Pharmaceutical Compositions for Colon-Specific Delivery

Abstract

Disclosed are pharmaceutical particulates which release a pharmaceutical compound into the colon following oral administration. A particulate comprises a core comprising a pharmaceutical compound, an inner coating surrounding the core, wherein the inner coating comprises a pharmaceutically acceptable polysaccharide that is susceptible to enzymatic digestion by one or more enzymes present colonic microflora, and an outer coating surrounding the inner coating, wherein the outer coating comprises a polymer which is stable at upper gastrointestinal pH but can dissolve at colon luminal pH in less than about 60 minutes. The core of a particulate can further comprise an excipient such as a diluent, a binder, a disintegrant, a lubricant, a glidant or a combination thereof. Particulates can comprise pharmaceutical compounds for treating colonic diseases such as C. difficile colitis, ulcerative colitis, and Crohn's disease.

Claims

1. A particulate comprising: a core comprising a pharmaceutical compound; an inner coating surrounding the core, wherein the inner coating comprises a pharmaceutically acceptable polysaccharide that is susceptible to enzymatic digestion by one or more enzymes present in colonic microflora; and an outer coating surrounding the inner coating, wherein the outer coating comprises a polymer which is stable at stomach pH and upper intestine luminal pH but dissolves at colon luminal pH, wherein the particulate dissolves at colon luminal pH in less than about 60 minutes.

2. A particulate in accordance with claim 1, wherein the pharmaceutical compound is selected from the group consisting of metronidazole, mesalamine, budesonide, mesalazine, vancomycin, fidaxomicin, rifaximin, ciprofloxacin, sulfasalazine, olsalazine, balsalazide, prednisone, hydrocortisone, infliximab, adalimumab, azathioprine, esomeprazole, mercaptopurine, vedolizumab, ciprofloxacin, golimumab, loperamide, methotrexate and pantoprazole, a pharmaceutically acceptable salt thereof and a combination thereof.

3. A particulate in accordance with claim 1, wherein the pharmaceutical compound is metronidazole.

4. A particulate in accordance with claim 1, wherein the core further comprises an excipient.

5. A particulate in accordance with claim 4, wherein the excipient is selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, a glidant and a combination thereof.

6. A particulate in accordance with claim 1, wherein the polysaccharide is a pectinase substrate.

7. A particulate in accordance with claim 1, wherein the polysaccharide is selected from the group consisting of a pectin, an amylose, a guar gum, an inulin, a dextran, a chitosan, a chondroitin sulfate and a combination thereof.

8. A particulate in accordance with claim 1, wherein the polysaccharide is a pectin.

9. A particulate in accordance with claim 1, wherein the polymer which is stable at stomach pH and upper intestine luminal pH but dissolves at colon luminal pH is selected from the group consisting of a polymethacrylate, a cellulose acetate phthalate (CAP), a cellulose acetate trimellitate (CAT), a hydroxypropylmethylcellulose phthalate (HPMCP) and a combination thereof.

10. A particulate in accordance with claim 1, wherein the outer coating is stable at pH≦6 but dissolves at pH>6.

11. A particulate in accordance with claim 1, wherein the outer coating comprises a polymethacrylate.

12. A particulate in accordance with claim 11, wherein the polymethacrylate is selected from the group consisting of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, and a combination thereof.

13. A particulate in accordance with claim 11, wherein the polymethacrylate is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.

14. A pharmaceutical dosage form comprising: a plurality of particulates in accordance with claim 1; and additional excipient material selected from the group consisting of a binder, a colorant, a disintegrant, a lubricant, a glidant, a flavoring, a preservative, a diluent and a combination thereof.

15. A pharmaceutical dosage for in accordance with claim 14, wherein the pharmaceutical dosage form is a tablet.

16. A pharmaceutical dosage form in accordance with claim 14, wherein the pharmaceutical dosage form is a capsule and further comprises a shell comprising a material selected from the group consisting of a gelatin, a hydroxypropylmethyl cellulose and a combination thereof.

17. A pharmaceutical dosage form in accordance with claim 14, wherein the pharmaceutical compound is metronidazole.

18. A pharmaceutical dosage form in accordance with claim 14, wherein the core further comprises an excipient selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, a glidant and a combination thereof.

19. A pharmaceutical dosage form in accordance with claim 14, wherein the polysaccharide is a pectin.

20. A pharmaceutical dosage form in accordance with claim 14, wherein the outer coating comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.

21. A pharmaceutical dosage form in accordance with claim 15, wherein the pharmaceutical dosage form is a tablet, the pharmaceutical compound is metronidazole, the total amount of metronidazole in the tablet is from 200-800 mg, the core of each particulate further comprises an excipient selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, a glidant and a combination thereof, the inner coating comprises a pectin, and the outer coating comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.

22. A pharmaceutical dosage form in accordance with claim 16, wherein the pharmaceutical dosage form is a capsule, the pharmaceutical compound is metronidazole, the total amount of metronidazole in the capsule is from 200-800 mg, the core of each particulate further comprises an excipient selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, a glidant and a combination thereof, the inner coating comprises a pectin, and the outer coating comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG. 1 is a schematic diagram of a particulate of the present teachings.

[0048] FIG. 2 is a schematic diagram of a capsule filled with particulates of the present teachings.

[0049] FIG. 3 is a schematic diagram of a tablet pressed from particulates of the present teachings and an excipient.

[0050] FIG. 4 illustrates dissolution testing at pH 7.0 in a basket apparatus at 50 rpm of cores described in example 3, with or without a seal (inner) coating of hydroxypropylmethylcellulose.

[0051] FIG. 5 illustrates dissolution profiles at pH 7.0, in a paddle apparatus at 50 rpm, of particulates having hydroxypropylmethylcellulose inner coatings and a polymethacrylate outer coatings.

[0052] FIG. 6 illustrates dissolution profiles at pH 7.0, in a paddle apparatus at 75 rpm, of particulates having a pectin inner coating and a polymethacrylate outer coating in the presence or absence of pectinase.

[0053] FIG. 7 illustrates the dissolution profiles at pH 6.0, in a paddle apparatus at 75 rpm, of particulates having inner coatings of pectin or hydroxypropylmethylcellulose, and a polymethacrylate outer coating.

[0054] FIG. 8 illustrates slow rate of drug dissolution at pH 6.0 of a mesalamine formulation of the present teachings.

[0055] FIG. 9 illustrates rapid rate of drug dissolution at pH 7.4 of a mesalamine &mutilation of the present teachings.

[0056] FIG. 10 illustrates that pectinase enhances the rate of drug dissolution of a mesalamine formulation of the present teachings.

DETAILED DESCRIPTION

[0057] The present teachings include descriptions that are not intended to limit the scope of any claim. The examples and methods are provided to further illustrate the present teachings. Those of skill in the art, in light of the present disclosure, will appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present teachings. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context indicates otherwise.

[0058] Methods and compositions described herein utilize laboratory techniques well known to skilled artisans. Methods of administration of pharmaceuticals and dosage regimes, can be determined according to standard principles of pharmacology well known skilled artisans, using methods provided by standard reference texts such as Remington: the Science and Practice of Pharmacy (Alfonso R. Gennaro ed. 19th ed. 1995); Hardman, J. G., et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, 1996, Augsburger, L. L., et al. Pharmaceutical Dosage Forms—Tablets, CRC Press, 2008, Thakur, V. K., et al. Handbook of Polymers for Pharmaceutical Technologies, Biodegradable Polymers, John Wiley & Sons, 2015 and Rowe, R. C., et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 2012. All publications cited herein are incorporated by reference, each in its entirety.

[0059] As shown in FIG. 1, a particulate (4) of the present teachings can comprise, consist essentially of or consist of a core (1) which is surrounded by an inner coating (2) which comprises, consists of, or consists essentially of a polysaccharide, and an outer coating (3) surrounding the inner coating, which comprises, consists essentially of, or consists of a pH-dependent polymer. Additional coatings or layers, such as, but without limitation, cosmetic coatings or non-reactive coatings, can also separate any of the layers or be used to further coat a complete particulate.

[0060] A particulate of the present teachings can comprise a single oral dosage form, or can be part of a multi particulate that is packaged into a larger oral dosage form. As illustrated in FIG. 2, a gelatinous capsule shell (5) can contain a plurality of particulates (4). A capsule (8) can include a body (6) and a cap (7). Upon oral administration, a gelatinous capsule shell can dissolve in the stomach and the plurality of particulates can then proceed to the colon. Alternately, as shown in FIG. 3, a plurality of particulates (4) can be combined with one or more excipients (9) and pressed into a tablet (10). In various configurations, a tablet can be further coated with a coating, such as, without limitation, a cosmetic coating.

[0061] As used herein, a “particulate” can be a bead, a pellet, or a mini-tablet, and can be a portion of a larger dosage form. A particulate, bead, or minitablet comprises a core, an inner coating, and an outer coating in accordance with the present teachings.

[0062] In various configurations, a particulate can be, without limitation, spherical or cylindrical in shape. In some configurations, a particulate can comprise from 1-10 mg of a pharmaceutical compound such as, for example, metronidazole. In some configurations, a particulate can have a diameter of from about 0.3 mm up to about 5 mm. In various configurations, the total weight of a particulate can range from about 1 mg up to about 25 mg.

[0063] In various configurations, a dosage form can be comprised of a plurality of particulates. A dosage form comprising a plurality of particulates can have, for example, from 250 mg-1000 mg, for example 500 mg of a pharmaceutical compound such as metronidazole.

[0064] As used herein, a core comprises a pharmaceutically active substance, and can further comprise one or more excipients in accordance with the present teachings.

[0065] As used herein, an inner coating comprises a polysaccharide that is sensitive to digestion by enzymes present in the lumen of the colon, in particular hydrolases harbored by colonic microflora. An inner coating can further comprise coating additives in accordance with the present teachings.

[0066] As used herein, an outer coating comprises a pH-dependent polymer that is stable at pH≦6.0, but dissolves at pH>6.0.

[0067] As used herein, a seal-coated core is a core coated with an inner coating.

[0068] Polysaccharides of the present teachings include polysaccharides that are subject to hydrolysis by enzymes of colonic microorganisms. Polysaccharides of the present teachings include, but are not limited to, amylose, arabinoga lactose, chitosan, cyclodextrins, chondroitin sulfate, pectin, dextran, guar gum, xylan and inulin.

[0069] Pectins are anionic polysaccharides extracted from plant primary cell walls. Pharmaceutical grade pectin is available under a variety of tradenames, e.g., GENU® (CP Kelco, Atlanta, Ga.). Pectin is commercially available in three grades depending on the degree of esterification: high methylester (HM), conventional low methylester pectin (LMC), and low methylester amidated (LMA).

[0070] Outer coating. As used herein, an outer coating is a pH-dependent enteric coating that is stable at pH 1-6 (stomach) but dissolves at pH>6 (i.e., at a pH range found in the lumen of the colon). pH-dependent coatings can include, without limitation, a polymethacrylate, a cellulose acetate phthalate (CAP), a cellulose acetate trimellitate (CAT), a hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (COATERIC™, Colorcon Ltd., Harleysville, Pa.), polyvinyl acetate phthalate (SURETERIC™ Colorcon, Ltd.), and cellulose acetate phthalate (AQUATERIC™, FMC Corp., Philadelphia, Pa.)

[0071] Hydroxypropylmethylcellulose phthalate. Hydroxypropylmethylcellulose phthalate is available in several grades under different tradenames, such as, without limitation, hydroxypropyl methylcellulose phthalate HP50 (HPMCP-HP50) (USP/N F 220824), HP55 (HPMCP-HP55) (USP/NF type 200731) and HP55S (Shin Etsu Chemical, Tokyo, Japan).

[0072] Polymethacrylate. Polymethacrylates include polymers that can be used in pharmaceutical coatings. Polymethacrylates are available under several trade names such as, for example and without limitation, EUDRAGIT® (Evonik Corporation, Parsippany, N.J.). Several polymethacrylates available under the tradename EUDRAGIT® can be used in a particulate of the present teachings, such as and without limitation, poly(methacrylic acid-co-ethyl acrylate) (L 30 D-55, L 100-55), poly(methacrylic acid-co-methyl methacrylate) 1:1 (L100, L 12,5), poly(methacrylic acid-co-methyl methacrylate) 1:2 (S100, S 12,5), and poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (FS 30 D). Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 is available in a 30% aqueous dispersion under the trade name EUDRAGIT® FS 30 D and dissolves at pH 7.0. Poly(methacrylic acid-co-ethyl acrylate) 1:1 is available as a 30% aqueous dispersion under the trade name EUDRAGIT® L-30-D-55 and dissolves at pH 5.5. Combinations of two polymethacrylates can be used to form coatings that dissolve at different pH levels; the relative amounts of polymethacrylates as well as coating additives can be adjusted to modify the pH stability of a coating.

[0073] Coating additives. A variety of materials can be added to the inner coating or the outer coating, such as a stabilizer, a plasticizer, and/or an anti-tacking agent. In some configurations, a stabilizer can be an emulsifier such as, for example, polysorbate 80. In some configurations, a plasticizer can be, for example, acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylate monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, glycerol, polyethylene glycols, polyethylene glycol monomethyl ether, polyvinylpyrrolidone, propylene glycol, sorbitol, sorbitan solution, triacetin, tributyl citrate, and triethyl citrate. In some configuration, an and-tacking agent can be, for example, colloidal silicon dioxide, fumed silica glycerol monostearate (GMS), magnesium stearate or talc. Commercially available coating additives can contain any of the foregoing types of coating additives in combination. For example, and without limitation, additives available under the tradename PLASACRYL™ (Evonik Corporation, Parsippany, N.J.), which contains a stabilizer, a plasticizer and an anti-tacking agent. PLASACRYL™ T20 can be used with polymethacrylates EUDRAGIT® FS 30 D and EUDRAGIT® L-30-D-55 (Evonik Corporation, Parsippany, N.J.). Other coating additives can include an opacifier or pigment, such as and without limitation, titanium dioxide (TiO.sub.2).

[0074] Excipients. Non-limiting examples of excipients include microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropylcellulose. Polyvinylpyrrolidone is available under several different grades, such as, for example and without limitation, K 15, K 25, K 30, and K 90. Hydroxypropylcellulose is available from various suppliers under a variety of trade names, such as KLUCEL™ (Ashland Inc., Covington, Ky.) HF Pharm, HXF Pharm, MF Pharm, MXF Pharm, GF Pharm, GXF Pharm, JF Pharm, JXF Pharm, LF Pharm, JXF Pharm, LF Pharm, LXF Pharm, EF Pharm, EXF Pharm, ELP Pharm; Nisso HPC (Nisso America Inc., New York, N.Y.) SSL, SL, L, and M.

[0075] Diluents. Non-limiting examples of diluents include microcrystalline cellulose, lactose monohydrate, lactose anhydrous, a starch such as maize starch, wheat starch, potato starch, or pregelatinized starch, a sugar such as sorbitol, mannitol, xylitol, dextrose, sucrose, or fructose, kaolin, calcium phosphate, calcium sulfate, and calcium carbonate. Non-limiting examples of microcrystalline cellulose include AVICEL® PH-101, PH-102, PH-103, PH-105, pH-112, PH-113, PH-200, PH-301 and PH-302 (FMC Corporation, Philadelphia, Pa.); PHARMACEL® 101, 102, and 112 (DFE Pharma, Paramus, N.J.); and GRINDSTED® (Danisco, Madison, Wis.).

[0076] Binders. Non-limiting examples of binders include microcrystalline cellulose, hydroxypropyl cellulose, such as KLUCEL™ (Ashland Inc., Covington, Ky.) HF, HXF, MF, MXF, GF, GXF, JF, JXF, LF, JXF, LF, LXF, EF, EXF, ELP, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, sodium carboxymethylcellulose, sucrose, liquid glucose, acacia, tragacanth, gelatin, starch paste, pregelatinized starch, alginic acid, cellulose, methyl cellulose, ethyl cellulose potassium alginate and sodium alginate.

[0077] Disintegrants. Non-limiting examples of disintegrants include pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, crospovidone, and sodium starch glycolate.

[0078] Lubricants. Non-limiting examples of lubricants include magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, glycerol palmitostearate, glyceryl behenate, sodium benzoate, and sodium stearyl fumarate.

[0079] Glidant. Non-limiting examples of glidants include colloidal silicon dioxide, silicon dioxide and talc.

EXAMPLES

[0080] Unless specifically presented in the past tense, an example can be a prophetic or an actual example.

Example 1

[0081] This example illustrates the preparation of uncoated cores of the present teachings.

TABLE-US-00001 TABLE 1 Ingredient mg/Dose % Cores Mesalamine 250 68.5 Microcrystalline cellulose 75 20.5 Avicel ® PH-101 (FMC, Philadelphia, PA) Polyvinylpyrrolidone 20 5.5 (Povidone K30, Kollidon ®, BASF) Sodium starch glycolate 20 5.5 Purified water* q.s — Total weight (mg) 365 100.0 *Added but not retained

[0082] To generate uncoated cores, mesalamine, microcrystalline cellulose, polyvinylpyrrolidone and sodium starch glycolate were mixed in proportions set out in Table 1 in a high shear granulator, then granulated with water to form wet granulation. The wet mass was extruded and spheronized into beads. The beads were then dried in a fluid bed to form drug-containing beads.

Example 2

[0083] This example illustrates the preparation of uncoated cores that can be used for forming particulates of the present teachings.

TABLE-US-00002 TABLE 2 Ingredient mg/Dose % Cores Vancomycin 125 50.4 Lactose monohydrate 50 20.2 Microcrystalline cellulose 50 20.2 Avicel ® PH-102 (FMC, Philadelphia, PA) Polyvinylpyrrolidone 15 6.0 (Povidone K30, Kollidon ®, BASF) Crospovidone 8 3.2 Purified water* q.s — Total weight (mg) 248 100.0 *Added but not retained

[0084] In this procedure, vancomycin, and excipients lactose monohydrate, microcrystalline cellulose, and crospovidone were mixed in proportions set out in Table 2 in a fluid bed equipped with a bottom rotor, then pelletized by spraying from the side with polyvinylpyrrolidone in a water binding solution. The resulting pellets were then dried in a fluid bed.

Example 3

[0085] This example illustrates the generation of seal coated cores having a hydroxypropyl methylcellulose coating.

TABLE-US-00003 TABLE 3 Ingredient mg/Dose % Cores Metronidazole 500 76.3 Microcrystalline cellulose 100 15.3 Avicel ® PH-102 (FMC, Philadelphia, PA) Hydroxypropyl cellulose EXF 33 5.0 Croscarmellose sodium 20 3.1 Magnesium stearate 2 0.3 Total weight (mg) 655 100.0 Inner Coating hydroxypropyl methylcellulose 30 4.6 (SPECTRABLEND ™ White, Sensient ® Pharmaceutical, St. Louis, MO) Purified water* q.s — Total weight (mg) 685 — *Added but not retained

[0086] Manufacturing Procedure:

[0087] To generate cores, metronidazole, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate were mixed in a blender in proportions set out in Table 3. The mixture was then compressed into mini-tablets on a rotary tablet press fitted with multi-tip punches. The mini-tablets were then coated with HPMC-based seal coat (SPECTRABLEND™ White) using a perforated tablet coater.

Example 4

[0088] This example illustrates a procedure for forming seal-coated cores having pectin for the inner coating.

TABLE-US-00004 TABLE 4 Ingredient mg/Dose % Cores Metronidazole 500 76.3 Microcrystalline cellulose 100 15.3 Avicel ® PH-102 (FMC, Philadelphia, PA) Hydroxypropyl cellulose EXF 33 5.0 Croscarmellose sodium 20 3.1 Magnesium stearate 2 0.3 Total weight (mg) 655 100.0 Inner Coating Pectin 30 5.0 TiO.sub.2 3 0.5 Purified water* q.s — Total weight (mg) 685 — *Added but not retained

[0089] Manufacturing Procedure:

[0090] To generate cores, metronidazole, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate were mixed in a blender in amounts shown in Table 4 and then compressed into mini-tablets on a rotary tablet press fitted with multi-tip punches. The cores were then coated with pectin-based inner coating in amounts shown in Table 4 using a perforated tablet coater to form seal-coated cores.

Example 5

[0091] This example illustrates the coating of HPMC seal-coated cores with a pH-dependent outer coating.

TABLE-US-00005 TABLE 5 Ingredient mg/Dose % Example 3 coated 685 100.0 Outer Coat EUDRAGIT ® FS 30 D 62 9.1 PLASACRYL ™ T20 6.2 0.9 Purified water* q.s — Total weight (mg) 753.2 — *Added but not retained

[0092] Seal-coated cores made in Example 3 were further coated with EUDRAGIT® FS 30 D and PLASACRYL™ T20 dispersion in amounts shown in Table 5 using a perforated tablet coater to add an outer coating.

Example 6

[0093] This example illustrates the coating of HPMC seal-coated cores with a pH-dependent outer coating.

TABLE-US-00006 TABLE 6 Ingredient mg/Dose % Example 3 coated 685 100.0 Outer Coat EUDRAGIT ® FS 30 D 36 5.3 EUDRAGIT ® L 30 D-55 6 0.9 Triethyl citrate 3 0.4 TiO.sub.2 23 3.4 Purified water* q.s — Coated weight (mg) 753 — *Added but not retained

[0094] Manufacturing Procedure:

[0095] The seal coated cores made in Example 3 were further coated with a mixture of EUDRAGIT® FS 30 D:EUDRAGIT® L 30 D-55 in 85:15 (% w/w), triethyl citrate and TiO.sub.2 dispersion in amounts shown in Table 6 as outer coating using a perforated tablet coater.

Example 7

[0096] This example illustrates the manufacture of particulates of the present teachings.

TABLE-US-00007 TABLE 7 Ingredient mg/Dose % Example 4 coated 685 100.0 Outer Coat EUDRAGIT ® FS 30D 62 9.1 PLASACRYL ™ T20 6.2 0.9 Purified water* q.s — Coated weight (mg) 753.2 — *Added but not retained

[0097] Manufacturing Procedure:

[0098] The seal-coated cores made in Example 4 with pectin inner coating were further coated with EUDRAGIT® FS 30D and PLASACRYL™ T20 dispersion in amounts described in Table 7. A perforated tablet coater was used to apply an outer coating and generate particulates.

Example 8

[0099] This example illustrates the manufacture of particulates of the present teachings.

[0100] Seal-coated cores comprising a pectin inner coating are generated as in Example 4. An outer coating is then added to the seal-coated cores by spraying with EUDRAGIT® FS 30D:EUDRAGIT® 30 D—55 in 85:15 (% w/w), triethyl citrate, polysorbate 80 and TiO.sub.2 dispersion in a perforated tablet coater.

Example 9

[0101] This example illustrates the construction of a capsule of the present teachings.

[0102] Mesalamine cores are generated as in Example 1. These cores are then coated with pectin and talc using a perforated tablet cower. An outer coating is then added by applying a dispersion of EUDRAGIT® FS 30 D, triethyl citrate and talc using a perforated tablet coater. The particulates are then filled into gelatinous capsules.

Example 10

[0103] This example illustrates the construction of a tablet of the present teachings.

[0104] Vancomycin cores are made as pellets in accordance with Example 2. These pellets are then coated with a layer of guar gum using a perforated tablet coater. An outer coating comprising cellulose acetate phthalate is then applied to the guar gum-coated pellets. These pellets are then mixed with microcrystal cellulose and lactose and pressed into a tablet.

Example 11

[0105] This example illustrates disintegration of particulates according to the present teachings.

[0106] Particulates equivalent to one dose of Metronidazole for particulates from each of examples 5-7 were immersed into 10 mL of various pH buffers and observed for disintegration time (DT). Results are recorded in Table 8.

TABLE-US-00008 TABLE 8 DT Time (min) Example pH 1.2 pH 5.5 pH 6.0 pH 7.0 5 no DT no DT no DT 5 6 no DT 10 10 7 7 no DT no DT no DT 10

[0107] Particulates described in Examples 5 and 6 had an inner coating comprising HPMC (SPECTRABLEND™ White) while particulates described in Example 7 had an inner coating comprising pectin. Particulates described in Examples 5 and 7 had an outer coating comprising polymethacrylate EUDRAGIT® FS 30 D and plasticizer PLASACRYL™. Particulates described in Example 6 had an outer coating comprising a mixture of polymethacrylates EUDRAGIT® FS 30 D and EUDRAGIT® 30 D-55, and plasticizer triethylcitrate. Particulates of Examples 5 and 7 did not dissolve at pH 6.0 or below. The presence of pectin in the inner coating of particulates (Example 7) doubled the disintegration time at pH 7.0 compared to particulates having an HPMC inner coating (Example 5).

Example 12

[0108] This example illustrates the results of in vitro dissolution testing at pH 7.0.

[0109] In these experiments, dissolution testing was performed in accordance with USP apparatus 1 (basket) or apparatus 2 (paddle).

[0110] In these experiments, uncoated metronidazole cores described in Example 3 (without an inner or outer coating) dissolved in the basket apparatus approximately 70% within 15 minutes during dissolution testing at pH 7.0 (50 RPM), reaching about 72% dissolution after 30 minutes (FIG. 4).

[0111] Cores seal-coated with HPMC (SPECTRABLEND™ White) as described in Example 3 dissolved approximately 55% in 15 minutes and 65% in 30 minutes in the same conditions (FIG. 4).

[0112] Particulates of the present teachings were tested for drug release rates using the paddle apparatus.

[0113] Particulates with an inner coating of HPMC and an outer coating of polymethacrylate EUDRAGIT® FS 30 D and plasticizer PLASACRYL™ (Example 5) dissolved approximately 40% in 15 minutes, and nearly 90% in 30 minutes (50 RPM for 20 minutes, 100 rpm for 30 minutes) at pH 7.0. (FIG. 5). An 85:15 ratio (% w/w) of EtlDRAGIT® FS 30 D:EUDRAGIT® L 30 D-55 (Example 6) yielded similar results (FIG. 5).

[0114] In contrast, particulates with an inner coating of pectin and an outer coating of polymethacrylate EUDRAGIT® FS 30 D and plasticizer PLASACRYL™ (Example 7) dissolved approximately 5% in 15 minutes, and >80% in 60 minutes when tested by the paddle method at 75 RPM, pH 7.0 (FIG. 6). These data indicate that a pectin inner coating can delay drug release at 15 minutes but can promote complete release by 60 minutes at pH 7.0. The particulates with pectin inner coating and polymethacrylate outer coatings of the present teaching can thus delay initial drug release prior to reaching the colon and provide complete drug release upon reaching the colon.

Example 13

[0115] This example illustrates dissolution of particulates having a pectin inner coating in the presence or absence of pectinase.

[0116] In these experiments, dissolution testing using the paddle method (pH 7.0 phosphate buffer 75 rpm) was conducted on particulates having a pectin inner coating as described in Example 7. These particulates exhibited 40% faster dissolution in 30 minutes in the presence of pectinase (1.% v/v) compared to dissolution in the same pH 7.0 buffer in the absence of pectinase (FIG. 6). Without being limited by theory, a pectin inner coating can promote targeted release of a pharmaceutical active in the colon lumen due to the presence of pectinase from microflora.

Example 14

[0117] This example illustrates the results of in vitro dissolution testing at pH 6.0.

[0118] Dissolution testing was performed in accordance with USP standards using apparatus 2 (paddle).

[0119] In these experiments, particulates with a EUDRAGIT® FS 30 D and PLASACRYL™ outer coating were tested for dissolution at 75 rpm paddle and pH 6.0. Under these conditions, the particulates exhibited drug release of no more than 5%, regardless of the inner coating (FIG. 7). These data illustrate that particulates of the present teachings are resistant to dissolution tinder acidic conditions such as found in the upper gastrointestinal tract.

Example 15

[0120] This example illustrates release of a drug formulation of the present teachings in colonic conditions compared to that of a commercial formulation.

TABLE-US-00009 TABLE 9 Ingredient mg/Dose % Cores Mesalamine 375 57 Microcrystalline cellulose PH101 250 38 Hydroxypropyl cellulose EXF 30 4.6 Magnesium stearate 3 0.5 Total 658 100.0 Inner Coating Pectin 50.6 7.7 Glycerin 10.2 1.6 TiO2 5.0 0.8 Purified water* q.s. — Total weight (mg) 723.8 10.0 Outer Coating EUDRAGIT ® FS 30 D 120.2 16.6 PlasACRYL ™ T20 18.0 2.5 Purified Water* qs — Total weight (mg) 862.0 19.1

[0121] In these experiments a mesalamine multiparticulate of the present teachings was manufactured with components as described in Table 9, with multiple particulates of Mesalamine cores coated with Pectin-based inner coating and EUDRAGIT®-based outer coating in 375 mg drug per dose.

[0122] The dissolution rate the mesalamine formulation was tested side-by-side with that of a currently marketed Mesalamine extended release capsule (APRISO™ (Salix Pharmaceuticals, Raleigh, N.C.), 375 mg). The inactive Ingredients of APRISO™ are listed as: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, simethicone emulsion ethylacrylate/methylmethacrylate copolymer nonoxynol 100 dispersion, hypromellose, methacrylic acid copolymer, talc, titanium dioxide, triethyl citrate, aspartame, anhydrous citric acid, povidone, vanilla flavor, and edible black ink. In these experiments, the compositions were subjected to stirring in a USP apparatus II (paddle) at 75 rpm at 37° C. The relative dissolution rate of each drug was measured at pH 6.0 and pH 7.4. During dissolution testing at pH 6.0. the APRISO™ formulation started releasing drug as early as 30 minutes, with 36% of the drug being dissolved at the 2 hour mark; in contrast, the formulation of the present teachings that was tested did not detectably release drug for at least 2 hours at pH 6 (FIG. 8).

[0123] In contrast, at pH 7.4, the mesalamine formulation of the present teachings showed a complete release within 60 minutes from the beginning of the test, whereas the APRISO™ formulation showed only about 50% release in the same time, taking four hours to release 90% of the drug payload (FIG. 9).

[0124] These results illustrate that compared to a commercial formulation, a drug formulation of the present teachings can exhibit greater resistance to dissolution at stomach pH but can more rapidly dissolve at colonic pH.

Example 16

[0125] This example illustrates that pectinase can increase the dissolution rate of formulations of the present teachings.

[0126] In these experiments, the mesalamine formulation in Example 15 was tested for dissolution in the presence and absence of pectinase. FIG. 10 illustrates that at pectinase concentration of 1.6% viv in dissolution medium at pH 7.4, mesalamine release at the 15 min time point was six times higher relative to mesalamine release in the absence of pectinase.

[0127] These data show that the dissolution rate of a drug formulation of the present teachings can be enhanced by pectinase, an enzyme present in the colonic environment.

[0128] All publications, patents, patent applications and other references cited in this application are herein incorporated by reference, each in its entirety.