MODIFIED RELEASE COMPOSITION OF ORLISTAT AND ACARBOSE FOR THE TREATMENT OF OBESITY AND RELATED METABOLIC DISORDERS

Abstract

The present invention relates to a modified-release composition comprising orlistat and acarbose, comprising individually distinct parts with different release patterns: a) a first part, G1, comprising from about 5 to about 70% w/w of the total dose of acarbose, b) a second part, G2A, comprising from about 30 to about 95% w/w of the total dose of acarbose, c) a third part, G2B, comprising from about 10 to about 90% w/w of the total dose of orlistat, and d) a fourth part, G3, comprising from about 10 to about 80% w/w of the total dose of orlistat, and the total concentration of acarbose and orlistat, respectively, in the composition is 100% w/w.

Claims

1.-34. (canceled)

35. A modified-release oral composition comprising orlistat and acarbose, comprising as individually distinct parts with different release patterns: (a) a first part (G1) comprising acarbose and one or more of a hydrophobic polymer, a lipid and a wax, wherein G1 comprises from about 5 to about 70% w/w of the total dose of acarbose present in the composition; (b) a second part (G2) comprising acarbose, orlistat, an enteric polymer and a surfactant, wherein G2 comprises from about 30 to about 95% w/w of the total dose of acarbose present in the composition, and from about 10 to about 90% w/w of the total dose of orlistat present in the composition; and (c) a third part (G3) comprising orlistat and one or more of a surfactant and a water-soluble polymer, wherein G3 comprises from about 10 to about 80% w/w of the total dose of orlistat present in the composition.

36. A modified-release composition according to claim 35, wherein (a) G1 is a DR.sub.DC-PR.sub.GASTRIC part that releases acarbose in a prolonged manner, (b) G2 is a DR.sub.EC-RR.sub.PROX SI part that releases acarbose and orlistat in the proximal small intestine, and (c) G3 is a DR.sub.DC-PR.sub.GASTRIC and/or DR.sub.EC-PR.sub.INTESTINAL part that releases orlistat in the proximal part of the small intestine until the end of jejunum.

37. A modified-release composition according to claim 35, wherein G1 is in the form of granules, pellets, minitablets, or spheres, or is incorporated into a two-layer tablet wherein G1 is contained in one of the two layers.

38. A modified-release composition according to claim 37, wherein G1 is incorporated into a two-layer tablet wherein G1 is contained in one of the two layers, and wherein the layer containing G1 is provided with a delayed release coating.

39. A modified-release composition according to claim 35, wherein G2 is in the form of granules, pellets, minitablets, or spheres containing an enteric polymer and/or provided with an enteric coating, or is incorporated into a two-layer tablet wherein G2 is contained in one of the two layers and the layer containing G2 is provided with an enteric coating.

40. A modified-release composition according to claim 35, wherein G3 is in the form of granules, pellets, minitablets, or spheres, or is contained in a two layer tablet wherein G3 is contained in one of the two layers.

41. A modified-release composition according to claim 35, wherein G1 comprises acarbose and a hydrophobic polymer, and the hydrophobic polymer is selected from ethylcellulose, acrylates or acrylic acid derivatives, gelatin, coating agents selected from copolymers based on polymethacrylic acid and methacrylates, ethyl acrylate and methyl acrylate, co-polymers of acrylic and methacrylic acid esters, hydroxypropyl methylcellulose phthlate, cellulose acetate phthalate, polyvinyl acetate pthtalate, and mixtures thereof.

42. A modified-release composition according to claim 41, wherein the hydrophobic polymer is ethylcellulose.

43. A modified-release composition according to claim 35, wherein G1 comprises acarbose and a lipid, and the lipid is selected from fatty acids, fatty esters, fatty alcohols, cetyl alcohol, stearyl alcohol, mineral oils, hydrogenated vegetable oils, vegetable oils, acetylated hydrogenated soybean oil glycerides, Castor oil, hydrogenated vegetable oils, and mixtures thereof.

44. A modified-release composition according to claim 35, wherein the hydrophobic polymer, lipid or wax is present in a concentration of from about 10% to about 50% w/w of the total weight of G1.

45. A modified-release composition according to claim 35, wherein G2 comprises an enteric polymer selected from acrylate, acrylic acid polymers, acrylic acid co-polymers, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate pthatalate, and mixtures thereof.

46. A modified-release composition according to claim 45, wherein the enteric polymer is selected from co-polymers based on polymethacrylic acid and methacrylates, ethyl acrylate and methyl acrylate, co-polymers of acrylic and methacrylic acid esters, and mixtures thereof.

47. A modified-release composition according to claim 45, wherein the enteric polymer is present in a concentration of from about 15 to about 50% w/w of the total weight of G2.

48. A modified-release composition according to claim 35, wherein G2 comprises a surfactant selected from anionic, cationic and non-ionic surfactants, and mixtures thereof.

49. A modified-release composition according to claim 48, wherein the non-ionic surfactant is selected from polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and polyvinylalcohol, and mixtures thereof; the anionic surfactant is selected from docusate sodium and sodium lauryl sulphate, and mixtures thereof; and the cationic surfactant is selected from benzalkonium chloride, benzethonium chloride and cetrimide, and mixtures thereof.

50. A modified-release composition according to claim 48, wherein the concentration of surfactant(s) in G2 is from about 0.5% to about 30% w/w of the total weight of G2.

51. A modified-release composition according to claim 35, wherein G3 comprises a water-soluble polymer selected from hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose and hydroxypropylcellulose, and mixtures thereof.

52. A modified-release composition according to claim 51, wherein the water-soluble polymer is present at a concentration of from about 70 to about 90% w/w of the total weight of G3.

53. A modified-release composition according to claim 35 in the form of a multiple-unit tablet, a bi-layer multiple-unit tablet, a coated tablet, a multiple-unit capsule or a multiple-unit oral powder.

54. A modified-release composition according to claim 35, wherein G1, G2, and G3 are in the form of pellets, granules, or spheres.

55. A modified-release composition according to claim 35 in the form of a multiple-unit tablet, capsule, sachet or powder.

56. A method of triggering the gastro-intestinal brake, comprising orally administering a modified-release composition according to claim 35 to a subject in need thereof.

57. A method for treating or reducing the risks of a condition selected from one or more of being overweight, obesity, type 2 diabetes, elevated blood glucose levels, impaired glucose tolerance, polycystic ovarian syndrome, disorders of lipoprotein metabolism, lipidemia, hyperglyceridemia; nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis; and metabolic syndrome, comprising administering a modified-release composition according to claim 35 to a subject in need thereof.

58. A modified-release oral composition comprising acarbose, comprising as individually distinct parts with different release patterns: (a) a first part comprising acarbose and one or more of a hydrophobic polymer, a lipid and a wax, wherein the first part comprises from about 5 to about 70% w/w of the total dose of acarbose present in the composition; and (b) a second part comprising acarbose, an enteric polymer and a surfactant, wherein the second part comprises from about 30 to about 95% w/w of the total dose of acarbose present in the composition.

59. A method of triggering the gastro-intestinal brake, comprising orally administering a modified-release composition according to claim 58 to a subject in need thereof.

60. A method for treating or reducing the risks of a condition selected from one or more of being overweight, obesity, type 2 diabetes, elevated blood glucose levels, impaired glucose tolerance, polycystic ovarian syndrome, disorders of lipoprotein metabolism, lipidemia, hyperglyceridemia; nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis; and metabolic syndrome, comprising administering a modified-release composition according to claim 58 to a subject in need thereof.

61. A modified-release oral composition comprising orlistat, comprising as individually distinct parts with different release patterns: (a) a first part comprising orlistat, an enteric polymer and a surfactant, wherein the first part comprises from about 10 to about 90% w/w of the total dose of orlistat present in the composition, and does not include acarbose; and (b) a second part comprising orlistat and one or more of a surfactant and a water-soluble polymer, wherein the second part comprises from about 10 to about 80% w/w of the total dose of orlistat present in the composition.

62. A method of triggering the gastro-intestinal brake, comprising orally administering a modified-release composition according to claim 61 to a subject in need thereof.

63. A method for treating or reducing the risks of a condition selected from one or more of being overweight, obesity, type 2 diabetes, elevated blood glucose levels, impaired glucose tolerance, polycystic ovarian syndrome, disorders of lipoprotein metabolism, lipidemia, hyperglyceridemia; nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis; and metabolic syndrome, comprising administering a modified-release composition according to claim 61 to a subject in need thereof.

64. A method for treating or reducing the risks of a condition selected from one or more of being overweight, obesity, type 2 diabetes, elevated blood glucose levels, impaired glucose tolerance, polycystic ovarian syndrome, disorders of lipoprotein metabolism, lipidemia, hyperglyceridemia; nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis; and metabolic syndrome, comprising administering to a subject in need thereof: (i) a modified-release oral composition comprising acarbose, comprising as individually distinct parts with different release patterns (a) a first part comprising acarbose and one or more of a hydrophobic polymer, a lipid and a wax, wherein the first part comprises from about 5 to about 70% w/w of the total dose of acarbose present in the composition; and (b) a second part comprising acarbose, an enteric polymer and a surfactant, wherein the second part comprises from about 30 to about 95% w/w of the total dose of acarbose present in the composition; and (ii) a modified-release oral composition comprising orlistat, comprising as individually distinct parts with different release patterns (a) a first part comprising orlistat, an enteric polymer and a surfactant, wherein the first part comprises from about 10 to about 90% w/w of the total dose of orlistat present in the composition, and does not include acarbose; and (b) a second part comprising orlistat and one or more of a surfactant and a water-soluble polymer, wherein the second part comprises from about 10 to about 80% w/w of the total dose of orlistat present in the composition.

65. A cosmetic method for reducing body weight, comprising administering to a subject in need thereof a modified-release composition according to claim 35.

Description

LEGENDS TO DRAWING

[0333] FIG. 1a-b. The pH dependent degradation of orlistat (ORL) and acarbose (ACA) when the solubility from a powder was investigated at 37° C. The degradation product was also observed in the chromatogram.

[0334] FIG. 2. A schematic overview of how digested nutrients act through various mechanisms to affect gastrointestinal motility and satiety.sup.35.

[0335] FIG. 3. A schematic view of the gastrointestinal simulation model. To the left, the seven ideal tanks of the gastrointestinal tract. To the right the interplay between general biopharmaceutical processes and the enzyme inhibition.

[0336] FIG. 4a-b. In the two set of figures above the modelling and simulations of the in vivo release profile based on (a) an ideal release profile and (b) measured in vitro release profile for acarbose are presented. a. In the two figures above the modelling and simulations of the in vivo release profile and the ideal release profile for acarbose are presented. Below in the four figures the local gastrointestinal amount of acarbose (both as a monomer and in the formulation) over time in the different GI segments 5 and 10 hours post dosing. It is clear that the highest luminal concentration of unabsorbed drug (amount left in the luminal GI-segment) is highest in the proximal small intestine and lower in the stomach and distal small intestine. b. In the two figures above the modelling and simulations of the in vivo release profile based on the measured in vitro release profile for acarbose are presented. Below in the four figures the local gastrointestinal amount of acarbose (both as a monomer and in the formulation) over time in the different GI segments 5 and 10 hours post dosing are shown based on the in vitro release data. It is clear that the highest luminal concentration of unabsorbed drug (amount left in the luminal GI-segment) is highest in the proximal small intestine and in the stomach and lower in the distal small intestine. This will provide this oral MR product with the target of the mechanisms of action as planned. If only the curves for acarbose or orlistat, respectively, are considered, these curves are models and simulations of the in vivo release profile based on the measured in vitro release profile for an acarbose-containing composition of the invention (i.e. without orlistat) or an orlistat-containing composition of the invention (i.e. without acarbose).

[0337] FIG. 5a-b. In the two set of figures above the modelling and simulations of the in vivo release profile based on (a) an ideal release profile and (b) measured in vitro release profile for orlistat are presented. a. In the two figures above the modelling and simulations of the in vivo release profile and the ideal release profile for orlistat are presented. Below in the four figures the local gastrointestinal amount of orlistat (both as a monomer and in the formulation) over time in the different GI segments 5 and 10 hours after dosing. It is clear that the highest luminal concentration of unabsorbed drug (amount left in the luminal GI-segment) is highest in the proximal small intestine and in the stomach and lower in the distal small intestine. b. In the two figures above the modelling and simulations of the in vivo release profile based on the measured in vitro release profile for orlistat are presented. Below in the four figures the local gastrointestinal amount of orlistat (both as a monomer and in the formulation) over time in the different GI segments 5 and 10 hours post dosing are shown based on the in vitro release data. It is clear that the highest luminal concentration of unabsorbed drug (amount left in the luminal GI-segment) is highest in the proximal small intestine and lower in the stomach and in the distal small intestine. This will provide this oral MR product with the target of the mechanisms of action as planned. If only the curves for acarbose or orlistat, respectively, are considered, these curves are models and simulations of the in vivo release profile based on the measured in vitro release profile for an acarbose-containing composition of the invention (i.e. without orlistat) or an orlistat-containing composition of the invention (i.e. without acarbose).

[0338] FIG. 6. Target drug release and cell/hormone disposition in the GI tract.

[0339] FIG. 7a-b. Target release profiles of acarbose (ACAR) and orlistat (ORL), where 0-3 hours corresponds to average hold time (First part release) in the stomach, 3.0-3.5 hours (Second part release) to proximal small intestine and 3.5-5.0 hours (Third part release) to jejunum. b. To each investigated fraction of the dosage form (G1 and G2 for acarbose and G2 and G3 for orlistat) a release model was fitted to the observed in vitro data (plot 7b.1-4). The observations are represented by dots and the model fitted curve is shown as a solid line. The two plots in the bottom (7b.5 and 7b.6) display the simulated overall combined release (solid line) based on the observed in vitro release data for acarbose (G1 and G2) and orlistat (G2, and G3), respectively. If only the curves for acarbose or orlistat, respectively, are considered, these curves are models and simulations of the in vivo release profile based on the measured in vitro release profile for an acarbose-containing composition of the invention (i.e. without orlistat) or an orlistat-containing composition of the invention (i.e. without acarbose).

[0340] FIG. 8. Five dosage form design principles. G=Granule.

[0341] FIG. 9. After oral administration together with any of the meals, the APIs will be delivered to the three different regions in the GI tract.

[0342] FIG. 10. Schematic overview of most relevant processes involved in drug release, absorption and bioavailability.

[0343] FIG. 11. Individual dissolution profiles for acarbose for Example 4H G1+G2+G3 multiple-unit capsule in 25 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min with addition of 0.5% SDS at 180 min.

[0344] FIG. 12. Individual dissolution profiles for orlistat for Example 4H G1+G2+G3 multiple-unit capsule in 25 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min with addition of 0.5% SDS at 180 min.

[0345] FIG. 13. Mean dissolution profile for acarbose, G1 ethylcellulose/HPMC-coated MCC-spheres (G1 346670) from Example 4H multiple-unit capsule in 25 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min with addition of 0.5% SDS at 180 min.

[0346] FIG. 14. Mean dissolution profile for acarbose, G2 enteric coated MCC-spheres (346626) from Example 4H multiple-unit capsule in 25 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min with addition of 0.5% SDS at 180 min.

[0347] FIG. 15. Mean dissolution profile for orlistat, G2 enteric coated MCC-spheres (346626) from Example 4H multiple-unit capsule in 25 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min with addition of 0.5% SDS at 180 min.

[0348] FIG. 16. Individual dissolution profiles for orlistat, G3 wet granulation from Example 4H multiple-unit capsule in 25 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min with addition of 0.5% SDS at 180 min.

[0349] FIG. 17. Mean dissolution profile for acarbose, G1 extruded ethylcellulose/HPMC (SG150313:1) from Example 1J multiple-unit tablet in 50 mM phosphate buffer at pH 6.8.

[0350] FIG. 18. Dissolution profile for acarbose, G1 extruded hard fat/GMS from Example 1M multiple-unit tablet in 50 mM phosphate buffer at pH 3.5 and 3.0% SDS.

[0351] FIG. 19. Dissolution profile for acarbose, G2 enteric coated extruded pellet core from Example 1K multiple-unit tablet in 100 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min.

[0352] FIG. 20. Dissolution profile for orlistat, G2 enteric coated extruded pellet core from Example 1K multiple-unit tablet in 25 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min with addition of 0.5% SDS at 180 min.

[0353] FIG. 21. Roche patent formulation (EP 0638317 A1). a: The release of acarbose from the composition. b: The release of orlistat from the composition. Both a. and b. are in 25 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min with addition of 0.5% SDS at 180 min.

[0354] FIG. 22. Chinese patent formulation (CN 102872062 A). a: The release of acarbose form a separate preparation of the acarbose containing half of the complete formulation. b: The release of orlistat from a separate preparation of the orlistat containing half of the complete formulation. Both a. and b. are in 25 mM phosphate buffer at pH 3.2 during time 0-180 min and at pH 6.5>180 min with addition of 0.5% SDS at 180 min.

[0355] FIG. 23a-d. a. In the two set of figures above the modelling and simulations of the in vivo release profile based on (left) a simulation of the release profile and (right) measured in vitro release profile for orlistat are presented from an oral solid dosage form according to patent EP 0638317 A1. Below in the four figures the local gastrointestinal amount of orlistat (both as a monomer and in the formulation) over time in the different GI segments 5 and 10 hours post dosing. It is clear that the highest luminal concentration of unabsorbed drug (amount left in the luminal GI-segment) is highest in the in the stomach and lower in the distal small intestine. This oral dosage form has a very different in vitro release profile than the invention

[0356] b. In the two figures above the modelling and simulations of the in vivo release profile based on the measured in vitro release profile for acarbose are presented an oral solid dosage form according to patent EP 0638317 A1. Below in the four figures the local gastrointestinal amount of acarbose (both as a monomer and in the formulation) over time in the different GI segments 5 and 10 hours post dosing are shown based on the in vitro release data. It is clear that the highest luminal concentration of unabsorbed drug (amount left in the luminal GI-segment) is highest in the in the stomach and lower in the distal small intestine. This oral dosage form has a very different in vitro release profile than the invention.

[0357] c. In the two set of figures above the modelling and simulations of the in vivo release profile based on (left) a simulation of the release profile and (right) measured in vitro release profile for acarbose are presented from an oral solid dosage form according to patent CN 102872062 A. Below in the four figures the local gastrointestinal amount of acarbose (both as a monomer and in the formulation) over time in the different GI segments 5 and 10 hours post dosing. It is clear that the highest luminal concentration of unabsorbed drug (amount left in the luminal GI-segment) is highest in the in the stomach and lower in the distal small intestine. This oral dosage form has a very different in vitro release profile than the invention

[0358] d. In the two figures above the modelling and simulations of the in vivo release profile based on the measured in vitro release profile for orlistat are presented an oral solid dosage form according to patent CN 102872062 A. Below in the four figures the local gastrointestinal amount of orlistat (both as a monomer and in the formulation) over time in the different GI segments 5 and 10 hours post dosing are shown based on the in vitro release data. It is clear that the highest luminal concentration of unabsorbed drug (amount left in the luminal GI-segment) is highest in the in the stomach and lower in the distal small intestine. This oral dosage form has a very different in vitro release profile than the invention.

[0359] The invention is illustrated by way of the following non-limiting examples:

Material and Methods

Material

[0360] Acarbose (Bayer Shering Pharma AG, Germany and Zhejiang Hisun, China), orlistat (Biocon, India, Chongqing, China, Zhejiang Hisun, China and Ranbaxy, India), microcrystalline cellulose (MCC, Avicel® PH-101, FMC, Ireland), lactose (α-lactose monohydrate, Inhalose® 230 and SuperTab® SD spray-dried, DMV-Fonterra Excipients GmbH & Co.KG, The Netherlands), mannitol (Parteck® M 200, Merck, KGaA, Germany), hydroxypropylmethylcellulose (HPMC K4M), ethylcellulose (with two different viscosities; Ethocel™ 10FP and Ethocel™ 100FP, Dow Chemical Company, USA), sodium carboxymethylcellulose (Blanose™, Ashland, USA) glyceryl monostearate (Alfa Aesar GmbH & Co KG, Germany), sodium laurylmonostearate (sodium stearyl fumarate, Pruv®, JRS Pharma, Germany), ethanol (99.7% w/w, Solveco Chemicals and Kemetyl AB, Sweden) sterile water (Fresenius AB, Sweden), sodium chloride (Sigma-Aldrich, Germany), potassium phosphate monobasic (Sigma-Aldrich, Germany), sodium hydroxide (Fixanal Fluka Analytical, Sigma-Aldrich, Germany), hydrochloric acid (Titripur, Merck KGaA, Germany), sodium docecyl sulfate (sodium lauryl sulphate or “SDS”, Sigma-Aldrich, Germany), hydrogenated vegetable oil, type II (“Hard fat”, Dynasan® P60, Sasol GmbH, Germany), polysorbate 80 (Tween™ 80, Alfa Aesar GmbH & Co KG, Germany), polyvinylpyrrolidone K25 (Povidone® K25, BASF SE, Germany) and croscarmellose sodium (Ac-Di-Sol®, SD-711, FMC, Ireland). Coating compositions Opadry® (HPMC-based) 03K19229 clear (Colorcon Ltd., UK) and Acryl-EZE® II 493Z120005 yellow (Colorcon Ltd., UK).

In Vitro Dissolution Methods

Method A, HPLC Detection

[0361] A composition of the invention aims at fulfilling the following dissolution pattern when tested in accordance with the in vitro dissolution tests described in the United States Pharmacopoeia General Test Chapter on DISSOLUTION <711>.sup.63 using Apparatus 2 (SAM SOTAX automatic sampler connected to HPLC apparatus or Fraction Collector AT7 SMART SOTAX). The following conditions are used; 900 ml vessel volume, paddle at 75 rpm, minigranules are prepared in capsules size TOO white/white, capsules are put into spiral stainless steel sinker 25-27×11 mm. Bi-phasic dissolution medium (900 ml and 37.0±0.5° C.,) is employed, for t=0 h to t=3 h, 25 mM KH.sub.2PO.sub.4 and pH=3.2 (corresponding to in vivo gastric fed state conditions) and for t=3 h to t=8 h, 25 mM KH.sub.2PO.sub.4 and pH=6.5 (adjusted by NaOH 5M) and addition of Sodium Dodecyl Sulphate to a total concentration of 0.5% w/w (corresponding to in vivo intestinal fed state conditions).

[0362] Samples are collected in time series. The amount of released API (orlistat and/or acarbose) is determined by HPLC (HPLC Agilent Technologies type 1100 or 1200 with DAD detector, monitored with OpenLab software, Agilent Technologies) as follows: 2 HPLC columns in series; Hibar, Purosphere, RP-8 (L=150 mm, internal diameter 4.6 mm, particle size 5 μm) and APS-2-Hypersyl (L=250 mm, internal diameter 4 mm, particle size 5 μm), flow rate 2 mL/min, injection volume 50 μL, sample temperature 25° C., column temperature 40° C., run time 15 minutes. Elution buffer solution: 0.6 g KH.sub.2PO.sub.4 and 0.35 g Na.sub.2HPO.sub.4, 2H.sub.2O in 1 L of water, mobile phase buffer solution: 28% v/v; acetonitrile: 72% v/v. Detection by UV spectrometer at 210 nm. A standard preparation of acarbose and orlistat in water/acetonitrile 50/50 v/v with 3 external calibration points was used. The samples was not prepared and put into amber vials.

Method B, UV Detection

[0363] The dissolution studies that were performed using a USP basket (USP I apparatus) dissolution instrument (PTWS 310, Hainburg, Germany) equipped with 1000 ml vessels. A standard volume of 500 mL at 37±2° C., sample amount of 150 mg and stirring rate 100 rpm were used. Acarbose absorbance maximum at 210 nm. The buffer dissolution media was prepared by mixing 250 mL 0.2 M potassium dihydrogen phosphate with 112 mL 0.2 M (23.31 g 1 M) sodium hydroxide and diluted to 1000 mL with deionized water. The pH was measured to be ˜6.8±0.1. Prior to filling the vessels, the compendial media was de-aerated according to the methodology described in the Ph. Eur., i.e. through heating (˜41° C.) followed by vacuum filtering (filter porosity 0.22 μm). The temperature of the dissolution media during testing was maintained at 37±0.5° C. Each dissolution test (n≧2) was preceded at the longest for about 3 hours. The stirring was initiated directly as the baskets were lowered in the medium whereas the stirring of the paddles was started prior to addition of granules. When using baskets the granules were weighed directly into a fine meshed plastic net bag placed at the bottom of the basket. When using paddles the granules were added directly in the medium thus enabling direct dispersion of the particles. The weight of the granules was chosen to correspond to doses of 20 mg drug.

[0364] Method B has only been used for spheronized G1 pellets containing acarbose and the dissolution rate limiting excipients ethylcellulose/hydroxypropylmethylcellulose or hard fat/glyceryl monostearate—see FIG. 17 and FIG. 18. All other in vitro dissolution tests have been performed with HPLC detection according to method A as described above or with slight differences in ionic strength and addition of sodium lauryl sulphate during development.

Example 1. Multiple-Unit Tablet

Example 1A, Orlistat 90 mg/Acarbose 30 mg

[0365]

TABLE-US-00006 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 0.2-1   Filler 0-20 Disintegrant 0-5  Binder 0-5  Prolonged release polymer 0-10 Coating polymer, 30-60 min delay 1-10 Sub-total: 1-51 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 4-12 Acarbose 2-4  Filler 0-10 Binder 0-5  Disintegrant 0-10 Solubilizer 0-5  Sub-coating polymer 0-5  Enteric coating polymer 1-11 Sub-total: 7-52 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 3-6  Prolonged release polymer 10-40  Coating polymer, 30-60 min delay 0-10

Example 1A, Orlistat 90 mg/Acarbose 30 mg

[0366]

TABLE-US-00007 Ingredient % w/w Sub-total: 13-56 Extragranular ingredients Filler  0-50 Glidant 0-2 Lubricant 0-2 Total: 100

Example 1B, Orlistat 90 mg/Acarbose 30 mg

[0367]

TABLE-US-00008 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 5 0.6 Filler 47 5.9 Disintegrant 5 0.6 Binder 3 0.4 Prolonged release polymer 30 3.8 Coating polymer, 30-60 min delay 10 1.3 Sub-total: 100 13 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 65 8.1 Acarbose 25 3.1 Filler 30 3.8 Binder 25 3.1 Disintegrant 30 3.8 Solubilizer 5 0.6 Sub-coating polymer 12 1.5 Enteric coating polymer 48 6.0 Sub-total: 230 29 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 25 3.1 Prolonged release polymer 215 27 Coating polymer, 30-60 min delay 10 1.3 Sub-total: 250 31 Extragranular ingredients Filler 211 26 Glidant 4 0.5 Lubricant 5 0.6 Total: 800 100

Example 1C, Orlistat 90 mg/Acarbose 30 mg

[0368]

TABLE-US-00009 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 5 6.3 Mannitol 47 5.9 Croscarmellose sodium 5 0.6 Polyvinylpyrrolidone 3 0.4 Ethylcellulose 30 3.8 Eudragit L30 D-55 (methacrylic acid - ethyl ace- 10 1.3 tate copolymer (1:1) dispersion 30 percent) Sub-total: 100 13 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 65 8.1 Acarbose 25 3.1 Microcrystalline cellulose 30 3.8 Polyvinylpyrrolidone, Povidone 25 3.1 Sodium starch glycolate, Primojel 30 3.8 Sodium lauryl sulphate, SDS 5 0.6 Opadry II Clear (macrogol 3350, polysorbate 80, 12 1.5 polyvinyl alcohol and talc) Acryl-EZE Clear (methacrylic acid copolymer 48 6.0 type C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhy- drous) Sub-total: 230 29 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 25 3.1 Hypromellose, HPMC K100 215 27 Eudragit L30 D-55 (methacrylic acid - ethyl ace- 10 1.3 tate copolymer (1:1) dispersion 30 percent) Sub-total: 250 31 Extragranular ingredients Isomalt 130 16 Mannitol 60 7.5 Xylitol 21 2.6 Silica, colloidal anhydrous 4 0.5 Magnesium stearate 5 0.6 Total: 800 100

Example 10, Orlistat 90 mg/Acarbose 30 mg

[0369]

TABLE-US-00010 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 5 6.3 Mannitol 47 5.9 Croscarmellose sodium 5 0.6 Polyvinylpyrrolidone 3 0.4 Glyceryl monostearate 30 3.8 Eudragit L30 D-55 (methacrylic acid - ethyl ace- 10 1.3 tate copolymer (1:1) dispersion 30 percent) Sub-total: 100 13 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 65 8.1 Acarbose 25 3.1 Microcrystalline cellulose 30 3.8 Polyvinylpyrrolidone, Povidone 25 3.1 Sodium starch glycolate, Primojel 30 3.8 Sodium lauryl sulphate, SDS 5 0.6 Opadry II Clear (macrogol 3350, polysorbate 80, 12 1.5 polyvinyl alcohol and talc) Acryl-EZE Clear (methacrylic acid copolymer 48 6.0 type C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhy- drous) Sub-total: 230 29 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 25 3.1 Hypromellose, HPMC K100 215 27 Eudragit L30 D-55 (methacrylic acid - ethyl ace- 10 1.3 tate copolymer (1:1) dispersion 30 percent) Sub-total: 250 31 Extragranular ingredients Isomalt 130 16 Mannitol 60 7.5 Xylitol 21 2.6 Silica, colloidal anhydrous 4 0.5 Magnesium stearate 5 0.6 Total: 800 100

[0370] The multiple-unit tablets of Example 1A-D are prepared as follows:

[0371] A small scale high-shear mixer, Diosna P1/6 with a 0.5 L granulation bowl was used for blending and granulation. The excipients and APIs were initially dry blended for five minutes (MM-act 690 rpm, CM-set 200 rpm, CM-set 4.4 rpm). For all three granules, the granulate liquid (purified water) was added drop wise to the mixture to avoid gelling and/or formation of lumps. The coating dispersions are prepared layer by layer; when preparing the dispersion place the impeller close to the bottom of the coating solution bucket. The stirring rate was increased until a deep vortex is formed. Add gently the powder to disperse in the vortex. Thereafter, adjust stirring rate so that sedimentation and foaming are avoided. Coat the granules in a standard pellet coater. The coating proceeds, with process controls, to a final target average weight increase after drying (dried to achieve loss on drying less than about 2% w/w determined at 105° C.). When the granules are dry and solidified; add isomalt, mannitol, xylitol and the congealed granules in a tumbling mixer. Mix during 10-30 minutes, depending on mixer. Sieve magnesium stearate through a 100-250 μm sieve, add the magnesium stearate to the tumbling mixer and mix for an additional approximately 2 minutes, depending on mixer. Transfer the final blend to a rotary tablet press and compress tablets with a total weight of 800 mg.

Example 1E, Orlistat 60 mg/Acarbose 20 mg

[0372]

TABLE-US-00011 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 2.0 Film-coating polymer, water-soluble  1-10 Delayed release coating polymer, poorly wa- 1-5 ter-soluble Coating sphere, filler 1-5 Sub-total:  5-20 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 7.2 Acarbose 1.4 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-85 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 2.8 Surface active agent 0-2 Filler 1-5 Sub-total:  3-10 Extragranular ingredients Filler  0-50 Glidant 0-2 Lubricant 0-2 Total: 100   

Example 1F, Orlistat 60 mg/Acarbose 20 mg

[0373]

TABLE-US-00012 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.0 Hydroxypropyl methylcellulose 1.6 0.3 Ethylcellulose, Surelease 6.8 1.1 Microcrystalline cellulose, Celphere CP 203 9.9 1.6 Sub-total: 30.0 5.0 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 7.2 Acarbose 8.3 1.4 Hydroxypropyl cellulose, Klucel 15.4 2.6 Microcrystalline cellulose, Celphere CP 203 109 18.2 Polysorbate 80, Tween 80 5.6 0.9 Opadry (HPMC low viscosity grade, 6 cps, tri- 9.4 1.6 acetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 16.6 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 1.7 Talc 74.6 12.4 Sub-total: 375 62.5 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 2.8 Polysorbate 80, Tween 80 5.8 1.0 Microcrystalline cellulose 7.5 1.3 Sub-total: 30.0 5.0 Extragranular ingredients Isomalt 84.0 14.0 Microcrystalline cellulose 75.0 12.5 Silica, colloidal anhydrous 3.0 0.5 Magnesium stearate 3.0 0.5 Total: 600 100

[0374] The tablets have good mechanical resistance and dissolution behaviour.

Example 1G, Orlistat 90 mg/Acarbose 30 mg

[0375]

TABLE-US-00013 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 18.0 2.3 Hydroxypropyl methylcellulose 2.4 0.3 Ethylcellulose, Surelease 10.2 1.3 Microcrystalline cellulose, Celphere CP 203 14.9 1.9 Sub-total: 45.5 5.7 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 65.0 8.1 Acarbose 12.0 1.5 Hydroxypropyl cellulose, Klucel 23.0 2.9 Microcrystalline cellulose, Celphere CP 203 163 20.4 Polysorbate 80, Tween 80 8.3 1.0 Eudragit L 100-55 (methacrylic acid - ethyl 199 24.9 acrylate copolymer (1:1) Type A) Triethyl citrate 20.1 2.5 Talc 99.9 12.5 Sub-total: 591 73.9 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 25.0 3.1 Polysorbate 80, Tween 80 1.4 0.2 Microcrystalline cellulose 9.3 1.2 Sub-total: 35.7 4.5 Extragranular ingredients Isomalt 65.0 8.1 Microcrystalline cellulose 54.8 6.9 Silica, colloidal anhydrous 4.0 0.5 Magnesium stearate 4.0 0.5 Total: 800 100

[0376] The tablets have good mechanical resistance and dissolution behaviour.

Example 1H, Orlistat 60 mg/Acarbose 20 mg

[0377] In this example, multiple-unit tablets are prepared. It is identical with example 1F, but G2 has been extruded and the pellet cores are spheronized.

TABLE-US-00014 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.9 Hydroxypropyl methylcellulose 1.6 0.4 Ethylcellulose, Surelease 6.8 1.7 Microcrystalline cellulose, Celphere CP 203 9.9 2.5 Sub-total: 30.0 7.5 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 10.8 Acarbose 8.3 2.1 Microcrystalline cellulose 65.8 16.5 Polysorbate 80, Tween 80 13.4 3.4 Mannitol 9.8 2.5 Croscarmellose sodium 5.9 1.5 Sodium stearyl fumarate, Pruv 2.1 0.5 Opadry (HPMC low viscosity grade, 6 cps, tri- 4.5 1.1 acetin, and talc) Acryl-EZE (methacrylic acid copolymer Type 59.5 14.9 C, sodium lauryl sulphate, macrogol, talc, so- dium bicarbonate and colloidal silica, anhy- drous) Sub-total: 212 53.0 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 4.2 Polysorbate 80, Tween 80 5.8 1.5 Microcrystalline cellulose 7.5 1.9 Sub-total: 30.0 7.5 Extragranular ingredients Isomalt 70.0 17.5 Microcrystalline cellulose 54.0 13.5 Silica, colloidal anhydrous 2.0 0.5 Magnesium stearate 2.0 0.5 Total: 400 100

Example 1I, Orlistat 60 mg/Acarbose 20 mg

[0378] G1 is extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose (HPMC).

TABLE-US-00015 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 2.0 Cellulose-based polymer, water-soluble  1-10 Delayed release polymer, poorly water-soluble  1-10 Lubricant 0-5 Sub-total:  5-20 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 7.2 Acarbose 1.4 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-85 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 2.8 Surface active agent 0-2 Filler 1-5 Sub-total:  3-10 Extragranular ingredients Filler  0-50 Glidant 0-2 Lubricant 0-2 Total: 100   

Example 1J, Orlistat 60 mg/Acarbose 20 mg

[0379] G1 is extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose (HPMC).

TABLE-US-00016 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.0 Hydroxypropyl methylcellulose 22.8 3.8 Ethylcellulose, Ethocel 10 FP 23.4 3.9 Sodium stearyl fumarate, Pruv 0.6 0.1 Sub-total: 58.5 9.8 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 7.2 Acarbose 8.3 1.4 Hydroxypropyl cellulose, Klucel 15.4 2.6 Microcrystalline cellulose, Celphere CP 203 109 18.2 Polysorbate 80, Tween 80 5.6 0.9 Opadry (HPMC low viscosity grade, 6 cps, tri- 9.4 1.6 acetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 16.6 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 1.7 Talc 74.6 12.4 Sub-total: 375 62.5 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 2.8 Polysorbate 80, Tween 80 5.8 1.0 Microcrystalline cellulose 7.5 1.3 Sub-total: 30.0 5.0 Extragranular ingredients Isomalt 70.0 11.7 Microcrystalline cellulose 60.5 10.1 Silica, colloidal anhydrous 3.0 0.5 Magnesium stearate 3.0 0.5 Total: 600 100

Example 1K, Orlistat 60 mg/Acarbose 20 mg

[0380] G1 is extruded and spheronized with ethyl-cellulose/hydroxypropylmethylcellulose (HPMC). G2 is extruded and spheronized pellet cores.

TABLE-US-00017 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.9 Hydroxypropyl methylcellulose 22.8 5.7 Ethylcellulose, Ethocel 10 FP 23.4 5.9 Sodium stearyl fumarate, Pruv 0.6 0.2 Sub-total: 58.5 14.6 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 10.8 Acarbose 8.3 2.1 Microcrystalline cellulose 65.8 16.5 Polysorbate 80, Tween 80 13.4 3.4 Mannitol 9.8 2.5 Croscarmellose sodium 5.9 1.5 Sodium stearyl fumarate, Pruv 2.1 0.5 Opadry (HPMC low viscosity grade, 6 cps, tri- 4.5 1.1 acetin, and talc) Acryl-EZE (methacrylic acid copolymer Type 59.5 14.9 C, sodium lauryl sulphate, macrogol, talc, so- dium bicarbonate and colloidal silica, anhy- drous) Sub-total: 212 53.0 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 4.2 Polysorbate 80, Tween 80 5.8 1.5 Microcrystalline cellulose 7.5 1.9 Sub-total: 30.0 7.5 Extragranular ingredients Isomalt 50.0 12.5 Microcrystalline cellulose 45.0 11.3 Silica, colloidal anhydrous 2.0 0.5 Magnesium stearate 2.0 0.5 Total: 400 100

[0381] The dissolution profile of G1 is shown in FIG. 17 and shows that the desired delay in acarbose release is obtained.

Example 1L, Orlistat 60 mg/Acarbose 20 mg

[0382] G1 is extruded and spheronized with hard fat.

TABLE-US-00018 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 2.0 Wax, water-soluble  1-10 Hard fat  1-10 Filler 0-5 Sub-total:  5-20 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 7.2 Acarbose 1.4 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-85 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 2.8 Surface active agent 0-2 Filler 1-5 Sub-total:  3-10 Extragranular ingredients Filler  0-50 Glidant 0-2 Lubricant 0-2 Total: 100   

Example 1M, Orlistat 60 mg/Acarbose 20 mg

[0383] G1 is extruded and spheronized with hard fat.

TABLE-US-00019 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.0 Glyceryl monostearate 18.7 3.1 Hydrogenated vegetable oil type II, Dynasan 14.6 2.4 P60 Mannitol 13.5 2.2 Sub-total: 58.5 9.8 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 7.2 Acarbose 8.3 1.4 Hydroxypropyl cellulose, Klucel 15.4 2.6 Microcrystalline cellulose, Celphere CP 203 109 18.2 Polysorbate 80, Tween 80 5.6 0.9 Opadry (HPMC low viscosity grade, 6 cps, tri- 9.4 1.6 acetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 16.6 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 1.7 Talc 74.6 12.4 Sub-total: 375 62.5 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 2.8 Polysorbate 80, Tween 80 5.8 1.0 Microcrystalline cellulose 7.5 1.3 Sub-total: 30.0 5.0 Extragranular ingredients Isomalt 70.0 11.7 Microcrystalline cellulose 60.5 10.1 Silica, colloidal anhydrous 3.0 0.5 Magnesium stearate 3.0 0.5 Total: 600 100

[0384] FIG. 16 shows the dissolution profile of G3.

Example 1N, Orlistat 60 mg/Acarbose 20 mg

[0385] G1 is extruded and spheronized with hard fat.

[0386] G2 is extruded and spheronized pellet cores.

TABLE-US-00020 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.0 Glyceryl monostearate 18.7 3.1 Hydrogenated vegetable oil type II, Dynasan 14.6 2.4 P60 Mannitol 13.5 2.2 Sub-total: 58.5 9.8 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 10.8 Acarbose 8.3 2.1 Microcrystalline cellulose 65.8 16.5 Polysorbate 80, Tween 80 13.4 3.4 Mannitol 9.8 2.5 Croscarmellose sodium 5.9 1.5 Sodium stearyl fumarate, Pruv 2.1 0.5 Opadry (HPMC low viscosity grade, 6 cps, tri- 4.5 1.1 acetin, and talc) Acryl-EZE (methacrylic acid copolymer Type 59.5 14.9 C, sodium lauryl sulphate, macrogol, talc, so- dium bicarbonate and colloidal silica, anhy- drous) Sub-total: 212 53.0 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 4.2 Polysorbate 80, Tween 80 5.8 1.5 Microcrystalline cellulose 7.5 1.9 Sub-total: 30.0 7.5 Extragranular ingredients Isomalt 50.0 12.5 Microcrystalline cellulose 45.0 11.3 Silica, colloidal anhydrous 2.0 0.5 Magnesium stearate 2.0 0.5 Total: 400 100

[0387] The multiple-unit tablets of Example 1E-N are prepared as follows:

[0388] As the formulation consists of three different active granules they can be denoted G1-G3; i.e. the DR.sub.DC-PR.sub.GASTRIC Granules can be denoted G1 (Granule 1), the DR.sub.EC-RR.sub.PROX SI Granules can be denoted G2 (Granule 2) and the DR.sub.DC-PR.sub.GASTRIC Granules can be denoted G3 (Granule 3).

[0389] The coated G1 granules are manufactured in a fluidized bed coater in bottom spray (Wurster) configuration (Example 1E-H), such as a bench size Glatt GPCG-1 or similar. Microcrystalline cellulose or sugar alcohol based spheres with an initial size of approximately 250 μm are used as cores in the coating. The coating is performed in two steps: step 1 include an aqueous coating solution with a mix of acarbose and a binder/coating film, such as HPMC, and in step 2 is consisted of a release-delaying coating layer with a mix of ethylcellulose and HPMC, i.e. an additional coating to the acarbose-containing coated cores. The final granules are approximately 400 μm in size.

[0390] The spheronized G1 granules are manufactured either by a standard wet-granulation (Example 1I-K) or by a melt-granulation process (Example 1 L-N) in a standard high-shear mixer, such as a Diosna P1/6 with a 0.5 L granulation bowl, with a following extrusion and spheronization in standard equipment, such as NICA model E140 and NICA S320-450. The adjusted combination of poorly soluble hard fat with waxy glyceryl monostearate, co-melted at 80° C., generates enough time to have a soft material during spheronization before solidification. The wet granulated G1 spheres with ethylcellulose/HPMC are dried in standard heating cabinets at 40° C. to be finalized. The final granules are approximately 1 mm in size.

[0391] The enteric coated G2 granules are manufactured either by using spheronized pellet cores with APIs distributed throughout the core or by using core spheres of microcrystalline cellulose or sugar alcohol with an initial size of approximately 250 μm with the active substances coated in a layer on the surface. The spheronized pellet cores are produced by using a standard wet-granulation procedure (Example 1H, 1K and 1N) in a standard high-shear mixer, such as a Diosna P1/6 with a 0.5 L granulation bowl, with a following extrusion and spheronization in standard equipment, such as NICA model E140 and NICA S320-450. The enteric coating is performed in a fluidized bed coater in bottom spray (Wurster) configuration, such as a bench size Glatt GPCG-1 or similar. The coating suspensions are prepared by using an overhead stirrer with wing impeller and added by a standard peristaltic pump. When using Eudragit L30 D-55 (methacrylic acid—ethyl acetate copolymer (1:1) dispersion 30 percent) the dispersion is in ethanol 99.5% and when using Acryl-EZE (methacrylic acid copolymer type C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) the dispersion is in water. For the coated cores and an addition of polysorbate 80, an additional talc amount is used in the coating-layer to avoid agglomeration. The final granules with microcrystalline spheres are approximately 500 μm in size and with extruded pellet cores approximately 1 mm.

[0392] The wet-granulated G3 granules are prepared by wet granulation. It is performed in a high-shear mixer such as a Diosna P1/6 with a 0.5 L granulation bowl with side-chopper. The impeller speed is 690 rpm in the 0.5 L bowl, i.e. corresponding to a tip speed of 4.0 m/s and the chopper speed is 1200 rpm. The water/ethanol granulation liquid is mixed together with polysorbate 80 (Tween™ 80) for 2 minutes in a 100 mL glass beaker with magnetic stirrer at room temperature. The liquid solution is then drawn into a 50 mL plastic syringe and a cannula is attached. The granulation procedure is performed in three steps with short breaks of approximately 30 seconds for visual inspection between every step: [0393] 1. 30 seconds—Dry powder mixing [0394] 2. 30 seconds-1.sup.st liquid addition; 17 mL (˜1/2) addition with an even pressure via syringe and cannula [0395] 3. 30 seconds-2.sup.nd liquid addition—17 mL addition (last ˜1/2) as above

[0396] In a fourth step of 30 seconds “Massing time” (wet mixing) is used for high liquid content batches. For low liquid content batches, no additional massing is needed. Directly after the massing, the wet granules are gently forced through a 1.0 mm sieve (standard sieve for sieve analysis, 200 mm diameter, 1 mm mesh size, Retsch GmbH, Germany) by help of a stainless steel spoon and distributed evenly on a drying tray. The tray is put in a heating cabinet at 35° C.—i.e. below the melting point of orlistat—to dry for at least 12 hours to finalize the G3. The final granules are approximately 500 μm in size.

[0397] When the granules are dry and solidified; add isomalt, mannitol, xylitol and the congealed granules in a tumbling mixer. Mix for 10-30 minutes, depending on mixer. Sieve magnesium stearate through a 100-250-μm sieve, add to the tumbling mixer and mix for additional approximately 2 minutes, depending on mixer. Transfer the final blend to a rotary tablet press and compress tablets with a total weight of either 400 mg, 600 mg or 800 mg.

[0398] Especially the compositions of Examples 1E, 1F, 1G have excellent properties. All other examples have good/acceptable properties.

Example 2. Bi-Layer Multiple-Unit Tablet

Example 2A, Orlistat 90 mg/Acarbose 30 mg

[0399]

TABLE-US-00021 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 0.2-1   Filler  0-20 Disintegrant 0-5 Binder 0-5 Prolonged release polymer  0-10 Coating polymer, 30-60 min delay  1-10 Sub-total:  1-51 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat  4-12 Acarbose 2-4 Filler  0-10 Binder 0-5 Disintegrant  0-10 Solubilizer 0-5 Sub-coating polymer 0-5 Enteric coating polymer  1-11 Sub-total:  7-52 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 3-6 Prolonged release polymer 10-40 Coating polymer, 30-60 min delay  0-10 Sub-total: 13-56 Extragranular ingredients, DR.sub.DC-PR layer Filler  0-50 Prolonged release polymer  0-10 Glidant 0-2 Lubricant 0-2 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer Filler  0-50 Disintegrant 0-2 Glidant 0-2 Lubricant 0-2 Total: 100

Example 2B, Orlistat 90 mg/Acarbose 30 mg

[0400]

TABLE-US-00022 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 5 0.6 Filler 47 5.9 Disintegrant 5 0.6 Binder 3 0.4 Prolonged release polymer 30 3.8 Coating polymer, 30-60 min delay 10 1.3 Sub-total: 100 13 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 65 8.1 Acarbose 25 3.1 Filler 30 3.8 Binder 25 3.1 Disintegrant 30 3.8 Solubilizer 5 0.6 Sub-coating polymer 12 1.5 Enteric coating polymer 48 6.0 Sub-total: 230 29 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 25 3.1 Prolonged release polymer 215 27 Coating polymer, 30-60 min delay 10 1.3 Sub-total: 250 31 Extragranular ingredients, DR.sub.DC-PR layer Filler 80 10 Prolonged release polymer 16 2.0 Glidant 2 0.3 Lubricant 2 0.3 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer Filler 112 14 Disintegrant 6 0.7 Glidant 2 0.3 Lubricant 2 0.3 Total: 800 100

Example 2C, Orlistat 90 mg/Acarbose 30 mg

[0401]

TABLE-US-00023 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 5 6.3 Mannitol 47 5.9 Croscarmellose sodium 5 0.6 Polyvinylpyrrolidone 3 0.4 Ethylcellulose 30 3.8 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 10 1.3 copolymer (1:1) dispersion 30 percent) Sub-total: 100 13 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 65 8.1 Acarbose 25 3.1 Microcrystalline cellulose 30 3.8 Polyvinylpyrrolidone, Povidone 25 3.1 Sodium starch glycolate, Primojel 30 3.8 Sodium lauryl sulphate, SDS 5 0.6 Opadry II Clear (macrogol 3350, polysorbate 80, 12 1.5 polyvinyl alcohol and talc) Acryl-EZE Clear (methacrylic acid copolymer 48 6.0 type C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 230 29 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 25 3.1 Hypromellose, HPMC K100 215 27 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 10 1.3 copolymer (1:1) dispersion 30 percent) Sub-total: 250 31 Extragranular ingredients, DR.sub.DC-PR layer Isomalt 80 10 Hydroxyethylcellulose 16 2.0 Silica, colloidal anhydrous 2 0.3 Magnesium stearate 2 0.3 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer Isomalt 112 14 Sodium croscarmellose 6 0.7 Silica, colloidal anhydrous 2 0.3 Magnesium stearate 2 0.3 Total: 800 100

[0402] The bi-layer multiple-unit tablets of Example 2A-C are prepared as follows:

[0403] The powder blends including granular (G1, G2, G3) and extragranular ingredients are prepared as described in Example 1A-D above but in two separate blenders—one for each layer. Transfer the blends to a rotary tablet machine with two filling stations adjusted for bi-layer tabletting in two steps; PR/D-PR to 450 mg and then additionally EC-BR 350 mg with a total tablet weight of 800 mg.

Example 2D, Orlistat 60 mg/Acarbose 20 mg

[0404]

TABLE-US-00024 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 2.0 Film-coating polymer, water-soluble  1-10 Delayed release coating polymer, poorly water-soluble 1-5 Coating sphere, filler 1-5 Sub-total:  5-20 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 2.8 Surface active agent 0-2 Filler 1-5 Sub-total:  3-10 Extragranular ingredients, DR.sub.DC-PR layer (G1, G3-layer) Filler  0-50 Prolonged release polymer  0-10 Glidant 0-2 Lubricant 0-2 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 7.2 Acarbose 1.4 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid copolymer 20-40 Sub-total: 45-85 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Filler  0-50 Disintegrant 0-2 Glidant 0-2 Lubricant 0-2 Total: 100   

Example 2E, Orlistat 60 mg/Acarbose 20 mg

[0405]

TABLE-US-00025 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.0 Hydroxypropyl methylcellulose 1.6 0.3 Ethylcellulose, Surelease 6.8 1.1 Microcrystalline cellulose, Celphere CP 203 9.9 1.6 Sub-total: 30.0 5.0 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 2.8 Polysorbate 80, Tween 80 5.8 1.0 Microcrystalline cellulose 7.5 1.3 Sub-total: 30.0 5.0 Extragranular ingredients, DR.sub.DC-PR layer (G1, G3-layer) Isomalt 60.0 10 Hydroxyethylcellulose 12.0 2.0 Silica, colloidal anhydrous 1.3 0.3 Magnesium stearate 1.3 0.3 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 7.2 Acarbose 8.3 1.4 Hydroxypropyl cellulose, Klucel 15.4 2.6 Microcrystalline cellulose, Celphere CP 203 109 18.2 Polysorbate 80, Tween 80 5.6 0.9 Opadry (HPMC low viscosity grade, 6 cps, 9.4 1.6 triacetin, and talc) Eudragit L 100-55 (methacrylic acid-ethyl acrylate 99.4 16.6 copolymer (1:1) Type A) Triethyl citrate 10.1 1.7 Talc 74.6 12.4 Sub-total: 375 62.5 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Isomalt 83.3 13.9 Sodium croscarmellose 4.5 0.7 Silica, colloidal anhydrous 1.3 0.3 Magnesium stearate 1.3 0.3 Total: 600 100

Example 2F, Orlistat 90 mg/Acarbose 30 mg

[0406]

TABLE-US-00026 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 18.0 2.3 Hydroxypropyl methylcellulose 2.4 0.3 Ethylcellulose, Surelease 10.2 1.3 Microcrystalline cellulose, Celphere CP 203 14.9 1.9 Sub-total: 45.5 5.7 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 25.0 3.1 Polysorbate 80, Tween 80 1.4 0.2 Microcrystalline cellulose 9.3 1.2 Sub-total: 35.7 4.5 Extragranular ingredients, DR.sub.DC-PR layer (G1, G3-layer) Isomalt 50.0 6.3 Hydroxyethylcellulose 16.0 2.0 Silica, colloidal anhydrous 2.4 0.3 Magnesium stearate 2.4 0.3 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 65.0 8.1 Acarbose 12.0 1.5 Hydroxypropyl cellulose, Klucel 23.0 2.9 Microcrystalline cellulose, Celphere CP 203 163 20.4 Polysorbate 80, Tween 80 8.3 1.0 Eudragit L 100-55 (methacrylic acid-ethyl acrylate 199 24.9 copolymer (1:1) Type A) Triethyl citrate 20.1 2.5 Talc 99.9 12.5 Sub-total: 591 73.9 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Isomalt 48.0 6.0 Sodium croscarmellose 4.2 0.7 Silica, colloidal anhydrous 2.4 0.3 Magnesium stearate 2.4 0.3 Total: 800 100

Example 2G, Orlistat 60 mg/Acarbose 20 mg

[0407] As Example 2E, but G2 is extruded and spheronized pellet cores.

TABLE-US-00027 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.9 Hydroxypropyl methylcellulose 1.6 0.4 Ethylcellulose, Surelease 6.8 1.7 Microcrystalline cellulose, Celphere CP 203 9.9 2.5 Sub-total: 30.0 7.5 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 4.2 Polysorbate 80, Tween 80 5.8 1.5 Microcrystalline cellulose 7.5 1.9 Sub-total: 30.0 7.5 Extragranular ingredients, DR.sub.DC-PR layer (G1, G3-layer) Isomalt 57.0 14.3 Hydroxyethylcellulose 8.0 2.0 Silica, colloidal anhydrous 1.2 0.3 Magnesium stearate 1.2 0.3 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 10.8 Acarbose 8.3 2.1 Microcrystalline cellulose 65.8 16.5 Polysorbate 80, Tween 80 13.4 3.4 Mannitol 9.8 2.5 Croscarmellose sodium 5.9 1.5 Sodium stearyl fumarate, Pruv 2.1 0.5 Opadry (HPMC low viscosity grade, 6 cps, triacetin, 4.5 1.1 and talc) Acryl-EZE (methacrylic acid copolymer Type C, 59.5 14.9 sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 212 53.0 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Isomalt 55.4 13.9 Sodium croscarmellose 2.8 0.7 Silica, colloidal anhydrous 1.2 0.3 Magnesium stearate 1.2 0.3 Total: 400 100

Example 2H, Orlistat 60 mg/Acarbose 20 mg

[0408] G1 is extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose.

TABLE-US-00028 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 2.0 Cellulose-based polymer, water-soluble  1-10 Delayed release polymer, poorly water-soluble  1-10 Lubricant 0-5 Sub-total:  5-20 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 2.8 Surface active agent 0-2 Filler 1-5 Sub-total:  3-10 Extragranular ingredients, DR.sub.DC-PR layer (G1, G3-layer) Filler  0-50 Prolonged release polymer  0-10 Glidant 0-2 Lubricant  0-2 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 7.2 Acarbose 1.4 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid copolymer 20-40 Sub-total: 45-85 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Filler  0-50 Disintegrant 0-2 Glidant 0-2 Lubricant 0-2 Total: 100   

Example 2I, Orlistat 60 mg/Acarbose 20 mg

[0409] G1 is extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose.

TABLE-US-00029 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.0 Hydroxypropyl methylcellulose 22.8 3.8 Ethylcellulose, Ethocel 10 FP 23.4 3.9 Sodium stearyl fumarate, Pruv 0.6 0.1 Sub-total: 58.5 9.8 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 2.8 Polysorbate 80, Tween 80 5.8 1.0 Microcrystalline cellulose 7.5 1.3 Sub-total: 30.0 5.0 Extragranular ingredients, DR.sub.DC-PR layer (G1, G3-layer) Isomalt 60.0 10 Hydroxyethylcellulose 12.0 2.0 Silica, colloidal anhydrous 1.3 0.3 Magnesium stearate 1.3 0.3 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 7.2 Acarbose 8.3 1.4 Hydroxypropyl cellulose, Klucel 15.4 2.6 Microcrystalline cellulose, Celphere CP 203 109 18.2 Polysorbate 80, Tween 80 5.6 0.9 Opadry (HPMC low viscosity grade, 6 cps, triacetin, 9.4 1.6 and talc) Eudragit L 100-55 (methacrylic acid-ethyl acrylate 99.4 16.6 copolymer (1:1) Type A) Triethyl citrate 10.1 1.7 Talc 74.6 12.4 Sub-total: 375 62.5 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Isomalt 54.8 9.1 Sodium croscarmellose 4.5 0.7 Silica, colloidal anhydrous 1.3 0.3 Magnesium stearate 1.3 0.3 Total: 600 100

Example 2J, Orlistat 60 mg/Acarbose 20 mg

[0410] G1 is extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose. G2 extruded and spheronized pellet cores.

TABLE-US-00030 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.9 Hydroxypropyl methylcellulose 22.8 5.7 Ethylcellulose, Ethocel 10 FP 23.4 5.9 Sodium stearyl fumarate, Pruv 0.6 0.2 Sub-total: 58.5 14.6 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 4.2 Polysorbate 80, Tween 80 5.8 1.5 Microcrystalline cellulose 7.5 1.9 Sub-total: 30.0 7.5 Extragranular ingredients, DR.sub.DC-PR layer (G1, G3-layer) Isomalt 43.9 11.0 Hydroxyethylcellulose 8.0 2.0 Silica, colloidal anhydrous 1.2 0.3 Magnesium stearate 1.2 0.3 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 10.8 Acarbose 8.3 2.1 Microcrystalline cellulose 65.8 16.5 Polysorbate 80, Tween 80 13.4 3.4 Mannitol 9.8 2.5 Croscarmellose sodium 5.9 1.5 Sodium stearyl fumarate, Pruv 2.1 0.5 Opadry (HPMC low viscosity grade, 6 cps, triacetin, 4.5 1.1 and talc) Acryl-EZE (methacrylic acid copolymer Type C, 59.5 14.9 sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 212 53.0 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Isomalt 40.0 10.0 Sodium croscarmellose 2.8 0.7 Silica, colloidal anhydrous 1.2 0.3 Magnesium stearate 1.2 0.3 Total: 400 100

Example 2K, Orlistat 60 mg/Acarbose 20 mg

[0411] G1 extruded and spheronized with hard fat.

TABLE-US-00031 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 2.0 Wax, water-soluble  1-10 Hard fat  1-10 Filler 0-5 Sub-total:  5-20 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 2.8 Surface active agent 0-2 Filler 1-5 Sub-total:  3-10 Extragranular ingredients, DR.sub.DC-PR layer (G1, G3-layer) Filler  0-50 Prolonged release polymer  0-10 Glidant 0-2 Lubricant 0-2 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 7.2 Acarbose 1.4 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid copolymer 20-40 Sub-total: 45-85 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Filler  0-50 Disintegrant 0-2 Glidant 0-2 Lubricant 0-2 Total: 100   

Example 2L, Orlistat 60 mg/Acarbose 20 mg

[0412] G1 extruded and spheronized with hard fat.

TABLE-US-00032 mg/ Ingredient tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.0 Glyceryl monostearate 18.7 3.1 Hydrogenated vegetable oil type II, Dynasan P60 14.6 2.4 Mannitol 13.5 2.2 Sub-total: 58.5 9.8 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 2.8 Polysorbate 80, Tween 80 5.8 1.0 Microcrystalline cellulose 7.5 1.3 Sub-total: 30.0 5.0 Extragranular ingredients, DR.sub.DC-PR layer (G1,G3-layer) Isomalt 60.0 10.0 Hydroxyethylcellulose 12.0 2.0 Silica, colloidal anhydrous 1.3 0.3 Magnesium stearate 1.3 0.3 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 7.2 Acarbose 8.3 1.4 Hydroxypropyl cellulose, Klucel 15.4 2.6 Microcrystalline cellulose, Celphere CP 203 109 18.2 Polysorbate 80, Tween 80 5.6 0.9 Opadry (HPMC low viscosity grade, 6 cps, triacetin, and 9.4 1.6 talc) Eudragit L 100-55 (methacrylic acid-ethyl acrylate co- 99.4 16.6 polymer (1:1) Type A) Triethyl citrate 10.1 1.7 Talc 74.6 12.4 Sub-total: 375 62.5 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Isomalt 54.8 9.1 Sodium croscarmellose 4.5 0.7 Silica, colloidal anhydrous 1.3 0.3 Magnesium stearate 1.3 0.3 Total: 600 100

Example 2M, Orlistat 60 mg/Acarbose 20 mg

[0413] G1 extruded and spheronized with hard fat. G2 extruded and spheronized pellet cores.

TABLE-US-00033 mg/ Ingredient tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.9 Glyceryl monostearate 18.7 4.7 Hydrogenated vegetable oil type II, Dynasan P60 14.6 3.7 Mannitol 13.5 3.4 Sub-total: 58.5 14.6 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 4.2 Polysorbate 80, Tween 80 5.8 1.5 Microcrystalline cellulose 7.5 1.9 Sub-total: 30.0 7.5 Extragranular ingredients, DR.sub.DC-PR layer (G1,G3-layer) Isomalt 43.9 11.0 Hydroxyethylcellulose 8.0 2.0 Silica, colloidal anhydrous 1.2 0.3 Magnesium stearate 1.2 0.3 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 10.8 Acarbose 8.3 2.1 Microcrystalline cellulose 65.8 16.5 Polysorbate 80, Tween 80 13.4 3.4 Mannitol 9.8 2.5 Croscarmellose sodium 5.9 1.5 Sodium stearyl fumarate, Pruv 2.1 0.5 Opadry (HPMC low viscosity grade, 6 cps, triacetin, and 4.5 1.1 talc) Acryl-EZE (methacrylic acid copolymer Type C, sodium 59.5 14.9 lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 212 53.0 Extragranular ingredients, DR.sub.EC-RR.sub.PROX SI layer (G2-layer) Isomalt 40.0 10.0 Sodium croscarmellose 2.8 0.7 Silica, colloidal anhydrous 1.2 0.3 Magnesium stearate 1.2 0.3 Total: 400 100

[0414] The bi-layer multiple-unit tablets of Example 2D-M are prepared as follows:

[0415] The powder blends including granular (G1, G2, G3) and extragranular ingredients are prepared as described in Example 1 above but in two separate blenders—one for each layer. Transfer the blends to a rotary tablet machine with two filling stations adjusted for bi-layer tabletting in two steps; first the DR.sub.DC-PR layer (G1,G3-layer) and then additionally the DR.sub.EC-RR.sub.PROX SI layer (G2-layer) with a total tablet weight of either 400 mg, 600 mg or 800 mg.

[0416] Especially compositions of Examples 2D-F gave excellent results. The other compositions had good/acceptable properties.

Example 3. Coated Tablet

Example 3A, Orlistat 90 mg/Acarbose 30 mg

[0417]

TABLE-US-00034 Ingredient % w/w PR Tablet core Orlistat 1-5 Acarbose 0-3 Prolonged release polymer 0-5 Filler 0-60 Disintegrant 0-5 Glidant 0-5 Lubricant 0-5 Sub-total: 1-88 Coating ingredients Seal coating polymer 0-5 Orlistat 6-18 Acarbose 0-5 Film forming polymer 1-25 Seal coating polymer 0-5 Enteric coating polymer 1-20 Seal coating polymer 0-5 Acarbose 0-5 Coating polymer, 30-60 min delay 0-5 Seal coating polymer 0-5 Total: 100

Example 3B, Orlistat 90 mg/Acarbose 30 mg

[0418]

TABLE-US-00035 Ingredient mg/tablet % w/w PR Tablet core Orlistat 20 3.3 Acarbose 10 1.7 Prolonged release polymer 5 0.8 Filler 236 39.3 Disintegrant 25 4.2 Glidant 2 0.3 Lubricant 2 0.3 Sub-total: 300 50.0 Coating ingredients Seal coating polymer 12 2.0 Orlistat 70 11.7 Acarbose 10 1.7 Film forming polymer 20 3.3 Seal coating polymer 12 2.0 Enteric coating polymer 97 16.2 Seal coating polymer 12 2.0 Acarbose 10 1.7 Coating polymer, 30-60 min delay 50 8.3 Seal coating polymer 7 1.2 Total: 600 100

Example 3C, Orlistat 90 mg/Acarbose 30 mg

[0419]

TABLE-US-00036 % Ingredient mg/tablet w/w PR Tablet core Orlistat 20 3.3 Acarbose 10 1.7 Ethyl cellulose, Ethocel std 7FP 5 0.8 Microcrystalline cellulose 150 25.0 Lactose 86 14.3 Croscarmellose sodium 25 4.2 Silica colloidal, anhydrous 2 0.3 Magnesium stearate 2 0.3 Sub-total: 300 50.0 Coating ingredients Opadry II Clear (macrogol 3350, polysorbate 80, 12 2.0 polyvinyl alcohol and talc) - Seal coat Orlistat 70 11.7 Acarbose 10 1.7 Opadry II Clear - Film former 20 3.3 Opadry II Clear - Seal coat 12 2.0 Acryl-EZE Clear (methacrylic acid copolymer 97 16.2 type C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) - Enteric coat Opadry II Clear - Seal coat 12 2.0 Acarbose - RR drug 10 1.7 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 50 8.3 copolymer (1:1) dispersion 30 percent) - Film former Opadry II Clear - Top coat 7 1.2 Total: 600 100

Example 3D, Orlistat 60 mg/Acarbose 20 mg

[0420]

TABLE-US-00037 mg/ % Ingredient tablet w/w PR Tablet core Orlistat 13.3 3.3 Acarbose 6.7 1.7 Ethyl cellulose, Ethocel std 7FP 3.3 0.8 Microcrystalline cellulose 100 25.0 Mannitol 57.3 14.3 Croscarmellose sodium 16.7 4.2 Silica colloidal, anhydrous 1.3 0.3 Magnesium stearate 1.3 0.3 Sub-total: 200 50.0 Coating ingredients Opadry II Clear (macrogol 3350, polysorbate 80, poly- 8.0 2.0 vinyl alcohol and talc) - Seal coat Orlistat 46.7 11.7 Acarbose 6.7 1.7 Opadry II Clear - Film former 13.3 3.3 Opadry II Clear - Seal coat 8.0 2.0 Acryl-EZE Clear (methacrylic acid copolymer type C, 64.8 16.2 sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) - Enteric coat Opadry II Clear - Seal coat 8.0 2.0 Acarbose - RR drug 6.7 1.7 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 33.3 8.3 copolymer (1:1) dispersion 30 percent) - Film former Opadry II Clear - Top coat 4.8 1.2 Total: 400 100

[0421] The coated tablets of Example 3 are prepared as follows:

[0422] Orlistat and acarbose is premixed with ethyl cellulose and sugar alcohol, such as lactose or mannitol, in a tumbling blender during approximately 10-30 minutes. The powder mix is dry granulated (roller compacted) and screen sieved through a 2 mm screen. Microcrystalline cellulose, croscarmellose sodium and silica colloidal, anhydrous is added and mixed for additionally 10-30 minutes depending on mixer. Sieve magnesium stearate through a 100-250-μm sieve, add to the tumbling mixer and mix for additional approximately 2 minutes, depending on mixer. The powder mix is transferred to a rotary tablet press to compress tablet cores of 200 mg or 300 mg. The coating dispersions are prepared layer by layer in a fluidized bed coater with bottom spray or similar to a final target average dry weight per tablet of 400 mg or 600 mg.

[0423] Especially the composition of Example 3D had excellent properties. The other composition had good/acceptable properties.

Example 4. Multiple-Unit Capsule

Example 4A, Orlistat 90 mg/Acarbose 30 mg

[0424]

TABLE-US-00038 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 0.4-1.2 Filler  0-20 Disintegrant 0-5 Binder 0-5 Prolonged release polymer  0-10 Coating polymer, 30-60 min delay  1-10 Sub-total: 1.4-51  DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat  6-16 Acarbose 3-6 Filler  0-10 Binder  0-10 Disintegrant  0-10 Solubilizer 0-5 Sub-coating polymer 0-5 Enteric coating polymer  1-11 Sub-total: 10-73 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 3-6 Prolonged release polymer 10-60 Coating polymer, 30-60 min delay  0-10 Sub-total: 13-76 Extragranular ingredients Glidant 0-2 Lubricant 0-5 Total: 100

Example 4B, Orlistat 90 mg/Acarbose 30 mg

[0425]

TABLE-US-00039 mg/ Ingredient capsule % w/w DR.sub.DC-PR.sub.GASTRIC Granules Acarbose 5 0.8 Filler 47 7.8 Disintegrant 5 0.8 Binder 3 0.5 Prolonged release polymer 30 5.0 Coating polymer, 30-60 min delay 10 1.7 Sub-total: 100 17 DR.sub.EC-RR.sub.PROX SI Granules Orlistat 65 11 Acarbose 25 4.2 Filler 30 5.0 Binder 25 4.2 Disintegrant 30 5.0 Solubilizer 5 0.8 Sub-coating polymer 12 2.0 Enteric coating polymer 48 8.0 Sub-total: 230 38 DR.sub.DC-PR.sub.GASTRIC Granules Orlistat 25 4.2 Prolonged release polymer 215 36 Coating polymer, 30-60 min delay 10 1.7 Sub-total: 250 42 Extragranular ingredients Glidant 5 0.8 Lubricant 15 2.5 Total: 600 100

Example 4C (Size 0, HPMC), Orlistat 90 mg/Acarbose 30 mg

[0426]

TABLE-US-00040 % Ingredient mg/capsule w/w DR.sub.DC-PR.sub.GASTRIC Granules Acarbose 5 0.8 Mannitol 47 7.8 Croscarmellose sodium 5 0.8 Polyvinylpyrrolidone 3 0.5 Ethylcellulose 30 5.0 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 10 1.7 copolymer (1:1) dispersion 30 percent) Sub-total: 100 17 DR.sub.EC-RR.sub.PROX SI Granules Orlistat 65 11 Acarbose 25 4.2 Microcrystalline cellulose 30 5.0 Polyvinylpyrrolidone, Povidone 25 4.2 Sodium starch glycolate, Primojel 30 5.0 Sodium lauryl sulphate, SDS 5 0.8 Opadry II Clear (macrogol 3350, polysorbate 80, 12 2.0 polyvinyl alcohol and talc) Acryl-EZE Clear (methacrylic acid copolymer 48 8.0 type C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 230 38 DR.sub.DC-PR.sub.GASTRIC Granules Orlistat 25 4.2 Hypromellose, HPMC K100 215 36 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 10 1.7 copolymer (1:1) dispersion 30 percent) Sub-total: 250 42 Extragranular ingredients Silica, colloidal anhydrous 5 0.8 Sodium stearyl fumarate 15 2.5 Total: 600 100

Example 4D (Size 0, HPMC), Orlistat 90 mg/Acarbose 30 mg

[0427]

TABLE-US-00041 mg/ Ingredient capsule % w/w DR.sub.DC-PR.sub.GASTRIC Granules Acarbose 5 0.8 Mannitol 47 7.8 Croscarmellose sodium 5 0.8 Polyvinylpyrrolidone 3 0.5 Ethylcellulose 30 5.0 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 10 1.7 copolymer (1:1) dispersion 30 percent) Sub-total: 100 17 DR.sub.EC-RR.sub.PROX SI Granules Orlistat 65 11 Acarbose 25 4.2 Microcrystalline cellulose 30 5.0 Polyvinylpyrrolidone, Povidone 25 4.2 Sodium starch glycolate, Primojel 30 5.0 Sodium lauryl sulphate, SDS 5 0.8 Opadry II Clear (macrogol 3350, polysorbate 80, 12 2.0 polyvinyl alcohol and talc) Acryl-EZE Clear (methacrylic acid copolymer 48 8.0 type C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 230 38 DR.sub.DC-PR.sub.GASTRIC Granules Orlistat 25 4.2 Hypromellose, HPMC K100 215 36 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 10 1.7 copolymer (1:1) dispersion 30 percent) Sub-total: 250 42 Extragranular ingredients Silica, colloidal anhydrous 5 0.8 Sodium stearyl fumarate 15 2.5 Total: 600 100

Example 4E (Size 1, HPMC), Orlistat 60 mg/Acarbose 20 mg

[0428]

TABLE-US-00042 mg/ Ingredient capsule % w/w DR.sub.DC-PR.sub.GASTRIC Granules Acarbose 3.3 0.8 Mannitol 31.3 7.8 Croscarmellose sodium 3.3 0.8 Polyvinylpyrrolidone 2.0 0.5 Ethylcellulose 20.0 5.0 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 6.7 1.7 copolymer (1:1) dispersion 30 percent) Sub-total: 66.7 16.7 DR.sub.EC-RR.sub.PROX SI Granules Orlistat 43.3 10.8 Acarbose 16.7 4.2 Microcrystalline cellulose 20.0 5.0 Polyvinylpyrrolidone, Povidone 16.7 4.2 Sodium starch glycolate, Primojel 20.0 5.0 Sodium lauryl sulphate, SDS 3.3 0.8 Opadry II Clear (macrogol 3350, polysorbate 80, 8.0 2.0 polyvinyl alcohol and talc) Acryl-EZE Clear (methacrylic acid copolymer 32.0 8.0 type C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 160 40.0 DR.sub.DC-PR.sub.GASTRIC Granules Orlistat 16.7 4.2 Hypromellose, HPMC K100 143 35.8 Eudragit L30 D-55 (methacrylic acid-ethyl acetate 6.7 1.7 copolymer (1:1) dispersion 30 percent) Sub-total: 167 41.7 Extragranular ingredients Silica, colloidal anhydrous 3.3 0.8 Sodium stearyl fumarate 10 2.5 Total: 400 100

Example 4F (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0429]

TABLE-US-00043 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 1-5 Film-coating polymer, water-soluble  1-10 Delayed release coating polymer, poorly water- 1-5 soluble Coating sphere, filler 1-5 Sub-total:  5-20 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat  5-10 Acarbose 0-5 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-95 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 0-5 Surface active agent 0-2 Filler 0-5 Sub-total:  0-10 Extragranular ingredients Glidant 0-2 Lubricant 0-5 Total: 100

Example 4G (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0430]

TABLE-US-00044 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.7 Hydroxypropyl methylcellulose 1.6 0.4 Ethylcellulose, Surelease 6.8 1.6 Microcrystalline cellulose, Celphere CP 203 9.9 2.3 Sub-total: 30.0 6.9 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 9.9 Acarbose 8.3 1.9 Hydroxypropyl cellulose, Klucel 15.4 3.5 Microcrystalline cellulose, Celphere CP 203 109 24.9 Polysorbate 80, Tween 80 5.6 1.3 Opadry (HPMC low viscosity grade, 6 cps, tri- 9.4 2.2 acetin, and talc) Eudragit L 100-55 (methacrylic acid-ethyl 99.4 22.7 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 2.3 Talc 74.6 17.1 Sub-total: 375 85.8 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 3.8 Polysorbate 80, Tween 80 5.8 1.3 Microcrystalline cellulose 7.5 1.7 Sub-total: 30.0 6.9 Extragranular ingredients Magnesium stearate 2.2 0.5 Total: 437 100

Example 4H (Size 00, Hard Gelatin), Orlistat 90 mg/Acarbose 30 mg

[0431]

TABLE-US-00045 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 18.0 2.7 Hydroxypropyl methylcellulose 2.4 0.4 Ethylcellulose, Surelease 10.2 1.5 Microcrystalline cellulose, Celphere CP 203 14.9 2.2 Sub-total: 45.5 6.8 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 65.0 9.7 Acarbose 12.0 1.8 Hydroxypropyl cellulose, Klucel 23.0 3.4 Microcrystalline cellulose, Celphere CP 203 163 24.3 Polysorbate 80, Tween 80 8.3 1.2 Eudragit L 100-55 (methacrylic acid - ethyl 199 29.6 acrylate copolymer (1:1) Type A) Triethyl citrate 20.1 3.0 Talc 99.9 14.9 Sub-total: 591 87.9 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 25.0 3.7 Polysorbate 80, Tween 80 1.4 0.2 Microcrystalline cellulose 9.3 1.4 Sub-total: 35.7 5.3 Total: 672 100

[0432] The in vitro dissolution behaviour appears from FIGS. 11-16. From these figures it is seen that the desired dissolution profiles are obtained for the individual granules G1, G2 and G3 as well as for the final composition, wherein G1, G2 and G3 are combined.

Example 4I (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0433] As 4G, but G2 extruded and spheronized pellet core.

TABLE-US-00046 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 4.3 Hydroxypropyl methylcellulose 1.6 0.6 Ethylcellulose, Surelease 6.8 2.5 Microcrystalline cellulose, Celphere CP 203 9.9 3.6 Sub-total: 30.0 11.0 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 15.9 Acarbose 8.3 3.0 Microcrystalline cellulose 65.8 24.1 Polysorbate 80, Tween 80 13.4 4.9 Mannitol 9.8 3.6 Croscarmellose sodium 5.9 2.2 Sodium stearyl fumarate, Pruv 2.1 0.8 Opadry (HPMC low viscosity grade, 6 cps, 4.5 1.6 triacetin, and talc) Acryl-EZE (methacrylic acid copolymer Type 59.5 21.8 C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 212 77.7 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 6.1 Polysorbate 80, Tween 80 5.8 2.1 Microcrystalline cellulose 7.5 2.7 Sub-total: 30.0 11.0 Extragranular ingredients Magnesium stearate 1.4 0.5 Total: 273 100

Example 4J (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0434] G1 extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose.

TABLE-US-00047 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 1-5 Cellulose-based polymer, water-soluble  1-10 Delayed release polymer, poorly water-soluble  1-10 Lubricant 0-5 Sub-total:  5-20 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat  5-10 Acarbose 0-5 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-95 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 0-5 Surface active agent 0-2 Filler 0-5 Sub-total:  0-10 Extragranular ingredients Glidant 0-2 Lubricant 0-5 Total: 100

Example 4K (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0435] G1 extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose.

TABLE-US-00048 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.5 Hydroxypropyl methylcellulose 22.8 4.9 Ethylcellulose, Ethocel 10 FP 23.4 5.0 Sodium stearyl fumarate, Pruv 0.6 0.1 Sub-total: 58.5 12.6 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 9.3 Acarbose 8.3 1.8 Hydroxypropyl cellulose, Klucel 15.4 3.3 Microcrystalline cellulose, Celphere CP 203 109 23.4 Polysorbate 80, Tween 80 5.6 1.2 Opadry (HPMC low viscosity grade, 6 cps, 9.4 2.0 triacetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 21.3 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 2.2 Talc 74.6 16.0 Sub-total: 375 80.5 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 3.6 Polysorbate 80, Tween 80 5.8 1.2 Microcrystalline cellulose 7.5 1.6 Sub-total: 30.0 6.4 Extragranular ingredients Magnesium stearate 2.3 0.5 Total: 466 100

Example 4L (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0436] G1 extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose. G2 extruded and spheronizes pellet cores.

TABLE-US-00049 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 3.9 Hydroxypropyl methylcellulose 22.8 7.5 Ethylcellulose, Ethocel 10 FP 23.4 7.7 Sodium stearyl fumarate, Pruv 0.6 0.2 Sub-total: 58.5 19.4 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 14.3 Acarbose 8.3 2.7 Microcrystalline cellulose 65.8 21.8 Polysorbate 80, Tween 80 13.4 4.4 Mannitol 9.8 3.2 Croscarmellose sodium 5.9 2.0 Sodium stearyl fumarate, Pruv 2.1 0.7 Opadry (HPMC low viscosity grade, 6 cps, 4.5 1.5 triacetin, and talc) Acryl-EZE (methacrylic acid copolymer Type 59.5 19.7 C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 212 70.2 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 5.5 Polysorbate 80, Tween 80 5.8 1.9 Microcrystalline cellulose 7.5 2.5 Sub-total: 30.0 9.9 Extragranular ingredients Magnesium stearate 1.5 0.5 Total: 302 100

Example 4M (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0437] G1 extruded and spheronized with hard fat.

TABLE-US-00050 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 1-5 Wax, water-soluble  1-10 Hard fat  1-10 Filler 0-5 Sub-total:  5-20 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat  5-10 Acarbose 0-5 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-95 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 0-5 Surface active agent 0-2 Filler 0-5 Sub-total:  0-10 Extragranular ingredients Glidant 0-2 Lubricant 0-5 Total: 100

Example 4N (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0438] G1 extruded and spheronized with hard fat.

TABLE-US-00051 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.5 Glyceryl monostearate 18.7 4.0 Hydrogenated vegetable oil type II, Dynasan 14.6 3.1 P60 Mannitol 13.5 2.9 Sub-total: 58.5 12.6 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 9.3 Acarbose 8.3 1.8 Hydroxypropyl cellulose, Klucel 15.4 3.3 Microcrystalline cellulose, Celphere CP 203 109 23.4 Polysorbate 80, Tween 80 5.6 1.2 Opadry (HPMC low viscosity grade, 6 cps, 9.4 2.0 triacetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 21.3 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 2.2 Talc 74.6 16.0 Sub-total: 375 80.5 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 3.6 Polysorbate 80, Tween 80 5.8 1.2 Microcrystalline cellulose 7.5 1.6 Sub-total: 30.0 6.4 Extragranular ingredients Magnesium stearate 2.3 0.5 Total: 466 100

Example 4O (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0439] G1 extruded and spheronized with hard fat. G2 extruded and spheronized pellet cores.

TABLE-US-00052 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 3.9 Glyceryl monostearate 18.7 6.2 Hydrogenated vegetable oil type II, Dynasan 14.6 4.8 P60 Mannitol 13.5 4.5 Sub-total: 58.5 19.4 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 14.3 Acarbose 8.3 2.7 Microcrystalline cellulose 65.8 21.8 Polysorbate 80, Tween 80 13.4 4.4 Mannitol 9.8 3.2 Croscarmellose sodium 5.9 2.0 Sodium stearyl fumarate, Pruv 2.1 0.7 Opadry (HPMC low viscosity grade, 6 cps, 4.5 1.5 triacetin, and talc) Acryl-EZE (methacrylic acid copolymer Type 59.5 19.7 C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhydrous) Sub-total: 212 70.2 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 5.5 Polysorbate 80, Tween 80 5.8 1.9 Microcrystalline cellulose 7.5 2.5 Sub-total: 30.0 9.9 Extragranular ingredients Magnesium stearate 1.5 0.5 Total: 302 100

Example 4P (Size 00, Hard Gelatin), Orlistat 60 mg/Acarbose 20 mg

[0440] As 4G, but G3 is coated in fluidized bed.

TABLE-US-00053 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.7 Hydroxypropyl methylcellulose 1.6 0.4 Ethylcellulose, Surelease 6.8 1.6 Microcrystalline cellulose, Celphere CP 203 9.9 2.3 Sub-total: 30.0 6.9 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 9.9 Acarbose 8.3 1.9 Hydroxypropyl cellulose, Klucel 15.4 3.5 Microcrystalline cellulose, Celphere CP 203 109 24.9 Polysorbate 80, Tween 80 5.6 1.3 Opadry (HPMC low viscosity grade, 6 cps, 9.4 2.2 triacetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 22.7 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 2.3 Talc 74.6 17.1 Sub-total: 375 85.8 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 3.8 Hydroxypropyl cellulose, Klucel 5.8 1.3 Microcrystalline cellulose, Celphere CP 203 7.5 1.7 Sub-total: 30.0 6.9 Extragranular ingredients Magnesium stearate 2.2 0.5 Total: 437 100

Example 4Q (Size 00, Hard Gelatin), Orlistat 60 mg or Acarbose 20 mg

[0441] Composition only containing acarbose (G1 and G2 without orlistat), or composition only containing orlistat (G2 without acarbose) and G3.

TABLE-US-00054 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 0-5 Film-coating polymer, water-soluble  0-10 Delayed release coating polymer, poorly 0-5 water-soluble Coating sphere, filler 0-5 Sub-total:  0-25 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat  0-10 Acarbose 0-5 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-95 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 0-5 Surface active agent 0-2 Filler 0-8 Sub-total:  0-15 Extragranular ingredients Filler  0-50 Glidant 0-2 Lubricant 0-5 Total: 100

Example 4R (Size 00, Hard Gelatin), Acarbose 20 mg

[0442]

TABLE-US-00055 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.9 Hydroxypropyl methylcellulose 1.6 0.4 Ethylcellulose, Surelease 6.8 1.7 Microcrystalline cellulose, Celphere CP 203 9.9 2.4 Sub-total: 30.0 7.4 DR.sub.EC-RR.sub.PROX SI Granules (G2) Acarbose 8.3 2.0 Hydroxypropyl cellulose, Klucel 15.4 3.8 Microcrystalline cellulose, Celphere CP 203 152 37.3 Polysorbate 80, Tween 80 5.6 1.4 Opadry (HPMC low viscosity grade, 6 cps, 9.4 2.3 triacetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 24.4 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 2.5 Talc 74.6 18.3 Sub-total: 375 92.1 Extragranular ingredients Magnesium stearate 2.0 0.5 Total: 407 100

Example 4S (Size 00, Hard Gelatin), Orlistat 60 mg

[0443]

TABLE-US-00056 Ingredient mg/tablet % w/w DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 10.6 Hydroxypropyl cellulose, Klucel 15.4 3.8 Microcrystalline cellulose, Celphere CP 203 121 29.7 Polysorbate 80, Tween 80 5.6 1.4 Opadry (HPMC low viscosity grade, 6 cps, 9.4 2.3 triacetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 24.4 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 2.5 Talc 74.6 18.3 Sub-total: 375 92.1 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 4.1 Polysorbate 80, Tween 80 5.8 1.4 Microcrystalline cellulose 7.5 1.8 Sub-total: 30.0 7.4 Extragranular ingredients Magnesium stearate 2.0 0.5 Total: 407 100

[0444] The multiple-unit capsules of Example 4 are prepared as follows:

[0445] The granules are prepared as described in Example 1 above except for the G3 granules in Example 4P, where the G3 granules are not prepared by wet granulation but by coating in a fluidized bed coater. When the granules are dry; add all components into a tumbling mixer. Mix them during approximately 45 minutes, depending on mixer, or add the granules to the hopper/s of a capsule filling machine separately by the use of multiple filling stations. When magnesium stearate is used as lubricant, add it after sieving during the last 2 minutes of blending. Transfer the final blend or separate granules to a standard capsule filling machine and fill HPMC-based or hard gelatin capsules of appropriate sizes in accordance with a powder content adjusted for the powder density and for the filling weight per capsule.

[0446] The composition of examples 4G, 4H, 4Q, 4R and 4S have excellent properties.

Example 5. Multiple-Unit Oral Powder

Example 5A (Filled in Sachets), Orlistat 90 mg/Acarbose 30 mg

[0447]

TABLE-US-00057 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules Acarbose 0.4-1.2 Filler  0-20 Disintegrant 0-5 Binder 0-5 Prolonged release polymer  0-10 Coating polymer, 30-60 min delay  1-10 Sub-total: 1.4-51  DR.sub.EC-RR.sub.PROX SI Granules Orlistat  6-16 Acarbose 3-6 Filler  0-10 Binder  0-10 Disintegrant  0-10 Solubilizer 0-5 Sub-coating polymer 0-5 Enteric coating polymer  1-11 Sub-total: 10-73 DR.sub.DC-PR.sub.GASTRIC Granules Orlistat 3-6 Prolonged release polymer 10-60 Coating polymer, 30-60 min delay  0-10 Sub-total: 13-76 Extragranular ingredients Glidant 0-2 Lubricant 0-5 Total: 100

Example 5B (Filled in Sachets), Orlistat 90 mg/Acarbose 30 mg

[0448]

TABLE-US-00058 Ingredient mg/sachet % w/w DR.sub.DC-PR.sub.GASTRIC Granules Acarbose 5 0.8 Filler 47 7.8 Disintegrant 5 0.8 Binder 3 0.5 Prolonged release polymer 30 5.0 Coating polymer, 30-60 min delay 10 1.7 Sub-total: 100 17 DR.sub.EC-RR.sub.PROX SI Granules Orlistat 65 11 Acarbose 25 4.2 Filler 30 5.0 Binder 25 4.2 Disintegrant 30 5.0 Solubilizer 5 0.8 Sub-coating polymer 12 2.0 Enteric coating polymer 48 8.0 Sub-total: 230 38 DR.sub.DC-PR.sub.GASTRIC Granules Orlistat 25 4.2 Prolonged release polymer 215 36 Coating polymer, 30-60 min delay 10 1.7 Sub-total: 250 42 Extragranular ingredients Glidant 5 0.8 Lubricant 15 2.5 Total: 600 100

Example 5C (Filled in Sachets), Orlistat 90 mg/Acarbose 30 mg

[0449]

TABLE-US-00059 Ingredient mg/sachet % w/w DR.sub.DC-PR.sub.GASTRIC Granules Acarbose 5 0.8 Mannitol 47 7.8 Croscarmellose sodium 5 0.8 Polyvinylpyrrolidone 3 0.5 Ethylcellulose 30 5.0 Eudragit L30 D-55 (methacrylic acid - ethyl ace- 10 1.7 tate copolymer (1:1) dispersion 30 percent) Sub-total: 100 17 DR.sub.EC-RR.sub.PROX SI Granules Orlistat 65 11 Acarbose 25 4.2 Microcrystalline cellulose 30 5.0 Polyvinylpyrrolidone, Povidone 25 4.2 Sodium starch glycolate, Primojel 30 5.0 Sodium lauryl sulphate, SDS 5 0.8 Opadry II Clear (macrogol 3350, polysorbate 80, 12 2.0 polyvinyl alcohol and talc) Acryl-EZE Clear (methacrylic acid copolymer 48 8.0 type C, sodium lauryl sulphate, macrogol, talc, sodium bicarbonate and colloidal silica, anhy- drous) Sub-total: 230 38 DR.sub.DC-PR.sub.GASTRIC Granules Orlistat 25 4.2 Hypromellose, HPMC K100 215 36 Eudragit L30 D-55 (methacrylic acid - ethyl ace- 10 1.7 tate copolymer (1:1) dispersion 30 percent) Sub-total: 250 42 Extragranular ingredients Silica, colloidal anhydrous 5 0.8 Sodium stearyl fumarate 15 2.5 Total: 600 100

[0450] The multiple-unit oral powders of Example 5A-C are prepared as follows:

[0451] The granules are prepared as described in Example 1 above. When the granules are dry; add all components into a tumbling mixer. Mix for approximately 45 minutes, depending on mixer. Transfer the final blend to a sachet filling and sealing machine and fill sachets with a powder content of 600 mg per sachet.

Example 5D (Filled in Sachets), Orlistat 60 mg/Acarbose 20 mg

[0452]

TABLE-US-00060 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 1-5 Film-coating polymer, water-soluble  1-10 Delayed release coating polymer, poorly wa- 1-5 ter-soluble Coating sphere, filler 1-5 Sub-total:  5-20 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat  5-10 Acarbose 0-5 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-95 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 0-5 Surface active agent 0-2 Filler 0-5 Sub-total:  0-10 Extragranular ingredients Glidant 0-2 Lubricant 0-5 Total: 100

Example 5E (Filled in Sachets), Orlistat 60 mg/Acarbose 20 mg

[0453]

TABLE-US-00061 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.7 Hydroxypropyl methylcellulose 1.6 0.4 Ethylcellulose, Surelease 6.8 1.6 Microcrystalline cellulose, Celphere CP 203 9.9 2.3 Sub-total: 30.0 6.9 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 9.9 Acarbose 8.3 1.9 Hydroxypropyl cellulose, Klucel 15.4 3.5 Microcrystalline cellulose, Celphere CP 203 109 24.9 Polysorbate 80, Tween 80 5.6 1.3 Opadry (HPMC low viscosity grade, 6 cps, tri- 9.4 2.2 acetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 22.7 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 2.3 Talc 74.6 17.1 Sub-total: 375 85.8 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 3.8 Polysorbate 80, Tween 80 5.8 1.3 Microcrystalline cellulose 7.5 1.7 Sub-total: 30.0 6.9 Extragranular ingredients Magnesium stearate 2.2 0.5 Total: 437 100

Example 5F (Filled in Sachets), Orlistat 90 mg/Acarbose 30 mg

[0454]

TABLE-US-00062 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 18.0 2.7 Hydroxypropyl methylcellulose 2.4 0.4 Ethylcellulose, Surelease 10.2 1.5 Microcrystalline cellulose, Celphere CP 203 14.9 2.2 Sub-total: 45.5 6.8 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 65.0 9.7 Acarbose 12.0 1.8 Hydroxypropyl cellulose, Klucel 23.0 3.4 Microcrystalline cellulose, Celphere CP 203 163 24.3 Polysorbate 80, Tween 80 8.3 1.2 Eudragit L 100-55 (methacrylic acid - ethyl 199 29.6 acrylate copolymer (1:1) Type A) Triethyl citrate 20.1 3.0 Talc 99.9 14.9 Sub-total: 591 87.9 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 25.0 3.7 Polysorbate 80, Tween 80 1.4 0.2 Microcrystalline cellulose 9.3 1.4 Sub-total: 35.7 5.3 Total: 672 100

Example 5G (Filled in Sachets), Orlistat 60 mg/Acarbose 20 mg

[0455] As 5E, but G2 is extruded and spheronized pellet cores.

TABLE-US-00063 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 4.3 Hydroxypropyl methylcellulose 1.6 0.6 Ethylcellulose, Surelease 6.8 2.5 Microcrystalline cellulose, Celphere CP 203 9.9 3.6 Sub-total: 30.0 11.0 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 15.9 Acarbose 8.3 3.0 Microcrystalline cellulose 65.8 24.1 Polysorbate 80, Tween 80 13.4 4.9 Mannitol 9.8 3.6 Croscarmellose sodium 5.9 2.2 Sodium stearyl fumarate, Pruv 2.1 0.8 Opadry (HPMC low viscosity grade, 6 cps, tri- 4.5 1.6 acetin, and talc) Acryl-EZE (methacrylic acid copolymer Type 59.5 21.8 C, sodium lauryl sulphate, macrogol, talc, so- dium bicarbonate and colloidal silica, anhy- drous) Sub-total: 212 77.7 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 6.1 Polysorbate 80, Tween 80 5.8 2.1 Microcrystalline cellulose 7.5 2.7 Sub-total: 30.0 11.0 Extragranular ingredients Magnesium stearate 1.4 0.5 Total: 273 100

Example 5H (Filled in Sachets), Orlistat 60 mg/Acarbose 20 mg

[0456] G1 is extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose.

TABLE-US-00064 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 1-5 Cellulose-based polymer, water-soluble  1-10 Delayed release polymer, poorly water-soluble  1-10 Lubricant 0-5 Sub-total:  5-20 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat  5-10 Acarbose 0-5 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-95 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 0-5 Surface active agent 0-2 Filler 0-5 Sub-total:  0-10 Extragranular ingredients Glidant 0-2 Lubricant 0-5 Total: 100

Example 5I (Filled in Sachets), Orlistat 60 mg/Acarbose 20 mg

[0457] G1 is extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose.

TABLE-US-00065 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.5 Hydroxypropyl methylcellulose 22.8 4.9 Ethylcellulose, Ethocel 10 FP 23.4 5.0 Sodium stearyl fumarate, Pruv 0.6 0.1 Sub-total: 58.5 12.6 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 9.3 Acarbose 8.3 1.8 Hydroxypropyl cellulose, Klucel 15.4 3.3 Microcrystalline cellulose, Celphere CP 203 109 23.4 Polysorbate 80, Tween 80 5.6 1.2 Opadry (HPMC low viscosity grade, 6 cps, tri- 9.4 2.0 acetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 21.3 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 2.2 Talc 74.6 16.0 Sub-total: 375 80.5 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 3.6 Polysorbate 80, Tween 80 5.8 1.2 Microcrystalline cellulose 7.5 1.6 Sub-total: 30.0 6.4 Extragranular ingredients Magnesium stearate 2.3 0.5 Total: 466 100

Example 5J (Filled in Sachets), Orlistat 60 mg/Acarbose 20 mg

[0458] G1 is extruded and spheronized with ethylcellulose/hydroxypropylmethylcellulose. G2 is extruded and spheronized pellet cores.

TABLE-US-00066 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 3.9 Hydroxypropyl methylcellulose 22.8 7.5 Ethylcellulose, Ethocel 10 FP 23.4 7.7 Sodium stearyl fumarate, Pruv 0.6 0.2 Sub-total: 58.5 19.4 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 14.3 Acarbose 8.3 2.7 Microcrystalline cellulose 65.8 21.8 Polysorbate 80, Tween 80 13.4 4.4 Mannitol 9.8 3.2 Croscarmellose sodium 5.9 2.0 Sodium stearyl fumarate, Pruv 2.1 0.7 Opadry (HPMC low viscosity grade, 6 cps, tri- 4.5 1.5 acetin, and talc) Acryl-EZE (methacrylic acid copolymer Type 59.5 19.7 C, sodium lauryl sulphate, macrogol, talc, so- dium bicarbonate and colloidal silica, anhy- drous) Sub-total: 212 70.2 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 5.5 Polysorbate 80, Tween 80 5.8 1.9 Microcrystalline cellulose 7.5 2.5 Sub-total: 30.0 9.9 Extragranular ingredients Magnesium stearate 1.5 0.5 Total: 302 100

Example 5K (Filled in Sachets), Orlistat 60 mg/Acarbose 20 mg

[0459] G1 extruded and spheronized with hard fat.

TABLE-US-00067 Ingredient % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 1-5 Wax, water-soluble  1-10 Hard fat  1-10 Filler 0-5 Sub-total:  5-20 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat  5-10 Acarbose 0-5 Film-coating polymer 2-6 Coating sphere, filler 10-30 Surface active agent  0-10 Enteric coating film based on methacrylic acid 20-40 copolymer Sub-total: 45-95 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 0-5 Surface active agent 0-2 Filler 0-5 Sub-total:  0-10 Extragranular ingredients Glidant 0-2 Lubricant 0-5 Total: 100

Example 5L (Filled in Sachets), Orlistat 60 mg/Acarbose 20 mg

[0460] G1 extruded and spheronized with hard fat.

TABLE-US-00068 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 2.5 Glyceryl monostearate 18.7 4.0 Hydrogenated vegetable oil type II, Dynasan 14.6 3.1 P60 Mannitol 13.5 2.9 Sub-total: 58.5 12.6 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 9.3 Acarbose 8.3 1.8 Hydroxypropyl cellulose, Klucel 15.4 3.3 Microcrystalline cellulose, Celphere CP 203 109 23.4 Polysorbate 80, Tween 80 5.6 1.2 Opadry (HPMC low viscosity grade, 6 cps, tri- 9.4 2.0 acetin, and talc) Eudragit L 100-55 (methacrylic acid - ethyl 99.4 21.3 acrylate copolymer (1:1) Type A) Triethyl citrate 10.1 2.2 Talc 74.6 16.0 Sub-total: 375 80.5 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 3.6 Polysorbate 80, Tween 80 5.8 1.2 Microcrystalline cellulose 7.5 1.6 Sub-total: 30.0 6.4 Extragranular ingredients Magnesium stearate 2.3 0.5 Total: 466 100

Example 5M (Filled in Sachets), Orlistat 60 mg/Acarbose 20 mg

[0461] G1 extruded and spheronized with hard fat. G2 extruded and spheronized pellet cores.

TABLE-US-00069 Ingredient mg/tablet % w/w DR.sub.DC-PR.sub.GASTRIC Granules (G1) Acarbose 11.7 3.9 Glyceryl monostearate 18.7 6.2 Hydrogenated vegetable oil type II, Dynasan 14.6 4.8 P60 Mannitol 13.5 4.5 Sub-total: 58.5 19.4 DR.sub.EC-RR.sub.PROX SI Granules (G2) Orlistat 43.3 14.3 Acarbose 8.3 2.7 Microcrystalline cellulose 65.8 21.8 Polysorbate 80, Tween 80 13.4 4.4 Mannitol 9.8 3.2 Croscarmellose sodium 5.9 2.0 Sodium stearyl fumarate, Pruv 2.1 0.7 Opadry (HPMC low viscosity grade, 6 cps, tri- 4.5 1.5 acetin, and talc) Acryl-EZE (methacrylic acid copolymer Type 59.5 19.7 C, sodium lauryl sulphate, macrogol, talc, so- dium bicarbonate and colloidal silica, anhy- drous) Sub-total: 212 70.2 DR.sub.DC-PR.sub.GASTRIC Granules (G3) Orlistat 16.7 5.5 Polysorbate 80, Tween 80 5.8 1.9 Microcrystalline cellulose 7.5 2.5 Sub-total: 30.0 9.9 Extragranular ingredients Magnesium stearate 1.5 0.5 Total: 302 100

[0462] The multiple-unit oral powders of Example 5D-M are prepared as follows:

[0463] The granules are prepared as described in Example 1 above. When the granules are dry; add all components into a tumbling mixer. Mix them during approximately 45 minutes, depending on mixer. When magnesium stearate is used as lubricant, add it after sieving during the last 2 minutes of blending. Transfer the final blend to a sachet filling and sealing machine and fill sachets of appropriate sizes in accordance with a powder content adjusted for the powder density and for the filling weight per sachet.

Example 6

Preliminary In Vivo Data (Clinical Investigation)

[0464] Preliminary in vivo data have been obtained from two male subjects who were investigated at two separate test days, where they either ingested a composition according to the invention (90 mg orlistat/30 mg acarbose, batch nr 326222) at breakfast and lunch, or just ingested the meals without any concomitant intake of the composition according to the invention. The composition was ingested 5 minutes after the meal was initiated to secure optimal mixing with the food. Blood samples were collected every 30 min until 300 min after onset of study (when the meal intake was initiated). Tolerability and appetite was monitored during the day using questionnaires. Subjects reported substantially higher feelings of satiety during the study day when the proposed product was taken together with food than without the proposed product (satiety scores around 8-7 out of 10 with product, and around 3 without product). This higher satiety seems to be related to the GI break mechanisms, which are the main target for invention. No side effects, apart from a temporary slight nausea and gastric distension, were noted. No orlistat could be observed in plasma using a detection method with a sensitivity of 0.05 ng/mL

Example 7. Patent Reference Examples

Example 7A, Coated Tablet, Orlistat 60 mg/Acarbose 50 mg

[0465] According to composition “Beispiel D” suggested in EP 0 638 317

TABLE-US-00070 Ingredient mg/tablet % w/w Tablet core Acarbose 50.0 19.6 Orlistat 60.0 23.5 Lactose 70.0 27.5 Hydroxypropylmethylcellulose 52.5 20.6 Polyvinylpyrrolidone 7.5 2.9 Talc 8.0 3.1 Magnesium stearate 1.0 0.4 Silica, colloidal anhydrous 1.0 0.4 Sub-total: 250 98.0 HPMC-coating Hydroxypropylmethylcellulose 2.5 1.0 Talc 1.25 0.5 Titandioxide 1.25 0.5 Total: 255 100

[0466] The in vitro release profile is shown in FIGS. 21a and 21b.

Example 7B, Two-Layer Tablet, Orlistat 60 mg/Acarbose 30 mg

[0467] According to composition “Example 3” suggested in CN 2011 1195582

TABLE-US-00071 Ingredient mg/tablet % w/w Orlistat layer Orlistat 60.0 6.3 Hydroxypropylmethylcellulose, 4M 40.0 5.9 Microcrystalline cellulose 20.0 0.6 Polyvinylpyrrolidone 0.8 0.4 Magnesium stearate 3.0 3.8 Sub-total: 123.8 13 Acarbose layer Acarbose 30.0 3.1 Sodium carboxymethylcellulose 4.0 3.8 Lactose 3.0 3.1 Polyvinylpyrrolidone 0.3 3.8 Magnesium stearate 0.2 6.0 Sub-total: 37.5 29 Total: 161.3 100

[0468] The in vitro dissolution profile is shown in FIGS. 22a and 22b.

[0469] The patent reference example of tablets are produced by using standard pharmaceutical manufacturing equipment in accordance with what is described in the patents.

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Specific Embodiments

[0592] 1. A modified-release composition comprising orlistat and acarbose, comprising: [0593] a) a first part comprising from about 5 to about 70% w/w of the total dose of acarbose, [0594] b) a second part comprising from about 30 to about 95% w/w of the total dose of acarbose, [0595] c) a third part comprising from about 10 to about 90% w/w of the total dose of orlistat, and [0596] d) a fourth part comprising from about 10 to about 80% w/w of the total dose of orlistat, and the total concentration of acarbose and orlistat, respectively, is 100% w/w, and wherein the individual parts are different.

[0597] 2. A modified-release composition according to item 1, wherein part b) and part c) is combined so that the composition only contains three different parts.

[0598] 3. A modified-release composition according to item 2, wherein the composition contains three different parts: [0599] a) a first part comprising from about 5 to about 70% w/w of the total dose of acarbose, [0600] b) a second part comprising from about 30 to about 95% w/w of the total dose of acarbose, and from about 10 to about 90% w/w of the total dose of orlistat, and [0601] c) a third part comprising from about 10 to about 80% w/w of the total dose of orlistat, and the total concentration of acarbose and orlistat, respectively, is 100% w/w.

[0602] 4. A modified-release composition comprising orlistat and acarbose, wherein the composition contains components with different release characteristics for release at different parts along the GI tract: [0603] i) a DR.sub.DC-PR.sub.GASTRIC part that is designed to release acarbose in a delayed, but prolonged manner, [0604] ii) a DR.sub.EC-RR.sub.PROX SI part that is designed to release acarbose and orlistat in the proximal small intestine, [0605] iii) a DR.sub.DC-PR.sub.GASTRIC and/or DR.sub.EC-PR.sub.INTESTINAL part that is designed to release orlistat in the proximal part of the small intestine until the end of jejunum.

[0606] 5. A modified-release composition according to item 4, wherein part i) of the composition is in the form of granules, pellets, minitablets etc. or part i) is incorporated into a two-layer tablet, where part i) is contained in one of the two layers, and the layer containing part i) is provided with a delayed release coating.

[0607] 6. A modified-release composition according to item 4 or 5, wherein part i) of the composition contains from about 5 to about 70% w/w of the total dose of acarbose.

[0608] 7. A modified-release composition according to any one of items 4-6, wherein part ii) of the composition is in the form of granules, pellets, minitablets etc. provided with an enteric coating or incorporated into a two-layer tablet, where part ii) is contained in one of the two layers and the layer containing part ii) is provided with an enteric coating.

[0609] 8. A modified-release composition according to any one of items 4-7, wherein part ii) of the composition contains from about 30 to about 95% w/w of the total amount of acarbose and from 30 to 90% w/w of the total amount of orlistat.

[0610] 9. A modified-release composition according to any one of items 4-8, wherein part iii) is in the form of granules, pellets, minitablets etc. or it is contained in a two layer tablet, wherein part iii) is contained in one of the two layers.

[0611] 10. A modified-release composition according to any one of items 4-9, wherein part iii) contains from about 10 to about 70% w/w of the total amount of orlistat.

[0612] 11. A modified-release composition according to any one of items 4-9 having the characteristics defined in any one of items 1-3.

[0613] 12. A modified-release composition according to any one of items 1-11 in the form of a multiple-unit tablet, a bi-layer multiple-unit tablet, a coated tablet, a multiple-unit capsule or a multiple-unit oral powder.

[0614] 13. A modified-release composition according to any of the preceding items comprising: [0615] i) granules containing acarbose DR.sub.DC-PR.sub.GASTRIC (denoted as Granule 1 or G1) [0616] ii) granules containing acarbose and orlistat DR.sub.EC-RR.sub.PROX SI (denoted as Granule 2 or G2), and [0617] iii) granules containing orlistat DR.sub.DC-PR.sub.GASTRIC and/or DR.sub.EC-PR.sub.INTESTINAL (denoted as Granule 3 or G3).

[0618] 14. A modified-release composition as defined in any of the preceding items for use in triggering the gastro-intestinal brake as defined in this application.

[0619] 15. A method for the treatment or prevention of: overweight and obesity; type 2 diabetes; Elevated blood glucose level (such as impaired glucose tolerance), Polycystic ovarian syndrome; Disorders of lipoprotein metabolism and other lipidemias (such as hyperglyceridemia); Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis; or metabolic syndrome, the method comprising administering a combination of acarbose and orlistat in a manner as defined herein, or as monotheraphies.