and a soluble filler; and drying the extrudates to form the plurality of pellets described elsewhere herein.

[0058] In one embodiment, the extrusion spheronization is preceded by the step of dry mixing the insoluble component or cellulose component and the soluble filler. In one embodiment, the dry mixing step is followed by adding water to the mixture of the insoluble component or cellulose component and the soluble filler to form the wet mass. In some embodiments, a mixture of the binder and water is added to the mixture of the insoluble component or cellulose component and the soluble filler to form the wet mass.

[0059] In one embodiment, the extrusion spheronization step comprises transferring the wet mass to extruder, forming extrudes, and spheronizing the formed extrudes to form pellets of the 15 DB1 / 148490793.1Attorney Docket No.059717-5025-WO disclosure. In one embodiment, the drying step comprises drying the pellets in a fluidized bed dryer.

[0060] In yet another aspect, the present disclosure provides a method of making a plurality of pellets comprising powder layering an insoluble component or a cellulose component and a soluble filler. In yet another aspect, the present disclosure provides a method of making a plurality of pellets comprising tumbling a mixture of an insoluble component or a cellulose component and a soluble filler in a rotary drum granulator.

[0061] In one embodiment, the method further comprises sieving the pellets. In one embodiment, the sieving separates pellets with the desired size range and / or desired sphericity range.

[0062] In one embodiment, the method further comprises coating the pellets with an active pharmaceutical ingredient (API) coating described elsewhere herein. In one embodiment, the method comprises coating the pellets with an aqueous powder coating or dry powder coating comprising the API. In one embodiment, the coating is applied using a conventional pan system, a perforated pan system, fluidized bed coating, or rotating disk granulation.

[0063] The conventional pan system coating consists of a circular metal pan mounted at an angle on a stand, the pan is rotated on its horizontal axis by a motor, the hot air is directed into the pan and onto the bed surface, and is exhausted by means of ducts positioned through the front of the pan. Coating solutions are applied by spraying the material on the bed surface. As coating is applied, the coating solution is dried off. It is common to dust powder mixtures onto wetted beads and dry the beads in layers. A final color and seal coating is often applied.

[0064] The perforated pan system has perforations along its cylindrical portion. It is driven by a variable speed drive. A supply of hot air and an exhaust of drying air are arranged to facilitate the coating system through stainless steel plenums positioned on both sides of the perforated coating pan. The pan is enclosed in an airtight housing provided with a suitable door and front glass window.

[0065] In a fluidized bed, a coat is introduced to cover the pellets inside the bed. In the process, a layer is deposited onto the surface of fluidized solid pellets by spraying them with a solution of the coating material. The fluidizing gas is also used to dry the deposited solution. There is considerable diversity in methods of using fluidized bed technology. For example, liquids can be 16 DB1 / 148490793.1Attorney Docket No.059717-5025-WO applied to fluidized pellets in a variety of ways, including top, bottom, and tangential spraying. For a given product, each method can offer markedly different finished product characteristics.

[0066] Fluidized beds are used for coating because of their high energy and mass transfer. Fluidized beds for film coating can be divided into three groups: top spray, tangential spray, and bottom-spray equipment. In the top spray bed, the expansion chamber is lengthened to allow powder to remain fluidized longer and to move with a higher velocity, so that agglomeration is minimized. The expansion chamber is conically shaped to allow uniform deceleration of air stream. The filter housing is larger and designed to shake the fines back into the bed interrupting fluidization; this reduces agglomeration tendencies. The nozzle is positioned low in the expansion chamber so that coating material impinge on the fluidized pellet a short distance from the nozzle; this reduces droplet spray drying and provides for longer subsequent drying of the coated particles. The top spray coater has been used to apply aqueous and organic solvent-based film coatings, controlled release coatings. Smaller pellets coated using this technique would allow for smaller final beads and / or thicker coatings. In bottom spray coating, the Wurster machine employs a cylindrical product container with a perforated plate. Inside the container is a second cylinder (coating partition) which is raised slightly above the perforated plate. Centered in the plate below this partition, is a spray nozzle used to dispense the coating solution. The perforated plated is designed with large holes in the area under the coating partition and smaller holes in the remainder of the plate, except for one ring of large holes at the perimeter. The design allows the pellets to be pneumatically transported upward through the coating partition, and downward outside this partition. Material passing through coating partition receives a layer of coating material, dries in the expansion chamber, and falls back in a semi fluidized state. Material circulates rapidly in this fashion and receives a layer of coating material, dries in the expansion chamber, and falls back in a semi fluidized state material circulates rapidly in this fashion and receives a layer of coating on each pass through the coating partition. The ring of large holes on the periphery of perforated plate prevents the accumulation of material at the container wall. This method can be used for coating small pellets, beads, tablets, and capsules.

[0067] The tangential spraying system, which is commonly fitted with a rotating bottom plate, can achieve film quantities nearly as good as the bottom spraying system. The rotation of the 17 DB1 / 148490793.1Attorney Docket No.059717-5025-WO plate nicely supports product movement, so that the required air amount is mainly used for drying process and only to a smaller degree for the product movement.

[0068] Rotating disk granulation utilizes a centrifugal fluidizing disk that can be moved up or down to create a variable slit opening between the outer perimeter of the disk and the sidewall of the container. Air is drawn into the product container through the slit under negative pressure. This fluidizes the material along the circumferential surface of the product container. At the same time, the disk rotates at varying speeds and moves the product by the centrifugal force to the outer portions where it is lifted by the fluidizing air stream into the expansion chamber. As the material decelerates, it descends to the center of the disk and repeats the same sequence. The fluidization pattern is often described as a spiraling helix or rope-like pattern around the inside of the rotor chamber.

[0069] Spray nozzles can be immersed in the bed of fluidized material and spray applied in tangential fashion with respect to the pellet flow. Coating pellets using this process allows for a starting controlled surface onto which the coating powder with API can be layered onto and held by a spray solution of coating materials in a rapid layering application approach. Based on the uniformity of both shape and size, these pellets allow for a uniform and rapid gain in weight and maintain separation readily versus standard crystal seeds currently used and starter material.

[0070] In some embodiments, the method comprises spraying the API coating on the pellets. In one embodiment, the spraying comprises spray atomization. In one embodiment, the API coating is dried. In one embodiment, the API coating is cured.

[0071] In one embodiment, the method further comprises sieving the API coated pellets. In one embodiment, the sieving separates pellets with the desired size range and / or desired sphericity range.

[0072] In one embodiment, the method further comprises coating the API coating with an additional coating described elsewhere herein. In one embodiment, the additional coating can be applied using a technique described elsewhere herein. In one embodiment, the additional coating is applied by spraying. In one embodiment, the spraying comprises spray atomization. In another embodiment, the additional coating is applied used a dry coating method. In one embodiment, the dry coating method is powder layering. In one embodiment, the additional coating is dried. In one embodiment, the additional coating is cured. 18 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0073] In one embodiment, the method further comprises sieving the pellets coated with the additional coating. In one embodiment, the sieving separates pellets with the desired size range and / or desired sphericity range. Uses of the Pellets

[0074] The pellets of the present disclosure are useful in various applications. In one embodiment, the pellets of the disclosure are useful in the manufacture of sustained and modified release beads for dosing active pharmaceutical ingredients (APIs) as multi-particulate systems or multiple unit particulate systems (MUPS). In one embodiment, the MUPS particles can further be processed into tablets, orally dispersible tablets, or mini tablets. In another embodiment, the MUPS particles can be filled into hard gelatin capsules. In yet another embodiment, the MUPS particles can be used in reconstitutable suspensions and in softgels. In another embodiment, the pellets are useful are carriers for APIs for subsequent manufacture into tablets. In another embodiment, the pellets are useful as a free-flowing excipient in the manufacture of mini-tablets. In another embodiment, the pellets are useful in the manufacture of API dispersions.

[0075] In one embodiment, the pellets are useful as a core onto which an API is layered either in a suspension, a solution, or a dry powder alternated with a solution to create a tacky surface and, if needed, a functional coating also applied. In some embodiments, the pellets are useful as a core which can be coated with an immediate, modified, and / or sustain released API and then included in sachets, capsules, and tablet formulations. In some embodiments, the pellets are useful as cores for coating with an API by a lyophilization process. In some embodiments, the pellet coated with API is referred to as a “bead.” In one embodiment, the pellet coated with an API and then further coated with the additional coating is referred to as a “bead.” In some embodiments, the pellets are useful for sachets and chewable tablets to reduce damage (to the API) during chewing, and to improve the mouthfeel of the tablet. In some embodiments, the porous pellets of the present disclosure can be used in all dosage forms to reduce final bead size yet allow for high API dose loading. In some embodiments, the pellets are useful as they may allow for a greater thickness of API coating and thus a wider range of release rate options for use of thicker coatings giving a slower release. In some embodiments, the pellets are useful as they may reduce the localized concentration of an irritative drug by providing a greater surface area. In one embodiment, the pellets are used as carriers for micronized APIs to achieve better content 19 DB1 / 148490793.1Attorney Docket No.059717-5025-WO uniformity of the active when blended with the API than could otherwise be achieved. In one embodiment, the pellets are used as cushioning or binding agents in conjunction with other taste masked or large particle APIs to give less segregation in blending processes and, given the inherent mouth feel and size, provide better organoleptics than MCC only pellets when formulated into orally disintegrating tablets (ODTs). Dosage Forms

[0076] In yet another aspect, the present disclosure provides a dosage form comprising the plurality of pellets described elsewhere herein. In one embodiment, the dosage form is a solid dosage form.

[0077] In one embodiment, the pellets or coated pellets (beads) may be used in a variety of dosage forms including, but not limited to, chewable tablets, swallow tablets, soft chews including tablets and soft gel capsules, orally disintegrating tablets, orally dispersible powders, mini-tablets, lozenges, film strips, gums, gels, ointments and creams, tablet inserts (eye, ear, vaginal), suppositories, hard shell capsules, liquid fill capsules, liquid suspensions, controlled release pills / tablets / gelcaps / capsules, and sustained release pills / tablets / gelcaps / capsules. In one embodiment, the dosage form is a swallowable tablet, a chewable tablet, or an orally disintegrating tablet.

[0078] In some embodiments, the dosage form may include a pharmaceutically acceptable ingredient including excipients, diluents, disintegrants, binders, fillers, bulking agent, organic acid(s), colorants, stabilizers, preservatives, lubricants, glidants / anti-adherants, chelating agents, cushioning agents, vehicles, bulking agents, stabilizers, preservatives, tonicity adjusting agents, local anesthetics, pH adjusting agents, antioxidants, osmotic agents, chelating agents, viscosifying agents, wetting agents, emulsifying agents, acids, sugar alcohol, reducing sugars, non-reducing sugars and the like used either alone or in combination thereof. In some embodiments, the pharmaceutically acceptable ingredients may include excipients, binders, lubricants, sugar alcohols, disintegrating agents, colors, flavors and the like used either alone or combinations thereof. In one embodiment, the solid dosage form comprises at least one of a cushioning agent, a disintegrant, a lubricant, a glidant, and a filler.

[0079] In one embodiment, the pellets or beads of the disclosure or a composition comprising the pellets / beads and one or more pharmaceutically acceptable ingredients, may be used in a 20 DB1 / 148490793.1Attorney Docket No.059717-5025-WO directly compressible dosage form. The term “directly compressible” means that the pellets / beads or composition comprising the pellets / beads can be compressed to tablet form on standard tableting machines (including, but not limited to, high speed tableting machines) using standard (i.e., without any specially machined, shaped, or coated surfaces) punches and dies, without any significant amount of the pellets / beads or composition comprising the pellets / beads adhering to the punches and dies by applying compressive pressure to the composition. In some embodiments, the compression pressure ranges from 60 MPa to 170 MPa. In some embodiments, the compression force ranges from 80 MPa to 150 MPa. In some embodiments, the compression pressure is at least 60 MPa.

[0080] The term “pharmaceutical formulation” as used herein refers to formulations containing the composition of the present disclosure in combination with carriers or excipients suited to a selected drug delivery platform, e.g., a capsule, an orally dispersible formulation, an effervescent formulation, a chewable tablet, a lozenge, a hard or swallow tablet, an orally dispersible powder, or the like.

[0081] “Carriers” or “vehicles” as used herein refer to carrier materials suitable for oral drug administration, and include any such materials known in the art, e.g., diluents, binders, granulating agents, disintegrants, lubricating agents, colorants, flavoring agents, and the like.

[0082] Various types of pharmaceutical formulations may be prepared using the presently disclosed pellets, beads, and compositions, including powders, chewable tablets, orally dissolving tablets, effervescent formulations, and liquid dispersions. For solid formulations such as powders, chewable tablets, orally dissolving tablets, and effervescent formulations, conventional carriers, excipients, and additives can be employed, including diluents, binders, granulating agents, disintegrants, flavoring additives, and the like. Examples of the normally employed excipients include pharmaceutical grades of mannitol, lactose, starch, and the like. Liquid pharmaceutical compositions containing the present pellets or beads will generally be prepared by dispersing or suspending the pellets or beads in a non-aqueous carrier which does not cause release of the drug, or else by dispersing the pellets, beads, or composition in an aqueous carrier immediately prior to administration to the patient. For example, the pellets, beads, or composition may be provided as a free-flowing particulate material, as in a sachet or other suitable package, and such a particulate material may be dispersed in an aqueous carrier. 21 DB1 / 148490793.1Attorney Docket No.059717-5025-WO These solid or liquid formulations may contain any amount of the pellets, beads, or composition needed to provide the desired amount of the active ingredient contained in the pellet, bead, or composition. For example, amounts of pellets, beads, or a composition comprising the pellets / beads on the order of about 10 wt. % to about 95 wt. % of the dosage form may be used. In some embodiments, the non-aqueous carrier or aqueous carrier comprises a pH modifying material. In one embodiment, the pH modifying material comprises an organic acid. Exemplary organic acids are described elsewhere herein. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art.

[0083] It will be apparent to one of skill in the art that various modifications and variations can be made in the methods and compositions of the present disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that the present disclosure covers the modifications and variations of the present disclosure provided they come within the scope of the appended claims and their equivalents. Methods of Treating a Disease / Disorder

[0084] In yet another aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a plurality of beads described herein, a composition comprising a plurality of beads described herein, or a solid dosage form comprising a plurality of beads described herein. In one embodiment, the beads comprise an MCC:mannitol “core” pellet coated with an API coating. In another embodiment, the beads comprise an MCC:mannitol “core” pellet coated with an API coating wherein the API coating is further coated with an additional coating.

[0085] In one embodiment, the disease or disorder is a gastrointestinal disorder, an allergy (such as seasonal allergies), inflammation, inflammatory disease or disorder, or pain.

[0086] The API can be any poorly soluble API known to a person of skill in the art to treat a disease or disorder in the subject. Exemplary APIs are disclosed elsewhere herein. Clauses of the Disclosure

[0087] Clause 1. A plurality of pellets comprising a cellulose component and a soluble filler in a weight / weight ratio of cellulose component to soluble filler of from about 50:50 to about 20:80, wherein the porosity of the plurality of pellets, ranges from about 3.0 x 10-3to about 9.0 22 DB1 / 148490793.1Attorney Docket No.059717-5025-WO x 10-3mL / g, the plurality of pellets comprising pores having an average pore size in the range of about 7.0 to about 22.0 nm.

[0088] Clause 2. The plurality of pellets of clause 1, wherein porosity is as measured by nitrogen adsorption.

[0089] Clause 3. The plurality of pellets of clause 1 or 2, wherein the cellulose component comprises one or more of microcrystalline cellulose (MCC), silicified MCC, hydroxypropyl methyl cellulose, methyl cellulose, and / or sodium carboxymethyl cellulose.

[0090] Clause 4. The plurality of pellets of clause 3, wherein the cellulose component consists essentially of MCC.

[0091] Clause 5. The plurality of pellets of clause 3, wherein the cellulose component consists essentially of silicified MCC.

[0092] Clause 6. The plurality of pellets of clause 5, wherein the silicified MCC is SMCC 90.

[0093] Clause 7. The plurality of pellets of any one of clauses 1 to 6, wherein the soluble filler comprises a polyol.

[0094] Clause 8. The plurality of pellets of clause 7, wherein the polyol is selected from mannitol, erythritol, sorbitol, maltitol, isomalt, and xylitol.

[0095] Clause 9. The plurality of pellets of clause 8, wherein the polyol is mannitol.

[0096] Clause 10. The plurality of pellets of any one of clauses 1 to 6, wherein the soluble filler comprises a sugar.

[0097] Clause 11. The of pellets of clause 10, wherein the sugar is lactose or sucrose.

[0098] Clause 12. The plurality of pellets of any one of clauses 1 to 11, wherein the pellets comprise about 60% to about 70%, or about 70% to about 80% by weight of the soluble filler.

[0099] Clause 11. The plurality of pellets of any one of clauses 1 to 10, wherein the weight / weight ratio of the cellulose component to the soluble filler is about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, or about 1:4.

[0100] Clause 12. The plurality of pellets of any one of clauses 1 to 11, wherein the pellets have a median diameter of about 100 µm to about 1,200 µm.

[0101] Clause 13. The plurality of pellets of any one of clauses 1 to 12, wherein the pellets have a median diameter of about 100 to about 600 µm, or about 375 to about 475 µm. 23 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0102] Clause 14. The plurality of pellets of any one of clauses 1 to 13, wherein the pellets have a sphericity of at least 0.90.

[0103] Clause 15. The plurality of pellets of any one of clauses 1 to 14, wherein the pellets have a friability of less than about 0.3.

[0104] Clause 16. The plurality of pellets of any one of clauses 1 to 14, wherein the pellets have a friability of less than about 0.1.

[0105] Clause 17. The plurality of pellets of any one of clauses 1 to 16, wherein the pore sizes follow a bimodal pore size distribution.

[0106] Clause 18. The plurality of pellets of any one of clauses 1 to 17, wherein the cellulose component used as a starting material to manufacture the pellets has a density of about 0.26 to about 0.31 g / mL.

[0107] Clause 19. The plurality of pellets of any one of clauses 1 to 18, wherein the pellets further comprise a binder.

[0108] Clause 20. The plurality of pellets of clause 19, wherein the binder comprises polyvinyl pyrrolidone (PVP).

[0109] Clause 21. The plurality of pellets of clause 20, wherein the PVP is PVP K30.

[0110] Clause 22. The plurality of pellets of clause 19, wherein the binder comprises a cellulose derivative.

[0111] Clause 23. The plurality of pellets of clause 22, wherein the cellulose derivative consists essentially of hydroxypropyl methylcellulose (HPMC).

[0112] Clause 24. The plurality of pellets of clause 23, wherein the HPMC is HPMC E5.

[0113] Clause 25. The plurality of pellets of clause 19, wherein the binder comprises maltodextrin, gelatin, or starch.

[0114] Clause 26. The plurality of pellets of any one of clauses 1 to 25, wherein the pellets further comprise a glidant or a lubricant.

[0115] Clause 27. The plurality of pellets of clause 25, wherein the glidant or lubricant is selected from colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, and glyceryl monostearate. 24 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0116] Clause 28. The plurality of pellets of clause 26 or 27, wherein the pellets comprise about 0.001% to about 10%, about 0.01% to about 5%, or about 0.05% to about 2.5% by weight of the glidant or lubricant.

[0117] Clause 29. The plurality of pellets of any one of clauses 1 to 28, wherein the pellets further comprise a super disintegrant.

[0118] Clause 30. The plurality of pellets of clause 29, wherein the super disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and magnesium aluminum silicate.

[0119] Clause 31. The plurality of pellets of any one of clauses 1 to 30, wherein the pellets further comprise an active pharmaceutical ingredient (API).

[0120] Clause 32. The plurality of pellets of clause 31, wherein the pellets are coated with a first coating comprising the API.

[0121] Clause 33. The plurality of pellets of clause 31 or 32, wherein the API is selected from a proton pump inhibitor, an antihistamine, a pain killer, a beta blocker, a calcium channel blocker, an anti-erectile dysfunction agent, an anti-migraine agent, or a non-steroidal anti-inflammatory.

[0122] Clause 34. The plurality of pellets of any one of clauses 31 to 33, wherein the API is selected from cetirizine, diclofenac, lansoprazole, omeprazole, pantoprazole, esomeprazole, metoprolol, propranolol, montelukast, albuterol, ibuprofen, sildenafil, zolpidem, furosemide, amlodipine, tramadol, atenolol, niacin, paroxetine, nifedipine, venlafaxine, desvenlafaxine, naproxen, famotidine, guaifenesin, bisoprolol, tadalafil, chlorpheniramine maleate, pseudoephedrine hydrochloride, indomethacin, disopyramide phosphate, diltiazem hydrochloride, carbamazepine, verapamil hydrochloride, tolterodine tartrate, methylphenidate hydrochloride, carvedilol phosphate, memantine hydrochloride, budesonide, mesalamine, and sumatriptan or a pharmaceutically salt of any one thereof.

[0123] Clause 35. The plurality of pellets of any one of clauses 32 to 34, wherein the pellets are coated with a second coating substantially covering the first coating comprising the API.

[0124] Clause 36. The plurality of pellets of clause 35, wherein the second coating comprises a polymer. 25 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0125] Clause 37. The plurality of pellets of clause 36, wherein the polymer is selected from cellulose, ethylcellulose, methacrylic acid co polymer, dimethyl amino methacrylate, butyl methacrylate, and methyl methacrylate copolymer.

[0126] Clause 38. A method of making the plurality of pellets of any one of clauses 1 to 37, the method comprising extrusion spheronization of a wet mass comprising the cellulose component and the soluble filler and drying the extrudates to form the plurality of pellets.

[0127] Clause 39. A method of making the plurality of pellets of any one of clauses 1 to 37, the method comprising powder layering the cellulose component and the soluble filler to form the plurality of pellets.

[0128] Clause 40. The method of clause 38 or 39, further comprising coating the plurality of pellets with a first coating comprising an active pharmaceutical ingredient (API).

[0129] Clause 41. The method of clause 40, wherein the coating step comprises aqueous powder coating or dry powder coating.

[0130] Clause 42. The method of clause 40 or 41, wherein the API is selected from a proton pump inhibitor, an antihistamine, a pain killer, a beta blocker, a calcium channel blocker, an anti-erectile dysfunction agent, an anti-migraine agent, or a non-steroidal anti- inflammatory.

[0131] Clause 43. The method of any one of clauses 40 to 42, wherein the API is selected from cetirizine, diclofenac, lansoprazole, omeprazole, pantoprazole, esomeprazole, metoprolol, propranolol, montelukast, albuterol, ibuprofen, sildenafil, zolpidem, furosemide, amlodipine, tramadol, atenolol, niacin, paroxetine, nifedipine, venlafaxine, desvenlafaxine, naproxen, famotidine, guaifenesin, bisoprolol, tadalafil, chlorpheniramine maleate, pseudoephedrine hydrochloride, indomethacin, disopyramide phosphate, diltiazem hydrochloride, carbamazepine, verapamil hydrochloride, tolterodine tartrate, methylphenidate hydrochloride, carvedilol phosphate, memantine hydrochloride, budesonide, mesalamine, and sumatriptan or a pharmaceutically salt of any one thereof.

[0132] Clause 44. The method of any one of clauses 40 to 43, further comprising coating the pellets with a second coating.

[0133] Clause 45. The method of clause 44, wherein the second coating comprises a polymer. 26 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0134] Clause 46. The method of clause 45, wherein the polymer is selected from cellulose, ethylcellulose, methacrylic acid co polymer, dimethyl amino methacrylate, butyl methacrylate, and methyl methacrylate copolymer.

[0135] Clause 47. A solid dosage form comprising the plurality of pellets of any one of clauses 1 to 37.

[0136] Clause 48. The solid dosage form of clause 47, wherein the solid dosage form is a swallowable tablet, a chewable tablet, or an orally disintegrating tablet.

[0137] Clause 49. The solid dosage form of clause 47 or 48, wherein the solid dosage form further comprises a cushioning agent, a disintegrant, a lubricant, a glidant, and / or a filler.

[0138] Clause 50. A method of treating a disease or disorder in a subject, comprising administering to the subject the plurality of pellets of any one of clauses 1 to 38, or the solid dosage form of any one of clauses 47 to 49.

[0139] Clause 51. The method of clause 50, wherein the disease or disorder is selected from a gastrointestinal disorder, allergies, inflammation, and pain. EXAMPLES

[0140] The following examples are given to illustrate the present disclosure. It should be understood, however, that the disclosure is not to be limited to the specific conditions or details described in these examples. Throughout the specification, any and all referenced publicly available documents, including but not limited to a U.S. patent, are specifically incorporated by reference. Example 1: Mannitol:MCC Pellets Introduction

[0141] A pellet system was developed comprising mannitol and other excipients as necessary (e.g., MCC). The pellets have a synergistic functionality in terms of solubility, robustness, and reproducibility of shape. These pellets are intended to be used as a core substrates for drug layering of API to form a bead and subsequent modification of drug release by application of an outer polymeric membrane. The disclosed pellet system offers significant advantages to the formulator over existing pellets. Ultimately, a range of different pellet cores could be formulated that differ in terms of particle size and composition so that a specific bead 27 DB1 / 148490793.1Attorney Docket No.059717-5025-WO could be chosen according to the more specific needs of the API that is being used with the beads. The pellets can be coated with an API to form beads can be used with controlled release or taste masked formulations as well as for the development of orally disintegrating tablets (ODTs) and multiple unit particulate system (MUPS) tablets.

[0142] Extrusion spheronization was used to produce the pellets. Different ratios of the mannitol powder and MCC were tried though the extrusion and spheronization process to determine which one could extrude and then later spherulite to form pellets which were spherical in appearance. After optimizing the ratio of mannitol powder and MCC, the formed pellets were subjected to a set to studies for evaluating parameters like sphericity and aspect ratio. The advanced morphology was evaluated by determining the circularity, convexity, and elongation ratio. SEM was performed to understand the surface topography. All the tests were performed for three cores (sugar, MCC, and the mannitol:MCC cores disclosed herein).

[0143] Additionally, each pellet core was subjected to drug loading, followed by functional coating with ethyl cellulose. The dissolution pattern was checked for all three (sugar, MCC, and mannitol:MCC) beads and compared. The mannitol:MCC beads demonstrated physical superiority over commercially available cores. The dissolution trend also shows positive impact, and it includes advantages of both swellable and soluble cores. Commercially Available Products Table 1. Physical characterization of commercial MCC pellets (Cellets) Product Name Cellets 350 Cellets 500 Cellets 700 White or nearly White or nearly Wh iption white or beige, hard whi ite or nearly Descr te or beige, white o most spherical har r beige, hard and al d and almost spherical and almost spherical Odor Odorless Odorless Odorless Batch no. 21C1019 22D1010 21G1058 Manufactured byIPC Process-Center,IPC Process- IPC Process-Center, (Glatt)Center, (Glatt) (Glatt) Loss on Drying (%) 4.3 4.0 3.5 Bulk density (g / cc) 0.82 0.82 0.81 Sphericity degree 0.96 0.97 0.97 Friability (%) 0 0 0 Swelling Index 1.8 1.8 1.7 28 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Table 2. Physical characterization of commercial sugar pellets (Pharm-a-spheres) Product name Pharm-a-spheres DescriptionWhite or nearly white or beige, hard and almostsphericalOdor Odorless Batch no. 21C1019 Manufactured by IPC Process-Center, (Werner) Loss on Drying (%) 4.3 Bulk density (g / cc) 0.82 Sphericity degree 0.96 Friability (%) 0 Excipient Selection Table 3. Excipients selected for the pellets, including grades and category Category Excipient Name Grade Specification Manufacturer Pellet forming MannitolMannogemPowder USP, EP SPISpheronizing aidMicrocrystallineUSP / NF, cellulose PH 101 Ph EurDFEBinderPolyvinyl pyrrolidone(PVP K 30) PVP K 30 USP JH NanhangGlidant Colloidal Silicon (optional*)DioxideCabosil M 5PUSP / NF, Ph EurCabotLubricant Sodium stearyl eLubrifarUSP / NF, (optional)fumaratmPh EurSPIDrug binder for Hydroxypropyl Colorcon, drug loading methyl cellulose Methocel USP / NF, Joinway (low viscosity grade) Pharmaceuticals Anti tacking agentTalc Talc Ph Eur Loba ChemiePlasticizer Triethyl citrateTriethylcitrate Ph Eur VertilliusFunctional Ethylcellulose, ready Aquarius polymer to use dispersion Control USP / NF Ashland (ECD) Development of MCC Mannitol Pellets

[0144] The ratio of the key ingredients (mannitol and MCC) was varied and the output was evaluated based on how the wet mass was extruded. The spheronization capacity of the extruded mass was also noted. The particle size, sphericity, and aspect ratio were the initial test 29 DB1 / 148490793.1Attorney Docket No.059717-5025-WO parameters used to arrive at the optimum ratio for preparation of the pellets. Once the values for test parameters was satisfactory, the formulation was taken ahead for further evaluation and comparison with commercially available pellets. Additionally, advanced morphological studies were performed.

[0145] Determining the optimal ratio for preparing the pellets by extrusion spheronization

[0146] FIG.1 depicts the basic steps of the extrusion spheronization process. The general process included dry mixing of ingredients before formation of wet mass. The wet mass was formed by addition of solvent or a combination of solvent and binder as per the requirement. The wet mass was then transferred to the extruder. Extrusion was done at a suitable RPM and using a desired screen type and size. The extrudes so formed were immediately transferred to the spheronizer. The spheronizer RPM was set as per the requirement of size and time to achieve spherical pellets. After spheronization, the pellets were immediately shifted to a dryer. Drying was continued until the pellets are dried to a sufficient loss on drying (LOD). The evaluation is discussed below. Table 4. List of the equipment used in extrusion spheronization Process stepEquipmentTechnical name Manufacturerspecification Wet massing: Powders added Rapid Mixer to bowl, mixed and binder Granulator / Karnavati d; 2-3 mins Planetary mixer(India2 litresolution adde)Extrusion ExtruderFuji Paudal10 to 90 RPM, single (Japan)screw Spheronisation SpheronizerFuji Paudal(Japan) 600 to 1800 RPMDryingFluid BedACG Batch capacity: 350 Processor(India) to 900 g Screening Manual Manual40# - 60#30#- 40 #

[0147] Trial compilation for ratio finalization of Mannitol:MCC

[0148] Pellets comprising mannitol and MCC were made while varying the mannitol:MCC ratio. The formulations, ingredients and other process parameters are shown in Table 5. 30 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Table 5. Formulations and ingredients Batch number202 / 202 / 202 / 202 / 202 / 202 / 202 / E011E012 E013 E014 E015 E016 E017 Mannitol : MCC ratio 75:25 75:25 70:30 65:35 50:50 0:100 75:25 Mannitol (g) 150 150 140 130 100 150MCC (g) 50 50 60 70 100 200 50 PVP K 30 (g) 1 1 (toblend)1 1 1 N / A N / AWater (g) 70 70 70 90 120 220 70 Binder quantity used (g)71 71 71 91 121220 (water)70Wet mass formation Dry mixing (min) 2 min 2 min 2 min 2 min 2 min 2 min 2 min Dry mixing (RPM) 100 100 100 100 100 100 100 Binder addition and 30 per 30 per 30 per 30 per 30 per 30 per 30 per kneading (sec) step step step step step step step Kneading (RPM) 200 200 200 200 200 200 200 LOD of wet mass (%) 25 27.1 27.66 30.72 35.6 51.6 26.05 Extrusion Screen used (mm) 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Screen type radial radial radial radial radial radial radial extrusion (RPM) 30 30 30 30 30 30 30 Spheronization Spheronization (RPM) 1200 1200 1200 1200 1200 15001000 -1200Spheronization time (min)7 min 7 min 7 min 7 min 7 min 7 min 7 minDrying Drying temp (° C) 60 - 70 60 - 70 60 - 70 60 - 70 60 - 70 60 - 70 60 - 70 Drying time (min) 45 45 45 45 45 45 45 LOD after drying (%) Less than 1%

[0149] Procedure 1) Mannitol and MCC were weighed as per the requirement of the batch and passed through 30# sieve and hand mixed in a polybag. 31 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 2) PVP K 30 was added to water under stirring. (In a batch it was added as a dry binder directly in the blend). 3) The dry mix was transferred to the RMG and the further processing was continued based on the parameters mentioned in table above. 4) After the wet mass was formed, LOD was checked and noted. 5) The wet mass was transferred to the extruder and extrudes were formed. 6) The formed extrudes were spheronized and the pellets obtained were dried in a fluidized bed dryer.

[0150] Of the various ratios tried, mannitol:MCC = 65:35 fared the best with respect to extrusion process, the type of extrudes, and formation of rope movement during spheronization. Spherical pellets were formed using this ratio. Mannintol:MCC = 75:25 also fared well, but the pellets were slightly less spherical after spheronization. Table 6. Comparative particle size distribution and sphericity of the pellets. PSD (micron)Mann : MCC Batch No.AverageD10 D50 D90Sphericity*75:25 202 / E011 263 393 581 1 75:25 202 / E012 335 455 620 1 70:30 202 / E013 244 382 592 0.9 65:35 202 / E014 309 417 565 1 50:50 202 / E015 378 494 648 1 0:100 202 / E016 298 426 606 0.9 *Average of 10 samples.

[0151] FIGS.2A-2B are representative microscopic images of a batch (202 / E014) with a mannitol:MCC ratio = 65:35.

[0152] All of the batches had good sphericity and aspect ratio. As the amount of MCC increased, the ease of process improved. The batches with mannitol content of more than 80 parts could not be passed through the extrusion spheronization process and thus these batches are not reported herein. Two ratios of mannitol:MCC (65:35 and 75:25) were selected for further studies.

[0153] One critical attribute of a pellet intended for further processing, such as drug layering and subsequent controlled release or taste mask coating, is the sphericity of the pellets. 32 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Sphericity can be calculated using the equation below and measuring the diameter, perimeter, and area of the pellets in question using a microscope. Sphericity = 4ΠA / P2where A is the area of a cross section of the pellet and P is the perimeter.

[0154] Trials with bigger batch size

[0155] Bigger batch sizes for mannitol:MCC ratios of 65:35 and 75:25 were prepared. Table 7. The formulation, ingredients, and other process parameters of the larger batch size 202 / E019 202 / E048AMannitol : MCC ratio 65:35 75:25 Mannitol (g) 650 1125 MCC (g) 350 375 PVP K 30 (g) 5 7.50 Water (g) 450 450 Binder quantity used (g) 500 457.5 Wet Mass Formation Dry mixing (min) 2 min 2 min Dry mixing (RPM) 250 250 Binder addition and kneading (sec) 30 per step 30 per step Kneading (RPM) 300 300 LOD of wet mass 32.25 24.10 Screen used (mm) 0.6 0.6 Screen type radial Radial Extrusion RPM 30 30 Spheronization Spheronization RPM 1200 1800,1500 Spheronization time (min) 7 min 1+3 Drying Drying temp 60 - 70 60 Drying time 45 40 LOD Less than 1% 33 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0156] Procedure 1) Mannitol and MCC were weighed as per the requirement of the batch, passed through 30# sieve, and dry mixed in planetary mixer. 2) PVP K 30 was added to water under stirring. (In a batch it was added as a dry binder directly in the blend). 3) The dry mix was transferred to the planetary mixer and the further processing was continued based on the parameters mentioned in table above. 4) After the wet mass was formed, LOD was checked and noted. 5) The wet mass was transferred to the extruder and extrudes were formed. 6) The formed extrudes were spheronized and the pellets obtained were dried in a fluidized bed dryer.

[0157] The process was smooth and pellets were formed. The sphericity was better (assessed visually) for the batch with 35 parts of MCC . The batch with a 75:25 ratio demonstrated less spherical particles with a smaller particle size range (Table 9). Table 8. Particle size analysis and average sphericity of pellets formed from 65:35 mannitol:MCC. Mannitol : MCC Batch NoPSD (micron)D10 D50 D90Average Sphericity*65:35 202 / E019B 307 403 529 0.9 *Average of 10 samples Table 9. Particle size analysis and average sphericity of pellets formed from 75:25 mannitol:MCC. Mannitol : MCC Batch No.PSD (micron)D10 D50 D90 Average Sphericity*75:25 202 / E048B 262 346 465 0.9 75:25 202 / E048C 184 244 322 0.9 *Average of 10 samples “B” batch stands for 40# - 60# fraction of the batch, “C” batch stands for 60# - 80# fraction of the batch.

[0158] Trials for smaller particle size

[0159] The trials above provided a larger pellet size wherein the D50 value was in the range of 400 to 450 micron. An attempt was then made to reduce the particle size of the mannitol:MCC pellets using a smaller screen size. The formulations, ingredients and other process parameters are shown in Table 10. 34 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Table 10. The formulations, ingredients, and process parameters of the reduced particle size trial. Batch number 202 / E042A 202 / E042B Mannitol:MCC ratio 65:35 65:35 Mannitol (g) 487.5 487.5 MCC (g) 262.5 262.5 SSF (g) - 3.75 Magnesium stearate (g) 3.75 - Colloidal silicon dioxide (g) 7.5 7.5 Water (g) 288 288 Wet mass formation Dry mixing (min) 2 2 Dry mixing (RPM) 200 200 Binder addition and kneading (sec) 30 per step 30 per step Kneading (RPM) 300 300 LOD of wet mass (%) 38.6 27.18 Extrusion Screen used (mm) 0.5 0.5 Screen type dome dome extrusion (RPM) 60 60 Spheronization Spheronization (RPM) 1800 1800 Spheronization time (min) 3 3 Drying Drying temp (° C) 60 60 Drying time (min) 40 40 LOD after drying (%) 0.8 0.93

[0160] Procedure: 1) Mannitol and MCC were weighed as per the requirement of the batch and passed through 30# sieve and mixed in the planetary mixer. 2) Water was used as the binder. 3) The dry mix was transferred to the planetary mixer and the further processing was continued based on the parameters mentioned in table above. 4) After the wet mass was formed, LOD was checked and noted. 5) The wet mass transferred to the extruder and extrudes were formed. 35 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 6) The formed extrudes were spheronized and the pellets obtained were dried in a fluidized bed dryer.

[0161] The particle size was reduced to a significant value. However, to aid extrusion through the smaller screen size and the dome shape, it was necessary to add a lubricant like magnesium stearate or sodium stearyl fumarate. Also, the use of a glidant (such as colloidal silicon dioxide) reduces the pressure exerted by wet mass on the screen. Although not wishing to be limited by theory, it is believed that the magnesium stearate may affect the dissolution tendency and thus further studies were not performed on this formulation.

[0162] Dissolution trials for sugar, MCC, and mannitol:MCC beads

[0163] The general scheme for the experimental trials is shown in FIG.3, wherein the goal was to conduct coating trials on different inert cores. Sugar beads, MCC beads, and the mannitol:MCC beads of the disclosure were observed for differences in the dissolution rates. The general formulation for the drug loading trial is given in Table 11, wherein the formulation is based on 700 g inert core loading (Sugar / MCC / mannitol:MCC). Table 11. Formulations and ingredients for the pellet API coating Ingredients Specification / Grade Quantity perQuantity weighed (g) Batch (g / batch)with 15% extra Inert core (sugar, MCC, or mannitol:MCC)USP 700.0 -Cetrizine HCl USP 70.0 80.5 HPMC (Methocel E5) NF, Ph. Eur 14.00 16.1 Talc USP 14.00 16.1 DM Water - 882.00 1014.3

[0164] Procedure for drug coating dispersion preparation: 1) The required amount of water was divided into two equal parts. 2) To one part of water, HPMC was added under stirring. 3) To other part, drug was added and dissolved. 4) Step (3) was added to Step (2) under stirring. 5) Talc was added to step (4). 6) The dispersion was passed through 40 # mesh before using it for coating. 36 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 7) The inert pellets were loaded in fluid bed coating equipment fitted with a Wurster column model GPCG 1.1 before initiating the coating process to form beads comprising the API.

[0165] The drug loading parameters are summarized below in Table 12. Table 12. Process parameters Process parameter Observed values Inlet temperature (° C) 50 - 60 Product temperature (° C) 35 – 42 Air flow (CFM) 55 – 65 Pump RPM 3 – 6 Spray Atomization 1.0

[0166] The process for drug loading was smooth. However, some core specific observations were noted: 1) The sugar pellets were brittle and underwent fragmentation during the fluidization process to form the API loaded beads. 2) The mannitol:MCC pellets were robust during the fluidization process to form the API loaded beads. 3) MCC pellets were tough and did not fragment during the fluidization process to form the API loaded beads. The representative formulation for the functional ethyl cellulose coating is given in Table 13. The formulation is based on a load of 350 g. Table 13. Functional coating ingredients IngredientsSolids Quantity perDispersion Quantity Batch (g / batch)per Batch Drug loaded pellets 350.0 - Aquarius CTRL ECD 77.00 285.19 Triethyl citrate 15.40 15.40 DM Water - 315.41 Total 92.40 616.00

[0167] Procedure for bead coating dispersion preparation: 1) To the required quantity of the coating dispersion, the weighed amount of water was added and stirred for 10 to 15 min. 37 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 2) To step (1), the weighed amount of plasticizer was added and allowed to stir for 60 min. 3) The dispersion was passed through 40# mesh before initiating the coating process. 4) The drug loaded beads were loaded in fluid bed coating equipment fitted with a Wurster column model GPCG 1.1. 5) Coating was initiated. 6) After curing was done at 60 °C for 2 hours, the impact of the core on the dissolution rate was checked. The bead coating parameters are summarized below in Table 14. Table 14. Process parameters Process parameter Observed values Inlet temperature (° C) 47 – 50 Product temperature (° C) 33 - 36 Air flow (CFM) 70 - 80 Pump RPM 3 -5 Spray Atomization 1.0

[0168] The coating process was smooth without any problems. The coated beads were then subjected to dissolution studies. The dissolution parameters were: media: 0.1 N HCl, 900 ml; USP apparatus II, 50 RPM; and time interval: 10, 15, 30, 60, 120, 360 min.

[0169] The results for the dissolution of the beads coated as detailed above (after 2 hour curing at 60 °C) comprising a mannitol:MCC core versus the beads formed from comparative cores are shown in Table 15. Table 15. Dissolution data Dissolution compilation Sample BatchTime (in minutes) Number0 10 15 30 60 120 240 360 380 Sugarsphere beads (Aquarius ECD)_20% Polymer 246 / E001A 0 18 27 55 86 95 96 97 97 Coat_20% Plasticizer Sugarsphere beads (Aquarius ECD)_20% Polymer 246 / E013A 0 23 36 61 85 93 94 95 95 Coat_20% Plasticizer Mannitol-MCC beads (Aquarius ECD)_20% Polymer 246 / E002A 0 41 58 77 88 93 96 97 97 Coat_20% Plasticizer 38 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Mannitol-MCC beads (Aquarius ECD)_20% Polymer 246 / E005A 0 36 56 78 87 89 90 90 90 Coat_20% Plasticizer Mannitol-MCC beads (Aquarius ECD)_20% Polymer 246 / E009A 0 44 61 80 89 92 92 93 93 Coat_20% Plasticizer Celphere (MCC beads) (Aquarius ECD)_20% Polymer 246 / E008A 0 22 39 62 76 87 91 92 92 Coat_20% Plasticizer Cellets 350 Glatt (MCC beads) (Aquarius ECD)_20% Polymer 246 / E011A 0 22 38 64 80 91 96 97 97 Coat_20% Plasticizer Celphere (MCC beads) (Aquarius ECD)_20% Polymer 246 / E004A 0 37 54 74 86 94 98 98 98 Coat_20% Plasticizer

[0170] FIG.4 is the dissolution study demonstrating the reproducibility of the mannitol:MCC beads. There is a trend observed based on nature of the core. The core of the mannitol:MCC beads is soluble and has the inherent nature to imbibe in water, thus encouraging faster dissolution and leading to fastest dissolution. The slowest was for the MCC core as it swelled in presence of dissolution media. These data showed an important differentiation between the mannitol:MCC beads and comparative beads. The beads comprising a mannitol:MCC pellet core can be used to enhance the dissolution of poorly soluble or practically insoluble APIs.

[0171] Particle size analysis of the final coated pellets

[0172] Method: Particle size analysis was performed on a Malvern Mastersizer 3000 instrument by dry dispersion method using air pressure of 1 barg, feed rate of 25%, and a measurement time of 10 seconds. Each sample was run in triplicate and the mean value is reported in Table 16. Table 16. Particle size analysis Sample Batch Number D10 D50 D90 Sugarsphere beads (Aquarius ECD)_20% Polymer 246 / E001A 302 367 446 Coat_20% Plasticizer Sugarsphere beads (Aquarius ECD)_20% Polymer246 / E013A 312 375 45139 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Coat_20% Plasticizer Mannitol-MCC beads (Aquarius ECD)_20% Polymer 246 / E002A 363 450 562 Coat_20% Plasticizer Mannitol-MCC beads (Aquarius ECD)_20% Polymer 246 / E005A 361 459 580 Coat_20% Plasticizer Cellets 350 Glatt (MCC beads) (Aquarius ECD)_20% Polymer 246 / E011A 464 531 601 Coat_20% Plasticizer Inhouse Mannitol:MCC (75:25) (Aquarius ECD)_20% Polymer 246 / E015A 323 409 512 Coat__20% Plasticizer Table 17. Comparison of particle size of the coated pellet, drug dissolution and substrate material D50 of coat % drug % drug % drug Core material Batch Number ed sample release after release after release after (µM) 30 mins 60 mins 120 mins Sugar 246 / E001AA 367 40 65 85 Sugar 246 / E013AA 375 36 59 81 Mannitol:MCC (65:35)246 / E002AA 450 59 90 98Mannitol:MCC (65:35)246 / E005AA 459 40 71 86Mannitol:MCC (75:25)246 / E015AA 409 38 70 91MCC (Cellets) 246 / E011AA 531 29 74 95

[0173] The results shown in Table 16 compare the dissolution of the water-soluble API cetirizine from sugar pellets, MCC pellets, or pellets of the present disclosure (Mannitol:MCC). The release of API from a drug layered pellet subsequently coated with an insoluble polymer, such as ethylcellulose, is driven by imbibition of the surrounding aqueous environment through the permeable polymer, dissolving the API, which then in turn diffuses out of the core through the polymeric film. The rate of drug release is generally influenced by the size of the coated pellet (larger pellets have a proportionally lower surface area to volume ratio and hence a lower rate of overall drug release). Another important factor that influences drug release are the physicochemical properties of the core material. It was expected that a core comprising an insoluble component (such as MCC) together with a soluble component (such as 40 DB1 / 148490793.1Attorney Docket No.059717-5025-WO mannitol) would result in a release profile that is between the release profiles for the two materials.

[0174] However, by looking at the drug released after 30 minutes, it can be seen that the mannitol:MCC pellets of the present disclosure demonstrate proportionally higher drug release than the pellets made from sugar only, even when taking into account the size differences in the pellets. This is somewhat surprising and suggests that it is not just the solubility of the pellet that is playing a role in the release of the cetirizine HCl. It can be seen from the results for the MCC pellets that the combination of mannitol:MCC gives the fastest overall release. These findings have utility particularly in the area of taste masking where the formulator wants to obtain a balance between retarded release to reduce the API being released in the mouth giving a bitter taste and having quick enough release to meet the monograph requirements for immediate release tablets. By altering the ratio of mannitol and MCC in the pellet, one can tailor the drug release properties to optimize for the above application. 41 DB1 / 148490793.1OW-52ht0iA5w9-181 B7 d0 0 55 7laE057525.77. 8. i5d0 .400 50 58.1 e7 t E / / 6 E / 9 5 77523 0a38521 6 4 09 a5 o 64 42 20R0 c2 2.oyltNnteeukc qo e 0s ADb5y u141 B8 04e s0 0E0 5 l2575.05 1. 6.ai5 5d0 .71 30 0 %0.nr d E / / 6 E / 11 3 7 442 0a354&&6 4 1o n6tt a4242 20R020 18<Anoi1taszeihncotraebhpA s9Bn09ero030ocr5 5 5.7 5l05iE E . 6 ai 0 .4000 5 %0s / / o7925 7751 .0 da38 83 6 4.1u6 2frt 4 0s 3 R 5 1 <x 2 2rete 48 eyb0Emae / d2ra0a2psm n ABs 2o 5 7ec4it0n030orp 5 5 5 7 4l76 ai045. 08eE E7 2 .77.9 .0 da- 480830654.0v / / n 9 5 5 203 5 1n6 2i4t20 o2it Raznienrr oruechephtSfonA7B nsoti2s0 7o0 43i 0s 5 5 5 7 5l46 ai5. 08el r0l eE E / Eurt7 2 . 7..d03 4 0 4065 .ep / 6 2 / 2x9 5 7 523 0aR8551 4 0psi0d 42 202 Erof essr olet uelle)mc de)alryah ost sgUs ) (nim( ) gptsenel hlersd cpeb)g )samd()g( )mm(epmeps nnu oietmp imni(yren tca aoB gn mu lotg( 0g3(tre de yt ryta itmeedsr l in i nnoitzimn tmrPCg.HnidahnCnCKetawfo ueier sunanorproit g iani tegtfa 181 etaol ctaMPWnecrt uq ezyrn.3o gaMVPDer Sx rhp inDiyD970enlibzi C uBe OrDroLcES edSonrierOh DL9484ait C Bp 1Tec S / 1BDAttorney Docket No.059717-5025-WO

[0175] Taste masking example

[0176] The pellets of the disclosure are well suited for utilization in taste masking applications. Mannitol:MCC pellets of the disclosure from Batch 246 / E005A were loaded with Cetirizine HCl, forming beads of the disclosure. The beads of the disclosure as well as MCC only Cetirizine HCl drug loaded beads (Cellets) were coated with various levels of the ethylcellulose coating dispersion Surelease to various weight loadings, namely 5, 10, and 20% using the procedure as follows:

[0177] Procedure for bead coating dispersion preparation: 1) To the required quantity of the coating dispersion, the weighed amount of water was added and stirred for 10 to 15 min. 2) To step (1), the weighed amount of plasticizer was added and allowed to stir for 60 min. 3) The dispersion was passed through 40# mesh before initiating the coating process. 4) The drug loaded beads were loaded in fluid bed coating equipment fitted with a Wurster column model GPCG 1.1. 5) Coating was initiated. 6) Coating was continued until the target weight loading was achieved.

[0178] The coated beads were sampled and the PSD was determined by laser diffraction. The particle size (D50) was found to be fairly similar across the equivalent coated beads. Table 19. D50 values as determined by laser diffraction of the mannitol:MCC and MCC drug layered coated beads Bead D50 (microns) Mannitol:MCC (w / 10% ethylcellulose) 434 Mannitol:MCC (w / 20% ethylcellulose) 459 MCC (w / 10% ethylcellulose) 468 MCC (w / 20% ethylcellulose) 497

[0179] The coated beads were then subjected to dissolution studies. The dissolution parameters were: media: deionized water, 900 ml; USP apparatus II, 50 RPM; and sample time interval: 5, 10, 15, 30, 60, 120 and 240 mins (FIG.5).

[0180] One of the challenges for taste masking is to achieve a retardation of drug release while the pellet comprising the drug (i.e., the bead) or the dose form is in the mouth to 43 DB1 / 148490793.1Attorney Docket No.059717-5025-WO reduce the unpleasant organoleptics but at the same time to ensure that drug release happens rapidly once the bead or dose form enters the stomach and the rest of the gastrointestinal tract. It can be seen from the data in FIG.5 that the pellets of the disclosure, when containing an API (thus forming a bead) are ideally suited to such applications as the pellet content combination of mannitol and MCC coated with 10% ethylcellulose results in an initial retardation of drug (required for taste masking) but ensures significantly high drug release thereafter. The beads comprising an MCC pellet retard drug release initially (e.g., at the 5-minute time point) but are insufficiently soluble to ensure that drug releases happens rapidly thereafter. Additionally, it is necessary for reasons of ensuring coating uniformity to have at least 5-10% coating applied to the beads to achieve the reproducibility required. It is unlikely therefore that the desired release profile could be obtained using MCC only pellets. Additionally, the use of a mannitol:MCC pellet also ensures 100% drug release in the example given while MCC only pellets have been known to demonstrate incomplete drug release.

[0181] Optimization of the mannitol:MCC pellets by varying processing parameters in the extrusion spheronization process

[0182] Further work was undertaken to understand the influence of the extrusion spheronization processing parameters on some of the key functional characteristics of the resultant pellets such as sphericity. Table 21 summarizes the various batches manufactured and the parameters used for each batch. FIGS.6A-6E demonstrate the influence of processing parameters on sphericity (via SEM) of pellets made from mannitol:MCC using extrusion / spheronization. FIGS.6A-6C show the influence of spheronization time and speed on the final morphology of the pellets. Although not wishing to be limited by theory, in general as the time and speed was increased, the sphericity improved. 44 DB1 / 148490793.1O wW-ol5 e061.4 6.0 2.2 2.3 3.0 8.0 7.4 3.0 0.1 7.0 2.0 1.1 esa2 B #h05st c de-n7o 0r681it).2.9.3.1.4.3.9.4.2.8.5.otanut7ce-09az 7 6 2 0 7 7 4 3 8 7 2 5 g ei 43 2 3 3 2 2 3 3 2 3 3 3 nifcol af5rfs # d0. nhr ci unise042.6.5.5.8.4.2.4.2.3.3.6oc daodlm(-03 3 5 4 4 9 5 5 9 4 6.7cIPmN3 3 3 4 4 3 4 4 4 5 5teei3# 5akYoAerec 0o 3i-D09.22 1.25 6.37 9.4.9.7.9.8. 72027213519112. 5t7 .041. ay5 rti5lwibstey# 3e:n5ul lr no o leie )ni6spott ta mi3 7 7 5 3 5 3 7 3 5 7 3awoitAzitm(nht ho) iolawe rcr dte 0 0 0 hC aheeMP 080800800800800500500500800 020202C t bpSpsR( 1 1 1 1 1 1 1 1 1 1 1 1ChtC i.MylhcaneMR R R R R:lw :ldoetvitenro erc6.oi 0 6.6.6.6. R6. R6. R6. R6. R6. R6. R6. oti erincefs0 0 0 0 0 0 0 0 0 0 0u S nnn ey apsdrtesxdeaa0 0 0 0 5 0 mlm eg 5r,uE eps 3 3 3 3 4 3030306030303mu 3 eord:5tusre )rf er 6 neiete gmi ni 1 1 1 1 1 1 1 1 1 1 1 1 n e hmmnairdTm(oitwT.1aa 0az dn s dnpen d )eKeeM 80280280280 0 0 0 0 0 0 0282828282828 8 8 in a da a 54htpP- - - - - - - - -2-2-2- sR0(50250250250250 0 0 0 0 0 0or 2252525252525252e 2ebmpdhernplmane )0 0 0 0 0sbraof082doietniimrd i1tm(:5 3:5 0:3 3:3 3: 033: 033: 033: 232: 232: 732: 832:3noTiosnit-,05ut dca uarfe 0 0 0 0 0 0 0 0rtdewto2l fudd )eM 5o25 5 5 5 5 5 504050505 x-2-2-2 2 2 2 2 2 2 2 2 e hgebennaieBpPsR0(00200- 200- 200- 200- 200- - - - -200200250150100 g202n iild mis hgiettmsehe ) uni d h hgdinac 3 3eehlhdtximitam3 3 3 3 3 3 3 3 3 3 rutgi eb m( tty0 0 0 0 0 0 0canish eepserllDd )eM 515 5 5 5 5 5050505 feepP-1-1-1-1-1 1 1 0 0 1 1 u lniaru gnpsR0 0 0 0 0-0-0-05 5 -0-0t di(0101010101010101 11010a e1mdec daCloer gonrpenCoi ti)C5 5 5 5 5 5 5 5 5 5 5 5 eis ekMt:l a nnC3-3-3-3-3-3-3-3-3-3-3-3-w s5 5 5 5 5 5 5 5 5 sec htahoRaM6 6 6 6 6 6 6 6 6565656 tto tiiM( :ell ort nwna oepN304P dgnireM 005006007008009000 1 2 3 401010101010 na dr ilor.hc1tE / E6 / E6 / E6 / E6 / E6 / E6 / E E E E E6 / 6 / 6 / 6 / 6 / 6 no cae.312 aB525252525252525252525252 ] itca d9e70el 3alum bi94b oan1 2 3 4 5 6 70 1 281 muirc 841Tr8 9S 1 1 1 00r d s[ofosed / 1BDOW-)5e2zi06 8.5.6. reesre0s -50 8-h 4 29213alw7s1ey hc7mbi9(5sd hw0n. oi 0e8rotc4-u stN a 0.4 8.4.43304 sa ellt rf3 e eek sm pc v eroa%zigD dyl 03- hseei0e4.m6 1.24 9. su372el scdnrY2 iottrnt aasAnoita)p( teln eni 3 3delezi oimitm3z pntora( izei rnetC c C hor )a Mpsede M 0 0 0ra htnhopiS epP 0sR 80 018181 hciw s(yult rrtn ehxee nu teeqgyb no erR6. R6. R6.es ot .bs )ed is cer u S 0 0 0utsrut sell aertxercE daefe0 0 0eepcwd ni 64up4 3 3ns 2et tha2 aeocgieme )0 0 0lb eswstelmni 3 3 3 ae reldeditm(:5:5:3Tnhpaitfmylre no lsootdin ) 0 0 0wo li pninB deeM 038 5apP-2-2- haste%0sR0 0 0(520202 ddn e 2(m: a ht nCd s osCe )Mmn erii 2 2 2utwi co rhapesxi tm( aufsmoomy0 0 0 un32 chrDd )0 5 0aelanIeeM2pP-1-2- m bsR0 0 0saaIsP (510101 telT. deSlfedsuoh )scltg(5.7 5.7 50 peteadni aatBezi0 00S5151 1hoTcaedn dDa eta.2o3 4 5 )n o1c.392N47elh04 4E0E0E ]o4it ylr 09bct / / / a a6B46 6 8 c242421 a0rafl 4f i841T0[idmis / 1BDOW-520)09m2065Dµ-(69 -5017 91 579 0) (5 5m4 h 80.Dµ(28se )98om 0mNteDkS 0)1m33c 0- µ01417o PDµ( 7 2 8 7Dyenyrbreottgnfre I ttaAPlM WSG ,,6 A3AA 0444 5 804 4 5eroN10E0E0E03 / 6 / 6 / 1oC.B38424624G 21250gd3 545uerdo0E0 0aN / E / E / .64646Dol B 2 24270)9m00 5045C Dµ(116921sdFae%00)5m206204b2Dµ( 9 801r fdmero of Duc)otSn01mµ639 9d PU D( 86678etaocB B B s A8A A telldee33510ptao0NE0 / E0E6 / / fo.6 6oC4 4 5nB 2 2 2oitazi%rsrd%r sr rets02ofa 0 ofuire ezicdaa_%0 deb2_%0 damcre) 2 eriC) 2 er uq yl ts )abD_t uD heC_t uAoP alHrC EaoC(C EaoC( (P42C. e3hsu C r Mre2 slz-losu C r 0rez0% 70eipsi 2%r1.rra e i t0 of39mci iila nra e ici)st_) 27_ d09bt aguqyl ts)aeu AoalHn4aum qyAl tosal H el4leDtCaeoru 48C41T DS ( P P 2M( P P 2CEC( / 1BDAttorney Docket No.059717-5025-WO Table 24. Formulations and ingredients for the pellet API coating IngredientsSpecification / Quantity per GradeBatch (g / batch) Inert core (sugar, MCC, or Mannitol : MCC)USP 700.00Diclofenac Sodium USP 70.00 HPMC (Methocel E5) NF, Ph. Eur 70.00 Talc USP 35.00 DM Water - 1575.00

[0185] Procedure for drug coating dispersion preparation: 1) The required amount of water was weighed accurately and HPMC was added under stirring for 10 -15 mins, kept aside until a clear solution was observed. 2) To Step (1), drug (diclofenac sodium) and talc was added and dissolved under stirring. 3) Stirring continued for 1 h. 4) Step (3) dispersion was homogenized for 20 mins. 5) The dispersion was passed through 60 # mesh before using it for coating. 6) The inert pellets were loaded in fluid bed coating equipment fitted with a Wurster column model GPCG 1.1 before initiating the coating process to form beads comprising the API.

[0186] The drug loading parameters are summarized below in Table 25. Table 25. Process parameters Process parameter Observed values Inlet temperature (° C) 50 – 60 Product temperature (° C) 37 – 47 Air flow (CFM) 70 – 90 Drive (%) 40 – 55 Pump RPM 2 – 5 Spray Atomization 0.8 – 1.0

[0187] The process for drug loading was smooth. However, some core specific observations were noted: 1) The sugar pellets were brittle and underwent fragmentation during the fluidization process to form the API loaded beads. 48 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 2) The mannitol : MCC pellets were robust during the fluidization process to form the API loaded beads. 3) MCC pellets were tough and did not fragment during the fluidization process to form the API loaded beads. The representative formulation for the functional ethyl cellulose coating is given in Table 26. The formulation is based on a load of 400 g. Table 26. Functional coating ingredients IngredientsSolids Quantity perDispersion Quantity Batch (g / batch)per Batch Drug loaded pellets 400.00 - Aquarius CTRL ECD 120.00 444.44 Triethyl citrate 24.00 24.00 DM Water - 491.56 Total 144.00 960.00

[0188] Procedure for bead coating dispersion preparation: 1) To the required quantity of the coating dispersion, the weighed amount of water was added and stirred for 10 to 15 min. 2) To step (1), the weighed amount of plasticizer was added and allowed to stir for 60 min. 3) The dispersion was passed through 60# mesh before initiating the coating process. 4) The drug loaded beads were loaded in fluid bed coating equipment fitted with a Wurster column model GPCG 1.1. 5) Coating was initiated. 6) A sample of the beads was removed after a 20% and a 30% weight gain and were cured at 60 °C for 2 hours and 24 hours.

[0189] The impact of the core on the dissolution rate was checked. The bead coating parameters are summarized below in Table 27. Table 27. Process parameters Process parameter Observed values Inlet temperature (° C) 40 – 50 Product temperature (° C) 33 – 36 Air flow (CFM) 75 – 95 49 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Pump RPM 2 - 4 Spray Atomization 0.9 - 1.0

[0190] The coating process was smooth without any problems. The coated beads were then subjected to dissolution studies (FIG.7). The dissolution parameters were: media: 0.05 M phosphate buffer, pH 7.5, 900 ml; USP apparatus II, 50 RPM; and sample time interval: 30, 60, 120, 240, 360 min.

[0191] It can be clearly seen from FIG.7 that the Batch 246 / E053AB (which comprises a mannitol:MCC (65:35 ratio) pellet) gives a much faster release profile when compared to the drug release from the sugar pellets (Batch 246 / EO38AB Sugar sphere), even when taking into account the slightly smaller size of the mannitol:MCC pellets when coated to form beads. The MCC pellets when coated to form beads also give slower drug release than that seen from the 65:35 mannitol:MCC batch of the disclosure.

[0192] While one may anticipate the slower release from the beads formed from a MCC pellet, it is somewhat surprising that the drug release from the beads formed from a mannitol:MCC pellet was significantly faster release than that from the beads formed from a sugar pellet given that the relative solubilities of mannitol and sucrose are similar and that the mannitol:MCC pellet only has 65% of the soluble filler.

[0193] Similar findings were seen for the 30% weight gain as had been seen at the 20% weight gain with the beads formed from 65:35 mannitol:MCC pellets (Batch 246 / 053BC) releasing the poorly soluble diclofenac sodium at a faster rate than both the beads formed from sugarsphere pellets (Batch 246 / E038BC) and the beads formed from MCC pellets (Batch 256 / E001BB) (FIG.8). Overall, as expected the release from the 30% weight gain product was delayed / slower than when compared to the 20% weight gain.

[0194] Porosity and surface area studies Table 28. Porosity and surface area studies Mannitol: Mannitol: Sugar pellets MCC pellets MCC pellets MCC pellets (HG (Asahi MCC pellets :35) (75:25) Werner) Kasei) (Gl Mannitol (65 att) beads 202 / E019B 202 / E048B 080511026 39A2 21C1019 Specific Surface area 1.487 1.689 1.139 1.397 1.330 0.809 (in m2g-1) 50 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Total Pore volume (in 4.2856 8.7767 1.6500 1.3502 1.4228 1.3339 X 10-3X 10-3X 10-3X 10-3X 10-3X 10-3cc / g) Average pore diameter (in 11.528 20.783 5.7944 3.866 4.278 6.5988 nm) Preliminary interpretationMesoporous Mesoporous Mesoporous Mesoporous Mesoporous MesoporousParticle Size 250-420 µm 250-420 µm 250-355 µm 300-500 µm 355-500 µm -

[0195] The mannitol:MCC pellets were found to be more porous than the competitor pellets (Table 28). Although not wishing to be limited by theory, this could explain the fast dissolution of drug from the mannitol:MCC pellets disclosed herein.

[0196] Additional trials

[0197] Several trials were performed to incorporate other polyols like maltitol into the pellets (Table 29). The procedure used to make the pellets of Table 29 was the same as the previous extrusion batches. 51 DB1 / 148490793.1OW- / 5643024 00 0 706. 6l.ai - 000 000o0 20 0020940 d06 95t86 85 E 1 4ar 5 1 1-717 / 638l4305305 5015 4. 6.aid000550 206096 3 480885 20E 3ar 4 1.o / 2N3 6l- 65 0 0 a 00 0t4e20 3653513 4.86.0id053020520606k E 4 2ar 4 1 1coD / y613 0 0 0 1l46 ai 05000e4 0 0 050..d 50 83 678n2 E 2 8 750a7 1r 4 rottA / 6043 020E00109 5 0 7085.86l.aid05040ar 5008830 016 6 / 690 0 0 3 6lai00 04220E065305 5530.0 .30 d0ar 50045 o1t 06301606 / 6842 520E3065350 3l15 14.46.ai 0000 30 030 dar 55451 6 6seviti / 672 0 4l0 0005 05 05 8. 6.aid5- 5050o 08 20 0d 4d20E6 3 5 482 0ar03 451 t16 5areht / 6 l 0 2o64200206530035423 6.a0i- d0 056508305605h2tEar 5 4 1iws / t650 0 0 5 6lai50 0el420 2 5 03 55 8.8 .l2 E 6 3 4 2 0 d0ar 35042 o1t 05301606ep / C6442000005 0 2l0 1. 6.aid0500r00 20 2C2 E 2 8 874 0a3 881 6 1M:lot / i632 0n4 0 00100 3l9096.26.a0id000a30098200621n2 E 5 r 1aM / 2f6420050 5la0257 5 00 5.66.0id05300820062o2 E 8a8 1 1s 4 rsec / or612 0 0l96 ai 0 00000 0p420E0901 5 1.0 dar 30 o1t221 6 6dna / 60 lal 4220000802 5 08232 6.a0id050a38020 o 01t 0220 616 6u E rmro)Fg ) )tmdnonop.(9l )g2o gt ((g( )l0ge dei 3(wf s seu) py ptr enresi uti at )zazneimetmi 1t) .39elnConCtitr o slKetanmn oi dyt)inminm( g gni70meme s niitg(o proeninim 94b a aDeMa P r (erc urt Bna rere m y yr (84a M MVWOPLcS Sx uq hphpit rD D1TE S S / 1BDOW-65 342 5. 00 l01 E / 050 6653 - - 5 - - -831.98a.i0da0103903545-6742R11276905.120.4o00 lN 9E 5 5 - - 5.- - - 07. 8a0.i4- 5. ot 70 00t 6 / .67925 7859 de042 0 aR0385 00 241 1kc2oD 2y0Be.n23658 e0r0oE 2 57- - -55.- 08 6. 5. m 0080 4tt / 211 3 1 7 462 0 oD6 451A8.9 012A 238.600 5E / 221555 0 75e. 5m 00000173 - - - 1 -.7546 .20 oD65454113.20s78 e55.v00 0 0 1 l3iE / 50ai 500653 - - 5 - -0.0 .1da030 040 tid204 3R4 1da2r6e58. h0t 4o06 e35hE 5 5 - - - 5.-576. 5. m 0700 4t / 7 27 176i 2709 5 5 2 0 oD6755125w.0stel9l6e 2000 0805 em0 0 002pE / 251 5 - - - 2 1 - 7 .7 .0 o 6 773.2C C02D18M2:4.l81oti2n0nE / 0 4 e023107 - - - 2 1 -097.45.0mo0609 0538a03 12D 5.1Mfos02 s2 6 la8.e0c 0orE / 0000- - 5 - - - 00 5.86.i0da0503002 11p 205 5 6 3 6 12R d7. n0aals )usm m) lyamm(yti n nrreto)g )g( r)a tm edfe p tnoitoit1a gnFi.(l )) g( 03 g(muiets e )eg wsup ryatn uaqzi azi)n.i39Dy03oti g( g(r esl Kisse etta mar(rfo n n ois r )gn n(ororm(709OrdL elnbnaaC Cag otucaP oVbnagr uaaeitd a ete eo maDererurtedn d ehe4h e84TM MS L PC MS SufWOLcScSxE i eBsupm SprpSmi t1 / 1BDOW-5205-7065147950.oNtek0c654oDyenro %ttA065 974.0% 0.01654 <065 174.045065407-0654065407-0654)ni gpm(niyme rdetmit r1e.gt 397ng fin a09yi 4ryrD84D DOL1 / 1BDAttorney Docket No.059717-5025-WO

[0198] The results in Table 31 show the favorable mechanical properties of the pellets of the current invention when compared to pellets made from other soluble materials such as sugar and pure mannitol. Table 31. Friability of different pellets made of different substrates. Core Batch No. Manufacturer Core Size Friability (%) Mannitol:MCC (65:35)202 / E056 SPI Pharma 18 # - 20 # 0.08 %Mannitol UR / SUS / 024 / B20 Umang 20 # - 25 # 1.47 % Pharmaspheres (sugar)080511 Werner 45 # - 60 # 0.34 %

[0199] Conclusions

[0200] The mannitol:MCC pellets of the present disclosure demonstrate a number of advantages over commercially available pellets (Table 32). Table 32. Comparison the mannitol:MCC pellets to commercially available sugar pellets and MCC pellets. Mannitol:MCC Sugar MCCSphericity *** ** ** Aspect Ratio *** ** *** Surface texture *** ** ** Convexity *** ** ** Circularity *** ** *** Elongation ** ** ** Granule friability *** * *** Brittleness *** ** *** Hygroscopicity *** *** ** Incompatibility *** ** ** Robustness during coating process *** ** *** Requirement of seal coat No Yes No Dissolution *** *** ** Cost ** *** * * = Average, ** = Good, *** = Excellent 55 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Example 2. Specific Surface Area (SSA) of Mannitol:MCC Pellets Compared to Commercially Available Pellets

[0201] The SSA of mannitol:MCC pellets of the disclosure was measured by gas adsorption and compared to the SSA of commercially available pellets. Gas adsorption ideally detects all of the types of pores depicted in FIG.9. The gas adsorption sample details are provided in Table 33.

[0202] BET is the most widely used technique to calculate SSA from gas adsorption data, wherein SSA is calculated using the following equation. wherein N is Avogadro’s constant (6.022 x 1023mol-1), a is the effective cross-sectional area of one adsorbate molecule in square meters (0.162 nm2for nitrogen and 0.195 nm2for krypton), m is the mass of test powder in grams, 22,400 is the volume in mL occupied by one mole of adsorbate gas at STP allowing for minor departures from the ideal, and Vm is 1 / (Slope + Intercept).

[0203] Gas adsorption experiments are used to characterize the surface area and pore size distribution of pores that are accessible from the surface of porous materials. FIG.10 depicts an equation to calculate pore size (Kelvin). Table 33. Gas adsorption sample details. Sr. no. Product Batch No.: Ratio(Mannitol: MCC)PSD (µm)1 Mannitol MCC pellets 202 / E043B 50:50 250-400 2 Mannitol MCC pellets 202 / E064B 75:25 250-400 3 Mannitol MCC pellets 202 / E040B 65:35 250-400 4 Mannitol MCC pellets 246 / E034B 100% MCC 250-400 5Sugar spheres (Pharm-a-sphere) 83301406 Sugar spheres 710-8506Sugar spheres (Pharm-a-sphere) 80511026 Sugar spheres 255-3557Mannogem XL ruby(Granulated) 121910323 100% Mannitol 250-4258 Mannitol MCC pellets 202 / E043D 50:50 590-850 9 Mannitol MCC pellets 202 / E064D 75:25 590-850 10 Mannitol MCC pellets 202 / E056B 65:35 590-850 11 Mannitol MCC pellets 202 / E019B 65:35 307-529 12 Mannitol MCC pellets 202 / E048B 75:25 250-400 56 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 13Celphere CP-708 (AsahiKasei) 77E1 NA 710-85014Celphere-CP-305(Asahi Kasei) 39A2 NA 300-50015 Cellets 350 (Glatt) 21C1019 NA 350-500 16 Cellets 700 (Glatt) 21G1058 NA 700-1000 17 Mannitol pellets NA 100% Mannitol 250-425

[0204] For the porosity studies, the mannitol:MCC pellets were found to be more porous than the pellets made from sugar or MCC only. Although not wishing to be limited by theory, this could explain the dissolution rate of drug from the mannitol:MCC pellets disclosed herein.

[0205] FIGS.11A-11B are examples of different types of isotherms while FIGS.12A- 12E are isotherms of the samples in Table 33. The isotherms in FIG.12A are Type IV isotherms, which are typical for mesoporous materials. The Celphere MCC pellets had rigid pores, no capillary condensation, monolayer coverage, and cylindrical pores. No chemisorption was seen for these pellets. The mannitol pellets in FIG.12A had ink bottle pores. The isotherms in FIG.12B are also Type IV isotherms with rigid cylindrical pores in the MCC pellets (Cellets) and ink bottle pores in the granulated mannitol (Mannogem XL). No chemisorption was observed with the MCC pellets while physisorption and chemisorption was observed with the mannitol pellets. The isotherms of the sugar pellets (pharm-a-spheres) in FIG.12C demonstrate similar properties to the MCC pellets. FIG.12D are isotherms of 100% MCC pellets compared to 1:1 mannitol:MCC pellets with different sizes. These isotherms are also Type IV isotherms, wherein the shape of the hysteresis for the mannitol:MCC pellet isotherms show ink bottle type pores more prominent in 1H materials. Chemisorption was also prominent in the Mannitol:MCC pellets. FIG.12E are isotherms of 75:25 mannitol:MCC pellets of different sizes as well as 65:35 mannitol:MCC pellets. These isotherms were also Type IV isotherms, with a similar isotherm shape to the mannitol:MCC pellets in FIG.12D.

[0206] FIGS.13A-13F are the density functional theory (DFT) curves of the samples in Table 33. The curves in FIG.13A demonstrate that the MCC pellets (Celphere pellets) have uniform pores and that the PSD does not have an impact on the pore size distribution. The mannitol pellets have a portion of a bi-modal DFT curve. The curves in FIG.13B again demonstrate that the MCC pellets (Cellet pellets) have uniform pores. The granulated mannitol sample (Mannogem XL) has a portion of a bi-modal DFT curve and deep pores. The DFT 57 DB1 / 148490793.1Attorney Docket No.059717-5025-WO curve for the 75:25 mannitol:MCC pellets in FIG.13C demonstrates that the pellets have a porous structure. The pellets in FIG.13D show a similar DFT pattern as cellet and celphere pellets. The DFT curves of the mannitol:MCC pellets in FIG.13E demonstrate that the PSD does not have an effect on the pore properties. The DFT curves of the mannitol:MCC pellets in FIG.13F demonstrate that the pellets have bi-modal pores and that the PSD does not have an effect on the pore properties.

[0207] The data for the samples in Table 33 is summarized in Tables 34-36. Table 34. SSA and porosity data for mannitol:MCC pellets Mannitol:MCC Mannitol:MCC Mannitol:MCC Mannitol:MCC Parameters [65:35] [50:50] [50:50] [75:25] B No.: 202 / E040B B No.: 202E043B B No.: 202 / E043D B No.: 202E064B SSA (m2 / g) by BET1.46 2.20 2.11 2.13SSA by DFT (m2 / g)1.13 1.55 1.42 1.58Porosity (cc / g) 3.4398* 10-36.3605* 10-34.6791* 10-37.1305* 10-3Average pore diameter (nm)9.3988 11.573 8.866 13.373C constant by BET13.67 5.68 5.21 7.88Langmuir method Intercept186.9 264.2 302.6 193.759PSD range 250-400 µm 250-400 µm 250-400 µm 250-400 µm Table 35. SSA and porosity data for mannitol:MCC and Mannogem XL Ruby. Mannitol:MCC Mannitol:MCC Mannitol:MCC Mannogem [75:25] [0:100] [65:35] XL Ruby, Parameters B No.: B No.: B No.: granulated 202 / E064D 246E034B 202 / E056B B No.: 121910323 SSA (m2 / g) by BET 1.39 1.10 1.92 13.38 SSA by DFT (m2 / g) 1.16 0.69 1.43 9.61 Porosity (cc / g) 5.7200* 10-31.4409* 10-36.0343* 10-33.0217* 10-2Average pore diameter (nm)16.427 5.233 12.600 9.100C constant by BET 11.33 4.96 7.52 6.81 Langmuir method Intercept222.642 597.618 233.301 36.58858 DB1 / 148490793.1Attorney Docket No.059717-5025-WO PSD range 590-850 µm 250-400 µm 250-400 µm 250-425 µm Table 36. SSA and porosity data for Pharma-a-sphere, Celphere, and Cellet pellets Pharm-a- Celphere CP Celpher s s e CP Cellets 700 Parameter phere B no.: 305 708 B No.: 83301406 B No.: 39A2 B No.: 77E1 21G1058 SSA (m2 / g) by BET1.50 1.39 1.40 1.67SSA by DFT (m2 / g)0.79 0.69 0.69 0.84Porosity (cc / g) 1.5605* 10-31.3502* 10-31.2914* 10-31.5086* 10-3Average pore diameter (nm)4.1642 3.8655 3.7511 3.61C constant by BET2.71 2.37 2.42 2.78Langmuir method Intercept891.8 1126.1 1120.7 812.4PSD range 710-850 µm300-500 µm 710-850 µm 700-1000 µm (#20-25 sieve)(#35-50 sieve) (#20-25 sieve) (#18-25 sieve)

[0208] The porosity and SSA of the MCC pellets were less than that of the mannitol:MCC pellets. The Langmuir intercepts show the formation of multilayers with the mannitol:MCC pellets. The C-values indicate the energy of adsorption was higher with the mannitol:MCC pellets than the sugar and MCC pellets. Although not wishing to be limited by theory, it is hypothesized from the data that the inclusion of multiple components in the pellet of differing physicochemical properties e.g., MCC and mannitol versus MCC only or sugar only significantly alters the internal morphology of the pellets. It has previously been reported for similarly manufactured materials dried to similar final moisture that combinations of MCC and lactose do not alter the porosity of the resultant pellets when manufactured by extrusion spheronization and dried by freeze drying. The data for SSA and porosity as detailed in Tables 33-35 show that in this case the combination of mannitol and MCC is having a significant influence on the final values for these two physical phenomena (SSA and porosity). It is also apparent that the process used to manufacture the pellets does not influence the final porosity or SSA values, this can be concluded by the result from batch 246E034B in Table 35. These pellets were made from 100% MCC by extrusion spheronization and have porosity and SSA values close to those of Celphere and Cellets (also 100% MCC) which are made using a rotary 59 DB1 / 148490793.1Attorney Docket No.059717-5025-WO granulation or similar process. For granulation processes, it is known that the resultant porosity of a solid system will depend on the amount and type of material incorporated into the original system versus the water used in the process. As the product is dried, water will be evaporated from the system, however some will remain and enable the formation of hydrogen bonds. MCC will tend to form these hydrogen bonds whereas soluble materials like lactose, sugar, and mannitol will crystallise out during the drying process. It is proposed that the differing crystallisation tendency of different soluble materials will result in significantly different internal morphology and water interaction between the MCC and the soluble component. These differences can explain the unexpected higher porosities seen for the mannitol / MCC combination versus MCC alone and the why similar differences were not seen with lactose. Combinations of mannitol and MCC have also been shown to possess different physical properties (in this case tabletability) when processed together via spray drying (U.S. Patent Application 2008 / 131505) although no explanation as to the theory behind why this combination performed differently than simple blends was given.

[0209] FIG.14 provides SEM images of Celphere pellets, mannitol:MCC pellets, and granulated mannitol (Mannogem XL). The SEM images demonstrate that the Mannogem XL Ruby sample has numerous deep pores on the surface and that the surface of mannitol:MCC pellets appear to be rough and porous compared to MCC only pellets, which correlates with the porosity and surface area. Example 3. Further Improvement of the Shape and Processing of the Formulation

[0210] In order to better understand the suitability of the formulation to produce pellets of optimum shape and porosity, other formulation factors such as binder type, level of granulating liquid, use of hydroalcoholic binder solutions, addition of lubricants, and type of cellulose additive were investigated. Specifically, the use of HPMC as a binder and the use of silicified MCC as a source of the insoluble cellulosic filler were investigated. In addition, processing factors such as extrusion speed and extrusion time were investigated. The method used to produce these pellets was the same as detailed in para.

[0149] herein. Table 37 summarizes the formulations and processing conditions used, where Mann = Mannitol, MCC101 = Microcrystalline cellulose PH101, PVPK 30 = Polyvinyl pyrrolidone K30, R = Radial, HPMC = Hydroxypropyl methyl cellulose, MCC105 = Microcrystalline cellulose 60 DB1 / 148490793.1Attorney Docket No.059717-5025-WO PH105, MCC301 = Microcrystalline cellulose PH301, IPA = Isopropyl alcohol, SMCC90 = Silicified microcrystalline cellulose 90. 61 DB1 / 148490793.1OW-5d2e)M00n 000000000000000000000005- oeipPR8181818181818181818181817 t1 aS (7 zi95 n0 oe )mni 7 7 5 9 7 7 7 7 7 5 5 7.roe ihTm(N peS ea e )ttkl zm0.0 0 0 0 0 0 0 0 0 0 0cPism . . . . . . . . . .o ( 2 2 2 2 2 2 2 2 2 2 2.2Dydenr ne)eMP0o o6060606060606060 0 060tip6 6 6tsSRu(Artx nEee &ec epR 6 R 6 R 6 R 6 R 6 R 6 R 6 R 6 R R R R rzySiS T.0.0.0.0.0.0.0.0 6.0 6.0 6.0 6.0egartendenci 5.rB0 5.0 5.0 5.0 0.1 5.0 5.1 0.1 5.1 5.1 0.1 0.1ePfofog -)- - -egnaittA5naldi 6 6 6 6 6 0 PI:.A 31 PI:)A)86 7 PI:5.A)77 PI5.7 6 6eu ucq.8.35.31.45.35.394re2t: .574re1t: . .28314re :5. :.14re :5. ..8383rneai Prl a .6a 8ta2 ta2gW( 7W9 9(W(W(26snor03030303030303030303ite eCsCsiddnmaKPKPKPKPKPKPKPKPKPMpc Mpc KPniB NVPVPVPV V V V V VPH5 PH5Voc P P P P P P Pg cnlia clclssTaTaT %5ec ) ) ) )%) )%)%.2oroit 0pa 30:304035ht53535ht5)3535h htidr0: : :707060 i: :w5 5 i: : tw5 5 iww)naC(1 (1 (71(1 )60(61(61)5(61(1 )5 53:sC0nM1010101 3:tlC C C C00710C1 3:C50610C1 3:C5 566(claoiaoltiC C C C(C C(C C( 1 TnM:M:M:M:101M:M:101M:M:10 011unnmann n nanananaCnnnanaCnnnC anaC C rofM C C C M M M M M M M M M M:f :M on:M:nynnnnnara anaM a M M M m.o4252620313233 4 5 6 8 9mN0 0 0 0 0 030303 3 3 3u E E E E E E E E0E0E0E0Sh.ct / 6 / 6 / 6 / 6 / 6 / 6 / 6 / 6 / 6 / 6 / E6 / 61.373aB525252525252525252525259270e9l4b .ar .o 1 2 3 4 5 6 7 8 901112 841TSN1 / 1BDOW-5200005800800800800800 0 0 0 0 0 0 0 +80808080808080808 0 0004-1 1 1 1 1 1 1 1 1 1 1 1 1 181 171797 5.6505 5 5 5 5 5 7 5 5 5 7 7+.3 1oNte0 0 0 0 0 0 0 0k.0c2.02.02.02.02.2.2.2.2.2.2.3.03.02.2oDyen 0 0 0 0 0 0 0 0 0r 6 6 6 6 6 6 6 6 606060606ottA RR R R R R R R R R R R R R6.6 6 6 6 6 80.0.0.0.0.0.60.6 6 6 8 8 80.0.0.0.0.0.05.5 5 5 5 5 0 5 0 5 5 0 00.0.0.0.0.0.2.1.1.0.0.1.16.6.6.6 6 6 6 6 6 6 6 6 68 1. . . . . . . . .3 3 3 3 3 4 4 3 48.3 48 8 8 8 8 1 1 5 434436C C C C C C C C 03030303MsPc MsPc MsPc MspsCp p p pspspspspPc MPc MPc MPc MPc MPc KPKPKPKPH5H5H5H5H5H5H5H5H5VPVPVPVP%1)5)5)2 00)5 hti )0)0)0) 30C)5) )3 3 3 3 3 3 3 3 C 3535:5: : : w65e : : : : : :3:(60(75(6)(0di070(70(70(7M ( :5)65(65(6(101 1039:0 xoi090909 509 511 101101017 01C:01 10C C C C(D C C CC51 1C C C C 1M0 nC C CC : C C C:1 oM M MCM0 C C CM M MSciSMS 7(M M M n:nn:n:nCli :S Sn:n: :n: :n:n:nanananC SaMnnanan nlaotnananaM M M M:annM M M MinM M M anaM M 041BAB B043044045046049041050 3565303A 0010A 111E / E E E E E E0 0 0 0 0 0 06 / / / / / / E / E5625625625625625625625 / E2 6 / E / E / E / E / E / 1.356252 858258 8 8 92525252709434 5 841 1 1617181910212223242521 / 1BD0n - -)600mµ 2 54520 1 1 0 1Ooi(2Wtc# 4-5 +20 0a0)4- m00 058 4 rf-002µ 55331171-1 1 h7c 3 4( 001ae# 6f0)795o50 + d3- - 500mµ 52828 5.2 lei2#6( 012 3oY7N 5-)te0ek.g3a2t-0021m 7µ50(0528333conec# 8Dr#)y ee P0 mµn202 73231ro> 58t(tA0)4- - 00mµ 232 9798979#4( 00 .60.0.0.0ytic )i0r3e--00mµ 39h 560. 898979p2# (10.0.0.0S 75)2- - 0021mµ 49. 79. 89. 79.#7( 050 08 0 0de)M0 0 + 0 + 0neoipP 0800t181 0804 010804aSR( 1 1 14zie ) 6nnomi 6 5ri7 7+eTm( 1+2hpS etale )z Pim0sm .(2 0.2 0.2 0.3dne)M0 0 0 0oe Pip R6 6 6 6sSu (rtx nee &eepR 6 R 8 R R ErczySiS T.0.0 8.0 8.0redeKnmia P0 K3P0 K3P0 K3P03BNVPVPVPVPlo oC)C)C)C)t iitnaC5r3n M:C535 5:C3C3aC:5n6M (:5:n6M (:5:n6M (:5n6(MCna 1n1n1n1M M0a a a1M01M01M01B11.0oA E7B0A1B1 / N0 1 1 11.85.28h3c 0 0tE / E0 0 3 / E / E / 97ea8 8 8 8 0lB5252525294ba.Tr . 84S o1N1 2 3 4 / 1BDAttorney Docket No.059717-5025-WO

[0211] Formulations made with Microcrystalline cellulose PH101 led to sticking of wet spheres on the spheronizer wall when spheronization continued beyond 3 minutes to enhance the pellets surface morphology as shown in FIG 18. Multiple trials were executed as summarized in Table 37 by varying the mannitol:MCC ratio, using different MCC grades, the addition of talc & silica, the quantity of granulating liquid, the binder level, the binder type and using a hydro-alcoholic mixture as the granulating liquid (as mentioned in Table 37). Sticking was not found beyond 3 minutes in formulations containing talc, silicon dioxide, silicified microcrystalline cellulose, microcrystalline cellulose PH105 or in formulations with microcrystalline cellulose PH101 made by granulating with hydroalcoholic mixture (water & isopropyl alcohol). However, sphericity was not as expected in these formulations.

[0212] After investigating the environmental conditions of the previous batches, it was found that controlling the environmental humidity to below 50% relative humidity (RH) and preferably 35% RH to 45% RH eliminates the sticking tendency in the formulations containing microcrystalline cellulose PH101. This finding was confirmed by executing reproducibility trials with maintaining the environmental humidity below 50%. FIG.18 shows sticking of the wet spheres on the spheronizer wall.

[0213] Further trials were run to evaluate the sphericity and percentage yield of mannitol:MCC pellets (65:35) made by employing different combinations of extrusion screens (radial - 0.6 mm, 0.8 mm), friction plates (2.0 mm, 3.0 mm), and spheronization times and speeds as shown in Table 38.

[0214] It is clear from Table 38 that the mannitol:MCC (65:35) beads with B No. 258 / E011A showed at least equivalent sphericity compared to marketed products (Table 39) and other mannitol:MCC beads / formulations in the same table (Table 38). Additionally, the majority of the yield was above 420 µm (#40 sieve).

[0215] Consequently, mannitol:MCC pellets were produced at bigger size (B No. 258 / E019 and B No.258 / E011A) with 10% diclofenac sodium loading, followed by a functional coating (performed on #20-25 size particles at 25% weight gain using Surelease ready aqueous dispersion).

[0216] Drug release from mannitol:MCC pellets coated with 25% Surelease and cured at 60°C for 2.0 hours and 8.5 hours were compared against similarly coated and cured marketed products MCC Cellets 700 (#18-25) & sugar Pharm-a-spheres (#20-25). FIG.19 65 DB1 / 148490793.1Attorney Docket No.059717-5025-WO provides SEM images of the mannitol:MCC (65:35) beads of #20-25 size cores used for functional coating B No.258 / E019. Table 39. Summary of the sphericity data of marketed products. Sr No. Pellet type Batch No. Size (µm) Sphericity 1 Cellets 350 (MCC spheres) 21C1019 350 - 500 0.96 2 Cellets 700 (MCC spheres) 21G1058 710 - 1000 0.95 3 Pharm-a-spheres (Sugar 80511026 250 - 355 0.96 spheres) 4 Pharm-a-spheres (Sugar 083301406 710 - 850 0.94 spheres) Table 40. Formulations and ingredients for the pellet API coating IngredientsSpecification / Quantity per GradeBatch (g / batch) Inert core (Sugar, MCC, or Mannitol : MCC)USP 800.00Diclofenac Sodium USP 80.00 HPMC (Methocel E5) NF, Ph. Eur 80.00 Talc USP 40.00 DM Water - 1800.00

[0217] Procedure for drug coating dispersion preparation (ingredients in Table 40): 1) The required amount of water was weighed accurately and HPMC was added under stirring for 15 mins, kept aside until a clear solution was observed. 2) To Step (1), drug (diclofenac sodium) and talc was added and dissolved under stirring. 3) Stirring continued for 30 min 4) Step (3) dispersion was homogenized for 20 mins. 5) The dispersion was passed through #100 µm nylon cloth before using it for coating. 6) The inert pellets were loaded in fluid bed coating equipment fitted with a Wurster column model GPCG 1.1 before initiating the coating process to form beads comprising the API.

[0218] The drug loading parameters are summarized below in Table 41. Table 41. Process parameters Process parameter Observed values Inlet temperature (° C) 50 – 60 Product temperature (° C) 40 – 47 66 DB1 / 148490793.1Attorney Docket No.059717-5025-WO Air flow (CFM) 45 – 60 Drive (%) 30 – 40 Pump RPM 2 – 6 Spray Atomization 0.9 – 1.0 Wurster column height 20 – 25 mm

[0219] The process for drug loading was smooth.

[0220] The representative formulation for the functional ethyl cellulose (Surelease) coating is given in Table 42. The formulation is based on a load of 450 g. Table 42. Functional coating ingredients IngredientsSolids Quantity perDispersion Quantity Batch (g / batch)per Batch Drug loaded pellets 450.00 - Surelease E-7-19040 157.50 637.65 DM Water - 412.35 Total 607.50 1050.00

[0221] Procedure for bead coating dispersion preparation: 1) To the required quantity of the coating dispersion, the weighed amount of water was added and stirred for 15 min. 2) The drug loaded beads were loaded into fluid bed coating equipment fitted with a Wurster column model GPCG 1.1. 5) Coating was initiated using step (1) polymer dispersion. 6) A sample of the beads was removed after 25% weight gain and were cured at 60 °C for 2 hours, 8.5 hours, and 24 hours.

[0222] The process parameters for Surelease coating (Functional coating) are summarized in below Table 43. Table 43. Process parameters Process parameter Observed values Inlet temperature (°C) 48 – 55 Product temperature (°C) 38 – 45 Air flow (CFM) 50 - 60 Pump RPM 3 - 5 Spray Atomization 0.9 - 1.0 Wurster column height 20 – 24 mm 67 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0223] The coating process was smooth without any problems.

[0224] The 25% Surelease coated mannitol:MCC (65:35) beads / pellets, Cellets 700, and Pharm-a-spheres were then subjected to dissolution studies (FIGS.20A-20C). The dissolution parameters were media: 0.05 M phosphate buffer, pH 7.5, 900 ml, USP II apparatus, 50 RPM and sample time interval: 0.5, 1, 2, 4, 6, 8, 10, 12 hours.

[0225] It can be clearly seen from FIGS.20A-20C that the mannitol:MCC (65:35) pellets manifested a much faster release of >85% in 4 hours compared to the drug release from the sugar spheres (Pharm-a-spheres) of >80% in 6 hours and MCC spheres (Cellets 700) of >80% in 8 hours.

[0226] Mannitol:MCC (65:35) beads showed faster drug release across 2 hours and 8.5 hours of curing time compared to reference product. Hence, the dissolution profile was evaluated in pH 6.8 phosphate buffer (FIG 21). Table 44. Summary of the PSD of Cores, drug loaded, and Surelease coated pellets. Particle Size Distribution (µm) Sample Mannitol:MCC (65:35)Cellets 7Sugar spheres (Pharm-a- pellets00spheres) D10 D50 D90 D10 D50 D90 D10 D50 D90 Uncoated core696 817 957 771 898 1060 703 824 96210% Drug loaded758 864 997 820 950 1100 768 893 105025% EC coated800 948 1120 899 1050 1240 860 989 1170

[0227] Swelling index was evaluated for uncoated mannitol:MCC (65:35) beads (#20- 25), Cellets 700 (#18-25), Pharm-a-spheres (#20-25) and the same products coated with 10% Diclofenac sodium and 25% Surelease. The initial diameter was measured for beads from each product under a microscope. Each type of product beads were transferred to HPLC vials (one bead / vial), 1.0 mL of pH 7.5 phosphate buffer was added to each vial containing beads, and the bead containing vials were soaked for 4.0 hours with intermittent shaking. After four hours of soaking, the media was removed from each vial by filtration to collect the bead and the bead was tested for diameter under a microscope. A summary of the swelling index study results can be found in Table 45. 68 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0228] Swelling index data shows the disintegration of mannitol:MCC uncoated beads after 4 hours due to the presence of soluble mannitol and insoluble MCC versus swelling found in uncoated Cellets 700 (MCC spheres). Similarly negative values in 25% Surelease coated Pharm-a-spheres (Sugar spheres) indicate the absence of swelling material in its core. Swelling was found in 25% Surelease coated mannitol:MCC beads due to the presence of mannitol and MCC in their cores but the percentage of swelling is less than the 25% Surelease coated pure MCC spheres (Cellets 700). Table 45. Swelling index results of uncoated mannitol:MCC(65:35) beads, Cellets 700, Pharm-a-spheres and 25% Surelease coated Mannitol:MCC(65:35) beads, Cellets 700, and Pharm-a-spheres. Sr.ProduBead Diameter (µm) % Avg. % No.ctNo. Initial 04 hours difference difference 1 880.009 Disintegrated NA Uncoated 2 825.065 Disintegrated NA 1 Mannitol:MCC 3 903.548 Disintegrated NA (65:35) beads 4 901.38 863.584 -4.19 NA (B No.258 / E019) 5 845.048 Disintegrated NA 6 792.129 745.439 -5.89 1 846.272 852.968 0.79 Uncoated MCC 2 1000.932 1003.565 0.26 2 spheres / Cellets 3 938.162 947.801 1.03 700 4 929.857 949.555 2.12 1.43 (B No.21G1058) 5 887.573 911.569 2.70 6 791.866 805.123 1.67 1 856.197 Dissolved NA Uncoated Sugar 2 858.563 Dissolved NA 3 spheres / Pharm-a- 3 928.662 Dissolved NA spheres 4 893.886 Dissolved NA NA (083301406) 5 827.183 Dissolved NA 6 820.803 Dissolved NA 25% surelease 1 1002.720 1006.885 0.42 coated 2 950.185 957.996 0.82 4 Mannitol:MCC 3 1043.114 1077.334 3.28 (65:35) beads 4 977.929 998.849 2.14 2.09 (B No. 5 1046.250 1076.952 2.93 258 / E023C) 6 1052.996 1084.169 2.96 25% surelease 1 1096.654 1131.735 3.20 coated MCC 2 1210.667 1259.730 4.05 5 spheres / Cellets 3 1154.165 1225.339 6.17 4.07 700 (B No. 4 1174.264 1211.502 3.17 258 / E022C) 5 1099.144 1125.088 2.36 69 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 6 1131.239 1192.858 5.45 25% surelease 1 1024.140 1016.418 -0.75 coated Sugar 2 1116.375 1087.197 -2.61 6 spheres / Pharm-a- 3 1118.796 1107.738 -0.99 spheres 4 1005.433 1008.047 0.26 -0.75 (B No. 5 1041.847 1030.649 -1.07 258 / E024C) 6 1018.662 1025.656 0.69

[0229] This data shows that the behavior of the pellets with varying compositions is different in both the uncoated and coated spheres and is dependent on several factors, including the solubility of the components used. Although not wishing to be limited by theory, the behavior of the pellets may also depend on the porosity of the cores. The mannitol:MCC cores have a swelling behavior somewhere between that of sugar and MCC, therefore it could be expected that the release of drug coated spheres would be somewhat intermediate between that of pure MCC and pure sugar. As this is clearly not the case, other factors such as porosity are having a significant and surprising effect. Example 4

[0230] Further experiments were carried out to evaluate the impact of the ratio of mannitol and microcrystalline cellulose in the formulation on the drug release from controlled release coated mannitol:MCC beads / pellets. The method used to produce these pellets was same as the flow chart in FIG.1. Table 46 summarizes the formulation and processing conditions used in Example 4 experiments, where Mann = Mannitol, MCC101 = Microcrystalline cellulose PH101, PVP K30 = Polyvinyl pyrrolidone K30, R = Radial, HPMC = Hydroxypropyl methyl cellulose. Table 47 summarizes the sphericity, aspect ratio, shape factor and percentage yield of Example 4 experiments. 70 DB1 / 148490793.1OW)-5 M0 02 P040 0)0 R5 (1-d +000 04 4- -0m752525848801 r80 + o 0324 µ0.0.0.0.0 4.07e 00 1 1810 tc # (061e79np 808 afS 1 1 e5oi0ta)pa.znih 5)2- -0moi µ 6536067595Nnto mSr ( 6 0 1e+1 9 7 7 6+ 21#7( 0.58 0.0.0.0.0e ek hcopmiSTDe0)4- -0m7 2 6 9 1y zeis )oit0324(µ0 00.1 1.1 0.1 0.1 1.1nr etm0.0.0.0.0.a # 6o2 2 2 2 2rtatl m( tPceApde) s5A2- -)0M1mµ 80. 40. 40. 40. 30.0 002 7( 051 1 1 1 1n eopPR6 6515451 # 8isS (urt0)x Enee& rceepR 8 R R R R4- -0mµ 7979694969Szisyt.0 8.0 8.0 8.0 8.0y0ti 324( 0. . . . .c00 0 0 0 0i# 6ergaretehp 5-)nden0 0 50ci.0 5 S 2- 01mµ 69. 89. 69. 69. 79rb1.1.0.1.0 02#7( 050 0 0 0.0efo 8f Poeggnai0ttdi6- -)105mµ8. 8.l781. i5.nalu6.e0 6.6 6.0 6.4 6. 04 2( 022 101N91cun qil 5 2 5 505 # 4reaPrg0)e 4- - m5 8 7 3 1msa0 pspsp00324 µ.( 05.15.23.23.342n303 c5c5cdle#06r K K5C CiedP PCYne 0-)iVPVPMPMPMP ga3- 00mµ 2.3 5.6.1.6.BH H Htn5e2#6( 01341521181o7ictraer1 P )C01 1 1 1510)10)10 02) 1 ) 1 )- - 000mµ 30.2 9.2 2.7 8.8 2.0C C0C0C C C2 7(54 1 2 4 2M C5loM:C 0 M2:C00 M5:C00 M5:C00 M5:# 80t:innn 5(:n8(:n5(:n5(:n5( )nanananana 0ma M M M M M2# µ>015. 76.7 3. 86.221.571M8(.o6A A A7 .N22h037 80 o62A2A7A8 70ct E / 03a85E030 0 / E / E EN / h0E 3 3 30 / 0 0 0E / .B 2 858 / 25825326 c2ta8 EB5 / E2 8 / E58 / 8 325252621.36. 94. 7 70elo 4e.o94bNa.r1 2 3 4 5lbN. 1 2 3 484T SaTr51S / 1BDAttorney Docket No.059717-5025-WO

[0231] The formulation with a 50:50 mannitol:MCC ratio produced the required larger fraction with an acceptable morphology like sphericity, aspect ratio, and shape factor. Therefore, the controlled release coating was performed on this formulation to compare it to the drug release versus the mannitol:MCC (65:35) beads.

[0232] A bigger batch of mannitol:MCC (50:50) pellets was made using same process as B No.258 / E037 and a coating of diclofenac sodium followed by 25% Surelease was performed on #20-25 (710 – 850 µm) size particles to evaluate the impact of the mannitol:MCC (50:50) on drug release through the controlled release polymer. The formula and procedure to prepare this batch are the same as paragraphs

[0151] -

[0156] . Coated pellets were cured for 2 hours in hot air oven at 60°C.

[0233] The 25% Surelease coated mannitol:MCC (50:50) pellets were then subjected to dissolution studies (FIG.22). The dissolution parameters were taken in 900 ml 0.05 M phosphate buffer, pH 7.5, USP II apparatus, and 50 RPM with sample time intervals of 0.5, 1, 2, 4, 6, 8, 10, and 12 hours.

[0234] Mannitol:MCC (50:50) pellets showed similar drug release as the Mannitol:MCC (65:35) pellets and significantly faster drug release versus controlled release polymer coated Cellets 700 and Pharm-a-sphere cores. Although not wishing to be limited by theory, this could be attributed to porosity of the core as there is no significant difference between the porosity values of 50:50 and 65:35 ratio (Table 48). Table 48. Summary of the total pore volume and average pore diameter data of mannitol:MCC beads / pellets of larger size 420 - 600 µm, 600 – 850 µm, and 710 – 850 µm. Sr. o.Composition BatchTotal pore Average pore NNo. Fraction / Sizevolume (cc / g) diameter (nm) 1Mannitol-MCC PH101(50:50) + 0.5% HPMC 5cps258 / E037AC#30-40 (420- 600 µm)6.2359 x 10-312.442 2Mannitol-MCC PH101#20-30(600- (50:50) + 0.5% PVP K30202 / E043D850 µm)4.6791 x 10-38.8657 3Mannitol-MCC PH101#20-30(600- (75:25) + 0.5% PVP K30202 / E064D850 µm)5.7200 x 10-316.427 4Mannitol-MCC PH101#20-2 (20:80) + 0.5% PVP K30246 / E0245 (710- 850 µm)2.4317 x 10-35.480 5Mannitol-MCC PH101#20-25 (710- (65:35) + 1% PVP K30 258 / E019 850 µm)3.6813 x 10-313.506 6Mannitol-MCC PH101(80:20) + 1% PVP K30258 / E032AB#20-25 (710- 850 µm)2.4131 x 10-310.023 7Mannitol-MCC PH101(65:35) + 0.5% HPMC 5cps258 / E035BA#20-25 (710- 850 µm)3.6348 x 10-315.258 8Mannitol-MCC PH101#20-25 (710- (50:50) + 0.5% HPMC 5cps258 / E037AA850 µm)3.9022 x 10-38.8119 72 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 9Mannitol-MCC PH101#20-25 (710- (50:50) + 1% HPMC 5cps258 / E038AA850 µm)3.3508 x 10-38.119 10 Mannitol-MCC PH101#20-25 (710- (50:50) + 1.5% HPMC 5cps258 / E039BA850 µm)3.8154 x 10-310.892 11 Mannitol-MCC PH101#20-25 (710- (65:35) + 1.5% HPMC 5cps258 / E041BA850 µm)3.6612 x 10-310.214 Mannitol-MCC PH101 12 (65:35) + 0.5% HPMC 5cps#20-25 (710- -annitol in binder258 / E045AA 850 µm) 3.33(10% M222 x 1011.58 solution) 13 Mannitol-MCC PH101#20-25 (710- (65:35) + 0.5% HPMC 5cps263 / E033AB850 µm)5.1639 x 10-39.90 Mannitol-MCC PH101 14 (65:35)+1% SSF+0.5%263 / E045B#20-25 (710- -3ps850 µ 7.2486 x 1017.04 HPMC 5cm)Mannitol-MCC PH101 15 (65:35)+1% SSF+0.5%263 / E047B#20-25 (710-3.41-3PMC 5cps850 28 x 109.61 Hµm)MCC = Microcrystalline cellulose, PVP K30 = Polyvinyl pyrrolidone K30, HPMC = Hydroxypropyl methyl cellulose, SSF = Sodium stearyl fumarate.

[0235] Table 49 summarizes the total pore volume and average pore diameter data of Mannintol:MCC beads / pellets of smaller size 250 – 420 µm. Table 49. Sr. Total pore Average pore No.Composition Batch No. Fraction / Sizevolume (cc / g) diameter (nm) 1Mannitol-MCC PH101#40-60 (65:35) + 0.5% PVP K30202 / E019B (250- 420 µm)4.2856 x 10-311.528 2Mannitol-MCC PH101#40-60 (250- (65:35) + 0.5% PVP K30202 / E040B420 µm)3.4398 x 10-39.399 3Mannitol-MCC PH101(50:50) + 0.5% PVP K30202 / E043B#40-60 (250- 420 µm)6.3605 x 10-311.573 4Mannitol-MCC PH101#40-60 (250- (75:25) + 0.5% PVP K30202 / E048B420 µm)8.7767 x 10-320.783 5Mannitol-MCC PH101#40-60 (250- (65:35) + 0.5% PVP K30202 / E056B420 µm)6.0343 x 10-312.600 6Mannitol-MCC PH101#40-60 (250- (75:25) + 0.5% PVP K30202 / E064B420 µm)7.1305 x 10-313.373 7100% MCC PH101 246 / E034B#40-60 (250-420 µm) 1.4409 x 10-35.233 8Mannitol-MCC PH101#40-60 (250- (50:50) + 0.5% HPMC 5cps258 / E037AC420 µm)6.2359 x 10-312.442 Mannitol-MCC PH101 9 (65:35)+1% SSF+0.5%263 / E033AD#40-60 (250- -3PMC 5cps420 6.3058 x 108.290 Hµm)MCC = Microcrystalline cellulose, PVP K30 = Polyvinyl pyrrolidone K30, HPMC = Hydroxypropyl methyl cellulose, SSF = Sodium stearyl fumarate.

[0236] A combination of mannitol:MCC with the ratio between 50:50 and 75:25 produced more porous pellets compared to MCC pellets (Cellets, Celphere CP) and Sugar spheres (Pharm-a-spheres). The total pore volume and average pore diameter for Mannitol:MCC beads (50:50 to 75:25 ratio) is 3.0 x 10-3to 9.0 x 10-3cc / g and 7.0 to 22.0 nm 73 DB1 / 148490793.1Attorney Docket No.059717-5025-WO respectively (Table 47) compared to the total pore volume and average pore diameter for MCC pellets (Cellets, Celphere CP) and Sugar spheres (Pharm-a-spheres), which is less than 2.0 x 10-3and less than 6.0 nm, respectively (Table 36). Example 5

[0237] Further development was carried out using a dome type extrusion screen to evaluate the impact of axial pressure (dome) versus radial pressure on the quality of the extrudes, which impacts attributes like porosity, sphericity, and surface morphology.

[0238] A few of experiments performed previously using radial type extrusion screen were repeated using the dome type extrusion screen keeping all other parameters unchanged. Table 50 summarizes the formulation and processing conditions used in Example 5 experiments where MCC101 = Microcrystalline cellulose PH101, PVP K30 = Polyvinyl pyrrolidone K30, HPMC = Hydroxypropyl methyl cellulose, and D = Dome type screen. Table 51 summarizes the sphericity, aspect ratio, shape factor and percentage yield of Example 5 experiments. Table 52 summarizes the reproducibility in sphericity, aspect ratio, shape factor, and percentage yield of multiple similar batches.

[0239] Among the mannitol:MCC (65:35) bead formulations evaluated using the dome screen (Table 50), the formulation with B No.263 / E033A showed good morphology including sphericity, aspect ratio, shape factor, and acceptable fraction yield. The porosity values are similar to mannitol:MCC (65:35) beads produced using radial type extrusion screen (Tables 48 and 49). FIG.24 depicts SEM images of B No.263 / E033A. 74 DB1 / 148490793.1OW0- )00200 0 0 020 0 0 052 d0 e5 eM 1-+12+12121217 npP1SR 000+00+00+00+00004-)0 m1 4 1 4 6 57oi(8 8 8 8 8 8 ro-0 24 µ0 6.9ta1 1 1 1 1 1tc3# (06 0 5.0 5.0 5.0 5.0 5.050zi.o n e )nomi 7 9 7 9 7 7afeNriteTm(+2+2+2+2+2+2pah 5)2-0m9 9 7 2 3 0eh S-0 17 µ0 5.0 5.0 5.0 6.6.6.kpe2(50 0 0co Szis ) # 8Dyem2 2 2 2 2 2etnarl m(0o4- -)0 m3 8 3 9 7 8oP i 0 2µ0.0.1.0.0.0.tta3 4( 001 1 1 1 1 1t ) # 6Adrne M 0 0 0 0 0 0tcoeis pP 3 3 3 3 3 3 ep)s52- m uSR(A-0017 µ 600. 610. 910. 310. 410. 40.rt2# (58 1 1xnEee& rceepD D D D D Szisyt 7.70.70.7D 0.0 7.7 )0.004- -02mµ 79. 7979898989eyt 03 4( 0 0.0.0.0.0.0garictendi#06reni 5.5e.5.5.5.5.hp 5-)crb0 0 0 0 0 0 S 20m8 8 7 8 8 8e f -0 1µ9.9.9.9.9.9.Po2#7( 058 0 0 0 0 0 0f5o7eggnai0)tt6- d -005mµ0 6.5 0.2 0.3 9.l2 i 0.1naleuiu6c n q.6il8.638.638.6.6.4#2(2N 3831414 4reaPrg0)4- -02mµ 2.6.4.2. 0. 3.d03 4( 00 52023202 751re0 0sps s lcpc0 pcei # 6Yde 3nim K3K5 53K5 eg0)3- -0mµ 6.9.1.2.4.3.Ban PVPC C PVPMPMPCaPV MtPn5e205 2 3 9 8 2#6( 012 2 2 1 1 27H HPHcreC1 1 1 1 1 1 P5--)20m1 5 0 5 8 2C01010 0 0 00207 µ0 .3.22.22.23.27.282MloC)C) 1C) 1C) 1 ) 1 ) # (58i C53C5C5C5C C5C C5otitnanrM: :n56M3::3n 56M: :3n 56M: :3n 56M: :3n 56M: :)n 5602 m#µ8.9 9.1 3.8 7.3 7.6 2.2an(an(an(an(an( (ana >0581 3 2 3 4 3MMMMMM M(..ABABAA o A5Bo9 A5 9 1 1 2 31B1A2A N2 2 3 3 3 3N2 2 3 3 333 h0hE0E0 0E0 0.c 0 0 0 0 0 0 ct / / 3 E / / E / E / 0t E / E / E / E / E / E / a3B6263 326263 32626 1.35a36363 363 3 .12 970e Bl2 262 26262 5e.o94b ..a ro 1 2 3 4 5 6lbN.r1 2 3 4 5 6841TSNaTS / 1BDOW-52r0o5- tc71 af27 64 1 0 89 .6 6 6 550e ezp0.0.0.0.0.iosahN) Ste mk µco05oD 8iy-te0arn0 t403040405r7 c .o( ep1.1.1.01.1tt5A2-s0A 2#yticir7 8 8 8e9h.9 9 989p0.0.0.0.0S0--)6005m µ00.6.8.2.7.4#2(21 1 1 1 140)4- - 00m2.2.0.8.8.32#4 µ(0401416141516760)3- - m 5020#6 µ 0.2.6.4.1.( 01120202021275)2- - 0020mµ 1.7 3 28.9.8.78.#7( 052 2 2 27280)2- - 80 mµ5.7 8 8 215#8(006.7.6.6.601 1 1 1 1) 181m #µ01.6.0.5.4.>0091161718171(.o4N454647484h0cE0 0 0 0t / E3 / E E E3 / / / a 6 6363 3. B 2 2 262621.3295. 7elo 09bN4a. 1 284Tr3 4 51S / 1BDAttorney Docket No.059717-5025-WO

[0240] Multiple batches of mannitol:MCC (65:35) beads were produced similar to B No.263 / E033A to check the reproducibility and to use #20-25 size cores for controlled release and delayed release application studies. The procedure followed in the preparation of mannitol:MCC beads is similar to flow chart in FIG.1. Table 53. Composition and process parameters Ingredient % / batch Mannogem powder 64.03 Pharmacel 101 34.48 Lubripharm 0.99 Hypromellose 5cps 0.50 Purified water 41.60 Granulation Dry mixing 10 min. at 200 RPM Kneading 01 min. at 350 RPM Wet mass LOD 29.67% Extrusion Extrusion screen 0.7 mm, Dome type Extrusion speed 30 RPM Extrudes LOD 28.95% Spheronization Spheronization time & speed 2+7 min at 1800+1200 RPM Wet spheres LOD 27.98% Drying Inlet temperature 60°C LOD after drying 1.69%

[0241] As a controlled release application study #20-25 sieve size cores were loaded with 10% diclofenac sodium followed by 25% surelease coating and 2 hours curing. The formula and procedure followed for drug loading and polymer coating is similar to paragraphs

[0217] -

[0222] herein.

[0242] The 25% Surelease coated mannitol:MCC (65:35) beads / pellets (B No. 263 / E043A) were then subjected to dissolution studies (FIG.23). The dissolution parameters were 900 ml 0.05 M phosphate buffer, pH 7.5, USP II apparatus, 50 RPM and sample time interval as 0.5, 1, 2, 4, 6, 8, 10, 12 hours.

[0243] Mannitol:MCC beads of 65:35 and 50:50 ratios produced by using radial and dome extrusion screen showed similar drug release to the previous examples as shown in FIG. 77 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 22 from the controlled release polymer. Specifically, the release from the MCC:mannitol beads was significantly faster than that from the sugar beads and MCC beads, respectively.

[0244] A delayed (enteric) release application study was also undertaken using mannitol:MCC (65:35) beads of #20-25 sieve size which were loaded with 10% diclofenac sodium similar to formula and process described in paragraphs

[0217] and

[0218] herein. Drug loaded mannitol:MCC (65:35) beads, Cellets 700, & Pharm-a-spheres were further coated with enteric polymer using Drugcoat L30D dispersion. Table 54. Enteric coating ingredients IngredientsSolids quantity per batchDispersion quantity per (g)batch (g) Drug loaded pellets 450.00 - Drugcoat L30D 112.50 371.66 Talc 45.00 45.00 Triethyl citrate 11.25 11.25 Purified water - 1259.59

[0245] Procedure for coating process 1. Talc was dispersed in purified water under stirring followed by the addition of triethyl citrate. 2. The dispersion from step 1 was homogenized for 10 minutes. 3. Drugcoat L30D was dispensed into a separate container under stirring before the dispersion of step 2 was added. Stirring was continued for 30 minutes. 4. The polymer dispersion from step 3 was filtered through #100 µm nylon cloth then taken up for coating. 5. The drug loaded pellets were coated with the enteric polymer dispersion of step 4. 6. The enteric coated pellets were cured in a hot air oven at 40 °C for 60 minutes. 7. The process parameters for enteric coating are summarized in Table 55. Table 55. Process parameters Parameter Observed value Inlet temperature (°c) 35 to 40 Product temperature (°c) 30 to 32 Drive open (%) 31 to 37 Air flow (cfm) 45 to 60 Atomization pressure (bar) 1.0 to 1.1 Spray pump speed (RPM) 3 to 4 Wurster column height (mm) 15 to 20 78 DB1 / 148490793.1Attorney Docket No.059717-5025-WO

[0246] The coating weight gain for each core was 15% enteric coating. All 3 coated core types (mannitol:MCC (65:35) beads / pellets (B No.263 / E056B), sugar, and MCC) were then subjected to dissolution studies (FIG.25). The dissolution parameters were 900 mL 0.1 N HCl for 2 hours (acid stage) followed by pH 6.8 phosphate buffer (buffer stage) USP I apparatus, 100 RPM and sample time interval of 2, 5, 10, 15, 30, 45, and 60 mins.

[0247] In all 3 cases, drug release during the acid exposure phase was less than 5%. The amount of drug release in the pH 6.8 phosphate buffer phase was found to be almost the same across the 15% enteric coated mannitol:MCC (65:35) beads, Cellets 700 (MCC) and Pharm-a- spheres (sugar).

[0248] Pellets are also utilized in MUPS tableting applications. For this reason, the crushing strength of the pellets was investigated using the following method. 1. Uncoated and coated pellets were passed through #20 sieve (0.85 mm) and #18 sieve (1.00 mm) respectively, particles stuck in the sieve aperture were taken for testing. 2. A single particle was placed on flat surface of the texture analyzer equipment and a force was applied with a moving probe. This test was repeated for 30 particles in each sample. 3. The testing parameters are as below: Test mode: Compression Pre-test speed: 0.10 mm / sec Test speed: 0.02 mm / sec Post-test speed: 10.00 mm / sec Probe: P / 0.5 Trigger force: 5.0 g The crushing strength of mannitol:MCC beads was found to be less than the marketed products Cellets 700 and Pharm-a-spheres. Although not wishing to be limited by theory, it is believed that this is indicative of a more porous nature of these mannitol:MCC pellets. The trend was the same in uncoated and coated pellets (Table 56), which could be attributed to the difference in the composition of mannitol:MCC beads versus the marketed products. However, despite these apparently mechanically weaker pellets, no significant difference was found in the friability of mannitol:MCC beads compared to the marketed products (Table 56). 79 DB1 / 148490793.1OytWi)- l5 i w / 62 b0 aiw / 07.08 0 5 7A A A A A A A r0.00.10.00.00.0N N N N N N N5- %7 F (179.5x 60).a .4 01 9.3.7.2. 8.7 6.63.5. 2.46. 4.1oN( 1 3 7 5 5 1 1 9 7 1 8 2h MNtetkgcnoeDrt.ni 1.2.6.1.4 41. 4 6 2 4 80.yse gM7 4 1 4.3.311.6.5.4.7.541nrnoitths eAurgCar 2e. 1 8 2 5 11 3 2 0v 11.7.2.5.4..45.1261.97.5 .141..781Ae)lcim trma(5800P e.z0.1i ssduettaa dto etScanoUC.o8 6 1A A A A2 ACAC A AB B B08N500440 53110 22424134556575hc1 1t0E / 040E / 0 0 0E0E0E0 0aG13336E / E / 36E / E / / 3 / 3 / E3 / E3 / 3B 2 8 2 858252 2 8582526262626262sdsadeaesb)bda0)5ebrer 5:3:)dend 0in 555(6( 3:bisber C C56(%5.%e05 hC Cse.100prs M-M- eChCs, , 7 -dssal-olti otips-M-l 00adseadsadatelmrnnna-oti7sbe)bebeblea anamn t5) ChPran ell35):35)30M M 5dhaes5:65:5:0et d(6(6(5(a et det det PMCoaoaoao det det dete er c c c c aoaoao.meCCCCCCCCese e easasasc c c 1.6a5n0ht0ps-M-lM-lM-lM-elle ele el aeel ciciciere3t ret re 970el c7b u sta-otototo rurururu n ntn9emininitninS S S S E E E484ado llrTrPeanananana% % % % % % %1ChP / M M M M52525252515151 1BD

Claims

Attorney Docket No.059717-5025-WO CLAIMS 1. A plurality of pellets comprising a cellulose component and a soluble filler in a weight / weight ratio of cellulose component to soluble filler of from about 50:50 to about 20:80, wherein the porosity of the plurality of pellets, ranges from about 3.0 x 10-3to about 9.0 x 10-3mL / g, the plurality of pellets comprising pores having an average pore size in the range of about 7.0 to about 22.0 nm.

2. The plurality of pellets of claim 1, wherein porosity is as measured by nitrogen adsorption.

3. The plurality of pellets of claim 1 or 2, wherein the cellulose component comprises one or more of microcrystalline cellulose (MCC), silicified MCC, hydroxypropyl methyl cellulose, methyl cellulose, and / or sodium carboxymethyl cellulose.

4. The plurality of pellets of claim 3, wherein the cellulose component consists essentially of MCC.

5. The plurality of pellets of claim 3, wherein the cellulose component consists essentially of silicified MCC.

6. The plurality of pellets of claim 5, wherein the silicified MCC is SMCC 90.

7. The plurality of pellets of any one of claims 1 to 6, wherein the soluble filler comprises a polyol.

8. The plurality of pellets of claim 7, wherein the polyol is selected from mannitol, erythritol, sorbitol, maltitol, isomalt, and xylitol.

9. The plurality of pellets of claim 8, wherein the polyol is mannitol. 81 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 10. The plurality of pellets of any one of claims 1 to 6, wherein the soluble filler comprises a sugar.

11. The of pellets of claim 10, wherein the sugar is lactose or sucrose.

12. The plurality of pellets of any one of claims 1 to 11, wherein the pellets comprise about 60% to about 70%, or about 70% to about 80% by weight of the soluble filler.

11. The plurality of pellets of any one of claims 1 to 10, wherein the weight / weight ratio of the cellulose component to the soluble filler is about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, or about 1:

4.

12. The plurality of pellets of any one of claims 1 to 11, wherein the pellets have a median diameter of about 100 µm to about 1,200 µm.

13. The plurality of pellets of any one of claims 1 to 12, wherein the pellets have a median diameter of about 100 to about 600 µm, or about 375 to about 475 µm.

14. The plurality of pellets of any one of claims 1 to 13, wherein the pellets have a sphericity of at least 0.

90.

15. The plurality of pellets of any one of claims 1 to 14, wherein the pellets have a friability of less than about 0.

3.

16. The plurality of pellets of any one of claims 1 to 14, wherein the pellets have a friability of less than about 0.

1.

17. The plurality of pellets of any one of claims 1 to 16, wherein the pore sizes follow a bimodal pore size distribution. 82 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 18. The plurality of pellets of any one of claims 1 to 17, wherein the cellulose component used as a starting material to manufacture the pellets has a density of about 0.26 to about 0.31 g / mL.

19. The plurality of pellets of any one of claims 1 to 18, wherein the pellets further comprise a binder.

20. The plurality of pellets of claim 19, wherein the binder comprises polyvinyl pyrrolidone (PVP).

21. The plurality of pellets of claim 20, wherein the PVP is PVP K30.

22. The plurality of pellets of claim 19, wherein the binder comprises a cellulose derivative.

23. The plurality of pellets of claim 22, wherein the cellulose derivative consists essentially of hydroxypropyl methylcellulose (HPMC).

24. The plurality of pellets of claim 23, wherein the HPMC is HPMC E5.

25. The plurality of pellets of claim 19, wherein the binder comprises maltodextrin, gelatin, or starch.

26. The plurality of pellets of any one of claims 1 to 25, wherein the pellets further comprise a glidant or a lubricant.

27. The plurality of pellets of claim 25, wherein the glidant or lubricant is selected from colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, and glyceryl monostearate. 83 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 28. The plurality of pellets of claim 26 or 27, wherein the pellets comprise about 0.001% to about 10%, about 0.01% to about 5%, or about 0.05% to about 2.5% by weight of the glidant or lubricant.

29. The plurality of pellets of any one of claims 1 to 28, wherein the pellets further comprise a super disintegrant.

30. The plurality of pellets of claim 29, wherein the super disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and magnesium aluminum silicate.

31. The plurality of pellets of any one of claims 1 to 30, wherein the pellets further comprise an active pharmaceutical ingredient (API).

32. The plurality of pellets of claim 31, wherein the pellets are coated with a first coating comprising the API.

33. The plurality of pellets of claim 31 or 32, wherein the API is selected from a proton pump inhibitor, an antihistamine, a pain killer, a beta blocker, a calcium channel blocker, an anti-erectile dysfunction agent, an anti-migraine agent, or a non-steroidal anti-inflammatory.

34. The plurality of pellets of any one of claims 31 to 33, wherein the API is selected from cetirizine, diclofenac, lansoprazole, omeprazole, pantoprazole, esomeprazole, metoprolol, propranolol, montelukast, albuterol, ibuprofen, sildenafil, zolpidem, furosemide, amlodipine, tramadol, atenolol, niacin, paroxetine, nifedipine, venlafaxine, desvenlafaxine, naproxen, famotidine, guaifenesin, bisoprolol, tadalafil, chlorpheniramine maleate, pseudoephedrine hydrochloride, indomethacin, disopyramide phosphate, diltiazem hydrochloride, carbamazepine, verapamil hydrochloride, tolterodine tartrate, methylphenidate hydrochloride, carvedilol phosphate, memantine hydrochloride, budesonide, mesalamine, and sumatriptan or a pharmaceutically salt of any one thereof. 84 DB1 / 148490793.1Attorney Docket No.059717-5025-WO 35. The plurality of pellets of any one of claims 32 to 34, wherein the pellets are coated with a second coating substantially covering the first coating comprising the API.

36. The plurality of pellets of claim 35, wherein the second coating comprises a polymer.

37. The plurality of pellets of claim 36, wherein the polymer is selected from cellulose, ethylcellulose, methacrylic acid co polymer, dimethyl amino methacrylate, butyl methacrylate, and methyl methacrylate copolymer.

38. A method of making the plurality of pellets of any one of claims 1 to 37, the method comprising extrusion spheronization of a wet mass comprising the cellulose component and the soluble filler and drying the extrudates to form the plurality of pellets.

39. A method of making the plurality of pellets of any one of claims 1 to 37, the method comprising powder layering the cellulose component and the soluble filler to form the plurality of pellets.

40. The method of claim 38 or 39, further comprising coating the plurality of pellets with a first coating comprising an active pharmaceutical ingredient (API).

41. The method of claim 40, wherein the coating step comprises aqueous powder coating or dry powder coating.

42. The method of claim 40 or 41, wherein the API is selected from a proton pump inhibitor, an antihistamine, a pain killer, a beta blocker, a calcium channel blocker, an anti- erectile dysfunction agent, an anti-migraine agent, or a non-steroidal anti-inflammatory.

43. The method of any one of claims 40 to 42, wherein the API is selected from cetirizine, diclofenac, lansoprazole, omeprazole, pantoprazole, esomeprazole, metoprolol, propranolol, montelukast, albuterol, ibuprofen, sildenafil, zolpidem, furosemide, amlodipine, tramadol, atenolol, niacin, paroxetine, nifedipine, venlafaxine, desvenlafaxine, naproxen, famotidine, 85 DB1 / 148490793.1Attorney Docket No.059717-5025-WO guaifenesin, bisoprolol, tadalafil, chlorpheniramine maleate, pseudoephedrine hydrochloride, indomethacin, disopyramide phosphate, diltiazem hydrochloride, carbamazepine, verapamil hydrochloride, tolterodine tartrate, methylphenidate hydrochloride, carvedilol phosphate, memantine hydrochloride, budesonide, mesalamine, and sumatriptan or a pharmaceutically salt of any one thereof.

44. The method of any one of claims 40 to 43, further comprising coating the pellets with a second coating.

45. The method of claim 44, wherein the second coating comprises a polymer.

46. The method of claim 45, wherein the polymer is selected from cellulose, ethylcellulose, methacrylic acid co polymer, dimethyl amino methacrylate, butyl methacrylate, and methyl methacrylate copolymer.

47. A solid dosage form comprising the plurality of pellets of any one of claims 1 to 37.

48. The solid dosage form of claim 47, wherein the solid dosage form is a swallowable tablet, a chewable tablet, or an orally disintegrating tablet.

49. The solid dosage form of claim 47 or 48, wherein the solid dosage form further comprises a cushioning agent, a disintegrant, a lubricant, a glidant, and / or a filler.

50. A method of treating a disease or disorder in a subject, comprising administering to the subject the plurality of pellets of any one of claims 1 to 38, or the solid dosage form of any one of claims 47 to 49.

51. The method of claim 50, wherein the disease or disorder is selected from a gastrointestinal disorder, allergies, inflammation, and pain. 86 DB1 / 148490793.1

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